Revolution Medicines Inc Stock

Thank you for standing by, and welcome to Revolution Medicines Corporate Update Call. [Operator Instructions] And now I'd like to introduce your host for today's program, Ryan Asay, Senior Vice President, Corporate Affairs. Please go ahead, sir.

Hello, everyone. Thank you for joining Revolution Medicines' webcast to discuss the FDA approval of daraxonrasib, now approved under the brand name RASONQUE. We have issued a press release announcing the approval and posted the presentation that accompanies today's remarks on the Investors section of our website.

Before we begin, I would like to remind everyone that today's discussion will include forward-looking statements regarding our business, commercialization plans, clinical development programs, and other future events. These statements are subject to risks and uncertainties that may cause actual results to differ materially from those described. Please refer to our SEC filings for a discussion of these risks.

Joining me today are Dr. Mark Goldsmith, our Chairman and Chief Executive Officer; Dr. Alan Sandler, our Chief Development Officer; and Anthony Mancini, our Chief Global Commercialization Officer. Dr. Wei Lin, our Chief Medical Officer, and Jack Anders, our Chief Financial Officer, will join us for the Q&A portion of today's call.

With that, I'll turn the call over to our Chief Executive Officer, Dr. Mark Goldsmith. Mark?

Thank you, Ryan. Today marks an historic step forward for patients living with metastatic pancreatic cancer. Eligible patients now have a new treatment option that directly addresses the main cause of their disease. I'm gratified to share that the U.S. Food and Drug Administration has approved RASONQUE for the treatment of adults with metastatic pancreatic adenocarcinoma who have received at least 1 prior systemic therapy or are not candidates for multi-agent systemic therapy. This approval validates more than a decade of work aimed at pancreatic cancer, a primarily RAS-driven disease and 1 of the most difficult challenges in medicine, cancer biology, and drug discovery.

RASONQUE, known generically as daraxonrasib, is an oral once-daily RAS(ON) multi-selective inhibitor targeting RAS proteins. This groundbreaking medicine is supported by compelling clinical evidence in this aggressive cancer that has been characterized by a high symptom burden, bleak prognosis, and few meaningful therapeutic advances. This approval confirms the potential for bold scientific innovation to fundamentally change how RAS-driven cancers are treated.

At Revolution Medicines, we invested our full resources and capabilities into 1 of the most important challenges in oncology, discovering and developing oral medicines capable of directly inhibiting multiple common cancer-causing forms of RAS, a disease target that had frustrated scientists for decades. Meeting this ambition requires scientific innovation while standing on the shoulders of others, boldly challenging dogma, deep collaboration, and perseverance across our organization and close partnership with investigators worldwide. Today, that collective effort has resulted in RASONQUE, the first FDA-approved targeted medicine in pancreatic cancer that defies its main cause, RAS.

Before going further, I want to thank every patient in the RASolute 302 clinical program and their families, the investigators, research nurses, study coordinators, and site personnel who made the results possible, the advocacy organizations that support this community, and the entire Revolution Medicines team. We are profoundly grateful for the trust patients place in us by generously participating in clinical trials even before our medicine is validated. With RASONQUE now approved, let me highlight 4 messages that frame what today means for patients and for Revolution Medicines.

First, the approval is grounded in the unprecedented overall survival benefit demonstrated in the registrational Phase III RASolute 302 trial, which we believe is 1 of the most meaningful treatment advances achieved in metastatic pancreatic cancer. Second, today's approval positions RASONQUE to becoming a practice-changing new standard of care for patients with previously treated metastatic pancreatic cancer and for those who are not candidates for multi-agent systemic therapy. We believe it has the potential to change expectations for patients across these settings.

Third, Revolution Medicines is launch-ready and fully operational in the United States. Our commercialization organization, manufacturing and supply network, market access capabilities, and patient support infrastructure enable us to begin serving patients immediately. Finally, beyond marking the successful development of a single pioneering medicine, this approval provides the first definitive proof point for our bold RAS(ON) strategy, advancing both multi-selective and mutant-selective inhibitors enabled by our proprietary tri-complex platform across multiple RAS-addicted cancers. And it is an important step toward building a leading global oncology company serving patients with RAS-addicted cancers. We view today not as a finish line, but as the beginning of a much larger opportunity to improve outcomes for patients.

Before we review the clinical data, I want to highlight what this image represents. For decades, RAS was viewed as being beyond the reach of direct inhibition, while meaningful treatment advances in metastatic pancreatic cancer, a disease primarily caused by RAS, remained limited. Today, RASONQUE represents a transformative step toward changing that. For patients, it represents the possibility of living longer than with chemotherapy and having more time before pain worsens or quality of life declines. For physicians, it represents having a new targeted medicine to offer eligible patients and with it, renewed hope in a setting where meaningful advances have been limited.

For investigators, it reflects years of scientific innovation, collaboration, and clinical excellence. And for the RevMed team, it marks the moment we have pursued tirelessly for years, delivering to patients a highly innovative and impactful medicine that we discovered and developed. I'll now turn it over to Alan, who will put the historical treatment landscape in context, explain how the early clinical evidence informed our Phase III development strategy, and then walk us through the pivotal Phase III RASolute 302 results that supported today's approval. Alan?

Thank you, Mark. Historically, metastatic pancreatic cancer has been 1 of the most devastating and difficult-to-treat cancers. Despite being predominantly driven by RAS, targeted therapies have been available only to a very small number of patients whose tumors carry rare, actionable non-RAS mutations. Published epidemiology and treatment pattern analyses indicate that approximately 55,000 patients are diagnosed each year in the U.S. with metastatic pancreatic cancer, including both new diagnoses and patients who progressed from a pre-metastatic stage of disease.

In the pre-RASONQUE era, approximately 74% of these patients or 41,000 per year received first-line treatment with cytotoxic chemotherapy, while approximately 26% received no systemic therapy. Of those who received first-line treatment, fewer than half, approximately 19,000 patients, went on to receive second-line treatment. Intravenous chemotherapy regimens based on either 5-FU or gemcitabine have been widely used across all lines of treatment for metastatic disease, typically requiring regular visits to a hospital or infusion center. These patterns illustrate both the aggressive nature of metastatic pancreatic cancer and the substantial attrition across lines of therapy that characterize the treatment landscape.

Against that backdrop, we look for evidence that directly inhibiting active RAS could produce meaningful clinical activity across RAS-driven cancers. Across separate Phase I studies, RASONQUE as a single agent demonstrated encouraging and differentiated antitumor activity in previously treated and first-line metastatic pancreatic cancer as well as in other tumor types, including previously treated RAS-mutant non-small cell lung cancer. The strong signals of clinical activity in single-arm studies across multiple tumor types and in different lines of treatment supported our decision to initiate a wide-ranging Phase III program, which is still underway, to rigorously evaluate RASONQUE in these settings.

This progression from early clinical evidence to broad registrational development is reflected in a first set of 5 randomized Phase III trials with RASONQUE shown here. More than 2,000 patients have now been treated with RASONQUE in a wide set of early and late-stage clinical studies in multiple tumor types and treatment settings, providing a substantial and growing body of clinical experience. So far, the Phase III program includes 4 trials in pancreatic cancer spanning previously treated metastatic disease, first-line metastatic disease, and the adjuvant setting for resectable disease, as well as a 5th trial in previously treated RAS-mutant non-small cell lung cancer.

RASolute 302, a global study comparing RASONQUE monotherapy to standard of care cytotoxic chemotherapy in patients with previously treated metastatic pancreatic cancer, is complete and led to today's approval of RASONQUE. This approval provides a significant element of Phase III validation for our RAS(ON) inhibitor approach to RAS-addicted cancers. The other Phase III studies are in progress, and uses beyond the approved indication remain investigational. I'll now summarize the RASolute 302 data supporting today's approval, followed by key elements of the approved label.

The results of RASolute 302 were presented in the plenary session at the 2026 ASCO Congress in May and published simultaneously in the New England Journal of Medicine. RASONQUE demonstrated an unprecedented overall survival benefit, reducing the risk of death by 60% and nearly doubling median overall survival versus chemotherapy with a manageable safety profile. As a medical oncologist, the most important point to me is straightforward. Patients treated with RASONQUE lived significantly longer. As shown in the intent-to-treat population, which included patients with and without an identified tumor RAS mutation, RASONQUE produced a statistically significant and clinically meaningful improvement in overall survival versus standard chemotherapy.

The overall survival benefit was also consistent across clinically relevant predefined patient subgroups. As with any subgroup analyses, these results should be interpreted with appropriate caution. Nonetheless, considered in aggregate, this consistency supports confidence in the robustness of the overall results. RASONQUE also demonstrated a statistically significant improvement in progression-free survival as assessed by blinded independent central review. The alignment of the overall survival and progression-free survival findings further strengthens the evidence supporting approval.

The patient-reported outcomes contribute an important patient-centered dimension to the RASolute 302 results. Compared with chemotherapy, RASONQUE significantly delayed deterioration in patient-reported measures of both pain and overall quality of life. For patients with metastatic pancreatic cancer, delaying worsening of pain and preserving quality of life are essential treatment goals, making these findings meaningful alongside the survival benefit.

Turning to safety. We did not identify any new safety signals in the profile observed in RASolute 302 compared to earlier studies. Treatment-emergent adverse events were generally manageable with established management and dose modification strategies, and treatment discontinuations due to adverse events were substantially less frequent than with chemotherapy. Together with the efficacy findings, these results support a compelling benefit-risk profile for RASONQUE.

The U.S. prescribing information reflects the strength of the evidence supporting this approval. RASONQUE is indicated for the treatment of adult patients with metastatic pancreatic adenocarcinoma who have received at least 1 prior systemic therapy or who are not candidates for multi-agent systemic therapy. Importantly, the indication is not restricted by tumor RAS mutation status, and no companion diagnostic is required. RASONQUE is administered orally once daily.

The prescribing information includes detailed guidance on dosage and administration, prophylaxis, management of key adverse reactions, and relevant drug interactions. Physicians should review the full prescribing information before prescribing. The label enables physicians to begin prescribing RASONQUE immediately for eligible patients, translating years of clinical research into patient benefit. RASONQUE is available beginning today. With that, I'll hand it over to Anthony Mancini.

Thanks, Alan. Today's approval is grounded in the unprecedented overall survival benefit and broader clinical evidence demonstrated in RASolute 302. It marks an important advance for people living with metastatic pancreatic cancer. From the outset, our commercialization strategy has been focused on the patient. We will ensure that eligible patients can access RASONQUE quickly, and we will support them throughout their treatment journey. With RASONQUE now approved, our focus shifts from preparation to execution.

Our launch strategy is anchored in 3 priorities: First, enable health care providers and eligible patients with the resources needed for an optimal treatment experience. Through education, patient services, and field support, we aim to enable rapid adoption and to help patients remain on therapy. Second, establish RASONQUE as the new standard of care for eligible patients with metastatic pancreatic cancer. The Phase III RASolute 302 results that Alan just described, including the near doubling of median overall survival, a statistically significant improvement in progression-free survival, meaningful improvements in patient-reported outcomes, and a manageable safety profile, position RASONQUE as a truly practice-changing therapy. And third, ensure broad coverage and seamless patient access from day 1.

Our market access organization and patient services capabilities are fully operational and engaged. This remains a setting of profound unmet medical need where patients have historically had limited treatment options and poor outcomes. We believe RASONQUE can meaningfully change the treatment outlook for eligible patients. A successful oncology launch requires more than a strong clinical profile. It requires reaching every stakeholder involved in the care of pancreatic cancer patients.

Approximately 40% of patients are treated at academic centers where many investigators and opinion leaders are already familiar with the RASONQUE clinical program, which we believe will help drive early adoption. The remaining 60% of patients receive care in community oncology practices, making broad community education and practice-level engagement equally important. We've built a world-class commercialization organization with deep experience in oncology, oral oncolytics, gastrointestinal cancer, and new product launches.

Our U.S. medical science liaisons have been active for over a year, engaging clinical experts through scientific exchange. Our thought leader liaison team has been engaging appropriately with opinion leaders to gather perspectives on the treatment landscape and potential implementation needs. Those insights have helped shape our launch readiness.

To date, our field-based market access teams have engaged key integrated delivery networks and large community accounts as well as payers representing more than 80% of covered lives through pre-approval information exchange. Our sales team is set to engage with the broad oncology health care provider community. Overall, our field-based teams are deployed to enable a coordinated launch by advancing clinical understanding, preparing the breadth of accounts, addressing access barriers, and helping eligible patients benefit from RASONQUE. Central launch priority is helping eligible patients begin therapy promptly and remain supported throughout treatment.

RASONQUE is now commercially available in the United States at a wholesale acquisition cost of $39,800 for a 30-day supply based on the recommended daily dose. We believe the price reflects the unprecedented overall survival benefit and broader clinical value demonstrated in RASolute 302. Our market access and patient services infrastructure is fully operational to support broad patient access across channels. Our comprehensive patient services program, (ON)Path, provides integrated support from prescription through ongoing treatment. The program includes coverage navigation, financial support, adherence support, and educational resources for patients, caregivers, and health care teams.

Importantly, our team will also be focused on ensuring continuity of care for patients who have been receiving RASONQUE through the expanded access program, supporting a smooth and seamless transition to commercial supply and applicable insurance coverage. Eligible commercially insured patients may qualify for co-pay assistance as low as $0. Dedicated support teams will work with providers and specialty pharmacies to navigate coverage and coordinate access. Our goal is simple: help remove barriers to access so physicians can focus on treatment and patients can focus on their care.

In the United States, our launch is now underway with commercial supply, distribution, patient services, and each of our field teams fully operational. Internationally, we have established teams in Europe and Japan and are rapidly expanding our capabilities in preparation for future potential launches. The European Medicines Agency's phased review of daraxonrasib is underway. We intend to address the broader international opportunity in phases market by market. I should note that outside the United States, daraxonrasib is investigational and has not yet been approved by any regulatory authorities.

We will, however, be able to respond to unsolicited requests from health care providers who have decided to prescribe daraxonrasib to suitable patients in countries where it has not yet received regulatory approval on a paid basis through global named patient access. This process will vary from country to country depending on local laws, regulatory, and access requirements. Additional information about global named patient access is available on our website. Together, these capabilities provide the foundation for a successful U.S. launch and position us for future global expansion as additional approvals are obtained. With that, I'll hand the call back to Mark.

Thank you, Anthony. As you've heard today, this approval represents more than the successful development of 1 pioneering medicine. It validates the strategy Revolution Medicines has long pursued. By combining deep biological insight, innovative chemistry, and bold but disciplined clinical development, we set out to create and validate new targeted medicines that transform outcomes for patients with RAS-driven cancers. Today, RASONQUE makes that vision a reality and begins our next chapter.

Our immediate priority is clear: deliver RASONQUE to eligible patients across the United States and establish it as a practice-changing new standard of care. In parallel with the U.S. launch, we are advancing launch readiness in Europe and Japan and expect to address additional international markets in phases subject to regulatory approvals. The RASONQUE NDA is included in the FDA's Project Orbis initiative, which provides a framework for concurrent review of oncology applications by participating international health authorities. Today's U.S. approval provides a foundation for our ambition to build the leading global pancreatic cancer franchise.

Our development strategy extends well beyond today's indication. Four additional global Phase III registrational programs are underway in pancreatic cancer, spanning first-line metastatic and resectable disease and using complementary monotherapy and combination strategies involving RASONQUE and zoldonrasib, our RAS(ON) G12D selective covalent inhibitor. These programs are designed to address diverse patient needs across the treatment continuum. Our ambition is not simply to participate in pancreatic cancer care, but to improve patient outcomes by redefining treatment across a wide range of cancer types caused by RAS. That ambition extends across our broader portfolio.

RASONQUE is the first approved targeted medicine to emerge from our broad and differentiated pipeline of oral RAS(ON) inhibitors spanning multiple RAS mutations, tumor types, and treatment settings. The experience of successfully discovering, developing, and now delivering RASONQUE strengthens every part of our organization. It deepens our understanding of patients, expands our relationships with physicians and treatment centers, reinforces our commercial capabilities, and creates scientific and medical insights that can accelerate the development of future medicines.

Discover, develop, and deliver are more than words on a slide. Together, they describe an integrated strategy for fulfilling our mission. Discovery fuels development. Development creates opportunities to deliver innovative medicines. Commercialization, in turn, generates scientific and clinical insights that inform the next generation of discovery and development.

With RASONQUE now approved and entering clinical practice, that virtuous cycle can operate in a fundamentally new way for Revolution Medicines. For the first time, our research scientists, development teams, and commercial organization are connected through an improved medicine in everyday clinical use, which will enable us to incorporate feedback from an even broader patient and prescriber universe as we continue driving innovation on behalf of patients.

This new phase provides a robust foundation for building an industry-leading global targeted medicines franchise. RASONQUE is the first approval proof point for this strategy, and our mission is to translate the breadth of our science and pipeline into multiple transformative medicines that improve outcomes for patients with RAS-addicted cancers. Today's approval is a compelling and exciting step toward realizing that vision.

Before we open the call for questions, I want to close where I began with patients. Behind every data point is a person and a family facing an extraordinarily difficult diagnosis. Bringing RASONQUE to these patients is central to our mission. To the patients and families, investigators, employees, collaborators, and shareholders who helped make today possible, thank you. We also recognize the creative vision of Greg Verdine and the pioneering scientists at Warp Drive Bio.

Their early work established both the initial technology foundation that became part of Revolution Medicines 8 years ago and a new paradigm that inspired our discovery work leading to this consequential milestone. We are honored by today's approval, committed to bringing RASONQUE to patients, and energized by what comes next as the revolution continues. With that, I'll turn the call over to the operator for the Q&A portion of the call.

[Operator Instructions] Our first question comes from the line of Michael Schmidt from Guggenheim.

Congratulations on this great accomplishment. It's clearly a great day for patients. Mark, as we think about the potential launch ramp here, just remind us of the patients that are already on the early access program, what are the logistics and timing for those to potentially roll over to becoming commercial patients? And what is your expectation longer term? How fast you can reach patients in the community as well beyond academic centers?

Yes. Thank you for your questions, Michael. I think Anthony Mancini can comment on both of those.

Yes. Thanks, Michael, for the question. The patients on the U.S. EAP following U.S. approval will be transitioning within a few months. I think it's important to note that (ON)Path, our patient support program, will be available to assist all patients who've been prescribed RASONQUE, including those in the EAP program and new patients.

For U.S. patients who are already receiving daraxonrasib in the EAP, we will work very closely with treating physicians at all sites to support transition to commercially available treatment as clinically appropriate. And those who are pending medical review or who had been medically approved but not yet shipped product at the time of approval, will need to access RASONQUE through commercial channels. So the EAP portal will be closing today, but available for a limited transition period. And our intent is really to support continuity of care for eligible patients and work very closely with all of the key centers to ensure this happens as quickly as possible, but we estimate that will take a couple of months.

And our next question comes from the line of Brian Cheng from JPMorgan.

Truly congrats on the approval. As we think about the launch here, what kind of metrics could we get during your upcoming earnings call to track the launch over time? And then we have a quick follow-up.

Thanks, Brian. You're giving Anthony more opportunity to speak than in any prior meeting.

Yes. Thanks, Brian. Yes, look, we're going to evaluate launch progress across a range of different indicators, including physician adoption, patient access, treatment continuity, and, of course, financial performance. We'll provide appropriate context on launch progress based on the indicators we believe are most relevant at each stage of the launch. And these will include things like net sales, some patient adoption metrics, prescriber adoption, and coverage. And that information, of course, may evolve over time as the launch matures and as we gain additional experience in the market.

Great. And then just on RASONQUE's potential usage in locally advanced setting. I'm just wondering if there's any potential for NCCN guidelines to enable usage there because we do see some usage for other therapies enabling usage off-label for locally advanced. So I'm curious if there's any potential there.

Thanks for that question. I think Dr. Sandler can comment on that.

Yes. Again, thanks for the question. I mean, we, in terms of locally advanced, that is an area certainly of interest that we're going to be looking to pursue specifically in the future. The label itself is based specifically, of course, on 302 on the previously treated population and then those patients not a candidate for multi-agent systemic therapy.

Dr. Lin, do you want to add something to that?

Yes. Historically, the NCCN guidelines does provide guidance based on the metastatic standard of care and translation of data for use in locally advanced. However, to date, I think that's going to be a decision that's going to be weighed by the physician and their patient.

Great. Congrats on the approval again.

And our next question comes from the line of Tyler Van Buren from TD Cowen.

Mark, congratulations on this transformative approval and milestone for patients. So I understand that RASONQUE is now available by prescription. But for the new non-EAP commercial patients, how long will it take for them to get commercial or paid drug in hands? Could this be faster than the EAP? And do you expect it to be a matter of days or weeks? And perhaps as a follow-up, how do you expect coverage to progress?

Thank you, Tyler. Nice to hear from you. Back to Anthony.

Yes. Thanks, Tyler, for the question. I think as far as availability of the product, as we discussed earlier, the product is available and physicians can prescribe it as of today. As far as coverage, just a couple of comments, I think, in terms of what is normal in an oncology launch is that in the early stages, we expect that very quickly that payers will prescribe their medical policy, will change their medical policy and publish those.

But in the meantime, it's quite common that approval will be gained through medical exception, and we expect that to happen with RASONQUE. And, but we expect patients to be able to access that relatively quickly. So we're, again, as I mentioned, we've had very robust payer pre-approval information exchanges, and we expect to be able to get approval through medical exception relatively quickly.

I hope that answers the question, Tyler.

And our next question comes from the line of Charles Zhu from LifeSci Capital.

Congrats on everything. A couple of quick ones from me. First, how is chemo ineligibility being defined? Are there clinical criteria only? Or is there some sort of a patient desire factored in as well? And the second one, can you comment a little bit more on the paid process for patients outside the United States to access daraxonrasib and perhaps how you might be thinking about ex-U.S. pricing in general?

Thanks, Charles. I think we'll start with Alan, and then Anthony can address your second question.

Yes. Thanks, Charles. So the U.S. prescribing information doesn't define specific criteria for determining whether a patient is a candidate or not for multi-agent systemic therapy. So that said, treatment decisions among approved options should be made by the treating physician in consultation, of course, with the patient and taking into account individual needs of the patient, circumstances, supporting evidence, and importantly, the risks and benefits of available treatment options. And this allows, again, for the flexibility for patients as with other treatment decisions to allow physicians those flexibilities in having multiple treatment options for interactions with patients.

So maybe, Charles, I'll start with the question on the global named patient access. And really, this is to support health care provider-initiated unsolicited requests for RASONQUE on behalf of eligible patients. It provides an interim and compliant pre-approval access pathway in countries where it's permitted under local laws and regulation. It reflects our commitment to responsibly expand access for eligible patients while we continue to advance clinical development, regulatory approval, and work towards broader commercial availability. Again, this is a program that is, that provides daraxonrasib on a paid basis and in accordance with terms that are specific to the country in question.

Our long-term goal is to make daraxonrasib available to the broadest possible patient population through regulatory approvals and through commercial availability. And maybe I'll comment a little bit on your ex-U.S. question as well. Clearly, we will make launch and access decisions market by market, taking into account regulatory requirements, local reimbursement and access consideration, and, of course, the evolving policy environment. And we've set a U.S. price really that's grounded in demonstrated clinical, patient, and societal value of RASONQUE, and we're optimistic about our overall pricing strategy and approach as we continue to build our launch plans in markets outside the U.S. And I think I'll leave it there, Charles.

And our next question comes from the line of Cory Kasimov from Evercore ISI.

Let me add my congrats on this landmark approval. So 2 questions for me as well. I suspect you're aware that there are other news out there this afternoon that the Trump administration plans to announce new drug pricing deals with several mid-cap biotech companies next week. I'm wondering if the timing of that is not a coincidence and if RASONQUE is part of this. Is this something you're able to comment on at all right now?

We don't have any comments on that at this point.

Okay. So the other question was just related to that with the pricing, how should we think about gross-to-net in the first handful of quarters? Should we assume something like roughly comparable to the G12Cs when they launched? Or is this, like should we be looking at this in a kind of completely different lens?

Thanks again for that question. Jack Anders, our CFO, has been waiting for his opportunity.

Thanks, Cory. Cory, we expect the gross-to-net discount to initially be in the range of 20% to 30%. This is ultimately going to depend based on the payer mix. We do expect a significant proportion of eligible patients to be covered through government payers, particularly Medicare Part D. And as you know, utilization through government payers comes with mandatory discounts and rebates.

And our next question comes from the line of Faisal Khurshid from Jefferies.

Congratulations on this milestone. I just wanted to ask if you could help us understand the interplay of dose reduction with realized price for the drug. I understand you're supplying the drug in 100- and 150-milligram bottles, but the label says that the dose reductions are 300, 200, and 150. So I just want to understand how that may or may not impact what you ultimately realize on a net price per patient.

Thanks for your question. Anthony?

Yes. So I'll address that, Faisal. Thanks for the question. So as you said, RASONQUE is available in 30-count bottles, both the 150 and the 100 milligrams, and those support the recommended dose in the approved prescribing information. Each is flat-priced. So the 100-milligram count bottle and the 150-milligram count bottle are priced at the same. So that should hopefully clarify things.

Got it. But if a patient has 2 dose reductions and they're at the 150 mg dose, what does that mean then?

Well, so the recommended dose is 300 milligrams, and the recommended dose reduction, which we saw in the clinical trial can happen, is 200 milligrams. We expect there to be very few patients below that.

And our next question comes from the line of Michael Yee from UBS.

This is Roy on for Michael Yee. Can you help us understand a little bit how baseline liver function could modify the real-world uptake? And in particular, like what proportion of PDAC patients might be ineligible or have trouble getting the drug because of this?

Thanks for that question. Wei, do you want to just comment on that just generally?

Yes. Generally, obviously, some patients will have liver elevation due to metastasis or other liver abnormalities at baseline. And those patients may not be eligible to receive any medicine in general. But I think a majority of cancer patients will be eligible for daraxonrasib.

Maybe Alan can add a point to that.

Yes. So we'll be, we are conducting studies looking at those patients with moderately elevated liver function tests to see how they are able to tolerate therapy as well.

Great. And then just as a second question, can you maybe provide a little bit more detail on the patient services program, which payers are participating in this? And what percentage of patients would you anticipate getting that $0 co-pay?

Yes. Look, I think, first of all, (ON)Path is a standard sort of set of offerings, and it's voluntary and patients sign up for this. So this is going to be offered very broadly, and we expect there to be a high level of participation. But again, it is voluntary. So I think that's the first part of the question.

I think your second part of the question is more asking specifics around what, what (ON)Path is. And for patients that opt in, there's 4 core service areas, and I'll expand a little bit on what they are. So the coverage navigation piece really helps patients and providers work through prior authorizations and payer requirements. The financial support component really is assistance programs to help reduce out-of-pocket burden. The adherence support piece, our resources to keep patients on therapy and managing side effects. And then there are educational materials for patients and caregivers and the care team.

As far as the mix, as Jack sort of alluded to in his answer, we expect the majority of patients to be Medicare Part D, the biggest subtype of our mix to be Medicare Part D. The second largest subgroup of patients will be commercially insured patients followed by others. For the commercially insured patients, it really depends on that commercial plan. So it really varies patient by patient. As you know, for a Medicare Part D patient, $2,100 is the maximum out-of-pocket based on the benefit redesign. And so for, that's across all of their medicines. So that's the maximum out-of-pocket cost for the biggest segment of patients that will receive RASONQUE per year.

And our next question comes from the line of Laura Prendergast from Stifel.

Congrats on the historic update today. Do you have any plans to pursue any type of accelerated approval path for first-line PDAC? Anything that would get us faster than, get approval faster than waiting for RASolute 303 to read out on OS? And then how should we think about time on therapy in the real world? I know you previously said patients had to come off drug upon progression on 302. Do you expect that to be reflected in the real world?

Laura, thanks for your questions. I'm going to comment on the second question, Wei, which is time on drug.

Yes, time on drug. So I think, well, every clinician when it comes to managing a patient, always thinks about the risk-benefit of maintaining the current treatment versus transitioning to that therapy and the risk-benefits from that. And oftentimes, that has to do with the rapidity at which the progression is occurring and how well is the patient doing symptomatically. I think 302, the studies designed this treatment at the time of progression or future trials are generating data to evaluate continuation or treatment beyond progression as a concept. And that will be, as the data emerges for that, I think it will provide evidence for the physician to make that judgment call for their individual patients.

And then the first question that had to do with first-line pancreatic cancer, as Alan described earlier, the label enables flexibility by a physician and the patient to determine what's the best course of treatment for them. In addition, as you pointed out, we have the 303 trial, which is a 3-arm trial, allows evaluation of daraxonrasib plus chemotherapy versus chemotherapy. And that's designed to establish the overall durability as you asked about. With regard to anything that might be an acceleration of that, as you know, we generally don't project that sort of thing into the future. So we don't have any particular comments to make about that today.

And our next question comes from the line of Jay Olson from Oppenheimer.

Congrats on this landmark achievement. We have a question about the patient-reported outcomes benefits from RASolute 302, such as the delay in pain deterioration and preservation of quality of life. How important do you think those benefits will be in driving treatment decisions versus the survival data alone? And are there specific physician or patient segments where the quality of life data should be especially important?

Thanks for the question. I think Alan would like to comment on that.

Yes. I think overwhelmingly, survival advantage is of significant importance. I think the key with this particular, the results from 302 is the fact that not only did you have an overwhelming survival advantage, essentially nearly doubling the median and a 60% improvement in survival, but you also had similar improvements in the -- with the PROs in terms of, as you mentioned, delay to onset of new treatments and delay to deterioration of quality of life. So I think most physicians and patients will view those in tandem and look at this as just a remarkable step forward to have not only an improvement in survival, but feeling well longer delay in symptoms.

Particularly because it's such a symptomatic disease. And so we think that, that's going to be very important for every patient.

And our next question comes from the line of Alec Stranahan from Bank of America.

I want to offer my congrats on the approval as well. Two questions. First, since the label seems to mostly reflect the RASolute 302 data. Curious if this maybe affects how you can speak about the totality of the data available at launch in your physician education materials, particularly thinking about the AACR data we saw from the broader metastatic population. And second, maybe you could just remind us whether the CNPV or any of your other designations for RASONQUE carry over for a frontline review or if this is something you'll seek in this setting as well?

Yes. Thank you, Alec. Well, of course, all of our commercial efforts will be compliant, and that means we'll cite the data that are the explicit basis for the approval. With regard to the CNPV, that we have now spent the CNPV. We have used that. But we have a very good relationship with the FDA. We're engaged with them on, obviously, every study that we have ongoing in every patient population, and we'll continue to engage with them. And I think their announcement today indicates a level of enthusiasm for the drug, a label that is very attractive for physicians and patients, and we'll just look forward to the future.

And our next question comes from the line of Gregory Renza from Truist Securities.

Great. Let me add my congratulations on this monumental day as well. Mark, maybe just following up on the CNPV status and the voucher. Just wanted to ask if you could provide perhaps a little more color on the drivers that went into arriving at the price that you've set today? And perhaps to what extent, if at all, did the voucher status play a role in determining the value and also the affordability for patients. Congrats again.

Yes. Thank you very much. I think to us, the CNPV was a reflection of the inherent value of the asset rather than a driver of the value. And we very much appreciate it, the engagement by the FDA and their very efficient process by which they supported all steps along the way, including opening the expanded access program and now moving with light speed to evaluate under the expedited review program. But I don't think from our point of view, it really had anything to do ultimately with pricing. And as Anthony described earlier, there are a number of factors that went into the pricing consideration. We think that it is appropriately priced and optimistic that it will serve everybody's needs.

And our next question comes from the line of Sean McCutcheon from Raymond James.

I'll throw on my congrats as well. A couple from us. Putting maybe a finer point on Charles' question from earlier. You noted 74% of patients received frontline treatment. What proportion of that 26% that do not do you see as potentially amenable for daraxonrasib monotherapy? And then secondly, can you speak to any early experience during the EAP period that you've had on cutaneous AE management educational efforts at centers that were not part of the clinical program?

Yes. Let me comment on the first point. So the treatment patterns that we're familiar with and that you just cited, of course, are the pre-RASONQUE era. So we really don't know what things will look like going forward, and we imagine there will be some change in those. It's also hard for us to say among any particular population, exactly what percent will choose to take RASONQUE. So I don't think we can provide any more color about that. With regard to the second question, can you remind me what that question was?

AE management.

AE management. I think the question was with regard to impact of our educational materials on investigator familiarity. Maybe you can add to that investigator experience also quickly growing their understanding.

Yes. I mean since 2022, when we dosed the first patient with RASONQUE to date, we certainly thousands of patients and gained a wealth of experience through the experienced investigators with the patients. So we have drafted a very clear guideline. That's part of the label, which our commercial medical care team will be actually distributing and working with physicians throughout the U.S. in implementing that. So I think it's actually very well thought-out plan and to be able to keep the patient on drug and to extend their survival has been reflecting in 302 trial.

Yes. Maybe just to complement Wei's comments, we learned a great deal from the clinical experience, and that data gathering has been happening for several years. And the educational program that we're launching with today reflects all of that learning, and we're really pleased with the input we've gotten from investigators along the way, and we're confident that we'll be well positioned to manage adverse events in the real world like we were able to do so in the clinical trial. And hopefully, we can continue to improve on that over time.

And we deployed those very similar materials in the expanded access program, which included some investigators who had a lot of experience, but also many physicians who had no prior experience. And so we've already had an opportunity to see how receptive they are to it and they are receptive.

And our next question comes from the line of Leonid Timashev from RBC CM.

Josh on for Leo, and congratulations on today's approval. So, the news today refers to not candidates for multi-agent systemic therapy. And I was wondering if you could just provide a bit more color on exactly what that means for how the dynamics might shake out for first-line PDAC patients.

Thank you for your question. Alan?

Sure. Just want to maybe help reiterate that the prescribing information does not define specific criteria for determining, again, whether a patient is candidate for that, as you pointed out. So therefore, these treatment decisions as often happens in other treatment settings as well, will be made by the treating physician in combination with the patient themselves to evaluate their specific situation and the risks and benefits that are specific to that particular patient moving forward. And I think as with all treatment decisions, this will allow for some flexibility for both the patient and the physician in making these treatment decisions.

And our next question comes from the line of Kalpit Patel from Wolfe Research.

Congrats on the approval today. I guess one on the label outcome here. Given that you have a broader label than expectations, how does that impact the enrollment timing for the ongoing first-line studies? And then second question, what percentage of the first-line market do you ultimately think remains truly inaccessible under today's label?

Okay. Thanks for your question. So the first question is potential impact on enrollment of ongoing studies and maybe Wei can comment on that.

Yes. As we've discussed before, I think on prior calls, we've been very thoughtful and forward-looking when it comes to the potential impact of the launch of RASONQUE in pancreatic cancer. And I think given the breadth of the label and the potential usage inside [indiscernible] areas. So I think we still have -- going to follow through with our operational plan, which is really focused on key U.S. sites, enroll the appropriate patients. And then, but the lion's share of the operational footprint will be outside the U.S. where RASONQUE is not commercially available. That would help us to be able to demonstrate the efficacy of both monotherapy RASONQUE as well as RASONQUE plus GnP compared to the current standard of care in the first-line setting.

And with regard to your second question, we understand your desire to get more clarity about it. We think it's fairly straightforward. Patients with and without prior systemic therapy may be considered for treatment with RASONQUE. For those who have received prior systemic therapy, treatment may have been initiated either at the initial diagnosis of metastatic disease or before recognized metastatic disease. And for patients who have not received prior systemic therapy, considerations should include whether the patient is a candidate for multi-systemic therapy. As to what those percentages will prove to be, that's something we'll find out over time, how doctors and their patients make those decisions. But we can't give you any forward-looking insight into that.

This does conclude the question-and-answer session of today's program. I'd like to hand the program back to Dr. Goldsmith for any further remarks.

Thank you, operator, and thanks again to everyone who joined us today. The approval of RASONQUE is a far-reaching milestone for Revolution Medicines, and it's a monumental step forward for patients with metastatic pancreatic cancer who now have a new treatment option. We're extremely well prepared to fulfill our responsibility. We're energized to enter this next chapter, and we're grateful for your continued support. We look forward to updating you as we bring RASONQUE to patients and advance our broader mission.

Thank you, ladies and gentlemen, for your participation in today's conference. This does conclude the program. You may now disconnect. Good day.

Good day, and thank you for standing by. Welcome to the Revolution Medicines Q2 2026 Earnings Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded.

I would now like to hand the conference over to your first speaker today, Ryan Asay, Senior Vice President, Corporate Affairs. Please go ahead.

Thank you, and welcome, everyone, to the second quarter 2026 earnings call. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive Officer; Dr. Alan Sandler, our Chief Development Officer; and Jack Anders, our Chief Financial Officer; Dr. Wei Lin, our Chief Medical Officer; and Anthony Mancini, our Chief Global Commercialization Officer, will join us for the Q&A portion of today's call.

We would like to inform you that certain statements we make during this call will be forward-looking because such statements deal with future events and are subject to many risks and uncertainties. Actual results may differ materially from those in the forward-looking statements. For a full discussion of these risks and uncertainties, please review our annual report on Form 10-K and our quarterly reports on Form 10-Q that are filed with the U.S. Securities and Exchange Commission.

This afternoon, we released financial results for the quarter ended June 30, 2026, and recent corporate updates. The press release and updated corporate presentation are available on the Investors section of our website at revmed.com.

With that, I'll turn the call over to Dr. Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive Officer. Mark?

Thank you, Ryan, and thanks to everyone for joining us this afternoon. I'll begin today's call with initial remarks focused primarily on pancreatic cancer, and then Dr. Sandler will provide highlights of recent results and plans in non-small cell lung cancer. Jack Anders will then summarize our second quarter financial results before I share some closing comments and open the call to questions and answers.

2026 is proving to be a transformational year for Revolution Medicines with substantial progress in many dimensions, supporting our mission to revolutionize treatment for patients with RAS-addicted cancers globally through the discovery, development and delivery of innovative targeted medicines. We've continued to build on strong momentum in pancreatic cancer, reinforced by compelling results from RASolute 302, our recently completed global Phase III study in patients with previously treated metastatic disease. Catalyzed by the unprecedented clinical results, we quickly expanded availability to patients through our FDA-cleared expanded access program, advanced regulatory activities in support of potential approvals, strengthened our commercial readiness globally and continue to expand our broad pioneering R&D pipeline targeting RAS-driven cancers.

I'd like to spend a few more minutes reviewing some of these activities in more detail. First, at the American Society of Clinical Oncology, or ASCO, Dr. Brian Wolpin presented the full results from RASolute 302, which were also published simultaneously in The New England Journal of Medicine. The data demonstrated paradigm-changing clinical outcomes with daraxonrasib monotherapy in patients with previously treated metastatic pancreatic cancer, including statistically significant and clinically meaningful improvements in overall survival, progression-free survival and patient-reported quality of life indicators compared to chemotherapy, along with a manageable safety and tolerability profile.

Second, based on these and earlier results, we believe daraxonrasib represents a major advance for patients facing one of the most difficult-to-treat cancers, and we are moving with urgency to make this potential new treatment available to eligible patients as quickly as possible.

In particular, since announcing our expanded access program shortly after disclosing top line results from RASolute 302, we've made significant progress establishing access through health care providers across the United States. It has been deeply gratifying to activate sites participating in the program in almost all 50 U.S. states and Puerto Rico, including both academic cancer centers and community oncology practices with many additional sites still coming online to begin treating patients through the program. To date, our team has approved greater than 90% of reviewed requests and has provided daraxonrasib on behalf of more than 2,000 eligible patients.

Our teams continue working closely with investigators, health care providers, patient advocacy organizations and regulators to make this possible, and we're proud of the progress so far on behalf of patients. I'm also very pleased to note that our new drug application for daraxonrasib in pancreatic cancer has been accepted for review by the U.S. Food and Drug Administration. We continue to engage constructively with the FDA as they review this application. We're also making progress with additional regulatory authorities around the world. The European Medicines Agency, or EMA, recently announced that it had designated daraxonrasib as a high priority under EMA's Cancer Medicines Pathfinder project based on its potential to address a high unmet medical need and that it has started a phase review of daraxonrasib with the goal of accelerating assessment by evaluating the data as they become available ahead of the submission of a full marketing authorization application. We look forward to continuing collaborative interactions with the EMA and other health authorities around the world as we work to bring daraxonrasib to patients as quickly as possible.

Third, we continue preparing for a successful launch. In the U.S., our medical affairs organization has been in the field for over a year and continues to actively engage the oncology community through scientific exchange. We have also built the commercial infrastructure needed to support launch. Our sales organization is in place. Our field access team is operational and our on-path patient services program, commercial supply and distribution network are ready. We are well positioned to serve patients with pancreatic cancer from day one. Internationally, we continue to build our launch capabilities at an accelerating pace, positioning us to support future commercialization across key markets. Subject to regulatory approvals, we believe we are well positioned to execute a strong launch and deliver daraxonrasib to patients quickly and broadly.

Fourth, with our commitment to pancreatic cancer extending well beyond previously treated disease, we continue prosecuting a comprehensive development strategy involving multiple RAS(ON) inhibitors across lines of treatment. With daraxonrasib, enrollment continues in the RASolute 303 and 304 Phase III programs in the first-line metastatic and adjuvant settings, respectively. With zoldonrasib, our RAS(ON) G12D-selective covalent inhibitor, the RASolute 305 Phase III trial in first-line metastatic pancreatic cancer is also enrolling and treating patients. Further, we recently initiated RASolute 309, evaluating the novel RAS(ON) inhibitor doublet of daraxonrasib plus zoldonrasib in the first-line treatment setting. These trials are supported by strong clinical data and continue to generate significant interest from investigators and patients around the world who recognize both the unmet needs and the underlying scientific rationale for these treatment strategies.

At last month's European Society for Medical Oncology's Gastrointestinal Cancers Congress, or ESMO GI, we presented new pancreatic cancer data for zoldonrasib that reinforced its compelling profile and the breadth of our development strategy in pancreatic cancer specifically, including the differentiated first-line treatment approaches underlying the RASolute 305 and 309 trials. In one study reported at ESMO GI, zoldonrasib, combined with standard of care chemotherapy showed compelling preliminary antitumor activity in first-line treatment of patients with RAS G12D pancreatic cancer, including objective response rates of 82% and 61% and disease control rates of 96% and 90% in combination with modified FOLFIRINOX or gemcitabine plus nab-paclitaxel, respectively. Longer follow-up will further establish the durability profiles for these regimens. These combinations also demonstrated favorable safety and tolerability profiles with treatment-related adverse events broadly consistent with the established profiles of each respective chemotherapy component. These encouraging findings strongly support the global pivotal Phase III RASolute 305 study of the zoldonrasib plus chemotherapy in first-line treatment of patients with RAS G12D pancreatic cancer.

In a second study reported at ESMO GI, the RAS(ON) inhibitor doublet of daraxonrasib plus zoldonrasib demonstrated compelling preliminary clinical activity in second and third line or later treatment of patients with RAS G12D pancreatic cancer, including objective response rates of 50% and 47% and disease control rates of 97% and 90%, respectively, observations that are consistent with earlier preclinical studies. Earlier indicators of durability for this combination are also compelling, showing median progression-free survival of 9.6 months and 7.6 months in patients in second and third-line treatment or later, respectively. Median overall survival in the second-line setting was not yet reached, while the median overall survival in the third line or later setting was 10.5 months.

The combination also showed a favorable safety and tolerability profile. Treatment-related adverse events were broadly consistent with the established profile of daraxonrasib monotherapy. These encouraging preliminary results support the planned global pivotal Phase III RASolute 309 study evaluating the combination of daraxonrasib plus zoldonrasib as first-line treatment in patients with RAS G12D pancreatic cancer. Our RAS(ON) inhibitors are also being evaluated in combination with other investigational approaches, including with MTA-cooperative PRMT5 inhibitors through clinical collaborations with Tango Therapeutics and Bristol Myers Squibb.

I'd also like to note that RMC-5127, our RAS(ON) G12V-selective inhibitor continues in the ongoing first-in-human study. To date, RMC-5127 has been well tolerated at all dose levels evaluated with no dose-limiting toxicities reported so far. Encouraging early signs of antitumor activity have been seen across multiple tumor types, including objective responses starting at the first dose level.

Overall, we are increasingly confident in our ability to help redefine the standard of care for patients with pancreatic cancer across the continuum of disease from early-stage settings to advanced metastatic disease and across RAS tumor genotypes. With these opportunities comes a profound responsibility for revolution medicines that we take very seriously. Recognizing that every patient's disease and treatment journey is unique and treatment optionality may best serve the collective unmet needs, we remain committed to developing a broad portfolio of potential treatment options as quickly as possible.

I'll now turn the call over to Alan to discuss our progress and expanding efforts in non-small cell lung cancer, along with other pipeline updates. Alan?

