Alx Oncology Holdings Inc Stock

Greetings, and welcome to the ALX Oncology First Quarter 2026 Financial Results Conference and webcast. [Operator Instructions] Please note, this conference is being recorded.

I will now turn the conference over to your host, Jason Lettmann, CEO. Please go ahead, sir.

Thanks, everyone, and welcome to our Q1 2026 results. I really appreciate you all spending time with us this morning and are looking forward to sharing these updates with you. On Slide 2 and before we start our presentation as housekeeping, here are our forward-looking statements for your review.

On Slide 3, here's the agenda and plan for today. We're going to be providing an update on our key accomplishments in the first quarter of 2026. Most notably, we are very excited to share with you the data set that was presented yesterday in Munich at ESMO Breast 2026 from the analysis of our trial evaluating evorpacept and zanidatamab, which clearly showed again that CD47 expression is a key predictive biomarker for increasing durable clinical response in heavily pretreated HER2-positive patients. This further validates the results we saw with Evo and HER2-positive gastric cancer from our ASPEN-6 trial.

We are also very excited today to be joined by Dr. Sara Hurvitz from the Fred Hutch Cancer Center at the University of Washington, who is a well-recognized expert in metastatic breast cancer. She will be presenting the ESMO breast data in detail and also share her views on evorpacept's significant potential within the current treatment paradigm for HER2-positive metastatic breast cancer.

Our CMO, Barb Klencke, will then recap our findings to date with Evo and HER2-positive cancers across now two different independent trials and indications, showing that patients with high CD47 expression derive the greatest benefit across all key efficacy markers, including overall response rates, duration of response and PFS versus those with low expression. These results support our targeted oncology approach with Evo, notably our ongoing ASPEN-09 breast cancer Phase II trial. Barb will then provide an update from our ongoing Phase I trial with our novel EGFR-targeted ADC, ALX2004, which also continues to track to plan, and we are enthusiastic about its potential to also change care in EGFR-expressing cancers.

So on Slide 4, we continue to advance both our programs, Evo and ALX2004 and are pleased with the progress on both fronts over the course of Q1 and remain well positioned to report on significant data readouts from these programs in the coming 12 to 18 months. On the Evo front, CD47, as you know, is incredibly important in oncology and has been a very difficult target to crack, yet it plays a fundamental role in tumor evasion and resistance. We've been happy to see Evo's differentiated approach to this target further validated in the clinic over now 5 different data sets, including randomized data. Further, the new data from this week's ESMO meeting and over the last year support CD47 as a strong and predictive biomarker. These new findings further support the drug is working as designed and also enables a targeted strategy, which allows us to focus on the patients who will benefit most.

On ALX2004, as you know, it is a highly differentiated EGFR-targeted ADC which was developed in-house by ALX and has the potential to be a first-in-class EGFR-targeted ADC. EGFR has also been a difficult target for ADCs historically, and ALX2004 was designed to address this with a novel epitope and linker payload construct. We have been pleased to see the strong preclinical data to date translate to the clinic and with the continued strong progress in dose escalation, where we have been able to further increase dose. Overall, both programs remain on track and well positioned.

Now on Slide 4, Q1 was a quarter of continued good execution and additional positive data as well as completion of key hires and a strong financing. As you'll hear more about shortly, this week's data validate again the power of CD47 in a late-stage patient population. Here, we observed that all patients who were confirmed HER2-positive and CD47 high achieved a response, including one complete response. We also yet again saw the durability that one hopes to see with an IO mechanism with a median duration of response of 20 months and a median PFS of 22 months, which is clearly far improved over the benchmarks.

While the focus for today will be on this new data set with Evo, ALX2004 is also progressing through dose escalation very well and remains on track for initial safety readout in the second half of this year. We remain as excited here about its potential as we do with Evo. Further, the financing from February, which was anchored by very strong investors, further strengthens the balance sheet and enables us to execute through these important data milestones.

And last but certainly not least, we added Jeff Knight, who is now our Chief Development and Chief Operating Officer, which really further strengthens our leadership team. Jeff, as you may know, is one of the best operators in biotech in terms of building companies at our stage through the next phase, including commercialization.

On Slide 6, briefly, this just highlights the execution, clinical development progress and time lines, which remain on track for both programs. Our evorpacept Phase II breast trial continues to progress well with strong enrollment globally and increasing site enthusiasm. Overall, clinical time lines remain on track as we're expected to read out 80 patients mid next year. ALX2004, as I mentioned, is also progressing well with enrollment and dose escalation ramping and are on track there for an initial safety readout in the second half of this year. Our goal and vision for both of these programs also remains unchanged as we aim to have both programs ready for registrational studies by end of next year.

On Slide 7 and my last slide, here is also a snapshot of our clinical pipeline. As you know, we're advancing 2 novel cancer treatments with key near-term catalysts. And again, ASPEN-Breast is on track. And we continue to also be encouraged by our ongoing study with our partner, Sanofi, testing Evo in multiple myeloma. Our two studies in HER2-positive cancers have now been completed as we'll focus on today and ALX2004 also remains on track.

I'd like to now turn the call to Barb, who will provide a quick reminder of our MOA, which is very important as we're clearly seeing it translate to the clinic, and we'll then turn the call over to Dr. Hurvitz to review the new data. Barb?

Thank you, Jason. These next few slides describe evorpacept's mechanism of action. What's so compelling to me is that the mechanism of action is entirely consistent with what we see in the clinical trials. So let me just go through this. Cancer cells commonly upregulate CD47 expression to evade immune detection. Evorpacept blocks the CD47 signaling, but it does so without an active Fc domain. So evorpacept by itself does not engage the phagocytic activity of a macrophage. We need to combine evorpacept with an anticancer antibody. And then the combination together strongly augments the ADCP activity of the antibody. And that's likely what results in the efficacy that we see in the studies that we'll talk about today.

Essentially, the antibody stimulates the eat-me signal, and the evorpacept inhibits the don't eat me signal. Therefore, the combinations of evorpacept with an antibody are selectively enhancing or augmenting macrophage phagocytosis of cells that express HER2, for example, in the case of a HER2-targeted antibody while also blocking the don't eat me signal.

On the next slide, we see how this mechanism of action translates into safety. Our clinical safety database is now more than 800 evorpacept-treated patients. And it also -- the clinical safety data is also entirely consistent with this mechanism of action that we show here. Evorpacept was designed again without an active Fc domain. That's shown on the right side of the slide.

So when we block the don't eat me signal on normal healthy cells, such as red blood cells, there is no macrophage activation, and we avoid on-target toxicities. This is really fundamentally different than what's been tried in the past by conventional CD47 inhibitors, which have essentially failed in the clinic. They attempted to use CD47 as a tumor-associated antigen with both an active Fc domain to activate macrophage at the same time of blocking CD47. That ended up being an indiscriminate approach because CD47 is so widely expressed on healthy cells, especially hematologic cells in particular. And that led to the potential for significant on-target toxicity.

So with that description of evorpacept, its mechanism of action and its differentiation, let me now turn the conversation over to Dr. Sara Hurvitz. On Slide 12, you can see her background here. She is a steering committee member for our ASPEN-09 Phase II study of evorpacept in HER2-positive breast cancer patients. She was an investigator on the evorpacept and zanidatamab trial that we'll discuss today. And she's a Senior Vice President, a Professor of Clinical Research and the Director of the Clinical Research Division at the Fred Hutch Cancer Center at the University of Washington in Seattle, where she's also the Head of the Division of Hematology and Oncology and the Smith Family and Dow Chair of Women's Health. She's an expert in the management of breast cancer and in the development of novel targeted therapies for breast cancer. Sara?

Thanks, Barb, and really excited to be here today. There have been remarkable changes in the management of HER2-positive breast cancer, especially since 2020, with new agents like trastuzumab, deruxtecan and tucatinib demonstrating benefits in pretreated disease. And with the results of DESTINY-Breast09 showing benefits with T-DXd in combination with pertuzumab, we have a new standard of care according to our NCCN guidelines as of this February. What we don't know is how we should be treating patients after they've received ENHERTU. This remains an area of unmet need.

On Slide 14, you can see this graph showing the outcomes that we have from patients who've received prior ENHERTU treatment with a median progression-free survival of only 4.1 months. What we don't have are randomized prospective data telling us as clinicians how we should manage patients after T-DXd, but observational and retrospective data sets are fairly consistent, showing that PFS rates of under 6 months is what patients experience post T-DXd.

On the next slide, on Slide 15, you can see the list of HER2-directed therapies that we have approved and in late-stage development on the left side. These include HER2-targeted antibodies and bispecifics, HER2-targeted antibody drug conjugates and HER2-targeted tyrosine kinase inhibitors as well. What we don't have are immuno-oncology therapies approved or in late-stage development outside of evorpacept. And so this remains an area that's very exciting to see developed now.

On Slide 16, you can see the range of CD47 expression in normal cells versus tumor cells. As explained before, CD47 is expressed on all cell types and is a marker of cells and cancer cells can take advantage of this by overexpressing CD47, allowing them to hide from the immune system. Focusing on the left there, you can see highlighted in blue, breast cancer cell lines, which actually do have higher expression of CD47 in tumors compared to normal, which is highlighted in black.

On Slide 17, you can see a meta-analysis of 38 cohorts across 17 publications, which included over 7,000 patients, demonstrating fairly consistently that CD47 overexpression was correlated with shorter survival in patients with cancer. So it's a negative prognostic biomarker.

On Slide 18, there are data here relating to CD47 expression in breast cancer, in particular, in HER2-positive breast cancer. On the left, you can see that CD47 expression is higher on HER2-positive breast cancer cells versus HER2-negative on the right. High expression is denoted in the dark blue, moderate expression in green and low expression in blue. So HER2-positive breast cancer cells appear to have a lot more CD47 expressed than HER2-negative breast cancer cells.

And in fact, if you look on the right side, you can see that CD47 high cells are more common in recurrent HER2-positive breast cancer shown on the left side compared to primary or initially diagnosed breast cancer. And so these data provide strong rationale for us to be evaluating evorpacept in HER2-positive recurrent or metastatic pretreated disease. On Slide 19, you can see some elegant data demonstrating that T-DXd treatment may actually upregulate expression of CD47, again, providing strong rationale to treat HER2-positive recurrent T-DXd pretreated breast cancer with evorpacept.

On Slide 20, you can see the title slide for the data presented recently at ESMO breast. This is an exploratory biomarker analysis from our Phase Ib/II trial of zanidatamab, a HER2-targeted bispecific in combination with evorpacept in patients with HER2-positive metastatic disease.

Slide 21 gives you an overview of the study design. This is a Phase Ib/II study, and we presented the safety dose escalation cohort data from 3 patients with HER2-positive breast cancer enrolled and data from Cohort 1, where 21 patients with HER2-positive breast cancer were enrolled who had received at least 3 prior regimens. The exploratory biomarker analyses focused on these 24 patients, and it's notable that all of the HER2-positive cohort received prior T-DXd and a median of 5 prior lines of HER2-targeted therapies. This is extremely heavily pretreated disease. The patients were allowed to enter the study based on prior local HER2 testing of their archival tissue. However, fresh baseline biopsies were obtained in most patients and tested retrospectively for HER2 status by central assessment. And we will be reviewing outcome results based on the central assessment as well as the intent-to-treat population.

In addition, patients' tumors were tested for CD47 expression on the fresh baseline tumor biopsies or on archival tissue if fresh biopsies were not available. Patients were treated with zanidatamab at 1,200 milligrams for those patients weighing less than 70 kilograms and at 1,600 milligrams for patients 70 kilograms or greater. The evorpacept was given at 20 mg per kg for these 3 patients enrolled in the Ia or at 30 mg per kg IV every 2 weeks for the rest of the patients.

Going on to Slide 22, we're jumping to the efficacy outcome data. What you can see here are the confirmed objective response rate on the top row based on all 24 patients, which is 33%. I find personally these data to be quite impressive in patients who've received a median of 5 prior lines of therapy, including T-DXd. If you go down to the duration of response, those patients who experienced a response had a duration of response of 20 months and a median progression-free survival of 3.6 months.

The next column shows the outcomes for the 6 -- excuse me, for the 10 patients who had centrally confirmed HER2-positive breast cancer, where the objective response rate was now 60%. The duration of response was 20.2 months and the median PFS was 8.3 months. These data, I think, are impressive as we reflect back on the fact that our retrospective and observational data suggests that patients pretreated with T-DXd have a median PFS of less than 6 months. So I find these data to be quite compelling and exciting. Those patients who did not have centrally confirmed HER2-positive disease had a lower objective response rate of 14%.

On Slide 23, we can now see breakdown based on the tumor CD47 expression levels. Using a cutoff of at least 20% for CD47 expression, there are 5 patients who had both centrally confirmed HER2-positive disease and CD47 positive or greater than or equal to 20% expression. All patients had an objective response in this cohort of 5 patients with a median DOR of 20.2 months. However, those patients whose CD47 expression was less than 20%, that's 4 patients, only one had an objective response. So this is beginning to give us data that CD47 expression level may be a marker to help us select patients particularly responsive to this targeted therapy.

On Slide 24, you can see a Kaplan-Meier curve for progression-free survival based on CD47 expression levels. So the progression-free survival with the CD47 expression level of at least 20%, you can see the PFS is 22 months for those patients less than 20% of the PFS is 3.4 months. Again, although these numbers are very small, we're talking about 9 patients total. The data are quite interesting, and I'm excited to see them hopefully confirmed in the larger study.

On Slide 25 are our conclusions for this exploratory analysis of our Phase Ib/II study. Evorpacept and zanidatamab showed promising antitumor activity in patients with heavily pretreated HER2-positive metastatic breast cancer, median of 5 prior lines of therapy, all of whom received prior T-DXd. Greater antitumor activity was seen in patients with centrally confirmed HER2-positive disease. Durable responses were seen in this patient population and seem to be largely observed in patients with higher CD47 expression, supporting a CD47dependent HER2-driven biology that resulted in this prolonged progression-free survival.

