IDEAYA Biosciences Inc Stock

Good morning. Thank you for coming this morning to the Morgan Stanley Healthcare Conference. My name is Ryuk Byun. I'm the Head of West Coast Healthcare Investment Banking at Morgan Stanley. I have the pleasure of hosting the management team from IDEAYA Biosciences, Yujiro Hata and Josh Bleharski. I'll just ask a couple of questions to get the conversation started.

So, Yujiro and Josh, for somebody that's encountering IDEAYA for the first time, what is maybe the simplest way to understand where the company is today?

Yes, so Ryuk, thank you for the introduction, and thank you to Morgan Stanley for the invitation at this year's conference. So, IDEAYA Biosciences, I think maybe the best way to summarize it, we are a leading precision medicine oncology company. We have a very deep and diversified pipeline in the area of precision medicine oncology in particular. Our lead program is an agent called darovasertib. We are in the process of submitting the final NDA submission under RTOR. Most of our analysts are projecting a launch timeframe in the first half of next year. In addition to frontline metastatic uveal melanoma, we have several additional Phase III studies ongoing, including in the neoadjuvant and adjuvant setting.

So, here, our view is this molecule has the opportunity to be hopefully standard of care across the uveal melanoma patient journey. Beyond that, Ryuk, as you know, we believe we have one of the deepest clinical pipelines in precision medicine oncology today. I would say next program to focus is on DLL3. This is a Topo-ADC. We recently announced a successful Type C meeting with the FDA with our intent to start a randomized Phase III study in later-stage small cell lung cancer. We do also believe there's an opportunity in neuroendocrine carcinoma. Beyond that, we have an exciting set of assets in MTAP deletion. This is a key tumor suppressor loss gene.

It represents about 15% of all solid tumors, including about 40% of pancreatic cancer. And Ryuk, as you know, we announced two collaborations with Roche in the last several months, both with our pan-RAS inhibitor, second with our KRAS G12D inhibitor, all in pancreatic cancer. We have multiple assets beyond that, but I think that's a good high-level summary.

Great. Maybe talking a little bit about daro and the regulatory path forward. You know, obviously showed a clear PFS and response rate benefit. And OS is still maturing. Between now and potential approval, what's the most important remaining question for regulators or physicians or investors?

There's not much remaining as part of the NDA submission under RTOR. It's primarily been QC related to clinical summaries of both safety, efficacy, and the broader clinical overview for the program. So, there's nothing specific gating. I would probably say the primary question that's open is what will be our label strategy. Ryuk, as you're aware, the randomized Phase III study was done in HLA-A2 negative. So, KIMMTRAK was approved in positive. We believe the negative population is the majority, approximately in that 60-40 to 2/3-1/3 split. Based on additional discussions with the FDA under RTOR, we do believe there is receptivity to an all-comers approach. So, we are still communicating base case as A2 negative with NCCN guidelines as base case, but I would say we're feeling more confident at least on that FDA receptivity piece.

Got it. So, in terms of how investors should be thinking about the A2 positive population, how -- where could you fit in terms of sequencing or even patient selection?

Yes, look, we think that the darovasertib has several components that are quite attractive relative to the peer agent that you mentioned. So, first, we have a confirmed response rate that's approaching 40%. We have a progression-free survival that's approximately 7 months. On both of those measures, we believe we're significantly above what's available, including KIMMTRAK or Ipi/Nivo. In addition, Ryuk, as you're aware, we have presented single-arm OS data, and we've reported just over 21 months at the Society of Melanoma Research last fall. We believe the control arm will come in 12 to 13 months. In addition, it is an oral available therapy versus a weekly IV infusion.

So I do think we're going to have a lot of benefit, and at least our perspective is we should get robust uptake, both in the frontline as well as pretreated setting of HLA-A2 positive.

Got it. Thank you. How are you thinking about, you know, getting gearing up for your commercialization efforts in terms of physician education, patient identification, so on and so forth?

Yes, that's a big emphasis for us right now, Ryuk. So, our senior leadership has been hired and is in place for the commercial launch. We're in the process of doing a lot of that market research, meeting with KOLs, talking to payers, really to the point you made, trying to raise awareness for the daro/crizo combo, educating people about the data set, the value proposition. So that's work that's been ongoing for, I mean, many, many quarters and will continue. I think the other piece of this is really trying to understand how patients are seen and where they are. And so, that's going to be a combination of some of the KOL networks that we've built and established over the years, as well as some technological tools that we're using to help identify patients, understand treatment paradigms, and make sure that we -- if we're approved, we can get to those patients efficiently as possible.

Great. Now, maybe think about daro beyond metastatic disease, what gives you confidence that the activity in the metastatic disease will translate into preventing or delaying recurrence in the adjuvant setting?

Yes, so, I think the good news here, Ryuk, is that we do -- as you know, we have a lot of confidence in the activity we're seeing in the metastatic setting. I think that hopefully bodes well in the pre-metastatic setting, as you mentioned, specifically as it relates to relapse or recurrence. In addition, I would just highlight, we just launched our Phase III randomized adjuvant study that is randomized against observation, right? So, we were essentially randomizing against nothing there. So, we think that's a very low benchmark. In addition, we've well-powered this study. It's about 450 patients. So, we feel good about the target hazard ratio, and what that benchmark looks like.

Got it. Now, could successful use in earlier stage disease reduce future metastatic population, and how do you balance that possibility against the much larger opportunity to treat patients across the disease continuum?

Yes, so, look, for -- so, the transition between neoadjuvant and adjuvant, Ryuk, as you're aware, the primary endpoints for neoadjuvant are quite different. So they're more ocular-related, including preservation of the organ, in this case the eye, for the enucleation patients, and then around eye preservation as well. There's a secondary endpoint around no detriment for event-free survival, which would have some parallels to the relapse-free survival in the adjuvant setting. So, that's the first, is that the endpoints and what we're trying to achieve are not exactly the same. The last part, I will say there is precedence in indications like breast cancer as well as others about re-challenging in the metastatic setting. So, there is going to be a fairly long duration from when patients are going from pre-metastatic to metastatic. And in many cases, you're talking 3 to 5-year timeframe.

Got it and thank you. Now, maybe shifting gears a little bit. In terms of DLL3, it's really become increasingly validated target in small cell lung cancer. As you think about 849, what do you believe will ultimately define a best-in-class DLL3 ADC?

Yes, so, Ryuk, we believe that DLL3, as you mentioned, is a highly validated target, obviously with a lot of the success with Amgen and IMDELLTRA. And, as you know, the small cell lung cancer space is getting crowded. And within that, we do believe DLL3 is the most compelling target. So, for us, to your question on what does success look like and best-in-class look like, it's going to be a balance between efficacy and safety. So, for safety, ideally we see confirmed response rates in the 60s. Obviously, will depend on what line you're in. We do see differences between second versus third line plus patients.

On the progression-free survival side, and there I should have mentioned, and then IMDELLTRA's response rate in their '24 approval was roughly in the mid-30s. For progression-free survival, they saw -- I believe it was 4.2 median progression-free survival. So, we think there, success would look like a PFS ideally with a 6 or 6.5 months. And then, OS, as we know, in their approval readout, they saw about a 12.5-month OS. So, at ESMO, we will be presenting about 100 patients worth of data, both response rate, PFS and 12-month landmark OS. So, based on that IMDELLTRA benchmark, ideally you see a 12-month OS percentage of greater than 50%. In terms of safety, ideally Grade III or higher SAE rates that are reasonable. So, I think here you're probably talking that 20% to 30% range.

SAEs ideally in that single digit percent range and hopefully very little ILD. So, I think relative to some of these other classes like B7H3, we do believe, directionally, you're seeing better safety with either similar or even potentially better efficacy. And that will become important when you think about combinations, whether that's checkpoint inhibitors, IMDELLTRA. We're pursuing a combination on PARG, so we believe hopefully that will give us more flexibility. The last piece I should have mentioned, as well as in neuroendocrine carcinoma. That's, I would say, more white space. We're clearly seeing monotherapy activity there.

So we do think that could be a unique opportunity that's more distinct to DLL3 because of its specific antigen expression.

Got it. And how, should investors think about upcoming catalyst timing and your trial plans for DLL3 specifically?

Yes, so, we have several initiatives that we're focused on for the program. So, first, as we mentioned earlier, is around the Phase III study in extensive stage small cell lung cancer. I would say one of the key points of differentiation versus a peer company that's launched a study here is that we will be exclusively focused on the post-IMDELLTRA population. We believe that's the more attractive study design and that it will be more of a homogeneous population versus having pre- and post-IMDELLTRA patients. And, Ryuk, as you know, Amgen had a recent readout in frontline maintenance in small cell lung cancer, which I think further punctuates that point. Second, so, that's the first we'd like to get going. We do have a meeting upcoming in the fourth quarter with the FDA around a potential registrational study for monotherapy approval in neuroendocrine carcinoma. So, we're hopeful that discussion goes well.

Once we have that, if there's a path forward, we'll communicate that externally. And then, I would say, lastly, is around a frontline small cell lung cancer study. So, there, I think we're still working through what that study design looks like. I would say several components of that. One, we're evaluating this novel PARG combination with IDE161. PD-L1, we think, is table stakes. So, those are, I would say, the variable pieces that we'd like to lock down ideally by the end of next year to make a go/no-go decision on that.

Got it. I guess on that note, in terms of, combination with 161, I think it's one of the more differentiated pieces of your strategy. I think scientifically and mechanistically, I think the rationale is compelling, but clinically, what type of signal would convince you that PARG is actually improving on the durability piece?

Yes, and so, for the listeners that may be less familiar with PARG IDE161, really the strategy here, Ryuk, is around, as we know, the payload of topoisomerase in terms of mechanism is in the area of DNA damage repair. So, if you're thinking about how do you enhance the efficacy, in particular here to your question, Ryuk, it's really going to be about can we extend the durability? You'd want to think about what synergizes with the DNA damage repair mechanism of topoisomerase. And here, there's been interest in targets like PARP1. We believe PARG is compelling, and that specific enzyme isn't directly involved in the repair of the DNA damage that's elicited with topoisomerase. So, here the objective is really simple. Can we have a well-tolerated combination effect while we see extended durability versus monotherapy.

If we can achieve that, A, this becomes a plug-and-play opportunity across the class of Topo-ADCs. But then we also believe it will open up multiple opportunities, that may not be available to others, including in areas such as frontline small cell lung cancer.

Okay. So, the PRMT5 field is obviously getting increasingly competitive. What characteristics of 892 do you think matter most clinically? Selectivity, therapeutic index, PK, the depth of PRMT5 inhibition, or combinability? And where do you think ultimately your competitors may run into limitations?

Yes, so, I think for here, I would say not too dissimilar to what we're seeing or what we have been seeing over the last decade in the KRAS/RAS field, which is with multiple iterations, these molecules are getting better, right? And we feel in the PRMT5 area, there's three core parameters that are critical for what a best-in-class molecule could look like. So, first is around a biophysics question around MTA cooperative versus SAM cooperative. Ryuk, as you're aware, the first-generation PRMT5 inhibitors were either SAM cooperative or SAM competitive.

And due to that, we saw myelosuppression and ultimately there was not a path forward. The second generation inhibitors are intended to be selectively MTA cooperative. However, we believe there's multiple compounds in the clinic that are not just MTA cooperative, they're also SAM cooperative, which would impact therapeutic window. So that's the first. The second is around this question of do you want a brain penetrant molecule or not? One of our significant focuses is in the area of pancreatic cancer, and in that indication, we believe there is not a benefit to have brain penetrance.

And we do believe that, that is more of a liability than a benefit based on the biology of both PRMT5 and MAT2A. Specifically as it relates to RNA splicing that we believe could manifest as it relates to CNS toxicity. Finally, third, is around drug-drug interaction. So, I would say similar to the RAS field, that is a question because of a lot of the chemistry scaffolds that are being worked on, that drug-drug interactions is not necessarily an easy nut to crack, and that's a property that we were extremely focused on for IDE892. And CYP3A4 in particular, I would say is a key enzyme you have to really think about based on how some of these other molecules were metabolized, including RAS, G12D, and MAT2A, and specific chemotherapies.

On the G12D point, the G12D collaboration is an interesting example of intersecting a tumor suppressor vulnerability with an oncogenic driver. Why should simultaneous PRMT5 and KRAS, inhibition be better than either approach alone? And which patient populations do you think offer the clearest proof of concept?

So, here for the KRAS G12D MTAP deletion population here, our focus with Roche Genentech will be specifically in the area of pancreatic cancer. If you look at the overlap of those two genetic alterations, we believe it's approximately 15% of all of pancreatic cancer. So, essentially what we believe we're doing is we are targeting the key driver oncogene in those patients, in that case G12D, with one of the key areas around tumor suppressor loss, in this case MTAP. And, Ryuk, as you know, there was some recent data, at least both on the G12D PRMT5 and the RAS PRMT5, where we saw quite exciting activities. So, I think here ultimately you'd want to place that into the frontline setting ideally and hopefully be able to enable a frontline registrational strategy. So, I think that would be quite exciting.

So, clearly one of the pieces we believe some of the early data early this year provided is in those pancreatic cancer patients that have KRAS. We believe MTAP is clearly playing a role.

Great. I think I already know the answer to this, but if we fast forward 2 to 3 years, you potentially have multiple registrational and combination opportunities across ADCs, MTAP, and your pipeline is going to be maturing. Outside of darovasertib, which program has the greatest potential to change how investors think about IDEAYA?

Yes, it's a great question, Ryuk. I know the answer was limited to one, but I'll provide two here. Look, I would say that the MTAP and KRAS we do think is something that has is fundamentally important, not just for us as a company, but for the area of precision oncology. Really advancing this concept that we just talked about of targeting the key driver oncogene and tumor suppressor loss biology. I think conceptually we're onto something there, and we believe IDEAYA is uniquely positioned to prosecute on that, not just with MAT2A and PRMT5 and MTAP, but also, as you know, we have an earlier program in CDKN2A that we hope will be in the clinic in the first half of next year. The second is around this Topo-ADC PARG mechanism that we mentioned because I think that's really one of the greatest areas of unmet need is how do you extend the durability of Topo-ADCs. So, this idea around DDR combinations with topoisomerase is a very sensible one and we think could make tremendous impact for patients.

As your portfolio broadens, how do you allocate capital across advancing wholly-owned programs, forming partnerships, investing in new discovery opportunities, and also more importantly, thinking about not deprioritizing assets? What is your decision-making process internally? How are you thinking about that?

Sure. Yes, so, you know, I would say at a high level, all of the things that you just talked about will be done from a perspective of having data. So we want to take a data-driven approach to the way we evaluate our programs, the way we prioritize our programs, the trials that we ungate and decide to pursue. And that is obviously the way we've approached building the pipeline thus far and how we've proceeded. I think obviously there's a lot in the pipeline. It's there for a reason. It's done with intent. But as you know, biotech is fraught, and we have to make these decisions based on what we see in the clinic.

I think the good news is we're well capitalized in order to take these programs to a point where we generate that data, and from there make the decisions around what the appropriate next steps could be. And those could be continuing to fund them on their own or seeking partners, or deprioritizing, again, depending on what we see. But I think we've intentionally tried to capitalize this company and align ourselves with the kinds of people that can help us make those informed decisions. We certainly talk to a lot of the larger players out there, keep them abreast of our progress. So, it's the kind of thing that will take shape as we have that data to evaluate. And in the meantime, what we want to do is remain really focused on executing on the things that we've talked about and the things in our pipeline that we are taking forward.

So, you mentioned the upcoming R&D Day. Why should investors expect to hear at your R&D Day in November in terms of key updates, guidance, etc.?

Yes, so, for R&D Day, we're going to have a significant focus on some of the areas we covered in terms of our broader clinical strategy and R&D strategy, Ryuk, in this area of MTAP, CDKN2A, and KRAS. And we believe this very critical intersection between those two genetically defined populations, in particular in the indication of pancreatic cancer. There's a lot of data, including preclinical data we're sitting on, that I would say has been informing our strategy and what people should expect to us, not just, through the end of this year, but into next year and beyond. We'll also have Dr. Frank McCormick from UCSF with us, who obviously is a world expert in the KRAS area. So, I think it's going to be a great event. It'll be that first Monday on and in London on that second week of November.

Great. I guess maybe a wrapping question. Looking ahead over the next 1 to 2 years, what are some of the key milestones investors should be thinking about looking out for that we haven't talked about?

Yes, so, we covered quite a lot from darovasertib, DLL3, and MTAP-KRAS. I would say probably what I would then dig into next is around the rest of our portfolio. I would say in particular programs like KAT6/7, which is a lysine acetyltransferase area, or also known as chromatin remodeling. Here we have a significant focus on several key indications, including breast cancer, colorectal cancer, and lung cancer. In addition, our dose escalation is going well. We cleared multiple dose cohorts. We believe we're now entering into a clinical efficacious dose range. Based on the preclinical data, we do believe at least we have the opportunity to drive monotherapy activity, where with KAT6 selective molecules, as you know, Ryuk, has been a challenge, unless they've combined it with fulvestrant.

So, I would say there, we also have two combination focuses. One is with SERD inhibitors, specifically in breast cancer, potentially in the setting of ESR1 mutant. And then I would say some interesting data we've generated with pan-RAS and KRAS CRC where we have demonstrated preclinical synergy. So, we're having several conversations on both of those fronts. So, I think, very exciting program, definitely one that's not, that's a bit under the radar, but hopefully we'll have a decent amount of data to look at by the end of the year.

Okay. And, maybe since you brought it up on the KAT6, what were some of the learnings from kind of folks like Pfizer that are slightly ahead? What are some of the relevant learnings and as you're thinking about the, maybe if you can expand on kind of competitive landscape and why you think you are differentiated.

Yes, look, I think we've learned a tremendous amount from Pfizer. So for those that may be less familiar, so Pfizer's now initiated a randomized, a Phase III study with their KAT6 selective inhibitor, specifically in combination with fulvestrant in breast cancer. So, I would say, for us, we've, through those learnings with Pfizer, I think we've clearly, you know, come to understand what is an ideal target TPP for KAT6/7. So, one, as I noted earlier, due to the dual mechanism, we do believe KAT6 and 7 is a critical bypass mechanism. Which, A, if we can demonstrate more significant monotherapy activity than KAT6, especially in breast cancer, we think that's a significant win. Second, if you look at what Pfizer is doing with their 6/7 inhibitor, which is -- they just started dosing this year, they're clearly focused on colorectal cancer, which is truly distinct than what they're doing in KAT6. And we think that's due to the underlying biology of KAT7. So, I think that also would be very exciting if we can have a path forward in CRC beyond just breast cancer. And then, we talked about seeing the single agent activity.

In terms of competitive landscape, the KAT6 field is getting more crowded. But the 6/7 area, there's only two companies that are in the clinic. It's us and Pfizer. And we believe we're neck-and-neck with them. So, I think that's a great position to be in. From a total addressable population, I think this program may be the largest program in terms of TAM that we're working on across our entire pipeline, which is saying a lot because we're working on some big opportunities.

Great. I'll pause here to see if there are any questions from the audience. All right. Thank you very much for getting here early. Good luck with the rest of your conference. And, yes. Hope your travel is smooth.

Great. Thank you, Ryuk.

Yes, thank you.

Hello everyone. We're on day 2 in the afternoon session of Citi's Biopharma Back to School Summit here in New York City. I'm Yigal Nochomovitz, senior biotech analyst at Citi.

We have our next company, which is IDEAYA, great platform, great pipeline and been covering them for a number of years, and it's really been a great journey and a lot more to come. So I'm pleased to introduce Yujiro Hata, who's the CEO, founder of the company. And then also we have Joshua Bleharski, who's the CFO; and Daniel Simon, the Chief Business Officer. So welcome all of you.

So Yujiro, a lot is going to happen in the next several months with regard to readouts. But before we get to all that, for those a little bit less familiar, just kind of identify the key programs that you're focused on and the key opportunities in the different market segments that you guys are pursuing.

Yes. First, thank you, Yigal, for the introduction, and thank you to Citi for the invitation to participate again this year. So IDEAYA Biosciences, we're a leading precision medicine oncology company. I think where we're unique is we have a very late-stage asset in darovasertib. The lead indication there is metastatic uveal melanoma. We are in the process of submitting the NDA under our RTOR -- the first 3 modules have been submitted, and we have the final module to submit here very soon. Most of our analysts are projecting a first half of next year commercial launch. So again, a very late-stage asset.

In addition to that, we have two additional indications we're pursuing, Phase III studies, both in the neoadjuvant setting as well as in the adjuvant setting. So a very broad set of clinical activities to also expand the opportunity into the earlier line settings.

In addition, we have an IDE849, a DLL3 Topo-ADC. We announced recently that we had a successful Type C with the FDA to advance into Phase III registrational study for monotherapy approval in extensive stage small cell lung cancer. Here, the primary endpoint for accelerated approval will be overall response rate for full approval, median overall survival.

Beyond that, Yigal, as you know, we have a very broad set of assets in the area of MTAP deletion and CDKN2A. We have announced two recent collaborations with Roche with their -- both our pan-RAS inhibitor and their KRAS G12D inhibitor, and that will be exclusively focused on the area of pancreatic cancer.

So for those that may or may not be familiar, the overlap between all of the KRAS mutations with MTAP deletion, we believe, is about 40% of that population. So a very significant population, and we announced those relationships in the last few months. We have more in the pipeline, but I think if we cover that, we would have done very well.

Okay. All right. All right. So let's go to the first thing. So you said you did 3 out of the 4 modules and potential launch in the first half of next year. So what's left to do with this -- what is the last module? What's left to do? And seems like you would need a PDUFA date assigned pretty soon in order to bank to do the 1 half '27 launch. So -- but you have the RTOR and you have the rolling submission, so you have some leverage there.

Yes, that's correct. We have Fast Track designation. So we'll have expedited review through that. And as you noted, our RTOR in terms of the rolling review. So we have -- there's no specific gating item at this point. It's largely QC that's been ongoing related to summaries of both clinical safety and clinical efficacy, as well as the clinical overview section. So that's the good news. We're getting very close. There's no specific gating item that's right now in front of us. It's mainly QC process that's ongoing.

Okay. But the stated guidance of submission is this year.

Correct.

Okay. All right. Now related to that, obviously, there's an important data set in the HLA-A2 positive group. So can you speak to that? I believe you're going to be showing some of that data relatively soon, and there's a potential for getting that sort of into the marketplace through the compendia potentially as a strategy. So just -- can you kind of elaborate on that?

Yes. So we have two fairly sizable updates that's going to be upcoming at ESMO. So first, Yigal, as you noted, we have about 100 patients with the data in metastatic uveal melanoma and HLA-A2 positive. So this is where KIMMTRAK is approved. We will share response rate, PFS, and median overall survival data. We will break that out into first line and then all patients, which is consistent with how we've presented in the past.

Our sense is that the biggest investor focus is even though it's going to be in the subset of patients, which is, what does the frontline OS data look like, as you can appreciate, that will be the second time we'll share OS data in the first-line setting.

And just as a reminder, at SMR last fall, we did share OS, which was just over 21 months. Here, we think the control arm will likely be in that 12- to 13-month range.

For neoadjuvant, we'll also have about 100 patient data set that's presented at ESMO. This will include both the enucleation and plaque therapy patients, consistent with prior disclosures related to preservation rate predicted visual acuity. We -- the actual visual acuity will be still too early. And my understanding is we'll have some commentary related to relapse. So I think that should be helpful as well.

And we will utilize this data with a strategy towards a NCCN guideline usage in the neoadjuvant setting with the anticipation of commercial launch in the metastatic setting.

Okay. And then as far as the -- so for the HLA positives, that would be also with this compendia strategy or that could potentially work its way into the label. Do you fold that into the rolling submission? Is that a plan of action or you may not need to say need to do that?

Sure, Josh?

Okay. Yes. So we've had a lot of good dialogue with the FDA and through the RTOR designation, have had the chance to share some of the data that we'll be having at ESMO, and they've seen that data now.

And I think -- our sense from the interaction is that they're actually -- they're encouraging us to try and seek a broader label. I think they understand the unmet need there. I think the data sets are remarkably consistent. And I think our intention is to have that dialogue with them and see if we can get an HLA-agnostic label and approval.

So that's a little bit of an evolution from where we started, but I think it's really a testament to the drug benefit and the unmet need, and I think the FDA has been very aligned with us and trying to move this forward as quickly as possible so we can get.

So that sounds like a relatively new development.

Yes, yes. I mean it is.

I haven't heard it quite like that before. So that sounds good.

Yes. And maybe part of that, Yigal, is we did have the pre-NDA meeting, and that was largely the focus of the recent meeting topics. And that's why now we had that meeting, we got that feedback. And so you're seeing our communication evolve from that feedback.

Which as recent data?

Correct. Yes, it was recent.

Okay. And then -- so then for neoadjuvant, as you pointed out, compendia listing, but does this mean you may take another thing as far as what to do with OptimUM-10.

Yes. I think in any scenario, we'll submit for compendia for guideline inclusion based on the data we've generated already. What we're thinking about now is just whether that's enough and whether in light of some of the enrollment delays we've had with the 10 study that we've talked about, would it be better for us to sort of pivot rely exclusively on the compendia strategy for the neoadjuvant subset and reallocate some of the funds we'd set aside to run that registrational study towards other high-priority programs in the pipeline.

And so -- we have not yet made a determination there, but we are actively kind of thinking through the options and trying to do the analysis to support the decision, which we'd expect would be before the end of the year.

Okay. And what -- so the gating factors there are just showing the data at ESMO getting more KOL buy-in on that data, I gather?

Yes. I mean, so we've had -- I mean the combination of our own market research and some of the work we've done with KOLs and people who have sat on the NCCN panel our take of that is that there's a reasonable likelihood that we would get included in the compendia. So if that were the case, it's a question of what would that mean commercially?

So we're doing some of those -- some of that work to try and understand that a little bit better. But suffice to say, we think -- that may be a viable route in light of some of the other challenges I highlighted and could allow us to invest in other things in the pipeline, we'll have to do.

All right. So related to all that, can we talk a bit about just the commercial setup, the build and you're getting very, very close, obviously, to a launch, which would be great, the first launch. So where are you with the commercial build? Who have you hired all the market intelligence work to set yourself up to launch?

Yes. So I think Josh and I could tag team on this. I mean I think it's a fairly straightforward build-out. We're just focused on the U.S. launch. As you know, Servier is handling ex U.S. for us. The sales force is, we believe, approximately 25 individuals, very similar to what Immunocore has done with KIMMTRAK.

The base commercial leadership team has been hired. So that's all set. Everything on the supply chain side is also very much on track. So we do have an early scenario commercial readiness and preparation that we'll be prepared for, but everything is all systems go right now.

And anything early that you can communicate in terms of how you see the early launch progressing relative to the obvious competitor, KIMMTRAK?

Do you mean specifically in the A2 population -- sorry, the positives?

Yes.

So -- look, we have seen and heard a lot of enthusiasm from the people that we've talked to about the profile of the drug. Obviously, when we were at ESMO presenting this, the discussion after our presentation, noted that this is a big advance for the field where there's a lot of unmet need still.

So we feel pretty good about the uptake, particularly in the A2 negatives where there are no approved therapies, but certainly in A2-positives, where there still remains a lot of unmet need. So time will tell, but we continue to believe that the drug delivers a lot of benefit. And for patients where there's quick progression or even in the post KIMMTRAK setting, we think that this is a nice viable alternative should it be approved for those patients, and we'd expect to see reasonably quick uptake.

Okay? So that sounds good. Well, let's move over to talking about DLL3 and -- so first of all, in terms of the Type C meeting and the alignment on the Phase III design, is that sort of square with your goals for what you wanted to get agreement on there in terms of the end points you mentioned obviously, ORR and OS?

Yes. It was Yigal. I think the biggest question for us when we had the Type C meeting was around how do we think about pre-IMDELLTRA versus post IMDELLTRA patients. And that was really the key question for us.

And the feedback was very clear that if we did do a pre and post IMDELLTRA study that it would be viewed as more of a heterogeneous population. And so at least for the U.S. approval portion. So we just felt that it was a cleaner study to do it as purely a post IMDELLTRA study population.

In addition, we also did it this way with the mindset that you always want to do a study that's going to be somewhat relevant as you -- at the time of hopefully potential approval. And we did anticipate that IMDELLTRA would hit their endpoint for frontline approval. And as you probably know earlier this week, they announced that they did hit their OS endpoint for frontline maintenance. So that exactly I think further just reinforces the trial design that we're pursuing.

I think the main questions we've been getting is, are we seeing responses post IMDELLTRA? Are you -- is there any concern that you might have DLL3 down regulation post IMDELLTRA? And I think there, we can confidently say at least what we know of that that's not a concern. And then second, we are clearly seeing responses in the post IMDELLTRA setting, which gives us confidence in the study design.

The last two parts I'll mention is we are interested in neuroendocrine carcinoma. So we are -- we believe we're clearly seeing monotherapy activity there. So we do have another meeting with the FDA set up in the fall, to get more clarity on what a registrational path will look like there for monotherapy, both accelerated and full approval.

Here, it's a lot less crowded an area, a lot less activity with antibody drug conjugates. We don't have really IMDELLTRA here as well. So there's a lot more white space. And then lastly, is around frontline small cell lung cancer. And there, I think we can maybe talk about it more, but we think we have more work to do and thinking through what the right strategy is for frontline.

What are the factors that need to be weighed on the front line that you're weighing?

Yes. So first is the landscape is evolving rapidly, right? So as we just saw IMDELLTRA hit their endpoint in frontline maintenance. They have another randomized DLL3 study that has not read out yet in frontline induction. So those type of things, it would be nice to get some sense of where that's all coming out, just so we know we have the right things in the comparator arm, so that's one.

I think second, when you think about what you combine it with, at least our view is PD-L1 is fairly table stakes. I think there has been some questions around plus or minus chemo. Obviously, our antibody drug conjugate. And then, of course, as you know, Yigal, we're quite interested in the PARP combination that we're doing, which is a novel combination. And if that does enhance durability, that would clearly provide us a differentiated path forward than others.

So if we did do a PD-L1 plus ADC versus PD-L1 plus chemo and now would possibly indulge in the control arm, that may be a high bar study, right? So I think that's what we want to think through before we just sort of launch into the trial that we have just a better sense of all of these various parameters.

Have the KOLs suggested like even combining 849 with IMDELLTRA? Or has that come up or not really?

Yes, it has. Yes. And that's -- that would be another piece of the story, right? But once you do that, you have to think about a lot of other considerations from costs, logistics. I think there's a lot of things that you would have to think through there.

So that's why, I think, as we mentioned, versus sort of rushing into a frontline study just making sure we have clarity on what is the highest POS study. And then in the interim, making sure that we get these monotherapy later line accelerated approval studies off the ground, first in small cell. And then next, we'll evaluate if there's a viable path forward for neuroendocrine carcinoma as we collect more information on this question on the front line because yes, you could consider it.

Because some other companies are combining, as you know, right?

That work has just begun. It doesn't look like it's going to be in the first wave of those front lines just because that dosing just began. But yes, those are the questions.