Thank you, Mark. While pancreatic cancer remains an important and immediate opportunity for Revolution Medicines, non-small cell lung cancer represents another major malignancy where despite meaningful advances in treatment, significant unmet needs remain. There is growing evidence that our RAS(ON) inhibitor portfolio has the potential to significantly improve outcomes for patients with RAS-driven non-small cell lung cancer.

We believe daraxonrasib has the potential to become an important treatment option for patients with non-small cell lung cancer. Based on encouraging previously reported non-small cell lung cancer results in patients with tumors carrying diverse RAS mutations other than RAS G12C the U.S. FDA granted breakthrough therapy designation to daraxonrasib for previously treated metastatic non-small cell lung cancer with KRAS mutations other than G12C who have received prior platinum-based chemotherapy and anti-PD-(L)1 or PD-1 antibody therapy. Building on these encouraging Phase I/II results, RASolve 301, our ongoing global Phase III registrational study in patients with previously treated RAS-mutant non-small cell lung cancer continues to see high demand and is enrolling well. We also believe that combining targeted RAS(ON) inhibition with innovative bispecific antibodies targeting both the PD-1, PD-L1 and VEGF accesses has the potential to improve outcomes for patients with previously untreated metastatic non-small cell lung cancer. In particular, through our ongoing clinical collaboration with Summit Therapeutics, we are evaluating daraxonrasib in combination with ivonescimab, Summit's PD-1 VEGF bispecific antibody and platinum doublet therapy in first-line non-small cell lung cancer.

With impactful targeted therapies available now for patients with non-small cell lung cancer with tumors harboring EGFR, ALK, ROS1, RET, KRAS G12C or other genetic alterations, we recognize that practitioners increasingly view treatment of lung cancer through a biomarker-directed lens. In the context of RAS-driven disease, significant unmet needs remain across patients with non-small cell lung cancer carrying diverse RAS mutations for which no approved targeted therapies have been approved. Revolution Medicines is uniquely positioned to address these needs through our broad and differentiated pipeline of targeted inhibitors.

Approximately 30% of patients with non-small cell lung cancer have tumors harboring a RAS mutation and our RAS(ON) mutant selective inhibitors, elironrasib, zoldonrasib and RMC-5127 targeting RAS G12C, G12D and G12V, respectively, have the potential to address over 70% of RAS-driven mutations in this disease. In the first-line setting, we're actively evaluating elironrasib and zoldonrasib in combination with the current standard of care regimen of pembrolizumab plus platinum doublet chemotherapy. We previously reported Phase I data for zoldonrasib and elironrasib monotherapy in previously treated RAS G12D or G12C non-small cell lung cancer, respectively, each exhibiting highly encouraging monotherapy efficacy and safety profiles.

Today, I'm pleased to share new observations for each of these compounds in combination with pembrolizumab and chemotherapy in patients with previously untreated non-small cell lung cancer, data which we believe demonstrate the differentiated and compelling potential of our RAS(ON) mutant selective inhibitors in this treatment context. I'll begin with zoldonrasib, our RAS(ON) G12D selective inhibitor. The baseline characteristics of patients enrolled in this cohort are representative of the KEYNOTE-189 study population, which evaluated pembrolizumab plus platinum doublet chemotherapy. The principal difference is a somewhat lower proportion of patients with high PD-L1 expression, while other key demographic and disease characteristics are broadly consistent with expectations for patients with previously untreated metastatic non-small cell lung cancer. Taken together, these baseline characteristics provide an appropriate context for interpreting the safety and efficacy observations I'll discuss next.

The safety profile of zoldonrasib was highly encouraging. Treatment-related adverse events were again broadly consistent with the established profile of pembrolizumab plus chemotherapy with no new or unexpected safety signals observed. With the data cutoff of May 11, 2026, the majority of adverse events were grade 1 or grade 2. No grade 5 treatment-related adverse events were reported, and there was a low incidence of liver enzyme elevations, which were manageable with standard dose modifications.

The combination of zoldonrasib with pembrolizumab and platinum-based chemotherapy demonstrated encouraging antitumor activity in patients with previously untreated KRAS G12D non-small cell lung cancer. With the data cutoff of May 11, 2026, and median follow-up of 3.4 months, the objective response rate was 82%, with disease control achieved in all evaluable patients. Importantly, responses were observed across PD-L1 expression subgroups, including patients with low PD-L1 expression, supporting the broad activity of this combination. And although follow-up remains early, these findings provide encouraging evidence supporting this differentiated treatment strategy. Overall, these findings support the continued development of zoldonrasib in combination with standard of care.

Turning now to elironrasib, our RAS(ON) G12C selective inhibitor. As with the zoldonrasib cohort, the baseline characteristics of patients enrolled in this study are generally representative of the population treated in pembrolizumab plus platinum doublet chemotherapy. The primary difference being a somewhat lower proportion of patients with PD-L1 negative subgroup and a higher proportion of patients with PD-L1 expression in the 1% to 49% subgroup. Overall, these baseline characteristics establish an appropriate context for interpreting the efficacy and safety observations I'll review next.

Elironrasib continues to demonstrate a manageable safety and tolerability profile in combination with pembrolizumab and chemotherapy. Treatment-related adverse events were consistent with the established safety profile of pembrolizumab-based chemotherapy with minimal evidence of additive toxicity attributable to elironrasib. We were particularly encouraged by the favorable liver safety profile with relatively few grade 3 or higher transaminase elevations and no unexpected safety findings.

Turning now to efficacy of elironrasib in combination with pembrolizumab and chemotherapy. Similar to what we observed with zoldonrasib, we have observed highly encouraging antitumor activity with elironrasib in combination with pembrolizumab and platinum-based chemotherapy in patients with previously untreated RAS G12C non-small cell lung cancer. Across the treated population with the data cutoff of May 11, 2026, and 8.7 months of median follow-up, the confirmed objective response rate was 85% with a disease control rate of 97%. Responses were observed across PD-L1 expression subgroups and like zoldonrasib, the elironrasib combination regimen appears to be highly competitive with the current standard of care of KEYNOTE-189 regimen. The early observations of durability were also encouraging with a progression-free survival rate at six months of 95%. We believe these early findings suggest that the responses observed are not only frequent, but also have the potential to be durable. We believe these results reinforce the significant potential for targeted RAS(ON) inhibition to further improve outcomes when combined with current standard of care.

Taken together, we believe these observations support continued development of elironrasib in combination with standard of care pembrolizumab and platinum-based chemotherapy. As a whole, and consistent with the impact seen in pancreatic cancer, these emerging data showing a well-tolerated and highly encouraging antitumor profile provide evidence that our RAS(ON) mutant-selective inhibitors have the potential to become important first-line treatment options for patients with metastatic non-small cell lung cancer.

We are observing that practitioners increasingly view treatment of lung cancer through a biomarker-directed lens and recognize the significant unmet needs that remain across patients with RAS mutant non-small cell lung cancer. With our broad and differentiated portfolio of RAS(ON) mutant selective inhibitors, we believe we are uniquely positioned to address these needs. Accordingly, in the next stage of our approach in non-small cell lung cancer, we are advancing both zoldonrasib and elironrasib into registrational development in combination with standard of care in first-line non-small cell lung cancer with the goal of addressing the majority of patients with RAS-mutant disease.

We recently initiated RASolve 308, a randomized placebo-controlled trial evaluating zoldonrasib with pembrolizumab plus doublet platinum chemotherapy in patients with RAS G12D non-small cell lung cancer. And we expect to initiate RASolve 307, a randomized placebo-controlled trial evaluating elironrasib with pembrolizumab plus doublet platinum chemotherapy in patients with RAS G12C non-small cell lung cancer. Further, with the encouraging initial observations mentioned earlier for RMC-5127 in patients with tumors harboring a G12V mutation, we anticipate studying RMC-5127 in the first-line non-small cell lung cancer setting as well.

While we conduct registrational studies for mutant selective inhibitors, we are also evaluating a broader set of first-line treatment strategies, including our multi-selective inhibitor daraxonrasib as well as our mutant selective inhibitors in combinations with emerging bispecific antibodies and chemotherapy. The additional information and insights we gain over time will inform decisions about potential future registrational plans. This layered portfolio strategy reflects our deep commitment to developing multiple targeted treatments across the spectrum of RAS mutant non-small cell lung cancer. As we have done in pancreatic cancer, we are advancing multiple potential solutions on behalf of patients with the goal of providing multiple first-line treatment options for patients with RAS mutant non-small cell lung cancer.

I'll now hand the call over to Jack.

Thanks, Alan. Our financial position remains exceptionally strong and continues to provide the flexibility needed to support the rapid advancement of our portfolio and our commercial preparations. We ended the second quarter of 2026 with $3.9 billion in cash and investments. This balance includes the proceeds from our concurrent public offerings of common stock and convertible notes in April of this year, resulting in $2.2 billion in gross proceeds before deducting underwriting discounts, commissions and offering expenses. The ending second quarter balance also includes the receipt of the second royalty tranche of $250 million from our funding arrangement with Royalty Pharma. There remains up to an additional $1.5 billion in committed flexible capital under this funding arrangement, subject to the achievement of specific milestones.

Moving to expenses. R&D expenses for the second quarter of 2026 were $395 million compared to $224 million for the second quarter of 2025. The increase in 2026 was primarily due to increased clinical trial and manufacturing expenses for daraxonrasib and zoldonrasib, increased personnel-related costs due to additional headcount and higher stock-based compensation expense related to increased headcount and changes in retirement provisions in 2026 previously described on our Q1 2026 earnings call. G&A expenses for the second quarter of 2026 were $110 million compared to $41 million for the second quarter of 2025. The increase in G&A expenses in 2026 was primarily due to higher personnel-related costs associated with higher -- with additional headcount, higher stock-based compensation expense related to increased headcount and changes in retirement provisions in 2026, increased commercialization preparation activities, and higher administrative costs.

Net loss for the second quarter of 2026 was $644 million compared to $248 million for the second quarter of 2025. Net loss for the quarter ended June 30, 2026, included a noncash charge of $151 million related to a change in the fair value of warrants we assumed as part of the company's acquisition of EQRx. This change in the fair value of warrants is due to the increase in our stock price. The additional increase in net loss in 2026 was due to higher operating expenses.

Turning to financial guidance. The company is updating its projected 2026 GAAP operating expense expectations and now expects full year 2026 GAAP operating expenses to be between $2.1 billion and $2.2 billion. This includes expected noncash stock-based compensation expense of between $270 million and $290 million. Today's updated guidance reflects our growing confidence in the breadth of our clinical pipeline and the magnitude of the opportunities ahead.

As a result, we plan to increase our investment and spend in 2026, driven largely by three main factors: First, we are accelerating and increasing manufacturing for both commercial and clinical supply of daraxonrasib and zoldonrasib to ensure we have sufficient supply to meet a range of potential demand scenarios. Second, we anticipate higher clinical development expenses as we continue to execute on our aggressive development strategy across multiple programs within our portfolio with increased confidence. And third, we are accelerating and increasing investments in our commercial readiness efforts to support our preparedness for potential U.S. launches while also expanding our international infrastructure to support potential future launches outside the U.S. These additional investments in 2026 position us to execute on our bold ambitions for our portfolio.

That concludes the financial update. I'll now turn the call back over to Mark.

Thank you, Jack. Before we open the call for questions, I'd like to briefly highlight our key upcoming priorities. Overall, we've begun the second half of 2026 with strong momentum and a compelling set of priorities. In pancreatic cancer, following the unprecedented results from RASolute 302, the U.S. FDA has accepted our full NDA submission for review. The EMA has initiated its phase review of daraxonrasib, and we are well prepared to execute a successful launch, subject to regulatory approvals. In addition, the global RASolute 303, 304 and 305 studies are actively enrolling, and we have initiated RASolute 309.

In lung cancer, we expect to complete enrollment in RASolve 301 this year, supporting an initial readout in 2027. We also continue following patients in the zoldonrasib monotherapy expansion cohort in previously treated RAS G12D non-small cell lung cancer and have initiated RASolve 308, evaluating zoldonrasib in combination with standard of care in first-line RAS G12D non-small cell lung cancer. We are also preparing to initiate RASolve 307, evaluating elironrasib in combination with standard of care in first-line RAS G12C non-small cell lung cancer in the fourth quarter of 2026. In colorectal cancer, we look forward to providing a data update and visibility into our development plans during the fourth quarter of this year.

With our earlier-stage pipeline, we expect to identify the recommended Phase II dose for RMC-5127 in the second half of this year and share initial clinical data in 2027. We also remain on track to initiate the first-in-human study of RM-055, our first inhibitor from our innovative new class of mutant targeted catalytic RAS(ON) inhibitors in the fourth quarter. Taken together, these milestones reflect the breadth, pace and ambition of Revolution Medicines today. We are preparing for a potential first commercial launch, conducting multiple registration programs and leading with further RAS innovation, all with intensity and continued excellence in execution. The progress we've made is the result of years of growing scientific conviction, disciplined investment and relentless effort by our team and collaborators.

We believe we are now in a strong position to redefine what is possible for patients with RAS-driven cancers, beginning with pancreatic cancer and lung cancer and colorectal cancer coming soon as well. With our differentiated know-how, organizational depth and financial strength, we intend to continue operating against our aggressive plan with the urgency patients deserve.

I'd like to thank patients and their families, our investigators and health care partners, our employees and our shareholders for their continued support and confidence. The ongoing support of all of our partners and constituencies is needed to deliver revolutionary advances on behalf of patients.

With that, I'll turn the call over to the operator for the Q&A portion of the call.

Thank you. At this time we'll conduct the question-and-answer session. [Operator Instructions] Please limit to one question and one follow up question. [Operator Instructions] Our first question comes from the line of Marc Frahm from with TD Cowen.

Congrats on the progress you've made so far. Maybe on CRC, we're going to be getting that. Just what's your latest thoughts on kind of what proof-of-concept looks like in that indication, particularly after we've seen adagrasib's confirmatory trial in the second-line setting kind of failed to demonstrate PFS or OS benefit despite what appeared to be pretty exciting response rate data?

And then just on the lung cancer side, can you maybe just walk through the confidence that on the G12C, not just that you can beat current standard of care, but there's also second-line trials or second-gen G12C trials running right now in the first line. Why do you think you're going to be better than those that will presumably have data faster than your trials?

Marc, thanks for your questions. On the CRC question, I think that's best addressed when we are able to frame our plans and provide some data. So I'm just going to ask that we defer that to a later time when I can be more concrete.

On the non-small cell lung cancer question with regard to elironrasib, maybe Alan Sandler can make a comment on that.

Sure. Thanks, and thanks for the question. So an important question. We believe that elironrasib has a very good profile, both safety and efficacy. And we're always data-driven in terms of our decision-making. And we felt that it was important to have a robust data set available in order to make this important decision.

Given that and given the data that we've shown you today, we believe that elironrasib has a highly competitive profile, both again, in monotherapy, potentially in subsequent lines of therapy and also in that first-line line of therapy in combination with pembrolizumab and doublet chemotherapy.

And in addition, what I would add is with our suite of mutant selective agents, we have a very compelling position in that setting as we will be able to target over 70% of the patients with RAS mutant non-small cell lung cancer.

Our next question comes from the line of Charles Zhu with LifeSci Capital.

Congrats on all the broad progress across the board. Maybe one for me regarding frontline non-small cell lung cancer. So great to see either current or ongoing plans with various mutant selective inhibitors in combination with standard of care. I think you had also mentioned evaluating further opportunities not only with novel bispecifics, which makes sense, but also with the multi-selective RAS inhibitors. Curious as to your thoughts around given the multiple mutant selective you have covering a lot of those patients, how might you position a RAS multi-selective in that frontline setting? And would -- did that terminology refer to daraxonrasib or possibly RM-055 as well?

Yes. Thank you, Charles. Appreciate the question. I think all possibilities are still on the table. We've intentionally pursued both the multi-selective as well as the mutant selective inhibitors to create the most optionality for us and then ultimately for patients. And I think all of this will play out over time. We still think it's premature to make any exclusive commitments down to any particular treatment regimen. And as long as there remains the possibility that more than one regimen might be complementary and provide options for various patients, we'll pursue them. So this will continue to play out.

You're now seeing are moving pretty aggressively with two mutant selective inhibitors and the third to come behind it. But by no means are we deprioritizing either daraxonrasib or RM-055 that's coming up or things that might come behind that as well.

Our next question comes from the line of Michael Schmidt with Guggenheim.

Congrats on all the progress and news today. I had a question on daraxonrasib. And I'm just curious if you have any early feedback from the EAP program and how the products perhaps are performing relative to the clinical trial experience?

And secondly, what could the regulatory time lines in Europe look like based on this Phase I review process that's underway there?

Thank you, Michael. The EAP is quite robust now. We're serving a lot of patients. We don't have a mechanism to get explicit or quantitative feedback from those who are prescribing it since that -- this is a clinical access program. It's not a clinical trial. So we really don't have quantitative information. And I'm not sure that we ultimately ever will.

Sort of on a qualitative basis, we certainly have feedback from some institutions that they're very enthusiastic. Some of the larger institutions have enrolled quite large numbers of patients, and they're continuing to enroll new patients. So that suggests that their experience so far is encouraging. We also do get anecdotal information from patients or their families, but that doesn't add up to a fair and broad-based representation. But from that anecdotal evidence, patients and their families are quite encouraged by having received access. So that's pretty much what we know from the EAP now, and I'm sure will continue to grow.

With regard to the regulatory time lines in Europe, there's really not much we can provide on that. The EMA made it clear that the phase review is intended to be an expedited review process. What that actually ends up meaning really is a question for the EMA, and we'll just support it as well as we can.

Our next question comes from the line of Cory Kasimov with Evercore ISI.

So I want to ask about your Phase III frontline PDAC studies. For patients that end up in the control arm, how do you plan to assess those that drop out potentially even after receiving just a single dose of chemo and then eventually go on to receive commercial daraxonrasib upon approval? How much of a risk might this dynamic pose to your frontline studies in terms of measuring OS and potentially even PFS?

And then a follow-up, just a clarification question. With the EAP, did those patients convert to commercial patients upon approval of daraxonrasib?

Thank you, Cory. I appreciate your questions. The first question is about first-line PDAC in the Phase III trial, I think you're really raising the question of crossover, some form of crossover risk for patients moving on to daraxonrasib.

Maybe Wei Lin, our Chief Medical Officer, can comment on that, and then I'll come back to the EAP.

Yes. Thanks, Mark. Thanks for the question. Yes. It is certainly a very important question that we have given a lot of thought and planning to because we want to ensure the success of the 303 trial in frontline PDAC while we're trying to making sure patients globally have access to daraxonrasib in [indiscernible].

I think the -- currently, the Phase III trial has a co-primary endpoint of PFS and overall survival. And then it's -- the dropout in control would not affect the PFS obviously, but it could potentially affect the overall survival analysis. And so right now, we're trying to be very thoughtful in geographically the sites that we're activating 303 trial in, knowing that the global approval as well as access will be graduated starting with the U.S. and the rest of the world in a gradual fashion. So that's certainly, I think, one area. And the other is really working with investigators to making sure that the patients really understand their options before they come on trials and then probably be conducted in a rigorous fashion so then the integrity of the center experiments.

So that's with regard to the frontline PDAC and crossover risk on the expanded access program, it's an important program, important pathway for eligible patients before potential approval. Once an approval occurs, our patient support services team will work very closely with treating physicians and health care providers. And the intention here, of course, is to help minimize treatment interruptions, provide seamless transition of care over to commercial supply. That is a top priority for us. These patients will have access to our comprehensive patient support services, as we mentioned, the on-path support that will include coverage navigation, financial assistance and adherence support. We expect most patients would transition within a few month period.

Our next question comes from the line of Brian Cheng with JPMorgan.

Just first, on the EAP, can you talk about whether these patients are being recruited in the sites that have had prior daraxonrasib experience? And you noted that more than 90% of the requests have been accepted. What is the common reason for patients to get rejected?

And then just one quick one on the 307 and 308 trial for frontline non-small cell trials. Are these studies setting any minimum or maximum threshold for the proportion of PD-L1 expression, depending on whether it's low or high that you're recruiting? Just curious if you can give us a sense of the trial design there would be great.

Nicely done. I think you squeezed in three questions into two questions. Well done. Maybe Alan can comment first on the 307, 308 PD-L1 expression topic.

Right. So yes, the -- we are not putting guidelines in terms of requirements of the numbers that have -- will let that play out in a large study such as Phase III study, there should be a natural -- a natural number of patients that appear on well representation of all three. What we will do, we generally want to stratify to make sure that there is equal representation on both arms. And I think that's the most important aspect of that.

It's more about balance than anything else. Yes. Thanks, Alan. And then the -- on the EAP, there are participants in the program who have been investigators and have treated patients before, and there are participants who have not and significant numbers of both. I don't know that I can quantitate that for you, but I think we're experiencing both kinds. We've certainly put a lot of effort into providing education and support to all of the prescribers. So the experience that the more experienced providers have obtained, we've learned from -- we've all learned from, and we've developed protocols, approaches that we have invested heavily in developing and also conveying through education to anybody who might prescribe daraxonrasib.

As to the greater than 90% rate, actually a very high rate as to who might be disapproved, it's really not subjective. It comes down to the eligibility criteria that are established in the FDA-cleared protocol. It's very well defined. There are very few edge cases where it requires some judgment. Most of it's really just making sure that somebody is actually eligible. And if they're eligible and the request comes through a U.S. licensed physician from a qualified institution that's met all the institutional requirements, then they will be approved.

Our next question comes from the line of Faisal Khurshid with Jefferies.

There's been a lot of investor excitement about PRMT5 combination data generated with your molecule from your partner, Tango. Just want to understand from your perspective, what's your latest thoughts on the potential of that combination? And do you feel like you need a PRMT5 within your own portfolio in order to kind of cover all of your bases?

Thanks for your questions. Yes, our position on PRMT5 inhibitors remains what it's been, which is that biologically, it's intriguing -- pharmacologically, it's intriguing hypothesis that's supported by preclinical work. Tango has now put forth some initial data that show high response rates. We think that body of evidence should be grown. And we know that Tango is working to do that, growing both in terms of numbers of patients, exposure to different dose levels, so dose optimization and a longer follow-up, and that will help us really establish a level of conviction about whether and if so, how to go forward with it. So certainly a credible idea, and we'll just continue to learn more about it as we support Tango in their efforts.

With regard to do we need a PRMT5 inhibitor in our portfolio, I don't think we need it. We have plenty to do that's high priority within RevMed as we've described now one looks at the pipeline, it's a pretty rich pipeline of work. And the other thing to point out, of course, is that there are many PRMT5 inhibitors, growing number out there, each with a slightly different profile. some with more or less propensity to drug-drug interactions that would have to be managed, different levels of potency and so on.

So I think there's a lot of opportunity out there. I think at the end of the day, daraxonrasib should be the backbone of therapy for zoldonrasib in the context of the right settings, G12D selective setting. And we may add various things, whether it's PRMT5 inhibitors, immunologic agents, other RAS inhibitors, chemotherapy, et cetera, a wide variety of possibilities there.

Our next question comes from the line of Michael Yee with UBS.

This is [ Madeline ] on for Michael. Just wanted to get your -- any updated commentary around -- obviously, there is some precedent in oncology to get accelerated approval in the first line based on similar data to what you have, along with the full approval that you're expecting for the second-line PDAC indication. So just wondering if you have any updated commentary around that now that your NDA has been accepted by the FDA.

Not really much to add to that. We're certainly aware of the history here. The NDA is primarily driven by the 302 data set, which is randomized data in patients being treated for second line -- in second line for metastatic pancreatic cancer. But there are additional data outside of that study that, of course, many people have access to, including the FDA, have access to it. And so how they want to deal with that, I think we'll just have to learn over time.

Our next question comes from the line of Alec Stranahan with Bank of America.

Two from us. First, on daraxonrasib in the metastatic RAS mutant lung cancer setting. Curious which data was shared with the FDA to support breakthrough therapy designation here? And if there's any read-through to be made to what we could see from RASolve 301. And I appreciate you probably aren't talking at all about pricing at this point. But from a qualitative perspective, assuming initial approvals with the 300 mg dose, how would you think about relative price in combos that are investigating a lower daraxonrasib dose like in the PRMT5 studies? If you have any thoughts here that you could share, that would be great.

So the first question was what data did we share with the FDA? Well, it's kind of a general rule of thumb. You have to share pretty much everything with the FDA. So anything they want to look at, they look at. I don't think we can provide any more specificity around that, unfortunately.

With regard to pricing, it's early for us to be talking about pricing. You're raising more of a kind of layered or nuanced question about pricing in combinations. And I guess I'd say the same thing. It's probably too early to be talking about that. We don't have a combination that's approaching commercialization today and nothing to address. I think you might have had another layer to it, but given that I didn't hit the first two layers, I'm not sure we'll make it to the third.

Our next question comes from the line of Laura Prendergast with Stifel.

"

Congrats on all the progress. I was hoping you could clarify what you mean by visibility into CRC development strategy expected in the fourth quarter. I guess the real question here is should investors expect to leave this update having conviction that you have a registrational path in CRC?

And then second question is, do you guys have any plans to make a registrational move outside the big three RAS indications, kind of maybe bringing back that tumor-agnostic approach question. Is that something that we could see down the road once you've read out pivotal data for your first two PDAC and lung indications?

Yes. Laura, thanks for your questions. Visibility into our development strategy we'll show some data, and we'll tell you what we plan to do with it. As to what investors will leave -- what impression they'll leave with that, that's up to investors to decide. I don't think it serves us to get out in front of that. But that's our plan. And typically, in the past, when we've announced a development strategy, we've supported it by data that justify it. So I think that would be a reasonable expectation.

Yes, regarding tumors outside of the big three, we're certainly interested in those. I mean our expectation is that daraxonrasib and other compounds as well, but daraxonrasib could serve a wide variety of tumors. Of course, there are smaller subsets of patients. And we have prioritized the big three as you put them, which makes sense to do. But we do have data across other tumor types. We've shown some of that data publicly. We have other data that hasn't yet made it out into the public domain. We have external research collaborations as ways to explore this.

So, yes, I think you should expect that daraxonrasib will continue to make its way into other context. But the exact strategy by which we develop those may differ from indication to indication, context to context.

Our next question comes from the line of Leonid Timashev with RBC.

Just wanted to ask on the commercial side. At least clinically, you guys have always been planning for success. I guess to what extent does that extend to the sales force sizing commercially? Are you planning a force that's commensurate with the second-line PDAC setting? Are you also going to size it for frontline and potentially non-small cell lung cancer right away? Or is this going to expand later?

And then maybe just a quick follow-up as well. Just on the EAP, are those 2,000 patient adds starting from May when the 1-ish when the FDA first made that announcement? I'm just trying to better understand sort of the cadence of how quickly patients came on.

Well, I'll comment on the second one, and then Anthony Mancini can comment on the commercial organization. The number that I gave was greater than 2,000. So it wasn't 2,000, greater than 2,000. And that is a cumulative number. As you might recall, I think that once we filed the EAP request, it was approved within a couple of days. And I think within three weeks, we were shipping the first drug on behalf of patients. And it started out more as a trickle and then expanded as you'd expect over time as sites became part of the program, completed their process for entering the program. So I don't know that you can quite get a rhythm out of it other than to say qualitatively, it's a very robust program. There's very, very high interest in it, and it continues to grow.

With regard to the commercial question, maybe Anthony can comment.

Yes, Javier, thanks for the question. We've been preparing for some time and are ready for a successful PDAC launch in the U.S. And as we think about commercialization infrastructure, there are parts of that commercialization infrastructure that are broad and that can apply to our future indications. But as for our sales force, which, as Mark alluded to in his prepared remarks, are fully trained and in place, we have a team of around 60 individuals that will fill the need for PDAC. But it's also important to note that there are many different stakeholders in the U.S. market, and we're prepared for those as well. So we have a fully operational field access team field patient services team, MSL team and thought leader liaison team that are in place. We're excited and ready to go. All systems go. But yes, we're ready for PDAC, and we will be ready should other indications come.

Our next question comes from the line of Kalpit Patel with Wolfe Research.

Gugan on for Kalpit. Just a quick one from us. Given Roche's head win against sotorasib and adagrasib in KRASCENDO-1, do you think you'd need to run a trial against divarasib?

Thanks for your question. Do you want to comment? The question is whether if divarasib is approved, I think, is what he's asking then would we be required to run an elironrasib frontline study against that?

Yes. We'll be having all of our discussions with the FDA. We basically -- really the control arm is dictated by the current state of affairs at the time that the study is initiated, and that requires not necessarily a positive study, but that requires a full approval. And so since that's not the case at this time, we don't feel that, that would be necessary.

Thank you. This concludes the question-and-answer session. I would now like to turn it back to Dr. Mark Goldsmith for closing remarks.

Thank you, operator, and thank you to everyone for participating today and for your continued support of Revolution Medicines.

Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.

Good day, and thank you for standing by. Welcome to Revolution Medicines Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker, Ryan Asay, Senior Vice President of Corporate Affairs. Please go ahead.

Thank you, and welcome, everyone, to the webcast. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive Officer; and Dr. Roy Lin, our Chief Medical Officer; Dr. Steve Kelsey, our President of R&D; Dr. Alan Sandler, our Chief Development Officer; Anthony Mancini, our Chief Global Commercialization Officer; and Jack Anders, our Chief Financial Officer, who will join us for the Q&A portion of today's call. As we begin our presentation, I would ask that you review our legal disclaimer on Slide 2. And with that, I'll turn the call over to Dr. Mark Goldsmith, our Chairman and Chief Executive Officer. Mark?

Thank you, Ryan, and thank you, everyone, for joining us. Today marks an important landmark for patients living with metastatic pancreatic cancer and a major milestone for Revolution Medicines. This afternoon in the ASCO plenary session, Dr. Brian Wilton from the Dana Farber Cancer Institute and the study's lead investigator presented results from Resolute 302, the first Phase III study of Draxon/RaSIb, demonstrating an unprecedented survival benefit in patients with previously treated metastatic pancreatic cancer. These results represent a potential turning point in treatment for a disease that has seen limited therapeutic progress until now. These findings also reinforce our conviction that RAS on inhibition can fundamentally change treatment paradigms across multiple cancers that are driven by RAS. Based on these data, we are working with great intensity to prepare a new drug application for the U.S. FDA as the first step towards bringing Duraxon/Rasib to patients globally. At the same time, we are executing or preparing to conduct multiple registration studies across tumor types, treatment settings and combination approaches. We have significant momentum with a robust pipeline and aim to build the leading targeted oncology company serving patients with RAS-addicted cancers, supported by a differentiated discovery platform, multiple pioneering investigational medicines and a broad pipeline designed for long-term impact. Powered by a highly productive innovation engine, deep sustainable asset portfolio, including groundbreaking investigational medicines and a strong patient-focused and science-driven organization, we are well positioned to achieve our ambitions. We are not pursuing RAS opportunistically, we are systematically building coverage across the RAS landscape through our clinically validated discovery platform. spanning oncogenic mutations, tumor types and treatment settings. Our strategy is designed to create long-term value through differentiated medicines, rational combinations and a sustainable multiproduct oncology franchise built on continuous innovation.

Our mission is bold, to revolutionize treatment globally for patients living with RAS-addicted cancers through the discovery, development and delivery of innovative targeted medicines. As pioneers in the RAS targeting field, we operate as a late-stage clinical oncology company, pushing the boundaries in 3 of the most common and difficult-to-treat segments in oncology, pancreatic, non-small cell lung and colorectal cancer both targeting areas of clinical unmet need today and creating a significant long-term opportunity. We have 8 completed ongoing or announced registrational Phase III studies an extensive aggregate clinical experience to date with more than 2,500 patients having received 1 or more of our RAS ON inhibitors. These include 4 RAS ON inhibitors in the clinic and a deep pipeline behind them. including a fifth on track to initiate clinical study this year and a rich set of innovative preclinical and discovery stage programs. Allow me now to briefly frame the RESOLUTE 302 study, and then Dr. Wallin will walk you through the Resolute 302 results. Pancreatic ductal adenocarcinoma or PDAC remains 1 of the most aggressive and lethal cancers. Most patients are diagnosed with advanced disease and current outcomes in the metastatic setting call for significant improvement. For patients whose disease has progressed following initial treatment, current chemotherapy options provide limited benefit with median overall survival generally measured in months. Mechanistically, pancreatic cancer is driven by and highly dependent on RAS signaling within the tumor. More than 90% of PDAC tumors harbor oncogenic RAS mutations. -- and tumors without an identified rasputation, often harbor an undetected RAS mutation and/or are dependent on RAS pathway signaling even in the absence of the mutation. Pancreatic cancer calls for RAS targeted medicines, but there are currently no approved draft targeted drugs for pancreatic cancer, representing 1 of the most significant unmet needs in oncology. Traxon Rasib is an oral once-daily RAS ON multi-selective inhibitor designed to target the active GTP-bound or RAS ON form of both mutant and wild-type gas. Mechanistically, direxonrasid acts as a synthetic molecular glue binding to intracellular cyclophilin A to form a binary complex that selectively engages Raton proteins and suppresses signaling by sterically blocking engagement of downstream as effectors. This resulted in broad inhibition of RAS-driven tumor growth. Importantly, data from a prior Phase I/II study recently published in the New England Journal of Medicine demonstrated encouraging clinical activity together with a manageable safety profile in previously treated advanced pancreatic cancer. RAS olute 302 was designed to rigorously evaluate whether these early signals would translate into a clinically meaningful survival benefit in a global randomized Phase III study. Wei, please take it from here.

Resolute 302 is a global randomized open-label Phase III study that enrolled patients with previously treated metastatic PDAC. Patients were randomized 1:1 to receive either direction acid 300 milligrams orally, once daily or investigator's choice of standard care chemotherapy. The primary analysis population included patients with RAS G12 mutant tumors. The broader overall population included patients both with and without identified RAS mutations. -- dual primary end points were overall survival and progression-free survival measured by blinded independent central review in patients with DraG12-mucent tumors. Key secondary endpoints included overall survival and progression-free survival in the overall population, objective response rate and patient-reported outcomes. The study design included 2 planned interim analysis for overall survival. The results we are presenting today are from the first interim analysis. Importantly, this prespecified analysis crossed the protocol defined boundaries force to scope significance and therefore, constitute the final analysis for all outcomes. A total of 500 patients were randomized. 248 patients were assigned to Daraxonrasib and 252 to chemotherapy. Notably, substantially more patients remained on treatment with Daraxonrasib at data cutoff compared with chemotherapy. In addition, fewer Daraxonrasib patients discontinued treatment due to toxicity or symptomatic deterioration. These operations are consistent with both meaningful clinical benefit and a manageable tolerability profile. Based on characteristics, we're well balanced across treatment arms and representative of patients typically seen with previously treated metastatic pancreatic cancer. Importantly, the study population reflected the expected distribution in pancreatic cancer with the majority of tumors harboring RAS G12D or G12B mutations.

Turning to efficacy. The dual primary end point of overall survival in the RAS G12 population was met. Daraxonrasib reduced the risk of death by 60% compared with chemotherapy. At a median follow-up time of 8.5 months, median overall survival was 13.2 months. with Daraxonrasib versus 6.6 months with chemotherapy, with has ratio of 0.40 and a highly statistically significant p-value. To our knowledge, no prior Phase III study in metastatic pancreatic cancer has demonstrated median overall survival exceeding 1 year in any line of therapy. These are unprecedented outcomes for patients with a devastating disease. The overall survival benefit was nearly identical in the overall intent-to-treat population, which included both the RAS G12 population and patients carrying the tumors harboring other RAS mutations as well as tumors without an identified RAS mutation. The risk redev was reduced by 60%. Median overall survival, again reached 13.2 months with Daraxonrasib compared with 6.7 months for chemotherapy with has ratio of 0.40. These clinical findings firmly established the biological relevance of RAS pathway inhibition in pancreatic cancer broadly and the survival benefit of targeting RAS in patients living with pancreatic cancer with or without an identified RAS mutation. Collectively, we believe these results establish a new benchmark for survival outcomes in briefly treated metastatic pancreatic cancer. The observed OS benefit of grain acid versus chemotherapy was consistent across prespecified subgroups, including tumor RAS mutational status. These findings support the robustness and consistency of the survival benefit observed with droximracid. The second dual primary end point progression-free survival was also met. Daraxonrasib reduced the risk of progression or death by 55% versus chemotherapy in the RAS G12 population. Median progression-free survival was 7.3 months compared with 3.5 months for chemotherapy. Results were consistent in the overall population. Taken together, the PFS findings complement the overall survival benefit and further demonstrate meaningful disease control observed with racinrastib treatment. Objective response rates were also substantially improved with ORR in the director acid arm approximately 3x higher than in the chemotherapy arm. In the overall population, gibjectriv response rate was 31.6% with Daraxonrasib compared with 11.2% for chemotherapy. These response data further support the broad antitumor activity of doctorasid in metastatic pancreatic cancer.

Turning to safety. Daraxonrasib showed a manageable safety profile with no unexpected safety findings. Importantly, treatment discomuniation due to treatment-related adverse events were very rare at 1.2%. Grade 3 or higher treatment-related adverse events were also less frequent with Daraxonrasib compared with chemotherapy. One patient in the Daraxonrasib 5 pneumonitis, which was considered possibly related by the investigator median dose intensity for directional asset remained high at over 93%, supporting the feasibility of sustained treatment delivery. Overall, we believe dramas tolerability profile is particularly notable in the context of the substantial efficacy benefit observed.

The most common treatment-related adverse events with Daraxonrasib were primarily low-grade dermatologic and gastrointestinal events. Importantly, severe events or infrequent and generally manageable through supportive care and dose modifications. Chemotherapy demonstrated the expected pattern of hematologic toxicity and peripheral neuropathy that are associated with these agents. We also observed meaningful improvements in patient-reported outcomes for patients receiving Daraxonrasib. In particular, Daraxonrasib delayed deterioration both in pain symptoms and in overall quality of life compared with chemotherapy, leading time to worsening of pain was more than doubled on Daraxonrasib versus chemotherapy. And patients receiving Daraxonrasib experienced longer preservation of global health status and quality of life. These findings are especially important in pancreatic cancer, where symptom burden is typically profound and sustained. Importantly, improvements in patient-reported quality of life with Daraxonrasib were consistent with a meaningful overall survival and progression-free survival benefits observed in the study.

In summary, Daraxonrasib demonstrated unprecedented statistically significant and clinically meaningful improvements across every major efficacy endpoint evaluated in Resolute 302. The study showed a 60% reduction in the risk of death and approximately doubling of meeting overall survival to greater than 1 year, doubling our progression-free survival and near tripling of response rate, superior patient report outcomes and a manageable safety and tolerability profile, along sustained treatment. We believe these results redefine treatment expectations in patients with previously treated metastatic pancreatic cancer support Daraxonrasib as a potential new standard care and firmly validate the clinical benefit of RAS ON inhibition in pancreatic cancer. Furthermore, these patient outcomes increase our confidence in the work we're doing to extend targeted therapy to other RAS dictate cancers. With that, I'll hand the call back to Mark.

Thank you, Wei. The implications of Resolute 302 extend well beyond this important individual study. These results established the first targeted therapy to demonstrate a transformative survival benefit in patients with metastatic pancreatic cancer, offering a compelling basis for becoming the new standard of care in a disease clinically proven to be primarily driven by RAS. These results also clinically validate our broader RAS ON inhibition strategy in pancreatic cancer and increased confidence in the studies we are conducting related to expansion into earlier lines of therapy, rational combination regimens and additional tumor types.

And finally, these results reinforce the value of the scientific and strategic foundation we've built at Revolution Medicines. What began as a differentiated discovery platform has evolved into what we believe can become a global franchise in targeted oncology medicines with what we believe is a significant opportunity to reshape treatment paradigms across rasentictede cancers. Given the compelling and consistent benefit for patients observed in Resolute 302 -- we at Rev Med feel a deep sense of responsibility to deliver this benefit more broadly to patients and are moving with urgency to enable potential commercialization. We are offering treatment crossover to patients in the chemotherapy arm of the RESOLUTE 302 study and have operationalized an FDA-authorized early access program in the United States. Many U.S. prescribers and institutions are now registered in the expanded access program, and drug is being shipped on behalf of their approved patients. We are also actively preparing regulatory submissions globally focused initially on a planned U.S. FDA submission under a breakthrough therapy designation and a commissioner's national priority voucher. Multiple components of the NDA and are advancing through a rolling submission process and the clinical data and analyses will be incorporated as soon as possible, recognizing the need for improved options globally, sequential filings are also planned across international regulatory authorities.

Operationally, we are well prepared to provide broader access. Over the past several years, we have built a strong commercialization organization with highly experienced leaders and staff with valuable collective oncology launch expertise. We have established core U.S. market infrastructure. and our U.S. field teams are in place, including having onboarded and experienced U.S. account manager team. We also continue to grow our international teams.

Taken together, we believe we are positioned to execute a successful global launch pending regulatory approvals. Before concluding, I want to briefly step back and frame what we believe investors should take away from today. Resolute 302 is not simply a compelling positive Phase III study in previously treated pancreatic cancer. We believe it represents validation of our productive bold and differentiated scientific platform, proof that RAS ON inhibition can deliver transformational outcomes for patients with RAS-addicted cancers and a catalytic step for creating an industry-leading global targeted medicines franchise for patients with RAS addictive cancers. We have a broad and innovative clinical stage pipeline focused on RAS ON inhibitors, including 4 groundbreaking and differentiated clinical programs. to RAS ON rated, the RAS multi-selective inhibitor, Zolonrasib, the RASM-G12D-selectiv inhibitor, Leronrasib, ArasG12C-selective inhibitor RMC-5127, Orason-G12V selective inhibitor and a fifth compound, a true catalytic restaurant inhibitor poised for initiating clinical study. Our development strategy for these assets is deliberately broad to maximize the clinical impact across tumor types and lines of therapy through both monotherapy and combination approaches. Importantly, this strategy creates rich opportunities for continuing value creation over time while reinforcing our leadership position in RAS-targeted oncology. Our capabilities extend beyond individual molecules -- we have built an integrated organization that connects discovery science, translational medicine, clinical development and commercial execution, insights generated from each stage continuously strengthen the next and fuel a virtuous cycle of innovation capable of producing differentiated medicines over many years. I'll conclude with our core purpose. Everything we do at Revolution Medicines is centered around patients and our impact is measured by patients experience. Rasadictive cancers, including, but not limited pancreatic cancer, remain among the most devastating diseases in oncology. For many patients, treatment options remain limited and outcomes remain poor. We believe the work we are doing has the potential to fundamentally improve those outcomes. Today's Resolute 302 results represent an important step towards realizing that vision. At the same time, we are investing at scale to build a durable industry-leading global oncology company aiming to provide exceptional long-term value for patients, physicians, caregivers, employees and shareholders. With that, I'll now turn the call over to the operator for the Q&A portion of the call.

[Operator Instructions] Our first question comes from the line of Marc Frahm from TD Cowen.

This is Ellen on for Mark. Congratulations on the fantastic data. That was a really powerful finery. I guess 1 question. We noticed that 57% of the patients in the control arm were treated with [indiscernible]. Have you compared Daraxonrasib to the subgroup specifically? And is there any reason to expect that the hazard ratio might differ in the patients treated that we're acting versus other regimens, it's almost like directors because it's already beaten gemabraxane, in a second-line trial, and so this just kind of would further support potential success in the front line .

Thanks very much for your question. I think Lynn can answer those comments about whether or not there's any more information relative to alternatives but as you pointed out, about 60% of patients received Daraxonrasib a 50% in the area 10% or base therapy including other clearly representative of the global usage in second line. So I think the trial certainly fair percentage with regard to specific chemo regimens and certainly given the high proportion anthrax efficacy conversion is very overall also houses a and with the economy

And I show our next question in the queue comes from the line of Charles Zhu from LifeSci Capital. .

This is Sue on for Charles. Congrats on the data. Obviously, this is the first innovative drug in pancreatic cancer in a really long time. How well do you think prophylaxis type measures on rash worked 432. And do you think rashevents, either any grade or grade 3 could be further optimized beyond what is presented today as physicians get more used to using direction asset? And can you talk about your plans regarding physician and patient education on implementing preventative measures .

Sue, thanks for your questions. I think back to Wayne who can comment on measures that we can take to help physicians and also their own experience and how that changes over time. Right Yes. So Certainly, it was recommended Daraxonrasib that are typical for each inhibitors, such as oral antibiotics. -- sun block as well as skin motions. Those were recommended. They were applied on throughout the trial. I think as we try to launch a product and making it hopefully available, those recommendations probably be put into clinical practice I think the -- we have -- we're certainly doing studies and generate data demonstrating the effectiveness of these prophylaxis. And there's wealth experience within the GI community, especially with F antibodies. -- with effective of these prophylaxis for patients. And I think we hope this becomes a common use for patients using Daraxonrasib as well. .