It's notable that most patients with centrally confirmed HER2-positive disease remained HER2 amplified at progression with T-DXd, supporting the continued use of HER2-targeted therapies. And so a biomarker-driven approach incorporating CD47 may optimize patient selection for this combination regimen and warrants further study.

So with that, I will turn it back over to Barb.

Thank you, Sara, for that excellent presentation. As we've seen, all of the patients who were centrally assessed as HER2-positive and who overexpressed CD47 in their cancer cells achieved confirmed response to the combination of evorpacept plus zanidatamab. What's new on Slide 27 in the table on the right side of this slide are the individual CD47 expression levels and the confirmed response assessments for each of the 10 patients with centrally assessed HER2-positive disease. An IHC assay was used to quantify the total membrane staining for CD47. A positive result was defined retrospectively as a score of 20% or higher, which we observed in the patients shown in the top 5 rows highlighted with deep blue.

All 5 of these patients with CD47 expression responded, including one patient with a complete response. That patient happened to be the only patient from the dose escalation cohort that was centrally assessed as HER2-positive. There was no evidence of CD47 overexpression in the 4 patients highlighted in light gray, one of whom responded to the evorpacept and zanidatamab combination. And then in the last row in this table is a patient who was unevaluable for either response or CD47 expression level.

On Slide 28, I want to highlight the consistency that we see between the results of the evorpacept, zanidatamab trial in HER2-positive breast cancer patients and in the previously reported HER2-positive gastric study. On the top half of the slide, you'll see the data that we've just reviewed. This includes a 33% response rate in the 24 patients enrolled based on archival HER2 status, the 60% response rate in the 10 patients centrally assessed as HER2-positive and the 100% response rate in the 5 patients who were also CD47 overexpressing.

On the bottom half of this slide, you see the data from ASPEN-06. This is a randomized Phase II study of evorpacept, trastuzumab, paclitaxel and ramucirumab versus the TRP regimen alone. Here, you see the response rate climb as we look across the slide at the same subset. In the ITT, the response rates in patients randomized to the evorpacept arm was 41%. Response rate was over 49% in the patients that retained HER2-positive disease, and it was 65% in patients whose tumors also expressed CD47. And recall, this was a large Phase II study of 127 patients. As you see, the data trends here are consistent across these 2 independent trials of evorpacept when combined with a HER2-targeted antibody.

On Slide 29, I'm again showing the results of the Evo-Zani study on the top and the ASPEN-06 HER2-positive gastric study on the bottom. The graph -- these graphs show the duration of response in the subset of patients who were HER2-positive and CD47 overexpressing in the 2 independent studies. The duration of response was remarkable in both settings at 20.2 months and 25.5 months, respectively.

On Slide 30, the same consistency across the 2 independent studies as seen with the PFS results in the subset of HER2-positive CD47 high patients. Both studies show a remarkably long PFS, especially in light of the later line settings for both indications. On the left, we see the median PFS for these patients in the evvorpaceptzanididatinib study of 22.1 months, while the median PFS for those without CD47 expression was only 3.4 months. And then in the gastric study, shown on the right, the median PFS was 18.4 months for the patients in the evorpacept arm and the hazard ratio in this subset in the randomized trial was 0.39.

So these data are really why we're so excited about moving forward with the development of evorpacept in HER2-positive breast cancer. Slide 31 shows our ongoing ASPEN-09 study in the HER2-positive breast cancer setting. Like the zanidatamab-evorpacept study population, all of these patients will have had to have had prior in HER2. This is going to -- this is a single-arm study that will enroll up to 120 patients and has a primary endpoint of response rate in the subset of patients who overexpress CD47. We're making very good progress with enrollment, and we're very much on track to achieve our stated milestone of having interim top line data from approximately 80 patients by the middle of 2027.

On Slide 32, we show the market opportunity. Ultimately, our aim, of course, is to bring this drug to market. We estimate that there are approximately 20,000 addressable patients who are HER2-positive and overexpress CD47, representing a $2 billion to $4 billion market opportunity in the United States, the 5 major European markets and Japan.

I'm now going to turn for the last few minutes of this talk to our second molecule. Slide 34 shows ALX2004, our EGFR antibody drug conjugate. This is actually a very unique molecule. It was designed by protein engineers and cancer biologists within ALX. EGFR is obviously a very validated target, but it's been very difficult to target EGFR in the past with an antibody drug conjugate. We selected amituzumab-derived EGFR antibody to minimize off-tumor skin toxicity and to maximize the therapeutic window. Also, the epitope is distinct from that of FDA-approved EGFR antibodies, minimizing the likelihood of resistance to prior EGFR antibody treatment.

The proprietary linker allows for liposomal cleavage of the linker payload like other deruxtecan ADCs, but the stability of the linker antibody has been enhanced to minimize systemic payload release. The molecule also contains a proprietary TOPO1 inhibitor payload. It has an antibody drug ratio of 8, and the payload has similar direct cytotoxic potency, but it has enhanced bystander activity compared to deruxtecan.

On Slide 35, we show the Phase I design. This is an ongoing study, and the study is designed for dose escalation, dose exploration and expansion cohorts. The study is limited to patients who have lung cancer, head and neck cancer, colorectal cancer or esophageal cancer as EGFR expression is higher in these indications. And in this study, we're also making very good progress with enrollment. We are certainly on track to achieve our stated milestone of reporting initial safety data within the second half of 2026. We previously publicly released information that we began dose escalation at 1 milligram. We then said we escalated to 2 milligrams. And then we announced that we had escalated to 4 milligram per kilogram dose cohort. But as we advance the enrollment and dose escalation in this trial, we are now shifting from providing granular updates to reporting initial safety data in the second half of 2026.

And I'll now turn the presentation back to Jason.

Thanks, Barb. And also a big thank you to Dr. Hurvitz for joining us today to share her views.

At ALX, we're advancing 2 novel cancer treatments with key near-term catalysts that have the potential to be both best-in-class and first-in-class in change care. And with this new data today, we have now demonstrated in 2 studies in 2 HER2-positive cancers that EVO is a very active drug and that a CD47 targeted approach can drive transformational benefit to patients. And again, although not the focus for today, we remain as excited about the potential of our EGFR-targeted ADC, which is also progressing quite well.

We now have a stronger balance sheet to fully execute through key milestones over the next year to 2 years, and this really sets us up well for further execution and further catalysts. In sum, Q1 was a strong quarter for us in terms of new data, new leadership within our team and a new financing. So the message for today is one of building momentum as our conviction in both programs remains high, and we're looking forward to additional updates very soon.

With that, I'll turn the call back over to the operator for questions. And again, thanks again for the time this morning.

[Operator Instructions] Our first question will come from Michael Yee with UBS Securities.

Congrats on the updates and progress. This is Kyle Yang for Michael Yee from UBS. Two for us. The first question for management. So congrats on the data today. So for your upcoming interim data readout in mid-2027 from your ongoing Phase II ASTENBreast study, what would you say is compelling results in terms of ORR and also DOR? And do you plan to put out data on NPFS? And what would be good data for MPFS? The second question for Dr. Hurvitz, could you please help us understand how do you plan to use this drug in the clinical setting if this is approved? Do you expect to test everybody for CD47 expression?

Great. Thanks, Kyle. Appreciate the question. So yes, on the first one, and I'll let Barb weigh in as well. I think we've been very pleased with enrollment to date on our breast study. It's going quite well. Certainly, this data, which we've been able to share just over the last couple of months with the investigators has furthered that enthusiasm. So I think as Barb highlighted well in her comments, feel very good about our time lines and delivering really meaningful data mid-'27. But Barb, do you want to weigh in more on just what we hope in terms of durability and PFS at that time?

Yes, absolutely. Well, as Dr. Hurvitz said, most of the available therapies are not producing very good outcomes for patients after ENHERTU. Much of the data suggests that the response rate may be 15% if you were to receive a trastuzumab chemotherapy treatment alone without evorpacept. So a 30% response rate would be a doubling of what we would expect to see without the evorpacept. So I think anything north of 30% would be a very, very good outcome with a duration of 6 months plus. As you've seen in the data that we reported previously, one of the things that's so compelling about evorpacept is that when we see a response, we see a very good duration of response.

By middle of 2027, I think the duration of response will be pretty preliminary. So I'm expecting that with 80 patients worth of data that we can assess response rate pretty well. Duration of response may be somewhat truncated, but I would hope to see somewhere in the range of 6 months plus with immature data. And I would think that PFS might be too immature to report, but it really depends on the continued progress. So we'll have to see.

Yes. And Dr. Hurvitz, whether you have comments on your expectations for the ASPEN-09 data or in particular, the second part of the question about the role of CD47 testing in the clinical practice if evorpacept is able to get to market.

Yes. Thank you, Barb. I fully agree with your -- what you stated about the ASPTEN-09 study. I mean I think seeing anything around 30% objective response rate and a PFS of 6 months would be pretty important in patients that heavily pretreated. So I echo your comments.

In terms of the additional question regarding how we would use CD47 expression, I think this is something that's really very compelling and interesting. And the ASPEN-09 study is going to allow patients, as Barb stated, with both CD47 low and high tumor expression so that we can validate these data. We have to keep in mind, it was a small number of patients, but the data were really pretty interesting and compelling. So if CD47 is validated as being a predictive marker for benefit from evorpacept, then I do think we will be probably seeing it developed as a companion diagnostic. But it's too little data at this point to see -- to make that statement definitively that that's how we'll be doing -- using it.

I've been treating breast cancer patients for over 20 years. And the data with ENHERTU were really exciting when we first saw them come out in 2019. I feel that same flurry of excitement seeing these data because it's pretty tough to treat patients post T-DXd now. Their progression-free survival, their duration of response to the next line of therapy is pretty short. And so these data provide patients a lot of hope. So I'm excited to see the data validated just taking into consideration that it is a small number of patients.

Our next question will come from Derek Archila with Wells Fargo.

Congrats on the update here. Just a few questions from us. I think, first, you alluded in the prepared remarks, but just remind us the population in ASPEN-09 and then how it compares to some of the patients from the update today, that would be helpful. And then just 2 quick ones. So I think you mentioned the 20,000 patients CD47 high post HER2. So does that assume greater than 20% CD47 expression? Or I just want to make sure the cutoff is the same? And then with the data here and the proof of concept with the zani combo, I guess, how do you think about further developing this?

Yes, sure. Those are great questions. Thanks, Derek. So I think in terms of the population that we're studying now, it is this population. That's what I think really derisk, if you will, this current study. I think as we walk through today, this is a late-line breast population. 100% of the patients in this cohort had seen prior in HER2. On average, it's seen 5 prior lines of HER2-directed therapy, et cetera. So I think the beauty of this design that we're pursuing now is it's effectively the same. So I do think that definitely contributes to our confidence in this study.

Then on the second question, and I can have Barb weigh in on this. I think we do know from the literature, we expect that the expression profiles to be will be different across different tumor types. That's certainly what we've seen when we look at breast and gastric. But again, I think what's so encouraging is that there's just a lot of room here in terms of choosing a cutoff, if you will. So Barb, do you want to speak to that a little more?

Yes. I think one of the most important things about what we will understand with the data from ASPEN-09 is what's the optimal cut point? Where on the total membrane staining scale, would we see the greatest differential between high response rate in the CD47 positive versus CD47 low. And it's likely to be a continuum, and we're likely to be able to not see a cliff where it's crystal clear. What we've seen in both the gastric and the breast study, though, is we're seeing about half of patients overexpress CD47. At least in our gastric study with a larger sample size, we shared at SITC in the fall of 2025, a variety of different cut points that range from 45% to 57%.

Gastric may be different than breast, though. And so with the Zani data, we have just such a small number of patients. So -- but what we saw in the Zani trial, again, about 50% were CD47 high. One of the biggest reasons we increased the sample size from 80 to 100 is just so that we could get more data because this point exactly what is the cut point? How does it differentiate response rates? And what does it do to the population in terms of potential commercial opportunity balanced against finding the best treatment effect for patients is a really important question.

So ASPEN-09 will help us optimize the cut point. My best guess today is it will be somewhere in the range of 50%, 60%, 70% of patients could be CD47 overexpressing, but we'll see. What also, of course, are the 2 slides that Dr. Herwitz showed where the rates are higher in patients who have more advanced disease. They are higher in the cell lines post ENHERTU, and they are higher in patients who are HER2 positive. So it could even be higher than 50%. We'll learn a lot from the ASPEN-09 on that exact question.

And I think your last question, Derek, just on zani, a couple of comments there. I think, one, really pleased with the partnership with Jazz and what we're seeing here for patients. I think no question that very strong activity with this combination. The second thing, and I think why it's important to look back at our mechanism is EVO works in combination with an Fc active antibody, and it was designed to do so. And so I think what's really promising about the totality of the data is whether we're combining EVO with TR, with zani, with Rituxan, with an anti-CD38 like Sirclisa, we see activity. And I think that's right on mechanism. And so for us, taking the combination of Evo plus going forward makes sense. Again, it's the exact same combination that we utilized in our ASPEN-6 study, which is a randomized study, as you know. So I do think that gives us a lot of conviction here going forward.

Moving next to Allison Bratzel with Piper Sandler.

This is Ashley on for Ali. Just two questions from us. So just curious to learn what's the latest on the companion diagnostic development. I know you guys have talked about this on previous earnings calls. So just looking for some updated thoughts there. And also just based on the data today and this data set, it looks like the CD47 biomarker strategy is being further validated. So does this impact the statistical powering at all for ASPEN-09?

Sure. That's great question. Do you want to go on the CDx front, Barb?