But we know in the past, right, Amgen had done B7-H3 ADC combinations, those were halted, right? So why were they halted? So I think those are the type of questions I think are going to be important to have answers to.

But for neuroendocrine, it's more white space, right? So like there you could do frontline more easily or not necessarily or...

There's not a real -- depending on which subtype of neuroendocrine carcinomas but some of the subtypes we're considering. There's not really a clear standard of care. So yes, absolutely, there's more white space. You see less activity from Amgen there as well with IMDELLTRA and the NEC space. And as you know, there's not as much activity ongoing with other ADCs.

So there could be a unique opportunity for DLL3 Topo-ADC and the NEC area. And as I mentioned, we are seeing clearly seeing activity there as a single agent.

Okay. And then the question of the dose. So 2.4, 3.5 of the finalists, I guess. So what's left to determine there? I mean 2.4 looked pretty good. What are you going to -- what else do you want to know about 3.5?

Yes. We know that our closest peer company has picked an expansion dose of 1.6 mg per kg, at 2.4, right, we're already 50% higher, at 3.5%, we would be over 100% more, right, which means it appears that we could deliver more payload. And now the question will be how will that translate into a response rate PFS and ultimately OS.

But I think the good news is we did share both -- all of the data we have with the FDA as part of the Type C meeting. they were in agreement as that those should be the two doses we should pick from. And it appears that we can go higher than Hengrui decided to expand at 2.4.

So if we can deliver that payload and we could do it safely, then I think 3.5 would be a great dose, but 2.4%, as you noted, Yigal, is also very viable dose.

Is this sort of under the Project Optimus umbrella? Or is it a little bit separate. And actually -- because sometimes the FDA just asks for this to check boxes, but you kind of -- you guys already know what you're going to do for Phase III. In this case, it sounds like there is real -- there is more of an actual debate as to which one to take forward or...

I mean -- I would say the majority or the vast majority of interactions we've had on dose optimization with the FDA as you enter into a registrational study, this is a regular topic now at this point.

So there was discussion around not a blinded but a randomized dose optimization that we do in this process as we initiate the Phase III. So we're going through that right now. So taking the existing data we have, but also doing these two cohorts right now.

Are you going to -- what's going to -- you're going to tell the markets, the answer by the end of the year? Or what's -- are you just going to announce the design and say that's the dose. Are we going to see the comparative data or not really?

Yes. We haven't said exactly when that would be, but we're defining that right now with the data that we're developing. But yes, we anticipate we will disclose ultimately what that dose is.

Okay. And then another important question just as you pointed out, they're competitors. So just it would be helpful if you could sort of delineate what you view as differentiated from your -- on your drug, both on the efficacy and safety side, both in terms of response rates, CNS activity, AE profile et cetera. How do you see it as a unique asset?

In terms of within the DLL3...

Within the DLL3, yes.

Look, I think at the end, our view is directionally. Obviously, we need to prove that with more data. That's one that's going to get presented. So I should have mentioned, we'll have about 100 patients with the data present at ESMO. About 2/3 of that will be in small cell, the remainder in neuroendocrine carcinoma. There will be a robust data set from response rate PFS and survival data. We'll also share full AE information. We'll also provide an update by the end of the year in our -- in the U.S/Europe population as well.

And big picture, our view is that we believe directionally, we believe we are seeing higher response rate. As you may know, in the World Conference on Lung Cancer, we also reported roughly a 6.5-month PFS, IMDELLTRA was roughly 4.5 months or so and their approval readout. And we will share for the first time, 12-month landmark OS data. You may know that IMDELLTRA is OS in that later line setting was 12.5 months.

So we think anything above 50% in terms of that landmark OS would be a win there. So -- and then I think from a safety perspective, we will share more information here. But I think big picture, we feel very good about what we're seeing.

Okay. That sounds good. All right. Let's talk a little bit about some of the other assets then because you have a lot in the MTAP pathway.

So tell us a little bit more about the scientific rationale for the combo work with both the Roche drugs, the pan-RAS and their KRAS, they're two, the pan-RAS the G12D.

I'll let Daniel on.

Okay. Great. Thanks, Yigal. Great question. So we've got these two collaborations with Roche that we executed early this year in the first. They are providing their pan-RAS inhibitor, which is a molecular glue, to us to combine with our PRMT5 inhibitor.

And in the second, we had additional conversations we're providing our PRMT5 to Genentech to combine with their G125.

Now as everyone is probably well aware, I think 92% of pancreatic, or PDAC, patients have got KRAS mutations, co-occurring in roughly 40% of those patients are MTAP deletions? And so the strong scientific rationale to hit both of those drivers simultaneously and clearly, the data that's already been put out there from the combination of darovasertib and Tango PRMT5 is hugely compelling. This to a 94% response rate with darovasertib. And then in the G125 population result on zoldonrasib, I think it was a 62% response rate.

So we're excited to have those two combinations going within the KRAS mutant population within PDAC, G125 mutations roughly 40% of those patients. So 40% times by 40% is roughly 15% and 16%. And so that's still a significantly sizable population within PDAC.

Okay. And then there are other -- there are some other combinations to beyond that, though, right? I mean, there's potential for even , if I'm not mistaken, a triple combination with the CDKN2A asset. Is that right? Or how you?

Yes. So there are several other combinations. So one is in the pan-RAS agreement with Roche, it is contemplated that we also have the ability to enable that to a PRMT5 and pan-RAS, that's one.

Yigal, as you mentioned, which will be part of the R&D Day in London that we'll showcase in the fall, which is CDKN2A deficiency, which we know is prevalent in roughly 70% of all pancreatic cancer. There, you could enable a doublet with pan-RAS. You could also do a double between pan-RAS and PRMT5. And then you could also consider triplet with all of those explored for pancreatic cancer.

So right now, we're probably most excited about the CDKN2A pan-RAS combination and some of that data that we'll have, we'll plan to share that at that R&D Day. And perhaps there, you may not even need to do patient selection.

Because the -- as you point out, there's a lot of combinatorics how you could do this. So maybe just to reiterate, though, for everyone, the one that you sort of see is the one you just mentioned, you see as the front runner? Or how do you sort of prioritize or her what's the hierarchy in terms of your views on all the putting all these different assets together?

Yes. With PRMT5 and CDKN2A because they're both on the 9p21 chromosome and they're about 2,000 base pairs apart, when MTAP is deleted, CDKN2A is almost always co-deleted. So because of the PRMT5 and the CDKN2A asset, we can pursue as a combo in any solid tumor indication. So that will be a plug-and-play all across all of those indications. And we obviously wholly owned that, right?

So in pancreatic cancer, because the CDKN2A deficiency is even higher now than MTAP, and we don't believe others have this molecule of this type, except for us if we get this into the clinic, that uniquely positions us to do a doublet with pan-RAS in pancreatic cancer to capture even larger population.

And yes, based on our preclinical data, we do believe that data actually looks the most exciting. So -- and we've -- we're building a larger and larger data set and hopefully by now until when we hope this molecule will be in the clinic, which is first half of next year. But we're already getting interest to do this doublet with KRAS in pancreatic cancer.

Now maybe we have time to go into some of the other assets like the KAT6 program. Can we talk about that one briefly?

Yes. So KAT6/7 and the lysine acetyltransferase area, we're also relevant to the biology of chromatin remodeling. Yigal, as you know, there's been a lot of activity with KAT6 in breast cancer, in particular, in combination with fulvestrant in the ESR1 mutant setting. Pfizer has presented multiple times and has now initiated a Phase III study. So clearly, in our eye is a validated target.

Where we think this could hopefully be brought to a step-change advancement in this area is by hitting what we'll describe for now is a parallel with KAT6 and 7. As you know, we presented that data in peer-reviewed settings like AACR multiple times where we clearly see more activity preclinically with a 6, 7 dual inhibitor versus both in breast, CRC models and lung models.

And so that's the plan. We're in dose escalation now. The priorities are breast, CRC and lung cancer. Pfizer also has a 6, 7. They're side by side with us. They're also evaluating CRC. It looks like they also have an arm of just monotherapy in CRC, which is exciting.

So we have been -- we have cleared multiple dose cohorts. We believe we're now entering into the clinical efficacious range. So hopefully, by the end of the year, we'll have a lot more information.

And the last part, I will mention two combinations we're focused on. One is with SERD in breast cancer. And then the second is with pan-RAS and KRAS. And we did publish that data as well at this last AACR.

Okay. And the significance -- because that's an important point that you hit the 7 isoform too, which gives you what exactly? What's the difference between that and the ones that are just hitting the KAT6?

Yes. So we have preclinical data, which we've published on publicly, both in vitro data as well as in vivo data. We believe there are specific bypass-type mechanisms with just KAT6 alone that you cannot fully suppress that pathway and by doing that, our hope is, can we then deliver monotherapy activity? Because as you may know with KAT6, it's largely been dependent on this fulvestrant combination.

So if you show real monotherapy activity right out of the gates, it's clearly delineated. We also know with KAT6 alone, there has never been a pursuit of CRC, but now that's being pursued by Pfizer with a 6/7. So again, I think clearly shows there's fundamentally important biology by hitting both 6 and 7.

So this is similar to how you think about CDK4 and 6 or MEK1 and 2, so no different.

Okay. And versus Pfizer, I mean, it's you're basically doing something relatively similar in terms of the molecule. Have you done the comping there has got more potency on one or both of the isoforms or is it more going to differentiate on the clinical development strategy because you pointed out that they're already in late-stage trial?

Yes. We haven't seen much information published from them. So it's hard for us to say at this point. All we know is that they started dosing in the clinic their year, as did we. So I think we're basically side by side right now. And hopefully, there will be more information data that's presented out there. But clearly an exciting area, an area that there's a lot less competition right now. There's only two companies with the 6, 7 inhibitor in the clinic.

Right. Okay. And then briefly on -- we want to ask all the companies about AI really fast. So if you could -- anyone want to comment on how you're using AI tools either with your rolling submission with clinical work with data analysis with internal efficiencies, other specific modules or platforms you're using more than the others, like Gemini versus Claude versus Copilot?

Yes, a little bit. I could tag team on this one. But yes, so all the answer is it is a priority for us. We're integrating across drug discovery, clinical site selection from a regulatory perspective. I know we're even having discussions around further downstream, such as reimbursement processes as well. I don't know, Daniel, do you want to add?

Sure. I think an answer to your question, I could just say yes and put the mic down. We're looking at this across the entire pipeline. We've been most public historically about the work that we're doing within discovery using AI.

So for example, if you know the protein structure and you've got a specific binding pocket you're trying to generate a hit for based on the distribution of large and small amino acid side chains, positive and negative, hydrophobic hydrophilic. There is a there's a physical constraints within that pocket that we use AI to then try and generate a series of hits that may optimally fit within that space.

We use additional software to then parse those molecules and so actually, of these 100 possible hits, we focused on making these 20. Clearly, that saves a huge amount of time and cost, and we also analyze molecules on both sides. And yes, the ones that the software recommendation make do seem to generally do better, although there's still some less good fits within those. There have been a number of discussions this year about using AI to improve the process around the incredibly heavy lift to get all these documents together, generate all the summaries within the regular documents, that is ongoing work and hope there'll be many more filings and regulatory documents to come.

Using AI to help identify where we'll find patients when it comes to commercialization to say nothing of all of the process efficiencies in gathering competitive intelligence, running analysis, helping with finance. It's been a big strategic priority this year, and there remains a lot to do to your other question. We use that ChatGPT, some uses Claude, we just started rolling out co-pilot. So we're exploring multiple platforms to support the company.

And any closing remarks or just maybe recap the key catalysts for the next -- through the balance of the year?

Yes. Sure, Josh?

Lots coming, exciting 12 months ahead. I think to recap ESMO updates on the DLL3 asset, the neoadjuvant study, NDA submission on track for the second half into next year, preparing for commercial launch, hopefully in the first half and additional progress that you should see throughout 2027 with regards to the MTAP portfolio, both the Roche collaboration the 892 program, hopefully getting additional registrational study started there. So lots more to look forward to.

And when is the London Day you mentioned?

Yes, it's November. It's during the Jefferies conference in London.

Okay. So maybe I need to get a plane ticket.

All right. All right. Thank you very much. Great discussion. Thank you.

Great. Thanks Yigal.

Hi, everyone. My name is Maury Raycroft, and I'm one of the biotech analysts at Jefferies. It's a great pleasure that I'd like to welcome the IDEAYA team today. We've got Yujiro Hata, the CEO; Josh Bleharski, the CFO; and Mike White, CSO. It's fireside chat format. To start off, Yujiro, maybe give a brief intro to IDEAYA, and you guys had an announcement this morning with the collaboration with Roche. Maybe provide some key highlights for that.

So Maury, thanks for the introduction, and thank you to Jefferies for the opportunity to participate at your Annual Global Healthcare Conference. So Maury, as you noted, in terms of IDEAYA, we did have an announcement this morning, which we'll cover. So IDEAYA Biosciences, we're a leading precision medicine oncology company. We just came from ASCO where we had a late-breaker oral presentation this past Monday, which was the full complete data set around our top line results for the frontline HLA-A2-negative metastatic uveal melanoma. We have begun the -- under RTOR, the pre-submission process -- pre-submission module 1 has been officially submitted as of a few days ago. So all of that is tracking forward. In addition to the frontline HLA-A2-negative metastatic uveal melanoma with our global partner, Servier, we have two additional randomized Phase III studies that are now either kicking off or ongoing, including in the neoadjuvant setting as well as in the adjuvant setting. Beyond that, we have a very deep pipeline, including a Phase II DLL3 Topo-ADC molecule that is being advanced for both small cell lung cancer and neuroendocrine carcinoma. We also have two clinical assets in PRMT5 and MAT2A, in the area called MTAP deletion with a significant focus in pancreatic cancer as well as non-small cell lung cancer. We did announce this morning a new collaboration with Roche, specifically to do a combination with their Phase I pan-RAS inhibitor. with IDE892, our potential best-in-class PRMT5 inhibitor. And this is specifically going to target MTAP deletion pancreatic cancer, and I'm sure we'll talk about that. Perhaps the last asset I'll mention is IDE574, which is a first-in-class dual inhibitor of KAT6, 7. Here, a significant focus in breast cancer, colorectal cancer as well as other indications.

Got it. Great intro. And we always run out of time at the end. So maybe let's start off with Roche first. Maybe talk about why you picked that compound. Did you see preclinical data or something that gave you confidence that this is the best drug to combine with? Maybe talk about that.

Yes. Look, the parties did your typical diligence as part of the discussion around the clinical collaboration. Our perspective on this is that the real, we think, significant opportunity moving forward is can you deliver a greater efficacy and patient value in the earlier line settings of indications like pancreatic cancer. And we believe a lot of that is going to be through enabling rational combinations. And within that context, Maury, our view is that we have the opportunity to have a potential best-in-class combination with their pan-RAS inhibitor with our PRMT5 inhibitor. Beyond that, I think Roche should be the better group to answer questions as it relates to their specific molecule. But we feel very good about what we're able to observe, and we're excited to get this collaboration going.

And anything more on where you're at with your PRMT5 and anything on time lines for getting to the combo and what that could look like?

Yes. So what I can tell you with IDE892, and we also have Mike White here, our CSO. So I'm sure Mike could also jump into why we're excited about the mechanistic rationale of this combination. The dose escalation has been going very well. We believe based on the human PK data that we've seen, we're going to have a very favorable pill burden size. We also believe we've substantiated some of the key sort of premises of this molecule and why we believe that has a potential best-in-class profile. We will be commencing the combination phase for this program in about a week. I actually just checked in with the clinical team yesterday. We already have multiple patients in screening to start the IDE892 and MAT2A combination, which, as you know, Maury, is a big focus for us in MTAP deletion lung cancer. So that should be within days that combination is going, which implies we've already cleared multiple dose cohorts. The monotherapy expansion will also begin here relatively shortly, we anticipate in the second half. There's significant focus on pancreatic cancer, obviously, to also generate the contribution of components data we would need for combination work we would do ultimately moving forward and then as well as in non-small cell lung cancer.

Got it. And all really helpful. And for your PRMT5, maybe talk about how you think about the dose range compared to the Tango drug and the Bristol drug.

Yes, Mike, do you want to take that? And obviously, we can't specify a specific dose at high level.

Yes. So we're very excited about this compound. When we made this, it was really with an eye towards optimizing specificity for MTAP, making sure that we were MTA cooperative, but also SAM competitive. So we're very clean. That meant that we have a safe starting dose that's very close to our anticipated efficacious dose. which means that we're going to be ready to go into combinations very soon. And we have a PK profile that together with what we're seeing with respect to tolerability and our perceived tolerability with respect to this profile, also a very nice PK, no pill burden, no getting up to high doses where we're going to start to engage other targets. So we're excited about that aspect of the combination as well.

And also, Maury, I did forget to mention for the Roche collaboration. I think what is also unique about our collaboration with them is we also have the ability, and this would require approval by both IDEAYA and Roche, but a combination triplet with the pan-RAS, our PRMT5 and MAT2A. And we do think that could be a key point of differentiation. Obviously, that's going to be further afield, but we think a key potential path to differentiation.

Got it. Really interesting. And then for the combo with MAT2A, how are you setting expectations there for what you want to see on response rate and safety? And I don't know if you're setting expectations for what you want to see with the pan-RAS inhibitor, too, if you've kind of thought about that already. Some other companies have commented there, but...

No. Look, I think for both combinations with non-small cell lung cancer, maybe we'll start with that one. We've already seen some clinical combination data and at least Mike should comment here. But our anticipation is that we will likely be at an efficacious range at the first cohort, the first combination cohort. Based on what we've seen in the past, our anticipation is that we should have the ability to identify several combination cohort doses we should be able to move forward with. Second is that we should see responses at subtherapeutic doses of PRMT5 monotherapy. And ultimately, the real premise of this combination is going to be to drive greater -- both response rate and durability. So I think that's our expectation. We're not going to throw out a specific number, but the bar will be high. So I don't know, Mike, do you want to comment on that or also on the pan-RAS comment?

Yes. So one of the things that's important to us is that combination, the PRMT5/MAT2A combination allows us to really reduce the dose intensity for both of those molecules and get spectacular preclinical efficacy and durability. And the durability piece is very important because what the MAT2A inhibitor brings on board is intercepting escape mechanisms, particularly escape mechanisms due to cell fate transitions and epigenetic alterations. And I want to bring that to the pancreas cancer piece, very excited there because the KRAS combination or the pan-RAS combination in the KRAS mutants, that's exciting in pancreas cancer. All -- virtually all MTAP pancreas cancer patients have KRAS mutations. And this combination, in particular, the triplet gives us multiple mechanisms of action that will combine with each other, we think, to give deeper and more durable responses. So one, you have the co-alteration piece of hit it from two different sides. But two, as was presented by a number of laboratories at the AACR this year, the mechanism of action of MAT2A and PRMT5 to perturb splicing also directly perturbs the machinery that KRAS uses to activate the MAP kinase pathway. So we actually weaken the ability of RAS to drive tumors. And the third piece is that the MAT2A inhibitor restricts the cell fate transitions that occur, which seem to be one of the major mechanisms that drive bypass to monotherapy, mono-RAS therapy.And the third piece is that the MAT2A inhibitor restricts the cell fate transitions that occur, which seem to be one of the major mechanisms that drive bypass to monotherapy, mono-RAS therapy. So that triple combination could do something really important in the pancreas cancer setting.

Got it. All really helpful. And let's shift gears. The daro story has been front and center for IDEAYA for a while, and you guys had positive Phase III data with a 6.9 months PFS, 0.42 hazard ratio, and you just presented this at ASCO as a late breaker. Maybe talk about just the key takes that investors need to know from this program and next steps as well.

Yes. I would first start with metastatic uveal melanoma continues to be extraordinarily high unmet medical need. Unfortunately, for patients, there are currently no FDA-approved therapies in HLA-A2-negative metastatic uveal melanoma. And we believe, based on the data that was just presented at ASCO has the opportunity, as the discussant noted at the presentation, the opportunity to be the new standard of care in HLA-A2-negative metastatic uveal melanoma. So that's extraordinarily exciting, Maury. And what is that based on? That's based on the strength of the data that was presented on Monday. First, just for the listeners that may be less familiar, when you look at the clinical efficacy profile, we demonstrated a confirmed response rate by both central review as well as investigator scoring that was trending towards 40%. Just put in context, the control arm response rate was sadly mid-single-digit percent. And in fact, by investigator scoring, it was roughly 2%, which shows you how challenging this indication is. Next, when you look at median progression-free survival, here, we more than doubled what was seen in the control arm, which was primarily ipi/nivo. So I think the clear win on progression-free survival. Hazard ratio was 0.42, was less than that by investigator scoring and a p-value of less than 0.0001. So all statistical measures, it's clearly mission accomplished. From a safety perspective, just high level, we saw less SAE rates, less discontinuation rates than the control arm. So as well as from a safety perspective, we think significant potential advantages when you look at safety. So obviously, with any kind of new therapy as a potential standard of care, you always want to look at both the risk as well as the benefit in both parameters, we think the molecule is positioned extremely well.

Got it. That's helpful. And you mentioned that the first RTOR module was submitted. Can you just clarify what was in there? And then what the time line could look like for the remaining modules?

Yes. So the FDA with the RTOR presubmission module 1, 2, 3, there's actually some fairly clear defined parameters of what they want to see within those modules. I'm not going to go through that -- all those specifics. You can actually go to the FDA website, and that's all available online. The next presubmission module is a few months away. And then the final third is typically filed with that final submission process. And typically, that would see companies in our peer group try to get that filed within roughly two quarters. And so we're tracking along that. As you know, Maury, we also have Fast Track designation. So we would get expedited review. And now with RTOR, we would anticipate having a further acceleration of that review process since they're now reviewing the data real time. So I think that's going to be great and hopefully can pull in that launch timing.

Got it. And you commented on the potential to include the HLA-positive data in the filing. I guess, where are you at with conversations with FDA around that? Have you already spoken with them on that point?

Yes. So the quick summary is, yes. Discussions have occurred with the FDA on the HLA-A2 positive piece of it. And those discussions will continue, including for the pre-NDA meeting that's already penciled in the calendar. So -- but the preliminary discussions have occurred.

Got it. And so that will be confirmed at the pre-NDA meeting. Are you saying more about timing for when?

We're not saying more about the timing. But yes, that's correct. We would anticipate we'll have further clarity as part of that pre-NDA meeting.

Okay. And would that be included as a rolling -- part of the rolling submission? Or would that be a major amendment for the HLA-positive data?

So one is we would have that conversation as part of this pre-NDA meeting. I think, Maury, here we probably don't want to get into too many specifics on regulatory pieces there. But I would say kind of base view is if that is the path forward that is available, we will submit that as part of the NDA. It would likely be staggered from the full submission.

Got it. Okay. And you've highlighted an early OS trend at approximately 10 months of follow-up with the potential to extend that by 6-plus months. What are the key drivers and options involved with your next OS cut for FDA? And do you see a path to stopping the study early given control patients can't cross over to combo?

Yes. So we are seeing an early trend in OS for the treatment arm versus the control arm. We noted that as part of the top line results. That was with fairly minimal follow-up with just over 7 months, but I think that's encouraging when you see an early trend even with only a fairly minimal follow-up in the study. So in terms of additional updates moving forward on OS, our view here is that the current projection for the interim OS analysis is middle of next year. But you are correct, Maury, that at the time of the NDA submission, the FDA will want to have as part of including the safety database update, where we are on the OS events. And as part of that, because there is no crossover in the study, there is a scenario we may get full approval. But just so this is clear, that is not what we view as base case, but potential upside scenario.

Got it. And for the amount of time of OS follow-up that you could have, are you commenting more on what that could look like, what the range could be?

In terms of -- at the time of the NDA submission, no, we're not. The cutoff for the top line results was end of January. So I think here, it's going to be roughly 6 to 7 months more follow-up, something in that time frame.

Got it. Okay. And you showed -- you got the hazard ratio of 0.42 from the study, which is meaningfully better than KIMMTRAK's 0.76 hazard ratio. How do you think about pricing here? Could you price at a premium versus KIMMTRAK -- or what other variables should we be thinking about?

Yes. So that's work that is ongoing right now, Maury. Obviously, as the data evolves, we want to take that into consideration as we think about pricing. I know as you throw out other competing drugs in the space, KIMMTRAK is obviously one analog. Yes, I think depending on how the data shakes out, we do think there's an argument to be made for pricing at parity or even at a premium to KIMMTRAK. But ultimately, we want to make sure that we take the full data set into account as we make those decisions.

Got it. That's helpful. And for the pivotal study, what are you seeing on median duration of treatment?

Yes. I mean what we've seen so far is 10 months. So that's sort of what our clinical trial experience has shown to date. I think there's a path for that to extend beyond that in the real-world setting, depending on where we are. But that's sort of what the data has told us thus far.

Got it. Okay. And for later this year, you're going to have the HLA positive data update expected at a medical conference. How should we think about the frontline versus second line post KIMMTRAK split within the 85-plus HLA-positive patient cohort? And how are you setting expectations for median OS, median PFS and ORR relative to what you've observed with the HLA negative?

Yes. So the majority of the patients, Maury, will be pretreated patients. So we're not sort of specifying beyond that, but the majority will be pretreated. And as you noted, we'll have a full data set for all comers as well as the frontline patient subset. -- including response rate, PFS as well as median overall survival, which will be important, obviously, because we are going into an important interim OS analysis. And then this will be the second time we're now sharing median OS again, granted it is from a single-arm study, but I think hopefully a useful data point. I would say the high-level takeaway, Maury, hopefully, people will take from the data set is that our view is the data is very robust and also consistent with what we've seen in HLA-A2 negative. And we've said that in the past that the fundamental underlying biology is around the activating mutation of GNAQ/11, and it is agnostic of specifically HLA-A2 status.

Got it. And for patient baseline characteristics, overall, those are pretty similar to the HLA-negative patients.

For -- yes. For the frontline patients, we would anticipate that would be the case, but this is a much more limited data set than what we just shared at ASCO, right? That was at least from a safety perspective, and that was over 400 patients.

Got it. Okay. Makes sense. And you're going to have the neoadjuvant data update at a medical conference second half of this year as well. How mature will the data be across the plaque brachytherapy and nucleation cohorts? And how many patients are going to be evaluable for radiation reduction?

Yes. So there will be roughly just about 100 patients. There will be more follow-up from what was provided in the past. That will be split a bit more, I believe, nucleation than plaque therapy. We're not saying how much data as it relates to actual visual acuity data.But Maury, as you know, even for that, it's still, I would say, early. I would say we need to have continued follow-up. We will have a refresh on the percent of patients that we preserve the eye, which just as a reminder, that is the primary endpoint for full approval in the nucleation cohort. So I think for the plaque therapy, it will likely be more related to this predicted visual acuity tools that we've shared in the past. And I think for EFS as well, we may have some high-level commentary, but I suspect for event-free survival, it will also be still immature. But we are tracking the EFS data from the single-arm study piece. And since we're on the topic of neoadjuvant, one other I will mention is that similar to our strategy for HLA-A2 positive with compendia, we will also likely pursue the neoadjuvant indication as well in the U.S. for compendia based on this data that we'll be publishing.

Got it. Okay. So that could get added to guidelines. You could potentially start getting some uptake there commercially once you're commercial setting. Okay. And for the adjuvant study, I wanted to ask about that, too. So starting first half of this year. It seems like the base case -- base case scenario, the study could take about 3 to 3.5 years. What can you say on powering assumptions for interims relative to Immunocore's adjuvant Phase III, which assumes hazard ratio of 0.55 with an interim analysis at 76 events and 56% probability of early stopping.

Yes. So the study, maybe just kind of base parameters here. So it's 450 patients. Primary endpoint is superiority for relapse-free survival, target hazard ratio of 0.65. So our study is more powered than the peer company that you noted. The randomization will be 1:1. The randomization will be against observation. And importantly, it will be agnostic of HLA-A2 status. So much larger pool of patients will not require HLA-A2 status testing. So I think those are hopefully answered most of your questions there.

Yes. Yes, that's helpful. And let's shift gears to -- well, I guess, anything more about getting that study up and running and how should we think about that?

No, we're ready to go. So we had the Type C meeting with the FDA with Servierrecently. We essentially got everything that we had hoped for and asked for. So now we have obviously a very deep relationship with all the key sites globally. And I think what we can say is there's a tremendous amount of enthusiasm to get this study. And our anticipation is that this study should enroll very rapidly. So -- and again, here, the drug is clearly working in the metastatic setting, including at least based on single-arm data survival. So we think this is a very high probability of success study. We're essentially randomizing against nothing.

Got it. Makes sense. So let's shift gears, talk about DLL3, your ADC there. Maybe starting off with the small cell update. How are you setting expectations on PFS? And could we get other efficacy details based on the patient's prior line and/or breaking it out by dose.

Josh, do you want to take that?

Yes. So we'll have 2 updates on DLL3. The first is actually Hungary's update from their Phase I study in China. There, we anticipate updates in both small cell and neuroendocrine. It will be a refresh of the data they shared last year at the World Lung Conference. We'll see updated PFS, obviously, safety, response rate, PFS. And then importantly, for the first time, landmark OS data. So that will be sort of, to our knowledge, the first look at how a DLL3 type 1 ADC performs from an overall survival standpoint. So that's very exciting. And then in parallel or sort of a similar time frame, we're going to have our update from our ongoing Phase I global study. And I think there, the focus will be primarily small cell. We do have some early look at safety and probably response rate. I don't think we'll have enough to comment on PFS at that point, but we'll see. And we anticipate that will be roughly 30 to 40 patients.

Got it. Okay. Helpful. And should we expect intracranial overall response rate data in patients with baseline brain mets in this update?

Yes. I would expect -- definitely Hungary had that data set originally in their data last year. We expect there'd be a full refresh of that as well. So yes.

Got it. And for the next -- the NEC population, should we expect a similar number of efficacy evaluable patients relative to Zai Lab's update where they had about 34 evaluable? And how should we think about tumor heterogeneity in the setting?

Yes. So the exact numbers, we're not going to specify here, Maury. But look, there will be enough patients on the neuroendocrine carcinoma. This is not for Hungary's data, where I think people will have a good sense of what we're seeing both in terms of response rate as well as progression-free survival. In addition, we've also begun enrolling in the U.S., Europe, outside of China, and we've also -- probably about half of our patients have been in neuroendocrine carcinoma. And really, the quick summary there is we believe we're seeing activity that there should be a monotherapy approval path forward here based on what we're seeing and based on what else is out there. In terms of the heterogeneity of this population, maybe Mike, you can talk about that. But yes, there are several indications of note. Some have higher DLL3 expression than others, but Mike?

Yes. We're obviously focusing on those indications where DLL3 positivity is known to be high. And that's something that we also are excited about with respect to IDE161, our PARG inhibitor. So what does heterogeneity mean? It means for an ADC that you could get less tumor exposure to the payload. IDE161, the PARG inhibitor, its mechanism of action is to amplify the therapeutic effects of what would otherwise be a suboptimal delivery of that payload. So that's where we see a real opportunity in the combination setting.