This is Alexandre. I just want to add to exactly what Wan said and just to emphasize that the point that you had made that the more experienced physicians have with direct unrated, the better they are in terms of anticipating and treating the rash. In addition, our medical affairs group will be coming up with standardized opts for the prophylaxis folks, particularly for those doctors who may be utilizing Draxton assets for the first time. And I think all of this will be an effort to ensure that patients are treated appropriately.

Yes. I might add 1 more thing to Alan's comment, which is that any or most of these investigators were not part of the Phase I/II experience. And so their first few patients on trial would be their learning experience. And that comes from expanding to 59 sites across 6 countries. So that reinforces the point that Alan just made. .

And I show our next question comes from the line of Fei Keshet from Jefferies.

This is Anantha for Fazal. Do you think you can get the first-line therapy on the label along with the initial approval in second line, maybe leveraging the Phase I data without having to wait for the Phase IIIs to read out. and maybe even something innovative where they give you a full approval in second line and accelerated approval for first line with the ongoing Phase III serving as confirmatory evidence. Just wondering about the possibility of that. .

Yes. We appreciate the point that you're raising here. Given that RAS biology underlies first-line disease, just as it does second line and later lines there's some logic to that. The fact that the -- in the 302 study, the second-line patients outcomes outperformed at least numerically outperformed the historical experience in first line. And then, of course, as you point out, also, the preliminary data we've shown in first line and single-arm studies that all adds up to a picture -- it's really up to the FDA. Our primary objective right now has to be to make sure that we get the 302 study to them in a way that's clear and supportive of a robust label but we understand the point that you're raising, and let's just let this all play out. And in the meantime, we are running, of course, a first-line trial, as you know, 3R trial, and we'll continue to have dialogue with the.

Thank you -- and our next question comes from the line of Laura Prendergast from Stifel. .

Congrats on a very exciting data today. Can you speak to the inclusion of some first-line patients in RASL302 who didn't seem to do well in their adjuvant setting therapy. -- their disposition of baseline, how they performed versus the second-line patients enrolled? And to follow up on the last question, any implications this could have for an FDA label -- we do you want to comment on that? .

Yes. So the patient referring to our patients who have received athlete therapy and then have progressed within 6 months and therefore, they're considered to be second-line patients. Now those patients in term prognosis are fleet the same the patients for uninitiated received a better treatment. So there is a -- we haven't done a detailed analysis in terms of product or experiences -- those patients are always treated as the same and they're prognostic for about the same. So .

So we don't think it represents much of an issue and it's a relatively small number of patients .

And just to add again that those patients who received the neoadjuvant or adjuvant setting and then failed to be able to go on study. They had to do that within a time period of less than 6 months. again, which sort of mirrors what the first line came out therapy would have been. .

And I show a next question comes from the line of Corey Kasimov from Evercore ISI.. .

This is Noah on for Cory. Congrats on the fantastic data. Just a bigger picture question for us. Given the discussing commentary on the call to action, into you Resolute 302 as a starting point for ongoing development in pancreatic cancer. I guess just like how public can you guys be about your future development plans for both the racks and acid and the broader pipeline to stay ahead of the growing competitive field. .

Yes, thanks for your question. We have a pretty expansive registrational program around Daraxonrasib both in pancreatic cancer and outside pancreatic cancer, we're covering most lines of therapy, and we're covering them in multiple ways. In some cases, including in first-line Daraxonrasib alongwith Daraxonrasib with [indiscernible]. So I think we have quite an extensive program and we'll continue to do that. I found the comment to be supportive of exactly what we were doing. I didn't think that there was much that we're leaving on the table. But we're, of course, scrubbing that every day and looking for other opportunities to expand even further. And then with the pipeline behind it, [indiscernible] our RMC5127, or G12D-slective inhibitor, we have opportunities to move and are moving to metselective inhibitors into pancreatic cancer studies as well. And then, of course, outside of pancreatic cancer, lung cancer and colorectal cancer. So I think we have a pretty extensive program in the pipeline chart outlined some of that. In some cases, I mean the chart so full that we had to compress a number of different things into a single line, but that information is all available on clinical trial staff go. It shows the many different things that we're doing, either preregistrational or as part of the registration strategy. .

Our next question comes from the line of Michael Schmidt from Guggenheim Securities.

This is Sara on for Michael. Congrats on today's data. Continuing on the theme of potential expansion opportunities for Daraxonrasib, I guess, wanted to ask if you had any updated comments on plans in frontline lung. We saw some data this weekend on D12Cs in the frontline setting. So I guess how does the evolving frontline landscape sort of impact how you're thinking about the opportunity for Daraxonrasib.

Yes. Thanks, Sarah, for the question. I'll just make a high-level comment. I don't know if anybody would want to add something to it here, which is that lung cancer is really the tumor type in which mutant identification of specific forms of forms of gas have already caused the stratification of disease types. There's a G12C lung cancer is a thing now. and G12D lung cancer will become a thing pretty quickly in G12D and probably beyond that as well. And so we are definitely paying attention to that. We want to be both drivers of it and also be compatible with how physicians think about things. So stay tuned as we continue to update our first-line strategy. But clearly, we -- it's a high priority for us in in non-small cell lung cancer justice. It is in pancreatic cancer and in dated colorectal cancer as well. So we'll continue to take that into account and clarify things over time. .

And your next question comes from the line of Brian Chang from JPMorgan.

This is Sarah on for Brian. Could you provide some color on the demand coming from the compassionate use program -- how many centers are now offering Dara in this program? And how should we think about the number of patients that can be in this program by the time that you get the approval? .

Yes. Thanks for your question, Sarah. We can't quantitate it for you at the moment is that it's constantly moving. But the demand has been very, very high, our call center and our Medipole receive a very large volume of inquiries, both from within the U.S. and outside the U.S. to acquirers come from individual patients. They come from doctors. They come from institutions. And we have field of those. We're very much on top of it. It's a fully operational program now. There are many registered institutions and physicians within those institutions within our expanded access program, and we're now shipping to exon rated to the individual doctors who have approved patients and who are coming from an approved certified institution. So we're well on our way to serve patients.

In terms of what the spoke will end up being -- that's hard to say. It's really hard to predict exactly as to the timing -- well, that's hard to predict, too. That depends also on when the FDA receives and then reviews and makes a decision about approval because that will have an impact also. There's not really -- if you're asking about whether there's sort of a cap on the number of people being served, there is not -- there is not ranking of individuals, anybody who is eligible and who is supported by an application from a U.S. license physician that has to be eligible themselves to their institution, they will -- they'll be served by our expanded access program. And I think that's clearly ramping up. But here we are, we're still in the month of May. This program was just cleared by the FDA earlier in this month, and we're already operational and delivering drug on behalf of patients.

And so our next question comes from the line of Michael Yee from UBS.

This is Matalan on for Michael. Congratulations on the data today. Just wanted to ask quickly about the duration of treatment, 6.2 months. Comparing that to the PFS number and just sort of thinking about that in the real world, -- could the difference between PFS and the duration of treatment be related to scan frequency. How do you think about the limiting factor in terms of 8.5 months median follow-up as well as what are you hearing from physicians in terms of treating past progression in the real world?

Madeline, thanks for your question. Those are 2 very important questions, and we'll be happy to comment on it, Wei. .

Yes, sure. The the treatment duration and the rev survival are analyzed by different school methodology. So they don't always correlate perfectly. And the progression is actually assessed by a true progression progression versus the treatment is really how long the patient is on the treatment cloud. And sometimes they may discontinue for reasons such as average spend on our other decisions. And so therefore, the treatment duration may be actually a different number than merchant pricing. We just had a train go by. So we'll pick up the there. Yes. So the -- I think -- so that's -- I think that's largely kind of explain the difference between the 2 numbers.

But there certainly are differences in duration of follow-up in this study compared to our earlier study if you're wondering about the median PFS values and how they may be a little bit different. And there are differences as well in the frequency of scanning under this protocol versus the other at least after a certain amount of time. So there are a variety of factors that go into that. This was statistically significant. It's the final read, but it doesn't mean it's the final ever looked at. It is the 1 that will be -- that's provided to the FDA, but we don't note today that it's actually representative of the true duration of treatment, which I'm sure you're trying to use to project things. As to treatment beyond progression, Alan, do you want to comment on that? .

Yes, yes. So there -- I think a couple of important points. So the treatment beyond progression was not part of the protocol for 302. However, it is formerly allowed in all of our subsequent protocols. And in terms of physicians who -- and what they're thinking there is certainly interest in the concept doing that, and we have anecdotal evidence of patients who seem to drive some benefit for it, which is why we're looking at it prospective manner in our clinical trials. It will be interesting to see what happens after the Daraxonrasib is approved and how physicians will do that. It's not -- certainly not unprecedented with other forms of therapy in oncology. So we'll see how that enplays out. But this dividend that we have prospectively may provide further evidence in order to support that use.

And if I may just add to that, back to the biology I think I said it earlier, RAS the cancer driver in pancreatic cancer, whether you're in first line, second line or third line of treatment and whether or not you progressed on a RAS inhibitor in all likelihood, you progress because the tumor has increased its RAS signaling. And so taking your foot off the brake seems like exactly the wrong thing to do from a biological perspective, I'm not speaking to the clinical outcomes yet is we don't really have that rigorously assessed. But from a biological perspective, it really doesn't make sense. -- to try to defeat a cancer that's hungry for RAS and to withdraw on the RAS treatment, but that has to be established through a collection of data. and huge congratulations.

And I show our next question comes from the line of Jay Olson from Oppenheimer.

Congratulations on this major accomplishment for cancer patients. And thanks for providing this update on a super busy day. The discussion spoke about the opportunity to expand the use of Daraxonrasib into combinations in earlier lines of PDAC therapy, including adjuvant and neoadjuvant -- and do you share a list of all the studies you're running, can you just talk about the read across from 302 study results to your other PDAC studies? And I think you suggested that your mutant specific RAS inhibitors could offer improved tolerability. Is that something that you'll be looking for? And then if you could talk about the time line of you would -- when you would anticipate having the G12 mutant level subgroup analyses such as TV and wild-type subgroups from RAS302 that was discussed I think someone said it could be shared later this year. Is that correct? .

Let's come back to that second point, but Steve Kelsey can comment on the first point, the main part of your question. .

Yes. So -- well, I think there were 2 parts, 2 questions. The first was how confident are we like a paragon confident are we in the other studies we're running with Repsol asset based on the readout from the 302 study SP1 I mean we generated a fairly substantial volume of Phase I/II data before we started most of our Phase III studies with the possible exception of the 304 study, which we inferred from the Phase I/II data that we already had in both second line plus and first-line pancreatic cancer I think the thing that's most trading is that the data that we made public maybe 8 months ago or so from the Phase I/II cohort of patients with second-line pancratic cancer was almost exactly reproduced in this randomized Phase III study that we did. And so I think we can then infer the A lot of our earlier data may be reasonably predictable what's going to happen in the other Phase III studies. And I think that does give us at least reinforces the confidence that we had in those studies when we started the diesel line and a very expensive study. So you have to have a reasonable degree of confidence they're going to work before you you starting off, but I think that that's been reinforced by the outcome from the 302 study. With regards to mutant selective inhibitor -- not all mutant selective inhibitors are created equal. It is still a matter of -- there's a big -- it's a conundrum to us why so many of the mutant selective inhibitors of G12C seem to demonstrate gastrointestinal toxicity that is at least as bad and not worse than the exon Reed, which is a RAS-muteinhibitor. -- when they are supposed to be absolutely selective for Golf -- having said that, our net Selecta G12D inhibitor is extremely well tolerated. And we're currently exploring that of all its with standard of care in pancreatic cancer and first-line pancreatic cancer, but also in combination with Daraxonrasib first-line penetrance. So I think the the place of the mutant selective inhibitors will fall out based on their own individual efficacy and tolerability profiles. But we believe that the rate real inhibitors that we have, which now include Eleanor G2C, solar rate and 5127 for G12V are pretty good with regards to tolerability and gives us a lot of flexibility. With regards to subgroup analysis, I think Wei Lin commented earlier in the call that we do intend to do exploratory subgroup analyses of the data I wouldn't expect too much definitive to come out of that because probably the only 2 mutant subgroups that are going to be sufficiently large to had anything determine on the G12D subrent subgroup. But those exploratory analyses will be performed now that the main analysis has been performed in a public.

It's hard to have much to what Steve said, but I'm still going to add something, which is pancreatic cancer is caused by RAS, first line, second line, third line, whether it's local disease, local resectable they're slowly advanced or where there's been static. And so the underlying biology is the same there, and so I'll take an even more bullish position on it, inhibiting RAS is going to make a difference across these. We just have to design trials and execute trials that will assess that normally, and that's what's being done now. Those trials are underway, and we'll learn the answers from them.

And I show our next question comes from the line of Sean McCutchen from Raymond James. .

Congrats again on stellar data. Maybe could you speak to the rate of high-grade stomatitis, how stomatitis is managed on the study and expectation for real-world mitigation strategies. .

Sure. Thanks for your question, Wei.

Yes. stomatitis it's actually also a part of the Rasmisin because -- the -- in addition to RAS, they became our kinase pathway is also effective with brass and vision and. So this is so much ideation revenues in Dampinhibitors. So on the study, we have implemented a management guideline very similar to the mTOR inhibitor, which is involving oral mouthwash with steroids, and that's been fairly effective. And so there's also -- as Alan mentioned, along with the rash management, our medical affair team will also be promoting additional management when it comes to stomatitis, which include not only management on stomatitis is after onset, but also there's operating potential to prophylax because that's another opportunity for improving the safe and tolerability of long-term use is is to use the store malware team to cover the onset in addition to growth by managing the stomatitis.

And our next question comes from the line of Jonathan Chang from Leerink Partners.

This is Sean on for Jonathan. Congrats on the data. SP1 Just 2 small questions on the non-G12V population. Can you provide more color on why these patients seem to the rabi benefit but not a PFS benefit from direct are -- and also, can you frame color resistance mechanisms to terexresib in this study? And how might that inform strategies for next-generation inhibitors and combinations.

Thanks for your question. I'm going to take the second question, which is resistance from this study. We don't have any data on resistance from this study. We have data that we've recorded now on several different venues, I think, on resistance mechanisms, and they typically involve the cell finding ways to increase RAS signaling that works around the initiator either amplifying the underlying oncogene and expressing more protein that can signal more that sort of thing. So we think the main thing to do for RAS inhibitor resistance in pancreatic cancer is to increase your inhibition of RAS and we have several strategies for doing that, including combining a second RAS inhibitor. We also, of course, have our newest innovative class of compounds that is catalytic in its activity represented by RM55. So there are various strategies for dealing with that, but we do not have any data today from the resl302non-G12X. Why did it appear to show that is not as compelling yet the OS value pine.

Yes. So I think there's a number of potential questions and issues, I guess, that's supposed with this. one, of course, overall survival is the most definitive evaluation of treatment effect. The second would be the fact that they are, of course, small numbers. And when you have small subgroups such as this, you can have treatment effects that very are certainly less precise because we just don't have the number of patients to look at that. And so the confidence intervals as a result, are quite wide. -- showing encompassing both effect and greater than 1. So I think that that's basically sort of the summary of it at this particular point. Numbers are quite small and variable. But let's not forget OS and the consistent benefit that we've seen across all of the subgroups throughout overall survival of the study.

And I show our next question comes from the line of Kalpit Patel from Wolfe Research.

This is Gugino for Culp. Today's 33% ORR in 2Pacess benchmark. What ORR would you need to see in the MTAP-deleted subgroup to feel confident loping metastatic are adding a signal over deroxanrasib monotherapy.

To see a benefit of adding what to Daraxonrasib rated, I couldn't wear that will be here that will be I see. Yes, I'm not going to answer that question. I think the underlying question really here is to what degree is response rate predictive of durability -- and we don't really have an answer to that question today. Certainly, we have some level of relationship between a higher response rate here in this study, as we saw in the Phase I/II study and and durability, but we don't know what that relationship really is since we only have 2 points on the line. We have everything else, and we have Daraxonrasib we nothing in between or on either side of that. So we don't know the answer I get why you're asking it, but we can't -- if we can't help you enter that today.

And our next question comes from the line of Kelsey Goodwin from Piper Sandler.

This is Brittany Stop on for Kelsey. Congratulations on the strength of the data and the powerful response from the audience during the plenary session. there's not much to poke out in the data, but just 1 small question from us. Given the median follow-up of 8.5 months at this analysis, do you have any thoughts on how PFS and OS benefit might evolve with more mature follow-up. And do you plan to provide additional analysis at any time in the future?

Thanks very much for your comments and for your question. Alan, do you want to comment on follow-up and could the survival parameters move? And if so, were you particularly would move to.

So obviously, it's not possible to predict. However, what we would say is with the results of the hazard ratio of 0.4 and that highly statistically significant finding, we anticipate that with additional follow-up, we'll continue to see the broad benefit that we have seen, particularly for the PFS, which is more mature than the OS. But we do believe that both are strong enough that will continue to be seen -- and although this is the final analysis as has been stated, we will be looking at a subsequent follow-up, although not with more in a descriptive p-value approach and not with an alpha spend. but we look forward to doing that as well.

I might add, though, we are now allowing crossover for patients who progress in the chemotherapy through for those patients who are still on study. And so that could have some impact on looking at overall survival, but shouldn't affect progression-free survival. Thanks for your question.

And so we have time for 1 more question. Our last question comes from the line from Ami Fadia from Needham.

Firstly, congratulations for this really strong data and the achievement. My question was really around the expanded access -- can you elaborate on the expanded access and if there is potential for that outside the U.S. And then within the U.S., do you think patients that are in third line could get access to Dara at this stage? And then just more broadly, given all the data that you've generated in PDAC and lung, -- can you give us some comments on how you're exploring colorectal cancer and what we might expect to see in the foreseeable future? .

You've asked 3 of your permitted 2 questions. So we'll do what we can. With regard to the expanded access program, right now, it's an FDA-authorized U.S. program that operates through licensed U.S. physicians and that's who we're authorized. And outside of the U.S., we understand the urgency for patients elsewhere as well. there are local specific requirements in each country. We have people on the ground exploring that and exploring that with the right officials as well and to understand that. The main thing we're doing outside the U.S. is expanding our clinical trial footprint. -- and we've increased the size of that footprint by an order of magnitude, and that will allow more opportunities for clinical trials as the nearest term thing that we can do. CRC, I'm just going to put it off to Dave, do you want to comment on the third line, who's eligible in the EAP with our third lineation cel.

The answer is yes for third line. So it mirrors the second line and beyond with the appropriate parameters that are seen in the 302 study, which is performance status at homes.

This concludes our Q&A session. At this time, I'd like to turn the call back over to Dr. Mark Goldsmith, Chairman and CEO for closing remarks.

Thank you, operator, and thank you to everyone who joined us today. We are indebted to patients and their families who participated in RESOLUTE 302 in other studies to investigators and scientific collaborators to investors who have financed the work and, of course, to our remarkably dedicated employees. We are highly motivated by these significant results from the RESOLUTE 302 trial from the potential therapeutic impact for patients with pancreatic cancer or other RAS-addicted cancers and the profound opportunity ahead for Revolution Medicines. We very much appreciate your continued interest and support. Thank you.

This concludes today's conference call. Thank you for participating. You may now disconnect.

Good day, and thank you for standing by. Welcome to the Revolution Medicines Q1 2026 Earnings Call. [Operator Instructions] Please be advised that today's conference is being recorded.

I would now like to hand it over to Ryan Asay, Senior VP of Corporate Affairs. Ryan, you have the floor.

Thank you, operator, and welcome, everyone, to the First Quarter 2026 Earnings Call. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive Officer; Dr. Alan Sandler, our Chief Development Officer; and Jack Anders, our Chief Financial Officer. Dr. Steve Kelsey, our President of R&D; Dr. Wei Lin, our Chief Medical Officer; and Anthony Mancini, our Chief Global Commercialization Officer will join us for the Q&A portion of today's call.

We would like to inform you that certain statements we make during this call will be forward looking. Because such statements deal with future events and are subject to many risks and uncertainties. Actual results may differ materially from those in forward-looking statements. For a full discussion of these risks and uncertainties, please review our annual report on Form 10-K and our quarterly reports on Form 10-Q that are filed with the U.S. Securities and Exchange Commission. This afternoon, we released financial results for the quarter ended March 31, 2026, and recent corporate updates. The press release and updated corporate presentation are available on the Investors section of our website at revmed.com.

With that, I'll turn the call over to Dr. Mark Goldsmith, Revolution Medicines' Chairman and Chief Executive Officer. Mark?

Thanks, Ryan. It's good to be with you this afternoon to discuss the tremendous progress we've made in 2026. This is a pivotal moment for our organization and for patients worldwide living with pancreatic cancer who are in need of new therapeutic options. It is anchored by the top line readout for RASolute 302 last month, in which duration rapid monotherapy demonstrated an unrepresented improvement in overall survival compared with chemotherapy in patients with previously treated metastatic pancreatic cancer. RASolute 302 results represent a transformative advance for patients. They also firmly validate our pioneering RAS(ON) inhibitor strategy and reinforce its potential to improve outcomes in RAS-driven cancers. High investor conviction enabled an historic $2 billion dual tranche capital raise that will allow us to continue our important work broadly, advancing our current portfolio of for groundbreaking clinical stage, oral RAS(ON) inhibitors and bringing forward the next wave of innovation, targeting RAS-addicted cancers, including our new class of catalytic RAS(ON) inhibitors.

On today's call, following my remarks, I'll pass the call over to Dr. Alan Sandler, who will provide an overview on the recent clinical progress we've made across our portfolio. including the most recent data presented at the American Association for Cancer Research Annual Meeting. Jack Anders will then summarize our first quarter financial results before we open the call to Q&A.

Let me first spend a few moments talking about RASolute 302, the global Phase III trial evaluating daraxonrasib nontherapy in patients with previously treated pancreatic cancer. The top line readout for daraxonrasib marked a major milestone in this disease, significantly raising the bar and the development of new treatments for patients living with pancreatic cancer, the most RAS-addicted of all human cancers. In RASolute 302, or [indiscernible] demonstrated unprecedented impact, meeting its primary and key secondary endpoints and showing statistically significant and clinically meaningful improvement in progression-free survival and overall survival compared to standard of care chemotherapy.

In the overall intent-to-treat study population, which includes patients carrying tumors with or without an identified RAS mutation, daraxonrasib drove a 60% reduction in the risk of death compared with chemotherapy and with a median overall survival exceeding 1 year. Daraxonrasib was generally well tolerated and no new safety signals were observed. These are dramatic practice-changing results and our focus now is on moving with urgency to bring this potential new option to patients. We intend to submit a new drug application to the U.S. Food and Drug Administration under the FDA Commissioner's national priority voucher program, and we'll also execute our plan to file with other global regulatory authorities.

And last week, we reported that the FDA issued a state to perceive letter allowing us to initiate an expanded access treatment protocol or daraxonrasib in patients with previously treated metastatic pancreatic cancer. This will allow us to move as quickly as possible to ensure safe and equitable access to daraxonrasib for eligible patients in the U.S. We were also pleased to announce recently that RASolute 302 will be featured in the plenary session of this year's American Society of Clinical Oncology, or ASCO, Annual Meeting in Chicago. We and the investigators look forward to sharing detailed results with the scientific community at that time.

I'll now pass the call over to Alan to walk through some recent clinical program updates. Alan?

Thanks, Mark. The extraordinary results from RASolute 302 validate our tri-complex inhibitor platform and give us increased confidence in direct onlasib's potential in earlier treatment lines in pancreatic cancer. This confidence was reinforced at AACR, where we shared updated clinical data from the Phase I/II studies for daraxonrasib monotherapy and in combination with chemotherapy in first-line metastatic pancreatic cancer. Both the monotherapy and combination cohorts demonstrated encouraging preliminary durability data. In the monotherapy study, while median progression-free survival and median overall survival were not mature as of the data cutoff, the Kaplan-Meier estimate at 6 months were 71% and 83%, respectively.

In the combination of daraxonrasib with gemcitabine and nab paclitaxel the Kaplan-Meier estimates at 6 months for progression-free survival and overall survival were 84% and 90%, respectively. Across both studies, daraxonrasib safety and tolerability profile remained consistent with earlier findings in this patient population with no new safety signals observed. These compelling results strongly support our decision to rapidly advance RASolute 303, our Phase III study evaluating both daraxonrasib monotherapy and daraxonrasib in combination with chemotherapy in first-line metastatic disease. The trial is enrolling globally.

In addition to our first and second line daraxonrasib registrational studies in pancreatic cancer, patient enrollment is ongoing in RASolute 304 and our registrational trial of daraxonrasib monotherapy in the adjuvant setting in patients with resectable disease following conventional surgery and perioperative chemotherapy. We are also making progress in 2 registrational studies for zoldonrasib, our covalent RAS(ON) G12D selective inhibitor in first-line pancreatic cancer. We have initiated RASolute 305, a randomized, double-blind, placebo-controlled registrational trial, evaluating zoldonrasib in combination with investigators' choice of chemotherapy, either gemcitabine and [indiscernible] or modified FOLFIRINOX compared with placebo plus chemotherapy. And we remain on track to initiate RASolute 309, our first registrational study to evaluate the RAS(ON) inhibitor doublet combination of zoldonrasib with daraxonrasib in the second half of the year.

Moving to non-small cell lung cancer, another focus with development for RAS(ON) with approximately 30% of non-small cell lung cancers harboring a RAS mutation, including 18% with non-G12C mutations, unmet needs in non small cell lung cancer remain priority that we aim to address through several ongoing and planned registrational studies. Beginning with daraxonrasib, we continue to enroll patients globally and RASolute 301 our global randomized trial evaluating daraxonrasib monotherapy in previously treated patients. Based on the strength of the Phase I results for daraxonrasib monotherapy in non-small cell lung cancer as well as additional confidence from the recent positive RASolute 302 results, we are expanding the RASolute 301 study to increase the statistical power of the overall survival component of the dual primary end point.

Enrollment is going well, and we anticipate substantially completed enrollment in the expanded study this year. We also expect to disclose our plans routing daraxonrasib combination therapy in first-line non-small cell lung cancer this year.

Turning to G12D non-small cell lung cancer. At AACR, we presented updated clinical data for zoldonrasib monotherapy in a subset of patients who had previously been treated with immune checkpoint inhibitors and platinum chemotherapy. Zoldonrasib was generally well tolerated and demonstrated a safety profile consistent with previously reported findings. Zoldonrasib demonstrated encouraging clinical activity with a confirmed objective response rate of 52% disease control rate of 93% and a median progressive-free survival of 11.1 months. Overall survival data were immature at the time of analysis. The estimated survival rate at 12 months was 73% and while the median had not yet been reached, which is encouraging data at this early look.

We continue to believe deeply in the potential of zoldonrasib given its compelling safety and tolerability profile and encouraging clinical activity, which strongly support our plans to advance zoldonrasib across monotherapy and combination setting in lung cancer and other RAS-G12D-driven cancers.

Building on the strength of our monotherapy data, we are preparing to initiate in the first half of this year, RASolute 308, a global double-blind, placebo-controlled registrational trial evaluating zoldonrasib in combination with the KEYNOTE-189 regimen, which is the standard of care in first-line treatment for metastatic non-small cell lung cancer. Compared to the KEYNOTE-189 regimen with placebo.

For patients with G12C non-small cell lung cancer, elironrasib, a RAS(ON) mutant selective inhibitor has demonstrated a differentiated and compelling clinical profile in both G12C inhibitor naive and G12C inhibitor experience lung cancer patients. We remain on track to share an update on our elironrasib registrational strategy this year.

Our third RAS-addicted cancer focus is colorectal cancer, which remains an area of high unmet need and interest for the company. We have a range of combination studies underway designed to better understand this genetically complex and heterogeneous disease. Including studies to evaluate RAS(ON) inhibitor doublet combination and RAS(ON) inhibitors in combination with current standards of care and with other targeted drugs. We remain on track to share combination data this year as we work to prioritize registrational opportunities.

I'll conclude with brief highlights on 2 of our early stage programs. We continue enrolling patients in the first-in-human trial of RMC-5127, our fourth RAS(ON) inhibitor. RMC-5127 is selective for last G12V, the second most common RAS variant in solid tumors. We expect to identify a recommended monotherapy Phase II dose for this compound in the second half of 2026.

Finally, AACR brought with it the opportunity to showcase our new class of innovative mutant targeted catalytic RAS(ON) inhibitors. These inhibitors are designed to promote the conversion of mutant RAS in its active GTP bound RAS(ON) state stepped to the inactive GDP-bound RAS off state. Thereby mimicking the normal physiologic regulation of wild-type breast. These preclinical data demonstrated that at well-tolerated doses RM-055 achieved robust and durable antitumor activity across [indiscernible] G12 mutant xenograft models of pancreatic cancer, non-small cell lung cancer and colorectal cancer. Notably, tumors that had escaped prior RAS inhibitor treatment were sensitive to RM-055, which drove deep and durable regressions Its compelling, differentiated profile warrants clinical investigation of its potential to counter emergent drug-resistant and to extend clinical benefit and we remain on track to initiate a first-in-human clinical trial in the fourth quarter.

With that, I'd like to pass the call back over to Mark. Mark?

Thanks, Alan. In addition to the substantial R&D progress we've made across our pipeline, we continue to be very gratified by the build-out of our commercialization infrastructure and operational capabilities to support the company's global commercialization ambitions. We've established the operational wherewithal required to move the speed and agility focused initially in the U.S. and extending into priority international regions. We are resourcing our efforts to ensure that we have the best strategies, tactics, operational capabilities and people to bring daraxonrasib with urgency to patients pending regulatory approvals. We expect to be launched ready under best case approval timing scenarios. We have experienced and talented executives leading our commercialization team across medical affairs, market access, marketing and sales -- these groups are deeply engaged in market preparedness and assessment, planning, position and advocacy engagement, sharpening operational capabilities and conducting other launch readiness activities.

We recently appointed several experienced leaders across the Asia Pacific and European regions, including Neil McGregor; as our General Manager for APAC and Tetsuo Endo as General Manager for Japan; and Martin Voelkl as General Manager for Germany.

I'd now like to turn the call over to Jack Anders, our Chief Financial Officer, to summarize our first quarter financial results. Jack?

Thanks, Mark. We ended the first quarter of 2026 with $1.9 billion in cash and investments and further strengthened our financial position after the quarter with $2.1 billion in net proceeds from our concurrent upsized offerings of common stock and convertible debt in April. Before we dive into the income statement for the quarter, I'd like to highlight that our stock-based compensation expense for the quarter was higher than usual and explained the reason behind it. Stock-based compensation expense was $87.3 million for the quarter ended March 31, 2026, compared to $25.1 million for the quarter ended March 31, 2025.

In the first quarter of 2026, the company updated its equity compensation program to introduce competitive retirement benefits for employees who meet specific minimum age and service requirements. The modification of this program resulted in an incremental $44.6 million in stock-based compensation for the first quarter of 2026. This incremental expense was primarily due to the accelerated timing of recognition of stock-based compensation expense originally scheduled in future periods for outstanding eligible awards. As a result of this timing pull in, we expect higher nonrecurring lumpiness in stock-based compensation expense for the first half of 2026 and with stock-based compensation expense decreasing and returning to a more normalized trajectory in the second half of the year.

As a result of this change, the company is increasing its estimate of full year 2026 stock-based compensation expense by approximately $80 million. and now expects full year 2026 stock-based compensation expense to be between $260 million and $280 million. Additionally, the company is also updating its projected GAAP operating expense guidance to reflect the expected increase in stock-based compensation expense and now expects full year GAAP operating expenses to be between $1.7 billion and $1.8 billion.

Moving to expenses for the quarter. R&D expenses for the first quarter of 2026 were $344.0 million compared to $205.7 million for the first quarter of 2025. This increase was primarily due to higher clinical trial and manufacturing expenses for duration rapid and zoldonrasib due to acceleration of the pace and expansion of these programs. R&D expenses were also higher as a result of increased head count costs and higher stock-based compensation expense as described earlier. G&A expenses for the first quarter of 2026 were $101.3 million compared to $35.0 million for the first quarter of 2025. The increase in G&A expenses was primarily due to higher stock-based compensation expense as described earlier. Increased head count costs increased commercial preparation activities and higher administrative costs. Net loss for the first quarter of 2026 was $453.8 million compared to $213.4 million for the first quarter of 2025. The increase in net loss was due to higher operating expenses.

That concludes the financial update. I'll now turn the call back over to Mark.

Thank you, Jack. The remarkable start to 2026 as the result of years of unwavering dedication relentless perseverance and hard work by our team and collaborators standing on the shoulders of others. With the unprecedented performance of daraxonrasib monotherapy in the RASolute 302 study, we believe we are in a position to change the standard of care for patients living with pancreatic cancer, subject to regulatory review and approval. The global response to the RASolute 302 data has been overwhelming. The news brings with it hope and possibility for patients, physicians, and the advocacy community that have all been waiting too long for new, more effective treatment options. We are now an important step closer to fulfilling our mission of discovering, developing and delivering innovative targeted medicines to patients living with cancer. We have an extraordinary opportunity, and we take very seriously the responsibility that goes with it.

Before I close, I'd like to recognize our continuing partnerships with patients and caregivers, health care providers and investors as well as the remarkable dedication and efforts of Rev Med employees. It requires the ongoing support of all of our partners and constituencies to do revolutionary work on behalf of patients.

With that, I'll turn the call over to the operator for the question-and-answer portion of the call.

[Operator Instructions] Our first question comes from the line of Cory Kasimov with Evercore ISI.

Congrats on all the recent very exciting progress. So I wanted to ask, you recently noted you could share data at a medical meeting that supports the rationale for RASolute 309, the Phase III front-line PDAC trial, looking at zoldonrasib plus daraxonrasib versus chemo. Would this include durability data or just response rate as we've seen with some of your initial disclosures? And maybe more importantly, how much additive efficacy would you be looking for here to say it's clinically meaningful to justify the combination over the exciting monotherapy results we've seen with both of these agents.

Thanks, Cory. I appreciate your comments and question. It's probably too early for us to lay out what that presentation would look like. We typically don't forecast it. we'll show what we have. We think it will justify our plans, and we'll provide that into course. The second question, also probably and unfortunately, it can't be too helpful about what's the threshold for added value that justifies doing that mean, of course, we look at the totality of the evidence. We look at the historical benchmarks. And ultimately, as you sort of implied in your question, durability is the most important parameter.

Our next question comes from Charles Zhu with LifeSci Capital.

[indiscernible].

Charles, we're not able to pick up what you're saying. Stacy, I don't know if there's anything you can do on your side to improve the audio quality.

Charles, are you in a good position to speak with us? Will get Charles back queued up. Our next call comes from Michael Schmidt with Guggenheim Securities.

Again, congrats on RASolute 302 data, looking forward to the full data presentation at ASCO. Yes, a question on the EAP program. I know this was just announced a few days ago. But Mark, I don't know if you could comment what you're seeing so far in terms of demand for the EAP program? And what do you think -- how many patients could particularly benefit from this to officially receiving FDA approval? And then maybe just if you could share your view of the size of the second-line pancreatic cancer opportunity based on your market research, how many patients in the U.S. do you think would be treatment eligible for the daraxonrasib based on the 302 study.

Thanks, Michael. Nice to hear from you. On the first question, of course, we're working hard to get in a position to be providing drugs to those who need it. The demand has been very clear from the moment that it was announced. And we don't expect that to slow down anytime soon. And we're putting all the resources that we can on it we'll meet that need. I can't really give you a projection as to the number. I don't know how we can make that projection. We'll just have to have to play it out. I think there is clearly a widespread knowledge of awareness of daraxonrasib and those calls started coming in within minutes after the announcement.

The size of the second-line opportunity way you might want to talk about this. We can't characterize it for you a great depth, but we typically think about roughly 60,000 new cases in each year, and then maybe Wei can comment on both what's historical attrition and then also whether or daraxonrasib might affect that.

Yes. Happy to do that. These are obviously just estimates based on clinical practice. A smart comment about 60,000 Americans or undiagnosed each year with pancratic cancer about 50% to 60% of those patients are diagnosed with metastatic disease. And so those patients are numbers what we see first-line therapy with formatics. And typically, because of both the breast and nature disease as well as the toxicity of chemotherapy. About half of the patients received first metastatic treatment received subsequent secatreatment. So that gives you a sense of the overall attrition as well as the size.

And just to add to that, that could certainly change in the context of first-line treatment, but we don't have anything to address that on that point today.

Our next question comes from Faisel Khurshid with Jefferies.

Just wanted to ask on the RAS(ON) 301 upsizing. Could you clarify what exactly led to the upsizing? What were you powered for before? And what are you powered for now? And does this change the time line from enrollment completion to read out?

Thanks a lot for your question. I'm going to answer the second question, and then Al and Anders is going to talk about the first. We don't think it will change the timing of the readout given the high pace of enrollment and where we stand today. So we don't expect to impact our projection that we'll complete or substantially complete enrollment this year. But the more subtle question about the sizing of the trial, Alan can comment on.

Sure. Thanks. So an important point is we've realized the importance of overall survival and given the results that we've seen in 302 and also the Phase I monotherapy data, we have a very high conviction that on our ability to obtain overall survival benefit. So as a result of that, we're going to further prioritize overall survival in 301 by expanding the enrollment, as you've noted. Going from 420 to 590 patients. That will increase the statistical power of that component of what is a dual primary end point -- and then again, as Mark has mentioned, we -- there's a great pace in terms of the patient enrollment, and we think that we will substantially complete the enrollment, even with the expanded study this year.

Our next question comes from the line of Brian Cheng with JPMorgan.

Mark, during the call, you said the best case timing scenario for darax launch across the globe. How should we think about the timing and the cadence then for the filing and launches specifically across APAC and European regions? And just on the NDA application towards the FDA. Can you give us a little bit more color, a little bit more granularity in terms of the things that are left to complete?

Yes. Thanks, Brian. I can't really give you any specific timing with regard to the filings outside the United States. But just generally speaking, we are starting with the U.S. filing as the initial priority. There will be some sequential framework for filing in other countries, and we're already engaged with regulatory authorities outside of the United States in order to make sure that we can deliver what they need and in as timely a matter as possible. for the NDA, your question was what's left to deliver? Is that how you put it?

Yes. What are the things that are left to complete before you complete the NDA application.

Yes. Well, we've been fully engaged with the FDA for a long time, as you know. And of course, with the CMPB and the breakthrough designation, we've had a high level of engagement than you might otherwise have and so we are providing them information as it becomes available, mature enough to provide to them. And ultimately, the clinical package is the thing that will be provided. I can't give you a specific timing on that. There's a full throttle effort to do it. We feel the urgency around it. Certainly, the question earlier about the provides a pretty strong signal about how urgent that is, and we'll continue to move this forward as fully as we possibly can.

Our next question comes from Marc Frahm with TD Cowen.

Maybe following up a little bit on Cory's question earlier, just on the zoldonrasib plus daraxonrasib combo. Can you maybe speak to the design, particularly in light of the 3 or 2 finding and the survival data, I mean looking better than anything we've ever seen even in first line. Just why is 30 comparing to chemo to the right design and -- or would it -- should it really be switched over to consider daraxonrasib monotherapy as the comparator arm there? At a minimum, one, to get the contribution of parts, but also just from a clinical execution perspective of where the ball is head seems to be headed in pancreatcancer.

Yes. Thanks, Mark. That's a good question. It's a subtle one. Of course, today, standard of care is chemotherapy. And until there's a data set that moves the FDA to approve a different treatment and a different treatment at the level that people consider the new standard of care than chemotherapy is the standard of care. I think you're sort of inviting me to comment that, of course, we think daraxonrasib has a real potential in monotherapy, but also in combinations in first line. And among those combinations, chemotherapy is 1 that we've already provided some early-stage data on and we're quite excited about. And that combination is in the 303 trial, so we're already going into combinations.

And it's really just a question of when that bar moves and -- but we have high confidence that the combination can deliver something that is differentiated from chemotherapy, but also even for monotherapy. I think the other thing to keep in mind is we do a lot of things where there's overlap in the patient populations that we might be able to serve in different ways -- we don't shy away from that. As you know, we've discussed that before, because every patient has his or her own specific needs and giving doctors options even if the outcomes on paper may look fairly similar across broad populations, there still may be reasons why 1 particular patient would benefit or be perceived to benefit from 1 particular combination or monotherapy approach versus another.

So providing the most fulsome set that we can based on the science and then ultimately on the clinical data, it increases the chance that we're the ones that are delivering the best possible options for patients. So that's the high level of comment.

Our next question comes from Jonathan Chang with Leerink Partners.

Congrats on the progress. Can you talk about your latest thinking on getting to a chemo-free option in frontline pancreatic cancer? What gives you confidence in being able to achieve this? And what do you think is the best strategy for giving us?

Yes. Thanks, Jonathan. Nice to talk with you. Well, we just talked about 1 of those strategies for a chemo-free frontline, which is monotherapy daraxonrasib. And I think the data single-arm data that we've shown so far are compelling enough that it just -- very much justified incorporating that into the Phase Phase III first-line trial, and we'll see how that performs. But we have or expectation that it could deliver chemo-free regimen. And then the second option is also 1 we just talked about, which is combining a mutant selective inhibitor with direxonerasib, that would be a chemo-free strategy. And that specific combination of zoldonrasib plus daraxonrasib of course, is for the 40% of pancreatic cancer cases that are carrying a RAS mutation.

We have other mutelective inhibitors directed against additional mutations that are common in -- or can be found in breast cancer, so we could and would likely fill out that collection of regimen. It just happens that so long or asset plus Traxon is on the vanguard, the work because of maturity of the compound and the data that we have so far. So I think those are very compelling chemo-free regimen. There are others that 1 can consider their immunologic agents that could be combined. There are other targeted agents that could be combined. We're already exploring, as you know, PRMT5 combination ringer combination, et cetera. I'm sure there will be other things to come over time.

Our next question comes from Charles Zhou with LifeSci Capital.

Thanks for giving me another step at this. Can you hear me now?

Yes. Yes.

All right. Perfect. I believe a bunch of clinical type questions were taken. So I'll ask 1 a little bit earlier, but RM-055, Nice to see your presentation at AACR as well as some of the work you helped support over at Perales lab that was just published yesterday. But can you comment a little bit perhaps on RM-055's ability to potentially address daraxonrasib of resistance mechanisms that go beyond that of a KRAS amplification. And can you also talk a little bit about perhaps how you might be achieving what appears to be at least preclinically a wider therapeutic window for RAS mutants over RAS wild types over that, which directs on as can achieve. Any color as to how you're accomplishing that mechanistically? And if you can also kind of see that in your precliclinical models as you advance that into the clinic?

Thanks, Charles. Sort of loud and clear. Yes, Steve Kelsey, I think I'll comment on both of those important topics.

Sure. Yes, I think the rest amplification can be received as a stand-alone mechanistic basis for escape and drag on asset, but it also acts as a surrogate for increasing flux through the RAS pathway generally. And in most of the experiments that we've done, RM-055 is a better inhibitor reflect flux through increased flux through the RAS pathway. Generally, particularly when it's going down through G12 mutation. So I think there is a general principle of escape from daraxonrasib occurring through reactivation of RAS pathway signaling. It's not just amplification of the mutant allele that can do that. And I think there's every reason to believe that remote may be effective beyond just pure [indiscernible].

Your point about therapeutic index, it's all to do with the relative importance of hydrolysis of Raton back to at or between cancer and normal tissue. Normal tissue most of the RAS in normal tissue was already in the off-state anyway. But it's being capitalized back the actigraph being capitalized back to grass very effectively by the naturally occurring gaps. And the whole point of RAS mutation cancer is that, that just doesn't happen. The ability of the mutant rats to withstand that catalytic hydro hydrostatic state is very different. And it varies from mutation to mutation. But what we've done is very selectively targeted the inability of particularly as a G12 mutant rates to be hydrolyzed back to was off by forcing it to be haggled back for us often-- it really has very -- this drug has almost negligible effect on all tissue in that respect and a very significant increased deactivation of mutant RAS and has itself.

Next question comes from the line of [ Michael Yee ] with UBS.

Congrats on the progress. Two quick ones. On the colorectal cancer data coming up, can you help guide expectations on how to think about combination with EGFR given overlapping rash and how to think about mitigation or how to interpret results given higher efficacy, but also trying to mitigate rash in that strategy. And then also in the first-line PANC study, which is enrolling, we definitely get huge feedback that it's going to enroll super fast in a number of different sites. Is it safe to assume that there's probably an interim in that study as well eventually once you complete enrollment?

Thanks, Michael. Nice to hear from you. Who wants to address the CRC. I mean maybe I'll just make the comment that it is true that Duration rate itself has essentially overlap with the eGFR antagonist from a perspective of suppression rest signaling that drives the skin side effects. So that is a harder combination to contemplate. That really doesn't apply at all with immune selective inhibitors -- and that's why the GLC selective inhibitors that launched the field essentially sotorasib and aggressive and now others can be combined pretty readily. And it really fundamentally addresses the whole gap in the EGFR coverage that occurs in the RAS-mutant tumors and the whole reason why EGF receptor antagonism is as Conto indicated typically in rescue tumors, you really need the RAS inhibitors.