Yes. Sorry, Jason. Yes, the Ventana laboratory is our partner. We are working right now on developing a companion diagnostic. What we want is by the time we are finishing the full data set of ASPEN-09, as I alluded to earlier, setting a cut point that could then be available for preselection of patients potentially in a Phase III trial. That's our base case assumption is that our Phase III would be in selected patients. So we will have an assay available. And then if that Phase III study is positive, of course, then we would work with our Ventana partner to not only bring evorpacept to market, but to ensure that the companion diagnostic were then commercially available.

In terms of statistical powering -- go ahead. Go ahead, Jason.

No, go ahead, Barb. I just -- I mean, to kick that off, I mean, I think, of course, we're not going to power the study at 100% ORR, and that's not what we're going to do. And I think -- but if you look at the beauty of a targeted approach, I think it allows and our hope is it will allow a much more targeted Phase III where we can run a tighter registrational study with assumptions that I think are reflective of what we've seen, which has been a really strong spread, if you will, both in terms of ORR as well as DOR and PFS. But go ahead, Barb, I know I cut you off there.

No, no, that's exactly right. I think with a single-arm trial, ASPEN-09, the statistics are really around estimating the point estimate of the response rate and narrowing the confidence intervals with a larger sample size. But what ASPEN-09 does is it allows us potentially greater precision with this larger trial of 120 patients such that we can then have a lot of confidence walking into a Phase III subsequently and really understanding the treatment effect in patients based on their CD47 status.

Moving next to Li Watsek with Cantor.

This is Daniel Bruner on for Li Watsek. We have a couple, one more technical and then one regulatory. We'll start with the technical one. On the poster from ESMO breast, you have the concordance of HER2 amplification by ctDNA and FISH. I was just curious how that translates into HER2 positivity in IHC. And then on the regulatory front, you mentioned registrational trials a few times in your opening remarks and in the previous response as well. Does that mean you're ruling out a potential accelerated approval based on ASPEN-09? Or are you keeping optionality here?

Those are great questions. Go ahead.

I'm sorry, I should stop doing that. And Dr. Hurvitz, I'll have you make some comments after I'll address the regulatory one first, give you a chance, but I'll have you talk a little bit to the HER2 data that was in the poster. So the regulatory strategy, Jason said a few minutes ago that we do not have an expectation that we could replicate 100% response rate. That's -- that would be fabulous if we could. And if we do, I think absolutely, we would talk to the health authorities, U.S. FDA about an accelerated approval strategy. I just think that, that is such a high bar, and we're also very, very aware that an advantage for patients would be anything north of, say, 30%. So we'll just have to wait and see what those response rate -- what the response rate is in ASPEN-09.

I think regulatory approvals for single-arm trials when you have a combination of two agents, very difficult to get an accelerated approval. It's also true that it's very difficult to get an accelerated approval with retrospective application of a companion diagnostic. We would need at least some additional prospectively selected patients. So there are a lot of regulatory considerations. But I think at this case, that is not our base case. Our base case is that a Phase III trial will be required because the bar is high for accelerated approval, but we'll just have to wait and see what the response rate is. If it's extraordinary, we'll talk about it. If it's somewhere north of 30%, but less than 100%, it's going to be an uphill battle. But obviously, that would benefit patients if we could bring it to market sooner, but we'll wait and see. So maybe I'll flip it back to Dr. Hurvitz to talk a little bit about some of this HER2 data in the poster.

Yes. Thank you, Barb. The HER2 data is actually kind of interesting. So there are 2 aspects. First, there was a difference in the central confirmation of HER2-positive disease that was shown in the poster where 10 of the patients out of the 24 were noted to have centrally confirmed HER2-positive disease and 14 were not. And I would just call out that this is not uncommon. It's been reported in other studies that there is discordance. And it may not necessarily mean that there's been HER2 loss that's occurred over time. It may actually be related to artifact from testing older tissue.

It's important to keep in mind that in order for patients to enroll in the study, HER2 status was based on archival tissue that was read locally. But once they got on the study, the assays that were done were done on fresh biopsy samples obtained at the start of the study from most patients, and those were tested centrally. And so the testing changed from local to central and also from archival tissue to fresh tissue after in HER2 for the vast majority of subjects. So either of those factors could have contributed to the differences between local HER2 positive results and central positive results.

Another point was in the poster in Table 2, there were some data presented looking at concordance between HER2 amplification status by the central tissue-based FISH as well as plasma ctDNA next-generation sequencing. And it's important to call out that of the 6 patients with HER2 amplification by FISH -- or excuse me, the 7 patients, 6 of them were also noted to have amplification by ctDNA. Just one of the patients there did not, and that may have just been due to the fact that there wasn't enough circulating -- there was a low tumor fraction. It was below the threshold of expression. But those that were negative centrally by FISH were also negative by ctDNA. And so that's reassuring and provides sort of validation that the central HER2 amplification is correlating well with circulating tumor DNA.

We'll go to our next question from Roger Song with Jefferies.

Congrats on the positive data and excited about the momentum going into ASPEN-09. Maybe two from us. So you previously mentioned we're seeing roughly half of HER2-positive patients being CD47 high. As we're into the early ASPEN-09 screening, is the observations you're seeing consistent with that half of HER2-positive patients being CD47 high? And then is tissue adequacy and turnaround time any potential gating factor here for enrollment?

Yes, sure. Good question. So I think on the ASPEN-09 front, of course, we're going to monitor that closely. And then in terms of the disclosure, we'll wait and disclose that when we get to the data readout on 80 patients. Obviously, I think it's something that's important, and we're able to monitor really quite quickly. So the lag has not been a concern. And of course, I think our team is focused on that. But Barb, do you want to add anything there?

Only that the ASPEN-09 study enrolls patients irrespective of CD47. So there is no urgency in terms of the turnaround. You're absolutely right that it would be something that we need to ensure that we work through those processes. for a future Phase III, assuming that, that future Phase III requires GD47 overexpression for entry. But this study does not. So the urgency is not there. But as Jason says, we're not going to disclose prevalence rates or any of the biomarker data until we come out with data in the middle 2027.

Moving next to Sam Slutsky with LifeSci Capital.

This is Oliver McCannon on for Sam Slutsky. So in the Phase Ib/II breast cancer study, you defined CD47 high as total membrane staining of 20% or greater. And in the past, you talked about 10% or greater IHC3+ as being a cutoff for CD47 high. Can you just discuss the nuances of the 2 cutoffs used and the selection process?

Sure. Thanks, Oliver. Again, I think Barb hit on this, but we fully anticipated even ahead of this data that the expression profiles would be would be different. There's, of course, a lot of similarities between HER2 positive tumor types. insofar as typically a drug that works in one will work in the other. That said, I think there will be a difference in expression, and we're seeing that here. And again, I would just highlight that if you think about defining a cutoff when you see ORR as high as we're seeing across both of those studies, it suggests there's probably many different right answers, if you will, in terms of the cutoff we could use. But Barb, do you want to expand on that?

Just in terms of total membrane staining and how that's calculated. So the proportion of cells that are 1 plus are multiplied by 1, the proportion of cells that are 2 plus IHC stain staining intensity would be multiplied by 2 and so forth. So IHC 3, multiply the proportion of cells that are IHC 3+ by -- and then you add those. So it's a cumulative total. So if I were to look at the threshold for gastric 10% or more of cells being 3 plus, that would potentially be about a score of 30. It may be that different labs and slightly different methods. But to put it in context, it's similar, but it's cut point was a little bit lower in the zanidatamab trial. It was zanidatamab-evorpacept was a very small trial. So we will look again once we have data from ASPEN-09 and optimize that. So it may change. In fact, that likely change much, much sample size, but technically we are doing it. And we modified the once we start work towards development with our partners at...

And this now concludes our question-and-answer session. I would like to turn the floor back over to Jason Lettmann for closing comments.

Great. Thanks, everybody. It was a strong quarter for us. I appreciate all the engagement here today. Both programs, as we mentioned, are on track and super excited about what we're seeing in both. So again, I appreciate the questions and support and looking forward to future updates. Enjoy your Friday and your weekend. Thanks so much.

Ladies and gentlemen, thank you for your participation. This does conclude today's teleconference. You may disconnect your lines, and have a wonderful day.

Greetings, and welcome to the ALX Oncology Fourth Quarter 2025 Financial Results Call and Webcast. As a reminder, this conference is being recorded. I would now like to turn the call over to your host, Jason Lettmann, Chief Executive Officer. Thank you. You may begin.

Thank you, and welcome to our Q4 and fiscal year 2025 results call. Appreciate you all spending some time with us this morning. As usual, we will be making forward-looking statements during the call, so please refer to our FLS slide in our corporate deck. With me today, we have Harish Shantharam, our CFO; as well as our CMO, Dr. Barb Clinkke. And in terms of the first bit of news, we're delighted to announce today that Barb will continue leading our clinical efforts as our permanent Chief Medical Officer. Welcome, Barb. As many of you know, after joining in an interim capacity in September 2025, Barb has been absolutely instrumental in driving our development programs forward over the last 5 months. Barb, as many of you also know, is an incredibly experienced oncologist and drug developer, having served as CMO at Sierra Oncology and having senior roles at both On-X and Genentech before that. We're beyond fortunate to add Barb during this critical inflection for the company and thrilled to welcome her permanently. And I'll turn it over to the call -- turn the call over to her later today to walk through some of our clinical updates. In terms of the agenda and the goals for today, we will review our key Q4 2025 and year-to-date accomplishments, referencing our press release and corporate deck available on our website. Then at the end, I plan to open it up for any questions you may have. In general, our focus at AOX remains on execution. We have made great progress on both of our programs, evorpacept and AOX-2004 in 2025 and positioned ourselves to achieve significant catalysts from these programs in the coming 12 to 18 months. Our goal and vision for each is to advance both programs to a stage where they're ready for pivotal studies by end of next year. Execution has been strong over the last quarter, and I'm very pleased to report that our clinical development progress and time lines remain on track. In terms of evorpacept or EVO, in 2025, we're coming off a year of massive amounts of data, really demonstrating the potential for evorpacept across a variety of combos and tumor types, which well informed our development strategy for EVO today. We've treated over 750 patients with EVO to date and are now highly confident in where the drug works and most importantly, where it works best. The MOA of combining EVO with antibodies and bispecifics has been well validated in the clinic and will pave the way for us going forward. Importantly, CD47's key role as a biomarker for increasing durable response with evorpacept in HER2-positive gastric cancer patients was further strengthened and validated by additional data in November at the SITC meeting. Here, we shared further data from our gastric study, demonstrating a transformative benefit for patients, both in terms of durability and PFS. In addition, we recently shared top line data from the Phase I evorpacept and zanidatamab breast cancer trial, which is now a second data set validating the role of CD47 and its importance as a biomarker. The follow-up analysis of this trial from the HER2-positive cohort showed that the responders to this combination treatment in a post- and HER2 setting were largely restricted to CD47 overexpressers, which is a similar finding that we had in our gastric study. Full biomarker analysis from this trial is expected to be presented at a medical conference in Q2 of this year. These findings taken together strengthen our confidence in the ongoing Phase II ASPEN-09 breast trial, where we will evaluate patient responses by CD47 level to further define the predictive potential of this biomarker among patients with HER2-positive disease that have progressed following in HER2. We launched the study last year and continue with site activations globally at a strong pace. We remain on track with our clinical time lines here and expect to provide top line data for 80 patients from this study in mid-2027. As shifts to the treatment landscape occur in breast cancer, EVO has the potential to provide both a best and first-in-class option for the 50,000 patients in the second-line plus breast cancer setting. And EVO is also poised to be the only therapy that can address CD47 expression in this large patient population. Overall, the results for EVO from these 2 HER2-positive cancer trials support the potential for us to pursue a targeted oncology approach to additional tumor types with EVO. And given the broad overexpression of CD47 in both solid tumors and heme malignancies, it gives us a real opportunity to pursue focused development strategy for EVO in combination with anticancer antibodies and bispecifics. We're excited about our study in breast. We're also excited about the NHL data, which we recently shared in December, which furthers the findings of EVO in the heme malignancies. We are also ongoing partnering with Sanofi, and we are excited about what we're seeing across both of those studies, and Barb will go into both in more detail. In terms of ALX-2004, turning to our ADC now, we are also very pleased with the clinical progress of ALX-2004, which, as you know, is our novel and potentially best-in-class EGFR targeted ADC. We cleared the first 2 dose cohorts and continue to progress development per plan with the 4 mg per kg dose now in the Phase I trial. We are now expecting full ALX2004 safety data from the dose escalation cohort later this year and second half '26. The potential of these 2 novel therapies, coupled with our substantial progress on their respective clinical programs contributed to the successful completion of our recent financing of $150 million, which we closed a few weeks ago. With our newly strengthened balance sheet, we now have the opportunity to deliver more robust and meaningful data readouts in both of our ongoing clinical programs as reflected in our milestone updates here. Our mission again is to have these 2 programs ready for a pivotal phase study by the end of next year, and we believe we can do so with continued focus on execution. I will now turn it over to Barb to walk through some of the clinical data and findings and plans in more depth. Barb?