Got it. And for picking tumor types, that's one thing, but I guess, could you select for patients that have high DLL3? I think Amgen's moving forward with a higher 30 mg dose, and they're seeing better efficacy in patients that have a higher DLL3 expression.

Yes. So for small cell lung cancer, we don't think that's going to be needed. For DLL3, that's something that we're discussing. So I think we don't want to give too much visibility in our regulatory strategy for competitive reasons. But I think here, I think more big picture, there are some neuroendocrine carcinomas that have very high DLL3 where we think that's not going to be needed. And then you can think about following that with, let's say, a pool of NECs where something like a diagnostic could be more helpful. So more to come on that front. And hopefully, we'll be able to share more before the end of the year on that. But we are clearly -- we have our strategy, and I would say we're -- we have a strategy on what we're going to do on that question.

Got it. Okay. Mike, you mentioned the PARP combo. Could we see some data from that by the end of this year?

We're pushing the team. So the dosing has just begun. For those that may not be as familiar, this is a proprietary combination that we have clinically. Our view is that the PARP mechanism may have the opportunity to extend the durability of the topo ADC class. We have very strong preclinical data to support that. We've now begun the combination dosing in patients with DLL3. So we'll push as hard as we can, Maury. I think a lot of it will just be about how many patients do we have. And to really get good visibility on this question, I think durability is going to be important.

Got it. Okay. And at ASCO, I was part of conversations around KAT6. People were talking about KAT6 and breast cancer. You've got the KAT6/7 that you're dose escalating in breast, prostate, colorectal and lung. Can you talk about the strategy here and what improvements you want to see in some of these indications, including breast cancer?

Yes, Mike?

So this is a very exciting asset. This is something where I think people are really starting to appreciate the importance of maximally suppressing the epigenetic mechanism. And to do that, you need to bring KAT7 on board. And so having a dual KAT 6/7 inhibitor, we've shown -- now Pfizer has shown as well that, that's an optimal profile to be able to drive monotherapy responses in a preclinical setting. We're expecting that to happen in patients as well. very excited about the opportunity in p53 mutant MSS, colorectal cancer, especially because that tumor is very heterogeneous because of epigenetic mechanisms that promote diversity. We intercept that with a KAT6/7 inhibitor. If you don't have KAT 7 inhibitor -- inhibition on board, you can't get that phenotype. We're also very excited about large lung cancer cohorts that are addicted to the alveolar type 2 lineage program. That's a large section of lung adenocarcinoma. Again, you cannot get efficacy in models, PDX models without having KAT7 on board as well with the breast cancer setting. Estrogen -- positive estrogen receptor positive breast metastatic breast cancer, we're expecting to see monotherapy activity there equivalent to what you might otherwise get with a KAT6 inhibitor together with an estrogen inhibitor. The reason the KAT6 inhibitor needs the estrogen inhibitor is because it cannot sufficiently suppress that pathway on its own. A dual inhibitor can do so independently of the presence of an RB mutation, independently of the presence of an estrogen receptor mutation. So we're very excited about that one.

And I think we're out of time. So maybe to close up, if you just want to highlight key catalysts ahead for IDEAYA.

Yes. I think the message for the second half of this year is we have a lot of catalysts upcoming. So I know we've covered a lot of it already today. But for darovasertib, obviously, everything that we're doing on the NDA submission in the second half, commercial preparation. We have about 100 patients worth of data in HLA-A2 positive. That's already been submitted for a major medical conference. The roughly 100 patients in neoadjuvant as well has already been submitted at a major medical conference. We have the DLL3 Phase II Topo-ADC. Our partner, Hungary will present about 100 patients worth of data in small cell neuroendocrine, including with landmark OS data. We'll also present on our side from the U.S., Europe, non-China studies. And we're pushing hard also on the bispecific ADC. We didn't cover B7-H3/PTK7. We have a clinical update. We're guiding towards by the end of the year. And obviously, now with our Roche collaboration moving forward, hopefully, we'll be announcing our MAT2A PRMT5 FPI combination start here very soon as well. So look for a very catalyst-rich second half.

Got it. Thanks so much for joining us today.

Thank you so much.

Hello everybody. Welcome back to the Bank of America Healthcare Conference. I'm Tazeen Ahmad. I'm one of the senior biotech analysts here at the bank. Our next presenting company is IDEAYA Biosciences. And sitting up here on stage with me are two members from the management team. We've got Yujiro Hata, who is Chief Executive Officer; and Josh Bleharski, who is, of course, CFO. Gentlemen, thank you for making the trip to see us today.

Tazeen, thank you.

Thanks so much for hosting us. Tazeen, really pleasure to have us. And Josh and I are looking forward to the discussion today. Thank you.

Okay. So really quickly, for those who may not be as familiar with the company, can you just give us an overview of IDEAYA sort of the platform, where you are in terms of developing some key data catalysts and we can go from there.

Sure. So IDEAYA Biosciences, we're a leading precision medicine oncology company. Our lead program is darovasertib. We just recently had top line results in first-line metastatic uveal melanoma. We also recently just received Fast Track designation. So we'll be submitting our first pre-submission for the NDA next week. And so that's all going as planned.

We also have two additional Phase III registrational studies that are ongoing beyond metastatic uveal melanoma, including in a neoadjuvant setting as well as in the adjuvant setting outside of the U.S. We have a global partner in Servier, which we're very excited about as well.

Beyond that, Tazeen as you know, we have a very deep pipeline precision medicine oncology. We're very excited about what's coming ahead as well in our next assets. And here, I will probably next focus on DLL3, our Topo-ADC IDE849. We are targeting to start a registrational study by the end of the year. Our partner Hengrui in China as well is planning to start registrational study by the end of the year. Here, the key indications are in small cell lung cancer as well as neuroendocrine carcinoma. We have 2 clinical data updates we're guiding towards as well in the second half.

Beyond that, we have a deep clinical pipeline and MTAP deletion, both what we believe is a first-in-class PRMT5 inhibitor as well as a potential first-in-class MAT2A inhibitor. Here, we have a significant focus on MTAP deletion PDAC as well as in non-small cell lung cancer.

We are also evaluating opportunities to enter into the RAS, KRAS space in terms of combinations, so more to come on that front, which we're quite excited about. Beyond that, I would say probably the next program I would mention is a Phase I KAT6 dual inhibitor. There are only 2 clinical assets here. It's us and Pfizer. We have key focus here in breast cancer, prostate cancer, CRC and so a lot of excitement and enthusiasm. So as you can see, a very deep pipeline going after very large solid tumor indications.

Okay. Yes, you've got a lot going on. Let's try to do some of these in order of near-term events. So for the top line that you reported for the OptimUM-2 study, can you give us a little bit of detail on that? And what the next steps are in that program?

Yes. So here, for folks that may be less familiar with this study. So this is a combined accelerated approval and full approval study that we designed. The primary endpoint for accelerated approval is median progression-free survival and for full approval is OS. What we reported was a PFS of 6.9 months in the treatment arm and 3.1 months in the control arm, which led to a hazard ratio of 0.42 with a p value of less than 0.0001. So great result really puts us on track for that NDA submission. So that's really been the focus.

You may also know that last fall, we also reported OS data. This was single-arm OS data just over 21 months. We think a historical OS here is going to come in roughly in that 12- to 13-month range. So we feel also good about OS. We did note as part of the top line results, a preliminary trend, a favorable OS trend as well. We will have an ASCO late-breaker oral presentation on Monday, June 1. So that's exciting. Here, we'll just provide a more fulsome update. So in addition to the PFS Kaplan-Meier curve, which we showed, we'll have a full CT scan waterfall, both treatment control arm, both by central review as well as investigator scoring, including just a full safety data set as well.

Okay. And can you just talk to us about what the competitive landscape looks like here?

Sure. Josh, do you want to take that?

[indiscernible] There really isn't any improvement. Current standard of care is checkpoint inhibitors and chemotherapy. And that was what we had in our control arm in the study that we just reported out. On the A2 side, there is an approved agent. So we'll also explore the efficacy of the [indiscernible] combo in that setting as well nature of the authorities with the FDA on that as well.

And what do you think is the total addressable market opportunity for your product once approved?

Yes. Look, we think this could be a very significant opportunity, obviously, within the A2 negative setting which is where we're primarily focused with A2. We think there's roughly what -- 1,500 patients in the U.S., the majority of which are A2 negative. Again, it kind of comes down to where we land on pricing and duration. Those would be 2 of the major drivers that dictate kind of market opportunity. But we think it's quite significant and you start to factor in a potential uptake in the A2 setting as well as in the primary setting in neoadjuvant and adjuvant setting, those opportunities start to add up.

Okay. For the A2 negative population, how easily are they found?

Yes. I mean so a lot of those patients are treated in concentrated centers [indiscernible] Fortunately, through the work we know where patients are, but there is a long tail of patients that are treated in the community setting. So we're working hard to identify them so that we can reach as many as quickly and efficiently as possible if and when we get approved. And that will rely on sort of a grassroots kind of feet on the ground strategy as well as data and analytical strategy that will complement our sales effort.

Okay. And so given that this is an ultra-rare indication, what's the range of pricing that we could use as comps. Obviously, you're not going to announce price to us today. But as people try to think about range, what do you think would be good comps here?

Yes. I mean that's work that's underway right now. As you said, I don't think we're ready to comment much specifically around pricing. Look, I think what we want to do is look at the totality of our data and price the drug appropriately based on the benefit that we deliver. There's obviously an approved analog out there that I think many people point to. That's not a bad place to start. Again, I think it will have to -- we'll have to see how our data matures, both on the PFS and then overall survival side. But we feel pretty good about the profile and the benefit that we've delivered.

Okay. And so in terms of investments in setting up for a commercial organization, how big of a footprint do you think you'll need for this indication?

Yes, that's a great question. So we think it's a pretty modestly sized sales force based on some of our peers in the industry and the model that they have employed, we think this would be a pretty conservatively sized sales force, and we will be able to effectively target this opportunity in the U.S. And that work is all underway right now.

Okay. And how long do you think it will take over time to expand into those larger populations that you just mentioned?

Yes. So I mean, I think, again, we'll -- we have those registrational studies up and running in the neoadjuvant setting. In the adjuvant setting, we will start that trial imminently with our partner, Servier. That data is going to take a little bit longer to develop and mature. So those are likely several years out on the metastatic launch. However, we will look at ways to accelerate getting into those patients, particularly in the neoadjuvant setting using some of the data we've already generated in the 09 study. So we're going to be looking to publish that data and look for ways to maybe accelerate that potentially through a compendia guideline strategy.

Okay. Go ahead.

And I think just on the other -- on the adjuvant side, we'll be launching that study here shortly, 450 patients. We think enrollment should go quite rapidly for that just based on the demand. There's nothing approved in the adjuvant setting. We will be HLA agnostic. And then also because we'll be focusing on the high to high medium metastatic risk population, also that RFS readout, hopefully will be expedited based on that as well.

Okay. In the few minutes that we have left, maybe we can talk a little bit about some of the pipeline programs, Yujiro, that you mentioned. Maybe let's talk about 849. You mentioned DLL3 positive tumors. How should we be thinking about the opportunities there?

Yes. Look, it's a very sizable patient population. So in terms of the indications of focus for DLL3, I would say first is small cell lung cancer, right? You're talking about an annual incidence globally that's at least 100,000 patients or more. Here, DLL3 is broadly expressed in small cell lung cancer. So we don't anticipate we're going to need to patient select. In neuroendocrine carcinoma as well, also a very sizable population. U.S. alone, you're talking 20,000, 30,000 patients a year. So I think a lot of significant interest there, very high unmet need, as you know, in the neuroendocrine carcinoma space, response rates are even in the teens range, typically, when utilizing chemotherapy. The last indication, we do have quite a bit of interest in is also in melanoma. We know DLL3 upregulation has been high there as well. We have not evaluated patients there yet, but that's also another area that we'll be focused on.

Okay. So how do you prioritize which indications you want to focus on first?

So I would say that right now, our primary focus is in small cell lung cancer and in neuroendocrine carcinoma. I would say the first registrational study we want to launch will be a monotherapy registrational study. We're evaluating both later-line small cell as well as neuroendocrine carcinoma. We're also considering sort of a basket type approach as well to see if we can pool all those populations together.

In terms of frontline strategy there, I think that's going to be mainly focused on small cell lung cancer. And for that, you will likely need to do that in combinations, looking at assets like PD-L1. You may know we've recently put a relationship in place with AstraZeneca. We're also doing a proprietary combination with our PARG inhibitor. That could also potentially enable a chemo-free regimen as well. So I think a lot of opportunity there. That will likely be more focused on for next year.

Okay. So in terms of data catalysts for this program, are you going to have -- it seems like you'll have a few next year.

So on DLL3?

Yes.

Yes. So actually, by the end of this year, we'll have 2. One will be our partner, Hengrui's update from their Phase I China study. So that will be over 100 patients. It will be a pretty robust data set both small cell and neuroendocrine carcinomas. And I'd expect that to be a pretty fulsome update from what they showed last year at the World Lung Conference, including potentially an OS cut, so landmark OS data for the first time. So that's exciting. And then in parallel, we'll look to provide an update on our Phase I, IDEAYA sponsored trial with DLL3. And that will be obviously in small cell and neuroendocrine carcinomas. We'd be hoping to show response rates in different tumor types and just probably get a sense of initial activity. It will be probably too early for PFS data, but hopefully, we'll get to see safety and some preliminary signs of activity.

And how many patients' worth of data would that be?

Hopefully, it's 30 to 40. That's what we're hoping for.

Okay. So it's basically a basket study.

Correct. Yes.

Okay. And sorry, Yujiro, you were going to say something.

And Hengrui's data is going to be over 100 patients. So in aggregate, it's going to be a large data set. And I think the other piece we can mention, even based on the early data, the data has been very, very consistent in China and outside of China.

Yes. How derisking is that Hengrui's data going to be for your own study?

We think it's going to be very derisking. And look, we think a lot of the key questions around the DLL3 Topo-ADC space is around durability and we did share some preliminary PFS data at the World Cancer Lung Conference last year, but there wasn't a lot of follow-up. Now there's a year more follow-up, a much larger denominator. We're seeing consistency with the China and non-China data. And now for the first time, we'll also have some landmark OS data. So we're going to answer a lot of questions. In our view, based on what we've seen is we believe we've got a potential best-in-class asset here. So definitely want to pay attention to it.

Okay. And are there other companies looking at the same mechanism?

So in terms of DLL3 Topo-ADC, there's us, there's another biotech company, Roche is also in Phase I with their asset. On the T cell engager side, there's Amgen and Delta. There are several other pharmaceutical companies. So a lot of activity here. I think our view is we have the opportunity to have a best-in-class DLL3 Topo-ADC, but also potentially have a backbone type therapy broad across all of DLL3 and small cell lung cancer.

Okay. And then last question is how do you think about the toxicity profile?

So, so far, it's been very, very solid. I mean I think here, it's been mainly around myelosuppression, I would say consistent with what you've seen with Topo-ADC. I think the advantage we may have with the DLL3 antigen versus, let's say, B7-H3 is I do think we are seeing less ILD in particular, and which we think makes it potentially the preferred antigen target for small cell lung cancer and that could become important as you start thinking about other combinations, whether that's with PD-L1 or with T-cell engagers.

Okay. Perfect. With that, our 15 minutes is up, but thank you guys for making the trip over here. And we appreciate you taking the time, and thanks, everybody, for listening.

Great. Thanks so much.

Thanks, Tazeen.

Good morning, and welcome to the IDEAYA Biosciences webcast. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the IDEAYA Biosciences website following the conclusion of the event. I'd now like to turn the call over to your host, Yujiro Hata, Founder and Chief Executive Officer of IDEAYA Biosciences. Please go ahead, Yujiro.

Good morning. I'm Yujiro Hata, CEO of IDEAYA Biosciences, and I will be your host today. Please note, we'll be making forward-looking statements, and please refer to our SEC filings as appropriate. I welcome all of our online attendees and speakers to discuss the top line results from the OptimUM-02 study. I'm delighted to introduce our webcast participants, including Dr. Meredith McKean, a distinguished KOL and oncologist from Sarah Cannon Research Institute, alongside Chief Medical Officer, Darrin Beaupre; and Chief Financial Officer, Joshua Bleharski. For today's agenda, Darrin, our CMO, will provide a brief introduction of darovasertib and the OptimUM-02 study design, followed by a summary of the top line results.

Once the prepared remarks have concluded, we will open up the line for the analyst Q&A portion of the webcast, where Dr. McKean will also participate alongside IDEAYA management. Today's Phase II/III registrational trial results are an accumulation of over 5 years of clinical development activities, where our organization worked in close partnership with the U.S. FDA, patient community and leading clinical investigators globally. Importantly, the PKC and c-MET combination rationale was discovered by IDEAYA scientists, and we went from research bench discovery to dosing our first combination patient in the clinic in less than a year.

The OptimUM-02 study represents the first frontline randomized registrational trial in HLA-A2-negative metastatic uveal melanoma, which we believe represents the majority of the mUM patient population. Next, this study is also the first randomized frontline registrational trial in mUM to utilize ipi/nivo in the control arm, which is the preferred investigator choice therapy in the U.S. versus PD-1 alone. Lastly, as Darrin, our CMO, will share, this is also the first time frontline randomized registrational trial in HLA-A2-negative mUM to demonstrate a statistically significant clinical benefit versus investigator choice therapy arm for both PFS and ORR, highlighted with a p-value of less than 0.0001. With that, Darrin, please take it away.

Thank you, Yujiro. So let's start the discussion this morning with a little background around uveal melanoma. Next slide, please. Uveal melanoma is the most common ocular tumor of the adult eye. Although fortunately, it remains relatively rare and is an aggressive form of cancer with a poor prognosis. In the United States, there are about 3,000 newly diagnosed cases per year and approximately 10,000 cases reported globally. Uveal melanoma comes in 2 forms, one that is HLA-A2 positive and a more common type, which is HLA-A2 negative. With respect to primary management of localized uveal melanoma, approximately 20% of patients will require enucleation for which the eye is removed.

The remainder typically undergo either proton beam or plaque brachytherapy, which may create permanent vision loss. Unfortunately, about half of the patients diagnosed with this disease will develop metastases, which is associated with a median overall survival of approximately 10 to 12 months and a 5-year survival rate of approximately 15% to 20%. There are limited treatment options available for patients with metastatic uveal melanoma. Liver-directed therapy is sometimes utilized, but most patients require some form of systemic therapy. For HLA-A2-positive subjects, there is one approved product known as KIMMTRAK. For HLA-A2-negative subjects, there are no approved therapies, although immune checkpoint inhibitors are often used off-label and have very limited clinical activity.

Next slide, please. The important biology associated with this disease is noteworthy for the majority of uveal melanoma tumors harbor mutations in G-coupled protein receptors that are responsible for the constitutive activation of protein kinase C. This pathway drives uveal melanoma growth and survival and is the harbinger of the disease. Darovasertib is a potent and selective inhibitor of protein kinase C and was found to have significant antitumor activity in preclinical models. In addition, overexpression of MET is often found in advanced uveal melanoma and is thought to play an important role in metastatic spread. It was determined in preclinical testing that the combination of darovasertib and crizotinib, a MET inhibitor, resulted in greater antitumor activity than either compound alone. This novel combination was, therefore, studied in Phase II in metastatic uveal melanoma subjects and was found to have a high response rate with an associated prolonged progression-free survival in treated subjects. This set the stage for the randomized Phase III trial, which we will discuss today.

Next slide, please. OptimUM-02 is a randomized Phase II/III trial that completed enrollment in December of 2025. 313 HLA-A2-negative metastatic uveal melanoma subjects were randomized 2:1 to receive either darovasertib 300 milligrams twice a day and crizotinib 200 milligrams twice a day orally each day versus standard of care therapy, which included either single-agent checkpoint inhibitors such as pembrolizumab, combined immunotherapy with ipilimumab and nivolumab or dacarbazine for those who would not tolerate immunotherapy. The primary endpoint was progression-free survival by blind independent central review for potential accelerated approval. And for Phase III overall survival was the key endpoint for potential full approval.

Secondary endpoints included progression-free survival by investigator, overall response rate, duration of response, disease control rate, of course, safety and several quality of life questionnaires were included. Next slide, please. The top line results from the study are presented here. With respect to the primary endpoint of progression-free survival, the darovasertib and crizotinib combination had a statistically significant improvement in median progression-free survival by blind independent central review of 6.9 months compared to 3.1 months in the investigator choice arm. The provided hazard ratio of -- this provided a hazard ratio of 0.42 with a 95% confidence interval of 0.3 to 0.59 with a p-value less than 0.0001, which equates to a 58% reduction in the risk of tumor progression in the treatment arm.

Next slide, please. Also highly noteworthy was the overall response rate. Darovasertib combined with crizotinib delivered an overall response rate of 37.1% compared to only 5.8% in the investigator choice arm with a p-value less than 0.0001. There are 5 complete remissions seen in the treatment arm, none in the control arm. There was also a trend in improvement in overall survival. In terms of safety, both arms demonstrated a safety profile that was expected based on prior studies, and the full data of this trial will be presented at a future medical conference. Next slide, please. In conclusion, the darovasertib and crizotinib combination represents a novel emerging therapy for those subjects with metastatic uveal melanoma who have HLA-A2 negative disease and has shown a significant level of superiority relative to standard of care immunotherapy and is likely to represent a paradigm-shifting therapy in a disease that has high unmet medical need.

With respect to darovasertib itself and the fact that it targets the driver of uveal melanoma, protein kinase C, we believe darovasertib either as a single agent or in combination with crizotinib has the potential to have a major impact across the entire uveal melanoma patient journey. And we have several trials either underway or being initiated to uncover the promising activity of this agent. In the neoadjuvant setting, darovasertib is being tested in primary uveal melanoma with very important endpoints that include both eye and vision preservation. Post primary local therapy, darovasertib combined with crizotinib will be tested in the adjuvant setting in subjects that are high risk for metastases to determine whether this combination can reduce both local and distant relapse.

And lastly, of course, in the metastatic setting, the OptimUM-02 trial has provided evidence of promising activity of darovasertib and crizotinib in HLA-A2 negative disease, but it's also being tested in the OptimUM-01 study in subjects who are HLA-A2 positive. Upon completion of these trials, we believe darovasertib will become a backbone therapy for all phases of uveal melanoma and will improve the lives of subjects that have to live with this life-threatening disease. I'll remind folks today that darovasertib is a breakthrough therapy drug designated by the FDA. And today is the first study where it's shown a really significant impact in patients with uveal melanoma, and we have several trials underway with more to come. So with this, I conclude my remarks, and I'll pass it back to you, Yujiro.

Thank you so much, Darrin. This now concludes the prepared remarks. And operator, let's now please transition to the analyst Q&A portion of the webcast. Please ask for our analyst to keep it to one question. We will also ask the operator provides a status check when we reach the 30-minute mark. Operator, you may now proceed to the first question.

[Operator Instructions] So our first question comes from Anupam Rama at JPMorgan.

Congrats on the data. Just a quick question. In the full medical conference presentation, will you be quantifying the overall survival separation? Or is this really a wait till the full analysis type scenario? And if the KOL is on the line, just based on this data as well as the early-stage clinical experience, where do you see the combination fitting into both HLA-negative and positive patients?

Yes, Anupam, on the OS question, we will not be specifically at the upcoming medical conference. As we noted, we have observed an early trend, which is encouraging. There's been about roughly 10 months of follow-up. So to see that early separation, we're quite encouraged. And as you know, we did report a robust survival result back in the fall at the Society for Melanoma Research. With that, Dr. McKean, if you're on the line?

Yes, sure. So it sounded like the question was where do we see this in practice for both potentially HLA positive and negative patients?

That's correct.

Okay. Yes, I mean I think this data, obviously, the randomized trial was for patients that were HLA-A2:01 Negative. However, the data that we've presented before at ESMO in 2023 and ESMO 2024 included patients with both HLA-A2:01 positive and negative, and we saw similar response rates. And so I think the excitement here is certainly that we've never had a systemic therapy with this type of response rate for these patients to be able to feel like we really have the opportunity to see improvement in their disease from the time of onset of medication. And so I think there's really kind of limitless possibilities of where we could use this medication for patients with metastatic uveal melanoma.

Our next question comes from Maury Raycroft at Jefferies.

Congrats on the update. And I'll follow up on the overall survival topic. So Yujiro, you've talked about a potential interim OS readout in first half '27. Could that time line change based on what you're seeing in the current data? And then also for Dr. McKean, if you could just talk more about how these data could influence your use in the frontline HLA-positive patients? And are the PFS and response rate data sufficient? Or is there something specific on OS you want to see there?

Darrin, do you want to take the interim OS?

Yes. So the interim OS is planned for midyear, of course, next year. But there'll be opportunities as we get into the filing to discuss with the FDA the progress of the trial and the data itself. So it will be evolving, but the plan is for the interim. But if an earlier look with the FDA makes sense because at this stage, we have such a very positive study here without an ability to cross patients over. So it really just depends on the maturity of the data, to be quite honest.

I can jump in. So obviously, this is just a huge day for patients with metastatic uveal melanoma. For patients that are HLA-A2:01 Negative, the only systemic therapy option we've had with ipi/nivo, right? And you can see how well that performed and really what we have been able to offer patients. So I think [darovasertib] is going to be an exciting option for those patients. For patients that are HLA-A2:01 positive, [indiscernible] there's still some questions about the long-term benefit with the overall survival that was seen in the clinical trial, but the response rates are single digits, right? So when patients come in with large volume disease, extrahepatic metastases, you still just have not had good options for those patients. And so I think this really is exciting for all patients with metastatic uveal melanoma to be able to have an agent, like I said, that shows such a significant response rate, allows stability of disease and potentially shrinking the disease to be able to get to the next line of therapy.

Our next question comes from Tyler Van Buren at TD Cowen.

Congrats on the data and a great execution of the study. So the 7-month median PFS clearly hit the bar and is consistent with what you guys have shown in the past. But just wanted to focus on the 0.42 hazard ratio for a bit. That's clearly an incredibly impressive PFS hazard ratio by any standard. So can you elaborate just on the significance of that magnitude of benefit in the context of the data that's been reported in the uveal melanoma population historically as well as the fact that ipi/nivo was included in the control arm?

Yes. Dr. McKean, do you want to maybe discuss the hazard ratio and kind of your view as a clinician? And as we noted in the beginning, I think the usage of ipi/nivo in the control arm, this is the first frontline randomized study where that was incorporated. So your comments here would be helpful.

Yes. I think there's going to be a lot of discussion in the field that -- the way the trial was designed, as investigators, we have the opportunity to give patients ipi/nivo, the only other combination systemic therapy option. And you saw the results here, and that's really what we felt for our patients. The only other data that's available has been retrospective single institution data sets. And there's obviously a lot of selection bias in which patients you're able to give ipi/nivo to versus central liver-directed therapies as the only treatment options. And so I think this is an important data set for the field as well because this is the most data that we have for patients treated with ipi/nivo.

And we've known that the response rate in uveal melanoma is far worse than anything we've seen in any of the other subtypes, cutaneous, mucosal or acral lentiginous. So I think that -- I think there's going to be a lot of discussion in the field about how ipi actually performed in a randomized trial because that fits with what we see and feel for our patients and having had kind of the lack of any other systemic therapies for these patients. And then as far as PFS and objective response rate, that really held with what we've seen for the number of patients treated on the Phase I, Phase II data. So I think pleased to see that, that was similar and what was expected from the patients we've treated before.

Our next question comes from Yigal Nochomovitz at Citi.

For Dr. McKean, I'm wondering if you could comment a little bit on how you see the potential in the other settings that IDEAYA is running studies in adjuvant and neoadjuvant given that we now have very favorable data in the metastatic setting in HLA-A2 negative.

Yes. I mean the field has really been waiting for an effective systemic therapy to be able to move these therapies forward. There's been some data presented for the neoadjuvant setting for patients potentially life-changing to be able to save their eye, not have to undergo enucleation, try to preserve vision. So I think there's certainly a lot of enthusiasm in the ophthalmology community about how else we can use this medication and the data presented thus far, I think most recently in [Rio] earlier this year, really demonstrating that using that high response rate to try to offer patients more options for local disease control.

And then the adjuvant setting is really exciting because we've had fantastic prognostic tools, whether that's gene expression profiling or chromosomal analysis to identify exactly which patients we know are high risk. So at the time of diagnosis, we can tell patients, unfortunately, you have a 50% likelihood of recurrence, but we haven't had effective therapies to then offer in the adjuvant setting. So I think there's a lot of excitement in the field about the other uses and potential situations for the monotherapy in combination.

Thank you. Dr. McKean. Darrin, anything else you'd add about neoadjuvant or adjuvant?

Well, it's funny, a few comments. I was just thinking about the prior comment, too, in terms of where we sit in the metastatic setting, when you review all the historical data, no matter what you look at, you end up at a response rate of 5% to 10% and a PFS of 3 months over and over and over. And now we're finally breaking away from that, which is great for patients. And as Meredith pointed out, I think in the neoadjuvant setting, we have shown we've been able -- with darovasertib as a single agent, able to save 60% of eyes for patients who would otherwise require enucleation.

And then for those with plaque brachytherapy being able to reduce radiation dose, improve vision while on treatment and have a predictive tool that suggests that down the road, their vision will be better for those who get plaque brachytherapy, great. But I think what everyone is really, really looking forward to is the adjuvant trial as well simply because there's a potential to save lives. Patients who are at high risk, as Meredith pointed out, with high-risk genetic features, Class II, monosomy 3, those are the folks that tend to have the highest risk of relapse.

If you could reduce that rate or push out the time to metastases, that would be incredible. And when you look at that curve that we presented, the progression-free survival curve, again, separation throughout the entire journey of that curve, the separation is real. It's big. And you would have to think that, that would translate into benefit in the adjuvant setting. And so that's why we're really excited to get that trial going as well.

Maybe just only other add is with this kind of data just gives us continued further confidence in that adjuvant opportunity. So I think with that, we'll move on to the next question.

Our next question comes from Michael Yee at UBS.

Great. Thank you for the comments from adjuvant. In HLA-A2 Positive, can you remind us, Yujiro, will you be able to have a good package of data to help file in your filing to address that with the potential also for compendia listing and with the doctors consider using that there and positive if you have compendia listing? And second question is in this study that you are reporting today, do you expect that duration of treatment is expected to be much longer than 7 months and the doctors continue to treat well past progression?

Maybe, Mike, I'll take the latter part first. So I would say, typically in the past, we've seen patients getting treated beyond progression roughly about 3 months. So -- and I think that's been consistent with what we've seen through this study, including the single-arm studies. In terms of HLA-A2 positive, very significant focus for us. So we do have a strategy both in terms of our efforts to get it on the label as well as vis-a-vis compendia. Darrin, anything else you'd highlight on this one and HLA-A2 positive?