So that combination is in principle something that can be pursued. Stay tuned. We'll talk about it when we're able to do so. The question about the first line, I got the tail end of the acoquestion part of it was have an interim announce to have an interim analysis. Wei, do you want to comment on that?

Yes. At this current state, we don't mind to disclose the analysis plan.

Our next question comes from Laura Prendergast with Stifel.

Thanks for the update. I was curious, what are some of the top variables still under consideration for daraxonrasib in first-line lung cancer as far as strategy goes, and then on the back of RASolute 302, showing such a unprecedented OS, what kind of pricing power are you guys thinking this could unlock? And are there any benchmarks for pricing that you guys are most focused on?

Yes. Laura, nice to hear from you. I don't think we can really comment on the pricing. Of course, the OS impact is something everybody is interested in starting with patients and their families and all the way up to insurers and payers in other geographies. So it will be relevant to their considerations, but that's about all we could say about pricing today. And then your question on first-line non-small cell lung cancer. Which was let the variables -- oh, I see. With regard to daraxonrasib in first line. Well, we've alluded to it. We commented that there are a couple of things going on. Probably 1 of the most important is that we're now dosing patients with ivanesimab, which may become -- we're all waiting to see how that progresses.

But it points towards potentially becoming the new standard of care for frontline non-small cell lung cancer, in which case, that that's something we need to take into account, which we hadn't really taken into account before we had the real relationship with Summit that's now very much active and we're dosing patients. That's probably the main variable I think the other thing just conceptually to comment on is the mutant selective inhibitors are already pretty well established simply because of the G12C inhibitors that launched the field. And that's sort of a paradigm that lung cancer doctors are now used to thinking that G12C as its own disease, which means G12D will be a some disease and GB will be its own seas and pretty quickly you've covered most of the locations in grass lung cancer. We happen to have a G12D selective inhibitor, which is performing particularly well. We happen to have a G12C selective inhibitor, which is quite differentiated and compelling.

We have a G12V selective inhibitor that's in the clinic now, and we expect good things from that. So there are multiple ways to cover that. And it is a field in which it's already broken down by genotype. That's 1 possible strategy. So those are kind of several of the major considerations.

Our next question comes from Jay Olson with Oppenheimer.

Congrats on all the progress and thanks for providing this update. How would you like to set expectations for the upcoming ASCO plenary presentation in terms of where you'd like investors to focus their attention.

I think my main expectation is this going to be crowded. I'm not sure really how to help you on that. I mean we'll be providing, I think, through the investigators of a full update on it. And the update will be consistent with what we've said so far, but provide significantly more information that the experts in the deal needs to see and evaluate in that setting.

Our next question comes from Kelsey Goodwin with Piper Sandler.

Congrats on all the progress recently. I think two quick ones for me. First, I guess, any additional color that you're providing on the sales force. And then secondly, I think, building on one of your prior answers in this question-and-answer session. I guess as we start to think about that front line to second line attrition rate, daraxonrasib comes on to the market. I guess, do you have a sense what percent of that 50% of patients that don't proceed to second line are fit for therapy altogether versus ineligible or unwilling to take another chemotherapy just as we start to model that out a bit more refined.

Yes. Thanks, Kelsey. Anthony, do you want to just comment on the sort of sales organization more broadly.

Yes. So thanks for the question, Kelsey. I think for the U.S. region, we're in the final stages of building out our field-based teams all across different functions in the field, MedAffairs market access and sales. We've had an MSL team and a thought leader leads on team in place for quite some time. We also have a market access account team that's been in place, that's been engaging with payers and organized customers. really around the unmet need pancreas cancer around the pipeline and the early clinical data for daraxonrasib through pre-approval information exchanges, and we're really pleased to say that we're in the final stages of onboarding our U.S. sales force. We're pleased with the team.

They have deep expertise in solvent tumors across GI malignancies and in oral oncology, and they'll be fully trained and ready to go with HCP engagements if we were to receive NDA approval.

Thanks, Anthony. And on the first line, the second line, it's a good question. It's an important question. It's a little bit hard to get a detailed and clear understanding of because in reviewing records and so on, it's not always clear as surprisingly have commented is that it's not clear why somebody hasn't gone on to second line. You don't always identify an obvious performance status issue or concurrent illness or disease status that would prevent somebody from moving on. And therefore, they might have decided not to proceed because of intolerability or they might have now to proceed because of perceived intolerability before they tried it or because they want to focus their life at this stage on family and not on chemo infusions. There's a wide variety of reasons. And then sadly, it's also true that patients who start chemotherapy in first line sometimes don't survive to second line.

So it's a great devastating illness as everybody knows. So there are a lot of different reasons. Some of those could be addressed by a regimen that is more convenient than it's better tolerated a once-a-day pill that really is generally well tolerated and safety issues are manageable, could sure impact somebody's decision. We don't know whether or not it will. We'll only know that. if we get to the finish line with an approval and and see how patients do in that context.

Our next question comes from Kalpit Patel of Wolfe Research.

Congrats on the trial ahead. So for RASolute 303, how should we think about that study's enrollment ramp versus the second-line study that you just completed in terms of timing of enrollment completion. And then can you remind us if crossover is allowed in that RASolute 303 study? And separately, any comments on potentially starting a registrational trial with daraxonrasib and a PRM D5 inhibitor.

Thanks very much for your questions. The timing of completion. We can't comment on that now. We're just not at a stage where we can project the time line with any confidence -- but maybe the even more important point would be we know there's very, very high interest in this. And sites that have activated or enrolling, but there are plenty of sites that still are yet to be online, and they are patients lined up at many of these facilities. We're aware of that. So we expect there to be very high demand for this for a variety of reasons, not the least of which is the disclosure of the 302 key findings, which steps do it. crossover is not allowed in the trial design. As you know, of course, up to any individual patient, they can cross over on their own if there is an approved therapy to crossover too. But in terms of actual crossover sign, we can't really provide it when OS is the is the standard, and that's the sort of conundrum of a Phase III trial for which overall survival is the endpoint. And where we're currently kind of in the process of transitioning from Equipoise to out of Equipoise and where we stand in that is sort of -- it's a matter of judgment and it's really a question for the regulatory agency. They have to make make that determination. And as long as OS is required, it's very difficult to achieve that with the crossover design. [indiscernible] want to take to those points.

The only additional comment I would make, again, because of the concern for overall survival being a primary endpoint is established a broad geographic footprint in order to mitigate the potential for impact of second-line therapy with daraxon moving forward. So smaller U.S. footprint, larger ex U.S. moving forward.

Good comment. And then the last thing was with regard to PRMT5. We don't have any update to provide on that today. We're enthusiastically engaged in collaboration with with several companies now who are evaluating PRMT5 inhibitors in combination with RAS inhibitors, and we're keenly interested in how that will go.

Our final question comes from the line of Alec Stranahan with Bank of America.

I guess, two from me. First, I would be interested to hear from your experience whether the initial ORR with daraxonrasib was a good metric for predicting PFS and OS benefit in larger studies? Like does the higher numerical ORR translates to better survival -- or is duration of response or time on therapy, maybe more telling for this? Just trying to think through some headline numbers we're seeing from others in the space. And quickly, will you be allowing third line plus patients into the EAP as well.

Thanks, Alex. On the last question, yes, the eligible population includes previously treated and it goes beyond the pure sector line that are in the -- that were in the 302 trial. Is ORR predictive of PFS or OS, who wants to comment on that.

We don't show analysis of that. The -- it's broadly with PFO has broadly correlates with PFS. It's not such a tight documetric relationship that you can actually say that the ORR is 5 percentage points higher than the PFS is going to be at on tire. But it is broadly correlated that there are better ways of predicting PFS. And which involve multiparametric analysis that include but are not restricted to. We have not made those broadly available to other people because obviously, is a competitive advantage for us to know that and not share it with our competitors. But definitely, LRR is a component of that that framework for sure. So I think it's -- we're learning more. And you're right, I mean, we're learning a lot more now, now that we have decent drugs for pancreatic cancer. We're learning a lot more about the relationship between all of these outcomes. But I mean, in other diseases, like lung [indiscernible] and breast cancer, colorectal cancer, took years and years and years to figure out these relationships, and they're still not totally clear. So yes, I think that you will see relationships emerging, whether they're causal or otherwise. But I wouldn't -- I wouldn't draw too many straight lines

Yes. That's -- I'll pile on on that. There's obviously some relationship, but what you can do with that and how you should interpret ORR data and have vision for what that's going to translate into premature. Yes. And the other thing is, of course, with [indiscernible] the numerical value are at any point in time isn't very accurate anyway.

Patients can take up to and sometimes beyond 6 months to fulfill the resist definition of response -- so at any given point in time, there, they still be people who might become responders who have not yet become responders. And the rest is definition of responses in a particularly robust endpoint -- so there's a lot of wage room and uncertainty around all of these analysis. It's very tempting to believe that the overall response rate determined by resets is a pure and absolute accurate measurement, but it absolute -- I can tell you absolutely is not. If you look at those CT scans and trying to compute the unidimensional measurements of the target lesions that you'll realize just how broad uncertainty the whole thing is.

Also, I'm glad.

This does conclude the question-and-answer session. I'd now like to turn it back to Mark Goldsmith for closing remarks.

Thank you, operator, and thank you, everyone, for participating today and for your continued support of Revolution Medicines.

Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.

So welcome back to the 46th Annual TD Cowen Healthcare Conference. I'm Marc Frahm, from the biotech team here at TD Cowen. Very happy to have with us Mark Goldsmith, President and CEO of Revolution Medicines for the next session, where we're going to talk a lot about different ways to target RAS.

So maybe to start off with, Mark, you kind of just level set people, high-level overview and kind of what you see as the key value creation events for investors over the next 12, 18 months or so?

Well, thanks for having me here today. It's a pleasure to talk to you. Well, I think the most standout event of the year is going to be the readout of the RASolute 302 trial, which is our trial in previously treated pancreatic cancer with daraxonrasib monotherapy versus chemotherapy. We expect that readout to occur in the first half of this year, which is marching along through the first half of the year right now. That's probably the most notable and substantial readout, which then, of course, would drive a variety of other activities.

We have a lot of other studies that are already underway. In fact, now a total of 5 Phase III studies have been initiated, 4 of them in pancreatic cancer. And those should make progress this year in enrollment. They won't have particular readouts this year. In first-line pancreatic cancer, we had shown previously monotherapy, daraxonrasib and daraxonrasib plus chemotherapy response rate data from a small cohort earlier last fall, and we do expect to provide some initial durability data for those 2 cohorts sometime in the first half of this year.

So I think those are some things to anticipate. We also expect later in the year to provide some initial data on colorectal cancer that would provide some guidance about where we're headed from a registration strategy point of view. And we also expect to provide clarity around Alere on Rasib an exciting G12C(ON) inhibitor much more competitive space, but we're developing our strategy around that and should be able to provide more clarity as the year goes on.

Okay. As you mentioned, the 302 trial is going to read out here shortly. Just what should -- maybe can you help us expectations for investors as to kind of what we should expect an initial top line release versus what needs to be held for a later presentations and medical meetings and stuff, which are obviously also important to the business. Because there's a lot of nuances in this trial right between different mutation subtypes and things in different hierarchical analysis there.

Right. So the trial design is a little bit complicated because we -- the fact that we simply have had more clinical data and also preclinical data in the subset of pancreatic cancer that carries a G12 mutation. We sometimes call that a G12X-mutation for all the different amino acids that can show up in the G12 position. That represents about 85% of pancreatic cancer.

So it's a large subset. But it's the subset for which we have the most data. Therefore, we have the most confidence. Therefore, we designed a trial in which those patients are kept together in a cohort that is at the core of the trial, that undergoes initial statistical analysis in the readouts. Then there's a second readout or a second analysis which involves that core plus everybody else in pancreatic cancer, which could include mutations that positions G13 or Q61 and also potentially patients who don't carry a RAS mutation and those get lumped back in together in the whole analysis.

So there really are potentially 2 different analyses and outcomes from each of those. This first analysis is a first analysis as the interim analysis, #1. It could also be a final analysis. It just all depends on what it shows. It's set up so that there are other opportunities to do later analyses, but we'll just have to see. It's possible that there could be a range of potential scenarios just being objective and not leaning into any particular scenario, we could not pass PFS, and therefore, not pass OS. We could pass PFS statistical significance and not yet be significant for OS or we could pass statistical significance for both PFS and OS. Those are just 3 objective potential outcomes and they lead to different consequences.

As to what we would show at what time that's TBD because of the complexity that you raised. And we really don't have a matrix we can share with you that says, if this, we'll do this and if that we'll do this. But generally, we would like to show data from that trial. It's obviously a very important trial. We're excited about it. It could potentially have far-reaching impact on standards of care for pancreatic cancer. We'd like to be able to share the actual data in a scientific context in a meeting context in which peers can challenge it and review it. But we'll see, let us see the data when it's unblinded, and then we'll be able to make a decision about how to present it.

Okay. And then One question we often get from investors is how to -- because you are starting first-line trials, including with the monotherapy, but how to think about kind of translating across lines. When we see this data obviously, it will have a huge impact potentially on second-line patients. But how does Revolution approach that question of what does this mean for the probability of success in a first-line trial when we see second-line data.

Yes. It's hard to give a formulaic answer to that question. Pancreatic cancer is a RAS-driven disease. It's RAS-driven, when you're first diagnosed, it's RAS-driven after you've had a treatment and you come back for follow-up treatment, it's RAS-driven in third line, it's RAS-driven in fourth line. It's a RAS-driven cancer. That doesn't go away.

And I think that's a really important point to make. About a year ago, there was sort of this rumor spreading that was really second and third line that would benefit from a RAS inhibitor, but not first line. And if we really understood the biological plausibility of that statement, and I think it makes no sense. And in reality, the data that we've shown so far, albeit a limited data set show that indeed in first-line treatment, treating with either RAS inhibitors monotherapy or in combination with chemotherapy delivers an encouraging impact.

So we do think it's important to suppress RAS regardless of your stage of disease, regardless of whether you've had prior treatment or not. So with that in mind, if one looks at the previously treated pancreatic cancer population that we've reported on with response rates with PFS and with OS that appear to be numerically quite significantly different from that of chemotherapy and even surpassing numerically the same parameters in first-line treatment with chemotherapy that it's pretty easy to make the -- draw the conclusion that we'll see benefit from a RAS inhibitor in first-line treatment.

But those are cross-trial comparisons. They're from single-arm trials and all the limitations associated with that. So we can't really make such a claim. It just seems obvious that one could draw those inferences.

Have you gotten a sense -- when you look across the broader landscape of targeted therapies since as you said, pancreatic is -- seems from the clinical data, but also the genetic data to be very clearly RAS-driven broadly. But when you look at broader targeted therapy space, just how much better does efficacy tend to get when you move up lines versus, look, it's the same disease. It's the same mutation. It's kind of you hit it whenever you hit it, and so it's the same.

Yes, in targeted therapies, if you look across the board, that generally, the benefits in earlier lines are similar to -- sometimes they're somewhat better but at least similar to hazard ratios tend to stay the same. But because the overall outcomes in earlier lines generally are higher, the same hazard ratio leads to absolute benefits in terms of number of months, if you want to calculate it in those terms. That's the general trend. I'm not sure why that should be different for pancreatic cancer and for RAS treatment.

But we'll just have to see. We'll have to establish that. We did see such a trend in the response rates. But we've made the argument now for 3 or 4 years that response rates are really not the proper readout for pancreatic cancer. Durability is the readout and although we've only shared response rate data in the first-line cohort that's because that's what we had at the time that we could share it. But ultimately, patients aren't really asking, doc, am I going to have a 32% or 37% response, they're asking, how long am I going to live? And how am I going to feel as long as I'm living. And so that's all about durability, and that's what we're focused on.

Okay. And once this trial reads out is hopefully positive. What's the status of everything else that needs to go into an NDA? And how quickly do you think Revolution can kind of turn around from data to an actual NDA submission?

Yes. I mean, independent of the national priority voucher that we have, we had been set up to move as swiftly as possible because there's a clinical and public health imperative to do so, that got heightened when the commissioner awarded us the national priority voucher for a review. But it hasn't really changed that much from our perspective.

We had already lined up our manufacturing to be supportive of a potentially early launch. We have our systems in place to be able to repair reports and things that are required as part of the documentation. We have gotten guidance from the FDA. We're very engaged with the review division. It's the same review division that had recommended us to the commissioner for the voucher. So it's not as if something was handed to them that they didn't expect.

On the other hand, it's a new policy. It's a new program. It's a pilot program, and they don't really have a preestablished mechanism in place. I think everybody has read about that. It's being created in real time. Everybody is incentivized here to move as swiftly as possible, everybody, including the FDA, but they want to do a good job and they want to make sure that they all make a mistake. And so we support that.

From a commercialization point of view, we have been investing for 2 years to build a platform and a presence sort of a premarket presence. We have had medical affairs operating in the United States really across all regions in the United States for a year now, MSLs covering all territories. And that has been important to establish relationships and to be teaching practitioners what they need to know about pancreatic cancer is a RAS-driven disease.

Not every doctor knew that. And many doctors who learned that at some point, probably forgot it because they got flooded with other information about something else. So we've had to remind people that we have an ongoing unbranded educational campaign called Expect RAS, which has had impact. It's caused practitioners to be anticipating daraxonrasib as a potential product.

From a true commercial point of view, we have strong leadership in place in the U.S., both at the top level with the Chief Global Commercialization Officer. We have a general manager for the U.S. who's been in place for 2 years. It was fantastic. We have a marketing team. We have access all of the pieces that are needed are in place. The only thing that was really left is the field sales team. We have a leadership organization across the U.S, but we haven't had a field sales team in place, and we announced those positions opening in January at the JPMorgan conference.

So we're moving to be in full position. There's a whole range of potential scenarios for timing. I can't speak to that. We'll move as swiftly as we possibly can. There's some sort of physics involved that you can't overcome. You just have to do certain steps, but we'll be as prepared as you possibly can be to move once the data are unblinded. We're pretty hardwired for analysis, interpretation, preparation of information. And we are providing material to the FDA in a sequenced and phased way. It's not going to come all at once at the last minute. Part of their trick for making this accelerated process work is to have information come in more like a rolling submission.

I don't know if it's formally called that, but more like a rolling submission where certain pieces that can be provided earlier than the clinical data will get provided earlier so that they can have their teams reviewing those parts and then let the final clinical data be the dispositive piece towards that.

And is that process already started because you have visibility to when the data...

I'm not going to speak to the details of what we're doing on any given day. I think we just generally wouldn't share that. But I can just tell you it's pretty well laid out what needs to be submitted when in what form and so on. And again, as I mentioned, I think the FDA, we have every reason to believe that they're highly incentivized to want to do this swiftly, to do it rigorously but to do it swiftly as well.

Okay. Then on the first-line trial that we touched on -- started to touch on a minute ago, but just I think the trial -- you announced that the trial was initiated in November. Have patients been dosed yet? And how should investors think about kind of the enrollment time line there? Obviously, it was quite fast in second line. But there's far less -- they're not great options in the first line, but there are options in first line. So how should investors think about likely enrollment timeline?

Yes. We haven't commented about enrollment yet, but we initiated the trial, which for us means operationalizing, which a number of months involved in doing that, getting sites set up getting through IRBs and doing all the mechanical pieces.

Again, there's a physics associated with that, that you can can't just skip over I'd love to be fully enrolled by now, but that's not the case. Once that platform is fully up and running, meaning that there are sites in the U.S. and ex U.S., it will enroll quickly. The demand -- sadly, the demand for access to daraxonrasib is extremely high. We hear about this on a daily basis. Patients across the spectrum of lines of treatment, they want access and their physicians want access. So we don't anticipate any barriers to enrolling that trial, but don't have any high-resolution information today.

I think one of the concerns that's come up just broadly in oncology is often is concern about crossover and particularly drugs that patients are very excited about once they're approved in the second -- in a later line that patients who find themselves randomized to not receive the drug that they really wanted kind of figure out a way to get to that second-line therapy. How is that dealt with in the first-line design, particularly because you could have fairly rapid approval here?

Yes. I mean it's an issue. It's sort of an intellectual conundrum that you want drugs to be very effective and to provide benefit to patients, but then we want to keep patients on an inadequate standard of care as a comparator group because we have to do a formal comparison.

I mean that's just -- there's no way to sort of reconcile those. It's just a fact, those 2 are intention, that particular trial is designed with 2 treatment arms that are experimental and then the control arm. So if you're randomized in that trial, if you enter that trial, you have a 2/3 chance of getting access to daraxonrasib. That's better than a 50% chance. But if you are randomized to chemotherapy, it's not so much that patients may look for an alternate treatment because generally, there aren't really alternate treatments, but they may choose to get chemotherapy in their home setting.

And if they travel a distance to go to a clinical trial and then find out that they're getting the same treatment that they might get at home, many patients, I'd be one of those, would prefer to get it at home. So we've learned from the ongoing 302 trial. We learned early on that some patients did that. They might travel across the country to get a slot in a clinical trial. And if they don't get the experimental treatment, they might quit the trial and go home to get chemotherapy. That's one form of sort of drop out, if you will. And we've discouraged that. We've encouraged investigators to treat people who are living within their locale to minimize that chance.

And that's actually helped quite a bit. In terms of accessing daraxonrasib, if it's approved for second line, well, it's a conundrum. Again, the approval would be on label for whatever the label says. I can't speak to that. We don't have a label yet, but whatever the label says is what we'll be able to support. And if that doesn't include first line, that doesn't mean patients and their doctors won't try to find a way to get access to it. And if somebody has had some form of chemotherapy, even if it's less than a full course of chemotherapy, they may find a way to declare themselves having been previously treated and therefore, eligible for second line. I think that's really a point that you were making, long-winded way to get to that. And that may happen. We have heard that, that will happen. We can't really address it. All we can do is promote to label. We can't even really support those doctors if they do that. But I understand it. I mean, we can all understand it. I'm sure the FDA understands it, too. They're humans as well.

Our approach to it, your real question, what are we going to do about it is to enroll as quickly as we can into the Phase III trial here in the U.S. before the product is approved and also build a footprint outside the U.S. where daraxonrasib would not be available until there are approvals in Europe, which would come outside the U.S. after the U.S. And we think from an operational point of view that we'll be able to squeak by and get this done and that there may be some degree of drop out, there may be some degree of crossover, but that it would not impact our trial given the way that it's designed and operationalized.

I think you've a number of occasions of the importance, right, of the second-line trial that we're about to see that you think it's a very high strategic importance that you show a survival benefit. How important is that in the first line, which gets?

Well, we assume it's the same in first line. We're not sure the FDA would be excited about having something less than overall survival. And outside the U.S., to be honest, in pretty much every country of the world, and overall survival is very important for approval and for terrible things like pricing.

So we'd like to show overall survival in anything that we can before it's too late. Once we show those benefits, it's going to be hard for our trials, and it's going to be hard for everybody else's trials, too. I mean it will -- that's the moat that gets created, sets a whole new standard that people have to overcome.

So there's a lot of value in establishing OS, starting with patient value. I mean we really do -- that's what matters to us is establishing real benefits for patients. And that will affect uptake in the market. That will affect how long people can benefit from it. And it sets a new standard and barriers for approving new products. That's just the way things work. Again, we can't overcome that. I would mention here that that informally, anecdotally, we have heard from a number of investigators that they have seen daraxonrasib continue to perform in some patients who had actually progressed radiographically, but we're still doing well clinically.

So just a reminder, a patient has a 10-centimeter tumor and you drop it down to 1 centimeter, that's a PR. And if it goes up to 1.2 centimeters 6 months later, that's suddenly disease progression. That's the criteria that are established under RECIST. And yet the patient may not even know about that other than being told you have radiographic progression. So in some cases, some of our investigators have said, "Hey, you're doing well on this drug. And even though your CT scan says you progressed, let's see what happens. And in some of those cases, patients have stayed on for a very long time afterwards for a very long time.

Now I can't really report on that quantitatively. I don't know what the numbers are. We haven't formally studied this, but we have heard it from a number of investigators. And now for a number of trials we have underway, we have encouraged physicians who are running sites to consider treatment beyond progression for those patients who are doing well on drug. Biologically, it makes sense. If a tumor is driven by RAS and you're putting the brakes on RAS, yet the tumor somehow finds a way to break through, does it make sense to take your foot off of the brake?

I mean that's just going to cause explosive regrowth. And so this concept makes sense to us even though we were kind of caught off guard by it when several investigators introduced us to it. We'll just see over time whether we can generate enough information to be able to formally declare whether or not that's a benefit.

And talking about the encouragement in your ongoing trials, does that include the 302 trial...

It does not include the 302 trial.

Is there allowed treatment.

They are not. No. So the 302 trial is strictly treat to progression. And the reason for that is we didn't know about this when we designed the trial and initiated it, and you can't change the criteria halfway through the trial. So that trial stays traditional. But in other trials, we've encouraged investigators to consider treatment beyond progression.

Okay. In first-line pancreatic, you're also starting 2 trials with the G12D inhibitor with chemo, but then also -- or that trial is, I guess, being initiated right now, but then also the daraxonrasib combo. Just how do all these trials fit together for that, call it, roughly half of the pancreatic patient population that has a G12D mutation?

Yes. Well, we're not taking a parsimonious approach to this because pancreatic cancer is such a devastating disease. Every patient is different. And it's better to provide multiple options to each patient, which also means potentially providing at least one option to every patient.

We also don't know how a mutant selective inhibitor behaves differently from a RAS MLD inhibitor. We know the potential benefits of each of them, but we just don't know how they stack up against each other. And we know that there are biases, there are assumptions in the field about it based on prior targeted therapies, but we don't know which assumptions are true.

So our approach is to be agnostic and to go test every compelling strategy that we have in our hands. And you've mentioned several different ones, daraxonrasib monotherapy, daraxonrasib combination with chemotherapy, zodonrasib, our G12D selective inhibitor, combines very well with chemotherapy because it's so well tolerated. In fact, most investigators have told us they can't differentiate between zodonrasib and placebo that their patients can't. The funny story is a patient who gets put on zodonrasib, they come into the office very sick. They start zodonrasib, they leave. They come back a month later. They walk in the door carrying a tennis racket, they're saying, I feel great. Oh, by the way, doc, am I on placebo? And that's because they're not experiencing side effects that tell them that they have an active drug even though they're getting the clinical benefit.

So that's quite remarkable. That's very uncommon in oncology drugs. It means that we can design trials around zodonrasib with a placebo, a blinded placebo strategy as opposed to taking a drug versus not taking the drug. Everybody knows if they're on daraxonrasib, but they don't know if they're on zodonrasib. So we can design placebo-controlled trials.

Zodonrasib is being evaluated in combination with chemotherapy in first line. And the way the trial works is it's chemotherapy plus zodonrasib versus chemotherapy plus placebo, and it's blinded to the patients and it's blinded to the investigators and to us. So that's that first trial that you're alluding to. That's the 305 trial, which we've initiated, and we're excited about it. We also will initiate a second trial with zodonrasib, which is combining it with daraxonrasib, as you mentioned. And that brings potentially 2 different ways to hit the mutation, the mutant driver as well as any other potential escape mutants that could come up in the setting of a mutant selective inhibitor. And that combination is exciting. We expect to initiate that later this year and to share data that support that strategy.

And can that be a simplistic design just against chemotherapy? Or do you need to, within that trial, kind of really define the contribution of the components?

Yes. The contribution of components is a regulatory topic. There are various ways to deliver the information the FDA needs to be able to convince themselves that the combination is delivering more than either agent alone. We, of course, will have lots of monotherapy data with daraxonrasib. We have not reported a zodonrasib monotherapy cohort in the first line. So we haven't reported those data, but there are various ways to solve for that. It doesn't necessarily have to be within the Phase III trial itself.

Okay. On your earnings call the other day, I think a number of investors kind of came away with the conclusion that you seem to be a little less aggressive about pushing daraxonrasib forward in first-line lung cancer. But then I think -- but also you were disclosing a first-line plan for the G12D inhibitor. You want to talk about kind of how those fit together and how that decision-making process is happening as to what to do in first-line lung.

Yes. They were sort of -- they're unrelated, even though I understand why they get related to each other, that really were unrelated decisions. daraxonrasib, we mentioned in the fall, we need to conduct further dose optimization. Daraxonrasib is not quite as well tolerated in lung cancer as it is in pancreatic cancer for reasons we don't fully understand.

So we need to make sure we get the dosing just right, whereas with -- in pancreatic cancer, we were able to just push it up to 300 and patients do pretty well with that. So that's not really news, and we're continuing that dose optimization in combination with platinum-based chemotherapy and keytruda pembrolizumab. So that work is ongoing. At the same time, everybody knows, we initiated a partnership with Summit Therapeutics around their compound ivonescimab, which is really the leading bispecific anti-PD-1, anti-VEGF antibody. And we initiated that last -- in the second half of last year, but the trial took some time to get started.

We now have that trial underway. We're dosing patients with ivonescimab plus our RAS(ON) inhibitors. And it's a really exciting thing to take the leading RAS(ON) inhibitors, the leading bispecific and put them together. It makes very good sense to do. So we're glad that's now underway. Because it's underway, and we're still dose optimizing daraxonrasib, we're just not in a position to declare definitively what we'll do and when we'll do it. We're at an interesting transition -- potentially transition moment with these bispecifics coming along and potentially threatening pembrolizumab as ultimately as a standard of care. And so when do we make the switchover?

Zodonrasib is a little bit of a different situation because zodonrasib is so well tolerated, we could combine it with other things, and we just don't see any issues associated with it at all. So there's not really much dose optimization to go with to deal with. And so therefore, we just decided to move forward with pembrolizumab and the KEYNOTE-189 regimen.

So yes, 2 different strategies. They're both tailored to the specifics of the situation.

The other lung cancer disclosure you had the other day was that you quoted the fully enrolled second-line plus cohort for the G12 pembrolizumab. Can you -- there is a -- unlike pancreatic cancer in lung cancer, there is a history of targeted therapies with accelerated approvals on single-arm data. Is that a pathway that is viable with that cohort?

Yes. I mean we expanded that because we saw compelling results with zodonrasib and have continued to see compelling results. And so we decided to expand that cohort to make it of a size that we could draw real conclusions from and potentially give the FDA the opportunity to consider that as well.

And that enrollment has gone well. Zodonrasib is a highly attractive compound, as I mentioned, for investigators and patients. And so they enroll it super quickly, and we'll see what happens there.

And I think based on the commercial performance of the G12C inhibitors and some other launches in later-line lung cancer, I think a lot of investors have grown kind of skeptical of what the actual commercial opportunity is in later-line lung cancer. Do you agree with that, that it's more modest? Or do you think people are missing something?

I think there are characteristics of those early compounds. They had -- they were breakthrough compounds, no disrespect to them. They opened up a field, but they delivered ultimately the median PFS in second-line previously treated lung cancers in a ballpark of 5.5 months. It's just not a whopping difference compared to chemotherapy. And I think people are disappointed for that. I think we've seen significant improvement with later generations of RAS inhibitors. We're most familiar with the RAS(ON) inhibitors that we've created, and we feel confident that they can deliver real impact compared to inadequate standards of care like daraxonrasib.

Okay. And then your promising CRC data. How much should investors expect -- there's a lot of different combinations that are happening in your CRC work. How much should investors expect this update to be, hey, we're seeing some interesting signals, but there's still a fair amount of optimization figuring out how this fits together versus a more complete picture of this is the path forward.

I can't provide much guidance about that. I mean we generally try not to tease about things. And we've indicated we think that we're going to be able to see a path forward in colorectal cancer, and we'll share that information when we have it, and then you can make a judgment about what the answer to your question is.

Okay. Unfortunately, we're over time, so we're going to cut it off there. But thanks a lot, Mark for joining us both everybody in the room and on the webcast.

Thank you very much.

Good day, and thank you for standing by. Welcome to Revolution Medicine's Fourth Quarter 2025 Earnings Conference Call.

[Operator Instructions]

Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today, Ryan Asay, Senior Vice President of Corporate Affairs. Ryan, please go ahead.

Thank you, and welcome, everyone, to our fourth quarter and full year 2025 earnings call. Joining me on today's call are Dr. Mark Goldsmith, our Chairman and Chief Executive Officer; and Jack Anders, our Chief Financial Officer; Mr. Steve Kelsey, our President of Research and Development, Dr. Alan Sandler, our Chief Development Officer; Dr. Wei Lin, our Chief Medical Officer; and Anthony Mancini, our Chief Global Commercialization Officer, will join us for the Q&A portion of today's call.

Before we begin, I'd like to remind everyone that certain statements we make during this call will be forward-looking because such statements deal with future events and are subject to many risks and uncertainties. Actual results may differ materially from those in the forward-looking statements. For a full discussion of these risks and uncertainties, please review our annual report on Form 10-K that is filed with the U.S. Securities and Exchange Commission.

This afternoon, we released financial results for the quarter and full year ended December 31, 2025, and recent corporate updates. The press release is available on the Investors section of our website at revmed.com. With that, I'll turn the call over to Dr. Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive Officer. Mark?

Thanks, Ryan. Good afternoon, and thank you for joining us. We will keep our prepared remarks brief today highlighting the substantial progress and growing momentum for our pioneering RAS(ON) inhibitor pipeline and outlining several important priorities for the year ahead. Jack Anders will summarize our financial results, along with financial guidance for the year ahead. At Revolution Medicines, we remain steadfast in our commitment to revolutionizing treatment globally for patients living with RAS-addicted cancers through the discovery, development and delivery of innovative targeted medicines directed against these common mutational drivers of human cancers.

As pioneers in the RAS targeting field, with a singular focus on RAS-addicted cancers and a great deal of validating data behind us, we are well positioned to continue building on important scientific drug discovery and clinical breakthroughs that have the potential to change standards of care for patients. Our efforts throughout 2025 strengthened our leadership position as we advanced our robust pipeline that includes 4 novel investigational drugs that target the major oncogenic RAS drivers: daraxonrasib, our most advanced program, a groundbreaking RAS(ON) multi-selective inhibitor; elironrasib, a differentiated, highly active and well-tolerated RAS(ON) G12C selective inhibitor; zoldonrasib, an innovative, highly active and well-tolerated rats on G12Z selective inhibitors; and our newest clinical compound, RMC-5127, a promising RAS(ON) G12V selective inhibitor. We have 8 ongoing or planned Phase III registrational trials and extensive clinical experience to date with more than 2,500 patients having received 1 or more of our RAS(ON) inhibitors in the aggregate.

This clinical work has built upon the foundation of a strong discovery and preclinical platform that continues pushing the boundaries. Our virtuous cycle of innovation fuels how we discover new ways of targeting RAS through our highly productive tri-complex platform, develop novel investigational drugs through robust and parallel clinical development plans and systematically expand our commercialization and operational capabilities to deliver potential new therapies to patients globally.

I'll provide an update on our clinical activities in pancreatic cancer, our most advanced clinical program. With more than 90% of pancreatic cancer is being RAS driven, there's a profound need for RAS targeted therapies, which we aim to address with multiple registrational trials underway or that we plan to initiate in 2026. Daraxonrasib, our pioneering RAS(ON) multi selective inhibitor has shown an unprecedented clinical profile across RAS mutations and lines of therapy, either alone or in combination with standards of care.

Our broad conviction around daraxonrasib was further strengthened by the U.S. FDA designation of daraxonrasib as a breakthrough therapy and its award of one of the agency's first commissioners national priority vouchers based on its potential to address significant unmet needs in pancreatic cancer. We are currently evaluating daraxonrasib in 3 randomized registrational studies in pancreatic cancer across lines of therapy. RASolute 302, a randomized registrational trial evaluating daraxonrasib monotherapy in second-line metastatic disease. As a reminder, RASolute 302 employs a nested trial design, the largest population of patients with tumors carrying a RAS G12 mutation in the core and the expanded population that includes patients with tumors carrying other RAS mutations and tumors without a detected RAS mutation.

The trial employs hierarchical testing to maximize the probability of success in the core population and potentially enable a broad label, not requiring biomarker testing. With global enrollment now complete, we expect a readout to occur in the first half of 2026. In earlier lines of therapy, 2 randomized registrational studies were recently initiated. RASolute 303 is evaluating both daraxonrasib monotherapy and daraxonrasib in combination chemotherapy in first-line metastatic disease, evaluating both monotherapy and combination approaches may enable treatment optionality for physicians and patients. RASolute 304 is evaluating daraxonrasib monotherapy in the adjuvant setting in patients with resectable disease after receiving conventional surgery and perioperative chemotherapy. The data we've collected to date support our strong conviction that these studies have the potential to establish new global standards of care across lines of treatment for patients living with pancreatic cancer.

Zoldonrasib, our covalent G12D selective inhibitor is another first of its kind compound that has shown a highly differentiated safety and tolerability profile. We recently disclosed encouraging initial data from patients with metastatic pancreatic cancer receiving first-line treatment with the combination of zoldonrasib and FOLFIRINOX. The initial safety and tolerability profile for the combination of both treatments was largely consistent with the well-known profile of modified FOLFIRINOX alone and a high zoldonrasib dose intensity was maintained. As of the data cutoff date, 63% of patients achieved a partial response, either confirmed or pending confirmation. The disease control rate was 95% and the vast majority of patients remained on treatment.

With these data reinforcing confidence in this compelling G12D selective inhibitor, we plan to advance 2 first-line registrational combination studies this year. Today, we're pleased to announce that RASolute 305 has been initiated. RASolute 305 is a randomized, double-blind, placebo-controlled trial that is evaluating zoldonrasib in combination with investigators' choice of either gemcitabine, nab-paclitaxel or modified FOLFIRINOX chemotherapy compared to investigators' choice of chemotherapy with placebo. RASolute 309 will evaluate the RAS inhibitor doublet combination of zoldonrasib plus daraxonrasib, and we plan to initiate this trial in the second half of 2026. We plan to share clinical data from the initial trial of the zoldonrasib plus gemcitabine nab-paclitaxel combination and the zoldonrasib plus daraxonrasib, RAS(ON) inhibitor doublet combination in PDAC at one or more medical meetings this year.

A second area of focus in which we've shown continued clinical advancement is non-small cell lung cancer. With approximately 30% of non-small cell lung cancers harboring RAS mutations, including 18% with non-G12C mutations, this tumor type remains a key priority. To date, we've shown encouraging initial safety tolerability and antitumor activity in patients with RAS mutant lung cancers across our 3 lead compounds that supports their potential to establish new standards of care and we are building a set of registrational trials accordingly. RASolve 301, our global randomized trial evaluating daraxonrasib monotherapy in previously treated patients continues enrolling patients across sites both in the U.S. and globally. We anticipate substantially completing enrollment this year.

We also expect to disclose our plans for advancing daraxonrasib combination therapy in first-line non-small cell lung cancer this year. With zoldonrasib and elironrasib, we've reported highly encouraging safety, tolerability and antitumor activity data from previously treated patients with lung tumors harboring RAS G12D or G12C mutations, respectively. The zoldonrasib monotherapy expansion cohort is fully enrolled. And earlier this year, zoldonrasib was awarded breakthrough therapy designation, making it our third RAS(ON) inhibitor to have received this distinction.

Building on these milestones, we are preparing to initiate RASolve 308, a first randomized registrational trial of zoldonrasib in combination with standard of care as a first-line treatment for patients with metastatic RAS G12D non-small cell lung cancer.

For elironrasib, we continue to evaluate this compelling G12C selective inhibitor that has demonstrated a differentiated clinical profile in both G12C inhibitor naive and G12C inhibitor experienced lung cancer patients. We've reported encouraging results with monotherapy or in combinations with either pembrolizumab or as part of a RAS(ON) inhibitor doublet with daraxonrasib. And as we consider multiple approaches, we plan to share an update on our registrational strategy for elironrasib this year.

The third area of focus, colorectal cancer, remains of high interest and engagement for the company. Approximately 50% of patients with colorectal cancer, harbor a RAS mutation. Given the genetically complex and heterogeneous nature of the disease, combinatorial approaches are key to maximizing clinical impact. We have a range of studies underway, including evaluating RAS(ON) inhibitor doublets and evaluating RAS(ON) inhibitors with current standards of care and with other novel approaches. We plan to provide visibility into combination data in colorectal cancer this year as we work toward prioritizing registrational opportunities.

Our development efforts include several clinical collaborations studying our RAS(ON) inhibitors with new targeted therapies in clinical development. Our collaboration with Tango Therapeutics is studying our RAS(ON) inhibitors in combination with avopimetastat, Tango's MTA cooperative PRMT5 inhibitor in patients with tumors carrying both a RAS mutation and MTAP deletion. We also recently entered into a clinical collaboration with Bristol-Myers Squibb to evaluate daraxonrasib in combination with [indiscernible], MTA cooperative PRMT5 inhibitor in patients with pancreatic cancer whose tumors carry both RAS mutation and MTAP deletion. This collaboration extends our commitment to evaluating novel targeted agents such as PRMT5 inhibitors that may be appropriate to combine with RAS(ON) inhibitors in some settings.

Our ongoing collaboration with Summit Therapeutics is evaluating our RAS(ON) inhibitor with Summit's PD-1 VEGF bispecific antibody, ibalizumab, across multiple solid tumor settings. The first patient in this trial was recently dosed. We recently brought our fourth RAS(ON) inhibitor, the RASON-G12V selective inhibitor, RMC-5127 into the clinic and announced that the first patient had been dosed in the first-in-human trial. We expect to identify a recommended monotherapy Phase II dose for this compound in the second half of 2026.

As leaders in developing treatment strategies for patients with RAS-addicted cancers, we recognize the importance of continuing to invest in new approaches that advance the science and have the potential to further transform treatment paradigms. Our discovery team continues pioneering novel approaches including an innovative new class of RAS(ON) inhibitors from our laboratory designed to overcome RAS-driven drug resistance and thereby extend the clinical benefit of RAS(ON) inhibitors.

As we disclosed in January, in preclinical pancreatic cancer and non-small cell lung cancer models that had developed resistance to daraxonrasib, treatment with a representative compound from this new class, RM-055 drove deep and durable regressions. This year, we plan to share more information about this new class of compounds at a scientific meeting and later in the year to begin clinical development of a first compound from this class as our fifth investigational clinical stage RAS(ON) inhibitor.

As late-stage programs, notably daraxonrasib advance toward possible commercialization, we are committed to building a world-class, end-to-end global oncology enterprise to deliver compelling targeted therapies to patients with RAS-addicted cancers. We have established a strong operational foundation to move with speed and agility to ensure a successful first commercial launch, initially focused in the U.S. market.

To that end, we have made key strategic hires to form a strong leadership team of professionals who have established track records and launched some of the most impactful oncology products in recent years. In addition to recently onboarding regional field sales leadership to support the U.S. launch recruitment for our first field sales team is now underway.

I'd now like to turn the call over to Jack Anders, our CFO, to summarize our fourth quarter financial results and forward-looking guidance. Jack?

Thank you, Mark. We ended the fourth quarter of 2025 with $2.03 billion in cash and investments. In 2025, we entered into our innovative and flexible strategic partnership with Royalty Pharma, which provided us access to up to $2 billion in committed capital under the terms of the agreement. We received the first royalty monetization tranche of $250 million in June 2025, and there remains an additional $1.75 billion and future committed capital under this arrangement.

Turning to expenses. R&D expenses for the fourth quarter of 2025 were $294.9 million compared to $188.1 million for the fourth quarter of 2024. The increase in R&D expenses was primarily due to increases in clinical trial and manufacturing expenses related to our multiple ongoing clinical development programs and an increase in personnel-related expenses and stock-based compensation expense associated with additional headcount.

G&A expenses for the fourth quarter of 2025 were $66.7 million compared to $28.2 million for the fourth quarter of 2024. The increase in G&A expenses was primarily due to increases in commercial preparation activities and personnel-related expenses and stock-based compensation expense associated with additional headcount. Net loss for the fourth quarter of 2025 was $364.9 million compared to $194.6 million for the fourth quarter of 2024. The increase in net loss was primarily due to higher operating expenses as described earlier. Net loss for the fourth quarter of 2025 also included specific noncash charges of $33.7 million in stock-based compensation expense, $12.6 million in noncash warrant expense related to a mark-to-market change in the fair value of warrants we inherited as part of our EQRx acquisition and $11.9 million in noncash interest expense related to the accounting treatment for our royalty pharma arrangement.

Full year 2025 financial results are available in our corresponding press release and also included in our Form 10-K that was filed with the SEC this afternoon.