Thank you, Jason. Well, let me start with some quick highlights of the strong results that we have seen with evorpacept in 2 HER2-positive breast cancer indications that we have reported on within the past 3 months. I'm referring now to Slides 14 to 18 in our corporate deck. In the randomized Phase II HER2-positive gastric cancer study, we saw impressive response rates with evorpacept when combined with a trastuzumab-based regimen in the subset of patients with HER2-positive overexpressing CD47 tumors. We've reported this data at the SITC conference in November of 2025. In this subset, the response rate was 65% in second and third-line gastric cancer patients compared to 26% in the control arm. This is a delta of nearly 40%. The median duration of response was also quite impressive. It was more than 2 years and more than 3x longer than that seen in the control arm. The median PFS was 18.4 months in the evorpacept arm and 7 months in the control arm with a hazard ratio of 0.39. And finally, the median overall survival was 17 months with evorpacept versus 10 months approximately in the control arm with a hazard ratio of 0.7 in this subset. In summary, this randomized study established the potential for CD47 to become an important predictive biomarker. In parallel, we worked with our partners at Jazz to evaluate the CD47 expression in patients enrolled in the Phase I/II study of evorpacept in combination with zanidapinib. As a reminder, this study enrolled HER2-positive breast cancer patients who had progressed on prior HER2-directed therapies, all of whom had received prior in HER2. We first reported data from this study at the San Antonio Breast Conference back in December of 2024. As you can see on Slide 22 in our corporate deck, at that time, we reported that in the 9 late-line patients with confirmed HER2 expression by central assessment, the response rate with evorpacept plus zanidapinib was a remarkable 56% -- the duration of response at that time ranged from 5.5 to nearly 26 months and the median PFS was 7.4 months. These data compared very favorably to benchmark data such as the data from SOPHIA trial, a predominantly second and third-line HER2-positive breast cancer trial, which produced a response rate of 22% for margetuzumab, whereas this data was obtained in patients who had a median of 6 prior lines of therapy. Now recently, in January of this year, we concluded the CD47 biomarker analysis from these patients. We recently announced that the responders were predominantly restricted to the patients who overexpress CD47. Full biomarker analysis from this trial will be presented at the ESMO Breast Cancer Conference in Q2 of 2026. The data from these 2 independent studies show the potential of evorpacept to drive very substantial benefit for patients with high CD47 expression. These extraordinary outcomes clearly validate Evorpacept's mechanism of action and provide increased confidence for our ongoing Phase II breast cancer. Before I provide an update on our ongoing Phase II breast cancer study, I also want to highlight the results that we have seen so far in the hematologic malignancy setting. These data are summarized on Slide 13 in our corporate deck. In 3 separate cohorts of indolent non-Hodgkin's lymphoma patients, we see very high complete response rates relative to published CR rates in relevant benchmark studies. The most recent study was presented at ASH in December, and these were in the treatment-naive first-line indolent lymphoma setting. These patients received evorpacept combined with Rituxan and Revlimid known as the R-squared regimen. They achieved a complete response rate of 92%, which is almost double that seen with R2 alone. These data are entirely consistent with the 2 studies of evorpacept with Rituxan or R2 in previously treated indolent lymphoma patients where the CR rates were also extremely robust and more than double the CR rates in relevant benchmark studies, as you can see on the slide. Together, these 5 data sets strongly support the potential of evorpacept to enhance macrophage-driven ADCP when combined with an Fc active anticancer antibody. These data give us high confidence for our ongoing evorpacept study in HER2-positive breast cancer. So let me now provide some quick updates on that study. The design of the study is provided on Slide 23 of our corporate deck. As a reminder, in this study, we evaluate evorpacept in combination with trastuzumab and single-agent chemotherapy in a single-arm design enrolling HER2-positive metastatic breast cancer patients who have progressed on in HER2. Following the strong validation of CD47 as a predictive biomarker of benefit with evorpacept plus zanidatinib, we've now decided to enlarge the current Phase II study to up to 120 patients from 80 to increase the number of HER2-positive patients with CD47 overexpression. In addition, we are updating the primary endpoint to a response rate endpoint in patients who have high CD47 expression. A key secondary endpoint will track response rate by HER2 status informed by ctDNA. This way, we will be able to track response rates both by CD47 expression on its own as well as in double-positive patients informed by high CD47 expression and HER2-positive status. As ENHERTU has now been approved as first-line therapy, the treatment landscape for the second line and subsequent therapies has really entered uncharted territory. The optimal sequencing of subsequent therapies is unknown. Several real-world evidence studies suggest that response rates and PFS or time to next treatment might actually be lower than expected with available regimens in patients who have failed in HER2 therapy. So we see a notable gap in the understanding of the optimal sequencing of available therapies and really a large unmet need for effective treatment options in this post-ENHERU setting. Based on the activity that I've described to you for the evorpacept across a number of settings when combined with an anticancer antibody, we believe that evorpacept has substantial potential for benefit in metastatic breast cancer patients in this setting. Furthermore, a CD47 biomarker-driven approach in HER2-positive patients could enable a highly targeted patient selection strategy. To be ready for a prospective selected registration study in the future, we've initiated work on developing a companion diagnostic for CD47 expression. With respect to enrollment in the ongoing Phase II trial, we're making good progress. While we're still early in the enrollment curve, the site activations remain globally on track. We're pleased to see that the investigator interest in the study remains strong, and we project being able to share meaningful efficacy and safety data, including response rate, biomarker results and early durability trends by mid-2027. Now let me turn our attention to the second clinical program, ALX-2004, our EGFR-targeted antibody drug conjugate. While EGFR is a validated target, developing an effective ADC has remained a significant challenge due to the narrow therapeutic window. We've leveraged historic learnings to develop ALX2004, our EGFR-targeted ADC, which was designed by our internal team of world-class protein engineer experts. The preclinical data set is particularly exciting as it demonstrates potent dose-dependent antitumor activity in numerous models across a broad range of EGFR expression levels and relevant mutations such as those in p53, KRAS, BRAF and others. EGFR-related skin toxicity and interstitial lung disease were notably absent in our GLP tox studies in nonhuman primates. The antibody, metuzumab has a unique affinity tuned epitope whose binding to EGFR is not affected by mutations in the binding domain for these -- for the other approved EGFR antibodies. In creating this ADC, we combined this antibody, the mituzumab antibody with our proprietary topoisomerase 1 inhibitor linker payload, which was selected for linker stability and for its robust bystander effect. Given the attention paid to both efficacy and safety in the design of this molecule, we believe that ALX-2004 is uniquely positioned to break new ground as a potential first-in-class therapy for EGFR-expressing solid tumors. Additional preclinical highlights can be found on Slides 26 to 33 in our corporate deck. I would also refer to the comprehensive preclinical data that was presented at the Triple Meeting Conference in October 2025 and more recently at the 2026 World ADC Conference. Finally, in terms of progress in the clinic, we're currently enrolling patients in our third dose cohort, having initiated dosing initially at a robust dose of 1 milligram per kilo, then escalating to 2 milligrams per kilo and subsequently to 4 mg per kilo based on seeing no DLTs at the prior dose levels. We believe that the 4 mg per kilo dose, our current dose level could potentially now be at the lower end of the therapeutic dose range. As a reminder, we're enrolling only patients who have non-small cell lung cancer, colorectal cancer, head and neck cancer or esophageal squamous cell cancer as these are EGFR-expressing tumor indications. In this Phase I trial, we'll perform both the dose escalation as well as the dose expansion component. These data will then ultimately set the program up to advance into a registration study. And we plan to now provide data from the dose escalation portion of the ongoing Phase I study in the second half of this year. With that, let me hand this over to Harish.

Thank you, Barb, and good morning, everyone. 2025 was a year of strategic prioritization and clinical validation for ALX, highlighted by the progress we made on our lead program, evorpaceet, and the clinical entry of our first ADC ALX-2004. In terms of financials, we finished the quarter of -- fourth quarter of 2025 with cash, cash equivalents and investments totaling $48.3 million before strengthening the balance sheet from our equity financing we closed earlier this month in February. The net proceeds from the offering were $140.4 million after deducting for the underwriting discount and other offering expenses. Following the cash inflow from this offering, we believe the cash and investments on hand are sufficient to fund ALX operating expenses through the first half of 2028. With our newly strengthened balance sheet, we now have the opportunity to deliver more robust and meaningful data readouts in both of our ongoing clinical programs over the next 12 to 18 months. The key milestones we currently guide to include: number one, the full biomarker analysis readout from our Phase I/II trial evaluating evorpacept in combination with zanidatamab in advanced HER2-positive breast cancer patients will be presented at the ESMO Breast Conference in May of 2026. Number two, the ALX2004 safety data from the dose escalation phase of the trial is anticipated in the second half of 2026. Number three, the readout on evorpacept top line data from 80 patients from the ongoing Phase II ASPEN breast cancer trial is anticipated middle of 2027. With respect to the latest quarterly financials, the GAAP net loss was $22.8 million for the 3 months ended December 31, 2025, or $0.42 per basic and diluted share as compared to a GAAP net loss of $29.2 million for the 3 months ended December 31, 2024, or $0.55 per basic and diluted share. The decrease in year-over-year spend can be primarily attributed to lower stock compensation, lower personnel and related costs as well as lower preclinical costs following pipeline prioritization. Please refer to the press release for the detailed breakdown on the R&D and G&A operating expenses for the quarter. Operationally, our team is now singularly focused on executing the ongoing Phase II trial in breast cancer for evorpacept and the Phase I trial for ALX-2004. Moving forward, the clinical spend will be largely driven by these 2 trials, partially offset by reduced spend in evorpacept legacy trials that are winding down. With that, let me hand the call back to Jason. Jason?

Thanks, Rish. As we discussed, we're coming off a very strong 2025, where we had an incredible amount of data with evorpacept really demonstrating our path forward. We're also very pleased with the progress on ALX-2004. We continue to advance through dose escalation and are looking forward to significant catalysts across both programs over the next 12 to 18 months. Our focus internally remains on execution, and that's what we will plan to do going forward. And again, very happy to remain on track in terms of the execution across both studies. So with that, I will now open the floor to any questions. Thanks again for your time this morning.

Our first question comes from the line of Allison Bratzel with Piper Sandler.

Just some follow-ups from me on EVO. So I think initially, we were expecting an interim look at ASPEN-Breast this year, but it does sound like that's off the table in favor of the 80-patient readout next year. So could you just confirm, is that correct? And Barb, I know you covered this in the prepared remarks, but just hoping you could talk some more to the rationale behind the upsizing to 120 patients, the change in the primary endpoint and just talk to how that informs on the regulatory strategy? And then maybe just secondarily, what kind of feedback are you getting from investigators on the biomarker approach? And just what do you expect to see on enrollment trends in ASPEN-Breast?

Great. Thanks. I appreciate the question. I'll let Barb take the second question. I think on the first question, that's correct. We're guiding towards 80 patients, full data from those 80 patients in mid next year. I think from our perspective, our goal internally and externally as well is to communicate full robust data. And I think at that point, we should have, I think, enough patients to really understand where the study is headed. We certainly are trying to guide to ensure we have enough CD47 positive patients in this study. As you know, the enrollment is essentially all comers. So guiding to the 80, we think, makes the most sense because we are confident at that point, we'll have real fulsome data across both the CD47 high population as well as the other buckets that we'll be looking at as well. So that's the plan. Certainly, it's an open-label study. Certainly, we have an opportunity to share earlier if we think it makes sense as well as talk to regulators earlier, but the current plan is mid-'27. And then on your second question, Barb, do you want to take that?

Yes. So yes, addressing the interim, Jason just did that, upsizing. Again, Jason hinted at that really just wanting to ensure really robust numbers of patients in various segments, various subpopulations. We'll have patients who can be confirmed HER2-positive in this setting by ctDNA or not. We'll have patients whose tissue has evidence of overexpression of CD47 or not. And we just want to make sure that we have robust numbers. I think the most important thing for this study because I really am coming into this study with a lot of confidence that this is going to work. But what we really want to know is what is the optimal cut point. We have to be able to have data that drives proposed cut point. FDA will be very interested in that. And I think we just wanted to make sure that we had enough patients who are CD47 overexpression that we can do that. In terms of the primary endpoint, it's always been a response rate endpoint trial. I think in the 2 studies that we talk about, the Gastric and the zanidatinib combination, it's really been pretty remarkable just how powerful CD47 is as a predictive biomarker. So I've just moved that up to the primary endpoint and response by HER2 status will still be an important key secondary endpoint, but just really feeling like the CD47 is going to be the most powerful predictor of response. So that's the justification for changing the primary endpoint. And you've asked about the investigators' perception of the study with a biomarker selection strategy. I think they're very excited about it. To have the ability to find a population for whom the therapy is going to really provide substantial benefit. And what we've seen in all of our prior studies that I talked about today, lymphoma, gastric breast cancer, we're seeing these remarkable response rates. And we're also seeing durability that's really both the 2 endpoints together really providing transformational benefit. So the ability to find a selected patient population where the treatment outcome can be so robust, I think, is very exciting to investigators. And then finally, you asked about the enrollment trends. Well, it's early. We had our first patient in, in January. So site activation is going extremely well. And we're still early on the enrollment curve, but I anticipate with the amount of enthusiasm that we're hearing from investigators, I just got an e-mail this morning from one who was thrilled to have their site opening up. So yes, we're excited about this study as are the investigators. So more to come later when we actually get to the point of releasing specific information.

Our next question comes from the line of Li Watsek with Cantor Fitzgerald.

This is Daniel Bruer on for Li Watsek. In addition to the update on the ASPEN-09 breast study, it also looks like you've moderately pushed out the safety data for ILX-2004. Can you give us some color on the underlying reasons for that, please?

Sure. Happy to. Thanks, Daniel. Yes, I think as Barb mentioned and we highlighted in our comments, both studies remain on track and the execution has been strong. I think the change post financing here has just been to ensure that we're communicating robust data. And I think if you look at what we have this quarter, next quarter versus towards the end of the year in 2004, it's really a step change in data. We should have towards the end of the year, really fulsome data from the dose escalation phase. And I do think that will allow us to be much more clear about what we're seeing. Ideally, we'll be able to communicate where we think the expected dose or 2 doses will shake out. And allow us to communicate that externally. So really, the goal is to -- when we provide updates to make them meaningful and full. And I think that's the thinking behind that guidance.

So if I may follow up on this, is it safe to expect up to 4 dose levels to be -- to have been tested at the point when you make the disclosure?

Yes. I think that's reasonable. As you know, Daniel, we went from 1 to 2 to 4. So we've doubled now doubled now twice. We do think we're at the low end of the therapeutic window as is and continue to progress that study very well. And I do think the fact that we've cleared 1 and 2 so rapidly without seeing DLTs is encouraging, certainly now into 4, things continue to go well. And I do think getting to 4 doses as part of that cohort is definitely a reasonable expectation.