No, I would just say with the 01 trial is continuing to mature. We have around 100 patients dosed that are HLA-A2 positive. Again, we presented data at ESMO in 2023 to show that really we don't see any difference between the 2 with respect to the kind of benefit that patients with HLA-A2 negative disease received the positives get that as well, best that we can tell thus far. So we're very enthusiastic about bringing that data forward and working with the NCCN panel as well as the FDA in order to make sure that patients have access to this kind of therapy because as shown in the randomized trial, it's making a big difference.

Mike, I think here also, we do have a very aggressive publication strategy for both HLA-A2 Negative and Positive. So you're going to start seeing quite a bit of data coming from us on that front for both fronts.

Our next question comes from Li Watsek at Cantor Fitzgerald.

I wanted to add my congrats as well, a great outcome. I guess for patients who progress, can you talk about subsequent therapies used in the trial? I'm curious if there are difference in the HLA negative versus positive patients in your observation? And then related to that for Dr. McKean, can you comment on your approach to sequencing once daro is approved just across the HLA status?

Sure. Darrin, do you want to take the first one and then Dr. McKean?

Yes. With respect to sequencing, probably we've had Meredith take that because the sequencing that occurred in this trial would be no different than the sequence of patients with standard therapy. Maybe you can Meredith speak to now in the context of the daro, crizo combination coming on scene, what your vision is of how therapies will be sort of sequenced in the future.

Yes. I mean I think to -- on study, patients could treat down progression, but you weren't able to do any local therapies, which we know is very important for these patients in their disease control. So I foresee there will be a lot of -- and we've seen other data in uveal of looking at combination approaches with liver-directed therapies. And so like I have a patient on compassionate use that has now been on daro, crizo for 3 years because we did Y90 to one progressing liver lesion. I think we're going to see a lot more of that now that we're going to have flexibility to be able to treat the patients in front of us using all the tools that we have.

So I think there's probably going to be a lot more kind of combination approaches. I think there's going to be patients that were previously ineligible to even receive liver-directed therapies. But then I think there's still probably a lot to be learned about sequencing with immune therapy. But I think at the end of the day, daro, crizo has the highest response rate, the best progression-free survival that we've seen. And so I think there's going to be a priority to make sure every patient receives this treatment and then how best can we reintroduce this later like other targeted therapies and see a renewed response rate again? Or can we -- but I think there's going to be a lot of combination approaches likely with trying to do liver-directed or other local therapies to try to keep patients on this as long as possible.

Just to add on what Meredith is saying there, too. I think just understanding the biology and protein kinase C and trying to stay on the driver and thinking about the patient journey, it's very likely that these studies all read out the way this one did, we'll be looking at the -- in the primary uveal melanoma setting, trying to get on the target with the darovasertib and helping the patients save their eyes, save their vision, also potentially maybe preventing metastases even in the neoadjuvant setting, although the current trial is not really designed to show that.

And then ultimately, after their primary therapy for those high-risk subjects, you still want to stay on the disease, on the driver and then you'd be able to continue to do that in the adjuvant setting. And then perhaps down the road, if the patient were to get their 1 year's worth of therapy and discontinue and then further down, develop metastasis, then again, you'd want to be on the driver. And then again, as Meredith pointed out, as you're thinking about combinations, you're thinking about strategies that are liver-directed it seem to me that you'd always want to be on the driver, which is protein kinase C, have that shutdown and try to take care of the rest. So I can see a therapy like this, just like any other targeted therapy like your EGFR inhibitors where people are talking about keeping folks on for as long as possible. You may see a similar thing here because it just seems like this disease really needs that pathway to begin and to thrive. And so being on top of that is going to be important.

Our next question comes from Charles Zhu at LifeSci Capital.

First of all, congratulations on the data. Can you talk perhaps a little bit about the subsequent therapies that your OptimUM-02 trial patients may be taking, whether they're post daro, crizo or post control arm and any potential impact to longer-term OS there? And maybe also related to that, I recall there was a dynamic where you had the option at some point to upsize the trial for OS. Is that the one option for you at this point? And do you even need if you could clarify that?

Yes. So I know for the therapy sequence, some of that was covered. But Dr. McKean, anything additional there? And then maybe just on the second question, we do still have additional time to ultimately make that decision, Charles. But Darrin, any comment there. I mean, based on the data we've seen and even on the early trend in OS, I think we're in really good shape. But Darrin, do you want to make...

Yes, I'd just say we're very comfortable with where we're sitting right now. We do have that option. That's the nice part of how the protocol was designed. But like I said, I think we're going to be watching the maturity of the data over the next -- as we are in the process of filing. And so we'll monitor that situation. But we're sitting in really great shape. I mean you just look at the data, you look at the separation of the curves, you look at the response rate, you look at the continuity of the data that we have now relative to what we've presented at SMR, and it's very, very consistent, which is beautiful.

I mean a lot of times you see data when you go from Phase II to Phase III, you may see some detriment to the efficacy outcomes. We haven't really seen much of that at all. Safety profile very much similar. Really, the SMR data tells it all, and you know what the OS looks like for the SMR data, that looked exciting. And so far, all the parameters that we've been following seem to be following in the same direction. So we're very, very bullish on the opportunity to get this across the finish line with full approval.

Dr. McKean, anything else you'd add on the sequencing?

Yes. I mean the reality -- the unfortunate reality for these patients that were treated on trial in HLA0201 negative is at the time of progression, right, if you were lucky enough to be on the treatment arm, you could receive ipi/nivo. Otherwise, it's just -- it's liver-directed therapies. And so for patients that had disease outside of the liver, you didn't really have any other options. And so you're -- really it's kind of local palliative radiation and in the liver, it's Y90 ablation or perfusion therapy. So there just really aren't -- this isn't like another cancer where you can just keep pulling up your next line chemo, there just aren't good options for these patients, whether they progress -- once they progress on daro, crizo or if they're on the control arm. It's really just local therapies.

Our next question comes from Paul Jeng at Guggenheim.

Let me add my congrats on the results today. I wanted to ask about the relative dose intensity that was maintained for the regimen and to what degree there were any dose interruptions or reductions to manage adverse events either for daro or crizo? And then a quick follow-up question just on the OS. So based on your doc feedback, how important is that OS data in driving uptake for daro in the HLA-Negative patients? Are there any physicians who may wait for those results before prescribing? Or is that more important as you think about potential utilization in the HLA-Positive segment?

Maybe for the first piece, Paul, we'll need to sort of stick to the disclosure. Obviously, I know we've got Dr. McKean on as well. I know there's also just sensitivity. We do have hopefully, an important upcoming presentation at a major medical conference where we'll share further detail. But I think we can say at a high level, the safety profile, including things such as discontinuation rates, dose intensity was very consistent with what we've reported in the past. And I would say also in relation to historical data on ipi/nivo. In terms of the other item here, Darrin, do you want to take that?

Well, again, as you know, the overall survival data is still maturing, and we'd be going to the FDA to talk about using the surrogate endpoint, progression-free survival, overall response rate, et cetera. The data from both what we've seen by BICR and investigator assessment of the outcomes. And if this gets approved, it's going to be used as the OS data matures. And I don't know, Meredith, if you want to pile on top of that, but I can't imagine once this gets approved, I think you're going to probably have another very important tool in your tool belt to use for these patients.

Yes, absolutely. And I think the question in regards to the HLA-A02:01 positive patients, maybe it's just we -- the Phase I/II study enrolled patients early on regardless of HLA status, right? So like Darrin said, there's a large number, it sounds like 100 patients that are HLA-A2 positive that were treated. And so I think more data to come in that space. But as a treating provider, we would generally -- the way it works is really just try to point to the data available and say this is why this is an option that we'd like to pursue for the patient.

And so that's looking at -- showing the data, hopefully, if it's added into the NCCN guidelines at some point, that will be helpful in just trying to demonstrate to the insurance companies why these patients, even for HLA-A02:01 positive, don't have a lot of options. So I think that's where as much data as we can put out there will be helpful.

Our next question comes from Silvan Tuerkcan at Citizens JMP.

This is Josh on for Sylvan. Congrats on the great data. You provided that 2 half '26 guidance on the time line to filing. Maybe if you can just discuss some of the gating factors to that filing. Will it be on a rolling basis and maybe discuss the potential for an expedited review?

Yes. So Darrin, do you want to take that?

Yes, we'll be working with the FDA in order to talk about how to most expeditiously get this filing completed. So those are on the table for sure. Now that we have the data in hand, we're going to have those discussions.

Yes. And I think on the expedited piece, we will be evaluating options around RTOR as well.

Yes, we have -- remember, we have fast track. We have breakthrough, we have Fast Track. We have orphan. We have just about every designation you can think of. So I think they're going to be very open to talking to us about that.

Our next question comes from Graig Suvannavejh at Mizuho.

My congrats to the IDEAYA team on great data. I did want to ask just about the adverse event profile. I think the syncope and hypotension were something that I had not been appreciative of before. I'm just wondering if there is a mechanistic rationale? Is it more maybe crizotinib driven? If just any color on that? And maybe for Dr. McKean, the KOL, thoughts on uptake. Does that, in any way, the safety tolerability impact how you think about uptake? And is there an immediate impact to KIMMTRAK in the HLA-positive setting?

Yes. So Graig, maybe I'll take the first part. So the hypotension, syncope is exactly consistent with what's been reported in the past, including at SMR and ESMO. So that's been known and reported for the last several years. Darrin, Dr. McKean for the second question?

Well, I can say, at least mechanistically, I mean, we think it's likely more darovasertib, and there has been some studies that imply that it may have -- may be secondary to the effect of inhibition of protein kinase C and its effect on smooth muscle cells. So -- but again, manageable, not different than what we've seen before, known. And again, the things there that we do typically is we ask patients to maintain their hydration, we stop their blood pressure medicine. We make sure that they're not running around right after they get their dose. And you can speak to the management of this and the outcomes. But I think in general, this is if you know and you expect it, it can be managed quite easily. But Meredith, I'll let you take that.

Yes. I think hopefully, this is data that we'll be kind of illustrating more as we publish the Phase I/II data because I think like Darrin said, we learned a lot, right, holding patients -- having patients hold their blood pressure medication once we got through the food effect, just seeing the significant importance of patients being able to take the medication with food, high protein breakfast. And so that's really helped navigate any hypotension or syncopal events. And then I think some of it through crizotinib can add some edema. And so just recognizing that early for patients and even short -- these medications have short half-lives. So for patients, any of the side effects, you're able to say, okay, hold crizo for 3 days and then restart, right? And patients feel immediate relief. So I think there's a lot of ways that we've learned to try to help navigate these medications and really find how -- with supportive medications, how to help patients be able to stay on treatment.

Our next question comes from Greg Renza at Truist.

Congratulations, Yujiro and the team for a really nice outcome today. Yujiro, maybe just on the OS expectations. I just wanted to ask if you could perhaps remind us of maybe some of the internal assumptions around the differentiation between the daro, crizo combo and the control arm. If the Phase III OS data were to trend shorter than, say, that 24 months previously observed, maybe just a comment on what range would you view as consistent with respect to a positive outcome?

And then secondly, let me throw in a strategic question, Yujiro. Now that you're staring at a potential filing and a transition to commercial, how do these data maybe impact your view of the IDEAYA pipeline? Does it reshape how you would prioritize and establish focus as you build out the portfolio?

Thanks for the question, Greg. So in terms of OS, I think the good news here is the response rate, the PFS, the data we observed has been very consistent from what we reported at the Society of Melanoma Research with a more limited data set to now a large, randomized Phase III study. So I think that's the good news. And Greg, as you know, the OS that we reported at Society of Melanoma Research, just as a reminder, was over 21 months. So our hope here is we showed consistency in response rate as well as PFS. And I do think that bodes well for the OS portion.

I would say on the control arm, as we've seen, the vast majority here is ipi/nivo. And I think, Greg, I know there was a lot of topic on what the PFS would come out at. And as you know, we've consistently were noting the published data, in particular, the PLOS paper, right, where that PFS came in exactly what we're reporting essentially 3.1 months versus 3 months. And also, just as a reminder, if you go to that paper, I believe the OS that was reported was about 12.5 months.

So I think that all sets up nicely. And I do think that past publication we've been pointing to did come in exactly as our study reported out. And lastly, as it relates to our larger portfolio, Greg, as you know, look, we think darovasertib is just the start for the company. We're tremendously enthusiastic about the progress on DLL3, MTAP, KAT6/7 as well as others. And we believe with darovasertib now hopefully transitioning towards commercialization phase, the tremendous progress, and we think we have one of the deepest portfolios in precision medicine oncology. What you're going to see us do as an organization is to drive forward to build that next leading precision medicine oncology. And that's exactly our vision, and this is exactly what we're moving towards.

Great. Thanks for the questions, Greg. So this hits the 30-minute mark on Q&A and all the time we have. I'll turn it back to you, Yujiro, for quick closing remarks.

Great, Tara. Thank you for that. This now concludes the prepared remarks and as well as the analyst Q&A portion of the webcast. So thank you, everyone, for participating in the webcast event today. And operator, you may now close the line.

Great. Thanks, Yujiro. So this concludes today's event. You may now disconnect.

Thank you so much to you and Evercore for hosting this fireside chat today with the IDEAYA management team. So IDEAYA Biosciences, we're a leading precision medicine oncology company. We have 9 programs in the clinic. So a very deep and diversified portfolio.

Umer, as you know, our most advanced program is Darovasertib, which is now currently in 2 Phase III randomized studies, one in the first-line metastatic uveal melanoma indication and then next in the neoadjuvant indication, we're looking to launch our third Phase III study this half.

Obviously, very much in focus is our upcoming guidance around our top line results for the first-line metastatic melanoma setting here. The primary endpoint is median progression-free survival, and I'm sure we'll talk more about that today. But beyond that, we have a very deep pipeline.

I would say next is a portfolio of assets in the ADC space. I would say probably most attention is to our DLL3 TOP1 ADC, IDE849. We are guiding towards a clinical data update on that program by the end of the year. And we believe this molecule does have the potential to be a best-in-class asset. As both you, Umer and John know, we did present a very robust single-agent activity as an oral presentation at the World Cancer Lung Conference last September.

Beyond that, we also have a deep pipeline in MTAP-deletion. We have 2 clinical assets here, both PRMT5 and MAT2A. We think a lot of interesting opportunities, both as monotherapy as well as combination. Also, as I think both of you have been following, a lot of interesting intersections between RAS and MTAP as well.

And then lastly, KAT6/7. So IDE574 has now entered Phase I. We think a really unique opportunity and perhaps one of the largest addressable patient populations, including in breast cancer and colorectal cancer. And Mike Whiter, CSO, is here, and we can definitely dive into the science of that as well. So I think that's hopefully a good summary and encapsulation of the company.

Got it. Okay. Great. Fantastic. So maybe just as we begin, could you just remind us sort of the timing and the expectation for this upcoming readout?

Yes. So the timing is going to be in the next couple of weeks. So we've now guided on or around the very end of March. So we're obviously going towards March now. So the data update is in the near term. In terms of sort of table setting on expectations, so Umer here, our perspective is what we believe we'll see in the control arm is going to be consistent with what's been published in large meta-analysis before.

And I know there's been some questions about Ipi/Nivo in the control arm. And I think here, probably the most, at least we feel reliable paper there is the [indiscernible] paper, which was a multicenter study. And there, we believe the PFS is going to come in roughly 2 to 3 months.

In the treatment arm, we reported a 7-month PFS in 2 oral presentations, one at ESMO several years ago and then most recently at the Society of Melanoma Research this past fall. And that PFS has been solid, approximately 7 months, including with roughly 2 years of follow-up. So we feel good about that number. And if we -- if that's what we see, we feel good about our prospects to hit [ STA sig ] as our primary endpoint.

Got it. Maybe I ask before we get too far off of what the trial design is, one of the things that I know we've spoken about in the past, and I am continually curious about is given you have an investigator's choice comp arm, Ipi/Nivo probably the most relevant thing that people are asking about, but there are other options.

You've got a combination on top of Crizotinib, which is not available in the compound. Can you give us some of your thoughts about what the potential variability is in the [ comp arm ], but what the contribution of parts is in the experimental arm and how we should be balancing the expectations there?

Darrin, do you want to take that?

Well, in terms of the contributions of the 2 components in the Daro/Crizo, that's pretty clear. I mean Darovasertib, we know what it does as a single agent. It's active. We've shown that in Phase I. Crizotinib, however, has limited activity, at least the MET inhibitors in this space. They've been tested before in small numbers in clinical trials, really haven't shown much in the way of activity.

However, it's very clear, at least preclinically, when you put the 2 together and you impact both pathways, protein kinase C and c-MET, you can see enhanced antitumor activity, and we've shown that pretty conclusively in the clinic, obviously, with the Daro/Crizo combination relative to what either agent can deliver alone.

And also, we've discussed this with the FDA. So contribution of components is pretty clear. We know that you need the MET inhibitor to enhance the activity in the metastatic setting. We also know in the neoadjuvant setting, you don't need the Crizotinib. It doesn't seem to add. We already have profound activity in the neoadjuvant setting with Darovasertib as a single agent. So our thoughts are we don't need the Crizo in that setting, but however, in the metastatic setting, different story.

With respect to your other question about the control arm, to be quite honest, there's been at least 2 meta-analysis published, thousands of patients. And I think we feel very, very comfortable with where the control arm sits, whether it's Ipi/Nivo, whether it's ipilimumab, whether it's a single-agent checkpoint inhibitor like nivo or pembro, they all sit right around 2 or 3 months.

And so with our long-term follow-up from the 01 trial, 2 years of follow-up where we maintain a rock-solid PFS of 7 months, and we only need to hit maybe 5.5 in order to be -- have a positive study. We think we have a great buffer zone. And again, I think we're just as well positioned as you possibly could be to beat the control arm in this particular situation. And our OS looks profound, too.

I mean that PFS translates into another metric, which is OS. We have 21 months of overall survival in the 01 trial. And so those 2 things go hand in hand. If you combine that with the fact that we're tripling the response rate compared to standard of care, we have a really rock-solid duration of response of 9 months, we just think we couldn't be better positioned to take on standard of care in this case.

Well, since you brought up OS, Darrin that was going to be my next question.

John, can we -- maybe just one second, can we just like set the trial? I want to go through all the data very carefully, but maybe let's just set the trial. So can you remind us the design of the trial, just so we're all on the same page?

Sure. So what we're talking about now is metastatic uveal melanoma. So patients with uveal melanoma, who have metastasized. They also have to be HLA-A2 negative, which is probably about 2/3 of the patients with uveal melanoma. And so it's a simple randomized Phase III comparison of either standard of care, which in this case is either single-agent checkpoint inhibitors, a combination of checkpoint inhibitors plus other immunotherapy like Ipi/Nivo or you could, if you happen to be a patient who couldn't get immunotherapy for whatever reason, you could get chemotherapy, but we think that's going to be a very small proportion of the patients treated.

And then of course, in the treatment arm on the other side, is the Darovasertib, Crizotinib combination, which we've tested extensively at the 300, 200-milligram dosing. And again, this is a study, where the primary endpoint is progression-free survival. So that will allow us to have a discussion with the FDA. And then, of course, that study will go on to read out for overall survival for full approval.

And what has happened so far in the trial? Has there been any interim looks so far?

No. So this is what's coming up now, our top line to look at our first look at progression-free survival.

How mature do you expect OS to be at the time of PFS maturity?

Very good question. So I think the maturity is one of those things where when we talk about the outcome for this particular study, some of the things that we're likely to talk about is, obviously, the response in the 2 arms, the progression-free survival in the 2 arms, of course, maybe some durability with respect to duration of response. But survival at this stage may be relatively immature. So if we don't say anything about it, it's not because it doesn't look good. It's because there may not be enough data to actually make a call on whether there's any trend, for example.

However, there will be opportunities down the road. We'll be obviously filing the NDA. We'll have the opportunity to once again provide the FDA safety information and perhaps efficacy information during the filing period. And then, of course, our first interim analysis for OS comes up at the beginning of next year or the first half of next year.

So there will be a couple of opportunities to look at OS. And it's very possible that during that period of time, we'll have enough events -- but at the first look, it's uncertain at this time, if that will be the case to really make a call.

If I -- sorry, John, just before we move on from the trial design, there's a Phase II here and there's a Phase III here. Could you just remind us, have you guys spoken to any dynamics around the Phase II data yet?

No. So at this point, again, this will be the first time that people have seen what we have evaluated with respect to progression-free survival as well as safety comparing the control to the treatment arms. We did have -- this was a sort of a 3-component study. We had a IIa part, where we actually looked at dose optimization to show that the 300, 200-milligram dose going forward was the optimal dose, had the best benefit risk profile for patients.

And then the IIb/III is the part that we'll be reading out now, which now accumulates patients to be able to have enough data to show that the progression-free survival, how it compares between the 2 arms, and then we'll follow that up with overall survival. So 3 component study, Part 2a completed, getting IIb/III getting ready to read out and then...

How many patients were in Part IIa?

So Part IIa was designed to look at the 2 doses and without getting into dramatic detail, essentially, it was a 2-stage component. So it depends on how you define it. But long and short of it, it was approximately 80 or 90 subjects to be able to look -- take that first look. Remember, they were randomized 2:1. So 2 to the control arm -- 2 to the treatment arm, 1 to the control arm. So it took about 90 patients to figure out what was the right dose.

We had additional patients that came on after that as we were continuing to enroll that were part of the IIa, but they weren't part of the initial analyses. But essentially, that was around that 90 patients or so is all that was required to determine what was the optimal dose and then you move forward from there.

So the reason I was...

And Darrin those 90 patients, those were both A2 positive and negative. Those...

No, no. So this study is only HLA-A2 negative. So if you...

Is it pivotal. But you did have a Phase II that had all HLA subjects.

Yes, that's a different component, and we'll probably get to that later. But that is a patient population that we haven't forgotten about that's critically important to us. We think this treatment should work there, no different than it does in HLA-A2 negatives. However, we're evaluating that patient population in our 01 trial. We'll have nearly 100 patients' worth of data, who are HLA-A2 positive.

The objective would be the following. As this study reads out, our view is that it will show an improvement in progression-free survival, ultimately an improvement in overall survival. And in parallel, we'll be able to present data to the FDA as well as the NCCN panel that puts together the guidelines for treatment that shows in 100 patients worth of HLA-A2 positive data from a Phase II trial setting that we have a similar overall response, progression-free survival, overall survival, durability of response that we do from our randomized Phase III trial.

And hopefully, that will allow people to look favorably at that data set and utilize it as appropriate.

There's no mechanistic reason to expect your drug to behave any differently in these 2 populations?

Absolutely correct, right? It's all about the mutations that drive the disease to begin with. So these tumors, 95% of the time have mutations in GNAQ, GNA11, G-coupled protein receptors that drive protein kinase C signaling, and that's why Darovasertib is so effective in basically knocking the wheels out of the driver for the disease.

Yes. HLA only, but HLA-A2 only matters because of KIMMTRAK already approved in that...

Exactly.

So maybe just on the trial design again because I just want to make sure -- I want to go through all those things, but just on trial design, there's a Phase II and there's a Phase III. And maybe let me just put up something that -- the reason I'm just trying to go step by step on this.

So here's something I was looking at just for my own sort of understanding of the trial. We know there's 440 patients that came in. And you said 80 of them were in Phase II. So that's kind of like consistent with.

That's not what I said exactly. So what I said was...

Maybe I could just step in -- so the number of patients, just to be really exact, the IIa portion is 124 patients.

124 patients.

124 patients, yes. And remember, the dose that's not moved forward gets dropped irregardless, whether we included the IIa in the analysis or not. So it turns out that roughly 75 patients were in the non-move forward dose would have been dropped irregardless. So that leaves you...

Right. So 360 -- sorry, go ahead. Are we get into Phase III?

Yes. So that -- what that leaves you is with 49 patients with the move forward dose as well as the control arm. So that was the question, should those 49 get included as part of the analysis or not. The decision ultimately that was made was that we were going to utilize that IIa for the Project Optimus dose optimization portion at the end.

The IIb and III now are the same. It's -- because it's an ITT analysis and because enrollment was ahead of schedule, when we submit -- when we do the analysis for the PFS, the full enrollment for the OS has also now been complete. So the IIb and III are 313 patients. So that's how you get to that 437.

So Phase IIB and Phase III is 313 patients you said?

Total, yes. And that will be for both the PFS as well as OS analysis.

So 313 is the number we're going. Okay. Got it. That makes a lot of sense. And the reason -- that's why I was like -- when John was sort of asking this question, the reason I kept coming back to the trial design is I just wanted to be sure that I understood, PFS -- because the way OS is being analyzed here, and I want to get into the relevance and significance of that in a second as well.

But this option 1, 2, 3 for OS analysis depends on what happened on PFS, right? And what I wasn't sure about was it kept saying PFS off of Phase II, like kept saying PFS and Phase II. It's not Phase II. It's PFS across the whole trial, Phase II and Phase III, all 313 patients, correct?

Correct. Yes, yes.

So the sample size of 200 PARG 2.55 hazard ratio. So this is actually 313. So you have more wiggle room technically.

That's correct.

I see. And...

And you also have a subset of these patients that are substantially more mature than the bulk Phase III, the patients that were enrolled later on in the study.

That's correct.

And Yujiro, is it fair to say that the interim is still being triggered by 130 events?

That's correct. It's going to be the first 130 PFS events that will drive that analysis. And as you have there, the OS is 253 OS events.

So interim equals 130 events out of 313 patients.

Exactly.

I mean the trial was designed. The IIa was for optimization, the IIb was for accelerated approval and the III was all for OS. But remember, as Yujiro pointed out, the IIb and the III collapsed together because the enrollment went so quickly. And the additional patients that he mentioned in the IIa are simply because we overenrolled the IIa to make sure we had enough patients to do the analysis.

Does that mean that your 130, 140 PFS events you need for the final read, almost half of those are coming from patients in the go-forward dose in the IIa that are presumably much more advanced. Is that fair?

No, no, no. IIa has only contributed 49 patients. IIb and III is really the trial.

If that 49 patients, presumably most of which -- most of whom have progressed much well advanced of the other patients, that's almost half.

No, no ITT, the way I understood it was a Part IIb and Part III. Am I mistaken there?

Yes, that's right.

You've got it correct. It's the IIb/III that drives both the PFS and the OS analysis.

When did Part IIb start recruiting?

So we noted in December of 2024 that the IDMC selected the move forward dose. So I would assume it's roughly -- I don't know, roughly a month before.

I see, so over the course of '25, basically, you guys recruited it in about 14 months and 2:1 randomization. So 100 patients should all have had -- so I'll tell you what I'm really getting at. Of the 313, you've basically got -- if I can have my thing here, you've basically got 100 versus 200 type of randomization going on.

All these 100 patients were presumably recruited over the course of 2025. And by now, almost everybody should have had an event and almost feels like this PFS -- the 130 events could have hit even sooner? Or has it already happened? I don't know if -- maybe it's happened and you guys are not unblinded to it yet.

Yes. So we have said, Umer, as part of this most recent earnings that the 130 PFS events has occurred with BICR. So we're now in the data cleaning process.

Okay. So that would be consistent. The reason Yujiro, you can imagine the reason I was going down that path was if the 130 has not been hit, yes, it sounds like control arm might be outperforming by a little bit, but that's not -- presumably, that would have been...

Or the treatment arm is doing better.

Or treatment. No, Darrin, I was just going by...

With 100 patients in the control arm, the treatment arm would have to be doing really spectacularly to not hit events at all.

Right.

The other reason that I wanted to...

Hang on, John, sorry, hold that thought for a second. Darrin, let's just go with what you just said a little further. Wouldn't that also mean that if the active arm was, let's say, tracking more like a 5-month and compared to at 3 months, these interim would have happened back in like October, November. So we can also rule out the scenario for a more narrow PFS benefit? Or am I going to an extreme there?

Well, listen, I don't want to speculate except to say I know that we've been rock solid in 7 months. So I'd be shocked for a way off on that, but the data is going to speak for itself.

Do you disagree with my logic there?

So repeat that one more time, Umer.

My point was if we know the comparator arm tracking at 3 months or so, and most of these 100 patients would have had a PFS event by late fall last year, let's say, 75 out of them or 80 out of them.

In a scenario where the active arm was tracking at a slightly lower-than-expected PFS, let's just call it 5 months for a second, we would have seen perhaps a pretty meaningful number of PFS events in the active arm too, to the point where this interim would have gotten triggered by September, October last year, if the active arm was tracking a little lower than previously. So the fact that this interim did not hit in September, October, doesn't that effectively become a validation for your prior efficacy got replicated?

I mean I think that's a logical conclusion, Umer. I mean, look, I think the key part here is what you mentioned earlier is that it's a 2:1 randomization, right, from the treatment to the control arm. So that control arm has got to be pretty wide range to the right, if that's what's really driving the analysis, right?

If it was flipped 2:1 from control to treatment arm. But again, it's 2 to the treatment, 1 to the control arm. So I think what you're saying, just high level makes sense to me. Just factual point because the question around when did the IIb/III portion start. I just was looking at my notes here.

So in that release, when we noted the IIb portion started once the IDMC picked the move forward dose, we mentioned that 124 patients in the IIa portion, either way, 75 were going to get dropped because it's not -- that wasn't the move forward dose. We noted in that release, there were 185 patients enrolled. So to your question, even at that time, end of '24, right, we were already roughly 60-some-odd patients into the IIb/III enrollment.

There were 60 patients already enrolled.

In the IIb/III, yes. So in the December '24 release, we noted that there were 185 patients already enrolled. We talked about before was in the IIa. So that by default, that means have to be 61 or more patients were enrolled by the end of 2024.

And Yujiro remind me when did you guys say interim has happened? You guys never said that. You definitely never said that at our conference in December.

That's correct. We did not. So...

It came in '26, whenever it did.

Yes. We clarified that the PFS events were not achieved through the end of last year. End of last year, we still had not achieved.

Yes. I think -- okay. That's very, very helpful. That's very, very helpful. And you will preserve -- and you -- I mean, my understanding is there is an expectation for you to hit OS in this setting. Would you agree with that?

Well, we wouldn't have done the study without it.

Yes. I mean I think all we can see the Umer is that we presented OS data at SMR, right, and we showed roughly over a 21-month OS number. So we feel good about that. It's obviously a single-arm study, relatively small denominator, but we think it's an encouraging signal.

So is it reasonable to assume that this is where you guys want to be in terms of the OS analysis, like the PFS comes in, I don't know, 0.55 or better and then you preserve a lot of alpha for OS?

That's correct.

And if you think about it, I mean, most people would argue that the therapies that are out there for HLA-A2 negatives right now are relatively ineffective, right? So you're talking about a therapy that doesn't do a whole heck of a lot, except for a few rare patients.

And you're talking about a therapy that has triple the response rate, double at least the progression-free survival. Overall survival looks amazing. We should hit on overall survival. But you have to do the study. That's what we're doing.

One last thing...

The reason you're asking about OS earlier is about timing on that. So you're going to file with the agency on the basis of PFS data, but you're going to show them the OS data. Presumably, there probably multiple opportunities to the agency to see that. Is there a chance that there's enough follow-up on OS to get to full approval before people expect or on the same time line as the initial submission?