Turning to financial guidance. We would like to note that we are switching the forward-looking financial guidance we provide from GAAP net loss to GAAP operating expenses for fiscal year 2026. Switch to GAAP operating expenses is intended to provide expectations on our anticipated level of spend for 2026 in a more straightforward and easier to follow manner. As GAAP net loss includes certain noncash items within nonoperating income and expense, such as the change in fair value of the warrant liability and noncash interest expense associated with our royalty pharma arrangement.

With that said, we expect full year 2026 GAAP operating expenses to be between $1.6 billion and $1.7 billion, which includes estimated noncash stock-based compensation expense of between $180 million and $200 million. The increase in expected GAAP operating expenses for 2026 is a result of the progression and expansion of our clinical development programs. In particular, the multiple ongoing and planned registrational studies we have outlined as priorities. We also expect higher expenses in 2026 as a result of increased commercial preparation activities as we continue to build and expand our organizational capabilities in preparation for becoming a global commercial-stage company. That concludes the financial portion. I will now turn the call back over to Mark.

Thank you, Jack. 2025 was a pivotal year for RevMed, and 2026 is poised to be one of substantial impact as we seek to create the industry-leading global targeted medicines franchise for patients with RAS-addicted cancers. We believe that each asset in our pipeline has the potential to transform the treatment landscape for these difficult-to-treat cancers. With key milestones across our clinical programs, advancing new programs to the clinic, continued investment in innovation and preparing for our first commercial launch, we are well set up for the future, building on our foundational achievements to date.

Of course, none of the work we do would be possible without the partnership and ongoing support of health care providers, patients and caregivers and investors and the remarkable dedication and efforts of RevMed employees. With that, I'll turn the call over to the operator for the Q&A portion of today's call.

[Operator Instructions]

Our first question comes from Jonathan Chang of Leerink Partners.

This is Albert Agustinus on for Jonathan Chang. I was just wondering, could you please share your thoughts or clarify on your plans to advance the daraxonrasib combination in first-line non-small cell lung cancer this year, are you still guiding towards the initiation of a registrational trial for in this setting?

Thanks, Albert, for your question. So I think you're asking about our plans for daraxonrasib in first-line lung cancer. We still have a high commitment to continue developing daraxonrasib in lung cancer, particularly in first line. Maybe Dr. Kelsey could comment on prior resolution answer to that.

The reality is that there are a number of options available to us. We continue to both dose optimize daraxonrasib in combination with the combination partners that you might expect us to use for that indication and also do efficacy testing to get the requisite proof-of-concept required to invest in a large base through trial. So as soon as we have that information and a plan to go with it, we'll be able to share it with you. And I think we've committed to providing more information on that during the course of this year.

Yes. And if I could just add, I think the other element to this, of course, is that we just started dosing patients with [indiscernible] in combination with our RAS(ON) inhibitors that obviously has fairly act on how we think about lung cancer.

Our next question comes from Brian Cheng of JPMorgan.

As we get closer to the top line for the second-line PDAC trial, what is your latest thought on the efficacy measure that we could get at the time of the top line and just curious if you can provide a bit more color on the rate of events towards this upcoming top line.

Brian, thanks for your questions. Of course, we've entered the period in which we indicated we'd be providing a disclosure. So I don't think we'll be able to give you higher resolution today, that doesn't seem like the right time to do that. It is an OS event-driven readout. And the study is powered for OS, but it's, of course, also overpowered than for PFS. So we'll have an interim read on that information. I don't think we'll be able to provide any expectations other than that we are directly comparing to standard of care and that will be the set of benchmarks that will be used in our analyses.

Our next question comes from Michael Schmidt of Guggenheim.

Congrats on all the progress. Mark, I had one on your ongoing implant studies in first-line pancreatic cancer. So obviously, there's a lot of excitement among physicians and patients in the pancreatic cancer community around daraxonrasib. We've heard from docs more recently that if approved, they think that over 90% of their second-line indications could go on daraxonrasib within months of approval. And so when you think about that, to what degree do you think daraxonrasib use in your first-line studies post-progression in the control arm could potentially impact [indiscernible] outcomes in RASolute 303 and 305? And how important is it to demonstrate OS in these studies in the first place?

Okay. I think I understand the question. To what extent does the availability of an approved daraxonrasib with a second-line label potentially provide complication with some form of crossover for patients from the chemo arm in the second-line study in the 302 study. There is some potential risk for that. Of course, the label would not necessarily indicate ability to cross over unless somebody was declared that they were now formally a second-line patient, we wouldn't be able to speak to what somebody might do off-label, but there is some risk associated with that. We have the ability to address that, both through timing. We're moving forward with that first-line trial, and it will be some period of time before to [indiscernible] review and potentially improve the product.

So I think during that period, we can probably establish some significant momentum and buffer against that concern. And the other contribution to solving that is geography. And we do expect that outside the United States, patients will enroll in the trial and contribute significantly and in those settings. It's not likely that the product would be approved yet during the early course of the study.

Our next question comes from Charles Zhu of LifeSci Capital.

Congrats on the progress. I have a couple regarding some of your ongoing partnered collaborations. First, can you talk about your decision to also combine pipeline assets with Bristol's PRMT5 inhibitor and how this kind of fits in context with your ongoing collaboration with Tango. And second, your collaboration with ivenezumab, at what point might you make go, no-go to decisions on later-stage clinical development with your pipeline assets? And how do you weigh not only the emerging combination data that you're generating, but also the broader landscape among the various HARMONY trials shaping out?

Thanks, Charles. I appreciate those questions. Really two different topics. One is PRMT5 inhibitors and why is this or support assessment of RAS(ON) inhibitors in combination with more than 1 PRMT5 inhibitor. To some extent, we had already established that precedence because we have an ongoing collaboration with both Amgen and Tango and the PRMT5 inhibitors appear to be emerging as a potentially important new [ property ] class of therapies for patients with MTAP gene deletion, so it makes sense for us to make that -- to make our compounds, which are differentiated and compelling and make them available to others who have PRMT5 inhibitors. This isn't really a signal or a vote on our part about any particular inhibitor. It doesn't speak at all to the work that's ongoing with Tango or Amgen. It's rather more of an inclusive approach and to allow [indiscernible] compounds to be considered in other context as well. With regard to the second question, which is [indiscernible] and how will we make decisions about when to advance into a late-stage trial probably the same way we make all such decisions. So it will be data driven.

It will depend on the context potentially this class of inhibitors could offer a significant advantage over the first-generation PD-1 inhibitors. There is growing value derivatives to support that. We don't have the definitive data yet and we are staying very much on the front lines of a combination of strategies involving IVO with our RAS(ON) inhibitors. So I think we'll be in a great position to make the decision with some data in hand.

Our next question comes from Marc Frahm of TD Cowen.

Congrats on all the progress. Maybe just first off on more of a bit of a housekeeping. Can you just confirm whether any event thresholds have been reached in 302 to trigger interim analyses yet or if just none of those have been hit yet. And then thinking more broadly about pancreatic cancer. Now you have several first-line trials either ongoing or getting started in the next handful of months. Just what is the kind of long-term vision you have for what the treatment paradigm in pancreatic cancer looks like in 4 or 5 years. How do daraxonrasib, zoldonrasib, chemo all get sequenced for maybe the typical patients.

Thanks for your question, Mark. I think I'll comment on the first one and then maybe Alan Sandler can comment on your question about sort of future landscape and future expectations for treatment paradigms. My comment is I don't really have any answer to your question. When the data are unblinded, that causes us to do an analysis, which then leads to a disclosure. And that's about all I can say to that. On your question about how does pancreatic cancer look a few years from now, Alan?

Thanks for the question. Well, I think we're -- we've said it very nicely with multiple studies to kind of a major say to what pancreatic cancer will look like in the next 3 to 5 years. with our early studies looking at second-line therapy with daraxonrasib moving into the first-line setting also with daraxonrasib looking at it both with respect to monotherapy, but also potentially in combination with chemotherapy and then we're doing that with a more specific agent such as zoldonrasib [indiscernible] and looking at that as well in combination with chemotherapy versus chemotherapy in the frontline setting, but also the novel ability to combine it with daraxonrasib also in that first-line setting.

This will provide patients with the optionality in first-line setting to actually potentially have a chemotherapy-free opportunity as well as building upon the results that have been seen with chemotherapy alone. In addition and potentially even more importantly, we have the opportunity to impact patients who have potentially curable pancreatic cancer by conducting, which is our adjuvant study for those patients who have had resected cancer in perioperative therapy. So we really are covering the gamut of patients of pancreatic cancer from second-line therapy all the way to resectable and potentially curable pancreatic cancer. And I think that covers probably 3 to 5 and maybe even a year or 2 beyond that as well. And then in addition, of course, as Mark mentioned earlier, there are other agents in our pipeline that we'll be looking at as well that will also potentially have an impact.

Our next question comes from Alec Stranahan of Bank of America.

With the ivinesumab study now dosing patients, I guess could you maybe speak a bit about the study design and which tumor types and lines of therapy you expect might enrich in the study as it enrolls and longer term, how is this combo maybe emblematic of how you're hedging your RAS therapies alongside potential shifts in standard of care.

I think Dr. Lin, our Chief Medical Officer, can comment on what's our approach to ivo and the initial Phase I context.

Thanks for the question. So like before been pointed out has been initiated, and that's the [indiscernible] study and involve all 3 kind of stage RAS(ON) inhibitors, that's daraxonrasib, zoldonrasib as well as elironrasib that covers all RAS, the G12D as well as the G12C population. There's a standard dose escalation involving [indiscernible] in combination with daraxonrasib, in combination zoldon and in combination with [ elironrasib ] and the dose escalation is standard all solid tumors and will be helped to define the safety and preliminary activity across some [indiscernible] major solid tumors that's going to be seen. And then once the dose has been defined and safety has been cleared, there is dedicated expansion cohort across the 3 major DCs of interest both Summit as well sa [indiscernible] medicine side. And it really is focusing on the 3 diseases that we have focused on today that include pancreatic cancer, non-small cell lung cancer and colorectal cancer.

And with -- do you want to repeat your second question, which has to do with, I guess, hedging how treatment landscape may evolve in the context of ivo?

Yes, just broadly, how you're thinking about combos as standard of care across these treatment setting.

Yes. Well, I think we're not holding anything up. We're certainly developing things in combination with pembro to the extent that, that makes sense to do, but we also have to recognize that field is evolving. And so we're right on the leading edge of it in collaboration with Summit to make sure that we're the first to evaluate RAS inhibitors and particularly class leading RAS(ON) inhibitors in combination with ivo, and we'll learn a lot.

With regard to non-small cell lung cancer, where pembro really is a dominant standard of care in most parts of the world, it will take more to knock that off and for that -- for there to be a real change and that will be up to go to prove itself, which is currently work that's underway. In the GI tumors, there's much less of a precedent here and the combination of a PD-1 and a VEGF inhibitor in the same molecule really opens up a real significant opportunity there.

And again, to be the first RAS inhibitors for the versions of those tumors in combination with ivos is an exciting thing to do. So we're playing all the time sort of like our overall strategy, everything everywhere all at once. And that's pretty much what we have to do in a rapidly evolving environment.

Our next question comes from Asthika Goonewardene from Truist.

I want to kind of go back to Albert's question at the beginning. Specifically on daraxonrasib and frontline non-small cell lung, I guess in previous calls -- earnings calls, we've talked about -- and you pointed out how pembro plus chemo is a backbone therapy and how it makes a lot of sense to consider that in combination with daraxonrasib. But when you talked about other options today, I wanted to just get a little clarity here. When you talk about other options, do you mean other PD-1s in combination with chemo, are there mechanisms like maybe involving PD-1 and CTLA-4 or are you thinking -- are you considering chemo-free options here for the ideal regimen you want to take daraxon into frontline non-small cell lung.

I think that was really in reference to first-line lung daraxonrasib and whether it should be combined with pembro and chemo or whether potentially ivo emerges during that period of time. I think that was the context for that narrow answer that we're now evaluating ivo, and so we'll have some of that information. But in the meantime, as Steve had articulated, we are doing -- continuing the dose optimization and efficacy analysis of daraxon plus pembro plus schema, the KEYNOTE-189 context. So those are running in parallel, and that will put us in a good position to to make the best decision.

Got it. If you can speak a quick one in. Any thoughts on whether you would use your commissions prior to review voucher for second-line PDAC when we had the RASolute 302 data in hand?

What's the question?

[ CMPV ] will be used for second-line PDAC?

I see. Yes, I think that's been made clear that it wouldn't really make sense to hold back the [indiscernible] was awarded on the basis of largely second-line and third-line data that we have shown publicly and shared with the FDA. And so I can't really see a scenario in which we wouldn't be operating under the CMPV in that second-line 302 data readout context.

Our next question comes from Laura Prendergast at Stifel.

In a recent public appearance, Mark, you brought up the concept of treating beyond progression in PDAC from the angle of patients progressing under daraxonrasib and [indiscernible] amplification of the RAS target Considering a pretty unique consideration in oncology where [indiscernible] the drug upon progression of PDAC [indiscernible] in the patients. [indiscernible] you go for some questions at our end. First, our investigators on the Phase III studies, the first and second on power encouraged [indiscernible] reprocessing is allowed for any protocols and you...

Since I could only hear every other word you're saying I'm going to have to sort of infer the question was about treatment beyond progression. We have made the comment that we've heard a number of anecdotes from investigators who have chosen to continue treating patients based on clinical criteria, even in the face of some sort of radiographic progression. And in that context, they've observed a number of patients who continue to do quite well on daraxonrasib for even long periods of time. And the biological context for that is that RAS doesn't disappear as a driver, it's the driver before we treat with a RAS inhibitor. It's the driver well. We're treating with the RAS inhibitor, and it's a driver -- actually stop treating with a RAS inhibitor. And so in reality, probably doesn't make much sense to discontinue if a patient is continuing to benefit and that that set of observations that we've heard syncs up nicely with that underlying biology. So -- but we don't have enough quantitative data to really say anything definitively. We're really giving you anecdotal comments here and theoretical comments, but now we'd like to collect some more data to determine if that really does establish an additional benefit over and above the benefit they've already received at that point in time.

That's my general comments, but I don't know what the actual question was. Can you clarify what you were specifically asking beyond that?

Yes. So specifically, as it relates to study protocols, was there any restrictions on how much -- on whether or not this is a possibility on the first line or second line Phase III? And then how you guys think this could impact overall survival of those studies?

Yes. Okay. I do understand the question now. So did we formalize this in the 302 study versus other studies? It's not in the 302 study because that study was already too far underway to make that modification that would be difficult to do in the middle of the study. And so progression beyond -- treatment beyond progression was not permitted, is not permitted in the 302 study. But as other studies come online, we've encouraged investigators to evaluate that possibility and where it makes sense to continue treatment beyond progression, particularly in the earlier line studies, and so we'll be able to generate a lot more information in those contexts.

Our next question comes from Jay Olson of Oppenheimer.

Congrats on all the progress. Since you're making a lot of headway in PDAC and non-small cell lung cancer. Can you talk about your vision and strategy in colorectal cancer? And how are you prioritizing the CRC opportunity for RevMed? I CRC an area that you would prefer to focus on with partnerships, for example, in combination with ivinesimab? Or is CRC something that you plan to pursue independently and from a BD perspective, would you consider in-licensing some molecules that have synergy with your RAS portfolio so you wouldn't need to rely on partnerships in CRC?

Yes, Jay, thanks for your question. Maybe Steve Kelsey can just comment in general on our approach to CRC and then if there's anything left on [indiscernible] at the end, I can come back and comment on it.

Yes. I mean colorectal cancer has never been deprioritized. We -- from -- right from the very first right from the start of the daraxonrasib over [ RAS dose ] escalation studies, we included patients with colorecal cancer. I think what we found, which was hardly surprising because a number of other people have also found this both for and since the colorectal cancer is an incredibly complex and heterogeneous disease with multiple subclones. Each of those clones often containing multiple genetic abnormalities. And as a result, what happens is that -- two things happened really. One is the overall response rates are lower than they are traditionally in the other RAS-driven diseases, which makes rapid decision-making of our future clinical development more complicated because you have now you have to wait for somewhat longer-term readouts like PFS.

And secondly, it's an obligatory -- when it comes an combination play, you really -- there really are no opportunities for developing a single agent in advanced colorectal cancer. In the late-stage colorectal cancer after chemotherapy failed, it's such a heterogeneous and genetically complex disease unique combinations.

And in earlier lines of therapy, you really need to combine with combination chemotherapy, which is standard of care. So it becomes more difficult and more time-consuming to reach a point where there's a clear path forward into pivotal trials. And I think that's what we have found, and it's got nothing to do with prioritization. It's got -- it's really down to the biology of the disease and how that translates into early-stage clinical trials.

And with regards to methodology, I mean our philosophy as a company is that we have made the decision to be a stand-alone global organization, and we are not looking to change that really based on disease or histotype. There may be opportunities for doing studies in collaboration with partners if the right partner if we believe that's the right combination and we have the right partner, we may choose to do with -- as part of a clinical collaboration or maybe even as some other type of business arrangement. But right now, that's not the preferred or even the base case plan. Our plan is to figure out which combinations involving a RAS(ON) inhibitor can make the biggest impact on colorectal cancer and prosecute those to registration.

I think your answer covered it pretty darn well. Maybe the one last little piece is would we bring in additional compounds into our pipeline. And that's always possible. We have a very robust process by which we evaluate other people's assets. We receive a lot of inbound proposals. And occasionally, we reach out to somebody else to look to learn more. So that's all just the practical considerations. The fundamental points I think Steve made are the fundamental points.

Our next question comes from Leo Timashev from RBC.

I wanted to ask a little bit on RM-055 in that class of molecules. I guess does this address secondary mutations? Or is it really only work directly on RAS mutations themselves. And I guess said another way, do you think you'll ultimately need to be selecting patients that might be amenable to this? And then just based on some of the preclinical work you've shown, it looks like it drives a very deep responses even relative to daraxonrasib. So are you seeing this ultimately be positioned as a next line option? Or can this be something that ultimately replaces and is a better daraxonrasib?

Yes. Thanks, Leo. Appreciate the question. All interesting ideas. I think that will become a little bit clearer when our scientific team has a chance to present more formally and in a more fulsome way at an upcoming scientific meeting. The one thing I'll say biologically is that point mutations have not emerged as the major form of resistance for daraxonrasib. What has emerged is reactivation of the RAS pathway through other means, typically amplification of the original mutant allele through increased signaling, for example, through RTKs to increase flux through the pathway and so on. And so daraxonrasib seems to do generally a very good job of suppressing new oncogenic mutations that might have otherwise emerged in the sending of a selective mutant selective inhibitor. So that really isn't the primary problem that we're trying to address or that the team had as his mission in developing this new class of inhibitors. But more to come. Stay tuned. Thanks for the question.

Our next question comes from Ami Fadia from Needham & Company.

This is Poorna on for Ami. Just wanted to understand how soon can you get to commercialization of data in case the first interim is positive? What are some of the aspects within the commercialization preparations that you still need to work through.

Thank you for those questions. So I think you're asking about what if we don't repair and what does the timeline look like? I think Anthony can step into that.

Yes. Thanks for the question. I think we're really pleased with how our launch ready as planned, we are advancing, and we continue to add highly experienced and talented members of the team, and we're really achieving broad organizational readiness led by the U.S., but also in Europe and in Japan. So we're really pleased with the launch readiness across the board. As Mark alluded to in his prepared remarks, that launch readiness in terms of the U.S. The first launch is actually proceeding quite well with leadership teams in place across commercialization and cross functions field-based leaders across med affairs, market access, marketing and sales. And as Mark mentioned as well, we've now initiated the posting of our further extension of our field-based teams, our sales team. So we're really going to be pleased with how with how the launch of [indiscernible] overall is coming together. And certainly, as we get closer to filing and launch, we'll provide some more color there.

Our next question comes from [indiscernible] Patel of Wolfe Research.

I guess how should we think about the disclosure of the pivotal update here in second line pancreatic if for any reason, you missed the interim PFS analysis and that does not cross the prespecified boundary. Would you expect to provide an update at that point? Or would you just wait for the OS driven readout thereafter?

Well, thanks for your question. I don't think we can give you much of an answer to that question right now. We'll see what the data show and decide what we consider as appropriate disclosure at that time. Just a reminder, it's OS event driven. It's powered for OS, which means it's more powered for PFS. So the possibility that it doesn't cross PFS is less likely than not crossing OS at that interim analysis. So if there's a split result, it could be PFS cross an OS has not reached statistical significance yet. That's conceivable, not emphasizing that, particularly, but it is one of the possible scenarios. And we'll just have to see what that looks like at that point in time and make an appropriate disclosure decision.

Our next question comes from Sean McCutcheon of Raymond James.

Can you speak to the staggering of enrollment for RASolute 302, 305 and 309 and the protocol components to ensure a representative sample of mutations in 303 and avoid an enrichment of non-G12B patients and perhaps germane to that as well. Can you speak to your expectation for the versus the G12D, G12V and G12R patients. And the GNP arm given G12D tends to be a bit more aggressive in chemo resistant.

Okay. I got the general idea. There were a lot of specifics in that, maybe just the staggering of enrollment, just to make sure we understood your question, were you linking the staggering of enrollment to the mutation representation? Or was that more of a broad question about getting access to patients and enrolling patients? I didn't quite follow that.

Yes. Linking is obviously 303 is all [indiscernible] there versus 305, 309 being G12D. So the staggering as it relates to kind of shuttling the patients -- avoiding struggling digital G12D patients to the 305 and 309 studies?

Do you want to comment on that?

Sure. I think some of this will be managed by the site selection, all 3 global trials. We're certainly mindful that we want to have a fair and equitable representation of RAS mutant in the [indiscernible] actually an all-comer population in the 303 study and the G12D mutant population in 305 as well as 309 and the control arm do vary among these 3 trials. So 305, specifically does offer both GMP as well as FOLFIRINOX versus 309 and 303 offers GMP as a control. So -- and as you know, there are local regional practices as saw in [indiscernible] practices when it comes to preference for GMP and FOLFIRINOX.

So we have a variety of sites region, country to select from. The PDAC patients are certainly -- they are very common. As you know, there's about nearly 60,000 Americans Union with PDAC every year, half of those are probably first-line metastatic patients in U.S. alone would account for about 30,000 in a year. And globally, certainly many more. So I don't think there'll be a lack of patients they'll be selecting from.

It's really trying to identify sites based on their local factors and investor interest in these trials and then offering these trials as option to their patients. So -- and we're so mindful about the site footprint overlap around these 3 studies to ensure that there say, the competition across these 3 studies are not going to be at individual site level.

Maybe mutations in their representation, 85% of PDAC cases have a G12 mutation. Things could be hard to [indiscernible] effect dramatically just from a few ongoing trials. And so there should be fairly similar representation across any of the multi-RAS inhibitor trials. And then in a G12D trial, it's going to be G12D mutation is going to be very specific for that. And then within any given trial, there should be balanced between the control groups and the treatment groups because there will be randomization after patients designated for particular chemo type if it's a chemo bearing the trial, then they would be randomized to treatment arm versus chemo.

So this should be balanced throughout these. I'm not sure that there's any inherent bias that would lead towards anything unusual.

Understood. Yes. And just on the expectation for it in the 303 study for G12D performance relative to G12V and G12R, given the respective expectations for each of those mutations being treated with GMP.

Well, you're asking a question as to -- the question is posed -- presuppose that there are very well-established differences amongst these mutations and how patients perform in a given treatment. I don't think that's so well established. In fact, if you look at multiple studies, you can find very conflicting results, it's just not particularly well established. So again, though, whatever it is, whatever the underlying biology is will be randomized and balanced in a given trial. So whatever that representation is should not -- shouldn't put a figure on the scale on control arm versus experimental.

Our next question comes from Faisal Khurshid of Jefferies.

I just want to ask now that you've had the commissioner priority review voucher for a little bit. Can you speak to what benefits you are either seeing now or expect to receive from that above and beyond what you'd otherwise get from programs like breakthrough designation in the real-time oncology review.

Yes. Thanks for your question. We don't have much to offer on this particular point. We don't generally disclose a great deal about our interactions with the FDA other than to say we do have a constructive interaction with the review team at the FDA with the division that's handling this. It's the same move that's been handling it all along. They just now have a CNP to to manage. And we found them to be very communicative and we have a good constructive dialogue underway.

The main advantage that's been describe to go with this would be a faster review process. That's really what it's all about. That's really a question for the FDA and not for us. What we'll do is we'll provide the data in the sequence that they're requesting it and as quickly as we can. And then their clock as they see it starts ticking once they accept a submission, which means after everything is in, they've reviewed it and decide that it's an adequate submission then they can accept it and they've given us a suggested time frame for how long -- how quickly they would review it, but that's not in our hands. So we don't really have any comments to make on that.

I am showing no further questions at this time. I would now like to turn it back to the Chairman and CEO, Mark Goldsmith, for closing remarks.

Thank you, operator, and thanks to everyone else for participating today and for your continued support of Revolution Medicines.

Thank you for your participation in today's conference. This does conclude the program, and you may now disconnect.

All right. So good morning. My name is Michael Schmidt, Senior Biotech Analyst with Guggenheim. And it's my great pleasure to welcome Mark Goldsmith, President and CEO of Revolution Medicines. Mark, welcome. Thanks for joining us.

Thanks for having us.

I'm just going to jump right into questions unless you want to provide a quick overview of the story?

Let's do it.

All right. So daraxonrasib, obviously, there's been a lot of focus on the upcoming phase. The first randomized Phase III data to read out, you guided for top line data in -- from the RASolute 302 study in second-line PDAC for the first half 2026. My understanding is that PFS and OS are a dual primary end point, which means, I think you've said before, the study could technically succeed on either being positive. But my understanding is the study will be triggered by a specific number of OS events.

And so my first question is how similar, compared to the prior Phase I/II study, do you expect patients in RASolute 302 to be? And what is your confidence that the data from the Phase I/II study was very positive will reproduce in a larger Phase III trial?

Yes. Thanks for the question. Well, let me clarify. So there are two primary endpoints, PFS and OS. The FDA has made it pretty clear publicly that they're seeking OS as the real driver because historically, there have been examples of PFS not translating. And so we really look at OS as the main endpoint, and therefore, the trial was designed as an OS event-driven program. So that the readout is triggered by a certain number of deaths that are, of course, based on our modeling of what sort of effect size and accumulated events.

Because it's powered for OS, it ends up effectively being overpowered for PFS. So once that number is hit, once we unblind the data, there are three possible scenarios. We may fail to cross statistical significance on both endpoints conceivably, we could succeed on both endpoints or we could pass significance on PFS but not yet be there on OS. So those are three different scenarios. That's why it's defined as an interim analysis. If it passes on both, well, then it's the final analysis.

In terms of patients and reproducibility from the Phase I data, we've really held the selection criteria, the eligibility criteria consistent from the early Phase I/II study to -- into the Phase III study. And we've compared those criteria to those of other Phase III trials. We've done a lot of cross-trial comparisons. And we feel pretty confident that the patient population should be very similar, and therefore, the results should be in the ballpark. Of course, we understand that there often is some sort of discount that occurs from Phase I to Phase III. I think that may often occur because of less careful matching of eligibility criteria, but we'll just have to see what the results show.

Okay. And what are your expectations for performance of the control arm chemotherapy essentially in the 302 study relative to the historic experience?

Yes. There have been a lot of Phase III trials. We've listed -- we've put a table of trials that we've referenced on our website that's available. And they consistently show that chemotherapy delivers a PFS in the range of three to four months in the previously treated pancreatic cancer patients and an OS in the 6- to 7-month range. I think there's really no reason to believe that anything has changed suddenly in 2026 that would give us a different readout from that. There's some play in the data across different trials, but I think those numbers are pretty consistent.

Okay. And then obviously, the vast majority of PDAC patients have a RAS mutation. But the study did include RAS wild-type patients as well. How do you expect it to impact study outcomes in the ITT analysis?

Yes. This is a really important question. It's quite remarkable how consistently it appears that pancreatic cancer is driven by RAS. We consider it to be biologically a RAS-addicted disease, and that comes from a variety of sources of information. The vast majority of tumor cell lines from pancreatic cancer patients have a RAS mutation and the vast majority of biopsy samples from pancreatic cancer patients who have a RAS mutation. There are some patients who don't have a detectable RAS mutation, but have other mutations in the RAS signaling pathway, either upstream, for example, RTK mutations or fusions or downstream Class I BRAF mutations.

So it's pretty much telling us. The biology is telling us that RAS is central to pancreatic cancer, whether or not you have a point mutation. And as far as we can tell, virtually all pancreatic cancer is RAS-driven disease. We also know that daraxonrasib is active in third-line patients and later, it's active in second-line patients, it's active in first-line patients. So anybody who has the idea that RAS addiction is something that occurs after some early treatment with chemotherapy, it's just disproven by the facts. Pancreatic cancer is a RAS-driven disease.

We haven't reported any clinical data on patients who have a so-called wild-type RAS genome but in the pancreatic cancer cell lines, the few cell lines we can find that don't have a RAS mutation, they tend to still be sensitive to daraxonrasib, consistent with the idea that RAS is driving their disease, whether or not there's a point mutation in a RAS causing an oncogene.

I'd also mention that we do have the nested trial design, which means that in the core of the analysis, it will focus on patients with G12 mutations. So only patients with G12 mutations represents about 85% of pancreatic cancer. So it's not a minor subset, but it's a very well-defined biomarker-defined subset. Those are the patients for whom we simply have the most data, therefore, have the most confidence and so we put it in the core of the analysis.

In the outer ring, which then gets included in the secondary analysis, we then have patients who have anything other than a G12 mutation. They can have a G3 mutation, a Q61 mutation or they might have no detectable mutation and they're all included in that broader population. So we've designed the trial to optimize to make sure we have the highest probability of success in the core, but we also think it could well be successful in the broader group.

One other comment, not having a RAS mutation means that in testing, whether it's a biopsy sample or liquid biopsy, no mutation was detected. That doesn't mean that there's no mutation in the tumor. It just means it wasn't detected and there is a false negative rate in testing, either because the biopsy missed the tumor or because the liquid sample simply didn't have a high enough tumor DNA burden to be able to detect it. So sometimes on retesting, you do find mutations. It's a RAS-addictive disease. It's the most addicted, RAS-addicted of all cancers, and we think most pancreatic cancer patients have the potential to benefit from daraxonrasib.

In order to receive a broad label in the ITT population, do you think success in ITT alone is sufficient? Or do you expect the FDA to look specifically at the non G12C subset to demonstrate a benefit there?

Well, the deal with the FDA is that they will -- they can and will look at everything. So they will cut it 100 different ways. However, they wish to it is predefined the hundred ways in which we'll cut it for them, but then they'll get the raw data and they can cut it other ways.

What they won't do is look for statistical significance in small populations. It's not meaningful. If it takes 500 patients to show a difference between treatment arms with G12 mutations, why would looking at 10 patients with wild type, be able to tell you the difference between chemo and daraxonrasib. It doesn't -- it wouldn't make any sense.

What they look for is they'll do a sensitivity analysis to look at the hazard ratios and see if something is really of concern such that you might be causing harm to patients a hazard ratio of significantly greater than one typically becomes a yellow flag that they would then consider. But it's up to them. They'll make the determination.

Okay. And so we get asked a lot, assuming the interim analysis is positive, how much information are you willing to share at that point in time versus just announcing success of this study?

Well, I think for a study as important as this, and it is being watched by every corner of the globe, people will want to see the data and want to see it in the most sort of rigorous context that you can do, which would be in a medical meeting. So I wouldn't necessarily expect that in an initial press release that we'd be releasing a lot of detailed data but I'd expect the top line results there and then a medical meeting of some sort after that.

Makes sense. And then assuming success, how quickly do you think you'll be able to submit an NDA, which obviously also incorporates a CMC package and other things?

Yes. I can't give you the specifics of that, but we'll move swiftly. Our organization is working really hard to set up the conditions for us to move efficiently once we unblind the data, but they're sort of built-in inefficiencies and just some things you can't do anything about. So we'll move swiftly after that.

From the FDA's point of view, there's, of course, a lot of information that has to be provided. We're going to be on track with that, how they process it, handle it and ultimately decide to accept the filing which, from their point of view, is when the clock starts ticking. It's only after they accept the filing. And so you can pack a lot in before that, which they'll be trying to do in order to give themselves as much time line for review as possible even with the CNPB.

Right. So I did want to speak now about your strategy for daraxonrasib in first-line metastatic pancreatic cancer patients, where you recently announced that the RASolute 303 study, which is your 3-arm trial is now open for enrollment. Maybe first question is how quickly do you think you'd be able to enroll in this study? And to what degree, can you leverage, I guess, clinical trial synergies from your 302 study here?

Yes. Moving daraxonrasib to first line is a really important high priority for us, and that's why we've initiated the 303 trial already. Because the data, the single-arm data that we've shown for daraxonrasib in second line and later lines was so encouraging, it actually even exceeded numerically the benchmarks for first-line pancreatic cancer chemotherapy treatment. Therefore, patients, their families and investigators are highly interested in getting access to daraxonrasib. So we expect from a patient and investigator point of view that there is and will be high engagement, high enthusiasm. On a global basis, we have a lot of investigators who are working really hard to get to the front of the line, to get onto the trial and to get slots allocated to them. And many of those are investigators who have had experience with daraxonrasib.

Our typical observation is that once an investigator treats a patient or two with daraxonrasib, they become addicted to daraxonrasib. They really want more of it, they want access to it, they want to give it to their patients. And so if you're an investigator who's had a few patients, you'll want to be in the first-line trial.

It sounds like -- so you expect swift enrollment. You mentioned the importance of demonstrating overall survival in pancreatic cancer earlier. To what degree do you expect potential daraxonrasib post-progression use in the first-line study to become an issue in a way? Can you correct for that, if needed, to demonstrate OS in first line?

Well, let me separate that into sort of two different concepts. One is should patients, who progress on daraxonrasib continue daraxonrasib. That's -- I don't think that's exactly what you were asking about, but I want to start with that, meaning if you are doing well clinically, should you withdraw daraxonrasib just because the CT scan shows a small new lesion or a slight increase in one lesion. And we don't know the answer to that.

But if you sort of pause and think about the biology, we've got the brakes on RAS signaling. We're pushing on it about as hard as we can. And if a tumor breaks through, it typically breaks through by increasing RAS signaling, if you take away the break, that tumor is just going to have unfettered ability to grow. So it's not clear that you really should stop treating patients just because they've progressed unless they've clinically progressed to the point where they can't take daraxonrasib any longer or where it's so obvious that you're not providing any benefit.

And we have heard anecdotally from investigators that some have continued treatment for patients who are clinically doing well on daraxonrasib but have a CT scan that says that they progressed under formal RECIST criteria and that some of those patients have stayed on for a very long time afterward and continue to do well. We have to study this, we have to quantitate it, so we really can't make any recommendations today. But we have encouraged investigators when they have such a situation to consider whether they should continue treating in order to collect more and more data about that.

I think the thing you're asking about really was crossover and whether patients who were randomized to chemotherapy in the second-line trial, whether they would go seek access to daraxonrasib after they progress. And if they were to do that and got the benefit of daraxonrasib, would that affect their overall survival and therefore, complicate interpretation. That's possible. And we are sort of in a race with ourselves here. We both want to get daraxonrasib about as quickly as possible, as many patients as possible from a humanistic point of view and to try to bend the mortality curve at the same time under a regulatory regime, both in the United States and actually globally, every other country in the world wants to see OS results.

So there's just this tension between those, and there's no obvious way to resolve those, except we just got to go as fast as we can on everything that we're doing. Now because approval outside the U.S. would likely come after approval in the United States, we do have some additional time there without sort of the complication of having prescription-based access to daraxonrasib for patients who have progressed on chemotherapy. So I think we'll definitely utilize that to our advantage to try to accomplish both of our goals. But there's no question, these are absolute intention with each other, and we don't have any magical solution to it except go as fast as you can on everything that we're doing.

Makes sense. How will physicians weigh potentially using monotherapy daraxonrasib first-line versus the limited GNP combination regimen? What else of the differences that you expect to see in...

We'll it's not a limit. It's a full GNP regimen. You mean the schedule being the every other week schedule for GNP?

Yes.

Yes. The word limited caught my attention. So right now, the data we have shows that both monotherapy in combination with GNP deliver quite encouraging response rates. We haven't yet shown any durability data sometime this year at a scientific meeting, we'll show an update that gives an initial view of durability, but we're quite encouraged. We think both of these are very active regimens.

Why bother doing both? It's funny. Sometimes I'm asked by an investor, "Well, if you're doing monotherapy, why bother doing chemo." and I'll explain that, well, there may be some additivity between them. And also, a lot of doctors are very used to using chemotherapy and are uncomfortable giving up that backbone. And then that same investor will say, "Well, if you're doing the combination, why bother doing the monotherapy?" Well, there are some patients who can't take chemotherapy. There are many patients who will either self-declare that they're ineligible for chemo and just don't want it. What happens to those patients? They go to hospice care. I mean it's really -- it's a disaster. And so offering a pill that most patients can take quite easily, and they can take it at home once a day does create an option for patients who simply are ineligible or choose not to take chemotherapy.

So from our point of view, we're really focused on trying to provide credible options for patients. Every patient has his or her own characteristics. And if we create all of those options, more patients will get access to and use Daraxonrasib, which will, we hope, help their disease.

Okay. So then I had a question on how you think about the first-line pancreatic cancer opportunity for your portfolio to play out longer term. So you recently announced two new Phase III studies in first-line PDAC for zoldonrasib, one in combination with chemotherapy, the other one in combination with daraxonrasib. So first, Remind us what drove your decision to initiate two studies, the two several studies. And then essentially a patient with a G12D mutation will have almost four choices, right, in terms of different combinations. How do you think this will play out longer term?

More choices is better for the reasons that we just talked about. We don't yet have any preview of whether one regimen is superior to another. We're just comparing them to chemotherapy right now, and we think all of them are going to be superior to chemotherapy. But is there a rank order among those three or four options that you just talked about? We don't know. It might take years to figure that out. So why would we sort of arbitrarily just do one or the other? Back to our commitment to serving all patients and giving as many options as possible.

Zoldonrasib seems to be a pretty remarkable compound. It is reported to be by investigators and patients extremely well tolerated. We see very little in the way of safety signals. The story I've heard multiple times now by an investigator is a patient comes in the office, very ill with pancreatic cancer, they can barely make it into the office. They're [ emaciated ]. They have pain. They start on zoldonrasib, discharge from the office. They come back a month later, feeling much better, walking in, looking a little healthier, saying, "Doc, I'm doing very well." Doctor says, "That's great." And then the patient says, "By the way, did you put me on placebo?" Because they experienced nothing from the drug that made them believe they had an active drug other than the fact that they're doing well in totality.

So it's a very well-tolerated drug. And because of that, we think it's the ideal drug to combine with other drugs that are poorly tolerated. Chemotherapy being the poster child for poorly tolerated drugs. And whether you're talking about GNP or FOLFIRINOX, these are not pleasant experiences for patients, adding anything on top of them that contributes to a side effect profile is a negative and might actually push them into having more dose interruptions and brakes in treatment. So zoldonrasib is a good idea.

So we're combining zoldonrasib with FOLFIRINOX with GNP. We've shown initial data on the FOLFIRINOX combination, it's performing very well, tolerated well. It's tolerated at the limits of FOLFIRINOX but not at the limits of zoldonrasib. So that regimen makes a lot of sense to do. FOLFIRINOX is used in certain parts of the world, so we should try it.

The combination with daraxonrasib is a really interesting different paradigm, which is taking a mutant selective inhibitor and combining it with the RAS multi inhibitor, and they deliver really different properties to the tumor that seem to be additive. And I would say so far now, when we've done a RAS(ON) inhibitor doublet, meaning two different RAS(ON) inhibitors put together. One is a multi inhibitor and one is a mutant selective inhibitor. In every experiment we've done we've seen improved efficacy from that combination. And we believe it might be because the mutant selective inhibitor is very focused on the mutant may do a very good job of suppressing that initial mutant. The multi inhibitor sort of pours a cold wet blanket over all the other mutant forms that might otherwise emerge in the setting of the selective pressure of the mutant selective inhibitor and so you get the benefit of the two. You also get increased total engagement of the tumor RAS mutations with the combination.

So we're excited about that. That could be a tumor -- a chemo-free regimen that would allow chemotherapy to be moved to later lines. So it's not as if we're displacing it entirely, but we push it back and maybe give patients a chemo-free regimen to begin with, that may be superior to Daraxon or Zoldon given alone. So that's why we're pursuing all of those back to our earlier conversation. The longer we wait, the higher the barriers are to being successful in the trial that will apply to every other competitor, everybody else who has a compound, they're going to find it harder and harder to do a trial, but so are we. So we're in a race against ourselves to get all of these things done as quickly as we can before these drugs are so widely available, that there's no study that anybody would ever be able to do.

So I did want to touch on colorectal cancer actually. It sounds like you've been making some progress there internally based on your comments last month. And so yes, just what is your latest thinking on how to approach colorectal cancer? And how much -- or what could we learn this year from your portfolio in terms of activity in that category?

Yes. Well, I can't give you much of a preview of what we'll learn until we share it. But we're very active in patients with colorectal cancer. 50% patients with colorectal cancer have a RAS mutation. It's obviously an important part of their disease.

Unlike pancreatic cancer, where it's quite clear suppressing RAS alone can have a dramatic effect, there are lots of other things going on genetically in those tumors, multiple things that contribute to tumor progression. And those tumors tend to be genetically and biochemically heterogeneous as well. So one part of the tumor may be driven by on collection, on genotypic profile and another part of the tumor might be driven by a different set of genes.

And so it's a very difficult thing to treat, and we believe it will take combination regimens. We've spent the last couple of years deeply into a variety of different combination regimens designed to suppress RAS, suppress RAS plus other non-RAS things going on and I think we're beginning to see the light. And sometime this year, we expect to share some additional data and some visibility into how we see registering in colorectal cancer.

So I just want to touch on another topic. I was really intrigued by your comments again last month about RM-055 actually, especially as I think about other pan-RAS inhibitors pan [indiscernible] inhibitors entering the market or the space, the trials.

Yes. I don't know if they're entering the market. But they're entering the space.

Trials, Phase I trials. So what can you tell us about RM-055? And how is it differentiated from daraxonrasib and perhaps other pan-RAS inhibitors?

Yes. We're really excited about this new innovative class of inhibitors. I realize we haven't really shared much about it. That will happen at an upcoming scientific meeting. Our scientists only would allow me to share what I shared. So I'm sort of limited to the information that we showed. But I think there was enough there to appreciate that the profile is dramatically different from really any other RAS inhibitor and it comes out of some fantastic discovery science that was done at RevMed. We'll share that mechanistic information, more insights at an upcoming scientific meeting, and I think that will clear the path for an expected initiation of a clinical trial with the first compound from that class by the end of this year, which will be our fifth compound in the clinic once that enters.

Okay. And then I just want to squeeze one more high-level question. And obviously, last summer, you announced this big $2 billion funding agreement with Royalty Pharma and I know you did consider other strategic opportunities, ex U.S. partnerships, for example, and you decided to do the global loan approach for now. And I guess my question is now 8 months later, as the development scale of your programs has evolved since. You're in a lot of Phase III trials, a lot more drugs entering late-stage development, at what point do you think revisiting this question of potentially having a global partnership, maybe value-added relative to your assessment last year?

I think we made the right decision. And I think the evidence is increasing that we made the right decision. So I don't know what it is that would cause us to reevaluate that decision. I think particularly with the pricing issues that have now arisen, the differentiation between U.S. and ex U.S. markets and the complexities of those, trying to manage that through a partnership would be actually a nightmare.

I can't say that we made the decision because of that, but I'm sure glad we made the decision. So we're all in on building the global capability and don't see any -- at least today, I don't have any idea of what would drive us to reconsider that. We're pleased with the decision.

Great. Well, this is a good time to wrap up. So Mark, thank you for your time this morning. I really appreciate it.

Thanks a lot.

Good morning. Thanks for joining us for another session at the 44th JPMorgan Healthcare Conference. I'm Brian Cheng. I'm one of the Senior Biotech Analysts here at the firm. This is a highly anticipated presentation. And we have the CEO from RevMed, Mark Goldsmith, I will now pass the mic to Mark for a short presentation followed by a live audience Q&A. Mark, the stage is yours.

Thanks for the introduction, Brian, and good morning, everyone. It's really great to be here at the JPMorgan Healthcare Conference and to share an overview of Revolution Medicines. We've made meaningful progress and have a transformative year ahead of us. As today's presentation will include forward-looking statements. Please refer to our legal disclaimer shown here on Slide 2.

At Revolution Medicines, our mission is bold. To revolutionize treatment globally for patients living with RAS-addicted cancers through the discovery development and delivery of innovative targeted medicines directed against common mutational drivers of human cancers.

We have been pioneers in the RAS targeting field, introducing a number of scientific drug discovery and clinical breakthroughs through creating breakthroughs that create compelling opportunities for patients. RevMed is a late-stage clinical oncology company pushing the boundaries in 3 common RAS-addicted cancers, pancreatic, non-small cell lung and colorectal cancer. With 4 RAS(ON) inhibitors in the clinic and a deep pipeline behind them.