Our next question comes from the line of Sam Slutsky with LifeSci Capital.

I guess 2 for me. One is that for the 80 patients in ASPEN-09, remind me what's the expected ratio of those with CD47 high versus low expression? And then on 2004, just on 4 mg per kg being at the lower end of the therapeutic dose range. I know looking at some of the other kind of EGFR ADCs that are using TOP01, it seems like they're at either 4.8 mg per kg Q3W or less in terms of dose. Curious on what's driving this difference in where the therapeutic range starts with your drug? Or is it that you would just consider that you have a wider therapeutic window, which hopefully leads to better efficacy versus others?

Sure. Thanks, Sam. I'll take the first one and Barb can handle the second one on the range. In terms of the percentages, what's nice about CD47 is it's really well studied in the literature and the specific question around CD47 expression has been well documented. So we know in our gastric study that about half of those patients that were confirmed HER2-positive were CD47 high. And we looked, as you recall, across 4 different cutoffs and showed that range to be roughly 40% up to around 57% of the population. So a really substantial percentage. We also know from the literature that, that percentage is relatively consistent in breadth. Again, we expect the cutoff and the expression profile to be different. But the patients that have CD47 high, we expect it to be around half. And again, the literature would support that. So I think it's important to run the study, of course, and see how that shakes out, but we're expecting to see a significant number of this population be CD47 overexpressers. Barb, do you want to take the question on therapeutic range with 2004?

Exactly. Yes. The highest nonseverely toxic dose in primates was 20, which equivalent is potentially around 6.5 milligrams per kilo in patients. There's definitely variability on that. But that was one way for us to think about where we might be able to get the dose to. So I think it will be data-driven. We'll start -- we're not -- I would never think that we would double again. We're now in a range where smaller incremental increases will be pursued. So we'll just have to see how things go in terms of the tolerability and toxicity that we see in patients. But we do think somewhere in the range of in the 4, 5, milligrams, maybe a bit higher because, as you know, the nonhuman primate data, there really wasn't any severe toxicity. So maybe we can go just a little bit above the 6 to 7 range, but we'll see. Anyway, we'll provide further updates later in the year, but that's the allometric scaling in terms of where we think we might start to see some toxicity.

Our next question comes from the line of RK with H.C. Wainwright.

A couple of questions on ASPEN-09 and one on 2004. On ASPEN-09, as you're expanding the trial to 120 patients, I'm just trying to understand a little bit of logic behind it. Can you discuss what's the prevalence of CD47 high in post and HER2 patients, especially if you're defining 47 high as ISC3 positive greater than 10%? And is this expansion driven more by statistical power or you're concerned about lower-than-expected prevalence of the biomarkers. So that's -- sorry, that's a long question one. On the second one is when we start thinking about physicians' choice of chemotherapy, should we be concerned about subsequent ADC use in this post trastuzumab patients that it can impact the CD47 expression? And then on 2004, with the safety data expected in the second half, how are you monitoring the interstitial lung disease and the skin tox?

Sure. Those are great questions. Thanks, RK. So on the 09 in terms of CD47 expression post ENHERTU, we think that the percentages should hold that I mentioned before. So roughly half of the population should be CD47 high. We did highlight in the past on our calls, a study -- a recent study from last year that showed that patients who are exposed to in HER2 overexpress CD47. So we do think it's certainly possible that those numbers are higher in this population. We know that CD47 is a key mode of evasion post ENHERTU. So we do think that is possible. Barb, do you want to take the next one on the various chemo options and how that may impact things?

Well, what we know in terms of CD47 expression, there is data in the literature that it rises after patients post in HER2. We don't have a lot of other data. Most of the data on CD47 comes from survival tissue from the time of diagnosis. So -- but the literature does support higher rates of overexpression postENhER2, which is absolutely perfect. That's our patient population. It's where there's an unmet need. And it's clearly the clinical setting that's the most wide open at this point in time. Personally, I'm not sure that I have any concern that different chemotherapy drugs will perform differently in patients who have CD47 expression -- when they're combined with trastuzumab, our main focus on mechanism of action is the combination of trastuzumab or some such antibody with an active Fc plus evorpacept. We certainly will look at the 5 different chemotherapy options across the different subsets to see if there's any major differences, but I'm not expecting to see really any much variability there. In terms of ALX2004, you asked about how we might be monitoring for both ILD and skin toxicity. Patients do go through CT scans on a regular basis as per protocol. And a lot of times, that's where initial phases of interstitial lung disease may be detected. You do want to detect it before it gets too symptomatic and having scans to watch for their cancer progression or response, that should be picked up. So there are guidelines in the protocol. They're all very cautionary, meaning it's just because this class of agents has in the past cause the payload itself has been associated with ILD, but we did not see any evidence of that in our nonhuman primate toxicology studies. So we will monitor for it, but we have a low likelihood based on our NHP work. In terms of skin toxicity, certainly, metuzumab was the antibody that we selected for just for the lower skin tox that's been shown clinically in the early investigational use of thatmetuzumab antibody. And that's obviously something that every time a patient is seen in clinic, they'll be examined and can report that. So that will be an early thing that we could pick up once we get into the various dose ranges. What else can I say about skin toxicity? I think our prediction is that we're not going to see skin toxicity at the lower doses. Certainly, cetuximab and panitumumab are known to have quite a bit more skin toxicity if you were to do a cross-trial comparison of safety data from the approved antibodies versus metuzumab's safety profile, that gives us a wider therapeutic window. So we don't expect to be too limited by skin toxicity. It allows us to move up higher into the dose range, similar to the question that maybe Sam asked earlier about maybe having a wider therapeutic window for this agent than based on the protein design that we have with this agent.

Your last question, RK, just on the sample size. So there was no change in the assumptions in terms of the percentages or efficacy. There's been no change there. The driver is really just to ensure that we have a very robust Phase II and in a position to derisk the Phase III as much as possible. So the ability to flex up to 120 allows us to do that. Of course, as we mentioned, it's an open-label study. If we see data that's even in the ballpark of the 56% we saw and the 60% we saw in the breast and gastric studies, respectively, I think we'll have plenty of room to clear the hurdle. And again, I think the goal of this is to inform the Phase III. So once we see a sufficient signal that will then, I think, spur into action conversations with the regulators and moving quickly to a Phase III.

Our next question comes from the line of Roger Song with Jefferies.

Congrats on the updates. This is Nabil on for Roger. Question on the CD47 cut point. Maybe this is asked, but I wanted to ask, again, is that IC cutoff for ASPEN-09 primary endpoint already locked in? Or could you maybe talk about those prespecified decision rules we're using to that point? And then on just the IHC evalability, how do you guys handle like borderline cases with maybe like some insufficient tissue? Is that ever a thing that comes on?

Yes, sure. Thanks, Shil. So the question on CD47 expression, I'd say what we know is that we would anticipate it to be different across different tumor types. So we know gastric as a baseline tissue type expresses CD47 more highly than breast. And so just as that is the backdrop, we expect it to be different. Again, encouraging with gastric was that it effectively didn't matter, meaning we could pick IHC3, IHC2/3 and continue to see a good response. So I'd say the EVO plus an study in breast informs that. I think we do have a, what I'd call a good estimate of how it could look. And I think going forward, it will be critical for us to run the study to really understand exactly where to set the cutoff. So that's part of the goals of this current study that we're in the midst of, and I think that will be informative. In terms of the missing tissue or different tissue types, we don't anticipate that to be a significant issue just because we're using tissue at time of diagnosis to base CD47. We expect CD47 to be to be relatively stable. And I think that should be pretty straightforward. But anything else to add on that, Barb, in terms of the tissue and how we.

Yes. Everybody will be required to submit tissue. I think there is always an estimate in most trials that you might have some missing data. I wouldn't expect it to be unusual, so 10% or less. So we anticipate being able to have measurable CD47 in nearly all patients. And it could be 100%, but I wouldn't be surprised if we ended up with a rare patient for whom the tissue just wasn't sufficient, but that shouldn't be a problem. IHC is a very standard assay methodology, so easy to perform, et cetera. So no major risks there.

Ladies and gentlemen, that concludes our question-and-answer session. I'll turn the floor back to Mr. Lettmann for any final comments.

Great. Thanks, everybody. Appreciate the good engagement and questions this morning. Again, exciting time at ALX here, a lot in front of us and continue to execute well. Looking forward to the next quarter here and the next year where we have a lot of important milestones here to lay out. So appreciate all the interest and support. Thank you.

Thank you. This concludes today's conference. You may disconnect your lines at this time. Thank you for your participation.

Good afternoon. Thank you all for joining us here today. My name is Henry Jiang. I'm with the banking team here at JPMorgan, and it's my pleasure to be introducing ALX Oncology today. Joining us on stage and presenting today will be Jason Lettmann, CEO; as well as Barbara Klencke, Chief Medical Officer. Just a reminder that we'll have time for questions at the end of the session. So please wait until then for any questions, and we'll get you a microphone. But without further ado, I'll pass it over to you, Jason.

Great. Thanks, Henry. Thanks for having us, and thanks to JPMorgan for the week, and appreciate you all spending some time. We heard that Thursday is the new Monday at JPMorgan. So thank you, thank you all. Here are our forward-looking statements. So really excited to be here. We've had a really exciting week, I think, for ALX. We're coming off an incredible year for the company, a year in which we had 7 different data sets read out. And I think we clearly understand a lot about both of our programs. So as a quick reminder, we're developing evorpacept and ALX2004, both clinical stage programs, both highly differentiated in their class and both have made very strong progress. So on the evo front, we were founded as a CD47 company back in 2015. And the story with evo is one of a target that is incredibly important to the immune system. It's incredibly important in oncology, and it's been a very difficult target to crack.

The story with us is our mechanism dating back from the Series A to today is unchanged, and we've watched that mechanism play through in the clinic and is now well validated in the clinic, and we'll walk through and have Barb walk through some of our data. We're now laser-focused on advancing the program in breast and in multiple myeloma, and both of those studies are ongoing and progressing well.

On ALX2004, this is a highly differentiated EGFR-targeted ADC. This is an internally developed asset that we have been working on through 2021, and it's now in the clinic. And we'll talk through what makes this ADC so unique and why we think it has the potential to be a first-in-class EGFR-targeted ADC. Again, great progress in the clinic. And as we shared last week ahead of this meeting, we are now in Phase I. We've cleared the first 2 dose cohorts and are making really strong progress on that program as well.

So as a reminder, we're coming off 2025, which was really a data-intensive year for the company. First and foremost, we presented at SITC just in November, updated ASPEN-06 data from our randomized study in gastric. What is so exciting and I think really interesting for this program is we know that evo is an active agent. We know it's a safe agent, and we now know exactly where to target the drug as CD47 is also an incredibly strong predictive biomarker. Barb will walk through this more, but we really have shared transformational data in terms of this targeted approach and are excited about where that's headed.

We also shared data from our collaborations with Jazz and Sanofi. Both have been great partners for us. These studies further validate what evo can do not only with antibodies, but with bispecifics like zanidatamab. This story for us is not limited to solid tumors. Importantly, we shared data out of MD Anderson in our study with R-squared. And there, again, in NHL, we showed a strong data set. Certainly not -- last but not least, we've advanced ALX2004 into the clinic last year. This program has been in dose escalation and really progressing well as well.

So this is a quick snapshot of our programs. We are laser-focused on ASPEN-Breast. We see an incredible opportunity post in HER2 in the HER2-positive space. As we announced last week, we're now enrolling patients. We have an incredible amount of enthusiasm from our sites, and that's been going well. Also continuing to work with Sanofi, we now have our combination with SARCLISA into dose optimization, and that's also progressing well.

We shared data from ASPEN-06 as well as from our study with zani over the last year, and that really forms the foundation for what we're now doing in breast. And then as I mentioned on 2004, that study has now clicked through the first 2 dose cohorts were on to 4 mg per kg, which is really encouraging because safety has been an issue in the EGFR ADC class.

So again, just as a reminder, and this is what makes us different on the CD47 front. There's no doubt it's been tough and there's been challenges, but we continue and have been the only company developing a CD47 in this way. Our mechanism is fundamentally different in that we bifurcate the eat me signal from the don't eat me signal. Our drug, evorpacept, as you can see in the red, blocks the don't eat me signal, blocks CD47. And then the uniqueness of our mechanism is using an Fc active antibody, whether that's a traditional anticancer antibody or bispecific to provide the eat me signal. And these 2 things working together is what has been proven in the clinic to be effective. And again, when we have these -- the presence of these 2 antigens, if you will, that's when we're seeing the strongest response.

This is very different than what's been tried in the past. And this cartoon depicts what happens with red blood cells. CD47 is expressed in almost every cell in the body. And because of that, it's very difficult to target with a conventional Fc active antibody. That's what you see on the left here. And what ended up happening with those programs is an impossible therapeutic window challenge, but they were not able to dose high enough without having significant on-target toxicities. Our program on the right, due to how we work, does not activate macrophages against red blood cells. Therefore, we've been able to dose much higher and we have not had the therapeutic window challenges that others have observed.

And this has played out. This thesis that we had dating back to the Series A has now played out in the clinic. And what you see on the top is a series of different combinations that we've run, Herceptin, zani, rituximab. This combination now has been validated across a number of different clinical studies. And there's no question that we're seeing consistent activity and safety that's differentiated versus the others.

In terms of the active approaches, at one point, there were nearly 20 of these. Now there's essentially a very small number. And the reason why I-Mab, Trillium, magro, et cetera, have failed or been discontinued is due to the approach of having an active Fc, which we now know doesn't work. And this differentiation for us has been critical. And I'll now turn it over to Barb to walk through some of the data that we've seen in the clinic.