I'm glad you brought that up because there's one thing here you have to know is that there is no crossover permitted until the OS reads out. And so I think that is very important that we need to look at this data and just be aware that patients are going to be looking for options. For HLA-A2-negative disease, there really aren't any good therapies.

And so if you're on the control arm and you've got an ineffective immunotherapy, it would be really important to be able to offer what's going on in the treatment arm, if possible. But we can't do that until we cross a threshold where everyone feels comfortable that we're looking at a PFS that's robust. We're looking at an OS that looks like there's a significant trend that it can't -- not unlikely to be reversed. But again, that will be an FDA call, and we'll give them every opportunity to look at the data in order to make that assessment along with the IDMC.

How long will it take -- sorry, John, were you asking the same question? There was an investor question.

Maybe -- no, no, I was also going to ask about the state of the Phase IIa data.

So yes, maybe let's just ask the investor question just before we move on to that. The question was, how long would it take to get the independent review of PFS done? And if you could remind us whether this is investigator-assessed or blinded?

So we're -- this is not a blinded study. However, we have blind independent central review because of that. And so that's part of the analysis. So they are obviously doing the imaging analysis to evaluate whether patients progress. We'll be looking at both investigator-assessed progression as well as independently assessed.

And which is primary?

Blind independent central review.

Okay. Blind independent central review. Okay.

Well I was going to say, well it would take you a few weeks, you said. Is that how long it would take?

Well, it's all in the process of doing that now, right? We're in the process of evaluating -- getting the data into the database, cleaning the data, producing queries. Ultimately, once the database is locked, then basically the data between the blind independent central review and the EDC has to be merged, analyzed statistically, and that's when you'll get the output. And that's what Yujiro was referring to when we're talking about targeting the end of March because that's kind of what's going on at the moment.

Makes sense. Sorry, go ahead, John.

No, I was going to ask about the Phase IIa, which obviously is in hand. And admittedly, there's 75 of those patients that are now on the go-forward dose. But do you have plans to submit that as part of the same package to the agency? Have they seen that data already? When can we expect to see that data as well?

The agency will see everything because what they want to know is what the safety is on every patient that was dosed.

But they haven't seen it yet. They didn't see it as part of the...

But the independent data monitoring committee has seen it, and they're the ones that evaluated it, said it was still -- the appropriate dose to go forward with was the 300, 200. They felt the safety profile was adequate to go forward. And so we should let the study read out, and that's what's happening in the next month.

Will you show that to investors ahead of time as well? I mean the Phase IIa data, I mean, it's -- presumably, it's already mature.

Yes. But remember, it's got much shorter -- it's similar data than you've seen with the 01 trial, right? And so -- and the 01 trial actually has 2 years of follow-up. So it's probably more of the same, except shorter follow-up.

Fair enough.

Okay. John, there were a few questions -- more questions from investors on these. Do you want to go through those first? Or do you want to go through your side first, either way?

Sure. One of the other questions that came that just came up was on -- more on that Phase III expectation side. On the safety side, do we expect to see safety comparable versus Phase I observations? And then what are the specific criteria for dose reduction and what the protocols are in the Phase III part of the trial there?

Well, I'd say we've done a really good job. Investigators learned with 01 how to manage the adverse events associated with the Daro/Crizo combination. So we have a group of people that are familiar with its use. And so I think you'll see a safety profile that looks relatively similar to what you've seen before.

I'm pleased to say that because investigators, there's 2 things. People are very motivated to take the therapy, as you might imagine, when you have a disease, where there's no good therapies and the only good one is the one you're on. So they really want to stay on the treatment and investigators are getting better at managing the adverse events associated with it.

Because of that, I think you'll see at the end of this trial is a really relatively low dose discontinuation rate due to adverse events. It's going to be more about keeping the patients on therapy. We know that's important. And the KOLs that we've worked with are getting really quite expert in how to manage that. So I think we'll be in good shape there.

What about discontinuation -- not discontinuation, what about dose reductions? I would expect to see in later-stage trials as docs get more familiar with the drug, you see fewer discontinuations. But do you have an expectation for the number of patients who are going to down dose?

We'll have to see about that. But I would say there's a few things that are going on here. And the reason why I can't give you a number. 1, obviously, we're talking about a trial that only a few people can see the raw data to; and 2, talking about experience I've had with 01.

But there's 2 things that people do. And again, this is usually due to Grade 3 toxicity, which isn't terribly common, right? But usually, they do 1 or 2 things. They usually do a very short pause. We're being told by some that a 1- or 2-day pause is sometimes all it takes to get rid of some of the toxicity. The other thing they do is they typically lower -- if they're going to lower anything, they don't lower the Crizo, they don't lower the Daro. So they'll lower the Crizo dose slightly.

Again, I think with those 2 moves, they're able to keep a motivated patient on therapy for most of the time. And by the way, we have some data accumulating now that also implies that the toxicity happens mostly in the first 2 months of therapy and thereafter kind of weans itself off. So it gets more easily tolerated, it seems, in later time points, and we'll be sharing some of that data as this data evolves. But I think those are what I could say about managing the toxicity.

Thus far, the people that are running the trials are getting quite good at it. It's manageable. The dose reductions and discontinuation rates hasn't been high in 01. I don't think it will be any different here. And I think patients just want to stay on the study because the therapy is just so good compared to what the options are.

Makes sense. Umer unless you've got more on 02, should we.

Yes. Maybe just -- and I do want to sort of over the -- in the next 10 minutes or so bring it back to the big picture and some of the other pipeline as well. But could you just remind us for the prior data? I was trying to find it, John, do you have the prior data because I couldn't find it in our folder.

I was trying to understand maybe if you could remind us what percentage of patients had liver mets? What percentage of patients had LDH disease? I just find that as we often try to translate from prior data to the new trials, sometimes we can lose track of the baseline. So I just want to make sure I had it for my purposes.

We have to remember with uveal melanoma, virtually everybody has liver metastases, right?

So I was looking at these...

That's where this disease goes. So it's actually to have extra hepatic disease only is pretty uncommon. If you have both, that's even worse.

So Darrin, I was looking at a couple of Nivo/Ipi references like the GEM-1402 trial, it says 80% liver mets and 50% had non-extra liver mets. So I was going to ask.

That's in addition to liver mets, mostly.

Right. Sorry. So you're saying everybody had liver mets in your trial.

Well, the vast majority of patients will have liver mets with this disease because this is where -- that's where the disease metastasizes to. Additionally, some will have disease beyond the liver. And that's why things like liver-directed therapies are so big, right? Because people think, well, I can go after the liver and I can get a lot of it. But eventually, if you go after the liver too much, it will end up somewhere else if you live long enough.

Yes. So Umer, I've got the numbers here. So our frontline study that we reported at SMR.

The prior data.

Yes, the prior data, over 90% of patients were either hepatic only or had hepatic and extrahepatic. So only about 5% had non-liver. The [indiscernible] Phase III study, very similar. So roughly 95% had either hepatic extrahepatic and about 4%, so very similar to what we reported had non-liver disease.

In terms of greater than upper limit or normal on LDH status, both our study were roughly 1/3 of patients and the [indiscernible] randomized Phase III are very similar. It was roughly -- so that fine from their New England Journal paper. I'm not looking at that.

Super helpful, it's fairly balanced.

Before we move on, the one other thing that I want to make sure we talk about on 02 is when you -- how long will it take you to prep the filing after the top line?

So just so you know, sort of we're going with sort of average metrics here, right? So we're talking about probably around that 6-month time period in order to put the package together. And then, of course, the FDA has to review it. That's probably another 6 months. So that's sort of general guidepost, but we're obviously going to try to do everything we can to expedite the process for sure.

But that puts us to the first half, that's how we get to that first half '27 expected. Make sense, okay.

Okay. On 01 and the A2 positive patients, can you talk about when you'll have a breakout of that and how rapidly NCCN guidelines could proceed after a potential approval next year?

So I can sort of give you a high level of the entire package since we're probably running a little limited on time, but there are multiple things we want to do. We obviously want to submit this, get it to the FDA, get it to the NCCN panel. In parallel, what we'd like to do is get the HLA-A2 positive data out, that 100 patients, get it published so that the timing lines up, where we'll be able to, again, say something about the overall response rate, the progression-free survival, the overall survival, talk to them about the biology, how it's no different when you're going after protein kinase C.

And therefore, they'll have a couple of pieces of data. They'll have a randomized Phase III. They'll have a single-arm Phase II both relatively good size. They will show them that the data is very similar. And then the NCCN panel can decide what they want to do that. We suspect that they'll overwhelmingly welcome this treatment into both category of patients very robustly.

In addition, we're going to talk to the FDA about the opportunity to potentially get the HLA-A2-positive patients in the label. Could a real-world data set help? Are there other things that we could do in order to make that happen? That's a discussion that has to happen.

And then in addition, in parallel to all that is the neoadjuvant trial, the 09 study. We would like to get that published in parallel. Again, we've presented that data recently at ESMO, really exciting tumor shrinkage in the majority of patients, saving more than half of the eyes, improving vision, not only during the neoadjuvant period, but potentially long term based on a visual prognostication score. So it would be great, if they also had that body of data for published in their hands so that they can decide what they want to do with that as our studies continue to evolve.

Now on that neoadjuvant side, because that, as you say, very potentially very exciting. The data you showed at ESMO was excellent, but it's also 5 or 6x the size patient population-wise versus the metastatic setting. So can we talk a little bit about patient journey into the neoadjuvant or adjuvant into the surgical setting, when patients get diagnosed and how physicians are choosing the initiation versus brachytherapy and where Daro would live?

So just from a very high level. So a patient walks in and says, I have trouble seeing optometrist looks in their eye, they say, "Geez, we see something there. I don't like it. I'm going to refer you to an ocular oncologist." They do a workup, a clinical workup and they make the determination that the patient has uveal melanoma.

From there, in general, the movement is pretty rapid within weeks, the patient can be set up for either a nucleation, which is the removal of the eye, and those are tumors that are usually large and too large in order to be controlled by radiation or if the tumor is smaller and they can show a plaque to the eye, which contains radiation, they can do that. And both of these things are typically happen within weeks of the diagnosis.

And again, the problems that come downstream with that is obviously, if you lose your eye, you lose your vision. And then even if you get plaque brachytherapy, you may have saved your eye, but you may eventually lose your vision due to the radiation doses. And also there are toxicities that happen downstream of radiation, radiation, retinitis, toxicity, et cetera.

And so what we hope to see is in the future, someday, a patient will come in and get the diagnosis and instead of being sent off to having something sold to their eye or having a surgical procedure that removes their eye, it will be as simple as, you know what, I'm going to write you a prescription. You're going to take pills for up to 6 months, and then we're going to decide what we need to do. So it will be completely different, paradigm changing for this disease. And now we get prescription and you don't have to go directly into your primary local therapy.

But is that being done in the trial, though, Darrin?

Yes, exactly. That's exactly what's being done in the trial.

So like how it has 1/4 of the patients are in nucleation and the other 3/4 are not. Is that -- is the active arm not removing the eye in the nucleation subset?

So remember, it's almost like 2 studies in 1. So if we focus on the nucleation group. So these are the guys with tumors, they're going to get their eye removed. Basically, they get randomized, either you go straightly to get your eye removed or if you're randomized to the treatment arm, you get 6 months of neoadjuvant therapy. We try to save your eye. If we do what we've done in 09, we're going to save more than half of them, and they can transfer to a less invasive or less surgically extreme kind of treatment.

So you keep the eye, even after that surgery in this group then.

No, no you don't have the surgery. You don't get the surgery, and that's in the control arm, go straight to a nucleation or you don't have the surgery, you get neoadjuvant therapy instead. And if all goes well, you get maybe a plaque place there instead. Obviously, there are some patients that will have to have the surgery because perhaps the tumor didn't shrink.

But the off-ramp from nucleation is radiotherapy. And then in the radiotherapy cohort where there maybe the tumor is small enough where nucleation wouldn't be the primary treatment option.

You're mixing the cohorts again.

That's the second trial.

Just -- so focus on. There's only 2 options. You're either going to have your eye removed or you're going to get neoadjuvant therapy and then hopefully, something else will happen, right? Like they'll get a plaque placed or they'll get proton beam or external beam radiation or something. But...

But that is getting radiation. So you're moving from...

Only in the treatment arm if the eye is saved. Only in the treatment arm if the eye is saved. The enucleation group just gets their eye removed. That's the enucleation cohort.

So Darren, let's just -- sorry, before we go to the non-enucleation cohort, I guess this is a question both for you and Yujiro. Unlike a typical neoadjuvant study, because we're talking eye preservation here, could this form the basis of a very rapid filing in much more than the first-line setting?

So the only limitation is, remember, another one of the important endpoints for the study is event-free survival. So we have to show that we're not creating any detriment to delaying the primary local therapy. So with that has to read out. But the fact that we'll have known about saving the eyes very early, as soon as we hit the EFS events, you're right, we could actually take that part of the study and go talk to the FDA.

And defined by disease progression?

What's that?

Yes, it's relapse. So yes, Umer also, I would just highlight, as you know, typically, a randomized Phase III neoadjuvant study, right, you have to show superiority on EFS. Here, all that FDA has asked us is a no detriment threshold, which is much lower. And because of that, typically for an EFS readout on superiority, you got to wait for most of those events to occur, right?

Here, we think with about 1/3 or 40%, we'll be able to establish no detriment. So it could be just generally, as Darrin said, especially if we try to submit that enucleation portion first with the no detriment that's pulled across both cohorts for EFS, I think it would be faster than your typical neoadjuvant study, right?

But [indiscernible] is not sufficient.

Correct. Yes. We want to see no harm to EFS, which at least based on our single-arm data in neoadjuvant, we don't see evidence of that at this point. So...

And the definitions must be pretty well established for what -- who counts as an enucleation eligible patient?

Yes. Correct.

Exactly.

It's all about size. When your eyes -- because the radiation can only penetrate so far. So if the tumor is too big, you have to get enucleated.

Sorry, John, I guess maybe I'm curious how you guys think about it. So 6 months of -- so -- the comparator arm will have 100% enucleation right away. How does the active arm get established versus comparator arm? You just have to go all 6 months to be able to do that? Or could you just do it within the first 3 months?

So once you have a tumor that requires enucleation, you get randomized. One group will go to get their surgery. The other group will get the neoadjuvant therapy.

Right. But how long are they supposed to stay on there to establish that, there's a meaningful differentiation between the 2 arms?

I'm not sure I understand you how long are they staying on the therapy?

My point is let's say we took 120 patients, 60 got immediate enucleation. The other 60 now are on the drug. They didn't get it enucleated for now, but some of them are starting to. I guess, how much into that process on that other sort of -- on that active arm, are you able to say, okay, we're now starting to see that there's a 50% reduction in enucleation because that number itself would keep fading, right? It might start at 100 and it's fading.

We typically know in about 4 to 6 months for that patient...

This is what's happening. They're getting a scan every month, ultrasound every month, and they're getting treated for 6 months. And as soon as the tumor shows the maximum reduction in growth, that's when you take them to your primary...

Which is to say as soon as it starts to grow again, you sort of take them off neoadjuvant and go to the -- either a new vision or radiotherapy?

That happens, yes. That happens in the minority of patients, but most usually, they drop down, they shrink and then they kind of level off at the end, and that's when you take them.

And there's no Ipi/Nivo used in neoadjuvant?

No. I mean remember if you're going to be in a neoadjuvant setting, you have to shrink the tumor. These treatments completely tumor.

Right.

You remember, it's not -- obviously, the drug has got to get to the eye, right? So I mean, I think we're fortunate that clearly, we're having an effect there, but I don't think that's a given. And as Darrin mentioned, IO therapies, here, the objective is to shrink the tumor. And we know that...

IOs get used in metastatic settings, presumably because they may be doing something against the metastases, but they're not going to do a ton in the eye.

Exactly.

Exactly. So -- and Yujiro, wouldn't this recruit like right away?

I mean the Phase I/II single arm was extremely robust once we got the sites up. So that's our expectation. I mean I know the team is also...

There's a tremendous amount of inclusion.

Like with less than 6 months to recruit. So I guess let me just push it to an extreme. You started the trial in early '26. You could be fully recruited by ASCO presumably because people are getting their eyes removed, they will probably say, let me try this out, presumably, it's only 120 patients. And you track them over 6 months, you could hit all the events by December, January. Is that too extreme a scenario?

So for the full trial, we're guiding towards first half of next year, but that includes the plaque cohort. So could the enucleation enroll first and we get that readout first? Yes, that's a possibility, I suppose. But as noted by Darrin earlier, we still need to wait for the pooled analysis for the EFS, right?

Okay. And also -- sorry, my last one on this. There was -- I remember Bristol ran the study back when John and I were covering sort of all the Ipi/Nivo trial readouts. There was a trial called NADINA, I think, in Stage III neoadjuvant. I thought that had become standard of care. Is that not the case? Like you give Ipi/Nivo before resection. I realize it may not have much activity in uveal setting, but in general, isn't everybody is supposed to be getting Ipi/Nivo?

Yes, you're talking about skin melanoma maybe...

Different disease.

Different. That's why this disease is so unique, it's a...

So there were no uveal patients in those trials. Is that right?

Basically, this is a treatment that doesn't work -- the biology is completely different. Tumor mutation burden in this disease, low. RAS mutations, RAS mutation is low, if not at all. So it's just a different disease. It just happens to be -- it's a melanoma, of course, but they're driven -- ours is driven by a different set of mutations. It's wired differently.

I just confirmed.

Why do we give immunotherapy -- because we don't have anything else.

No, they excluded uveal. You're right. I just checked as well. Okay. Great. Great. Wow, so this neoadjuvant, usually, I see neoadjuvant, I was like, okay, that's like 5 years away, but that's not the case here.

We're hoping we can do faster than that.

Okay. Great. So in the last 10 minutes then, I want to do 2 things. A, I want to make sure we take care of any investor questions there are. But also just ahead of that, could you just sort of lay out for us sort of the size of commercial opportunity as well as sort of the highest conviction programs beyond this because I feel like there's other things happening, which we usually catch up on.

Sure. Josh, do you want to take the commercial market piece?

Yes, sure. So on the uveal melanoma side, so in the metastatic setting, we think that's between 4,000 and 5,000 patients incident globally. And that's really U.S., Europe, Australia. That's where those patients are concentrated.

And what's U.S.?

U.S. is roughly 1,500 a year.

U.S. is 1,500. Okay. And you're thinking of pricing as orphan?

So I mean, look, we're a big proponents of value-based pricing. It's going to come down to the sort of benefit that the therapies can offer. I think one benchmark people point to is obviously the [indiscernible] price, which is approaching $90,000 a month. So we'll see what our data looks like, but that's one benchmark out there to consider.

Okay. And then, Yujiro, from your perspective, this takes the company to profitability, this launch in metastatic alone?

So we haven't put out that specific guidance on profitability, Umer, but obviously, some of it will also be driven by our spend. We have other registrational studies across other programs we're looking to launch. So I think some of it will be depending on how we ungate a lot of upcoming studies.

But yes, look, we do think depending on the trajectory of that launch, Obviously, we have other readouts, including neoadjuvant that will be trailing. I think that's going to be part of the conversation as we move forward, absolutely.

Makes sense. And if you could remind us the cadence of readouts beyond this program for some of the rest of the pipeline?

Yes, sure. So I would say the next one probably most in focus is our [ DLL3 TOP1 ADC ]. Their enrollment in the U.S. and outside of Asia is starting to pick up. So we are targeting a clinical data update for that program for monotherapy by the end of the year. And at least based on the monotherapy activity that we and our partner are seeing, we do hope there is some monotherapy approval path that's going to be available to us.

In addition, we have current guidance around an MTAP clinical data update here with Trodelvy. We'll be pushing as hard as we can. Also, you may know we have a PRMT5 inhibitor that's now in Phase I. And so we'll see how that develops as well. So I would say those are several of the pieces. And I know our bispecific ADC is also in Phase I and that we anticipate that enrollment should also go quick. So we'll be closely monitoring the progress of that. But I would say that's probably another possibility as well.

One thing you didn't just mention that I want to make sure we touch on something we talked about at JPMorgan that really fascinates me every time we talk about it is the PARG, which I know is a potential combination agent for any of the Topo-ADCs. You said you're going to start those combinations with the DLL3 this year. Given how rapidly late-stage patients in small cell progress, fair to say that we could see those initial combination cohorts early in the next year time line, and we'll be able to look at them side-by-side with the DLL3 monotherapy data?

Yes. I mean we're planning -- Darrin, you should comment here, but we're planning to dose that combination here very shortly in about a month or so. So I think we should be in good shape on that one, John. And we've done a lot of work on PARG dose optimization. At least my personal sense is I think we'll get a sense of where we are pretty quickly, right, on that combination. So we could have data fairly rapidly on that. And I know the team is, I would say, very enthusiastic about that.

Even ahead of next year, could we have it...

Yes, it's possible. I think it's going to depend on how much follow-up we want and kind of the expectation around that. But there's obviously a durability piece, but there's also just around just pure response rate and do we...

PD-1, PARG as a mechanism with Topo is that something that we could get ahead of durability?

That's the idea. Yes. That's the idea. I mean that could be a differentiating factor for us really to put us above the rest. And it could apply to other ADCs as well. I mean that could be a unifying message that if you have a PARG inhibitor along with an appropriate ADC good target that carries a Topo payload, this could make a difference. That's -- we hope that will be the first test, but it won't be the last in DLL3.

Makes sense. Okay. So last 2, a couple of investor questions. One, expected timing of filing for accelerated approval after the March readout?

Darrin, do you want to hit that? We haven't given specific...

Yes. We kind of basically spoke to that before, right, about 6 months to put the data together and then 6 months to -- so something that's kind of where we're sitting.

And that 6 months is presumably also to get some OS looks. Is that right, Darrin?

Yes, yes, absolutely. I mean we'll share as much as we can. Again, we'll get some of that at the top line, but it may not be very mature. We'll probably get more of that during the filing period. And then, of course, the first interim will read out the first half of next year.

So you don't need to wait for first interim?

We will be providing follow-up data with the FDA. They're going to want to see follow-up safety data during -- once you initially file, they're going to ask for 120-day follow-up information. And so that could be part of the package potentially.

You give them what you have presumably at that point.

So the idea would be you file by August, September. And then the 120-day update allows you to get that first OS interim in there. Okay. Makes sense.

I wouldn't call it a first interim, I would just call it an evaluation, the data could be available for the FDA to review at that time. The official interim won't happen until the first half of next year.

Per stats plan deal.

That's exactly. Per the statistical analysis plan, right? Exactly.

Okay. The last program I think we didn't touch on is KAT6/7, which obviously is getting started in Phase I imminently. We saw Pfizer make their announcement on the dual inhibitor. Can you give us the 3 -- the 2-minute pitch on where your version of this inhibitor stacks up relative to some of the others we've seen in the clinic?

Sure. Mike do you want to take that?

Yes, absolutely delighted to talk about that program. This is potentially very meaningful for patients. It's part of our central strategy to address tumor heterogeneity. What we have found, what we've shown is you want dual potency on KAT6 and KAT7 in order to be able to intercept these tumor genic transcription factors that are present in breast cancer, lung cancer, colorectal cancer.

Our asset with respect to the clinic is the only one that I'm aware of that has that profile. We have not profiled Pfizer's asset, but we do know that the other assets that are out there in the KAT6A/KAT6B space, we think do not have the capability to deliver that profile on KAT7. And that is critical because KAT 7 can substitute for KAT6A, KAT6B and the regulation of chromatin. And that's also critical because we and others have shown that KAT7 brings on a very meaningful biology that will intercept both intrinsic and acquired resistance, and those are 2 of the big conundrums facing precision medicine.

So KAT7 inhibition together with KAT6 that can kill tumor-resistant cells that are drug-tolerant persistor cells, therapy-resistant drug-tolerant persistence. So that's an intrinsic heterogeneity mechanism. And then also KAT7 is required for the self-renewal of tumor-initiating progenitor-type tumor cells, these so-called cancer stem cells that are a wellspring of acquired resistance. So a very exciting program, large patient populations available to us based on intercepting lineage-specific transcription factor activity, as I noted, breast cancer, lung cancer, colorectal cancer.

Mike, the one thing that I want to make sure we tease out of what you just said is the dual potency against KAT6 and KAT7. We've seen numbers from Pfizer's program from some of the others that suggest that you get good nanomolar or single-digit nanomolar potency against 6A, 6B and then maybe you could have in the order of 1.5 to 2 orders of magnitude before KAT7 and then 3 orders of magnitude before you're getting to KAT5 and KAT8 where you'll have the toxicity.

So when you say you want to hit both at the same time, in your opinion, is getting 10x or 50x more selectivity for 6A, 6B, is that like enough hitting 7? Or do you really need to be right on top as your curves look like?

I think that's a great question, and it's really important for people to be able to actually deeply evaluate the mechanism of action here. So what we have seen is you want dual potency, you want low nanomolar potency on KAT6A/B and 7. I have seen a lot of data, our own data, other assets, data. When people are looking at a 10- to 50-fold window for biochemical activity, what we have seen is that translates to a 200-fold window or more, sometimes as much as a 1,000-fold window with respect to cellular target occupancy.

Biochemical activity does not take into account the multivalent complexes that are controlling these enzymes. -- and are making a big contribution to your ability to cover that enzyme in cells and compete with everything else that's going on in that setting. So super important to have a clean line of sight on your PD to understand what your target coverage needs to be.

And we have shown empirically that this matters a ton. If you're looking at your preclinical models, PDX is coming from patients that have progressed, for example, on Ibrance fulvestrant, you cannot cover these with the clinical KAT6 inhibitors. You can't even cover them in combination with palbo and fulvestrant, but we can hit them with the KAT6/7 dual. So very, very clean, very, very robust demonstration of the exposure profiles that you need when you have a dual potent KAT6/7 that you can't get if you don't have that low nanomolar potency in that very small window between the 2. And you do have to stay away from KAT5 and KAT8, as you noted.

Yes. Excellent. Well, I think we're unfortunately out of time. I feel like we could get -- Mike, I'd love to have just you on the next webinar, so we can really get nerdy on the biochemistry there.

Yes. Fabulous. Obviously, a lot to talk about. We spent most of our time on Daro today, but there's a whole ADC platform, PARG, MTAP and KAD6/7 to talk about as well. So thank you guys so much for being on with us. We really appreciate the time this afternoon. Thank you.

Thank you for having us.

Thanks so much for the time today. Bye for now.

Bye-bye.

All right. Great. Welcome, everyone, to Citi's 2026 Virtual Oncology Leadership Summit. We have a smattering of small mid-cap and large-cap companies over the next 2 days doing fireside chats. We also had a KOL call this morning on breast cancer.

But this session, a very important one, is with the senior management of IDEAYA, and it's my great pleasure to introduce three of the executives at the company. Josh Bleharski, CFO; Michael White, CFO; and Darrin Beaupre, CMO. And just remember, for those listening, if you have questions for any of these gentlemen, please e-mail me at my Citi e-mail address, and I can relay them over to the company

So welcome, everyone. Thank you very much. Josh, maybe we could just start off, if you don't mind, with a kind of a quick level set. You have a lot of programs, but you have obviously a very important catalyst coming up in MUM. So just give us a few high-level thoughts as far as where the company is now and what are some of the key things to look forward to in the next quarter or 2.

Yes, sure. Thanks, Yigal, and thanks to Citi for hosting us today. So IDEAYA is a clinical-stage precision medicine oncology company. We have about nine programs in the clinic today led by darovasertib, which is our lead molecule for uveal melanoma. I think as you mentioned, we have an upcoming top line data release for the combination of darovasertib and crizotinib in the metastatic setting of uveal melanoma.

As we noted in our Q4 earnings release, we have triggered the 130 events required for the top line analysis. And we are in the process of collecting that data and analyzing that data and expect to put it out at the end of March. So very exciting data event on the near-term horizon here. Beyond the metastatic setting, we're also exploring darovasertib outside of the metastatic setting in the adjuvant and neoadjuvant settings, we're already enrolling in neoadjuvant study and expect to begin enrolling in the adjuvant study in Q2 of this year.

So exciting to see where darovasertib can add benefit beyond this initial metastatic indication. Beyond darovasertib, we do have a deep pipeline, I'd say, next asset is our DLL3 Topo-I ADC that is expected to begin, well, it is in a Phase I study currently in the U.S., we're enrolling patients. We've guided to providing an initial Phase I data update from that trial by the end of this year. And also to initiate a registrational study as a monotherapy in sort of later line small cell or NEC at the end of this year as well.

We also have a number of assets focused on the MTAP space, led by IDE397, our MAT2A inhibitor that we've been exploring in combination with Trodelvy for MTAP-deleted urothelial cancer. We'll look to provide an update from that study in 2026 at a medical meeting. And then obviously, earlier in the pipeline, we have a number of assets that are entering the clinic now led by our bispecific B7H3/PTK7, Topo-I ADC that's entering Phase I studies right now in our KAT6/7 dual inhibitor IDE574, which is also entering Phase I studies right now.

We ended the quarter with about $1.5 billion in cash, and our runway is into 2030. So I feel like we're well positioned for 2026 and looking forward to the top line release.

Okay. So that's a very good outline for the next 45 minutes. So if we could start maybe with the immediate catalyst. I know there's a limit to what you can say since you just got to lock the database of understanding or in the analysis phase.

But can you just kind of at a high level, just remind us what the study -- how the study is designed, what are the key -- what should be the expectation in terms of a positive scenario for the study? What would you expect to see both in your -- in the combo arm, as well as in the control arm. And maybe we could talk a bit about some of the patient demographics as well after that.

Right. So I can give an overall summary. In terms of the patients that are enrolled, that we think the patient population is going to be very, very similar to what we've seen in our 01 trial and the TEVI study. So we're talking about now a study in metastatic uveal melanoma, specifically in HLA-A2 negative patients. Where we're asking the simple question is how does the darovasertib crizotinib compare to what would be considered standard of care in this space.

And today, it depends on what part of the world you're in, in the United States. First-line therapy typically is immunotherapy, which often includes the ipi/nivo combination. If you're in Europe, they frequently use single-agent checkpoint inhibitors. And if you're not a candidate for immunotherapy, occasionally chemotherapy is used. And so those are what the treatments are -- which are available in the comparator arm. That's the control arm.

So what are the expectations for the kind of output you might see? What is -- what are people aware of in terms of benefit from those kind of therapies? So focusing in on the control arm. There were two large meta-analyses that we've presented in our SMR abstract nice curves, both from PFS and OS. One of them was the Rental publication enlargement analysis, thousands of patients, same with the Australian meta-analysis. But both of them show that in general, the expectation for standard of care therapy in this space is a median progression-free survival of about 2 to 3 months. That's pretty standard.

And then in terms of overall survival, you're looking at about 13 months. Now if you look at the darovasertib in crizotinib combination, the data that we presented recently at SMR and asked, okay, so what does that data look like? There, we presented that the median progression-free survival in first-line patients was about 7 months in the median overall survival was about 21 months. So significantly better than what's been reported with standard of care agents in terms of progression-free survival and overall survival.