We have 8 ongoing or announced registrational Phase III trials and extensive aggregate clinical experience to date with more than 2,500 patients having received one or more of our RAS(ON) inhibitors. Today, our clinical stage pipeline consists of 4 investigational drugs that target the major oncogenic drivers. Daraxonrasib, our most advanced program is a groundbreaking and promising RAS(ON) multi-selective inhibitor.

Elironrasib, a highly differentiated, highly active and well tolerated RAS(ON) G12C selective inhibitor. Zoldonrasib an innovative, highly active and well-tolerated RAS(ON) G12D inhibitor and our newest compound, newest clinical compound RMC-5127 a RAS(ON) G12V-selective inhibitor. And as I'll briefly describe later, these clinical programs are backed by a rich pipeline of preclinical and discovery programs, including an innovative and exciting new class of inhibitors that has provided a fifth RAS(ON) inhibitor drug candidate on its way to the clinic.

As a company singularly dedicated to RAS-addicted cancers, we are well positioned to bring forward new treatments aimed at changing the global standards of care for patients with common cancers. In pancreatic ductal adenocarcinoma for which cytotoxic chemotherapy remains the standard of care for most patients more than 90% of tumors harbor and oncogenic RAS mutation.

There is a profound need for RAS targeted therapies for this devastating disease. Likewise, approximately 30% of non-small cell lung cancers carry an oncogenic RAS mutation including 18% with non-G12C mutations, new effective targeted treatments remain a significant unmet need.

In colorectal cancer as well, more than 50% of tumors carrying oncogenic RAS mutation, and they remain high needs there. The depth and breadth of our RAS(ON) inhibitor portfolio designed to target oncogenic RAS mutations broadly allow us to aim for clinical impact across RAS-driven settings, including early and late-stage lines of treatment and directed against tumors carrying diverse RAS driver mutations.

Our integrated scientific workflow focused on RAS-addicted cancers is engineered as a virtuous cycle of innovation that leverages the research bench, the clinical bedside and commercial insights that inform how we discover new ways of targeting RAS through our highly productive tri-complex inhibitor platform, develop new investigational drugs through robust and parallel clinical development plans and systematically expand our commercial and operational capabilities to deliver potential new therapies to patients globally.

I'll review highlights of each of these 3 areas of our mission beginning with development activities. Pancreatic cancer is our most advanced area of clinical development with multiple registration trials already underway or planned for initiation this year. Daraxonrasib an unprecedented clinical profile across lines of therapy, across RAS mutations and across treatment regimens. The clinical durability observed so far in second line appears promising relative to PFS and OS rates reported for cytotoxic chemotherapy in the second or first line treatment settings.

This investigational drug was recently recognized by the U.S. FDA through the awarding of a commissioner's national priority review voucher, which noted Daraxonrasib's potential to change the way pancreatic cancer is treated. In first-line metastatic disease, we have also seen a compelling emerging profile, both as monotherapy and in combination with chemotherapy.

Daraxonrasib is currently under investigation and evaluation in 3 randomized registrational studies in pancreatic cancer. RASolute 302, our second-line metastatic Phase III trial recently completed global enrollment and will read out in the first half of this year and RASolute 303 in first-line metastatic disease in RASolute 304 in resectable disease have both been initiated.

Zoldonrasib, our covalent G12D selective inhibitor, with a highly differentiated safety and tolerability profile has also shown encouraging antitumor activity in pancreatic cancer. We are advancing this compound towards first-line combination registrational trials in pancreatic cancer in 2026. RASolute 305 will evaluate zoldonrasib for pancreatic cancer in combination with chemotherapy. And RASolute 309 will evaluate the RAS(ON) inhibitor doublet of Zoldonrasib plus Daraxonrasib as a chemotherapy-free approach for patients.

I'd like to briefly summarize the clinical rationale for this collection of trials starting with Daraxonrasib. RASolute 302 addresses an urgent unmet need for patients provides the fastest entry point into pancreatic cancer, and is an important opportunity to potentially establish an overall survival benefit.

RASolute 303 in the first-line metastatic disease setting is evaluating Daraxonrasib monotherapy and in combination with gemcitabine, nab-paclitaxel or GnP. This study tests 2 important and independent hypotheses, a chemotherapy-free RAS-targeted monotherapy treatment paradigm and a combination regimen containing a RAS-targeted drug plus chemotherapy.

This parallel approach is intended to create treatment optionality for patients and their physicians with the potential for an improved survival benefit supporting new standards of care in first-line treatment. RASolute 304 in the adjuvant setting evaluates daraxonrasib monotherapy following surgery and perioperative chemotherapy in patients with resectable pancreatic cancer and has the potential to show improved long-term disease-free survival for these patients.

If successful, these trials together could establish new standards of care for the majority of pancreatic cancer patients across lines of therapy. Finally, the highly attractive safety and tolerability profile seen so far with zoldonrasib also allows us to test 2 distinct hypotheses for patients in first-line metastatic pancreatic cancer carrying a RAS G12D mutation including both a first of its kind registrational study of a chemotherapy-free RAS(ON) inhibitor doublet and a combination treatment regimen with chemotherapy.

Building on encouraging monotherapy results in previously treated pancreatic cancer patients, we have been evaluating Zoldonrasib in combination with cytotoxic chemotherapies that are current standards of care treatments. Today, I'm pleased to share initial clinical data from the combination of zoldonrasib with FOLFIRINOX.

As of a December 1, 2025 data cutoff date, the initial safety and tolerability profile for the combination of full dose zoldonrasib that is 1,200 milligrams QD and full dose in the modified FOLFIRINOX regimen was largely consistent with the well-known profile of FOLFIRNOX alone. And a favorable dose intensity for zoldonrasib was also maintained. 63% of patients achieved an objective response, including both confirmed and pending confirmation parcel responses.

The disease control rate was 95% and the vast majority of patients remained on treatment as of the data cutoff date. We believe that zoldonrasib in combination with chemotherapy could be an important option for patients with pancreatic cancer harboring a G12D mutation. This year, we also plan to share supporting results from zoldonrasib plus GnP combination and from the RAS inhibitor doublet old ones plus daraxonrasib at a medical meeting or meetings coming up.

These findings support our intention to move swiftly into registrational trials with these regimens for first-line treatment. A second area of focus where we saw considerable advancement in 2025 was non-small cell lung cancer. We've shared encouraging initial safety tolerability and antitumor activity data that strengthen our belief that our first 3 assets may have a role in the non-small cell lung cancer treatment armamentarium as monotherapy or in combination.

First, daraxonrasib has shown a compelling profile as monotherapy in previously treated patients. RASolve 301, a global randomized registrational study currently underway evaluating Daraxonrasib monotherapy in previously treated metastatic non-small cell lung cancer patients continues to enroll well. inside the U.S. and internationally.

Early combination data from first-line patients treated with daraxonrasib plus pembrolizumab were encouraging, and we are planning a first-line registrational trial. Second, let's consider our mutant selective inhibitors, zoldonrasrib and elironrasib patients with non-small cell lung cancer harboring RAS G12D or G2C mutations, respectively.

We have reported highly encouraging initial safety tolerability and antitumor activity for sold on restive monotherapy in non-small cell lung cancer, and we continue enrolling an expansion cohort of second-line and beyond patients. Just last week, we announced that this investigational drug has received breakthrough therapy designation from the FDA, our third BTD award for our RAS(ON) inhibitor. We are in advanced planning for RASolve 308 our first registrational study of zoldonrasib combination regimen in first-line metastatic non-small cell lung cancer.

Elironrasib, our RASG12C-selective inhibitor has shown a strong and differentiated clinical profile in G12C inhibitor naive and G12C inhibitor experienced patients as monotherapy in combination with pembrolizumab alone or as part of a RAS inhibitor double with directors. We are continuing to evaluate both monotherapy and combination approaches with Elironrasib to inform our registrational path forward.

Colorectal cancer is another area of high interest for Revolution Medicines. Given the genetically heterogeneous profile of these cancers, we learned early on that combinatorial treatment approaches would likely be necessary to maximize clinical impact in this setting. We have a range of combination studies ongoing that include evaluating daraxonrasib and zoldonrasib as part of a RAS(ON) inhibitor doublet and evaluating each asset in combination with current standards of care and other approaches.

We also continue supporting our collaboration with Tango Therapeutics studying the combination of a RAS(ON) inhibitors with vopametostat, a PRMT5 inhibitor in patients with tumors carrying both a RAS mutation and MTAP deletion. We are also now initiating a first-in-human study evaluating the combination of our RAS(ON) inhibitors with Summit Therapeutics ivanesumab, a PD-1 VEGF bispecific antibody across multiple solid tumor settings.

Finally, we have initiated the first-in-human study of RMC-5127 or RAS(ON) G12V selective inhibitor as our fourth RAS-targeted compound to enter clinical development. In addition to our parallel development program for clinical-stage ration inhibitors, we also recognize the importance of continuing to invest in potential new approaches with the potential to provide significant additional impact for patients living with these cancers.

We are committed to sustaining our leadership position through continuous innovation, leveraging the productive virtuous cycle I described earlier. Our singular focus -- ongoing focus on targeted therapeutics for patients with RAS-addicted cancers has produced large and diverse clinical data sets, yielding important translational insights, differentiated expertise and know-how.

We continue investing to strengthen and expand our proprietary discovery platform in order to identify new potentially groundbreaking options for treating patients with RAS-driven cancers. I would like to share with you an example of the exciting output from this continued investment in innovation.

To frame the context, we've reported compelling clinical durability from daraxonrasib treatment in patients with pancreatic cancer that is highly consistent with our earlier preclinical findings. The Kaplan-Meier plot on the left recapitulates the encouraging overall survival we've observed for patients with the second-line pancreatic cancer treated with daraxonrasib race and the graph on the right shows the preclinical progression-free survival effect of daraxonrasib across a panel of models of RAS G12D-pancreatic cancer.

These data highlight the strong preclinical to clinical translation observed for daraxonrasib activity. They also illustrate the harsh reality that most RAS-driven cancers, eventually will find ways to develop resistance and circum that RAS inhibition. Most commonly by increasing RAS signaling. We owe patients do solutions for this eventuality and have concentrated our efforts in this area.

Here, we're proud to briefly introduce an innovative new class of RAS inhibitors specifically designed to overcome RAS-driven acquired drug resistance and thereby extend the clinical benefit of RAS(ON) inhibitors. We intend to advance the first compound from this class into the clinic this year. Let me briefly illustrate with the preclinical data on this slide.

The 2 graphs on the left show the antitumor activity of Daraxonrasib in 2 standard preclinical xenograft models, a RAS G12D pancreatic cancer xenograft on the top and a RAS G12C non-small cell lung cancers xenograft in the bottom. In both models, daraxonrasib shown in green, drove deep and initially durable tumor regressions relative to the control arm.

But upon longer follow-up, we saw emergence of on-treatment escape and tumor regrowth. We used tumors that escape from treatment with a RAS multi -- RAS(ON) multi inhibitor to derive resistant models for further study as shown in the middle panels, the resistant pancreatic cancer variant exhibited increased RAS signaling as its apparent mechanism of drug resistance and the resistant lung cancer variant carries an increase in RAS gene copy number.

As expected, daraxonrasib showed significantly reduced antitumor activity in these models selected for resistance.

In contrast, compound RMO-55 from our innovative new class of RAS inhibitors shown in the orange tumor curves, defeated acquired RAS-dependent resistance in these settings and drove especially deep and sustained regressions. Treatment with RMO-55 across a wide range of active doses was well tolerated.

In a related experiment shown on the far right, treatment with RMO-55 arrested tumor growth and drove deep durable and durable regressions in the parental tumor models even after they've begun progressing during initial treatment with daraxonrasib.

Hence, we believe that RMO-55 and other compounds in this promising new class of RAS inhibitors have the potential to offer additional benefit for patients with RAS-addicted cancers by countering common RAS-dependent mechanisms of resistance.

They may enable exciting sequential and/or combination treatment strategies designed to extend even further the durability of therapeutic effect. This year, we plan to share more information about this class of compounds at a scientific meeting and to bring the first compound into the clinic as our fifth investigational drug targeting RAS.

This vignette is a direct output from our continued investment in elucidating the fundamentals of bass cancer biology, uncovering the clinical and molecular effects of treatment with RAS(ON) inhibitors and deploying our differentiated drug discovery engine. We are building a world-class end-to-end global oncology enterprise to deliver RAS(ON) targeted therapies to patients living with RAS-addicted cancers. As our late-stage programs progress, we are ensuring that our organization is ready for successful commercialization.

We've established the operational foundation necessary to move with speed and agility, focused initially in the U.S. and extending into priority international markets. Leading this work are seasoned executives with track records of launching some of the most impactful oncology products over the last 2 decades, and we continue expanding our capabilities in order to deliver these important new therapies to patients.

Our aim at Rev Med is to create the industry-leading global targeted medicine franchise for patients with RAS-addicted cancers. To date, our organization and collaborators have discovered major insights and created valuable know-how and advancing groundbreaking ran inhibitors, developed pioneering RAS(ON) inhibitors and advance into multiple late-stage registrational trials across a range of indications and lines of therapy. And scale the organization, positioning Rev Med to deliver global launches.

A strong financial position with $1.9 billion as of the end of the third quarter with an additional $1.75 billion in committed capital available to us under our agreement with Royalty Pharma, enables broad execution to serve unmet needs across the important opportunities I've outlined today.

2026 will be a year of growing impact for Rev Med with key milestones to track across our clinical programs as well as in advancing new programs and growing our capabilities. In pancreatic cancer, we expect to provide several important data disclosures on daraxonrasib in the first half of 2026, including an expected readout for the RASolute 302 trial and sharing updated monotherapy and combination data in the first-line metastatic setting with initial durability measures.

We also plan to initiate 2 registrational trials with zoldonrasib in the first-line metastatic pancreatic cancer setting this year.

As I mentioned, RASolute 305, studying the combination of zoldonrasib plus chemotherapy to initiate in the first half of this year and Resolute 309 chemotherapy-free RAS(ON) inhibitor doublet evaluating daraxonrasib plus zoldonrasib to initiate in the second half of the year. In non-small cell lung cancer, we aim to substantially complete enrollment this year for Resolute 301, our ongoing daraxonrasib monotherapy study. And 2 first-line metastatic registrational trials in non-small cell lung cancer are planned for 2026.

RASolve 308 will evaluate the combination of Zoldonrasib with standard of care expected to begin in the first half of 2026 and a trial of daraxonrasib in combination with standard of care expected to initiate in the second half of the year.

We also expect to provide an update on our registrational strategy for elironrasib.

In colorectal cancer, we plan to share an update on combination strategies in 2026 as we look forward toward pivotal trial opportunities. In earlier programs, activities related to RMC-5127 are ongoing to enable us to identify a recommended Phase II dose in the second half of 2026. And finally, we plan to initiate, as I mentioned, the first-in-human Phase I trial with a first investigational drug from the innovative and exciting new class of RAS inhibitors that I previewed earlier today.

Our organization is driven by a tireless commitment to patients living with RAS-addicted cancers. We believe that each asset in our pipeline has the potential to transform the treatment landscape for difficult-to-treat RAS-addicted cancers.

We strive to achieve such impact every day through every trial and for every patient enrolled in our studies. I'd once again like to thank the patients, caregivers, clinical investigators and advocates who partner with us in this critical work and to acknowledge the extraordinary team of revolutionaries who drive transformative science on behalf of patients. Thank you very much.

Well, thank you, Mark, for the wonderful presentation. Let's start with Q&A. [Operator Instructions] Mark, maybe just to start off, big picture question.

Do you see yourself building something bigger? How do you balance your goal in building a bigger machine than taking strategic transactions in front of you? And ultimately, where do you see Rev Med 6 months and 5 years?

I'm shocked.

Maybe not 5 years.

Well,I have very little to say about the latter part of your question since obviously, we have a well-established company policy of not commenting on rumors or speculation. So I won't be able to address that particular question. But with regard to what are we building, it's not our goal to build something big.

It's our goal to build something that's impactful. And we have tremendous momentum that I just summarized. We have an extraordinary organization that grew by something like 400 people in 2025, reaching into every corner of all disciplines that we need to be able to deliver these products on behalf of patients eventually around the world. So we're committed to that vision.

There's a lot to do between where we are today and achieving that vision, and we'll need to continue adding to those resources in order to achieve it.

Historically, when you look at the data disclosure from RevMed, we have seen data at your own time. We have seen it at conferences we've seen it at earnings -- what's your tech in disclosing data today, which I totally welcome, what's the rationale in disclosing today at the conference of the year.

Why did we disclose data at the conference -- the most important conference of the year. Is that what you asked?

Yes.

Look, our general feeling is, and I think most investors who talk with us understand that we share data when the data are mature enough to share to show something that indicates a direction that our program should go. And I think the 2 things I showed today are very much linked to what's going to happen later in the year.

Sometimes conferences aren't convenient. Their abstract deadlines don't happen. They don't check with us when they set the dates for abstract deadlines. So we just choose to keep moving things forward with their urgent needs that need to be met. And the only way for us to move clinical programs forward is to provide the data that supports it in order for investigators to understand why they should participate and for patients to make decisions about whether to participate. So I think we'll continue to do that.

Maybe turning to the second line trial that you're running. Can we talk about the risk that you see in the study? There's certainly a lot of vehicle room for error when you look at what you have presented for the daraxonrasib performance. in the second-line PDAC setting. What keeps you up in relation to the second-line studies outcome?

Well, I mean, at this point, it's going very well. It enrolled extraordinarily rapidly. We've completed enrollment. We've covered the territories that we needed to cover, which took some management to get that accomplished. And we'll await the data. Of course, it's an experiment. And so while we think there are a lot of data that justify conducting the study, and we certainly have high hopes for it, it's an experiment. And we'll see the results when we see them.

You have narrowed your guidance for the second line to now first half. Have you seen the data in the blinded setting? And do you have a sense of how close you are to the events? And I hear this question quite a lot, where there are some question of whether you've seen the interim. What's your take on those questions?

Well, the thing that we do track is OS events deaths in the trial because it's an event-driven trial. So we have to track that. There's no way around that. It's, of course, blinded, so we don't -- all we know is a total number, and we have a target number after which we will be able to unblind the data. So I mean, it's a very process-oriented thing. There's really not a lot of wiggle room in it and we don't get to take a peak until we unblind it.

As we look into the top line in the first half, what can we expect there? And can you talk about what was it carries towards path to approval?

I'm sorry, say it again.

Is it sufficient for you to file for an approval based on the top line in the first half?

Well, we don't know that because we don't know the results. So it is -- it may be an interim analysis. I mean, it starts as an interim analysis under the plan. And remember, it's overall survival driven.

So it's powered for overall survival, but that means it's overpowered, if you will, for progression-free survival. And when the data are unblinded, we'll have those numbers. And there are several different scenarios that could play out in it.

And one of those could mean that the trial is completed and we move forward. And one of those could mean we have some of the results that we need and not all of them.

We just don't know. I mean of course, we've designed it with some assumptions in mind and a great deal of statistical work behind it. But at the end of the day, we just have to see the results, and then we'll know which way it will go.

If I do my math, let's say, midyear top line. In the most blue sky scenario, where this top line is efficient, submission potentially the fall. You have CNPB, so potentially 1 to 2 months of review. Do you think that it's possible that you could get approval this year?

Yes, I wouldn't want to speculate on that. I mean, there are so many factors in there that we don't control. Probably if you ask your question more broadly, what do I lose sleep over. It's things we don't control as opposed to things that we do control, and there are a lot of macro external events.

Very high-level macro events, but then there are practical things like the FDA and how it prosecutes things. And they've made a public commitment to be very efficient and to move very quickly and that we're working very well with them on that, but we don't know what all that will actually translate into and we have no control over it. So I think for us to speculate today would literally just be speculation.

I'll take one question from the audience. No question. How should we interpret zoldonrasib's performance here that you presented here today relative to Dara's performance in the past, mono or combo of chemo that we reported back in September.

Right. Zoldonrasib is performing very well. Daraxonrasib has also performed very well. They're different in their characteristics. And I think only over time, once we've completed randomized Phase III trials will we really be able to compare them. And our feeling is that we have to have some humility about it.

We can make guesses about how certain things are going to play out, but we just need to conduct those studies. I think they're both exciting compounds. They're even more exciting in combination, we believe, which is why one of the arms of our first line or one of the studies will be a combination RAS(ON)-inhibitor doublet.

We're also able to combine sold on race because of its very favorable tolerability profile. We're able to combine it with FOLFIRNOX, quite readily. And that gives us an opportunity that we did not choose to take with daraxonrasib. So I think there's both complementary and then some actual overlap, and I think that's good for patients.

As we think about the setup of 305 and 309. I think just to play devil's advocate, why not just combine both 305, 309 and just one study in a sense that chemo combo in one arm, dara combo in one arm and then the chemo control. What is the benefit ultimately of doing 2 parallel studies for the frontline for Dara in the front-line PDAC setting?

Yes. It turns out to be entirely an operational question. So it's not actually -- it seems like it's interesting, but it's not that interesting. The cost is about the same. So it's -- there's really not a cost savings to run that trial as a multiarm trial.

And so then it comes down to what's most practical. And a larger trial will take longer to run as opposed to running 2 smaller trials in parallel.

So that's one consideration. And there are various other just logistical aspects of it. So we make those decisions on a case-by-case basis, as you know, for our daraxonrasib trial. We're running a monotherapy arm and a combination arm compared to the same control. But think about the fact that you have to have the same control as well as complicated.

Going back to the CNPV that's in place for Dara.

I know we talked a little bit back at ESMO. At that point, I don't think you fully know whether the CNPV is applicable just for PDAC or it's for all the indication or whether there is some restriction around the line setting.

Do you have that clarity today? And since you've got the CNPV. Has that impacted your planning for dara or even other combination partnerships?

Yes. I think these vouchers as far as we can tell, are for a single indication, they're generally not for a whole class or for a whole program. And of course, we just spent the last 25 minutes talking about exorasib in the 302 study. So it's clearly the thing that most urgently needs to get out there.

So I think that you can sort of infer from that. We've had a great relationship with the FDA. They've been very committed to working with us, including under the CNPV regime. They're kind of inventing it as they go because it's a pilot program. And so we're kind of inventing along with them. But we're very positive about the interaction.

As you think through zoldon's positioning, we have seen a few G12D out there. How do you see your differentiation? What's your edge there with zoldonrasib?

Well, I think there are a number of characteristics that are -- that give it an edge, it's probably been studied in substantially more patients than any of the others. So we have a much more mature view of how it behaves. It's tolerability profile is so attractive that investigators and their patients considered to be analogous to placebo and therefore, can be run in a placebo-controlled way, which I don't know of any other compound like that.

And its activity level seems to be as high, higher than anything that we've seen so far with anything close to the same tolerability profile.

So it's a -- we think it's a class-leading compound. That will -- those sorts of things play themselves out over time. But we've had a pretty vast experience with it now, and I think we're pretty confident that this will be an important part of drug treatment options for patients.

And then turning to G12C, elironrasib. Where does that go in terms of your priority list? It's laying our plan near term. Does it make sense? And does it hinder the growth of Rev Med in any way?

Does eliron hinder the growth of Rev Med?

Or just from a strategic standpoint, that's laying out a plan for G12C. Does that have any impact in terms of your thinking around where the portfolio could go?

I have to admit, I'm not quite understanding is your question whether telling people what we're going to do with it has an impact or whether actually doing something with it has an impact.

What are the next step, laying out a plan for the next step will have any impact in terms of how your potential discussions are going or your plan for daraxonrasib and also zoldonrasib.

Yes, whether we disclose what we're doing, you're not disclosing it, we have to make our own plans. We think elironrasib is a really outstanding compound. It's a little bit the little brother, a little sister of the others because they've just addressed such important gaps in treatment regimens. And the G12C space is obviously much more crowded. So we're being much more thoughtful.

We need to be much more thoughtful and careful and deciding how to move it forward. And before we advance it into a registrational trial, we want to make sure what we're doing is going to serve an unmet need and it's going to have a place in the marketplace. And there are several ways in which that could happen. And when we're ready to move that forward, we'll tell everybody about it and explain our rationale.

Great. Just to wrap up, can you remind us how we should think about the data cadence this year? Which data update are you most excited for?

Which data update are we most excited for? Why don't we take a poll in the room and find out what the answer to that is. We probably agree with that. Thanks very much.

Thank you,. Thanks for your time.

Good morning, everyone. Let's get started. Welcome for joining us for Jefferies London Healthcare Conference. My name is Clara Dong, a biotech analyst here at Jefferies. So sitting next to me, we have the Chief Executive Officer of Revolution Medicines, Mark Goldsmith. Welcome, Mark.

Thank you.

So Mark, maybe for the audience who might be less familiar with the story, can you maybe start setting the stage by giving us an introduction of -- an overview of RevMed, what's the current pipeline and what have kept you busy for the past year?

Yes. Thanks for having us. Revolution Medicines is a company focused essentially exclusively on the most common genetic cause of cancers that is RAS-driven cancer. We have developed a very rich pipeline of inhibitors of various RAS cancer drivers. In fact, we have compounds that cover essentially all the variants of RAS that cause human cancer.

Our mechanism of action involves inhibiting the active or on state of RAS cancers. We have 3 compounds in the clinic prior to today, and they're all making good progress across RAS-driven cancers, most highly RAS-driven cancers, pancreatic cancer, which is essentially entirely driven by RAS, 50% of colorectal cancers and 30% of non-small cell lung cancers are driven by RAS.

So this is a very important cause of these devastating diseases. And our strategy is to develop RAS inhibitors and various combination approaches to try to maximize impact on behalf of patients.

So your daraxonrasib, we definitely want to spend a lot of time to talk about this a little bit later. But you recently also received a national priority voucher and orphan drug designation for dara in pancreatic cancer. So maybe just talk about what kind of engagement you've had with the FDA about this voucher? And how do you foresee this voucher being really implemented in your clinical development?

Yes. So you're talking about a compound known as daraxonrasib or sometimes called daraxon, previously called RMC-6236. This is an inhibitor of essentially all forms of RAS that cause human cancer. We've made significant progress in pancreatic cancer, which I'm sure you're going to want to talk about. And the regulatory agencies investigators and patients have been very enthusiastic about it.

And so this compound has the distinction of having received a breakthrough designation and orphan drug designation and was one of the first 9 recipients of the Commissioner's National Priority Voucher about a month ago. And that voucher is intended to signal that the FDA plans to move in an accelerated way in its review once it receives a submission from us for an NDA based on a global Phase III randomized trial that's currently underway with daraxonrasib in pancreatic cancer -- in second-line pancreatic cancer. And exactly how that will work is something we're still learning about.

I think the FDA is still, frankly, developing the approach for that, but we've had deep engagement with the FDA for many years now across our programs, across indications. So we're very familiar with the channels there. And now that conversation has turned to what steps we need to take in order to prepare them for a potential NDA submission so that they could review it.

Their time frame, their stated time frame is to be able to review that NDA over a 1- to 2-month period. But we'll see how that all plays out, but it certainly signals enthusiasm by the regulatory body for daraxonrasib, and we'll do everything we can to help them in that ambition.

It's certainly very encouraging for us to see the daraxonrasib being one of the first to receive the voucher. And as you alluded, there might be an accelerated time line for the review. But what might be the other implications for this voucher in terms of the time line of commercialization maybe following your pivotal readout in second-line pancreatic cancer in 2026 as well?

Well, the review time at the FDA is certainly part of the time line. And so to the extent that, that can be compressed, that will be favorable for ultimately launching the product. We have planned for a wide range of scenarios, both for timing of an NDA submission as well as for timing of a launch, and we'll be prepared for the most accelerated conceivable time line. And if the FDA can help us get there even faster, we'll be able to deliver to patients even faster.

Great. And maybe let's take a step back, actually talking about the pivotal Phase III trial you're running in pancreatic cancer. So maybe just talk about what are the specific endpoints would constitute success for RASolute 302, which is the pivotal Phase III for daraxonrasib in second-line pancreatic cancer. And what are the evidence so far give you this confidence that the trials -- in trials outcome?

Yes, it's an important area. Pancreatic cancer today is treated essentially exclusively by cytotoxic chemotherapy for first-line, second-line, later-line adjuvant treatment. Essentially, all patients receive chemotherapy. There are some patients who receive surgery for resectable disease, but even those patients also receive chemotherapy and the 2 most common cytotoxic chemotherapies are GEM/abraxane and FOLFIRINOX or some form of a 5-FU-based regimen. These regimens are not very effective, very disappointing for patients.

In second-line pancreatic cancer, cytotoxic chemotherapy delivers a median PFS, progression-free survival of on the order of 3 months and a median overall survival of about 6 months. That's about as good as it gets in pancreatic cancer. It's pretty dismal. We have been studying daraxonrasib. We've now studied it in roughly 1,000 pancreatic cancer patients.

So we have extensive experience with it across different lines of therapy and in various strategies, both monotherapy and in combinations. And based on a monotherapy cohort in second-line pancreatic cancer, we reported a median progression-free survival of over 8 months as compared to the standard of care 3 months and a median overall survival of 13 to 15 months. So really a substantial difference.

If you're willing to make a cross-trial comparison, we understand that, that's difficult to do with these single-arm trials, but nonetheless, we all do it. And we understand from investigators, patients and their families and advocacy groups that their experience of being treated with daraxonrasib qualitatively very much matches the numbers that we've reported.

So we feel quite optimistic that these data are very encouraging and increase the probability that the Phase III trial would be successful. That trial is running globally. It's a randomized 2-arm trial. Patients get randomized either to standard of care chemotherapy, and I've mentioned what those cytotoxic chemotherapy regimens are or to receive daraxonrasib as monotherapy and reflecting the data that I just alluded to earlier. I'm actually really pleased today to report that there has been great enthusiasm and receptivity to this trial, both in the U.S. and internationally. We have had rapid enrollment in it.

And as of now, we have fully enrolled that trial. We've completed enrollment, and now we're monitoring patients, and we expect to readout in 2026. So we're very excited to have reached that important milestone.

And in terms of the patients you're enrolling for the pivotal trial, should we expect any patient characteristic difference versus the previous phase -- early phase trial in the context of enrollment eligibility?

We really don't expect any difference. We carefully constructed that cohort that we reported out to reflect what we expect to receive in terms of enrollment in the Phase III trial. The eligibility criteria are very, very similar.

We've also matched those eligibility criteria and even the patient profiles from that single-arm cohort that we've reported against all of the Phase III trials that we had access to in terms of patient demographic and other characteristics.

So we feel encouraged that what we saw in the Phase I/II trial will be reflected in some form in the Phase III trial. Of course, we can't be certain there can be differences that we just don't know about. But structurally, we'd expect those patients to be quite similar.

And next year, before the pivotal readout, should we expect any interim analysis as well?

The trial has in place the opportunity for interim analysis. That interim analysis is driven by overall survival, which sort of gets to one of the earlier questions you raised, which is what are the endpoints.

Overall survival is really the critical primary endpoint. It actually has a dual primary endpoint, overall survival and progression-free survival, but it's powered for overall survival, which means it's actually overpowered for progression-free survival. And patients, physicians and regulatory bodies in pancreatic cancer really want to see changes in overall survival. And so that's what we're focused on.

It is an event-driven trial, meaning there's not a date upon which it stops simply because of the Gregorian calendar, but rather it is driven by the number of overall survival events that is deaths that we statistically projected to indicate whether or not there would be a difference between the groups. So we're just awaiting the accumulation of those events.

And when we read it out and sort of open the envelope, we'll know whether that's an interim read or whether that's the final read. It's possible that we hit on neither of those endpoints. That's conceivable, not very high probability, but conceivable. It's possible that we will have hit on both of those endpoints at that time at that first read, in which case it's the final read and the trial is over. It's also possible that we hit on PFS but have not yet reached statistical significance in OS, in which case, it would become an interim read and there would be a follow-up read subsequently.

Beyond second-line pancreatic cancer, you also have a Phase III in the frontline pancreatic cancer. So you also recently announced a trial design for that trial. So maybe just talk to us about the rationale for the 3-arm design and the chemo -- the choice of chemo in the trial as well.

We're very committed to patients with pancreatic cancer. We believe, based on feedback from leading authorities in pancreatic cancer that daraxonrasib has delivered so far really unprecedented benefit for patients in the single-arm trials. And so we are interested in all the indications for pancreatic cancer. They're all driven by RAS and therefore, the treatment with a RAS(ON) -- effective RAS(ON) inhibitor should be similar across all of these.

We announced 2 additional pivotal trials beyond the RASolute 302 trial. One of them is for patients with adjuvant disease or -- for adjuvant treatment of resectable disease. That trial we announced a few weeks ago has initiated. Those patients received surgery and perioperative chemotherapy according to standards of care and get randomized either to observation or daraxonrasib monotherapy for a period of 2 years and will follow a disease-free survival for those patients. So that study has been initiated.

The study you just alluded to, which is called RASolute 303 is the first of our first-line studies in pancreatic cancer, our global Phase III first-line studies. It is a study with a 3-arm trial design, as you mentioned, that is comparing standard of care cytotoxic chemotherapy versus daraxonrasib monotherapy versus a combination of daraxonrasib plus chemotherapy. So those are the 3 arms.

It's a very attractive trial design for patients. It means everybody has a 2 out of 3 chance of receiving daraxonrasib. They have a 2 out of 3 chance of receiving chemotherapy as well. We had indicated we expected to initiate that trial in the fourth quarter of this year. I'm also pleased to announce today that we have, in fact, initiated that trial as well. So we're now running 3 global Phase III trials in pancreatic cancer. We're looking to cover every possible indication in pancreatic cancer, and we'll continue to build on that with additional trials.

So maybe just a little bit more on the frontline pancreatic cancer trial. So you do have this monotherapy arm and also [indiscernible] chemo combo arm. So when we look at your early phase monotherapy data, it's, in fact, already very highly encouraging as a monotherapy even in the context of frontline. So how should we think about in the frontline monotherapy versus chemo combo under what scenario you think monotherapy might have a shot as well?

Well, pancreatic cancer is a RAS-driven disease. And it turns out if you treat it with a really good RAS inhibitor, you can modulate that disease. So the data you just alluded to were that in the second-line monotherapy trial that we performed previously, the PFS and OS outcomes were not only superior with daraxonrasib to standard of care in second line, they were also superior to standard of care in first-line pancreatic cancer. I think that's the point you were just making.

We also reported a cohort of first-line patients treated with daraxonrasib monotherapy, and those patients also showed very good outcomes. From a response rate perspective, we've not yet reported durability from those, but we expect that to be durable also. So I think the evidence supports the biology that pancreatic cancer is a RAS-driven disease and daraxonrasib is very active against that disease. So why bothered with cytotoxic chemotherapy?

Well, the question has been changed. It used to be why are we running monotherapy. That was before we reported the monotherapy data. And now the question is why bother with cytotoxic chemotherapy. And it really comes down to just our philosophy that we're trying to find the most effective regimens for patients with RAS-driven diseases. And it is conceivable that cytotoxic chemotherapy combined with a targeted RAS agent will simply deliver the greatest effect. We don't really know that.

In the cohort I mentioned of first-line patients, we actually compared monotherapy with cytotoxic chemotherapy as a combination. So we compared mono versus the doublet. And the response rate for the monotherapy patients was 47% and the response rate for those with GEM/abraxane plus daraxonrasib was 55%. Are those different? We don't really know. This is not a randomized controlled trial of the size that would answer that question. But it certainly is a trend towards a possible difference.

And in preclinical work, we've seen that a cytotoxic agent combined with daraxonrasib does deliver greater at least initial efficacy. And so it makes sense for us to evaluate that in the clinic. And the best way to answer the question is simply do the experiment. It may turn out that different patients will prefer monotherapy versus the combination with cytotoxic chemotherapy.

A 45-year-old robust patient might say, "Doc, I want to receive the most aggressive therapy you have available, give me the strongest chemotherapy and give me daraxonrasib." A less robust 85-year-old might say, "I don't think I can handle chemotherapy, but I can certainly take a daily once-a-day pill. And so I'd rather have monotherapy." I think in this world today, especially with such a devastating disease, creating options for patients and their physicians is really the best way to go.

That's fair. And then in terms of the frontline response rate you just alluded to, should we expect an update on that data in the near term?

We do expect at some point to report out durability data from the treatment arms that I just mentioned, the monotherapy and the combination with cytotoxic chemotherapy. Those data are maturing. We tend not to report durability until we have stable numbers that we think can hold up for the long term. We prefer that instead of getting out ahead of ourselves. So we'll report it when we have stable enough information to share.

Great. And then I just want to quickly touch on the adjuvant opportunity as well. I mean, in this setting, maybe people are less familiar in terms of how large exactly is the opportunity? And then how should we think about if we use daraxonrasib in adjuvant setting, how does that change maybe how physicians will sequence the drug in the frontline setting and the second line as well?

Right. So roughly 25% of patients are radiologically identified in the first diagnosis as being resectable, meaning the surgeon looks at a CT scan and says, I think I can remove this. Of those 25%, about 2/3 of them proved to have truly resectable localized and resectable disease, which is a surgical pathologic diagnosis. So 15% versus the 25% who radiologically look like they might be. So that's the number. It's about 15% end up being have a formal pathologic diagnosis of resected disease.

Those patients will have received cytotoxic chemotherapy either before surgery or after surgery or some doses before surgery and some doses after surgery. It varies from practitioner to practitioner and from country to country. But generally, almost everybody who received surgery will also receive cytotoxic chemotherapy. So it's not an insignificant population.

There are 56,000 new pancreatic cancer diagnoses in the U.S. each year. So if we say 15% of those, so roughly, let's say, 7,500 patients each year in the U.S. alone, and you can globalize that number, really deserve to have the chance for a potential cure. Now of those patients who receive surgery and cytotoxic chemotherapy, maybe 20% of them will have long-term durable benefit from the surgery and chemotherapy. That means 80% don't. And adding an agent that biologically targets the pathway that's causing the disease seems like it gives a chance to actually increase that overall survival rate and potential cure rate.

And at a minimum, it may extend people's lives. So we're excited to do it. We think that trial will enroll very readily, and it's compelling to do.

Got it. And then also for your G12D inhibitor, zoldonrasib, you also have very strong data in pancreatic cancer. So how should we think about the position of this asset in the kind of your -- in your clinical development strategy in terms of the pancreatic cancer franchise?

Yes. Thanks for mentioning zoldonrasib, sometimes called the zoldon at Revolution Medicines, zoldonrasib. And it is a G12D selective inhibitor. It's an interesting agent. It's orally bioavailable. It's once a day, and it is a covalent modifier of the aspartate-containing variant or the G12D variant. It's the only compound actually in history to go into the clinic to do that. It is -- carries with it a remarkable tolerability and safety profile as reported by investigators.

Many patients can't distinguish it from taking no drug at all, which is quite amazing for a targeted agent. And it also carried with it significant antitumor activity in patients with pancreatic cancer and a G12D mutation. Back to our philosophy, we're very deeply committed to patients with pancreatic cancer and other RAS-driven diseases. And so we want to bring forward any compound that looks compelling and try to find its place in the armamentarium for treating pancreatic cancer patients.

Zoldonrasib is clearly a compelling compound and deserves that. Whether it should be studied as monotherapy or in combination is something to be determined. We expect that it will be more of a combination agent than a monotherapy agent, particularly because of its high tolerability profile. We expect that it could be combined with cytotoxic chemotherapy of any form, but we also think it could be combined with deraxonrasib.

And if deraxonrasib emerges as really the backbone of treatment for patients with pancreatic cancer, then it might make sense to combine with a mutant selective inhibitor. We've shown strong preclinical data supporting the thesis that the combination of a mutant selective inhibitor, zoldonrasib plus deraxonrasib actually delivers greater antitumor punch as measured by deeper responses, more frequent responses and more durable responses. We believe that combination can counter some of the major forms of resistance that can occur to a RAS inhibitor. So we're excited about all of those.

We've announced that we expect in the first half of 2026 to initiate a zoldonrasib Phase III pancreatic cancer trial that would likely be in earlier disease, a first-line trial. And we're just developing the strategy now, and we'll lay out the details of it around the time that we initiate that trial, but that will be our fourth pancreatic cancer Phase III pivotal trial.

We spent a lot of time on pancreatic cancer, but I also want to make sure we also talk about non-small cell lung cancer development as well, and you do have a pivotal trial with daraxonrasib monotherapy in non-small cell lung cancer. So maybe talk about the time line for that trial? And then what's your overall vision and strategy in lung cancer?

Yes. That trial is known as the RASolve 301 trial. It is also a global Phase III randomized trial. This is a daraxonrasib versus standard of care in second and third-line non-small cell lung cancer containing a RAS mutation, which, as I mentioned before, is 30% of all non-small cell lung cancer patients. That trial is also enrolling well. I don't have any particular update on it, quantitative update, but it is meeting our targets for enrollment, and we'll continue to enroll those patients.

And we're very excited about that, and that's our first foothold into non-small cell lung cancer, and there's more to come. We've indicated that we expect to initiate a first-line non-small cell lung cancer regimen in a global Phase III trial, and that would be a combination of daraxonrasib with pembrolizumab and chemotherapy. The details of that trial, we haven't laid out, but that's the basic design comparing that to the KEYNOTE-189 regimen alone and more to follow after that trial as well.

And for maybe the last 30 seconds, let's talk about your balance sheet, your cash position and your recent deal with Royalty Pharma, your AI collaborations.

Well, we're fortunate that we have a strong balance sheet. We're in a strong financial position. We just reported an update to that. Our cash balance was on the order of $1.9 billion. We had developed in June of this year and announced a really groundbreaking partnership with Royalty Pharma that put $2 billion at our disposal.

We've drawn down $250 million of that, but we still have another $1.75 billion available, and we'll draw that down on a selective basis as needed to support our program. So we think we have the capital to pursue a very aggressive clinical trial strategy across RAS-driven indications.

Great. Really looking forward to the next updates. And thank you so much for your time, Mark, and thank you, everyone, for joining us in person and online. Enjoy the rest of the conference. Thank you.

All right. So we'll get started right away. So I'd like to welcome Mark Goldsmith for the next fireside chat here, President and CEO of Revolution Medicines. Mark, welcome. Thanks for joining us.

So we'll jump right into Q&A. So obviously, an exciting time for the company with pivotal studies underway for daraxonrasib, more to come. And so just jumping right into a question.

Your most advanced registration study is the second-line pancreatic cancer trial, RASolute 302, that's ongoing and nearing completion of enrollment. And yes, as we look forward to the first registration data disclosure next year. The Phase II data was obviously very promising. What have you done to ensure that the Phase II data translates into the Phase III study?

Yes. Thanks for the question. I think that we found that the patient population in our Phase I/II trial was very similar to the populations that have been studied in a variety of Phase III trials in pancreatic cancer, very consistent across the board. We really didn't find a risk profile that differed much. If anything, the patients in the Phase I/II trial were slightly worse off, had worse prognostic factors than those in conventional Phase III trials that have been reported. So I think on that basis, we would assume that we had a representative population and therefore, would expect it to be relatively similar in the Phase III trial.

Great. And then, can you talk a little bit about the mechanics of the trial itself? So you have PFS and OS endpoints and you also have built in a -- sequential analysis rather in different patient populations in the study. Just remind us how the analysis is done and sort of what triggers the unblinding of the study, so to speak?

Yes. So the main goal of this trial really is to demonstrate an OS benefit. That's something that the FDA has indicated that they would really prioritize in pancreatic cancer. We support that. We think that from a global perspective, having OS data will make the most difference for prescribers and for patients, of course.

So it's an OS-driven trial. There's a predefined number of OS events that's based on our statistical modeling. That event number, once we fully enrolled and once we hit that number, we're enabled to look at the data. And that could then lead to either just an interim analysis or it could be a final analysis. Of course, it depends on the outcome. In that analysis, we will be able to see both OS and PFS. Because the trial is powered for OS, that means the PFS is likely to be overpowered. So the likelihood of reaching PFS significance is very high in that interim -- that first interim analysis, the likelihood of OS is whatever we've powered it for. If we haven't reached OS, there's the opportunity to go on and continue to follow patients for an OS outcome later.

The hierarchical testing that you alluded to is because there are multiple RAS mutations that drive pancreatic cancer and the most common of which, 85% of which are what we call G12 or G12X mutations, meaning some substitution at position G12, about 85%. It's clear from our preclinical studies that the G12 mutations showed the greatest sensitivity in tumor models to daraxonrasib, our RAS-multi inhibitor. Although actually every mutation that we've ever tested has shown sensitivity to daraxonrasib, just in terms of the totality of the evidence we had, it was just stronger evidence in the G12 population.