Thank you, Jason, and good afternoon. So I will be really focusing for this first part of my talk on just going deeper into the data that Jason has just alluded to. Here we go. CD47, incredibly important for cancer cells. It is one of the main ways that cancer evades the immune system. There are just a wealth of data looking at CD47 as a negative prognostic biomarker meta-analysis that we display here in 38 cohorts across 17 published studies, 7,000 patients, all with the conclusion that CD47 overexpression correlates with low survival. And you could see all of the tumor types on the right there where this has been shown just in this meta-analysis alone.

So going into the clinical data, here's -- I'm going to tell you a little bit more about 5 different data sets. These are the first 2. And in fact, I'll come back and talk deeper about these, but the gastric study on the left, which we've already mentioned, ASPEN-06. This is a randomized Phase II, a relatively large study, allows us to look at subsets, including very important subset of patients who overexpressed CD47 as well as being confirmed as retaining HER2 positivity.

In there, in that population, the response rate, 65%, nearly a 40% delta from the control arm. On the right, we have a smaller study. But again, we're seeing this remarkable response rate. This is a late-line patient population, 9 patients with zanidatamab that were confirmed centrally as being HER2-positive. The control here is a standard published benchmark. But at best, you're not going to see a late-line population receiving anything better than about a 20% response rate. And all of these 9 patients happen to have also had ENHERTU.

3 studies in a row have shown Rituxan plus evorpacept as again showing an unbelievably high response rate. These are complete response rates. It's either a Rituxan combo or Rituxan-Revlimid, so R-squared. The first one was our own work in a Phase I study in relapsed/refractory indolent lymphoma. The second one in the middle there is an MD Anderson, second-line indolent lymphoma CR rate of 83%. And now in the first-line setting, and this was just at ASH last month, 92% complete response rate in the first-line setting.

So coming back, as I said, I would come back to some of these data sets to go deeper. This shows the trial design of ASPEN-06, the gastric cancer study in HER2-positive patients. These are second and third-line patients. They all must have had prior HER2 targeted therapy. We enrolled 127 patients, and you see the randomization there. TRP is trastuzumab, ramucirumab and paclitaxel, either alone or with evorpacept. Out of the patients that were enrolled, 75% or 95 patients were confirmed as having retained HER2 status. This was determined either on fresh biopsy following their prior HER2-targeted therapy or on ctDNA. Out of those patients, we performed a prespecified preplanned analysis based on CD47, and that's the data that I will really be focused on in the next couple of slides.

So this shows you the first subset is the retained HER2-positive patients. These are 95 patients, and you see a nice response rate of 49% versus 25%. But when we further subset by CD47 overexpression or lack of evidence of CD47, we see further enrichment in the CD47 high group. And this is the data that I showed you before.

This -- once again, on the far left is the response rate, same patient population. But now we're seeing the durability, 25.5 month duration of response when you combine evorpacept with the trastuzumab-based therapy. And this translates obviously into a good PFS and OS. The hazard ratio for PFS is 0.39, and you can see the hazard for survival, 0.63.

Safety. We've looked at safety across all of our studies, of course. And what we see is a very consistent profile across 750 or more patients now treated with evorpacept. This is just a tornado plot just from the 06 study. It shows -- it demonstrates that the rate by grade of adverse events due to any cause is comparable across the 2 arms. So in general, our -- sorry, our treatment is characterized by generally manageable and reversible adverse event profile.

I'm going to focus now on how this data supports moving forward in further studies in breast cancer. So this is the zanidatamab trial. We've stated it a couple of times now. The patients who were centrally confirmed as HER2-positive are shown in the middle there, 56% response rate. So this is pretty remarkable because these are sixth-line patients. They happen to be -- they must have had at least 3 lines. These patients had a median of 6. They all had in HER2. And the duration of response isn't mentioned on the slide. The duration median was not reached, but the range was from 5.5 to 26 months and the PFS was 7.5 months.

So this trial published about a year ago, gives us further support. Now interestingly, we're also looking this quarter at the CD47 to understand whether CD47 might be a predictive biomarker in this patient population. I don't have the data for you today, but we will be presenting that at a congress in the first half of this year.

So then just what is the unmet medical need. There are a lot of agents approvable -- approved for HER2-positive breast cancer. Obviously, also the ENHERTU has been a spectacular addition to the armamentarium, and that is moving up. There is now a first-line label a couple of years ago, a second-line label. So this is an amazingly good opportunity for patients. However, what do you do after that? It's really somewhat uncharted territory. There are a lot of active agents, but how well do things work post ENHERTU. And what generally is being seen is things are not working quite as well as you would like. No good optimal sequencing of treatment has been described.

And some of this data comes from real-world evidence. There was a 600-patient trial, real-world evidence report out of ESMO from Japan. Response rates were in the 15% to less than 20% range. In the U.S., there have been a couple of large real-world evidence studies, short time to next treatment, short time for PFS of 4 or 5 months at best and some like SG producing even lower rates.

So what we are excited about is if we can replicate anything like what we saw in the gastric HER2 setting or in the zanidatamab HER2 combination, this will become a very important regimen for patients.

We are currently active in this protocol. This is an 80-patient single-arm trial of HER2-positive patients. They must have had prior HER2-targeted therapy, including ENHERTU. 100% of patients will have had ENHERTU. Response rate is our primary endpoint. Importantly, just like in gastric, we're targeting what is the response rate in patients who retain HER2 positivity. We'll be assessing that through ctDNA. And then our key secondary endpoint is what is the response rate in patients who are determined to have overexpression of CD47 in this setting.

This study is enrolling. We've predicted interim data in Q3 of this year. The addressable patient population is also large. So here, we show that 20,000 patients are in this patient population by our estimates. So it's a $2 billion to $4 billion market opportunity. We get there through thinking about in the U.S., 48,000 HER2-positive patients, most -- the majority of whom will retain HER2 positivity. We've assumed here 60% to 80% and half or more of those patients should be overexpressing CD47.

So with that, I'm going to turn this over to Jason for an introduction to ALX2004.

Great. Thanks, Barb. So the quick history with ALX2004. Back in 2021, we as a company made the decision to continue to expand our pipeline and brought together a group of really world-class protein engineers, chemists, scientists in Palo Alto to do so. And then from 2021 up until this past summer, did not disclose the program by intent. We certainly felt that the competitive nature made it better, frankly, to keep it under wraps. So that's what we did and made the decision to wait until we are close to the clinic.

And I think the opportunity that we really saw is if you look at the validated targets in oncology, there are very few that don't have approved products or late-stage trials that will clearly define standard of care. EGFR has been challenging. It's been challenging because of the target itself, but also, we think because of the design of the prior ADCs. And here with 2004, what we've done is really spent an incredible amount of time and effort in the lab designing this ADC. So I think what's been demonstrated in ADCs is that the epitope selection matters, the antibody matters. And that's been the case with EGFR ADCs. And here, we chose a unique epitope, matuzumab, and we are the only ADC in development with this antibody.

And what makes it unique is a big pharma developed antibody that was designed specifically to avoid the on-target tox associated with the EGFR antibodies. So this antibody has -- continues to have great binding and activity against EGFR without having the known toxicities.

Importantly, the second part of what we did is to really spend a lot of time optimizing the linker payload. Barb will walk through some of our preclinical data, but our goal was to use the most validated payload, which is topo I and spend time optimizing the linker payload. And through that, we were able to improve the on-target delivery as well as have superior bystander effect relative to ENHERTU.

So that design, that approach then carried through our preclinical work, which we'll give you a very quick snapshot of today. But in a range of models, you'll see a dozen models here quickly, we showed dose-dependent activity irrespective of EGFR expression, which was really important. That carried through into the work we did with CRC-derived model and CRC models and patient-derived models, where we showed both in homogeneous and heterogeneous tumors, great activity as well.

Importantly, on the safety front, in our NHP work, we did not see the typical EGFR-related tox that you'd expect, which we think is indicative both of the affinity here as well as the epitope. And we also did not see evidence of ILD, which is important as that's been a known safety issue with the topo class.

So quickly, just in terms of the competitive setup and where we see the opportunity. In ADCs, what's been successful is targeting a single target. That's been the simplest approach. That's been what's been easiest to optimize, and that's our approach here. We've taken, again, the most validated payload, which is topo I, spent a lot of time optimizing the construct with topo I, we know we're going against a validated target. And as a singular target versus a bispecific ADC, we know exactly how to optimize that, which I think enables better targeting as well as potentially better patient selection because we can use EGFR as a way to select patients.

Certainly, last but not least, our antibody has been optimized, and it's different. Most of the ADCs and bispecific ADCs out there are using cetuximab or panitumumab and our differentiation with matuzumab is really key here.

So with that, I'll turn it over to Barb to walk through some of the preclinical data.

All right. So yes, again, I'm going to show 3 or 4 slides that really drive -- that demonstrate the proof behind the statements that we are expecting -- we designed a molecule that should have better target delivery, better bystander effect, lower toxicity and better efficacy.

So this slide really shows you how by stabilizing the linker payload deconjugation, we minimize linker payload release in circulation. This is a study of nonhuman primates, nonhuman primate studies, PK study. And it really shows how the linker was designed to deliver more payload to the tumor and not to the periphery and thus reducing exposure to normal healthy tissues.

This study here, there's a few studies on this. These are CDX mice models. The first 3 parallel bars there are showing how the rigorous payload linker payload selection strategy process really matches or exceeds the activity of a DXd linker payload in these models, both in terms of direct killing and on the right, the bystander effect.

So these first 3 set of bars show several CDX models. They have varying degree of EGFR expressions. And again, what you're seeing here is the proportion of mice that have experienced complete tumor eradication. And you see better or equal results for the ALX2004 molecule versus a comparator.

On the fourth set of bars on the right, we show the effect of a bystander model. This contains a mixture of EGFR high cells and EGFR ultra- low cells that you would not expect a targeted molecule to be able to target directly and would only be eradicated through a bystander effect. So again, here, ALX2004 outperforms the DXd comparator, really supporting the statement that we have improved bystander effect.

This Slide 29 really shows a snapshot of efficacy data, and we've done a very thorough evaluation. These are tumor types of EGFR expression across a wide variety of EGFR expression density on the cell. There are cells up here that contain TP53 mutation or a KRAS mutation or a BRAF mutation. And across all of these different tumor types, what we see is very remarkable tumor suppression or regression or even tumor eradication. And we're doing so, we're accomplishing this sometimes with 1 milligram. All of these are 1 milligram per kilo dosing or show a dose-dependent relationship here. But what we're seeing is either with 1 single dose or a dose of once weekly times 3, we're seeing these types of outcomes.

This really sort of confirms the broad applicability of ALX2004 in EGFR positive tumor types. This is the NHP summary of our toxicology results. And as you can see, we have both the NOAEL and the HNSTD described here. All findings were minimal to moderate, fully recoverable. This justified a pretty robust starting dose for our Phase I study of 1 milligram per kilo in our human -- first-in-human study.

And speaking of that, this is my last slide. It is the study design for that first-in-human study. We've been quite pleased that we were able to start at 1 milligram. We've doubled the dose, which we publicly announced to 2 milligrams and then once again, doubled the dose again to 4 milligrams. So we are actively enrolling as of last week to the 4-milligram per kilo every 3 weeks. This is a study that includes both a dose escalation component and a dose expansion component of the trial. And it's limited to 4 tumor types where we feel that EGFR expression will give us a good chance of seeing efficacy over time. Those tumor types include non-small cell lung cancer, head and neck cancer, colorectal cancer and squamous esophageal cancer.

And with that, I think I will pass it back to Jason.

Great. Thanks, Barb. Just to wrap up here in terms of where we're heading, I think 2025 really was a year of data and execution, which sets us up for 2026 here where we have a number of catalysts that are going to be important for both programs. We think we have the opportunity to have 2 agents that can be first-in-class and best-in-class. And our goal at the end of this year is to have both heading on registrational paths. And so looking forward, key for evo is going to be sharing the interim data in Q3, which I think will further validate this biomarker-driven story and again, set us up for a registrational study in HER2-positive breast.

On the 2004 front, our goal is to continue to ramp dose escalation, continue to execute at pace as we have and ultimately share data in the first half of this year to elucidate the promising safety profile that we're seeing. So a lot going on this year, very excited about what we have in front of us. And again, thank you all for the time.

Thank you, Jason. So we'll open it up to questions. If you have a question, please raise your hand, and we'll get you a microphone. Otherwise, I can kick us off. So we know there's been quite a few high-profile failures in the CD47 space. What differentiates ALX's platform? And why do you think evorpacept can succeed in this space?

Yes. I think as we talked about at the beginning, the key is our mechanism. It was different at the time of our company's founding, and it remains differentiated today. It is a fundamentally different way to attack this target. The others use CD47 as a tumor-associated antigen. And ultimately, that didn't work. And a lot of times in oncology, you don't learn that until the randomized studies. And I think that's what has been demonstrated. What's different for us and again, demonstrated in a prospective randomized study is just the strength of the activity and the differentiated safety. And I think that's what is so exciting about this biomarker story is it's right on mechanism. When we have, for example, HER2 expression and CD47 expression, our drug is working and driving transformational benefit to patients.

We have a question over here. Yes. We'll give you a microphone real quick.

Super presentation. I have a question mechanistically on ALX2004. I mean, great design in the way that you've really derived that molecule and the test and the data package presented. Beyond monotherapy, what are the combination approaches that we know already EGFR agents are succeeding. For example, you mentioned KRAS and potential synergisms there. Where would you be once you have that safety established and the dose, the next steps for this agent?

I think in head and neck and lung, I think of PD-1 as a potential way to combine given its activity there. As you mentioned, a BRAF inhibitor or other things in colorectal cancer. I think what we'll do is see which tumor types we see the best activity. I think one of the exciting things about a single agent, if it's got a sufficient response rate, we can go after an accelerated approval with a single agent. But then you do have to have a confirmatory trial. You're often also trying to get it up into earlier lines of therapy, and that's where the importance comes in, in terms of having a strategy for combination.