In terms of response, again, standard of care therapies delivers a response rate of around 10%. And then that SMR presentation, we showed that we have a 30-plus percent overall response rate. So in all of the major parameters, ORR, PFS, you're looking at, at least a doubling to tripling of what standard of care therapy does and then with OS an approximate doubling. So that sets the stage for this randomized trial, which, again, as Josh has pointed out, we have the events necessary to begin the data cleaning process. The query resolution process and the data evaluation process to generate the data set.

Again, success criteria here. We're expecting that the control arm will produce a median progression-free survival of 2 to 3 months. And based on our success criteria of 5.5-month median progression-free survival in the daro crizo arm would equate to success. But we think we're going to beat that. We think we're going to beat it by a lot. What we would implore people to consider as they look at the data as we will share it at the end of this quarter around that period of time is to really look at the hazard ratio, right?

Because it's really the comparison between the two arms that really tells you the story. We don't expect some people have are, oh, maybe the control arm is doing better. But you have to remember, we're scanning people every 6 weeks. And so therefore, we're likely to see events earlier than some of the other trials that have been conducted. And so I think it's unlikely that the control arm is going to do much better than what's ever been published before. Very unlikely.

And so therefore, this 7 months or so of what you see with darovasertib is likely to be magnified. But again, the data will speak for itself. We'll see it soon. And so what may you hear at the time of the top line, the kind of things that would likely to provide you are, what was the overall response rate for the treatment control and the control arm. What was the durability of that, maybe in the case of duration of response. We obviously will provide what kind of progression-free survival we've seen and maybe a confidence interval.

But one of the other things I wanted to point out, if we don't say anything about overall survival, that doesn't mean there's a problem with overall survival. What it likely means is that there'll be -- there's just not enough events to make a call at this time. So again, we're looking at this early. The first interim for OS happens at the beginning of 2027. However, during that period of time, the FDA will have the opportunity to look at overall survival from data generated from the study, not only at the time of the top line analysis, but also, during the filing, as we provide updated safety data, we're likely to provide an efficacy update there as well.

So long and short of it is, we think we have a high probability of success based on the data that we showed at SMR. We believe that the control arm is going to perform exactly as what's -- how it's performed in thousands of patients based on two large meta-analyses. We think the data from our SMR publication is very robust. It's got 2 years of follow-up and the data has been very solid through that entire period of time. So really, hopefully sets the stage for a very important study for patients with uveal melanoma, which you know have very few options, only one approved therapy, and that one approved therapy has a response rate of around 10% and a median progression-free survival of 2 to 3 months. So this, we think, will be an improvement on what therapy is out there for this disease.

Okay. So that's very, very helpful. So if I understand correctly, your point is that because you're scanning at this higher frequency every 6 weeks, therefore, you should be able to capture some of the early progressions. And therefore, that pushed this expected range of 2 to 3 months to the lower end?

It might. I mean, I'm speculating. But remember, when you get a scan at 3 months as that's the first time you get a scan, you could have progressed 2 months before that. You never know it because nobody scanned them, right?

So -- and with immunotherapy, sometimes they even treat post progression, right? So the progression events could actually happen earlier, not later. But you know what, the data will speak for itself. I don't believe, based on all of the data that's been published that the control arm is going to be much better than what we've seen in these meta-analyses.

And if that turns out to be the case, and we're doing earlier scans and we have a rock solid 7 months for progression-free survival, with our daro crizo combination, I just don't see how it could lose. But you know what, the data will speak for itself.

And you mentioned that you think you beat the -- the 5.5 is sort of the threshold number, whereby if you get 2 to 3 in the control and you hit 5.5% in daro criz, then it works?

Correct.

And -- but you said that you think you could beat that 5.5 by a lot. And that's based on -- tell us more about that, that's based on the Phase II experience? Are there other factors that drive that statement?

Yes. No. So well, the statement is around the 7 months. So 7 months is clearly better than 5 months, 5.5 months, right? So that's what I'm talking about. I'm thinking we're going to be better off than 5.5 months. But again, how much, I don't know. But when the data reads out, that's when it will tell us. But that number has been pretty stable, pretty stable.

Okay. And then there was also some discussion, I think, over the last several months related to the relative proportion of ECOG 0 versus ECOG 1 and that relative proportion may give you some tailwind. Can you just expand upon that?

Well, there was some more patients with -- like if we're comparing across the TEVI study to our 01 trial, there were more performance status in our study relative to the TEVI study, suggesting that the data that we have may actually be better in a similar patient population to the TEVI study. But the reality is, is in the registration trial, I suspect all these things even out. It will be a patient population that's very much akin.

Now in terms of the geographic, there may be some variance there because that's another question that comes up a lot. We're probably -- if I had to guess, we're going to have probably about 60% U.S., 40% EU, and it might have been sort of flipped with the TEVI study.

So obviously, they didn't have any ipi/nivo in that particular study, but we'll have a significant proportion of ipi/nivo in our study, probably at least half of the patients will have ipi/nivo. So those are some interesting distinctions between the two. But again, most people -- ipi/nivo, this is going to be the study where Marlana Orloff said it herself just yesterday is an interesting study because people are going to also be able to look at how does ipi/nivo compare to single-agent checkpoint inhibitors. And if you -- based on everything we know today, we would expect it to be more toxic. So that wouldn't surprise us if we saw that.

And then in terms of efficacy, many people believe especially in terms of overall survival, even in PFS, there's probably no difference between single agent checkpoint inhibitors and the combination. You might have a little bit of a leg up with a response rate with ipi/nivo, but she says, you know what, those are all been small studies. This will be the largest study that actually looks at that. And the way we've designed it, we've designed it purposely to say that, you know what, we're the king, we're the best therapy out there. You can't argue that we didn't have the right controls. You can't argue that we didn't have the right designs, I can't argue that we didn't have the right output with a strong PFS, and it all set, I think, the new standard for what goes on in uveal melanoma. But again, the data will speak for itself, and we'll be hearing about that soon.

Now what you mentioned also that OS, you may say something, you may say nothing, don't interpret saying nothing as a negative in any way. But what would -- what sort of -- what percent of events accrued in OS would be enough to be able to make some sort of statement on a trend or otherwise?

Yes. Like many people think it's around 30% or so. If you're kind of less than 30%, what can you really say? You're starting to get above that 30% threshold, you start getting some confidence. Obviously, the higher you get above that, the more confident you become. So if we're sort of at a threshold where it's still a bit too early, we'll just probably be silent on.

But it sounds like you -- I mean, it's not so far away that it's a definite no. It sounds like you may be getting close to that. Is that fair?

Well, and like I said, we have -- there's this opportunity that we have to look at the data during the filing as well, as well as the time of the first interim. So between the top line -- and the first interim that happens at the beginning of next year, there will be an opportunity to look at the data. And then we'll see how it matures.

Remember, an important factor here is this study doesn't allow crossover, right? There's no crossover because we want to preserve overall survival. That's what the FDA wants to do, right? But if there's an obvious trend to improvement in overall survival, and it's unlikely that it's going to reverse.

Now we have an ethical dilemma, don't. We have something to think about for patients. How long are we going to wait before we allow them to cross over. And so that's a discussion that has to be had with the FDA as the data evolves. It's a discussion that has to be had with our independent data monitoring committee. And again, it's all about the data and how it evolves. And if it evolves in the positive direction, highly positive, really, these are the kind of discussions we have to have.

Okay. So but for the immediate situation for the end of March, we should not expect anything to be said about OS. Is that the plan?

I wouldn't say that. I would just say that if you don't -- what I said was is if you don't hear anything, don't misinterpret it.

Okay. And then -- but the -- but then you have a formal interim OS at the beginning of 2027, which would be triggered by what percent?

Yes. So that number of events will be north of 30% for sure.

Okay. Got it. And then, maybe we could just turn to like assuming you hit as well it seems very, very, very possible with the numbers that you've cited. What would the filing time lines look like for accelerated approval? What would you -- how would you approach the HLA-positive group, for example? Can you speak to those questions?

Yes. So standard metrics just in terms of filing an FDA review in a case like ours, again, we're going to try to compress this as much as we can, but it's about 6 months to file. We'll try to compress that. And then obviously, the review by the FDA will be 6 months at least. So that's the time period.

And then in terms of the HLA-2 positives, we're very excited about that group. The biology says there shouldn't be any difference. We presented data at ESMO in 2023 to show that HLA-2 site patients behaves the same as HLA-2 negative at least when they get treated with the daro crizo combination. We have a data set that's evolving from our Phase II trial, the 01 study that is accumulating about 100 patients' worth of data who are HLA-A2 positive, some of which are treatment naive, but I think a significant proportion of them will be heavy exposed. And we hope over the next year to be able to present that data in two chapters.

Chapter 1 will be maybe the first half of the patients because there we'll have about 6 months of follow-up data from that first group of patients that was enrolled. Where we'll be able to share the overall response rate, progression-free survival and perhaps even some OS data depending on how mature the data is.

Again, what the idea is showing that the combination is very active in this patient population. And then around the time of the filing, around the time of the approval, what we want to do is get this publication out on HLA-A2 positives that will be that whole 100 patient sample size where at the minimum, we can publish that data provided to the NCCN group to evaluate to consider as part of the NCCN guidelines for therapy with patients -- for patients who are HLA-A2 positive. As you know, their treatment options are very limited. With the only approved systemic therapy being TEVI, so it will be an opportunity for patients in the United States to get access there.

But we're also discussing ways we could have a discussion with the FDA about how we could potentially get this on the label. As you know, we're talking about an orphan indication with a large unmet medical need with a very short overall survival in general. So it will be interesting to have that discussion with the FDA around their thoughts. Potentially real-world data could be interjected in the discussion.

But also, there's something to be said about just the fact that the biology says that this combination doesn't work any different. We'll have data to support that it doesn't work any different. And so talking to the FDA about the opportunities for the label will be something that we'll be doing over the next -- over this year as we get into the launch phase.

Okay. Well, let's move on to quickly talk about the other -- some of the other lines you're looking at. Adjuvant and neoadjuvant. What are the -- remind everyone what the time lines are there for getting to the critical readouts for those populations?

So just recall, the registration trial for neoadjuvant darovasertib single agent and primary uveal melanoma has two cohorts, right? The first cohort of patients with large tumors those who are destined for a nucleation where the primary endpoint is saving the eye.

And then the second cohort are patients with smaller to midsized tumors where plaque brachytherapy is the therapy of choice. And there, it's preservation of vision as the primary endpoint.

An important endpoint for both cohorts though is event-free survival. We need to show that by providing neoadjuvant darovasertib in delaying primary local therapy, we don't provide any detriment to patients. And so what we'll do that is show that by using neoadjuvant darovasertib, we provide no detriment with respect to local or distant relapse. So that's the tumor coming back in the eye or the tumor metastasizing. What we have to show is there's really no detriment to subjects when we give this neoadjuvant therapy.

In terms of enrollment, it's going to take probably a year to 1.5 years to enroll subjects and the readouts will take about 1.5 years from the time of primary local therapy. Now with respect to the readouts, it could be that the enucleation cohort actually reads out earlier than the plaque brachytherapy cohort.

You can imagine that being the case when you're only giving up to 6 months' worth of neoadjuvant therapy. And so within that period of time, you'll know whether you save the eye or not. So the rate-limiting step really will be the event-free survival readout. But again, we may not have vision data from the plaque brachytherapy cohort at the same time that we have all of the nucleation data.

So therefore, it remains possible that we read out on the nucleation first. We present that to the FDA, followed by the plaque brachytherapy data. However, if the two data sets come out closely opposed in timing, we may try to file them both together. It really just depends on the timing, but our suspicion is we'll be able to read out a little bit earlier with the nucleation cohort relative to the plaque brachytherapy cohort.

Okay. And so that would put -- if they are kind of proximal to one another, that would be roughly when in a calendar time frame?

Well, again, as I mentioned, 1.5 years to enroll and then 1.5 years from the time of the primary endpoint. So a minimum 2.5 years. We just started dosing.

Yes, Yigal, what we've guided to is being done on enrollment for neoadjuvant in the first half of next year. So that's all.

About 1.5 years from there.

All right. And then what about the adjuvant study?

Adjuvant study, great question. So that one is on the slate. We're actually putting it together now, plan a discussion with the FDA coming up Type C meeting. We have a trial design in hand. Again, there, we're going to take patients who are at high risk of metastases, which is at least half of the patient population. They're going to be randomized to your standard observation, which is what we're doing today, just monitoring patients, waiting for them to relapse.

And again, the median time to relapse is about 3 years. So there's a huge proportion of patients at least in this group, probably 70% to 80% that will metastasize by the 3-year time point. And so what we'll be looking at is a comparator of daro crizo for up to 1 year versus observation -- and so what we'll be attempting to do is show that by providing the darovasertib crizotinib combination that we can reduce the number of metastases down the road in patients who are high risk for metastatic uveal melanoma. So that trial is sort of in swing. It's underway, and we hope to get that launched by midyear.

Okay. All right. Let's move on and quickly to some of the other important topics, and we covered a lot on uveal melanoma. So for the ADC program for the DLL Topo-I ADC, maybe you could just talk a little bit about the time lines there on small cell and neuroendocrine and when we could expect the next readouts?

So that -- so you've seen, obviously, the data from China, it's presented at the World Lung Congress highly exciting, very high response rate with this molecule, 70% with progression-free survival, 6 months or better based on some of the early reads. So it looks very exciting. Our U.S. study based study has just launched just starting to enroll. We think by the end of this year, we're going to have safety data.

The nice thing about this study is we were able to start the dosing at a therapeutic dose level. So there really isn't any subtherapeutic dosing envisioned for the trial. So right from the get-go, right from the first patient, we can start expecting some efficacy data to come in. So there will be a dose escalation that goes on in U.S. patients with our antibody as a monotherapy, but in addition, we'll also be combining it with 161, which will be triggered in the second quarter as we get the first initial data from the first cohort of enrollment for this study.

And in addition, what we'll be enrolling is both extensive stage small cell lung cancer patients, but also neuroendocrine carcinoma subjects. So by the end of this year, what we hope is we'll have maybe two handful or more worth of patients where we'll be able to provide some preliminary response data, maybe some durability of response data.

We'll be able to provide safety data both as a monotherapy and in combination with 161, and we'll be able to provide some early data in some subjects with neuroendocrine carcinoma. Again, we won't have a lot of follow-up because, again, we're just starting to enroll now, so it won't be long-term follow-up, but the initial safety and efficacy data is what we hope to put out sort of by the end of this year. That's sort of where we stand with the Phase I currently.

Maybe I can ask Michael this one or you, Darrin, the combo you mentioned with the PARG, the 849 plus 161, what's the -- just remind us why that is potentially synergistic. What is the biological rationale there?

Yes, absolutely, Yigal. So first of all, DLL3, it's an amazing target. This asset is doing really well as a monotherapy. But as you know, the value proposition is also around durability. And with respect to ADCs with topoisomerase payloads, the ability of the payload to kill those cells is a function of DNA damage as well as DNA repair.

And if you get enough payload in, you kill the cells, if you don't, you get progression. And so what we're looking for with this combination is to get durability by maximizing the therapeutic benefit of the topoisomerase payload. The mechanism of action behind that is a very special role that PARG plays with the resolution of topoisomerase I cleavage complexes. So the way these inhibitors work is they bind topoisomerase I, they clamp it on the DNA together with a break in the DNA. That complex gets correlated by PARP. And then it becomes a substrate for DNA repair.

However, in order for that to be repaired, it has to be deporelated first so that the proteasome can come in and chew off the topoisomerase. There's only one enzyme in the cell that does that, PARG. So PARG is essential for the resolution of topoisomerase I cleavage complexes. So whatever topoisomerase inhibitor gets in there, we are trapping that cleavage complex on the chromatin replication for comes through and it collapses.

So we are amplifying the therapeutic benefit. If we have suboptimal payload delivery, we can get now a more optimal therapeutic response. Very exciting mechanism of action. So we are really looking for enhanced durability beyond what you would be able to get with a monotherapy opportunity. which leads us, by the way, into our selection of IDE034, B7H3/PTK7 bispecific. We have another opportunity there that's distinct, if you want to talk about that at some point.

Let's do that right now. Yes, tell us what's the synergistic thinking there?

Yes. So the point for a bispecific for us is to be able to maximize tumor-specific delivery of the topoisomerase inhibitor. And we pick B7H3/PTK7, these are both targets that have been validated in the past. Both of these targets make biological contributions to the tumor itself. PTK7 is particularly interesting because it is enriched on the surface of tumor initiating cells that are the cells that produce diversification and tumor heterogeneity that leads to adaptive bypass mechanism.

So very nice if we could get rid of those cells within ADC. The point of the bispecific is we have an asset that has been built to have enhanced binding to double positive cells, B7H3/PTK7 double-positive cells. There are abundant evidence using protein for large populations of tumors in important indications like lung, colorectal, triple-negative breast cancer, ovarian, prostate, head and neck, that have double positive tumors. And the only normal tissue where we're seeing double positivity is endometrial, otherwise is single positive.

So bispecific, much more enhanced binding to tumor versus normal, get good therapeutic window. That can come at a cost for payload delivery, the amount of payload that you get in, we are going to maximize that with IDE161. So we're expecting this ADC, IDE034 to be really exciting for monotherapy. And then in combination with IDE161, PARG inhibitor, will maximize the therapeutic impact of that payload that's delivered precisely to the tumor. So we're expecting nice response rates with durable responses in some really important tumor types.

Yes. I think that's the part, Mike. It's going after the big tumor types, too. So the potential here is very broad, and it's within the big tumor. So the commercial opportunity, this drug is active could be quite large to say the least.

So the ones that express B7H3 and PTK7 would be what you mean like lung, breast....

Yes, all the big ones, all the good ones.

Significant populations of lung adenocarcinoma significant populations of BA triple-negative breast cancer, HRP, ovarian cancer, prostate, head and neck.

And have we seen anything yet clinically for that?

Just starting to dose now, just starting the dose now, getting ready to dose.

All right. So then moving on, it's a lot to cover in 40 minutes. But so the MTAP is a huge topic, obviously. So we're expecting an update, I believe, for the MAT2A 397 and Trodelvy. So you've gotten some good data so far, and I think you've arrived at a dose. So can you just talk about what the -- what you envision seeing there with this combo in the next update?

Yes. So just from a high-level point of view, as everyone knows, we've been working on this Trodelvy 397 combination in MTAP deficient bladder cancer. We've presented that data previously. So essentially, that data set has grown since the last you've heard and the data continues to look quite promising with a high response rate and the durability continues to mature.

I think what it's done for us is it's really helped us prove the principle of if you get in there and you inhibit -- you get in there with a MAT2A inhibitor and you add in a toxin like Trodelvy carries, you see some special activity. We think we're clearly doing better than Trodelvy could do in this patient population by itself.

And so from that perspective, we think we've generated some proof-of-concept data that's exciting about other -- that raises the potential about other ADCs that could be used with a similar toxin.

Again, as you know, we're expanding out into lung also. So in lung cancer, that data is still evolving. We're still early days needs more data maturity. But suffice it to say, I think we've kind of proven the point that we have an active regimen here, clearly in bladder cancer, still evolving in lung and we're still discussing exactly how to proceed going forward. But we're really, really encouraged by what we've seen so far. I don't know, Mike, if you want to speak anything to just sort of the proof of principle of the biology here.

Yes. I think I'm right with Darrin on this one. I think it's very exciting that we essentially have proof of concept of the notion that we can amplify replication stress with a combination like this one and do something special.

This is something that we've been looking at from a mechanistic perspective for quite some time. alternative splicing, you mess that up, you cause pausing of RNA polymerase that gives you transcription replication conflict, replication stress and then IDE397 because of its role in the methionine cycle is reducing the capacity of these tumors to be able to produce the nucleic acids by the de novo synthesis and salvage pathway that they need to be able to deal with repair.

So we're increasing damage, we're reducing the ability to repair and we're seeing that work in patients. So very excited about that. And don't forget the magic here is the ADC with the Topo-I payload. We've got proof of concept with urothelial with Trodelvy. I think there's no reason for us to think that this would not work with other ADCs and other indications. So a lot of room here for us to think about additional opportunities with this combination in MTA all tumors.

Okay. And the thinking with the other combo with 892 and PRMT5 is totally different combo, but what's -- how is that -- what are the advantages of that one versus Trodelvy? It's obviously a totally different thesis biologically.

Yes, totally different mechanism of action. And this one is also very important, very exciting, particularly, we think in the context of lung cancer.

Lung cancer is a very mechanistically heterogeneous disease. It has lots of adaptive bypass mechanisms. We know that tumors on PRMT5 inhibitors have acquired resistance. We know that PRMT5 inhibitors cause alterations in chromatin architecture that enhance phenotypic plasticity that leads to resistance.

And we know that IDE397, an MTAP inhibitor -- sorry, an MTA, a MAT2A inhibitor will intercept that modulation of chromatin in order to be able to give us a durable response. So that combination, we can inhibit bypass mechanisms of PRMT5 inhibitors, but we can also maximize the ability of perturbation of alternative splicing to work in MTAP null cells because the whole synthetic lethal principle for MTAP loss is MTA accumulation. MTA accumulation allows MTA cooperative PRMT5 inhibitors to work.

They allow MAT2A inhibitors to work, but MTA accumulation in tumors is variable. It depends on the extent of polyamine synthesis. It's a byproduct of the production of polyamines. And that combination we have shown can maximize the MTA/SAM ratio to be able to maximize the synthetic lethal effect. So we think we will get deeper responses in the combination setting because we extinguish the pathway in the MTAP in all cells, and we think we'll get more durable responses because a MAT2A inhibitor intercepts adaptive bypass mechanisms that otherwise occur with PRMT5 inhibitors.

Okay. And then there was a third one you just nominated, the CDKN2A candidate. How -- that's also sort of in this pathway broadly. How does that play into the biology? And what additional tumor types could you access by attacking that?

Yes, that's a great question, Yigal, because the 15% of the tumors have MTAP loss, maybe 15% of lung cancer, 20% to 30% of pancreas, 25% to 40% of urothelial, 20% of esophageal, 17% head and neck, big populations.

Those get -- those happen because actually CDKN2A is lost. So CDKN2A loss is the most common co-alteration with MTAP loss because CDKN2A harbors two of the most important tumor suppressors known to mankind. You lose those things, you release cell cycle progression.

We have a way in to be able to attack that co-alteration and use that as another mechanism of action to deploy with PRMT5 inhibitor, MAT2A inhibitor or actually maybe even a triple combo to be able to maximize the insult on the tumor that has these 9p21.3 regions. So CDKN2A loss drives MTAP loss. So everywhere you have MTAP, pretty much you have loss of CDKN2A. So we're excited about this combination. And as long as we're on the topic of combos, we're really trying to do as much productive damage as we can in this MTAP space and in pancreas cancer, where the frequency of MTAP loss, CDKN2A loss is upwards of 30% CDKN2A deficiencies are even higher, perhaps the majority of pancreas cancers.

The big co-alteration there would be KRAS, right? So KRAS is mutant in pretty much all pancreas cancers. And so we have also been looking into that combination. We've been talking to some folks who are excited about doing that. We're in a unique position in pancreas cancer potentially for KRAS PRMT5/MAT2A triple combo. That's a very, very hard space to play in pancreas cancer. So you need a very effective therapy with a good therapeutic window.

Okay. Well, we're not able to get to everything because you have a lot, and we're kind of out of time. So we'll leave some of these other topics on KAT6 and Warner for the next meet up. But I appreciate all the details and the thoughts on melanoma and MTAP and the DLL3. And we're, of course, looking forward to the readout at the end of March, as you point out. So thank you again very, very much.

Thank you, Yigal.

Welcome, everyone, to the 44th Annual JPMorgan Healthcare Conference. My name is Anupam Rama. I'm one of the senior biotech analysts here at JPMorgan. I'm joined by my squad, [ Priyanka Grover ], [ Joyce Sau ] and [ Roti Pinhe ]. Our next presenting company is IDEAYA, and presenting on behalf of the company, we have CEO, Yujiro Hata.

Well, thank you, upon for the introduction. And thank you again to JPMorgan for allowing us to present at the 44th Annual Healthcare Conference at JPMorgan.

Please note, we'll be making forward-looking statements today and please refer to our SEC filings as appropriate.

Since IDEAYA's founding 10 years ago, we've had several strategic guideposts that have led our organization, including first-in-class targets, predictive biomarkers, rational combinations and early-stage disease. Those strategic focus areas has led us today to have 4 clinical pipeline focus areas that we'll cover during today's presentation.

The first is darovasertib. This program is now in a registrational study and we are guiding towards top line results this quarter to enable our potential first accelerated approval filing in the United States. We believe darovasertib is truly a unique molecule and has the opportunity to potentially define this indication up melanoma across both the neoadjuvant, adjuvant and metastatic settings.

Next is our focus in the area of ADCs and damage repair. For many of you that have known us for the last 10 years, know that DNA damage repair has been one of the core scientific focus areas for the company. And we believe one of the greatest opportunities in antibody reconjugate space is to identify combination opportunities to extend durability and ultimately, survival.

Next. Third is our focus in the area of MTAP deletion. For those that you may know, MTAP deletion is often co-deleted with another key tumor pressure gene called CDKN2A, which is on the 6 P12 chromosome. Unfortunately, today, there are no currently approved therapies for this biomarker-defined patient population, which represents roughly 15% of solid tumors. And I would say, alongside RAS, MTAP perhaps represents one of the largest patient selection biomarkers being pursued by the industry today.

Lastly is our focus to address what we believe is one of the greatest scientific challenges in the area of cancer, which is the challenge of tumor heterogeneity. If I were to highlight one program that really highlights our commitment to address tumor heterogeneity, it's our recent Phase I molecule IDE574, our dual CAT 67 inhibitor, which, alongside another major, pharma company, we are -- have the opportunity to have another potential first-in-class agent in the clinic.

What has fueled this productive pipeline and engine is a proven drug discovery engine. And I'll highlight just several key points on this slide. First is that we have internally discovered 6 clinical-stage molecules across 6 potential first-in-class targets, including very difficult target classes such as helicases, polymerases and glycohydrolases. In addition, we've also pioneered key select selectivity profiles across very key parallels and protein families, including kinases and lysine acetyltransferase, as an example of KAT6/7.

What this has resulted in is what we believe is 1 of the deepest clinical precision medicine oncology pipelines in the biotech industry. We have currently 9 clinical stage molecules that are advancing. As noted earlier, darovasertib, our most advanced program. And really, the strategic promise of building this type of deep pipeline is really in 2 areas. First, as this will enable us to have wholly owned combinations across critical nodes of key pathways. Second is the ability to address multiple solid tumor indications of high unmet need including uveal melanoma, small cell lung cancer, colorectal cancer, breast cancer, among many others.

Our lead indication is uveal melanoma. Uveal melanoma, unfortunately, is a rare but very aggressive form of cancer. And unfortunately, for patients, this indication has 1 of the worst prognosis in terms of solid tumor indications. Survival typically ranges roughly 10 to 12 months. And as you can see here, the 5-year survival rate, this 15% to 20%. And unfortunately, for these patients, there are limited treatment options. Majority of these patients have no approved therapies available to them in the metastatic setting. There are no approved systemic therapies in either the neoadjuvant or adjuvant setting.

The mechanism that our lead molecule, darovasertib, is targeting is in the G-coupled receptor protein family, specifically a key activating mutation of GNAQ and GNA11. What makes this indication quite fascinating scientifically is that essentially 95-plus percent of these patients have either a GNAQ or GNA11 activating mutation. So in this instance, the indication is the diagnostic. Darovasertib was specifically designed to block this PKC activation pathway that is turned on by this mutation of GNAQ and 11.

As I noted in my introduction, our strategy for darovasertib is to position this molecule to be the new standard of care across the entire uveal melanoma patient journey, including neoadjuvant, adjuvant and the metastatic first-line metastatic uveal melanoma setting. Alongside our strategy here, as we noted in our JPMorgan guidance on Sunday, we are targeting to have 3 randomized Phase III trials initiated in the first half of this year.

So why are we so excited about this compound, the opportunity that we have in front of us at metastatic uveal melanoma? We presented data last fall at the Society of Melanoma Research in Amsterdam and we recorded an overall response rate of approximately 35%. And as you can see here, a median duration response of 9 months. To provide context, historical response rate has been reported at roughly mid-single-digit percent. So clearly, a market improvement from what patients currently have available to them today.

Beyond response rate, PFS and OS are obviously critical endpoints. And for those that are aware, PFS is the prime endpoint for accelerated approval and OS is the primary endpoint for full approval. At SMR, we reported a PFS of 7 months. Historical PFS based on large meta-analysis has ranged from 2 to 3 months. And overall survival, we reported an OS of over 21 months and historical OS has sadly been in the 10- to 12-month range.

So this is the high-level design of our current randomized Phase III study. Several pieces that I'll highlight here. First, the 437 patients we need for full enrollment is now fully enrolled as of December. And as noted earlier, we are now on the precipice of being able to provide our top line results to hopefully enable our first approval filing here in the U.S. In terms of investigators choice, there's several therapies that will be on that arm, including checkpoint, PD-1 plus CTLA-4 and the chemo DTIC.

Beyond the metastatic uveal melanoma setting, we're very excited about the indication expansion opportunities that are in front of us that we believe will enable darovasertib to be a bona fide blockbuster opportunity. In front and center as part of that indication expansion opportunity is in the neoadjuvant uveal melanoma setting. For those I may have not followed this program very closely, we did receive breakthrough therapy designation from the FDA in the spring of last year. We believe we're the only second company to receive breakthrough therapy designation in the neoadjuvant setting in the area of oncology. So I think really punctuates the importance of the data that I'm going to share with you on this slide.

As you can see on the left, the primary endpoint, there's 2 cohorts here, is enucleation. And as you can see to the bottom, over half of these patients that were scheduled to get their eye removed due to the ocular tumor, we were able to preserve their eye. Quite a remarkable result. And we believe the key data that really convinced the FDA to give us BTD designation in the enucleation setting in specific.

Second, as you can see, over half of the patients, we saw a 14-letter vision gain during the neoadjuvant treatment before the plot procedure. Again, remarkable data that gives us confidence, not just in the integration cohort of the plaque therapy quarter as well. This is the high-level design of the randomized Phase III study that we've launched in neoadjuvant melanoma. We launched this trial in the middle of last year. So now this study is fully up and running. We're going to be targeting to enroll a total of 450 patients, roughly 120 and the inoculation cohort 330 in the plot therapy cohort.

As I noted earlier, the primary endpoint in the enucleation with eye preservation and the plaque therapy cohort will be a 15-letter BCVA vision test, and there will be a pooled analysis across both cohorts on event-free survival, where we need to demonstrate new detriment. So this study, we also did recently guide as part of our JPMorgan working guidance that we will target to complete enrollment of the study in the first half of 2027. So our hope here is assuming we have the ability to get accelerated approval in the metastatic setting. By the time we are in that phase of hopefully commercialization that the neoadjuvant Phase III randomized study has the opportunity to hopefully be fully enrolled.