On the basis of that, we have a hierarchical testing strategy where the first evaluation is in that G12 subset, that 85% subset. If we've reached statistical significance there, then a second analysis is done of the broader group that includes all RAS mutations as well as RAS wild-type patients. It's a very small percentage of pancreatic cancer patients have no detectable RAS mutation. Those are included in the broad secondary analysis to give the possibility of an all-comers label.

Okay. And just to confirm, so the analysis is triggered by the OS event rate in the G12X subset. Is that correct?

No, it's an overall event rate number. There's a single number, but it's largely driven by what we expect in the G12 population because we just have the most the deepest data set around that and therefore, can make stronger predictions around it. But it is an overall number that's a minimum threshold above which we can then begin to look at the data.

Understood. And then in terms of potential regulatory review, you obviously already have announced recently the breakthrough therapy designation. You also have received the Commissioner's Priority Review Voucher. And so what are the implications of that on the potential regulatory review process in your opinion?

Yes. Daraxonrasib in pancreatic cancer is somewhat special in that it has breakthrough designation. It now has an orphan drug designation, and it was one of the first 9 Commissioners' National Priority Vouchers to be issued. So it's got the triple crown. Now it just has to deliver in terms of the data.

All of those create some opportunities to accelerate the review process, particularly the breakthrough designation gives us access to greater communication. We're likely to end up with a priority review even without the voucher. And then with the voucher, the FDA has indicated that their intention is to work with us to try to streamline the review process so that it could happen in as short as 1 to 2 months after they accept an NDA filing. That's an important consideration. That 1- to 2-month number that Dr. Makary has used is really relevant only after they've accepted an NDA filing, which we won't be able to do until we've completed analysis of the data.

So there are some steps that take place that really nobody can accelerate. They're just sort of the physics of running the trial. Once we have those data, of course, we'll move as quickly as possible to get it in the hands of the FDA. Right.

And then perhaps moving to first-line pancreatic cancer. You obviously recently announced plans to initiate the RASolute 303 study there, which is a 3-arm trial. And so maybe just remind us of the decision process that went into designing that trial and how you're tracking towards initiating the study?

Well, I'll work backwards. We're on track to initiate that study in 2025, and we have about 7 weeks left to deliver on that promise. Now the first-line data or first-line trial is supported by really 2 completely different sets of data. We have the second-line data that really is the foundation of the RASolute 302 trial. The Phase I/II data showed very strong initial both tolerability safety as well as efficacy with the results of both PFS and OS, not only exceeding the benchmarks in the field for second-line pancreatic cancer, but also exceeding the benchmark -- significantly exceeding the benchmarks for first-line pancreatic cancer. So those data alone are sufficient to drive our conviction that a first-line trial should be pursued.

In addition, we recently disclosed data -- actually in first-line patients, and we had 2 sets of data. One is patients who received monotherapy daraxonrasib, and those data are quite encouraging from an ORR point of view. We don't have durability data yet, but the ORR in that patient population was roughly 47%, again, exceeding the best reported results in first-line patients with standard cytotoxic chemotherapy.

In addition, we reported a reasonably sized cohort of patients who were treated concurrently with GEM/abraxane, one of the 2 major standards of care for pancreatic cancer treatment, plus daraxonrasib. And those patients also did well. They tolerated the regimen. They had a good dose intensity, and we reported a response rate of -- in the ballpark of 55%.

So both of those data sets really complement the much larger data set that we've had and longer follow-up we've had in second line that all suggest that pancreatic cancers are RAS-driven cancers, they're RAS-addicted cancers, whether they're first line, whether they're second line, whether they're third line, it is the underlying biology of pancreatic cancer. And so treating with a very effective RAS inhibitor and particularly a RAS(ON) inhibitor from Revolution Medicines is a compelling thing to do. So that led us to design the first-line trial.

We think there are 2 opportunities to win in this trial with 3 arms. Patients will be randomized 1:1:1, so equally across 3 different treatment regimens. One is standard of care chemotherapy. The second is daraxonrasib monotherapy and the third is daraxonrasib plus chemotherapy. So mimicking the data that we have from the first -- from the Phase I trial.

So from a patient perspective, that means they have a 2 out of 3 chance of being randomized into a daraxonrasib containing arm. That is a highly attractive clinical trial for patients. It also means they have a 2 out of 3 chance of receiving standard of care cytotoxic chemotherapy. So that's encouraging. And only 1 out of 3 chance of receiving only cytotoxic chemotherapy, which is the standard of care. So we're excited about that trial and look forward to getting that off the ground.

Question on the study. So if both treatment arms succeed, which is plausible or even likely over chemotherapy alone, how would physicians weigh whether to use daraxonrasib monotherapy or the combination?

Yes, it's an interesting point. From our point of view, the best thing we can do is create as many options as possible for patients and their caregivers. This is a very devastating disease. It doesn't make sense for us to sort of pre-guess what's the one thing that ought to be made available for patients. If we have multiple regimens that we think could offer patients better quality of life and longer life, we ought to make those available, let each patient and their doctor determine what approach they want to take.

If somebody is a 45-year-old robust, has no other medical problems, they might say to their doctor, I want to do everything I can to shrink this tumor. Give me whatever chemotherapy you have, give me whatever targeted therapy, I'm ready for it. I'm robust enough to take it. If somebody is an 82-year-old who has other medical problems, they might say, I can take a daily pill. I don't want to go to an infusion center. I want to use every day to spend time with my grandchildren. Those are 2 extremes, and there might be everything in between.

So we absolutely believe that creating multiple options if we can, is the best thing to do, and we don't need to predefine for doctors what regimens they must choose. And I'd say that even extends to the rest of our pipeline, where we have other RAS(ON) inhibitors that are proving to be quite compelling as well. And some of the indications that are associated with those may overlap. with indications for which there may be approved daraxonrasib-based therapies. That's fine. More options means more patients will have access, more patients will find a regimen that's appropriate for them.

Okay. Then a question on your recently initiated study in locally advanced pancreatic cancer, which is sort of in the adjuvant setting. Perhaps just remind us of sort of what are outcomes for patients today in the adjuvant in this treatment setting? And yes, what degree of improvement do you think would be necessary to demonstrate for folks to use daraxonrasib for the, I think, 2-year time frame?

Sure. Thanks, Michael. Let me just clarify. This is for patients with resectable disease, which is distinct from locally advanced, which is considered unresectable disease. So just to differentiate those. Resectable disease means that CT scan showed a surgeon convinced the surgeon that they think they could go in and remove enough of the tumor to give the patient a chance at a cure.

Now in reality, of those patients who go to surgery, about 2/3 of them end up actually being truly resectable, meaning fully resectable with clear margins or minimal cancer remaining in the margins. Those patients are called resectable, surgically resectable or resected. And those patients typically do receive standard of care chemotherapy. Some physicians use FOLFIRINOX, some use GEM/abraxane, some use capecitabine. So there are a few different variants of the regimen around the world.

But in virtually all cases, patients will receive chemotherapy either before after or both before and after surgery. And then they tend to have a fairly long disease-free period, but almost everybody progresses. Of the truly resectable patients, 80% of patients will recur with metastatic disease, roughly 20% will have long-term durability out of it. So there is the chance to have a cure or something approaching a cure, but it's rare for those patients even with the cytotoxic chemotherapy.

The question is whether daraxonrasib might change that. And we've designed a trial. I think it's a very simple and attractive trial design. It allows patients to receive standard of care, whatever their local standard of care is, with a minimum of 4 cycles of chemotherapy, which may be before, after or both before and after surgery, so perioperative chemotherapy, surgical resection, and then they get randomized to receive either daraxonrasib monotherapy or no treatment at all and observation. And those patients will simply be followed. And the chance of increasing cures or prolonging disease-free survival is -- there's a high enough chance that this is a very worthwhile study to do. It's going to be very easy for patients to enroll in, and it's an exciting approach.

Great. Is there opportunity to leverage surrogate endpoints in the study? Or would you have to just wait for events to occur?

I think it's going to be event-driven. I wouldn't rule out that there will be some biomarkers tested here. But the real gold standard is disease-free survival, which is the equivalent of progression-free survival, but it's what's used in a postsurgical setting. So disease-free survival. And if we can lengthen that for patients or even convert some of those patients into cures, that would be a fantastic addition to the field.

Okay. Okay. Then perhaps moving to non-small cell lung cancer where you have the RASolve 301 study up and running in second-line patients. Maybe just remind us how the study has been enrolling relative to expectations given that lung cancer can be a little bit more competitive for clinical studies?

Yes. That trial is doing fine. Daraxonrasib potentially serves all RAS mutants, all RAS mutations that drive non-small cell lung cancer. So that's about 30% of non-small cell lung cancers. It's not an insignificant population. Right now, the only subset of patients who are served by a RAS-targeted agent are those that have the G12C mutation, which is -- represents about 12% out of the 30%, so a little bit more than 1/3 of those. The other, let's say, 2/3 are non-G12C for which there are no targeted agents at all.

In this trial with daraxonrasib, a patient with any RAS mutation can enroll. So that means potentially daraxonrasib might serve across the entire 30% of non-small cell lung cancers that are RAS driven. We are enrolling that patient now -- patients into that trial in both the U.S. and outside the U.S. in the EU and Japan, and it is on track to our projections. We're doing well with it.

Great. And then in first-line non-small cell lung cancer, the market is a bit more fragmented with different patient subsets. And you did recently announce or confirm plans to initiate a registration study there as well of daraxonrasib in combination with chemo and pembrolizumab, right? Just help us how you made the decision to include chemo versus pursuing a chemo-free regimen?

Yes. About 1/3 of patients with first-line non-small cell lung cancer have a PD-L1 high phenotype, and those patients can receive just pembrolizumab alone. But any regimen in first-line lung cancer right now is going to include pembrolizumab. That's pretty much standard of care, except in maybe some parts of the world. I think in China, they use a different PD-1 antibody from BeiGene BeOne. But generally, Keytruda is the standard of care around the world. So that's the first thing you have to be able to do with any RAS inhibitors to combine with pembrolizumab.

Daraxonrasib from all of our studies so far is readily combinable with pembrolizumab. We've not seen any evidence of particular toxicities that are created by combining the 2, which already differentiates it from many other RAS inhibitors in the field. So we know we can combine with pembrolizumab. We also know we can combine with chemotherapy, first-line chemotherapy, platinum-based doublets.

So it makes sense for us in going into first line is to really try to differentiate by combining all 3 of those agents, chemotherapy, platinum doublet chemotherapy, pembrolizumab and daraxonrasib. We think that gives patients the greatest chance of having an outcome that is differentiated from what they might have with either pembro or pembro plus chemo alone.

Right now, in the U.S., patients are free to take chemo plus pembro regardless of their PD-L1 status. And so that makes it a universal treatment as opposed to pembro alone, which is just for that small subset. So we're taking the approach of going with the broad-based strategy. Everybody would receive the KEYNOTE-189 or chemo plus pembro plus daraxonrasib.

Great. And then help us understand on your latest thinking on how to incorporate your mutation selective inhibitors into the lung cancer treatment paradigm longer term?

So we have 2 mutant selective inhibitors that are in the clinic now, both of which are, I think, quite distinguished molecules. We have a KRAS -- RAS G12C(ON) inhibitor. It's the first of those to enter the clinic. And it's an exciting compound. It's very well tolerated, has really a de minimis safety profile. Investigators are excited by it, and it's done very well as monotherapy. It also appears to be combinable with pembrolizumab and to be part of really whatever regimen can make sense.

It's most distinguishing feature right now from a profile perspective is that we've shown that patients who have been on a RAS(OFF) inhibitor, one of the first-generation RAS G12C inhibitors and then progressed. If they go on to take elironrasib, that's our G12C(ON) inhibitor as monotherapy, we've reported a response rate that's above 40% and a PFS that's above 6 months, which is quite remarkable for these third-line patients. These data were first reported or a subset of these data were first reported 2 years ago when we first announced the elironrasib's initial results. But now with longer follow-up at a larger sample, it has continued to show essentially the same results plus the durability that I alluded to.

I think the field is quite excited about that, and that is a place where we think we can make a real difference right off the bat. That patient population, that is patients who have progressed on a RAS(OFF) inhibitor, a G12C(OFF) inhibitor, will continue to grow. So that population will be a growing unmet need that can be served by elironrasib. So stay tuned for our plans. We've not yet announced any plans, but we're excited about that opportunity.

We also think there's going to be room for elironrasib in other lines of therapy. We're evaluating that. We know that we're entering a crowded space. We don't do that lightly. So we would want to go into that competition with the greatest possibility of moving the needle for patients, and we're working to make the determination about what's the best way to do that.

Okay. And on zoldonrasib, your 12D inhibitor, you did recently announce plans to initiate a registration study in first-line pancreatic cancer.

Yes.

Just maybe talk a bit more about the thought process in terms of how a study could potentially look like and how this could be positioned relative to the daraxonrasib?

0 So zoldonrasib is a RAS G12D selective (ON) inhibitor. So it follows the same paradigm as our other RAS(ON) inhibitors. It's also a covalent inhibitor. It's the only covalent inhibitor of any target that's aspartic acid containing. It's the only covalent inhibitor that targets that D or aspartic acid. It's never been done before in the pharmaceutical industry. It's the only protein of any disease that's targeted by a covalent agent. And the advantage of that is that it permanently disables the molecule, the target. Once it binds, it's irreversibly bound. It takes it out of commission. That's a dead molecule at that point. It's orally bioavailable, and it has a safety AE profile that's very attractive. It's often been described by patients and investigators as being indistinguishable from placebo, which, again, moves it into really a rarity among RAS inhibitors.

That gives us the potential to apply it in a variety of different ways. It could be used as monotherapy, but it could also be applied with the most aggressive chemotherapies that are out there because it won't add -- it's not expected to add toxicity on top of those chemotherapies. So we have a range of possibilities.

One of the things we're excited about with zoldonrasib is combining it with chemotherapy. Another thing we're excited about is combining it with daraxonrasib. We have found in a variety of preclinical studies and now reported in 2 different clinical studies, one in lung cancer and one in colorectal cancer that combining a RAS mutant selective RAS(ON) inhibitor with the RAS multi-selective daraxonrasib leads to greater activity than either agent alone in many instances. And that creates a unique opportunity for us to really try to hit the mutant very hard with the mutant selective inhibitor while also suppressing all the other forms of RAS in a tumor cell that might be contributing to oncogenesis.

So those are 2 very prominent options we have in a first-line pancreatic treatment strategy. We've not yet announced that strategy, although it will be a combination regimen, and we will clarify that as we approach initiation of that trial. I wouldn't necessarily assume that we'll only pursue one approach. We think that there are 2, 3, 4, 5 potential approaches. We'll pick the regimen or regimens that we think have the most promise.

Sounds good. Well, with that, I think we need to wrap up. Thank you so much, Mark. Really appreciate it.

Thank you. All right.

Good day, and thank you for standing by. Welcome to the Revolution Medicines Q3 2025 Earnings Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded.

I would now like to hand the conference over to your first speaker today, Ryan Asay, Senior Vice President of Corporate Affairs. Please go ahead.

Thank you, and welcome to our third quarter 2025 earnings call. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive Officer; Dr. Wei Lin, our Chief Medical Officer; and Jack Anders, our Chief Financial Officer; Dr. Steve Kelsey, our President of Research and Development, Dr. Alan Sandler, our Chief Development Officer; and Anthony Mancini, our Chief Global Commercialization Officer will join us for the Q&A portion of today's call.

I'd like to inform you that certain statements we make during this call will be forward-looking because such statements deal with future events and are subject to many risks and uncertainties. Actual results may differ materially from those in the forward-looking statements. For a full discussion of these risks and uncertainties, please review our annual report on Form 10-K and our quarterly reports on Form 10-Q that are filed with the U.S. Securities and Exchange Commission. This afternoon, we released financial results for the quarter ended September 30, 2025, and recent corporate updates. The press release and updated corporate presentation are available on the Investors section of our website at revmed.com.

With that, I'll turn the call over to Dr. Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive Officer. Mark?

Thanks, Ryan, and good afternoon. At Revolution Medicines, we are tireless in our commitment to revolutionizing treatment for patients with RAS-addicted cancers through the discovery, development and delivery of innovative targeted medicines. With robust operational capabilities, financial strength and the compelling clinical stage RAS(ON) inhibitors, we are building the leading global RAS-targeted medicines franchise that we believe has the potential to transform treatment for patients living with pancreatic, lung and colorectal cancers. In the quarter, we continued to make substantial progress as we scale the organization and advance our pipeline to fulfill our global development and commercialization ambitions.

Today, we'll begin by highlighting recent progress across our pipeline, beginning with daraxonrasib in pancreatic cancer. I'd like to note that daraxonrasib has received 3 special designations from the FDA, recognizing its potential role in treating patients with pancreatic cancer an aggressive disease that is nearly always caused by a RAS mutation. Previously, daraxonrasib was awarded breakthrough therapy status. And recently, it received both orphan drug designation and an FDA commissioner's national priority voucher for accelerating review of a new drug application. These highlights the significant unmet medical needs in pancreatic cancer, and the potential of this investigational drug to transform treatment for patients living with this devastating disease.

I'd like to invite Dr. Wei Lin to walk through our most recent clinical updates in pancreatic cancer, Wei.

Thanks, Mark. Daraxonrasib our RAS(ON) multi-selective inhibitor with a promising clinical profile in multiple indications, including pancreatic cancer. In September, we presented long-term follow-up data from the Phase I [ director ] monotherapy cohort of patients with second-line metastatic pancreatic cancer. These results reinforce our understanding of the strong clinical antitumor activity and durability. The acceptable safety and tolerability profile remained consistent with earlier findings with no new safety signals observed. Slide 10 shows that with longer follow-up, durability outcomes remained encouraging. The estimated median progression-free survival for patients with both the RAS G12X and all RAS-mutant groups exceeded 8 months. The estimated median overall survival was 13.1 months and 15.6 months for patients in the G12X and RAS-mutant groups, respectively, with a lower bound of 95% confidence interval at approximately 11 months. These results are particularly compelling. Especially in the context of standard of care cytotoxic chemotherapy regimens that were reported in randomized controlled trials to provide a median over survival of 6 to 7 months in the second line. And approximately 11 months in the first-line setting. RASolute 302, our Phase III registrational trial in patients with second-line metastatic PDAC. Is winding down enrollment globally as we near completion of enrollment across all U.S. and international sites. We remain on track for an expected data readout in 2026.

In September, we also shared encouraging initial results for daraxonrasib in first-line metastatic pancreatic cancer, both as monotherapy and in combination with standard care chemotherapy. As shown in Slide 11, daraxonrasib monotherapy induced tumor regressions in most patients with an objective response rate of 47% and disease control rate of 89%. The majority of patients remained on-site treatment as of the data cutoff. While the data were not sufficiently mature to estimate the median progression-free survival or overall survival. We continue to follow these patients to assess the durability of clinical benefit. The acceptable safety profile of daraxonrasib monotherapy in the first-line metastatic setting, was generally consistent with what has been reporting in patients with second-line metastatic disease. On Slide 12, the combination of daraxonrasib plus gemcitabine, nab-paclitaxel or GnP, chemotherapy also delivered significant antitumor activity, represented by deep and sustained tumor regressions. With a rejected response rate of 55% and disease control rate of 90%. Both patients remained on treatment as of the data cutoff. Again, Longer follow-up is required to estimate median progression-free survival and overall survival.

As with monotherapy, the combination regimen showed an acceptable safety profile. The rates of premium related adverse events were additive of the individual agents. No new safety signals were observed. We expect to share updated data from patients treated with daraxonrasib with or without GnP in first-time PDAC, including preliminary durability in the first half of 2026. But on the encouraging early phase data in the first line and second settings, we are advancing RASolute 303, a randomized 3-arm Phase III trial in patients with first-line metastatic PDAC, as shown on Slide 13. This recreational trial will compare daraxonrasib monotherapy or daraxonrasib plus GnP followed by daraxonrasib monotherapy to a comparator arm of GnP low. The design of this 3-arm study provides 2 distinct opportunities to demonstrate potential survival benefit for patients. treatment with daraxonrasib as monotherapy in first line, followed eventually by chemotherapy in second line or alternatively, treating concurrently with both daraxonrasib and chemotherapy in first line.

Both strategies have scientific and clinical merit and deserve to be evaluated. We remain on track to initiate RASolute 303 this year. I'd like to provide an overview of the current standard of care in the setting of resectable PDAC. Of surgery, along with [indiscernible] chemotherapy offers patients the possibility of a cure. The relapse rate is high at approximately 80%. The current standard care for perioperative treatment is cytotoxic chemotherapy, either modify FOLFIRINOX or gemcitabine, [ capecitabine ] the publicly reported disease-free survival rate on these chemotherapy regimens ranges from 13.9 months to 21.6 months. Our 3-year disease-free survival ranges from approximately 20% to 40%. We believe there remains significant room for improvement that may be served with RAS targeted therapy. The strength of the daraxonrasib monotherapy data so far in both first and second-line Metsa disease provides a compelling rationale for advancing daraxonrasib into the Aspen setting. And Slide 15 shows our Phase III trial design, RASolute 304 in parotid therapy. We plan to evaluate approximately 500 patients after surgical reception and 4 months or more parotid therapy with the local standard of care, either FOLFIRINOX or gemcitabine, capecitabine. [indiscernible] before and/or after surgery. Patients will be randomized to either observation or drug from acid monotherapy 300 milligrams daily for 2 years. The primary endpoint will be disease-free survival with secondary endpoints of overall survival and safety. We have initiated this trial and site activation is currently underway. Also touch briefly on [indiscernible] our covalent RAS(ON) G12D selective covalent inhibitor in pancreatic cancer. Zoldonrasib has demonstrated a compelling clinical profile with encouraging anti-tumor activity and a particularly favorable safety tolerability profile. With this differentiated profile, we believe zoldonrasib as high potential to contribute as a key component of a combination therapy in first-line PDAC with current standard care chemotherapy and/or with daraxonrasib, as a RAS(ON) inhibitor doublet. The potential for this doublet was featured at last month's triple meeting. For new preclinical data demonstrated that the combination of zoldonrasib with daraxonrasib can maximally inhibit RAS G12D and improve both the depth and durability of response. We expect to initiate our first zoldonrasib combination registrational trial in first-line metatatic PDAC in the first half of 2026. We look forward to share the trial details and additional supporting data around that time frame.

I'll now return the call to our CEO. Mark?

Thank you, Wei, following closely behind pancreatic cancer, our non-small cell lung cancer clinical program remains an area of strategic priority, and we are progressing well in our efforts. Focusing first on daraxonrasib the RASolute 301 registrational trial studying daraxonrasib versus docetaxel in previously treated patients with RAS-mutant non-small cell lung cancer continues to enroll patients across sites in the U.S. and is now also enrolling in Europe and Japan. We also continue advancing plans to initiate a registrational trial in the first-line metastatic setting in 2026 and evaluating daraxonrasib in combination with pembrolizumab and chemotherapy, and we expect to disclose study details around the time of initiation.

As a reminder, this plan was based on the encouraging initial data we presented in May showing the combination of daraxonrasib with pembrolizumab with or without chemotherapy was well tolerated and demonstrated encouraging early antitumor activity. In the G12C non-small cell lung cancer space, we continue to make progress with elironrasib, our RAS(ON) G12C inhibitor. Last month, at the triple meeting, we presented encouraging monotherapy data in heavily pretreated patients with G12C non-small cell lung cancer who had received a median of 3 prior lines of therapy, including treatment with a G12C inhibitor. As shown on Slide 22, elironrasib demonstrated a confirmed objective response rate of 42%, a disease control rate of 79% and a median duration of response of 11.2 months.

On Slide 23, the median progression-free survival was 6.2 months in these heavily pretreated patients. While the median overall survival had not yet been reached, 62% of patients were alive at 12 months. We are encouraged by the strength of these data in late-line KRAS G12C OFF inhibitor experienced patients and continue to expand enrollment in this and other elironrasib monotherapy in combination studies while exploring a number of options for continued development of this differentiated RAS(ON) G12C selective inhibitor. Regarding zoldonrasib in lung cancer, we are evaluating a Phase I monotherapy expansion cohort of patients with previously treated non-small cell lung cancer as well as exploring combination regimens, including zoldonrasib with pembrolizumab and zoldonrasib with daraxonrasib. In addition to plans mentioned earlier to initiate a registrational trial for a zoldonrasib combination in patients with first-line metastatic pancreatic cancer in the first half of 2026. We expect to initiate one or more additional pivotal combination trials in 2026 to incorporate either zoldonrasib or elironrasib. We also continue to advance RMC-5127, an oral tri-complex RAS(ON) G12V selective inhibitor. As a reminder, approximately 48,000 patients are diagnosed with a KRAS G12V mutant cancer in the U.S. each year, including non-small cell lung cancer and gastrointestinal cancers, such as pancreatic and colorectal. RMC-5127 has been shown to induce deep and durable regressions in preclinical models, and it has been advancing towards clinical development. We are on track to initiate the planned first-in-human trial in Q1 2026. Based on the progress we've made across our 3 clinical stage assets, we are confident in the potential of our RAS(ON) inhibitor portfolio to change the standards of care across pancreatic, lung and colorectal cancers. We also have several discovery and clinical collaborations designed to expand the range of treatment strategies we can bring to bear for patients with RAS-addicted cancers. These collaborations enable us to explore diverse combinations of our RAS(ON) inhibitors with inhibitors of novel disease targets, including [ ovoprimetastat ], a PRMT5 inhibitor under our agreement with Tango Therapeutics and [indiscernible] , a bispecific PD-1 VGF inhibitor under our agreement with Summit Therapeutics.

With our rich promising clinical and preclinical pipeline, we continue making investments to scale our organization to meet the extraordinary range of opportunities that affords. In support of this work, we've made new key appointments across late-stage functions. In our R&D organization, we announced that Dr. Alan Sandler joined RevMed as our new Chief Development Officer. As an accomplished leader in oncology with a strong track record in cancer drug development, Alan brings valuable insights and expertise to our organization. We likewise expanded and strengthened our global and regional commercialization capabilities with additional appointments across our commercialization functions, including 2 key regional leaders. Alisha Gardner was appointed Senior Vice President and General Manager of the U.S. region, and Gerwin Winter, recently joined RevMed as Senior Vice President and General Manager of the European region. .

I'd now like to turn the call over to Jack Anders to summarize our third quarter financial results.

Thanks, Mark. We ended the third quarter of 2025 with $1.93 billion in cash and investments. This balance includes the receipt of the first royalty monetization tranche of $250 million in June 2025 from our partnership with Royalty Pharma, and there remains an additional $1.75 billion in future committed capital under this arrangement. Turning to expenses. R&D expenses for the third quarter of 2025 were $262.5 million compared to $151.8 million for the third quarter of 2024. The increase in R&D expenses was primarily due to increases in clinical trial-related expenses and manufacturing expenses for our 3 clinical stage programs with daraxonrasib being the largest driver of the increase given the ongoing Phase III trials Personnel-related expenses and stock-based compensation expense also increased in 2025 due to additional headcount. G&A expenses for the third quarter of 2025 were $52.8 million compared to $24.0 million for the third quarter of 2024.

The increase in G&A expenses was primarily due to increases in personnel-related expenses and stock-based compensation expense associated with additional headcount, increased commercial preparation activities and increased legal expenses. Net loss for the third quarter of 2025 was $305.2 million compared to $156.3 million for the third quarter of 2024. The increase in net loss was primarily driven by higher operating expenses. We are reiterating our 2025 financial guidance and expect projected full year 2025 GAAP net loss to be between $1.03 billion and $1.09 billion, which includes estimated noncash stock-based compensation expense of of between $115 million and $130 million.

That concludes the financial update. I will now turn the call back over to Mark.

Thank you, Jack. We are highly encouraged by continuing momentum as we seek to build a leading global targeted medicines franchise for patients living with RAS-addicted cancers. We believe our strong financial position expansive development plans for our compelling pipeline assets and global commercialization ambitions will allow us to establish new global standards of care. We've made great progress across our pancreatic and lung cancer clinical programs and continue to generate encouraging data that informs our plans in colorectal cancer. Underpinning the passion and drive at RevMed is our collective commitment to patients. November is recognized globally as both pancreatic cancer awareness month and lung cancer awareness month, which align with 2 highly visible cornerstones of the clinical development efforts by our organization.

We have expanded our partnerships with the advocacy community to better understand the dynamics that affected patients experience with RAS-driven cancers. Insights from these engagements will continue supporting our development of patient-friendly clinical protocols, access solutions and educational initiatives. We hope you will join us in supporting the high-impact work by advocacy organizations as they seek to improve outcomes for patients through educational resources, support and research. Before closing, I'd like to acknowledge the continued support of our patients and caregivers, clinical investigators, scientific and business collaborators, advisers, shareholders and importantly, the remarkable team of revolutionaries who drive exciting steps forward on behalf of patients.

This concludes our prepared remarks, and I'll now turn the call over to the operator for the Q&A session.

[Operator Instructions] Our first question comes from the line of Jonathan Chang of Leerink Partners.

How are you thinking about the impact of receiving the commissioner's national priority voucher on daraxonrasib time lines and your plans?

Jonathan, thanks for your question. Well, obviously, we're very proud to have received 1 of the first 9 vouchers. Actually, it's the only oncology product that's featured in that particular set. The stated goal of that voucher program, the pilot program is to accelerate the review time lines by some significant amount potentially making the review time line short just 1 to 2 months, and we'll do everything we can to support that. But we've been aggressively preparing for the data readout and then an expected submission of an NDA and to be ready at the earliest possible time for launching a product. I don't think at this point in time, we anticipate that we would have any difficulty meeting whatever time line might be delivered under the CNBB process.

Our next question comes from the line of Charles Zhu of LifeSci Capital.

Congrats on the progress. I've got a couple regarding RASolute 304. The adjuvant or axon RASolute trial. This might be a little naive, but can you help us understand and perhaps educate us on the decision to randomize against observation in perioperative chemotherapies setting. And is there, I guess, clinical value in maybe at some point, evaluating whether or not one could displace chemotherapy in this particular disease setting as well. Can you also help talk about -- help us understand and talk about the requirement for at least 4 months of perioperative chemotherapy as an eligibility criteria prior to randomizing against the 2 arms?

Thanks a lot, Charles, for your question. I think Dr. Sandler would be happy to comment on the rest of the RASolute 304 trial.

Great. Thanks. Sounds like it's a 3-part question, and hopefully, I'll remember all 3 parts. So the aspect of -- I'll start with the 4 months of therapy, that's considered to be the standard of care that's been established previously. And so we wanted to add to that. So we're requiring that patients received standard of care therapy. And for that, and that's at least 4 months of therapy. So that's number one. Then the idea is to randomize patients to no further treatment or 2 years of additional adjuvant therapy with daraxon. And the idea then is to build upon the success that has been seen modest but success that has been seen with chemotherapy in this setting. And so this, I think, offers the best approach to patients with [indiscernible] pancreatic cancer. Your last question, I think, was to potentially replace chemotherapy. And I think based on what we see from the adjuvant study, we'll reassess a plan accordingly. But I think we've -- we're very excited about this particular opportunity already and are looking forward to initiating the trial.

Our next question comes from the line of Michael Schmidt of Guggenheim.

Congrats on all the progress. couple of questions on PDAC. So as we think about RASolute 302, how would you expect results from the Phase II study to translate to the large global Phase III study? Are there any anticipated differences, for example, in patient characteristics when you go from a smaller Phase II to a large global study? And secondly, I guess, in anticipation of positive data next year, how are you tracking towards commercial readiness in terms of CMC, manufacturing capacity and then ramping up commercial infrastructure?

Thanks, Michael. Appreciate the questions. Maybe Dr. Lynn can first comment on the Phase III versus Phase I/II question.

Thanks for the question. So it's certainly an important question that we thought very deeply before initiating Phase III. So we look extensively at the patient's road in the Phase I cohort compared to the Phase III randomized studies that have been reported historically. I think our population since fairly similar in looking at all the baseline characteristics that are prognostic or predictive of response to either chemotherapy or one therapy. There's a almost all the metrics are either comparable or in some measures, the historical Phase IIIs were actually a little worse. So I think we do have a patient population in the Phase I setting that's fairly representative, of what we expect to enroll on the Phase III.

And furthermore, the RASolute 302 is a global study, the predominant enrollment will occur in the U.S. with representing enrollment in Europe and in Japan. And therefore, another reason why we feel that the population on the Phase I will translate into the Phase III. So -- and then finally, look historically, the trial for, there's a dereconsistency over a period of a decade or 2 all the Phase III trial delivering very, very similar performances with the chemotherapy. Again, I think we expect the performance certainly on the control arm will perform historically similar. So all these give us a large measure of reassurance that we can replicate to a large net measure because the patient population as well as the performance of the treatment historically are operating representation.

And then the question regarding commercial readiness, maybe I'll answer a comment part of it and then Anthony Mancini can comment on the other part. With regard to manufacturing, we have a very strong organization and supply chain that's really been prepared over the last number of years, we're already scaling at the proper level to be able to support whatever level of uptake there might be, should we be able to launch a product. So I think we're in a very strong position there and don't anticipate anything that could pose a significant problem for us. with regard to commercialization readiness beyond that, maybe Anthony can comment. .

Yes. Thanks, Mark, and thanks, Michael, for the question. We're really pleased with how our launch readiness plans are advancing. We've as was outlined earlier, we now have experienced and talented executives leading our commercialization team, including now building into the region. So across multiple functions, including medical affairs, market access, marketing and sales. And we're deeply engaged in market-shaping activities and planning and KOL and advocacy organization engagement and building broader organizational capabilities around launch readiness. We continue to add highly experienced and talented team members as we advance our organizational launch readiness, including U.S. field-based teams, and we're making great progress there. And we're confident in our ability to continue to attract the right talent with the right experience and capabilities, which is a key success factor for a successful launch, and we're confident that we can do that.

Our next question comes from the line of Andrea Newkirk of Goldman Sachs.

This is Morgan on for Andrea. Based on the initial frontline metastatic PDAC data, how do you think about the efficacy of combination treatment relative to monotherapy, rather greater time on treatment could increase the delta on ORR and DCR and then with regard to updated daraxonrasib monotherapy and combination data in the first half of next year in frontline metastatic PDAC, how should we be thinking about durability?

Thanks for the question, Morgan. Wei would you like to comment on those -- the first question being the difference -- what level of difference is there between monotherapy versus combination and will that clarify over time.

Yes. So the monotherapy versus combination in frontline, I think as discussed previously, really test 2 very distinct hypotheses. I think one is really the sequential treatment by introducing additional line of therapy because currently stand of care, only 2 lines of effect therapy are exist for patients at an based and a 5 view based. And by using daraxonrasib monotherapy we used a third monotherapy. And could that introduction a third-line therapy with very promising data in the second-line setting translate to [indiscernible] overall survival. And then the other chemo combination are really test very distinct hypothesis, which is a potential synergy by combining the those patients still get 2 lines of therapy, but then the first line therapy is actually a combination regimen of a [indiscernible] plus center extending the progression survival that can also translate to on overall survive. So I think these hopefully will translate into surviving benefit as well as different options for patients who get tolerated a more potent regimen versus who are seeking better quality of life and for the -- that provides by monotherapy.

And just to add to that, of course, there's really no way to answer the question about how those 2 regimens compare, except to test them both. And they're both very credible in the meaty scientific apace. The second question, I think, had to do with what sort of update can be expected next year with regard to the durability of the effect that we have already reported. Yes -- we will -- we do intend to provide an update in the first half of 2026.

Our next question comes from the line of Brian Cheng of JPMorgan.

Just first on your voucher. What additional pieces of information have you learned on the use of it since you received it in mid-October Specifically, do we know which line of setting the vouchers for since the language in the press release seems to be more broadly applicable to a PDAC. And then we have a follow-up?

Yes. Thanks for your question, Brian. We don't really have any additional information to share with you today. We are certainly in ongoing dialogue with the FDA and learning more about how this voucher system will work. and what impact it might have on how we approach preparing an NDA, but no other comments available today. .

Okay. And then just quickly on Sodon's combo Phase III fund line PDAC now that you have 303 on track to start later this year. I'm just curious if you can talk a little bit about just some consideration that you currently have when it comes to the selection of the doublet versus triplet and I think also the active comparative piece, how should we think about which active comparator arm you should put in to make it -- make sure that physicians understand how they look at soon combo in the future?

Yes, that's a great question, and it perfectly tees up when we present some information about that, we'll be able to address all of those questions. But I assure you, we will comment on all of that. Maybe the big picture right now is just that we are taking multiple approaches to treating this devastating disease. And we're in the second or third inning of this battle. And we're going to keep investing in it until we've really moved the needle as much as we possibly can. So we're excited to bring that approach forward, and we'll give you more color about it when we are able to lay that out much more explicitly.

Our next question comes from the line of Marc Frahm of TD Cowen.

Congrats on all the progress. Maybe just sort of on that zoldonrasib first-line trial. Just the idea of only pursuing combinations. I guess, should we read into that the monotherapy maybe doesn't seem as durable as daraxonrasib as a monotherapy since you were interested in pushing forward the monotherapy in first line in that setting? And then I'd like we have a follow-up.

Thanks, Mark. I'm not sure about that last comment. I'm not sure that we ever gave any inclination with regard to zoldonrasib in first line and what sort of strategies we might pursue. So I don't think we need to explain something that I don't think we ever committed to daraxonrasib alone, we're setting in first line as monotherapy. We're going to learn a lot from that study. And zoldonrasib is an ideal combination agent because of its pretty remarkable safety and tolerability profile. So it is a real opportunity to see how far we can push things. And in terms of further differentiating options for patients we will certainly continue to be committed to that. So I don't think you should infer anything from that decision and that strategy other than we're looking for the best possible ways to deliver impact for patients that would complement the other options that are coming out of our portfolio.

Okay. That's helpful. And then on 302, now that you're getting pretty close to the end of enrollment, can you maybe speak to kind of how the event rate has been trending maybe relative to kind of how you guys were projecting it when you designed the trial? And then as the interim start to get taken, just what's the latest thoughts on disclosure strategy will you inform investors whenever an interim is taken or whatever the result of that was or likely only speak if the interim results in some sort of stoppage of the trial?

And personally, Mark, I think you're open to on those questions. Anything to comment on either of those at this time.

Our next question comes from the line of Leonid Timashev of RBC. .

Just wanted to ask on sort of the commercial opportunity, I mean, given that you recently hired President of EU strategy, just how you're thinking about the landscape in the European Union with respect to where patients lie in terms of commercial opportunity, the concentration there, awareness, diagnostic opportunities? Just anything you can speak to to how you think the European strategy might take shape?

Thank you. I appreciate that question. It's a gigantic question. So I'm immediately going to ask Anthony to address.

No. Look, it's -- there's been a lot of thought put into how we're thinking about bringing daraxonrasib patients. Clearly, different from many companies' opportunities with a first launch and a first indication. We think the second-line pancreatic cancer indication is a meaningful one -- so you can look at the in the key European markets, starting with Germany and the EU 4 and beyond, and there are many patients to treat. We think that will bring a compelling value proposition in Europe. And we think it's going to be a meaningful opportunity in Europe, in the U.S. and Japan. And so we're pursuing that. I think there's nothing more to comment on, except that those are our priority markets, and we intend to bring our best foot.

Our next question comes from the line of Clara Don of Jefferies.

This is Jen on for Clara. Could you talk about if there were any rationale behind starting the adjuvant study before the first-line study?

Jenna, thanks for your question. That's pretty straightforward. There's nothing profound underneath it. It's a simpler study, obviously, it's a single treatment arm and we're just able to get that up and running a little bit earlier, but I don't think it will materially differ in terms of the overall conduct of it, of course, that is going to be a longer study in terms of the readout given the time lines that we talked about. So it doesn't make much difference. And it just happened that we were able to proceed with it.

Our next question comes from the line of Asthika Goonewardene of Truist Securities.

So you've described what resistance mechanisms emerged with daraxonrasib and PDAC. And you should have a considerable amount of data with daraxonrasib non-small cell lung cancer, 2 underhood. So I'm just wondering, do you expect non-small cell lung cancer to also follow a similar path of resistance as PDAC or are there any new resistance mechanisms that are emerging that you can tell us about? I'm wondering how this guided your choice of selecting pembro and chemo for the combination versus just a chemo-sparing pembro combo? And then I have a follow-up.

Thanks for your question. That's sort of a subtle comment at the end of that question. Maybe Dr. Kelsey can discuss resistance what we know about PDAC expectations across other tumor types? And how has that affected our thinking for trial stuff.

The data that we have on emerging mechanisms of resistance to daraxonrasib non-source lung cancer is probably not sufficiently mature for public disclosure at this stage. There are a number of confounding issues around that. The first is, as you know, we declared our recommended Phase II dose for nonsense lung cancer after we had declared the recommended last dose in pancreatic cancer. So the information that we would only really be important at the recommended Phase II dose. The second is the number of people that actually have progressed and been documented to progress. And the third issue there are the number of patients with progression that actually has detect circulating CTDNA in order to make an assessment of whether there's anything to see. The other thing is that traditionally in non-small cell lung cancer, they appear to have been from the literature that's available a lot of resistance mechanisms that are possibly not even genomic. And so it's going to take a little bit more time to figure that out. And I think that all bets are off really mapping mechanisms of resistance in pancreatic cancer to mechanisms of resistance in non-small cell lung cancer.

We already know that the biological resistance mechanisms and portal cancer, for instance, to G12C inhibitors are different from the biological resistance mechanisms to G12C inhibitors and non-sale lung cancer. They are qualitatively similar and overlap but they're not, they're not identical. And I don't think that we can infer anything at this stage. With regards to how that information informs how we move forward with combinations, it really has no bearing on it. The selection of pembrolizumab as a partner for any of our RAS on inhibitors is driven really by 2 things.

One, one is the almost ubiquitous inclusion of pembrolizumab or an equivalent checkpoint inhibitor into the standard of care for non-small cell lung cancer. And the second is the increasingly compelling body of evidence that suppressing RAS does actually made pembrolizumab more effective because it profoundly changes the immune microenvironment for the and allow the immune system much more access to the tumor for a whole lot of reasons that we have published and a number of other groups have published. So -- when we have the data, we will disclose it, and it may influence how we move forward, and it may not. There are really 2 separate issues there.

And then if I can just tag on to Charles' previous question. By requiring in the 304 study, by requiring patients to have 4 months of chemotherapy, does this help select out patients who are deemed to be borderline resectable?

Yes, I'll take that. No, the -- first, I'll talk about the purpose of it was, again, the 4 months of standard of care. The question about your border line and the readily resectable. What we've done is we've allow those patients to undergo the standard treatment that they would locally and whether they're surgically resected not. And then the only way they're able to enter on study is if they are pathologically completely resected either with totally clear or narrow margins, the RAS0 or R1 that was shown on the slide. And then those patients are then randomized to the treatment as such. It -- in a sense, it eliminates those patients who are not able to be resected, but it also allows those patients with the borderline resectable, an opportunity to receive adjuvant therapy if they're perioperative therapy and surgery was successful. So it broadens the number of patients who have access to this therapy in the study.

To also add one point about the question of why 4 months. There is a variety of different approaches that people take in treating that disease. They all center around using chemotherapy before, after or both before and after and by requiring a standardized duration of treatment, we can make the patient population more uniform and easier to compare the 2 groups to each other. And avoiding balances in their treatment regimens.

Our next question comes from the line of Alec Stranahan of Bank of America.

Congrats on the updates. Two from us. First on zoldonrasib, Curious how you're thinking about the opportunity for zoldonrasib top of chemo versus daraxonrasib plus chemo and RASolute 303? Do you plan to enroll similar patients in both studies or maybe try to subset the frontline opportunity -- and secondly, how important is the RAS doublet in terms of your ideal commercial strategy longer term, specifically thinking about zoldonrasib in the front-line PDAC?

Okay. Maybe I can just comment on the second one and then maybe Wayne can comment can address your first question. So with regard to RAS inhibitor doublets, we still have high conviction about it. We just showed some data on zoldonrasib plus daraxonrasib in preclinical models, just last month at the triple meeting. And we're we feel like it's a compelling option. Just stay tuned as we roll out the various studies that will be coming in the future, I think we have high interest in that. The first question I think had to do with zoldon versus daraxon each in a first-line population and are we selecting patients differently between those obviously, one is all RAS mutations and the other is just KRAS G12D mutations. So there's that difference between them, but are there any other differences Way?

Clinically, the liability otherwise are no different. And I think in the Phase I setting when we're doing the combination with the chemotherapy, it's truly the ability are really mainly decide to make adequate organ function out to deliver a chemotherapy. So we are actually also very, very similar.

Our next question comes from the line of Joe Kevin Zaro of Mizuho.

Just maybe one quick one from me. As it relates to CRC, just wondering if there are any sort of key data points you are looking towards before maybe committing to earlier line later-stage trials and whether we should expect any of those data points in 2026. Thanks.

Thanks for your question. Thanks for joining us. Steve, do you want to comment on CRC.