I have another one. So the ASPEN-Breast trial, what -- this will be two-pronged. What data do you expect to -- or results do you expect to be read out in the third quarter of this year? And given that it is a single-arm uncontrolled trial, how will you interpret those results?

Sure. I'll take the first part. But the goal, both internally and externally is to deliver meaningful data in Q3. Again, I think what's really important about the design of the study is we have both CD47 high and low, and we'll have patients that we know will be HER2 positive and some that will have not retained expression. And so that set up for us, the ability for us to compare across those groups is going to be very instructive. And if we see data, again, that even remotely approaches what we've shown in these 2 other studies, to me, that is a whopping success. But do you want to...

In terms of an 80-patient single-arm study, how do you interpret the results? And that's pretty much why I focused on talking about some of these real-world evidence studies. In the past, we had large data sets because breast cancer is so common. And we know that trastuzumab and chemotherapy, whether you're -- whichever chemotherapy backbone, your response rate is about 20%. And we are not seeing that, that has gone up post ENHERTU. If anything, it's going down. So I think we have a very solid benchmark of published data. And if we see good results, we'll know that we have something special.

Great. And assuming those results are robust, what are your plans after that? What else is needed to get evorpacept to market?

We would need to do most likely, it's hard to say if we had a sky high response rate, maybe we have an opportunity. But essentially, our assumption is a Phase III randomized comparative trial. I would expect that to look like trastuzumab chemotherapy, dealer's choice and compared to trastuzumab chemotherapy plus evorpacept. We are preparing for the likelihood that it would be a CD47 selected patient population where we would expect transformational benefit. But that is really one of the main reasons to run this current 80-patient trial is to have the level of evidence that FDA would require in terms of setting the defined cut point for a patient selection strategy in a future Phase III.

[indiscernible] your point number 3 on ALX2004 being a highly differentiated ADC, I presume the linker is a key component there. And what comments might you make on why that linker strategy is proving apparently to be very successful?

Yes. I think that's a great question, and we walked through, I think, just a real high-level snapshot of the internal work we did to optimize that. But it all comes back to the science and the work in the lab. Our team synthesized, I'd say, over 60 different linker payload constructs. We used in HER2. We used [indiscernible] as key comparators. And we -- and through that work, we were able to really hone in on this linker. And I think it's important because if we look at the failures from AbbVie, Amgen in this space, they did not have the same linker construct. We know that, and they did not have the same epitope. And I think in terms of modern ADC lessons learned, those things are really important. And there's certainly others that are focused on this. And again, I think we've benefited from the history here to really optimize this in the lab.

Maybe one more. Could you talk a little bit more about your partnership with Sanofi for evorpacept in combination with SARCLISA in multiple myeloma?

Sure. So I think Barb did a nice job of highlighting on one slide our data in solid tumors, but then also our data in heme. And we have 3 different data sets in NHL that really validate that evo is also very active in heme malignancies. And if you go back to the history of CD47, it really was in heme. And the reason why it started in heme is because we know CD47 expression in heme malignancies is very high. So that's what was the basis for the partnership with Sanofi. That resulted from an inbound outreach from them. They have a really interesting asset with SARCLISA. And the game in multiple myeloma right now is to develop the right combinations.

So we're really excited about that study. We're part of a basket study called Umbrella. We communicated over the summer that it met Sanofi's bar to move to the next phase and very excited about what that could mean. We see a really large opportunity in multiple myeloma. It's an incredibly large commercial opportunity. And Sanofi has been a great partner. So we're excited about that as well.

Awesome. Thanks, Jason. And thanks, Barbara. I think that concludes our session today. Thank you all for joining us.

Thank you.

Thanks, everyone, and welcome to our Q3 2025 results. I appreciate everybody spending some time with us this morning, and I'm looking forward to this update.

On Slide 2 here before we start our presentation of housekeeping here are our forward-looking statements for your review. So on the next slide, Slide 3 here, here is the agenda and our plan for today. We're going to be providing an update on our key accomplishments in the third quarter of 2025. Most notably, we are very excited to share with you the data set that will be presented at SITC this weekend from a preplanned analysis of our ASPEN-06 trial that showed CD47 expression as a key predictive biomarker for increasing durable clinical response with evorpacept in HER2-positive gastric cancer patients.

So our goals for today are most importantly to share these detailed results with you as we believe this data set now clearly validates the role of CD47 in HER2-positive cancers. We will then give you a sense of how this data now impacts our development strategy for evorpacept going forward. We will also be providing an update on our novel ALX2004 EGFR-targeted ADC, which is now in the clinic.

Today, we are also excited to be joined by Dr. Peter Schmidt from Barts Cancer Institute in the U.K., who is a key opinion leader in breast cancer and investigator in our evorpacept Phase II breast cancer study. He will be presenting his views on evorpacept data and its potential within the current treatment paradigm for HER2-positive metastatic breast cancer. Then our CMO, Barb Klencke, will provide an update on our novel EGFR-targeted ADC, ALX-2004, which is currently dosing patients in our Phase I trial.

Now on Slide 4. In the third quarter, we made significant advances in both evorpacept and ALX2004 clinical programs. We again are excited to present the full data at SITC that is demonstrating the potential of CD47 expression as a predictive biomarker and highlight a clear opportunity to now identify patients who are most likely to achieve the greatest benefit from evo.

As Barb will present in detail in our clinical section in this analysis, we saw that patients with high CD47 expression derived the greatest benefit across all key efficacy markers, response rates, duration of response, median PFS and overall survival from evorpacept versus those with low expression. The data is very clear as the magnitude of benefit across many of these metrics was double or even triple those observed in the control arm and also clearly compare very favorably with the large benchmark studies in second-line gastric cancer.

Most importantly, these results support the potential to pursue targeted oncology approach to additional tumor types with evo. And given the broad overexpression of CD47 in both solid tumors and heme malignancies, it gives us a real opportunity to really focus evo now as a targeted IL therapy. Our Phase II clinical trial in breast cancer, which is designed to pursue a CD47 and HER2 biomarker-driven strategy based on this strong data is on track to dose its first patient this quarter. And as we've discussed, evo has the potential to represent the first and only option for metastatic breast cancer patients who overexpress CD47, which we know can lead to worse outcomes and a poor prognosis for these patients.

And with our second pipeline product, our novel EGFR-targeted antibody, ALX-2004, which is a highly differentiated ADC, we presented preclinical data and design of our Phase I trial at the Triple Conference a few weeks ago. So we're excited to announce today that we are currently enrolling patients in the second dose cohort. We're rapidly clearing the first dose cohort in this Phase I trial.

Turning to our financials quickly. We reported a total cash balance of $67 million, and that cash is expected to provide us runway into the first quarter of 2027, which positions us to achieve the value-enhancing data milestones for both ALX2004 and evorpacept that we have coming next year.

Now turning to Slide 5. It has been very well established that CD47 is widely overexpressed across almost every type of cancer. And it is also clear that CD47 overexpression matters as it is clearly a negative biomarker for patients. So when you look at research in CD47 over the last decade plus, it is a very strong foundation that CD47 is clearly a negative prognostic biomarker. And what you can see here is a meta-analysis of 38 cohorts across 17 publications, which includes over 7,000 patients. And there really is no question that CD47 is clearly associated with shorter survival and worse outcomes. And you can see on the right, the wide range of tumor types where this has been established.

Now turning to Slide 6. And as a reminder that during our Q2 call just a few months ago in August, we presented the top line data, which support that CD47 overexpression is a clear predictive biomarker for response with evorpacept in HER2-positive gastric patients. In this analysis, patients with both confirmed HER2 positivity and CD47 high expression had a dramatic response to evorpacept as compared to those in the control group who did not have vivo.

And as you can see here on the ITT population, we saw a strong response of a 41% ORR in the evo arm versus 27% ORR in the control arm. And if you look at the data now in patients that clearly have CD47 high expression, there is a magnitude of benefit for those patients where we had an ORR of 65% in the treatment arm versus 26% in control with a nominal p-value of less than 0.05.

Now as you can see on Slide 7 and what we're very excited to share with you now and at SITC later today, this strong ORR benefit with evorpacept in combination with TRP and CD47 high patients was also reflected and translated well to DOR, PFS as well as survival as it's clear that patients who overexpress CD47 and retain HER2 expression is driving the effect here. This is very important as this clearly validates EVO's dual mechanism of action. And again, this is a second-line plus gastric population, which has historically been a very tough cancer to treat.

So in addition to the ORR benefit, which had a delta of almost 40% versus control, the median duration of response here for those patients is over 2 years, which is more than triple the control. The median PFS was over 18 months in the evorpacept arm versus just 7 months in control with an impressive hazard ratio of 0.39. And then we were also pleased to see these gains further translate to a benefit to overall survival where we saw a median OS of 17 months with evo versus about 10 months in control and also a strong hazard ratio of 0.63.

Barb will walk through this data in more detail and the full data set will be shared at SITC here soon. What is clear is that this data shows the potential for evorpacept to drive really substantial benefit for these patients with high CD47 expression.

On the next slide, this just shows the focus set of milestones that we're driving to now. In summary, we're laser-focused on these 2 programs. First, driving evorpacept into ASPEN-Breast, which is our study investigating patients post in HER2 and again, focused on CD47 high and understanding the impact of that biomarker. We continue to execute well against the milestones that we've communicated in the past and are anticipating first patient in Q4 of 2025, with interim data expected Q3 2026. ALX2004 also remains on track and continues to proceed very well. We dosed our first patient in August of 2025, and we continue to expect initial safety data first half of 2026.

Turning to the next slide, and in summary, before I hand the call over to Barb, we had a strong quarter, both in terms of execution, continued tight discipline around our capital and are excited about the key value catalysts for ALX in 2026. And as you can see here on Slide 9, this is a snapshot of our current clinical pipeline. As we have communicated previously, we are pursuing a focused development strategy for evo in combination with anticancer antibodies, given the consistent proof of concept that we have seen in various clinical studies with different monoclonal antibodies, and this data here today further builds on that.

In addition to our HER2-positive breast cancer program with a CD47 biomarker-driven approach, ALX2004, again, our EGFR-targeted ADC continues to progress well, and we are also very excited about our partner program with Sanofi Sarclisa in multiple myeloma, which is now in dose optimization phase.

So next, we'll turn this over to Barb, who will take over and provide more details on the evorpacept CD47 biomarker data presentation coming here at SITC. Barb?

Thank you, Jason. I will start by describing evorpacept's mechanism of action. CD47 has broadly overexpressed on cancer cells as a means of abating the immune detection. And it does so by sending a don't eat me signal. Evorpacept is a fusion protein, and it's designed to block that signal. Evorpacept's Fc region is engineered to be inactive and since it's particularly effective when given in combination with an anticancer antibody such as Herceptin. The active Fc domain on the anticancer antibody can then trigger very effective phagocytosis, which otherwise would have been suppressed by the CD47 signal.

Slide 12 shows that the evorpacept's approach to blocking CD47 is different from the conventional approach pursued by other CD47 targeted agents. While CD47 is overexpressed in cancer cells, it is also expressed in healthy cells, such as red blood cells. The conventional approach to block CD47 with an antibody that then also binds to macrophages through an active Fc has caused significant toxicities in some patients, and thus, this approach has largely failed. In contrast, the evorpacept approach using an inactive Fc spares normal cells and our safety database in more than 750 evorpacept-treated patients confirms the safety of this approach.

Slide 13 shows the design of the ASPEN-06 gastric study that Jason has introduced earlier. We enrolled 127 second-line or third-line HER2-positive gastric cancer patients, all of whom had received prior HER2-directed therapy. Patients were randomized to evorpacept, trastuzumab, ramucirumab and paclitaxel or the TRP alone. The primary endpoint was objective response. Importantly, because there can be loss of HER2 expression following prior HER2-directed therapy, we wanted to look beyond the HER2 status as diagnosed on archival tissue.

Based on the known mechanism of action for evorpacept, our drug is not going to work as effectively if HER2 is not overexpressed on the cancer cell surface. To this end, ctDNA was obtained at baseline in all patients. And in addition, 48 patients underwent a biopsy, either at study entry or at some point following their prior HER2-directed therapy. In total, 95 patients or 75% of the enrolled population were confirmed as having retained HER2 positivity by either the ctDNA or on fresh biopsy. 90 of these 95 patients were evaluable for CD47 expression in tumor cells using either archival tissue or where available, a fresh biopsy sample.

High CD47 expression based on a cut point of IHC3+ staining in at least 10% of the tumor cells was present in 48% of these 90 patients. The expanded results of this preplanned exploratory analysis of efficacy by CD47 expression level in patients who retained HER2 positivity is the focus of the data that I will review with you today.

Slide 14 shows the objective response rate in key subsets. As we've previously reported, in the 95 patients who retained HER2 positivity, we see a robust response rate of 48.9% for the avorpacept CRP arm versus 25% in the control arm. And in the subgroup by CD47 expression level, evvorpacept produced a response rate of 65% compared to 26% in the control arm amongst patients with the high CD47 expression levels. The response rate in the control arm was consistent across CD47 expression levels and lower than that in the avorpacept arm in both the CD47 and CD47 -- in the CD47 high and CD47 low groups.

Moving to Slide 15. I'm now displaying the duration of response in these same subgroups. Again, we see the potential of CD47 expression as a powerful predictive biomarker for evorpacept benefit. The duration of response in all HER2-positive patients, irrespective of CD47 expression was 15.7 months for evorpacept plus TRP compared to 9.1 months for responders in the control arm. In the CD47 high group, the duration of response was 3x longer for patients in the evorpacept trastuzumab RP arm compared to the control with a median duration of response of 25.5 months versus 8.4 months. In the CD47 low group, evorpacept TRP had a median duration of response of 11.2 months compared to 12 months for TRP.