So now we're going to transition from darovasertib to our next program that we've now guided our goal to have in a registrational study this year. And that's our DLL3 TOP1 ADC program, IDE849. As we know, the antibody drug conjugate field has drawn significant intention in the oncology community. And we believe one of the greatest areas of unmet need that needs to be filled is how do we make ADCs more durable. And we believe there are several key opportunities here, and we believe in center as part of this is clinical combination opportunities with DNA damage repair small molecules. Within that, Idea has been a research pioneer, has evaluated multiple mechanisms to achieve this goal, and we believe PARG and specific PARG with our clinical molecule IDE161, has the opportunity to be tested in the clinic and test this hypothesis of enhancing the durability of the TOP1 ADC class.

And through that, about 1.5 years ago, we've been executing on a strategy to also bring internal potential first-in-class TOP1 ADCs with into IDEAYA. And through that, we in-licensed IDE849, the DLL3 TOP1 ADC and also another potential first-in-class bispecific B7H3/PTK7. And as you can see below in 2 models, one with our DLL3 ADC, the second, whether bispecific ADC, we see very robust combination results. That makes us very excited and confident about this opportunity to bring these 2 agents together to test this hypothesis about extending durability of this important class of therapy.

So this provides more details scientifically. I will truncate this summary to the top right. But essentially, we know that PARG enzyme specifically play a key role in the resolution of the DNA damage that's elicited by 2-point summaries. So we are essentially directly targeting this mechanism through PARG inhibition. And as we showed earlier, we not only have we generated in vitro data, we will also generated in vivo data across multiple preclinical models with multiple TOP1 ADCs, including approved ADCs. And the result is consistent. We've been able to enhance the durability of multiple TOP1 ADCs in combination with IDE161.

So now with DLL3, why are we and many companies focus in this area of DLL3. One of the main reasons is because one of the key applications in the area of small cell lung cancer. For those I may not be aware, small cell lung cancer represents roughly 15% of all lung cancers and perhaps continues to be one of the highest unmet need areas within lung cancer specifically. Unfortunately, survival is very short, and there are very few available therapies to the patients. And this is one of the key holes that we're targeting to build beyond small cell lung cancer, we believe there will be broader opportunities, including within the neuroendocrine space as well as indications such as melanoma..

So this is data that we presented at the World Cancer Lung Conference last September. I think this waterfall speaks for itself. This molecule is quite active. We reported a confirmed response rate in the second-line setting of roughly 70%. And as you can see, most of these bars are going down, and we also are seeing very deep responses as well. We also reported preliminary progression-free survival. And here, we're reporting PFS just north of 6 months. And just to provide context, obviously, cross-trial comparisons, a DLL3 T cell engager that has been improved in the small cell lung cancer space has reported a response rate roughly in the 40s and a PFS roughly 4 months. So we believe based on each of those measures, IDE849 is well positioned not only to be a potential first-in-class asset, but a leading asset in the broader DLL3 space.

So this slide summarizes our broad clinical development strategy. So there are essentially several strategies that we're pursuing. One is on the small cell lung cancer as another is more broadly in the neuroendocrine tumor space. We did provide guidance on Sunday that our goal is to initiate our first registrational study for this program that we would target to be a monotherapy accelerated approval study in addition. We'll be evaluating combinations, including with standard of care, which would largely include chemotherapy such as platinums, PD-L1 and of course, as I mentioned earlier, the PARG combination. And based on that data, we will also, in the future, look to pursue a line study in small cell lung cancer.

So our first thing -- potential first-in-class TOP1 ADC pipeline has been growing. So now we have another Phase I asset in IDE834 which is a first-in-class that we know the first of its kind, bispecific that's not enter the clinic, which is a B-cell H3 PTK7. And why is this important? This is important for several reasons. First, the co-expression of these 2 antigens is very high in several key indications, including lung, CRC, breast as well as several other solid tumor indications. A second, as you can see below, based on this specific bispecific antibody we've seen superior efficacy versus the mono TOP1 EDC, specifically versus the B7-H3 and PTK7. And we believe that's based on enhanced internalization of this bispecific ADC versus the monos. And as you can see below, we're seeing very robust regressions across each of these models. In addition, we will also be evaluating our IDE161 PARG combination as we will with DLL3 to build a portfolio of asset opportunities across this area.

So we'll now shift gears to the third area of focus for us is in the area of MTAP deletion. And as I noted in the introduction, why we're so excited and focused in this area of MTAP deletion, as I noted earlier, which is around this biology around chromosome 9p. And as we know, one of the most common deletions of the tumor pressure genes that are their most common in cancer is both MOP and CDKN2A. These 2 tumor suppressor genes are roughly 20,000 base pairs apart. Because of that, when MTAP is deleted, CDKN2A is almost always co-deleted.

So why is this important? It's important for several reasons. First, this is very common in cancer, unfortunately. This occurs in roughly 15% to 20% of lung cancer, roughly 20% of pancreatic cancer. And unfortunately, for patients there are no FDA-approved therapies for these MTAP deletion patients. There are 3 core strategies that we'll be pursuing here. First is around pursuing this interplay between the period and per median pathway in folate, and this is what we're pursuing with Gilead around leveraging the topoisomerase DNA damage in connection with MAT2A. We're guiding with Gilead to provide a clinical data update at a major medical conference this year.

Second is this combination with MAT2A and PRMT5. We are one of only 2 companies in the industry that have clinical stage molecules. This is continuing to leverage the biology and our expertise on the MTAP pathway. And here, the primary focus will be in non-small cell lung cancer. And then finally, I would say, is an area that has become a growing focus and importance in the industry, which is the key question of what else is co-authored with MTAP.

I highlighted CDKN2A is the most common call duration MTAP and the other most common alteration is RAS. And we obviously know the focus of a specifically in indications such as pancreatic cancer, and roughly 90% of patients that have MTAP-deletion in pancreatic cancer would also have a RAS alteration. And because of that, it creates a rational combination specifically in pancreatic cancer. So as you can imagine, if you're a pancreatic cancer patient, you have a RAS alteration and you have an MTAP alteration, both alterations are known to cause cancer, unless you're addressing both sets of biology will you be able to deliver maximal response to those patients. So we believe this is going to be continuing to be a very exciting field for the whole industry and definitely an area to watch for over the next several years.

I covered most of this slide, I would just highlight here our focus with an MTAP deletion currently is in the area of urothelial cancer, lung cancer and pancreatic cancer.

This waterfall is data that we presented at R&D Day last September. And really, the takeaway message here is we're seeing a response rate of roughly 40% in aggregate. The durability data is still immature. However, we can see we have several patients at the dose level 2 now that have extended beyond 200 days. In addition, as part of this in terms of a go/no-go decision, what we publicly communicated is we'd like to see a result rate north of 40%. We're still doing dose evaluation in non-small cell lung cancer and we hope to be able to select an expansion dose in that indication over the next couple of quarters.

Next is our Phase I PRMT5 inhibitor, 892 a Obviously, there are several molecules in the clinic against this target class, as I mentioned earlier, what differentiates us is we are 1 of very few companies that have wholly owned clinical assets that target both PRMT5 and MAT2A. And we believe both of these targets are foundational assets to hopefully deliver maximum value to patients with MTAP deletion solid tumors. As you can see, the monotherapy data preclinically demonstrates strong tumor regressions. And really what gets us excited about this is the ability for MAT2A to help address specifically acquired resistance mechanisms in the PRMT5 pathway. And as you can see, deep durable regressions we've been able to deliver through this combination.

The last section that I'll walk through is our next-generation molecules that are now both in Phase I, which is and 1 is in Werner Hillecase with ID-275and the second is ID our dual KAT6/7 inhibitor. And due to time for now, I'll focus on the KAT6/7 program, which has recently entered Phase I -- for those that may have seen Pfizer just several days ago, announced their first KAT6/7 7 molecule just entered Phase I this past Friday. Those may know Pfizer recently started a registrational study on the KAT 6 selective molecule. We believe KAT 7, which is specifically in the lysenacetal transfer area of biology, specifically targeting a very important area of cancer biology called chromatin remodeling.

We believe this target pathway has now been clinically validated, and we believe here the opportunity is to drive greater efficacy from what KAT 6 has delivered through this dual inhibition of these paralogs of both KAT 6 and KAT 7. As you can see to the bottom right, we see significantly greater efficacy versus the KAT 6 selective molecules here. we will most likely be focused clinically on the hormone receptor positive setting of breast cancer as well as prostate cancer and other indications, including CRC and lung cancer. Within all of the assets that we're working on in the clinic, which now amazingly represents 9 clinical stage programs, we believe 7 perhaps represents 1 of the largest clinical opportunities in terms of addressable patient population.

So we just covered, I think, quite a lot, and I hope my clock is correct that I have 15 minutes left here. So maybe that's with the Q&A portion. But we're here to the last slide. So Hopefully, you get a sense that Idea is really now at a key precipice as we are getting very close to having our top line results as I noted earlier, to hopefully enable our first accelerated approval filing in the U.S. with darovasertib.

Next, we're investing heavily on the next wave of growth. And here, as we talked about earlier, is our focus on extending the durability of TOP1 DCs, our deep commitment in the area of MTAP deletion biology. And then lastly, with KAT6/7, we think one of the most exciting opportunities to address one of the key challenges, which is tumor heterogeneity.

So with that, Anupam, thank you very much, and we're done with the prepared remarks.

Thanks, Yujiro. Yes, I'll ask the first couple of questions, but if anybody in the audience has questions, feel free to raise your hand, and I can get help -- get your question in. So I just wanted to quickly ask about the metastatic uveal melanoma study. Data is in 1Q. I'm assuming that you're looking at sort of blinded events and you've looked at it recently enough to reiterate your guidance that the data will be in 1Q. Is that a fair statement?

Yes. So yes, we're not providing specifics sort of where we are within that continue on a pump as you appreciate, there are sort of several steps in the process. But really for now, our public guidance is around being able to provide those top line results this quarter.

And I wanted to ask a bit of a broader market question. What have you learned from the Kemtrak launch here in the U.S. about uveal melanoma that you can apply to daro up here?

Yes. So are those two mics active?

Yes.

Can I bring maybe Darrin and Stu to join me at the front? I think it's much better the are functional leaders or in strain. .

Obviously, you're going in a different subtype.

Yes. Go ahead, Stu.

Stu Dorman, I'm the Chief Commercial Officer at IDEAYA. And with regard to Kemtrak and Immunocore, I mean, obviously, they've done very well in this market. What we've seen from them though is a market share that has really plateaued. And they've spoken openly about getting into the community and their challenges there, their continued efforts to do that. We feel that we have a plan in place to be able to action on that ourselves in a way that will allow us with the oral nature of the darovasertib and crizotinib combination to enter that market quite a bit faster.

Questions from the audience?

Yes. Thank you so much for your wonderful presentation. It's a multi combo story and I'm just curious about the -- how about the single agent access site and what about the monotherapy data such as IDE161?

Yes. So for us, we're going to really follow the science and the biology. So we have several programs where monotherapy is going to be a focus, including for DLL3 IDE849, in addition, the KAT6/7 molecule. But for several programs, as you highlighted, combination is really front and center, including the MTAP readout.

Additional questions from the audience? Yujiro, you talked a lot about the combination potential right now, right and having the science drive you. What led you to 161 kind of reemerging back into the pipeline here is now potentially a backbone combination product for the company?

So when you look at the ADC arena, as we know, there's been several key mechanisms that have been pursued, including microtubule mechanisms, obviously, topoisomerase, which would land you in the area of biology, around DNA damage repair. And so for us, our view is topoisomerase obviously is a critical payload mechanism. And so if you're really trying to think through what are the right combinations from a scientific perspective, ideally, you're focusing in the general biology area of DNA damage repair.

So then that leads you down a pathway of several different targets, including PARG, PARG theta, we know PARP1 is also another that people are interrogating. And that's really what led us to this area. Within those set of targets, based on the data that we've generated, we believe PARG is one of the most promising to extend the durability. And hopefully, we'll now be the first company in the industry to this hypothesis in patients and we anticipate we'll be able to test this hypothesis across multiple clinical stage topo ADCs.

How much myeloid toxicity do you see with these DNA damage inhibitors on their own? I ask because, obviously, the main issue with the topoisomerase payload that you have for Trodelvy is significant neutropenia. Do you risk making that neutropenia significantly worse by adding another drug that has hematological toxicity in its profile?

Yes. Obviously, there -- it's all going to be about what you do in the clinic, and that's the whole point of dose optimization. I don't know, Darrin, if you have anything to add.

The only the other thing I'd add is it depends on your schedule, too. If you can deliver your DNA damaging agent in a way that's less myelotoxic, then putting the 2 together may not be as problematic as you think. And then we think we've been able to do that with 161.

And I would also just remind folks, I think there is obviously also an opportunity, you may not need full dose for both agents, right? And so that's something that we'll have to test in the clinic ultimately.

Could you just repeat that for the audience?

Yes. I think the only point our CSO in the back is making, not every ADC is created equal, right? So that's sort of a general question. You obviously have quite a wide range of myelosuppression even across the ADC class, whether it's the linker, whether it's the payload, whether it's the antigen

But for Trodelvy, since this is the combination you're exploring?

Trodelvy, it's with 397.

Maybe while we're on 397 and Trodelvy, I think in your comments, you said you wanted a certain response rate to kind of move forward. Is that right?

Yes, I would say for the Trodelvy IDE397, I would say, ideally, we're seeing a response rate that's north of 40%. Obviously, equally important, perhaps more important, will be around durability I think good news is 2 things. We're seeing this phenomena where we're seeing the drop in that spare plot fairly quickly and dramatically that we haven't seen before. So I think that's encouraging. And second, we're now starting to see these patients followed up. And that's why I mentioned we've now have several that are at the 200 days that I've heard recent now, we even have a patient pass 500 days. So I think that's encouraging. And so we just need more data, more follow-up. But obviously, we can live with that kind of response rate with good durability. We should have some path forward.

And then on the safety side for that combination of 397 and Trodelvy, you are -- remind us, you are testing different doses and lower doses of Trodelvy, hoping to get -- navigate that therapeutic window?

Yes. So for the combination, I think we're in good shape. I mean -- and maybe, Darrin, once you answer this question?

Well, we are testing have been testing more than 1 dose level, but we think we found an optimal opportunity with the full dose of 397 and a reduced dose of Trodelvy of 7.5 milligrams per kilogram, it seems to have the best safety profile. It seems to have the best efficacy profile. That's where we sit today. We feel very comfortable with that. We still have to do some more within non-small cell lung cancer, there's the potential to maybe increase the dose there. We'll have to look at that. But we think we have a dose that's well tolerated.

And I think the efficacy is very promising especially if you think about the patients in that cohort that we've studied that have had EVP in the fast and fortumab pembro, they tend to not do as well with Trodelvy or other agents after that kind of therapy, and we think we're showing a highly respectable response rate in the patient population like that. So we're really excited about the opportunity here. But as Gerald points out, we just need a bigger end and we need more time to see how durable it is. And so far, the ability looks encouraging, but we just need more time.

Questions from the audience? Yes, right there.

We see a lot of companies now moving in the direction of the dual payload approaches. And here, obviously, you're focusing on a systemic DDR rather than as a payload in combination with the topo 1 and a dual payload. Could you speak perhaps to a little bit of the advantages of using it as a systemic therapy combination rather than as a dual payload?

Yes. No, thanks for the question. At the end of the day, the concepts are the same, right? You're essentially trying to deliver 2 mechanisms to enhance durability. I would say kind of the pros and cons, I'll give the very short end version. I think with dual payloads, a lot of it is, at least, I believe, around -- can you drive additivity versus synergy, right? And a lot of that is going to be driven by the art of the DAR of each payload. Unfortunately, once you set that DAR, it's fixed in the clinic right that the advantage I believe you have with a systemic agent, right?

Because ultimately, you're delivering 2 ultimately not different payloads and essentially trying to deliver that same result, but you don't have a set DAR, right? So obviously, both of the payloads and the incident of the dual payload is being delivered by an antibody. So I think that's probably the advantage there. So it's an area, obviously, we would have interest in because we have, obviously, already 2 novel small molecule mechanisms part would be an obvious second payload to consider.

Any final questions from the audience? Thank you, Yujiro and team.

Great. Thank you all so much.

Welcome, everyone, to day 1 of Citi's Global Healthcare Conference here in sunny and hopefully very warm Miami. I'm Dov Nochomovitz, one of the biotech analysts at Citi. So the first session, it's my pleasure to have with me the management of IDEAYA Biosciences. We've been covering them for quite a long time. I think since the first day they were public, if I'm not mistaken. And I have Yujiro Hata, the CEO; and Joshua Bleharski, who is the CFO. So welcome. Thank you both very, very much. And I was just saying to Yujiro, that time is flying. They just had their big R&D Day in New York just a few months ago.

So Yujiro, a lot's happened. You have a lot of updates over the last several months. You have a big catalyst coming as we know. But maybe just to start out, if you could provide just a quick overview of IDEAYA, what the generating thesis was for the company? What are the big programs, and we can move into some of the big updates coming.

Yes, for sure. So thank you so much, Yigal, for inviting us again this year to your annual Healthcare Conference at Citi. So IDEAYA Biosciences, we're a leading precision medicine oncology company. We have now 8 programs in clinical development. Yigal, as you know, our lead program, darovasertib, is in our first-line registrational trial in metastatic uveal melanoma. We are moving closer towards our top line results to hopefully enable our first accelerated approval filing here in the U.S., which is soon approaching. Our guidance is year-end this year to Q1 next year.

In addition to the metastatic uveal melanoma, we have 2 Phase III registrational trials that are either ongoing or we're preparing to launch in the next quarter or two. And that's also in the neoadjuvant uveal melanoma setting as well as an adjuvant. Earlier this spring, we did receive breakthrough therapy designation for this program in the neoadjuvant setting specifically. Beyond that, as you know, we have a very broad and diversified pipeline. I would probably say the next program and area of focus is on DLL3, our TOP1i ADC, IDE849.

We had recent data that was presented at the World Cancer Lung Conference in Barcelona. And then we also have 2 clinical stage assets in the MTAP-deletion space with IDE397 MAT2A and also a Phase I PRMT5 inhibitor. So I think we have a lot to talk about today, but those will really be the 3 key highlights.

So maybe we could start with the first-line MUM setting. As you pointed out, the data is imminent essentially. But you had some important updates recently, I believe, at the Society of Melanoma Research, where you talked about some of the prior data supporting the current Phase III trial. So if you could kind of walk through what we know about the efficacy of Daro-Crizo in this setting, what the Phase II data look like and how that points to success as we get close to this PFS readout?

Yes. So maybe just quickly, you got the table set. In the indication of metastatic uveal melanoma in the frontline setting, we believe the median PFS is about in that 2- to 3-month range, very likely more in the 2.5-month range. And historically, what we presented, including at SMR, which we had an oral presentation in Amsterdam fairly recently, we noted a PFS of about 7 months. So we think a very meaningful improvement based on historical. Second, when you look at response rates as well here, historical response rates have been in that single-digit percent ORR. As you know, we've reported response rates north of 30%. We think a very robust median duration of response as well. So with those two together, we feel good as we go into these top line results.

And as far as the -- you also had some data on preliminary OS data in the Phase II. So I know we're not necessarily going to get that at this update, but how does that impact your overall thinking in terms of the potential of the program?

Yes. No, thanks for bringing that up, Yigal. So that's correct. So historical OS here, we believe, will be in roughly that 12-month range. The data that we reported at SMR was just north of 21 months. And as you know, that data could continue to mature where that number could continue to go up. So we think based on that, we think a meaningful delta based on historicals. And obviously, we have our randomized readout that will also be following the median PFS, and that enrollment for full approval should be done here very soon.

And as far as what specifically we're going to get in this update, obviously, the PFS data, anything on OS or that would be a later look? How much are you going to be able to tell the markets about that?

Yes. We'll try to provide as much data and information that we're able to you. So of course, response rate, DOR, PFS. Is there a trend in OS, I think it's going to be the sort of the key question and whether OS will be sufficiently mature by the time of the PFS readout.

And maybe just talk a little bit about the market. I mean, obviously, there's one drug approved, but it's not approved for everyone. You have a potentially label that's not genetically determined. So could you just talk about what that implies as far as size of the market and how you could be competitively positioned versus the player that's already out there?

Josh, do you want to take that?

Yes. So as you pointed out, there is a competing drug on the market in the HLA-positive setting. Of course, we're going after the HLA negative population, at least as a primary priority. We think there's about 4,000 to 5,000 patients in that market broadly. We think the split between the positive and negatives is roughly 60-40, 2/3, 1/3 in favor of the negatives. So it's quite significant. And so I think initially, as I said and as Yujiro said, the goal is to get in -- get the negatives on the label, but we do think there is a path to darovasertib being used as the standard of care across the patient spectrum regardless of HLA status.

And anything else you want to say about just the baseline demographics of the study or any other factors that point to or position you for a successful outcome? Obviously, what you cited on the PFS is quite a wide margin and it puts you in good standing for a positive outcome. But is there anything else that's engineered into the trial that's going to help result in a positive outcome?

Yes. Yigal for us, when you look at the patient baseline characteristics from the Phase II data we presented at SMR recently are relative to our registrational trial and compared to other registrational trials that have been done in the frontline setting, we do feel the baseline characteristics are fairly comfortable with the exception of ECOG performance status. And so here, in the Phase II study, we saw roughly 40% of patients ECOG 1, 60% were ECOG 0. And the sort of peer company registrational study that was done both in the treatment and control arm, the ECOG performance 1 percentage was half of that, roughly 20% versus 40%.

We have looked at the data cut based on ECOG 1 versus 0, and we do see a correlation across all of those efficacy parameters that I mentioned. So we do think there could be the potential for further upside, which is why I'm mentioning sort of the 7- to 8-month PFS as obviously a potential scenario, but we'll have to see for that what the readout.

And you briefly mentioned neoadjuvant, and we can also talk about adjuvant. Just can you outline the development strategy in neoadjuvant? What are the pieces of the puzzle there? Because just so we understand clearly what the cohorts are and what are the endpoints and signals that you're looking for in each of those to determine a label?

Yes. So look, first, we'll see neoadjuvant uveal melanoma, we think an extraordinarily exciting space for this program, an extremely high unmet need. Some of the numbers Josh just mentioned, now annual incidence goes up to 10,000 to 12,000 patients. We believe prevalence would likely be multiples of that. There's nothing approved, no systemic therapy is approved here, and this would be agnostic of HLA-A2 status.

In terms of the cohorts, there's two patient cohorts here in consideration. One is the Enucleation Cohort. These are patients that otherwise would get their eye removed to their primary tumor. Second is the Plaque Brachytherapy Cohort. So these are -- majority of these patients are getting these radiation plaques that are exposed to the eye to the shrink the tumor. So those are the two cohorts. Primary endpoint for enucleation is eye preservation rate. We talked about that, which is where we believe we got the breakthrough therapy designation based on that very robust number we saw and we shared with the FDA.

For the Plaque Brachytherapy, it's a visual acuity readout based on a 15-letter BBCA test. For both cohorts, we need to hit a no detriment threshold for event-free survival. And as we've mentioned in the past, based on single-arm data so far in the Phase II study, we've seen very few events. So we do feel that we should have a good shot at hitting also that no detriment threshold for EFS. So that's neoadjuvant. I'm also happy to go through adjuvant as well.

What else? Who are you competing with in neoadjuvant? It doesn't seem like there's a whole lot.

That's exactly right. Yes. So unfortunately, for these patients, we think really the competition here is extremely limited. In terms of systemic therapy, we think we're really the main company that's pushing ahead here in a registrational study. So -- and obviously, based on the patient unmet need and the fact that, unfortunately, these alternatives are really not great alternatives.

Is there a thinking as to why there's been just sort of a dearth of innovation in this specific area? I mean, given the severity and the lack of going blind, I mean, these would be seem to be high areas of interest for drug developers, but you seem to be the first that I'm aware of to do any kind of late-stage work here.

Yes. So I think there's probably 2 parts to that, Yigal. So first is here, it's a unique situation, right, where the tumor is located in the eye. So as you can imagine, would a systemic therapy really able to successfully and consistently shrink these tumors in the eye. I think we're fortunate. It's based on empirical data where we believe we're clearly delivering that value. And then second, as a reminder, most of these patients are getting those ocular tumors because of an activating mutation at GNAQ or 11. And our drug is directly hitting that activation mutation through the PKC pathway. So we think based on those two unique aspects, we were, I think, very fortunate. And hopefully, we can bring this to patients as quickly as possible.

Are you able or in a position to give some time lines on these because everyone is super interested. As you pointed out, it's a bigger market. It's an untapped market. What can you say about the time lines with those -- how are those cohorts tracking too, by the way, that kind of tumor?

Yes. So basically, we're going to try to enroll this study in roughly 5 quarters. It's 120 patients in the Enucleation Cohort, 330 in the Plaque Therapy. The Plaque Therapy Cohort, you know Yigal got reduced by 70 patients based on statistical modifications we made related to alpha usage. In terms of the readouts timing, the first we'll get is the eye preservation data. We get that data roughly in about 6 months. Second, we anticipate will likely be the no detriment EFS threshold. And then the last would be around visual acuity, which the first interim analysis would be 18 months from last patient enrolled. So that's the sequence of the event readouts.

So just to be clear, that's 6 months from today or 6 months from a future point, just…

So the 120 patients for the enucleation, let's say, that last patient by 6 months, we should know that last patient's answer. But again, because the threshold is only 10%, right, and the 2:1 randomization here, we should know if we exceeded that 10% threshold, we think relatively quickly.

So there, you have -- I mean, what we've seen in the early data just...

It could be very quick.

Very significant cushion there. And then for the vision, I mean, you talked about at the R&D Day, you talked about the predictive tool. But what other data points or clues do you have that you're going to see that visual benefit because that also is a novel endpoint, is it not for this disease?

Yes. It's a very novel endpoint also as the primary endpoint for an oncology indication. It is, we think, quite unique. In terms of the key data for the plaque therapy cohort and related to vision, one would be the simulation data, both in terms of radiation reduction, predictive future vision. But the data that we shared at ESMO that I do think got people more enthusiastic about this cohort was specifically the actual vision impact we saw during the neoadjuvant treatment before the plaque procedure.

And there, Yigal, as you know, we noted on average across both of the enucleation of the plaque therapy cohorts, we saw a median letter vision gain of 14 letters. That's significant because the endpoint is connected to a 15-letter BBCA vision letter improvement. So if you have a cohort, which would be on treatment, where you're seeing this very meaningful letter gain, but you would obviously not see that. We don't anticipate you would see that in the control arm. We would hope that, that would stack in the favor of the treatment arm versus the control arm. In addition, you would have this dramatically -- at least dramatic effects we're seeing to ocular shrinkage, which should also lead to less radiation.

Yes. And knowing the retina space pretty well, if you get -- I mean, 3 lines, 14, 15 is 3 lines, that's quite significant. That's more than what you see in some of the anti-VEGF trials in the old approval trials for the anti-VEGF. So it's a big -- it's a good number. And then let's talk about adjuvant because that's a newer topic. So what is the structure of that study? And what can you say about how you're going to do that one?

Yes. So we're going to be doing this with our partner, Servier, which is our ex-U.S. partner. We're guiding with Servier to initiate the study first half of next year. We're still finalizing the protocol, but I can help at a high level here. It will likely be roughly about 450 patients. We will most likely target the high and high medium metastatic risk population. Here, most likely randomized 2:1 and here, the primary endpoint being superiority for relapse-free survival. So we're excited to get that study going. This will be irrespective of HLA-A2 status. And at least right now, our view is we think that should be a high probability study based on the fact that we're seeing strong activity in the metastatic setting. Here, I should also mention, we will do this as a Daro-Crizo combo. And then second, we anticipate the treatment duration will be a year.

And Josh, do you -- what about the market size for adjuvant? I mean, is it sort of in between the two you mentioned already? Or how does it shake out?

Yes, it could potentially even be the largest of the three. I think clearly, the goal here is to get patients on therapy earlier, right, so that we can really intervene in disease before it metastasizes to the liver and elsewhere in the body. So I think the combination of the prevalent pool, the incident pool and then the duration that we think we can have these patients on therapy really, when you add these three indications up, it starts to get into the $1 billion [ZIP] code, right? So we think there is a path to this being a blockbuster opportunity.

And so these are patients that had some form of surgical intervention. Could it also be the plaque brachytherapy or not necessarily? Or who -- what is the defined patient population in the adjuvant? Is that correct, that group of patients?

Yes. So the adjuvant patients would be all essentially postoperative. So either post-enucleation procedure or post-plaque procedure. Some may have gotten proton beam radiation, although we anticipate that would be a small [indiscernible].

So they could have had enucleation as well.

It could have, correct.

Okay. Interesting. Just so to prevent the metastatic spread.

Exactly.

So switching topics then over to MTAP and MAT2A. So that's a space which is obviously getting a lot of attention from you, obviously, as well as larger players. So just kind of -- could you just summarize the thinking there as far as what are you doing with MTAP and MAT2A, what's the therapeutic goal? It's, again, a potentially very large market segment? And how are you positioned competitively given it is becoming more of an intensely competitive area.

Yes. So look, we think MTAP-deletion is an exciting opportunity for several reasons. One, Yigal, as you noted, it represents a large patient population, roughly about 10% of all solid tumors, including double-digit prevalence in important indications like lung cancer, tDAC as well as urothelial cancer. We believe this area the core aspect in terms of, we think, success in terms of clinical strategy, we believe will be about implementing rational combinations as well as who can wholly own the key components of those combinations.

And that's where we believe, based on that criteria, we believe we're one of the industry leaders in the MTAP-deletion area with a Phase II MAT2A inhibitor IDE397, a Phase I MTA-Cooperative PRMT5 inhibitor IDE892. And Yigal, as you know, we have a third MTAP program that's now approaching development candidate nomination that we believe is targeting a major co-alteration of MTAP-deletion, which we'll note here at the conference here today, which is around CDKN2A co-alteration. So the co-alteration of MTAP and CDKN2A is the most common, more common than RAS.

And so we think would be relevant not just for combination studies for indications like tDAC, but as well as lung cancer as well as others. So we don't believe there's another company out there that has that diversity of assets. Now we have 2 clinical stage and now our objective in the next couple of quarters will have 3, and we think that will put us in a very unique position within the broader sector.

So this is -- just so we're clear, this is a new statement today. This is we've heard of the CDKN2A program. And how close are you to the filing -- you're close to a development candidate and then the IND would be sometime down the road?

Correct. Yes. So the development candidate, I would say, is fairly imminent. We've made a huge amount of progress. So just maybe context here, we've been doing chemistry well over 4 years. The chemistry is extremely complicated. There isn't another molecule of this profile in the clinic at this time. We have data around combinations that we think are going to be quite important. And then hopefully, an IND towards the end of next year, that would be the goal.

So was this one of these super challenging chemistry exercises like what you've talked about with the Werner Helicase? Or did it not rise to that level? Or was it still tough?