Yes, I'm happy to do that. I'm not going to comment on timing because we haven't really guided to data disclosure with regards to colorectal cancer. But I think we have previously made it pretty clear that due to the biological complexity of rapid and colorectal cancer, we believe that combination therapy is absolutely essential. In order to maximize clinical benefit and the studies that are designed to figure out which combinations are most efficacious in that context are currently ongoing. And so as soon as we figured it out, then we can both a path forward. We also don't forget that we have the -- there are several dimensions to this issue.

I mean you mentioned one of them, which is line of therapy, whether or not we, Brian, go into the first-line status setting or whether we just tackle patients in the third and fourth line who are essentially being salvaged after chemotherapies failed. There are several different biologically rational combinations, including combinations with our own -- within our own portfolio, RAS(ON) doublets. And so we just need the opportunity to figure that out. It's a very complex -- colorectal cancer very complex disease. It's not entirely clear that RAS-mutant -- RAS is the only driver, the only oncogenic driver even in situations where it's actually mutated. So -- we've got -- we just sort of to happen.

Our next question comes from the line of Sean McCutcheon of Raymond James.

This is Yang on for Sean. We have 2 quick ones. First one, regarding the first-line zoldonrasib what kind of threshold for efficacy by looking at anticipating that you have the update for the front line and also commenting on the daraxonrasib and elironrasib combination in the first-line [indiscernible] ?

Thanks for your questions. Let me make sure I understand. The first question had to do with an update on first-line PDAC with direct assets.

No, sorry. Yes, that's a non-small cell lung cancer, frontline arose what's the threshold efficacy bar you're looking at?

Okay. So in lung cancer, since we indicated that we'll proceed with a trial, and we'll provide information later, Yes. I mean, obviously, we look at standards of care and what we see in a single-arm trial versus standards of care, even though they're not immediately comparable since it's not randomized data. But we'll look at standard of care and see if we can improve upon that. We typically wouldn't provide guidance as to what we consider an acceptable improvement. That's something that's a complicated topic. And that's between us and the statistical analysis plan and the FDA and so on. So no pre guidance to be able to offer you today on that. And your second question?

Yes. The second question is related to the combination potential with your RAS and G12C elironrasib in first-line [ CLC ]?

Okay. That's back to the RAS inhibitor doublet. And in this case, it's the doublet of elironrasib plus daraxonrasib and that, too, is a very interesting combination. I think I'd just reiterate that we are -- we believe that the combination of a mute selective inhibitor with the darax multi inhibitor provides potentially the benefits of both of those compounds as complementary and delivering the greatest impact, and we've now shown 2 clinical data sets that support that 1 in colorectal cancer and 1 in lung cancer. Both of which were directionally quite similar. As to how we prioritize that relative to other options, that's a very complex matrix of considerations. And don't have anything to be able to guide you too specifically today about that.

Our next question comes from the line of Laura Prendergast of Stifel.

I was just curious if it's possible, any sort of accelerated approval pathway could be there for first-line PDAC, whether that's an early cut for the Phase III study or something or anything else Also, how are you factoring daraxonrasib being approved in second line into how you're thinking about the statistics for OS in the first-line study?

Okay. Laura, thanks for your questions. Maybe I'll comment on the AA question and then maybe Wayne comment on the ones -- no comment.

That's basically. That's always a question for the FDA. That's not so much of a question for us. And I think there's no doubt that the initial data that we showed were quite encouraging. And I'm sure they're viewed that way by many people with what the FDA how they view it in a formal sense and what they want to do with it would be the subject of future dialogue and so on, really nothing that we can say about that. I would say, just generally speaking, we've had a pretty strong habit of focusing on full approval strategies, which I think has served us well with regard to PDAC for sure so far. We're not at the -- not the end game yet, but it seems to have made sense. And we'll continue to prioritize that. There may be some situations in which an accelerated approval can make sense to get something to patients as early as possible and where we think it makes sense and the FDA. More importantly, things that make sense, then we could always welcome that opportunity.

Yes. Regarding the design is to take is of the frontline, given our sand-mine efforts and data, I think probably there are several years to maybe that question. So on the first there is we're still designing a fully powered randomized trial to enable restoration based on more survival. And from that regard, doesn't really impact the fact that we deliver more survival. We do intend to deliver over so in front line, even [indiscernible] in the second line. I think the data taht we have reviewed so far, I think give us further confidence about the monotherapy benefit and therefore, give us confidence about the arm with molecule PS as a combination. Therefore, we're actually fully evaluating and fuel powering both arms and dependent testing them.

So that does affect in that that's the second layer. That's the second year. The third layer is, I think you may be hinting at a question we addressed previously, which is with the second approval in the U.S. that may be impact on crossover and whether when you pack our design. It doesn't really impact our design per se. Elena impacts our operational and our footprint, I think we'll certainly assigned the sites more on ex U.S. to minimize the impact of crossover due to the availability of daraxonrasib for segmentation in the U.S.

Our next question comes from the line of Ami Fadia of Needham.

And Apologies if this has been asked already. I've been judging some calls here. So my question is regarding the acquired alterations post dara monotherapy that was presented at the triple meeting. How do you see that potentially impacting the durability of response in first line? And where you're studying in combination with chemo, would you consider exploring combinations with other mechanisms at this stage?

Thanks, Ami. I'm trying to get to the gist of that question. Would we consider combining daraxonrasib with other compounds that target other potential drivers that are resistance mechanisms in order to increase [indiscernible] .

That's right.

Sure. We're already considering and we're already actively exploring some of those and are open to and may well expand that there's obviously many potential targets that could influence the outcome if you were to inhibit them. And we look at these opportunities all the time. We have a significant operation studying those, and we have a lot of inbound requests to combine things. And we try to prioritize them based on their scientific data behind them. And for sure, we'll continue to do that.

Thank you. This concludes the question-and-answer session. I would now like to turn it back to Mark for closing remarks.

Thank you, operator. Thank you to everyone for participating today and for your continued support of Revolution Medicines.

This does conclude the program. You may now disconnect.

Thank you for standing by, and welcome to Revolution Medicines Conference Call. Today's program is being recorded. [Operator Instructions]

I'd now like to introduce your host for today's program, Ryan Asay, Senior Vice President of Corporate Affairs. Please go ahead.

Thank you, and welcome, everyone, to this afternoon's webcast. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicines' Chairman and Chief Executive Officer; Dr. Steve Kelsey, our President of Research and Development; and Dr. Wei Lin, our Chief Medical Officer.

As we begin our presentation, I would ask that you review our legal disclaimer on Slide 2. And with that, I'll turn the call over to Dr. Mark Goldsmith, our Chairman and Chief Executive Officer. Mark?

Thanks, Ryan, and thank you to everyone who has joined us today. Slide 3. At Revolution Medicines, we remain committed to revolutionizing treatment for patients with RAS-addicted cancers through the discovery, development and delivery of innovative, targeted medicines.

We are making important strides in pursuit of this mission as we advance broad development programs for our first 3 highly innovative RAS(ON) inhibitors in the clinic, daraxonrasib, which targets a broad array of oncogenic RAS variants and 2 RAS mutant selective inhibitors, elironrasib and zoldonrasib for RAS G12C and G12D, respectively. Our ambition is to address unmet medical needs in common RAS-addicted cancers, including pancreatic cancer, lung cancer and colorectal cancer. To date, we've disclosed encouraging clinical progress.

Today's presentation will focus on our first-line treatment strategy for patients with metastatic pancreatic cancer, a highly RAS-addicted disease centered on daraxonrasib, a promising and our most advanced investigational RAS(ON) inhibitor. Momentarily, Dr. Steve Kelsey, our President of R&D, will provide an overview of current clinical practice and outcomes in first-line treatment and the new approach we are developing. Dr. Wei Lin will then present 3 new clinical data sets supporting this approach and concluding with our RASolute 303 trial design. I'll then close with a few remarks and open the call to Q&A. Steve?

Thanks, Mark. Moving on to Slide 4. Pancreatic adenocarcinoma, or PDAC, is a devastating disease. It remains the third leading cause of cancer death in the United States with an urgent need for better treatment options.

PDAC is the most RAS-addicted of all major cancers. More than 90% of PDAC tumors harbor a RAS-driver mutation. And in PDAC, as in other RAS-driven tumors, excessive signaling by RAS in the active or on state or RAS(ON) is a primary driver of tumor growth and a major contributor to drug resistance.

Approximately 56,000 patients are diagnosed with PDAC each year in the U.S. alone, and the unmet medical need remains huge. Most patients are diagnosed with metastatic disease, and those who are not will eventually progress to metastatic disease. Five-year survival is only 3% despite the best available current therapies.

Cytotoxic chemotherapy is currently the standard of care in all lines of therapy for metastatic PDAC, although patients with resectable disease may typically receive chemotherapy with surgery. Not all patients with metastatic disease ought to receive or are fit enough to receive first-line chemotherapy, which typically consists of either a 5-FU-based or gemcitabine-based regimen. Of those who do receive chemotherapy in the first-line setting, nearly half will progress and die during treatment, less than half of patients may receive a second-line therapy. Significant improvements in the treatment of advanced and metastatic PDAC are required.

A deeper look at conventional outcome measures for patients receiving first-line chemotherapy for metastatic PDAC further highlights the need for treatments with improved efficacy and tolerability. Slide 6 outlines reported results from Phase III trials evaluating both 5-FU-based and gemcitabine-based regimens. These 2 types of cytotoxic chemotherapy are used globally, albeit with some geographic differences due to physician preferences.

In the United States, most people are considered eligible for gemcitabine with nab-paclitaxel or GnP, while the modified FOLFIRINOX or NALIRIFOX regimens are generally reserved for patients with superior performance status. Efficacy and safety outcomes across the 2 regimens are generally similar. Commonly, GnP and 5-FU-based regimens have had reported objective response rates in the 30% range with selected examples reaching the low 40s percent. Note that sometimes unconfirmed responses are included in the ORR reporting.

The disease control rates are generally in the 60% range for both types of regimens with selected examples reaching as high as the mid-70s. The high end of the reported range for median progression-free survival for both regimens reaches approximately 7 to 8 months, and the upper end of the reported range for median overall survival for both regimens is short of a year at 11.7 months.

Chemotherapy is generally challenging for patients and usually requires dose modification. The Grade 3 or higher treatment-related adverse event rate was reported to be approximately 70% for both GnP and 5-FU-based regimens. Dose reductions and dose discontinuations due to treatment-related adverse events were reported to be approximately 50% and 25%, respectively, for each regimen. Overall, patients who receive first-line combination chemotherapy for PDAC typically spend most of their final year of life receiving chemotherapy and managing the difficult side effects thereof.

Since pancreatic cancer is commonly caused by excessive RAS(ON) signaling due to oncogenic RAS-driver mutations, targeted treatment with a RAS(ON) inhibitor seems like a compelling opportunity. Daraxonrasib is a groundbreaking RAS(ON) multi-selective tri-complex inhibitor that is designed to inhibit all or nearly all oncogenic variants of RAS, including wild-type RAS. It also suppresses many of the common drug resistance mechanisms that are mediated through RAS signaling.

Preclinically, daraxonrasib has shown deep and durable monotherapy and combination activity across numerous cancer models, including pancreatic cancer xenografts and PDX models. And importantly, we have reported promising clinical activity for daraxonrasib with an acceptable safety profile in patients with previously treated PDAC, non-small cell lung cancer and other solid tumors.

Furthermore, the FDA recently granted breakthrough therapy designation for daraxonrasib in previously treated metastatic pancreatic cancer with KRAS G12 mutations. We are currently conducting the RASolute 302 global randomized Phase III trial of daraxonrasib in second-line PDAC.

Today, we'd like to explain our rationale and plans for developing daraxonrasib in first-line metastatic PDAC. As previewed in this high-level schema, we are preparing to conduct a randomized 3-arm Phase III study that will compare each of 2 new treatment regimens to GnP, an accepted and widely used standard of care. The first regimen is daraxonrasib monotherapy. The second treatment arm will be daraxonrasib with concurrent GnP followed by daraxonrasib.

Our previously reported data in second-line PDAC provides some confidence that the efficacy profile of single-agent daraxonrasib could exceed combination chemotherapy in first-line metastatic PDAC. In addition, the tolerability profile of the first-line therapy could be improved by a targeted agent like daraxonrasib and intensive chemotherapy could be held in reserve for salvage second-line therapy. The rationale for the chemotherapy combination arm will be covered later in this presentation.

In a few minutes, Dr. Lin will provide additional details of the RASolute 303 study. But before doing so, he will present 3 new clinical data sets that support our plan. First, updated data from long-term follow-up of the patients in the daraxonrasib monotherapy cohort of the first of the Phase I trial in patients with second-line metastatic PDAC that reinforces the strong underlying proof of concept.

Second, a first disclosure of data on daraxonrasib monotherapy in first-line metastatic PDAC. And third, a first disclosure of data on daraxonrasib combined with GnP in the first-line metastatic PDAC setting. Wei?

Thank you, Steve. I'll begin with an update on the long-term follow-up for daraxonrasib monotherapy in second-line metastatic pancreatic cancer. As a reminder, reported efficacy in second-line PDAC for current standard of care regardless of the chemotherapy regimen evaluated is characterized by median progression-free survival in the range of 2 to 3.5 months and median overall survival of approximately 6 to 7 months.

Slide 10 shows an updated waterfall plot, demonstrating robust antitumor activity in PDAC patients previously treated with 1 line of systemic therapy and median follow-up of approximately 17 months.

Daraxonrasib at 300 milligrams daily achieved an objective response rate of 35% in RAS G12X mutant PDAC and 29% in the broader RAS mutant PDAC population, with a longer follow-up since the last data we shared for this patient population. All the responses have been confirmed. The disease control rates were 92% for RAS G12X patients and 95% for all RAS mutant patients. Of note, 6 patients remain on study treatment as indicated by the small arrows beneath the waterfall.

I also want to note here that the tolerability and safety profile in this cohort has remained stable with a longer follow-up and is generally consistent with our earlier report.

Slide 11 shows the updated progression-free survival analysis from this longer follow-up. The median PFS in the second-line population exceeds 8 months for both RAS G12X and all RAS mutant groups. The lower bounds of 95% confidence intervals are around 6 months. More than 80% of patients were progression-free at 3 months and over 60% at 6 months. These compelling data suggest a sustained suppression of RAS as a key driver in pancreatic cancer may translate to prolonged response and disease control.

Slide 12 shows the updated overall survival analysis. With a longer follow-up, the median OS is now estimable at 13.1 months for the RAS G12X group and 15.6 months for all RAS mutant group. Of note, the estimated median overall survival is over 1 year in both groups, something that hasn't been achieved previously in any reported line of treatment for patients with metastatic pancreatic cancer.

The lower bounds of 95% confidence intervals are nearly 11 months. The proportion of patients who were alive at 6 months is over 90% and at 12 months is over 50%. We're encouraged by the potential for long-term clinical benefit suggested by these data, which show consistency with earlier readouts and strengthen our belief that daraxonrasib is highly differentiated from chemotherapy in terms of antitumor activity, durability of effect and tolerability. The ongoing RASolute 302 pivotal study in second-line metastatic PDAC will evaluate these potential long-term benefits in a randomized Phase III trial.

Now I'll share our newest daraxonrasib data in first-line metastatic pancreatic cancer. Slide 14 shows that the safety profile of daraxonrasib monotherapy in the treatment-naive setting is generally consistent with what was observed and reported in the second-line setting. As of the July 28 data abstract, 40 treatment-naive patients carrying RAS mutant pancreatic cancers had been treated with daraxonrasib at 300 milligrams daily. Approximately 1/3 of patients experienced a Grade 3 treatment-related adverse event or TRAE. And there were no Grade 4 or 5 TRAEs.

Similar to the second-line setting, the 3 most common TRAEs were rash, diarrhea and stomatitis/mucositis. For individual TRAEs, the rates of Grade 3 events were all 10% or less. These adverse events were manageable with routine clinical interventions based on our learnings from the previously treated setting and implemented here as well as in our ongoing RASolute 302 pivotal trial.

The rates of selected adverse events such as liver enzyme elevation and cytopenias, both of which are relevant to the combination development of daraxonrasib with standard of care chemotherapy remain low. This observation has implications for combination regimens we're developing in the first-line setting, which I'll present later in this presentation.

Slide 15 shows that the safety and tolerability profile of daraxonrasib has translated to an acceptable rate of dose modification, achieving a favorable dose intensity. Approximately half of patients were able to stay on daraxonrasib without any dose interruption, 2/3 of patients remained on 300 milligrams daily while on treatment with only 1/3 requiring a dose reduction.

The rate of discontinuation due to treatment-related adverse events was a modest 10%. This resulted in a mean dose intensity of 85%. Similar to the experience in second-line patients, these data suggest that daraxonrasib at 300 milligrams daily can be given consistently to PDAC patients in the first-line setting, a property that is designed to translate into sustained inhibition of RAS signaling in tumors.

Slide 16 shows the impact of this approach on tumors. This slide focuses on 38 patients with first-line metastatic PDAC. Note that 2 patients in the safety cohort did not meet the definition of first-line metastatic disease and were excluded from efficacy assessment. One patient had locally advanced PDAC and the other had a synchronous neuroendocrine tumor.

Daraxonrasib monotherapy induced deep tumor regressions in many of the patients with first-line metastatic PDAC. The objective response rate was 47%, and the disease control rate was 89%. The majority of patients remained on study treatment as of the data extract date of July 28. These initial findings demonstrate that daraxonrasib is highly active in the first-line setting and are highly encouraging with regard to daraxonrasib's potential as a first-line treatment for patients with PDAC. We continue to follow these patients for deepening of response and to evaluate durability of the clinical benefit.

Next, I plan to share our data for the combination of daraxonrasib with gemcitabine, nab-paclitaxel or GnP, in first-line metastatic PDAC. Before doing so, I want to provide the rationale for advancing this combination.

First, why a combination with chemotherapy? As shown in the patient flow Steve presented earlier, attrition from first line to second line is high, and the majority of first-line patients do not receive second-line chemotherapy. Therefore, some physicians will have a preference for a combination regimen in first line, aiming to ensure that patients may gain survival benefits from both daraxonrasib and chemotherapy.

Furthermore, resistance to therapy is often due to tumor heterogeneity, meaning that the tumor may be a mix of 2 or more cancer cells with different phenotypes. In principle, potential heterogeneity in cellular sensitivity to different treatments may be overcome by combining the different mechanisms of action of daraxonrasib, a targeted RAS(ON) inhibitor and chemotherapy.

Second, why a combination with GnP? It is a globally used standard of care in first-line PDAC. Its safety and tolerability profile means that more patients are eligible for GnP than for FOLFIRINOX, while the clinical outcomes from the 2 types of regimens are objectively quite similar. So if one were to select only one first-line chemotherapy for combination development, it will be GnP. I'll comment a little further on FOLFIRINOX later.

Slide 18 shows the preclinical data that support development of the combination of daraxonrasib with GnP. In the left panel, our daraxonrasib monotherapy itself proved superior to GnP in a KRAS G12V PDAC model at clinically translatable doses. The combination of daraxonrasib plus GnP further deepened and sustained tumor regressions.

In the right panel, our treatment with daraxonrasib monotherapy delivered greater progression-free survival than the GnP in this experiment, studying 10 different PDAC xenograft models. The combination of daraxonrasib with GnP significantly prolonged the PFS compared to either regimen alone. These preclinical experiments provide a strong basis for our clinical evaluation of the daraxonrasib plus GnP combination.

Slide 19 summarizes the rationale for the selection of the doses and schedules for the daraxonrasib plus GnP regimen. In constructing this regimen, the objectives are to sustain continuous suppression of RAS signaling via high dose intensity for daraxonrasib to leverage the antitumor contribution of chemotherapy and to achieve an overall safety profile that is competitive against standard chemotherapy.

For daraxonrasib, we considered our prior experience with monotherapy in second-line pancreatic cancer in which daraxonrasib showed robust antitumor activity at 160 to 300 milligram daily with small dose-dependent increases in exposure, activity and side effects observed within this range.

For monotherapy treatment with daraxonrasib in PDAC, we regularly use 300 milligrams daily in order to maximize the potential antitumor activity for each patient while maintaining an acceptable safety profile. In combination with GnP, we evaluated a few exploratory cohorts of patients at different daraxonrasib doses and selected 200 milligrams daily as the go-forward dose in order to optimize the risk benefit in the context of concurrent GnP with its characteristic side effects. We know from our experience in second-line PDAC that 200 milligrams is a highly active and generally well-tolerated dose of daraxonrasib.

Regarding GnP dosing. In clinical practice, both gemcitabine and nab-paclitaxel are routinely given at the approved full doses regardless of frequency, and we did not make any adjustment to full dose in combination with daraxonrasib.

Regarding dosing frequency. GnP is typically given under 1 of 2 standard schedules over a 28-day cycle, dosing on days 1 and 15 or dosing on days 1, 8 and 15. It is understood among many practitioners that the days 1, 8 and 15 schedule is associated with higher rates of dose interruptions and reductions due to bone marrow toxicity and neuropathy. Often patients started on a days 1, 8 and 15 schedule are unable to consistently receive all doses and practically end up converging on a days 1 and 15 dosing regimen.

Further, studies from the Mayo Clinic and MD Anderson suggested that the days 1 and 15 schedule significantly reduced cytopenias and neuropathy while maintaining efficacy similar to that of the days 1, 8 and 15 schedule. In this context, based on a small number of exploratory daraxonrasib plus GnP cohorts, we selected the days 1 and 15 regimen for GnP as the go-forward schedule for the improved safety, tolerability and patient convenience, while aiming to preserve its potential contribution to efficacy in the combination.

I'll next present the clinical data from patients with first-line PDAC treated with daraxonrasib 200 milligrams daily and full dose GnP with biweekly dosing.

Slide 20 shows an acceptable safety profile for this daraxonrasib plus GnP combination. The TRAEs are additive of the profiles of individual agents and the rates are as expected based on the monotherapy safety profiles. No new safety signals emerged.

The combined Grade 3 or higher TRAE rate was close to 60%, largely due to the inclusion of chemotherapy. The key overlapping toxicity of diarrhea was 13% for Grade 3 with no Grade 4 or 5 TRAEs related to diarrhea. Grade 3 were higher anemia and neutropenia are around 20% and Grade 3 liver enzyme elevations were in the single digits. There were no Grade 5 TRAEs.

The safety profile of the combination regimen translated to an acceptable degree of dose modification as well as favorable dose intensity for daraxonrasib, as shown on Slide 21. Approximately half of patients were able to receive daraxonrasib without interruptions caused by TRAEs and 3/4 did not require a dose reduction. The rate of daraxonrasib discontinuation was only 5%. This rate of dose modification resulted in a mean dose intensity exceeding 80% for daraxonrasib. For GnP, a dose intensity of over 60% is consistent with expectations for GnP alone.

The daraxonrasib dose modification rate and dose intensity are consistent with those observed with daraxonrasib monotherapy at 300 milligrams. By selecting daraxonrasib at 200 milligrams to combine with GnP, we aim to achieve sustained RAS inhibition similar to that of daraxonrasib monotherapy while gaining an additional contribution to antitumor activity from cytotoxic chemotherapy.

Slide 22 shows the encouraging preliminary efficacy of this daraxonrasib plus GnP combination. Here, we're showing data for 31 patients who received a first dose of daraxonrasib plus GnP, at least 18 weeks prior to data cutoff date. The waterfall plot shows that deep and sustained tumor regressions were achieved in the majority of patients, most of whom remained on study treatment as of the July 28 data abstract date. The objective response rate was 55% with an associated disease control rate of 90%. These initial findings are highly encouraging with regard to daraxonrasib's potential as a first-line treatment for patients with PDAC. With a median follow-up of a little over half a year, median PFS and OS are not mature enough to be estimated at this time.

We presented 3 main sets of data in support of late-stage development of daraxonrasib in first-line PDAC, the mature overall survival provided by daraxonrasib monotherapy in second line, the highly encouraging antitumor activity and acceptable safety profile of daraxonrasib monotherapy in first line and the highly encouraging antitumor activity and acceptable safety profile of daraxonrasib plus GnP in first line.

In aggregate, these findings support initiation of a pivotal trial in patients with treatment-naive metastatic pancreatic adenocarcinoma to evaluate the efficacy of daraxonrasib monotherapy and daraxonrasib in combination with GnP. The schematic of the expected design is shown here on Slide 23.

We plan to randomize approximately 900 all-comer patients with first-line PDAC regardless of RAS status to evaluate these 2 experiment regimens as well as full dose GnP as the comparator. Study participants will be stratified by RAS mutation status to balance potential differences in outcome due to prognostic or predictive value of RAS mutation.

Daraxonrasib monotherapy will be given at 300 milligrams daily. Daraxonrasib will be given at 200 milligrams daily in combination with GnP, which will be given at full dose on the days 1 and 15 schedule and patients will transition to daraxonrasib 300 milligrams daily after completion of chemotherapy. In all 3 arms, treatment will continue until disease progression or intolerance.

The primary endpoints will be PFS and OS. Each investigational arm will be compared independently with the control. The protocol has not been fully finalized yet, so some details of the study design may change by the time the study is initiated.

In addition to the daraxonrasib plus GnP combination, we also evaluated the combination of daraxonrasib with FOLFIRINOX. We observed robust antitumor activity, further validating the concept of combining RAS inhibition with cytotoxic chemotherapy. However, FOLFIRINOX itself has a wide range of toxicities than GnP, especially GI toxicities. And patients receiving a combination regimen required a high level of management by the physician, making it less practical to implement on a wide basis across diverse institutional settings.

Furthermore, as noted, treatment with FOLFIRINOX demands a higher baseline performance status, limiting its use to less than half of metastatic pancreatic cancer patients.

Finally, GnP is the most widely used first-line therapy in Japan and certain countries in Europe. Therefore, based on these considerations, we have elected to develop daraxonrasib in combination with GnP in our effort to change the standard of care globally for patients with treatment-naive PDAC. We are optimistic that daraxonrasib as both monotherapy and in combination with GnP could be options that help achieve our goal. We plan to reserve potential combination with FOLFIRINOX for our mutant selective inhibitors such as zoldonrasib.

With that, I'll hand the mic back to Mark.

Thank you, Wei. I'll conclude our prepared remarks with Slide 25, which highlights our bold vision for daraxonrasib to become a new global standard of care for patients with PDAC in metastatic and non-metastatic disease settings.

As noted throughout this presentation, current treatment options for PDAC leaves significant room for improvement. Today, for those who receive standard of care chemotherapy, outcomes are clearly suboptimal, and many patients are simply not able to receive or benefit from such treatment.

Daraxonrasib's highly innovative mechanism of action, breadth of RAS mutation coverage and extensive preclinical profile suggests it is well matched to counter the oncogenic drivers of PDAC. And we have generated substantial and growing evidence of daraxonrasib's compelling profile across lines of treatment for PDAC.

The long-term follow-up data we reported today for monotherapy in patients with second-line PDAC reaffirms the promising activity, durability and acceptable safety and tolerability we have previously reported. The new findings we presented this afternoon for monotherapy in the first-line PDAC setting are highly encouraging and monotherapy represents a core component of our first-line Phase III trial.

Additionally, the new initial findings we presented for a combination with chemotherapy in the first-line setting are also highly encouraging and combination treatment is a second core component of this trial. Both monotherapy and combination with GnP hold great promise in support of our ambition to improve treatment outcomes for patients with first-line PDAC.

As noted, we are conducting a broad-based late-stage global development program to evaluate daraxonrasib in multiple lines of treatment for PDAC. We have either initiated or are on track to initiate this year 3 Phase III clinical trials across lines of therapy in PDAC. RASolute 302 in patients with second-line metastatic PDAC has been enrolling well, and we expect to complete global enrollment this year to enable an expected data readout in 2026.

As described today, RASolute 303 in patients with first-line metastatic PDAC is progressing toward a Phase III trial initiation in Q4. And RASolute 304, evaluating adjuvant treatment for patients with resectable PDAC, is also progressing toward a Phase III trial initiation in Q4. We have intentionally kept today's focus on the first-line metastatic setting and plan to share the trial design for RASolute 304 next quarter.

With each clinical achievement, we advanced one step further toward developing the leading global targeted medicines franchise for patients living with RAS-addicted cancers. Based on the compelling data shared today, we are increasingly confident in the potential to establish daraxonrasib as a new global standard of care for patients living with pancreatic cancer.

I'll now turn the call over to the operator for the Q&A session.

[Operator Instructions] Our first question for today comes from the line of Jonathan Chang from Leerink Partners.

This is Albert Agustinus dialing in for Jonathan Chang. Congratulations on the progress. So my first question is regarding the efficacy in first-line PDAC. How should we think about the relatively similar response rates between daraxonrasib monotherapy and daraxonrasib plus gem nab-pac? And I guess as a follow-up on that, how should we think about the potential durability of responses in monotherapy versus daraxonrasib plus gem nab-pac?

Thanks very much for your question. So I guess there were 2 parts to that. One is how similar was monotherapy to combination and what about durability? Wei, would you like to comment on that?

Yes, sure. Thanks for the question. So I think the -- certainly, we're very encouraged by the improvement in the monotherapy activity going from second line to first line, and that's typically seen in any drug, and this certainly holds. And it just highlights to the degree of addiction of these tumors and also the lack of other treatment creates higher degree of sensitivity.

Now 47 and 55, they are within 10 points each other, of course, but we do see some contribution of chemotherapy, I think, to the addition of the regimen. And I think one of the hypothesis we're testing in this is really in terms of long-term benefit of the patients, is it more important to give them together or sequentially, right? I think that's one of the outcomes of this 3-arm design.

So in terms of long-term durability, I think it's a little too early to assess. I think many of our experiences, it really shows that disease control rate does have some -- is one of the earlier correlates. And certainly, we have a very high 90% disease control rate. And so with longer follow-up, we'll be closely monitoring and then reporting on those long-term durability benefits.

Yes, if I could just add a comment to that. In our view, across these 3 different data sets, results are really unprecedented for pancreatic cancer patients with metastatic disease, the second-line responses, but more importantly, the durability, the OS benefit that Wei alluded to, the first-line monotherapy with a 45% response rate but a high DCR rate to go with it. And then the combination strategy delivering a 55% response rate with a similar DCR rate. All 3 of those are encouraging.

And again, to emphasize the point that Wei made, we really are testing 2 independent hypotheses here. And ultimately, the OS will inform each of those hypotheses as to their validity and may create multiple options for physicians caring for patients.

And our next question comes from the line of Michael Schmidt from Oppenheimer -- or Guggenheim.

Congrats on the nice update here in PDAC. Could you expand a bit more about your decision to go with the 200 milligrams daraxonrasib dose with full chemo as opposed to maintaining the 300 milligrams QD daraxon and using a lower chemo dose for the combination arm? So that's question one.

And then the other question I just had on durability, do you think you'll need to see more mature durability data, including PFS in order to sort of finalize powering for the RASolute 303 study?

Thank you, Michael. Nice to hear from you. I think Wei can give us probably a more fulsome comment here. I would emphasize that 200 milligrams delivers an exposure level that, as you know, from several years of looking at this is very attractive with regard to its antitumor activity in preclinical species and correlates quite nicely in humans. So we've always felt that 200 to 300 were pretty similar, although there is some subtle difference between them.

Yes. So happy to address this question. So as Mark pointed out, there's a slight dose response in the range from 160 to 300. But across the entire dose range, we have achieved what we have preclinically predicted as a very active. So we believe as long as we're in that dose range, we'll be delivering fully outstanding clinical benefit to patients, and that's being tested.

The 200 milligram really allow us to deliver that in combination with chemotherapy. And then we do acknowledge there's some safety AEs overlapping between daraxonrasib and chemotherapy. And then giving at 200 milligrams really allow us to achieve sustained RAS inhibition, which in our experience is what really drives long-term clinical benefit. And so be able to give at 200 milligrams and keep that in a sustained way such that RAS inhibition can be maintained throughout the treatment duration and then transitioning to 300 milligrams without the chemotherapy where that RAS inhibition can be continued is the optimal way that we have discovered. And hence, that's the regimen we have landed on.

The second question has to do with powering the study and whether or not we need PFS to help guide that. Do you want to comment on that?

For the powering of the study, this is, again, a study that's designed for demonstrating overall survival similar to our second-line trial. I think as Mark had pointed out, this is -- the outcome even in the second line has been really unprecedented because no one has broken the 1-year barrier, and that's really the goal we're trying to strive for. And now so OS is still the metric because even in the first-line setting, people do not live for yet a year. So given that, that is the primary endpoint, so the sample size and all the testing is really revolving around the OS and so the readout and so on.

And then I also want to point out that there's independent testing between the 2 arms, and hence, it's actually powered such that both the monotherapy and then the chemotherapy will be evaluated independent of each other.

And our next question comes from the line of Charles Zhu from LifeSci Capital.

Congratulations on the pretty strong data out here and formalizing a lot of these plans where we had a lot of questions. Maybe also just if I could squeeze in 2 real quick for me. How do you think [ about ] of a daraxonrasib plus GnP relative to FOLFIRINOX, especially in patients that are hyperfit for FOLFIRINOX, how many of them do you think you could peel over to something like daraxon plus GnP?

And also similarly, maybe one on the time lines for this frontline study. Could you provide color around how much time this could take? Could this overlap with, for example, the availability of a commercially available daraxonrasib in the second line? And how have you kind of baked that possibility into some of your trial design assumptions?

Charles, thanks very much for your question. So the first one was, if I understood it correctly, will patients who might otherwise be eligible for modified FOLFIRINOX be interested in the either monotherapy or GnP combination strategy. Probably depends on how it performs in the Phase III trial.

Certainly, the evidence is pretty encouraging right now, given that there -- really it's not a consistent difference in the literature between GnP and modified FOLFIRINOX. I think we can be pretty encouraged that these results will be attractive to people. But as to what happens, I think we need to see what the final definitive results are, and then it will be up to patients to discuss with their doctors. Wei, anything you want to add to that?

Yes. I think there's -- just to address the efficacy of FOLFIRINOX versus GnP, I think there's this perception that GnP may have inferior OS compared to FOLFIRINOX. And that was certainly true, I think, for the initial registration trial a decade ago. But I think since then, subsequent trials have really shown that the overall survival with GnP can approach that of FOLFIRINOX. So I think even meta-analysis show that there's not a substantial difference between those 2 regimens.

And the other consideration is when a patient is discussing their -- with their physician about the option joining this trial, they're not joining the trial for option to be treated with FOLFIRINOX, they're joining the trial really looking for an opportunity to receiving daraxonrasib. And this trial, given a 3-arm design and 1:1 randomization, the patients have 2 out of 3 chance of getting daraxonrasib. So I think this trial should be highly attractive to any patients who are looking for vascular agents that has the potential really to improve their survival.

I think that's a critical point. I mean what we're trying to do here is stop the debate as to whether people should get a chemotherapy that's toxic and might be marginally better than another chemotherapy that's toxic. We want to change the narrative to should they get an inhibitor of the primary oncogenic driver of their disease versus not an inhibitor of the primary oncogenic driver of disease irrespective of whether they get chemotherapy with it or not.

And so this is a complete paradigm shift. And we're trying to get away from that thread the needle in between whether oxaliplatin is better than gemcitabine. It's really hopefully will become a completely obsolete question at the end of this study.

And then your second question was whether the availability of daraxonrasib at some point in the future were that to happen, would that create a crossover challenge? I guess that's what was implied by your question. It could. That could be a variable that will come into play. We certainly have considered that in the design of the trial, the kinetics of everything that we're doing, and we expect to be able to manage that.

And our next question comes from the line of Andrea Newkirk from Goldman Sachs.

This is Morgan on for Andrea Newkirk. Congrats on the data. Can you please speak to the rationale for transitioning patients from the combo to daraxonrasib mono versus keeping them on combination regimens the entire time? And then over what time frame do you expect the switch from combo to daraxonrasib mono would occur? And is it at the physician's discretion or based on tumor response?

Thanks for your question. Wei?

Sure. Yes. So I think -- again, I think to Steve's earlier point, I think we certainly believe that the long-term driver here is RAS, and hitting RAS hard is going to -- what's going to carry out the longest clinical benefit for patients. And therefore -- so that's one strong consideration to -- for this specific design.

Now chemotherapy, so there are 2 key considerations. I think one is the amount of benefit patients derived from chemotherapy is really achieved mainly in the first 4 to 6 cycles. And beyond that, number one, the benefit becomes reduced. And number two is majority of patients would have either dose reduced or have dropped one or both agents. And therefore, maintaining the chemotherapy along with daraxonrasib 200 doesn't really gain that much going beyond 6 cycles. And so it's actually more optimal knowing that daraxonrasib is really the largest carrier of clinical benefit in this regimen.

After the chemotherapy have really done their job in the first 4 to 6 cycles, the transition will actually happen and go on to daraxonrasib at 300 milligrams to really maximize the RAS inhibition and achieving the longest-term benefit for patients.

And I would just sort of emphasize that it is actually key to continue on daraxonrasib, that's the compound that appears to be showing significant durability and there's no chemotherapy that can provide that, Wei.

Yes. And I think that's -- I think most patients would look forward to the day when they can stop chemotherapy. And this really -- this design offer them an improved quality of life when that chemotherapy can be stopped.

And our next question comes from the line of Ellie Merle from UBS.

Congratulations on the results. Just in the frontline patients, what was the median duration of response and the proportion of these patients that are still in response?

And for the adjuvant Phase III PDAC design, I guess, what are you looking for at this point to finalize the design? And can you walk through some of the differences that you could see in the trial design versus in the frontline setting?

Thanks, Ellie. Appreciate the questions. Let me just say, I think for the first-line median duration of response, we don't have that information yet. We didn't report it in this particular set. At some point, we'll have it, but we just don't have it today.

With regard to the adjuvant, we'll talk about adjuvant next quarter. There's not additional information that we're seeking associated with that. We just wanted to keep this investor discussion today focused on first line. Was there anything specific in your question you want to ask?

I think the only other thing, Ellie, the patients that are still on study are indicated on the waterfall by an arrow underneath. So we don't usually provide swimmer plots because we don't like them. But we do put the arrows on the chart and they're still on treatment at the time of the data abstract, so that should give you some sense of what's going.

Steve is saying you can do your own calculation, but we won't do it at this stage.

Well, I'm not going to give you [indiscernible]. If the median is NE, then we can't report it.

Right, that's the issue.

And our next question comes from the line of Marc Frahm from TD Cowen.

Congrats on all the data that you're disclosing. Maybe put a finer point on the FOLFIRINOX debate that's out there. I get, as you guys were saying, the data is pretty equivocal as to whether it really is a better regimen or not, but there is that kind of impression out there. Can you maybe speak to just the powering that's in this Phase III design and what that implies about like if any -- if either arm is positive, how it will almost certainly compare to even the most aggressive kind of FOLFIRINOX comparisons?

Yes. I mean the primary endpoint going to be OS. And as we pointed out, I think the highest OS that's been reported is under a year. The OS that we've reported for second line, albeit in the single-arm trial is well over a year. The ORR tells us that we're moving into greater activity in early lines as we -- exactly as we'd expected and predicted, as you know, from many previous conversations. So it seems likely that OS would deliver in that context and deliver a significant advantage. So I'm not sure how FOLFIRINOX could ever catch up with that. I mean it's pretty well characterized. Maybe I'm missing something here, but it seems like that's pretty much the answer to that question. Is there something more? Marc...

I think that's helpful, yes. And then just back on this operational aspect of the combo arm of kind of the switch to higher dose maintenance dosing of daraxonrasib. Is it entirely driven by patients reaching a 6-month time point on the combination? Or is there an ability with some of the earlier patients who may be doing very poorly with tolerating chemotherapy and dropping dose very quickly to kind of rapidly move to 300 milligrams because they've gotten to a dose of gem/Abraxane that really is kind of pointless even if they haven't gotten to 6 months.

Sure. That will be structural, but Wei go ahead.

Yes. No, absolutely. It's -- for the GnP combination, it's up to 6 cycles. And so a standard practice, if a patient -- some patients actually discontinue GnP entirely before 6 cycles, and they have option to go up to 300 milligrams. And that's typically how it is done in the adjuvant setting. So adjuvant setting, the chemotherapy is given for 6 cycles and not everyone actually achieved it if you look at how things are reported. In fact, majority of patients do not achieve all 6 cycles.

And our next question comes from the line of Kelsey Goodwin from Piper Sandler.

Congrats on the update. I guess how important do you think physician education on RAS inhibition will be specifically in the community setting for frontline uptake of daraxonrasib longer term?

Thanks for your question, Kelly. The underlying assumption to your question is valid that a lot of people don't know that RAS drives pancreatic cancer. They might have heard it at some point in the past or they might not have even been taught that in medical school or residency because it didn't matter. There was nothing you could do about it. And so given the flood of detailed technical information that doctors are exposed to every day, they sort of have to pick and choose what to bother using ATP to fire on in their nurse and try to remember.

So -- and as you move further away from academic centers, that awareness goes down. It's actually quite high, although not 100% in academic centers, and then it does get discounted the further, maybe the greater the distance to your community center. So there will be need for education.

That education will be a lot easier with data. And here are data certainly, that will be noted. It will be noted at scientific conferences. It's noted by KOLs. And then there will be more data that we hope would support approvals in which case that data will become widely available and will be much easier for physicians to remember it. So yes, there is going to be a need for education.

We're actively engaged in education now. Our medical affairs organization is highly engaged with physicians broadly, but it will tend to stick more when there's an even stronger reason for it to stick when people have a drug they can prescribe.

And our final question for today comes from the line of Asthika Goonewardene from Truist.

I offer my congratulations as well on the data. I want to talk a little bit about resistance mechanisms. So for the frontline daraxonrasib monotherapy, did that data resemble the resistance data that you presented at AACR? And then for the daraxon plus GnP, I know you only had 2 patients who progressed, but what's your hypothesis on the resistance mechanism there?

And then second question is that in frontline pancreatic, you still get a significant amount of patients who opt for palliative chemotherapy as these patients generally would be intolerant to the combo chemo regimens. Do you envision that daraxonrasib will be an attractive option -- monotherapy daraxon would be an attractive combination option for these patients instead of palliative chemo? And how are you putting guardrails on recruitment so you don't kind of skew that the daraxon monotherapy arm with maybe patients who would have been intolerant to the combination chemotherapy?

Thanks very much for your questions and for your coverage. First, with regard to the palliative first line, it was your second question, if a patient wants to enroll in the trial, they'll have to be eligible for chemotherapy because they may be randomized to chemotherapy or chemotherapy plus daraxonrasib or daraxonrasib alone. So they'll have to be of a condition and willingness to be able to participate in that. And there may be some people, I suppose, on the edge. It will be up to sort of the criteria -- enrollment criteria to be applied appropriately, and that should be balanced because they'll be randomized after they enroll. So I think that's probably the best that we can do with that.

With regard to resistance, we don't have -- certainly aren't reporting today any resistance data from the first-line cohorts. These cohorts were all conducted this year. And we just simply don't have enough data to be able to declare what the resistance mechanisms are. It will be interesting to find out over time, although they're not large data sets, but we might be able to get some glimpses about what's going on there. Anything else you want to add to it?

Only that, as Wei alluded to in the initial remarks that we don't have any evidence that RAS -- that pancreatic cancer is more or less addicted to RAS depending on the line of therapy. And so the fundamental biology of the disease is the same, whether the patient has received chemotherapy previously or hasn't received chemotherapy previously. And so in that respect, you may be able to make some predictions as to what we're going to see. But Mark is right, although we are collecting the same samples from this cohort as we did from the second-line cohort, we don't have any actual data to corroborate that.

Yes. And as Steve pointed out, the little arrows indicate there's hardly any patient who progressed on either monotherapy or the chemo combo. So for the sake of these patients, I hope that it will take a long time for us to learn about...

Yes. Maybe I can just reinforce something Steve just said, which is, I think, a prevailing question over the last year, question we didn't really fully understand, but nonetheless, we heard was whether or not first line would somehow be less sensitive to a RAS inhibitor than second line. And I think it's pretty clear from these data, both for the monotherapy and the combination cohort that just as Steve said, pancreatic cancer is a RAS-driven disease from the beginning. It doesn't become a RAS-driven disease after you had first-line treatment. And so the fact that we're seeing some improvements in the outcomes measured by ORR and DCR, particularly ORR in the first line is consistent with past experience with other targeted agents in other cancers and suggests that this is how these are going to play out here, too. So I think we've now validated biologically, these are no different from second line, and we're very excited to have a compound that can be used and explored now in a Phase III trial.

This does conclude the question-and-answer session of today's program. I'd like to hand the program back to Mark Goldsmith, Chairman and CEO, for any further remarks.

Thank you, operator, and thank you, everyone, for joining us today and for your ongoing support of Revolution Medicines.

Thank you, ladies and gentlemen, for your participation in today's conference. This does conclude the program. You may now disconnect. Good day.