No. Look, I think we have a phenomenal research organization. And it was a very big challenge. But I would say our view is that we made multiple major breakthroughs starting from last year into this year that gives us the confidence to be able to provide this communication today.

And so what would the combos be? Are you saying -- because you have three now. So how would you pair them off? Are you talking about triples or that's all to be determined?

Yes. So I think those are the questions that we'll continue to answer here. But let's just say at a more high-level summary for lung cancer, for example, we think the MAT2A-PRMT5 perhaps checkpoint would be the most exciting, especially when you think about a frontline type study. For tDAC, as we mentioned, the co-alteration strategy, we think could be an interesting one. Obviously, there are PRMT5 perhaps, this third program. There's also obviously thinking about RAS as well. There's different conversations ongoing on that front. Urothelial cancer, obviously, we're doing the TROP-2 combination around this pyrimidine folate pathway. So I think we have several shots on goal here. And depending on the indication, we may prioritize different combinations. But essentially, with these three targets, we feel we've covered our full basis in this whole [indiscernible] area.

And then for -- just can we just run through some of the clinical progress? I mean you've talked about the cohorts for urothelial and non-small cell lung cancer. What's the next tranche that we're going to get out of those studies?

Yes. So we're planning to submit an abstract for presentation at a major medical conference in the first half of next year with Gilead on the Trodelvy combination with our MAT2A inhibitor, IDE397 that will likely be focused in MTAP-deletion urothelial cancer. We may follow that with a second medical conference update in the second half that would focus on non-small cell lung cancer. So that's our I would say, more near-term focus and guidance.

Now here, we're also now in the clinic with our, we think, a potential best-in-class PRMT5 inhibitor. Obviously, there, we could think about monotherapy data. But of course, for us, as you know, Yigal, we're very focused on the MAT2A combo. So can we generate that data quick enough to be able to present data next year. So we'll likely give more visibility on that in January, but we're going to do our best.

So for there, you're still ramping on the dose escalation. What's the -- what can you say that at this point?

Yes. So for PRMT5, basically, our strategy is the following. Once we clear the first cohort, and this has already been okay based on what was in our clinical protocol with the FDA. Once we clear the first cohort, we can start the combination work with MAT2A in the second cohort. We believe in that second cohort based on our preclinical modeling. We should already be at a very efficacious combination dose. So we think we'll be at an active dose quite quickly. We know exactly what dose to use for our MAT2A inhibitor IDE397. So that should also expedite the speed of that data generation. So our view is we should be able to move quite quickly. So -- and we're also cognizant, you may know, Yigal, there's a peer company that's already also guiding to their first MAT2A-PRMT5 combo data in the second half of next year.

And what -- and this is in -- just remind us in which tumors or how broadly are you looking?

So in the escalation, we will look at multiple tumor types. In the combination, we'd like to be as focused as possible in non-small cell lung cancer, which based on our preclinical data, we believe should be the most sensitive tumor type for this compound. And the largest market, we think in MTAP is in non-small cell lung.

Do you have sort of internal thresholds for what's going to be your good enough, go, no go -- I'm not going to tell us that today.

Look, I think we've seen the data from the PRMT5 side and MAT2A, right? So let's just say, roughly in that 20% to 30% response rate, I think durability has ranged. We clearly want to see more than that and to beat the doubling of that, hopefully fairly readily and can we also make a meaningful improvement in durability. I think if you do that, then you got a real shot in a first-line type study with something like a checkpoint inhibitor. And that's the goal here.

Did we ever see the preclinical with your proprietary PRMT5? I mean, we saw the [indiscernible] looked amazing, obviously, but you have your own now. But I don't know -- I don't remember, do we ever see that?

We did publish some data at R&D Day. We will publish more data in the first half of next year at a medical conference. I know abstracts have already been submitted. No, look, it's a great molecule. It was a molecule that was made fit for purpose to be combined with IDE397. And that's the advantage that we have now is that versus sort of just assembling different molecules together, we picked this molecule to be combined with IDE397.

Another -- let's go to another big topic, the Delta-Like Ligand, the DLL3. Again, another space which the competition is ramping quickly. You have a very competitive molecule. So tell us more about it. What makes it competitive? What are the differentiating features? How is it designed? And what's the next step?

Josh?

Yes, we're pretty excited about the DLL3. I mean, we obviously have published data on it at the World Cancer Lung Conference earlier this year. It's obviously focused on small cell lung cancer right now. We think we're seeing really compelling response rates and importantly, durability, at least early days. We looked at data, almost 100 patients worth of data from doses that we think are going to be pretty active, expansion doses well north of where some of our competitors have been. So we think there's a chance to differentiate on efficacy and durability.

And I think a lot of what's driving that is the differentiation between our linker system and those of some of our competitors. So we think we have an ability to dose a little bit higher because of that linker and avoid some of the common tox that you might see otherwise as associated with that. And really, the difference is where that payload is cleaved off, right? [RS] is intracellularly cleaved, whereas our competitor linkers are more tumor microenvironment linkers. So there's a higher chance for some of those off-target tox profiles that you see.

And the types of tox that you're trying to avoid or that you've seen less of or what sorts of things are you seeing less of so far? Or is it too early to make a definitive statement yet?

Look, I think for the ADC side, I mean, it's really around heme tox and blood-related heme tox. So that's been really the primary area of focus. I would say there, we're observing an AE profile that looks very comparable to other approved Topo-ADCs. So I think we're in a really good position from that perspective. And so I think for us now, it's really about optimizing dose and ensuring, especially around where do we get the maximal both confirmed response rate, in particular, in this indication, we think really the core focus is going to be around durability.

And you mentioned going beyond small cell potentially. What like -- I guess, neuroendocrine tumors, right? Would that be a possibility? Or where else could you see the supply?

Neuroendocrine tumors for sure, which is going to be a compilation of different types of neuroendocrine transformations, including pancreatic, colorectal, obviously, components of lung as well, of course, small cell lung cancer. We do think there is meaningful DLL3 upregulation based on several recent papers and publications in melanoma as well. We think that could be interesting. So I think we would like to do sort of an exploratory basket in DLL3 upregulated tumors. So -- but we do think this is an opportunity that extends well beyond small cell lung cancer.

And how close might you be -- I mean, if you keep getting good data here, how close are you going to just go into a pivotal right away? Like what's the -- and you have a dose you've identified, as I understand. So how close are you to starting such a registrational study?

Yes. So we're going to give more guidance on this most likely early next year. In our mind, Yigal, there's really two registrational trials that are of focus for us. So one will be where do we focus a potential monotherapy accelerated approval study. And there, your options include extensive stage small cell lung cancer, possibly in the neuroendocrine tumor space. And we're thinking through that carefully. I think we have been developing that strategy over the last several months, and we'll be prepared to communicate that here shortly.

The second will be where do you focus in small cell, in particular, what does that study look like in frontline small cell. So I think those are really the two focus areas for us. Within that, and especially that frontline small cell, I think it's also going to be about the data we generated on the key components, including standard of care agents like chemo, checkpoint and as you know, Yigal, we're very focused on this IDE161-PARG combination, a, because it's a proprietary combination to IDEAYA. Second, we believe it may have the ability to extend durability, which would position us very uniquely in potentially several indication settings.

And the idea there is to offset or prevent the DNA damage repair along with the ADC. Is that the idea?

Yes, so -- yes, I think that the quick summary there, Yigal, that's essentially correct. So -- but it's really around the topoisomerase payload, as we know, that mechanism is specifically linked to DNA damage repair, unlike other payloads that might be based on mitotic mechanisms. This is specifically around DNA damage repair. So as you know, Yigal, one of the areas that the company has built deep expertise is in the area of DNA damage repair, and we're essentially leveraging that biology expertise.

So we've been looking at various targets in the DDR space that we think can amplify essentially the DNA damage that's delivered by topoisomerase. So we think one of the key targets that can do that is PARG. And now we've validated that preclinically, both in vitro and in vivo in multiple models, multiple cell lines across multiple ADCs. And now we're getting prepared to enable that clinically. So we do think this is going to be a very exciting strategy and also one that can really differentiate us, which is, as you know, becoming a crowded ADC space.

So that's where the PARG is going as this combination. It's not going to do the -- we're not going to do a monotherapy approach. I mean originally, that wasn't clear what was going to happen, right? But now that seems to have been clarified.

Yes, that's correct. And where we've been spending the time in the clinic is really thinking through what is that really optimal dosing approach to maximize the PD while having the most favorable AE profile. Now we believe we've optimized that, and now we're prepared to enable that combination for the clinic.

And you had another announcement. I'm losing track of time, but I think it was yesterday, where you announced a new -- another ADC, the B7H3-PTK7. So tell us a little bit more about that. That target, the PTK7 is less familiar to probably a lot of people. So if you could expand a little bit on the significance of that. B7H3, most people are familiar with. So what is that doing that bispecific? Is it the same linker because you mentioned the linker ability tell us about the design?

Yes. So it's a tetrapeptide cleavable linker. So that's the same. It's a topoisomerase payload, so that's similar as well. I would say what makes this program unique, one, it is first-in-class. So it's the first clinical stage bispecific with the format of B7 targeting both B7H3-PTK7. Second, it's unique in that it's an AND format. So you may know bispecifics either come in an AND format or an OR format, and means it needs to bind to expressing both versus either OR, OR becomes broader activity. Here, what we're really focusing on is amplify the efficacy in the dual expression population. Therefore, you can have a wider therapeutic window and drive greater efficacy in that dual expression population.

And the reason why we picked this program over many other bispecifics that we have evaluated was because the co-expression of these 2 antigens are actually very high in the key priority tumor types for us, including non-small cell and colorectal cancer. This molecule is very active preclinically, and we do see greater efficacy versus those mono formats, B73 or PTK7. So we do anticipate we should see more efficacy versus those mono ADCs in those dual expression areas. And again, here, absolutely one of the core reasons why we brought this in as well because of the ability to do this combination with PARG IDE161.

And you would expect sort of a similar benefit to adding the PARG, whether it's with 161 or with 034. It's the same rationale?

It's the same exact rationale.

Right, right. Okay. You have more. There's a lot.

We do.

So we can try to get 5 minutes in 20 seconds. But I have -- so there's IDE574. This is the KAT6/7 inhibitor. Give us a quick status update on where that is, and it's a dual. So that has some advantages, as I understand, relative to picking just one of those isoforms.

Yes. This is another exciting program. And it's interesting. I was just thinking about this recently. But when you look at the last couple of years, some of these programs that have been hitting kind of multiple targets within the pathway or paralogs have shown some actually quite exciting clinical data, which I think for us, at least further reinforces the strategy that we're taking both in the MTAP space as well as in this area, KAT6/7, which is the mechanism specifically around lysine acetyl transferases, which directly impact a very important area of biology called chromatin remodeling, which we know impacts specifically gene modifiers, which if they're disruptive, unfortunately cause cancer.

Next, we know KAT6 specifically has now been clinically validated by Pfizer. And our view that by having this more broader dual inhibition of KAT6/7, we should be able to enhance the activity, drive greater durability and even a scenario where we may be able to drive efficacy without combining with agents like fulvestrant. And if we're able to do that, clearly, we would widen the opportunity for where KAT6 and Pfizer has really paid the groundwork for. Just quickly here, they did report data in the past, including a median duration response of over a year. So clearly seeing exciting durability, and that was with fulvestrant. So can we show greater efficacy? Can we expand this to other indications beyond breast cancer into indications like non-small cell?

So where would you start with the development, which setting, which breast cancer setting, like you go post-CDK 4/6? Or what do you -- there's a lot of options there.

Yes. I think we would likely -- so the answer is yes, I think there. And also, we would likely mimic what Pfizer has done with KAT6. Here, we would look at it likely with an agent like fulvestrant, but as well as without and try to answer that question directly.

So breast cancer would be the primary focus, and then we would then extend into other indications depending on if we can confirm and validate that data in that setting into areas like lung cancer.

I briefly mentioned the Werner Helicase program, and there's also the Pol Theta program. So let's try to squeeze those in quickly. I think there's been a lot of -- I've been anticipating seeing the first clinical data for the Werner program for a while. I know you had some biomarker data earlier there. What is the latest timing on seeing that? Because that's considered a really interesting pan-tumor target.

Yes. So Werner Helicase for those that may not be as familiar with the target. So this is synthetic lethal with a genetic biomarker setting called MSI-High. We think one of the most important targets in synthetic lethality in terms of the robustness of that synthetic lethal interaction. Here, indications of relevance include gynecological cancers like endometrial cancer, ovarian cancer, and also colorectal cancer.

I would say where some of the past published data on this area, which has not been so great has been in colorectal cancer. And that's where can we drive greater activity in CRC because, as you know, we have a different binding domain and interaction when we don't believe we have that susceptibility with that cysteine 727 binding interaction, which the other molecules do. So that's the question we'd like to answer…

That's in Novartis...

That's both the Novartis and Roche molecule, we believe, has that interaction with that cysteine that our molecule doesn't. And as you may know, point mutations around cysteine is very common and the MSI-High setting, in particular, you have to very carefully monitor around these point mutations because that's really the key liability, we believe, which is why it's hard to treat those patients with targeted therapy. So here, we'll be in coordination with GSK on that disclosure. I would hope we would have some ability to share data on that sometime next year. Here, you would also, at some point, likely consider a checkpoint combination.

And then the other one, the Pol Theta program, we hear less about that one?

Yes. So Pol Theta Helicase, another first-in-class asset. This is all about combining with the PARP mechanism. So just as kind of maybe take 2 steps back. We know when you see PARP acquired resistance in BRCA2 breast cancer, there have been published papers where we've seen the majority of acquired resistance is connected to a backup DNA repair mechanism called microhomology end joining. And within that, we know Pol Theta is Achilles heel.

So here, what you're essentially trying to do is to directly target the main mode of acquired resistance to PARP inhibitors, specifically in indications like breast cancer. So if you can do that, can you enhance the durability? We don't anticipate this program will have monotherapy activity. So we've been in escalation, combination studies have started with GSK's PARP inhibitor. So that's the current status.

Niraparib.

Niraparib. Correct.

And that's under the -- they're going to control those.

They're driving that forward correctly.

Well, we will keep going, but unfortunately, we have to call it there. So thank you very much. I think we covered a lot of ground. So looking forward to the top line readout soon.

Yes. Well, thanks so much, Yigal. Great to see you, and good luck for the rest of your conference. Thank you.

Thank you very much.

Thank you, Yigal.

All right. Great. Hopefully, everyone is connected. Well, I'm Yigal Nochomovitz, biotech analyst here at Citi in New York City. It is my pleasure to introduce the next iteration in our virtual C-suite fireside chat series with Yujiro Hata, who, of course, needs no introduction, the CEO of IDEAYA.

If you guys have questions for Yujiro during the course of the conversation, please e-mail me, [email protected], and I will hopefully see those and relay them over to Yujiro.

So Yujiro, welcome. Thank you. A lot has been happening. You had a great R&D Day at the -- right after Labor Day. A lot of activity at several medical meetings as we well know. So maybe it would be helpful if you could just kind of review maybe some of those key milestone markers with the pipeline. And then we'll move into a discussion across all of the programs, but just that would be a good place to start, I think.

Yes. So first, Yigal, thank you so much for hosting this fireside chat, and thank you to Citi as well. So Yigal, as you mentioned, this past quarter, it probably has been one of our most productive quarters that we've had since the company's founding. As you noted, we had several updates at major medical conferences, including at the World Cancer Lung Conference for DLL3 in Barcelona. We also had an oral presentation at ESMO for darovasertib in neoadjuvant. We also had the Society for Melanoma Research oral presentation at Amsterdam, where we reported our first survival results.

And as you know, our lead program is getting closer to our objective around the randomized PFS results to hopefully enable our first accelerated approval filing in the U.S., which right now is guided from year-end. So we're getting about a month to December to Q1. So we are getting closer and closer to that.

Enrollment is going great. We're almost finished with full enrollment. So that study is also in the process of getting wound down. So I would say we're probably going to be done with full enrollment for the OS, randomized OS as well portion in about a week or so.

Beyond that, we're firing on all cylinders on -- which is continuing to be a growing pipeline, DLL3. We did dose our first patient in the U.S. We're ramping up sites globally to accelerate that. Obviously, a big focus in small cell neuroendocrine tumors as well. And MTAP as well here with our partner, Gilead, on Trodelvy. We picked an expansion dose recently in urothelial cancer. We've dosed several patients already in lung cancer, and that enrollment has been extremely robust. And just as a reminder, as part of our earnings, we did note a confirmed 57% response rate in the MTAP urothelial cancer setting.

Beyond that, our PRMT5 asset is now in Phase I. We got IND clearance. We also filed an IND on our B7H3/PTK7 bispecific ADC as well. So a lot happening and we expect hopefully a very catalyst-rich next several quarters.

Okay. That's a good start. Well, maybe if we could just kind of go big picture first and go through what you sort of see as the opportunity across the uveal melanoma landscape, because as you pointed out, we're looking at metastatic, neoadjuvant, adjuvant. And so if you could kind of just outline the scope of those opportunities and how crowded or not crowded each of those are?

Sure. Yes. One of the areas that we're very focused on is to ensure that darovasertib has the opportunity to be the standard of care across the uveal melanoma patient journey. So Yigal, as we just talked about, we're getting close to hopefully our randomized PFS results for frontline metastatic uveal melanoma. As you know, we launched a second registrational study in neoadjuvant uveal melanoma. And now we're guiding with our partner, Servier, to launch a Phase III randomized study in adjuvant in the first half of next year.

In terms of metastatic annual incidents, we believe this is about 4,000 to 5,000 patients. Prevalence would be higher than that. We're seeking approval in the A2 negative population where there is nothing approved. So we would be a frontline treatment in the scenario we make it to market. We also believe the [ agent ] is going to be equally active in the A2 positive setting. And we do believe we will capture market share in that segment.

For neoadjuvant, that number of annual incidents goes up substantially from 4,000 to 5,000 to at least double that. So we think that's more in the 10,000 to 12,000 range. Here, average treatment duration in neoadjuvant roughly in that 6-month range. And then in adjuvant same thing, 10,000 to 12,000 patients. There, treatment duration, we're anticipating -- or we're discussing with Servier is a 12-month treatment duration. And in the adjuvant setting, we anticipate we'll pursue that with our partner as a daro-crizo combination as well. And also in adjuvant, there's nothing approved, as you know, Yigal. So here, we would anticipate that we'll be randomizing against placebo in the adjuvant setting.

Okay. So I think it would be helpful if you can kind of walk through the neoadjuvant data that you showed at ESMO because there were 2 cohorts. Obviously, the enucleation and the brachytherapy. So what were the key conclusions in each of those? And did they meet or exceed your expectations as far as the endpoints that you're aiming for there?

Yes. So maybe just to table set here, Yigal. We received breakthrough therapy designation from the FDA in the spring based on a good portion of the data that we just shared at ESMO, in particular the enucleation cohort. We shared about 95 patients worth of data. Roughly 60% of that was from the enucleation cohort, the remainder in the plaque therapy.

In terms of eye preservation rate, what's in our current Phase III clinical protocol, which we had alignment with the FDA was we needed to exceed -- or we need to exceed a 10% eye preservation rate with a 95% confidence interval to receive a full approval. So that's our primary endpoint for the enucleation cohort. What we demonstrated is the majority of patients, we are preserving their eyes and getting them off of the enucleation track. So we are obviously well above that 10% threshold for full approval.

For the plaque therapy cohort, the primary endpoint here is around visual acuity, which is a 15-letter BVCA vision test. Here, I would say several pieces of information that were new. First is that we are seeing very -- what we think is a very meaningful vision improvement during neoadjuvant treatment before the plaque therapy. So Yigal, you may recall, at our R&D Day, we noted a median letter improvement during neoadjuvant treatment of 7 letters at R&D Day. And at ESMO with a larger data set, more follow-up. If you pull both of those 2 cohorts, we saw on average, roughly a 14-letter vision gain. So that's a fairly significant jump from 7 to 14 as we went into more patients with more follow-up.

And then lastly, based on the level of consistent and robust ocular tumor shrinkage we're seeing, at least based on visual radiation prediction tools and visual prediction tools, we believe the amount of predicted vision loss is going to be substantially less in the treatment arm versus the control arm. So that's the setup.

As you know, there's also a no detriment requirement of event-free survival, which is going to be a pooled analysis across both cohorts. There's no specific hazard ratio we need to hit. All we've said with the FDA is that they need to be overlapping confidence intervals that we're not doing harm to the patient. And we have publicly noted, Yigal, here that so far, we've seen very few events in the single-arm Phase II study. So we feel good about that no detriment to EFS requirement as well.

Okay. And then given the 10% level that you mentioned with regard to eye preservation and then the 10% to 17% range on the improvement in letters. How are your -- the Phase IIIs, the pivotal structured such that you're well positioned to be better than those or at least in that range for the vision and I presume much better on the eye preservation? Just -- if you could just review the cushion you have on the Phase III to get to those -- that type of efficacy.

Yes. So on the eye preservation one, Yigal, I think that one is pretty straightforward, right? Where it's a 10% threshold, 95% confidence interval, which means you want to ideally be at a 15% eye preservation rate or higher. Here, we're already multiples north of that. So I think that one should be relatively straightforward.

For the plaque therapy, so the way this is going to work is the treatment versus the control arm. We wanted to be able to demonstrate 20% of patients or greater are passing that 15-letter BVCA vision test in the treatment arm versus the control arm. So that's what we need to show to hit our primary endpoint.

So the reason why we feel good about this endpoint is because, as I just noted, Yigal, during the neoadjuvant treatment, the treatment arm patients should have better vision because during neoadjuvant treatment, we're seeing this vision gain that's occurring, which in the control arm, that shouldn't occur. And then second, the patients of the treatment arm should have much smaller ocular tumors because daro is shrinking those tumors and therefore, getting less radiation to the critical eye structures and therefore, less vision loss. So now you have 2 stacking events, right, that should hopefully push it in our favor to be able to hit that primary endpoint.

Okay. And are you -- I mean visual acuity is obviously kind of a gold standard measure. Are you looking at anything else in terms of position of the tumor in the eye or anything related to center versus noncenter lesions looking at retinal imaging, for example? Or is that all secondary?

Yes, those are secondary. So the primary endpoint is around this BVCA 15-letter vision test. We have other secondary endpoints, including response, prevention of macular edema as well as others. So -- but the primary endpoint is this 15-letter BVCA test.

Okay. And then you also reported that apparently a certain percentage of patients had gained over 5 letters consecutively at consecutive visits. Why is that important for people to understand as opposed to not consecutive or over a longer period of time?

Yes. Great question, Yigal. So I know you also track the ocular space. So at least from what we understand, the consecutive visit readout is actually quite important in that -- in the setting of just sort of a visual improvement that it's not just at one time point, but through multiple consecutive visits, they're seeing the sort of consistent maintained visual improvement. So I think that data also improved since our R&D Day. So we're excited to see that as well.

Okay. And just again, on neoadjuvant, the time lines are for data. When is the -- what is the latest statement on that?

Yes. So the way -- yes. So you may have seen that the plaque therapy cohort, we reduced the number of patients we need to enroll from 400 to 330, and that was based on FDA feedback around the statistical plan, and we didn't need to split the alpha between the 2 cohorts. So that's great for us. It makes trial size smaller, which means we can enroll it faster.

So right now, what we've said is that we -- our target at least is to try to enroll this study in roughly 5 quarters. The first data we'll likely see will be the eye preservation data from the enucleation cohort. The second data set would most likely be the no detriment to EFS. And because of that no detriment threshold, we believe with about 35% to 40% of the events, we'll know that answer.

And then the last one is the visual acuity results from the plaque therapy cohort. And that first analysis will be approximately 18 months from the last patient enrolled. So that's the sequence.

And when did this clock start on these 5 quarters?

So we are right now in that process of -- the study has just launched. So essentially right around now.

Okay. All right. Got it. So then usually, when companies talk about changes to power, usually the press release says that they had to raise things, right? In this case, interestingly, it could go in the other direction. So was that -- clearly, you had the buy-in from FDA and you did it. I just -- was that controversial or not? I mean you could have kept it, I suppose, and had more of a cushion, but it sounds like in this case, it simply was not necessary and not a wise use of R&D capital.

Yes, exactly. No, look, I think the FDA collaboration has been great. We're obviously very grateful for them to provide us that feedback that we didn't need to split the alpha between those 2 endpoints. And yes, sort of simple statistics, not needing to split that alpha enabled us to reduce the patient enrollment number.

Okay. So then -- so that's neoadjuvant. And then adjuvant, anything else you want to -- you briefly mentioned the design there. Can you just go into a little bit more detail perhaps on the timelines? And then...

Yes. So here, Yigal, it's going to likely be in that 400 to 450 patient enrollment range. We want to ensure that this study has sufficient power. Second, with our partner, Servier, we did discuss, do we do it as a company sponsor versus a cooperative group? We decided we're going to be able to move a lot faster to do it as a company-sponsored study with Servier. Second, our partner will be side-by-side with us in terms of to ensure rapid enrollment for this trial. Next is that the patient population will be HLA-A2 agnostic. So we're not going to have any kind of HLA requirement here.

In terms of the metastatic risk population, we haven't made the final decision there, but it's most likely going to be the high risk and the high medium risk group. So that's the setup.

And in terms of the control arm, as you know, Yigal, there's nothing approved here. So we believe the control arm will be essentially placebo. This will likely be a superiority endpoint around relapse-free survival.

Okay. So then sort of in the marketplace, if people get daro neoadjuvant, I assume they would not be eligible in the adjuvant to get it again? Or like how does that whole logic work?

Yes. So once commercialized -- so one is, as you know, for the neoadjuvant, it's monotherapy. There will be likely some clear out period, which there typically is anyway between neoadjuvant, you have the primary procedure before you start adjuvant care. And for adjuvant, it would be as a combination. So for the actual trial, I would assume here that we will not let patients that were on the neoadjuvant portion flow into the adjuvant, especially on the control arm side, as you can imagine.

Okay. Makes sense. And then -- so of course, the phase -- well, let's talk then about the metastatic MUM, which we're getting very close, as you pointed out. So I think everyone is very familiar, but just to remind everyone, maybe what is the expectation for control and active for PFS? You mentioned your very close to finishing on the OS enrollment. So can you just talk about when that might potentially be available and whether there be any commentary on OS towards the end of the year? Or that would be a future update?

Yes. So for the PFS here, at least we feel based on historical data, the control arm is going to come in somewhere between 2 to 3 months. We feel the treatment arm, as we reported, most recently at ESMO -- sorry, at SMR as well as ESMO earlier, it was a 7-month PFS. I would hope that it's going to land in that 7- to 8-month range, which would put us in a solid position to hit stat sig for accelerated approval.

In terms of OS, Yigal, as you know, there, we feel the historical data in treatment-naive has been in that 12- to 13-month range. At SMR, we reported a 21-plus month OS. So I think as long as we're in that range or obviously above, we should be in good shape for the full approval OS as well.

Okay. And at this point, are you -- I mean it's November 6. So are you kind of getting -- are you in the database lock portion of this right now? Or are you still -- that is yet to occur?

That has yet to occur. So the events are continuing. So yes, that's still ongoing in terms of the collection of the event. So the database lock has not occurred.

Okay. And the data from Society of Melanoma Research, which was a very good number, the 2021 and change, how does that -- in terms of thinking about how that would work in translating to the Phase III of those patient populations very similar that, that's a good translatability. Can you make that statement with high confidence that, that over 20 months is a good a good proxy for what could occur in the Phase III?

Yes. Look, it's a frontline patient population. I think, Yigal, if I were to sort of highlight one patient baseline characteristics where maybe we might see some improvement was around the ECOG performance status. So as you may recall, from the SMR data we presented, the ECOG performance 1 percentage of patients was about 40%. ECOG 0 was 60%. And the peer company of ours, randomized Phase III, both in their treatment and control arm, the ECOG performance status percent was about half of that. So ECOG 1 was 20% versus 40%.

So I think there, the question is if we had that type of population, might we see some additional benefit in survival? And as you know, Yigal, there is published data on how ECOG performance status does impact things like survival. So that's one for us to watch. But yes, so otherwise, it's a frontline patient population. And otherwise, I would say the patient baseline characteristics are going to be similar.

Okay. And then it sounds like you're not speaking about OS for the myeloma -- for the MUM study, that's not going to be something you're ready to talk about until sometime in 2026. Is that a fair statement?

Yes, when the IDMC looks at the PFS, randomized PFS, Yigal, they will look at OS, but our anticipation is that it's going to be too early.

Okay. Okay. That makes sense. All right. Well, let's move on then to talk about some of the other topics. So IDE397, maybe to start out with just that MTAP deletion market is a very interesting market. What is the commentary there in terms of the opportunity set?

Yes. So for MTAP deletion, this is an indication where there is multiple tumor types that are relevant here. I would say, for us, the tumor types of greater priority for us is lung cancer is one, urothelial cancer, and I would say, PDAC. There are other tumor types as well that we're evaluating. But I would say those are going to be the highest 3 priorities.

And obviously, here, Yigal, as you know, we're 1 of only 2 companies that we're aware of that have 2 clinical assets in the MTAP space, obviously, MAT2A and our MTA-cooperative PRMT5 is now in Phase I as well.

Okay. And what -- if you could just kind of give us a quick synopsis of what you've seen so far with 397 in both the monotherapy and you've shown some combo data as well. And then what is the go-forward strategy there for both monotherapy and combo?

Yes. So for IDE397 monotherapy, we've seen a confirmed response rate in that 25% to 30% range. The expansion initiatives have been largely focused on the lung cancer and urothelial cancer. And now we've shifted the focus to the Trodelvy combination, which is data that we shared at our R&D Day recently. And there, as I noted, at the expansion dose that was selected for urothelial cancer, which is 30 mg once a day with IDE397, that's our monotherapy expansion dose. And Trodelvy at 7.5 mg per kg. And so that's an infusion once every 3 weeks.

And as you know, Yigal, Trodelvy is approved at 10 mg per kg. So it's below the approved dose. And that dose in urothelial cancer, at least right now, it's a small data set, but we're observing a confirmed response rate that's in the 50s. So that's good to see. We're still monitoring durability. But so far, I would say, we've continued to see not just confirmation scans, but continued confirmation even post the confirmation scan. So I think that's encouraging to see.

We're now expanding that work in lung cancer. So we've already dosed several patients there. And then, of course, now our PRMT5 asset is in the clinic. Our plan is to launch that combination work as fast as we can. So based on the starting dose the FDA agreed with us on our PRMT5 molecule, we believe by the second cohort, we should be at an efficacious dose. So -- and we have -- based on the protocol, have the ability to enable that combination once we're in that second dose cohort. So we'll get that moving rapidly. And there, I would say, our #1 priority for that combination will be in lung cancer.

We have other, I would just say, strategies here around coalterations without getting into too many specifics, including in our internal pipeline, which is our third MTAP program, which is targeting, we believe, the largest coalteration of MTAP and that would give us 3 potential clinical assets in MTAP, and we would be very unique in that regard. And then all I could say is we're having other conversations about enabling other coalteration combinations in the MTAP arena at this time.