In Slide 16, we are now showing the progression-free survival in patients with confirmed HER2 positivity and high CD47 expression. The hazard ratio is 0.39 with a median PFS of 18.4 months for the evorpacept trastuzumab RP arm, which is more than double the 7 months seen in the TRP alone arm, again, suggesting the potential for CD47 expression as a powerful predictive biomarker for evorpacept benefit.

Slide 17 shows a similar pattern of longer survival observed in the HER2-positive CD47 high evorpacept arm. Median overall survival was 17 months compared to 9.9 months for the control arm with a hazard ratio of 0.63. All of these data being presented at the SITC conference this week are based on mature follow-up. The median follow-up for survival, for example, was 25 months.

Slide 18 shows some of the various cut points that we examined for CD47 expression based on the range and strength of IHC testing. As shown here, we look at the median -- we looked at medium or high intensity staining defined as IHC 2+ and 3+ in at least 10% and in at least 25% of tumor cells. And we also looked at high-intensity staining or IHC 3+ in tumor samples with 5% or more or 10% or more of cancer cells expressing that high-intensity staining. The prevalence of CD47 high across these ranges from 40% to nearly 60% of HER2-positive patients depending on the cut point. The key takeaway from this slide is that we see consistent improvements in response rates, PFS and OS in the evorpacept treatment arm, irrespective of the cut point for CD47 expression.

On Slide 19, I'm showing a cross-trial comparison of our evorpacept efficacy data in patients with retained HER2 positivity and high CD47 expression relative to benchmark trial data in HER2-positive gastric cancer. With the usual cross-trial comparison caveats in mind, evorpacept data directionally compares very favorably to recent ENHERTU data from the DESTINY gastric04 study in the second-line setting. In that trial of nearly 500 patients published earlier this year in the New England Journal of Medicine, those patients required confirmation of HER2 status by fresh biopsy following a trastuzumab-containing regimen, and they randomized these patients to ENHERTU or to RP as a control arm.

As effective as ENHERTU was in the second-line setting in that trial, our second and third line evorpacept data generated in patients with high CD47 expression, a known negative prognostic biomarker appear much better.

Turning our attention now from gastric cancer to HER2-positive breast cancer. Slide 20 introduces a Phase Ib/II trial in HER2-positive breast cancer patients conducted by Jazz that evaluated the safety and efficacy of evorpacept plus zanidatamab in patients who progressed on prior HER2-directed therapy. These patients were heavily pretreated with a median of 6 prior lines of therapy. In 9 patients confirmed to retain HER2 status by central assessment, the response rate was 56%.

The median duration of response for that group ranged from 5 months, 5.5 months to nearly 26 months with the median not reached and the median PFS being 7.4 months. These data compare favorably to benchmark data, including, for example, the SOPHIA trial, a predominantly second and third-line HER2-positive breast cancer trial, which produced a response rate of 22% for MARI2'etuximab.

Moving to Slide 21. We've now demonstrated in these 2 studies, the potential of evorpacept to engage the innate immune response, validating the mechanism of action of evorpacept given in combination with anticancer directed antibodies in both HER2-positive breast cancer and in HER2-positive gastric cancer. This gives us strong conviction of evorpacept's potential and its path forward in the HER2-positive breast cancer setting, which we'll talk about next.

Slide 22 describes briefly the opportunity that we see for evorpacept in breast cancer, which now has a high probability of success, having been derisked by the 2 positive data sets in 2 different HER2-positive settings. A CD47 HER2-positive biomarker-driven approach with evorpacept enables a highly targeted strategy, potentially addressing the high unmet medical need in the evolving breast cancer landscape, which includes patients who have now progressed on ENHERTU.

It is now my distinct pleasure to introduce Dr. Peter Schmidt, a Professor of Cancer Medicine and Center lead at the Center of Experimental Cancer Medicine at Barts Cancer Institute. He's a well-known global lead investigator on multiple ongoing Phase III trials in metastatic and localized breast cancer. Just 2 examples of trials with immunotherapy agents he is a global lead investigator on the pembrolizumab KEYNOTE-522 study and the atezolizumab IMpassion130 study.

With that, I turn this over to you, Peter.

Thank you, Bob. The treatment options for patients with metastatic HER2-positive breast cancer are currently undergoing. I would also say, a dramatic change. We obviously have seen a very active drug moving initially into second and third line treatment with trastuzumab deruxticam, but everyone is aware of the data that now placing T-DXd increasingly in the first-line setting. And I think that's where the drug will ultimately end up. That is fantastic from a patient perspective. We have a very powerful new first-line treatment option.

But the challenge that comes out of this is there is no standard of care for patients who have been treated with trastuzumab, the sequence we had previously that patients would get a treatment called TPH, first line with trastuzumab, pertuzumab and second-line T-DXd and then third line other options has just been turned upside down. So at the moment, there's a number of options we can choose from, but none of those options have actually been specifically approved and tested in patients with prior T-DXd therapy.

So the options we have to choose from is tucatinib trastuzumab in combination with capecitabine. PD-1 is still an option. Some investigators and clinicians may give chemotherapy and trastuzumab HER2 TKIs play a smaller role and increasingly are less and less being used. But of course, we're also hoping to have other HER2-targeted therapies. So there is a significant unmet need for patients with HER2-positive breast cancer who have progressed on or after T-DXd. And I can see that well percept has a possibly exciting role to play that has demonstrated activity in patients post trastuzumab deruxtecan in combination with other HER2-targeted agents.

Now if you look at what we would hope to see in such a situation, our challenge is to bring in new agents that can overcome the resistance to T-DXd. The need for agents in the HER2-positive breast cancer space at this point is to find novel agents ideally bring a different mechanistic approach to target HER2. And we can see for evorpacept that it has a different mode of action by killing cells via enhanced ADCP versus the classic payload-based ADCs or other drugs we are currently using.

The second thing we want to achieve is we want to have a drug that obviously has demonstrated activity post HER2-directed treatment after ADCs and after monoclonal antibodies. And at the out of the room here is always trastuzumab deruxtecan. Now we've seen from the data in the gastric study, but also in some of the HER2 pretreated breast cancer studies that evorpacept has shown activity post trastuzumab in gastric cancer and following up to 4 more lines of patients with HER2 breast cancer with prior HER2 treatment.

We would like to have a treatment that can supplement and enhance the current standard of care rather than replace the backbone treatment. And again, if you look at the way how evorpacept works, it is really designed to work synergistically alongside the key therapies and the key backbone, obviously, for HER2-targeted therapy is trastuzumab or similar antibodies. We are keen to have a drug that's safe and safer than ADCs. We have to learn over the years ADCs have quite substantial possible toxicity, which is obviously driven by the payload as it is ultimately targeted chemotherapy. And the safety profile of evorpacept is very different to what we know and seems to be much more favorable compared to some of the ADCs.

Finally, having immunotherapy agents that can really drive what we see sometimes in HER2-positive breast cancer, this long tail we as clinicians often go on about that is what ultimately patients need to have a long-term benefit in survival. And we feel that there's an immune component to that. We know already that there's a small percentage of patients who have very, very long survival on HER2 target therapy. But enhancing that immune effect by giving a CD47 targeted drug can possibly increase the tail for patients, that is at least my hope.

If you look at CD47 as a selection strategy, and again, I think that is really important for this program is that we're not going into this blindfolded. We actually have a very powerful biomarker. And as you have seen from the gastric data, it's a very clearly better signal for this concept in patients with high CD47 expression. Now as you can see, there's a number of breast cancer studies that have looked into this, and I'm not going to go into each of those trials and the scoring methods in too much detail.

The bottom line is about 1,000 patients, and they're relatively consistently showing a CD47 high expression rate of around 50%. So 54% is the average if you go through those trials. And that's a substantial proportion of patients and actually allows us to drive that program forward without having a target group that is ultimately too small to select for clinical trials.

Now a couple of preclinical data, I think, are really interesting. Now preclinical data, you may say it's a little bit nerdy, but I think it's really helpful for us to understand the biology. So if you look at this slide on the left side, you see the CD47 expression in HER2-positive breast cancer cells compared to HER2-negative cells. Green means low expression, red means high expression, this black or blue color is moderate expression. And it's very obvious to see that we have a higher percentage of CD47 expression in HER2 high disease.

If you move to the right side of the slide, again, probably even more important for what we're aiming for is this is -- this compares the CD47 expression in primary disease on the right side and in recurrent disease, of pretreated disease on the left side. And again, it's very obvious that we have more positivity, CD47 positivity in tumors and therefore, in patients who have prior HER2 treatment and have recurrent HER2-positive breast scans. And this is exactly the target population we are aiming for.

If you then look at emerging data and again, cell line-based data for cell lines that were treated with trastuzumab deruxtecan. And as I said earlier, this is the new standard of care in the first-line setting. So our prediction for the future is all patients will have T-DXd pretreatment. And we have to focus on patients who have persistent to T-DXd. As you can see here, in orange, these are cells that have been T-DXd pretreated in purple DM1 and then in white is ultimately controlled. And it shows the percentage or the number of CD47 positive cells.

And as you can see very, I think, impressively is that we have a markedly higher expression of CD47 in cell lines that were prior exposed to trastuzumab deruxtecan, and that is the target group we are aiming for. So the target population is very clearly a substantial population of patients with HER2-positive breast cancer. The population is probably even bigger in patients who have prior CD47 pretreatment. But it also may be one of the ways these tumor cells evade the ADC treatment effect and therefore, may be a really fantastic opportunity for us to target this clinically.

Now the clinical trial that is ongoing, the ASPEN trial you're very much aware of is, in my opinion, serves one key focus. So as a clinician, I have asked that question before, I'm keen to see this move forward into a Phase III as quickly as possible because we know it works. We know what the target population is, and we know there's a huge need post T-DXd. But what we don't know exactly is how to do the statistics for a Phase III trial by having the exact response rate at PFS and other endpoints, which we obviously need to do to size up and design the Phase III trial properly.

So this trial, therefore, is a nonrandomized Phase II trial in patients with HER2-positive metastatic breast cancer with measurable disease with prior treatment with trastuzumab deruxtecan and are then offered treatment with evorpacept in combination with trastuzumab and patients of physician's choice chemotherapy. Very pragmatic design. This is the real world out there. But what we want to learn from this trial is really how -- what the response rates are in patients who are ctDNA positive for IL-2, but also what the duration of PFS overall survival is and in patients with CD47 high, but also CD47 low tumors to get further confirmation from the biomarker data we have already obtained from gastric cancer, which ultimately allows us to fine-tune the Phase III design going forward.

Thanks, everyone. I would like to pass back to Barb, please.

Thank you, Peter. Well, let me wrap up this section with a brief breakdown of the addressable patient numbers in the core markets. As you can see, there are roughly 48,000 breast cancer patients in the second plus line setting who are HER2-positive. Of that, we believe that at least 60% to 80% of these patients will retain HER2 positivity following prior therapy. Of that group, 50% to 70% will have high CD47 expression.

As Peter highlighted, there are a number of publications to support that CD47 overexpression in HER2-positive breast cancer patients will be upregulated post ENHERTU treatment. We believe that this represents approximately 20,000 addressable patients who are both HER2-positive and CD47 high. If you boil this down and use conventional estimates on pricing, we get to roughly a $2 billion to $4 billion market opportunity, again, just in patients that are CD47 high and HER2-positive, representing a significant opportunity for evorpacept.

On Slide 31, I now want to provide a quick update on ALX2004, our EGFR antibody drug conjugate program. As shown on Slide 32, our company's first ADC, the ALX2004 molecule was a result of rigorous internal drug design process. Our goal is to create a best and potentially first-in-class drug designed to maximize the therapeutic window and to overcome the historic toxicity challenges that others have encountered in targeting EGFR with an ADC.

With ALX2004, we have optimized all 3 components to do this, including the payload, the linker antibody to create a truly novel molecule against a very well-validated target. ALX2004 uses matuzumab-derived EGFR antibody selected to minimize skin toxicity and to maximize the therapeutic window. Its binding epitope is distinct from the U.S. FDA-approved EGFR antibodies such as cetuximab and panitumumab. Additionally, ALX-2004 has a proprietary linker payload and TPO 1 inhibitor payload engineered to offer improved linker stability for on-target delivery of payload and enhanced bystander effect. At the recently concluded Triple Meeting in Boston in October, we presented preclinical data highlighting these elements in greater detail.

Moving to Slide 33. Here are the preclinical data highlights. Both in vitro and in vivo animal models support impressive dose-dependent activity and a differentiated safety profile. Importantly, nonhuman primate toxicology studies did not demonstrate EGFR-related skin toxicities at clinically relevant doses, and there was no evidence of payload-related ILD in the animals. This overall profile supports our conviction that this molecule could potentially demonstrate efficacy with a manageable safety profile in patients.

Slide 34 shows a snapshot of the efficacy data from our in vivo models. ALX2004 showed regression and tumor suppression across a panel of xenograft models, representing a broad spectrum of cancer types and EGFR expression levels. Notably, ALX2004 was effective in models harboring KRAS, BRAS and p53 mutations. ALX2004 shows excellent tumor suppression activity at doses as low as 1 milligram per kilogram given either once or once weekly times 3, leading to complete tumor eradication in several of the models. These results confirm the broad applicability of ALX2004 in targeting EGFR-positive cancers.

Slide 35 shows the key findings from our 6-week repeat dose with 6-week recovery period in the GLP nonhuman primate tox study. All findings were minimal to moderate and fully recoverable. Thus, these data support the design of the ALX2004 study and the likely safety margin for clinical use.

Slide 36 highlights our clinical development plan. We are targeting EGFR-expressing tumor types, namely lung, colon, head and neck and esophageal squamous cell carcinoma in this dose escalation and dose expansion trial. We dosed our first patient in August, and we have completed our first dose cohort at 1 milligram per kilogram without any DLT. We are currently dosing patients in our second dose cohort at 2 milligrams per kilogram. We are on track to provide initial safety data from the Phase Ia portion of the study in the first half of 2026.

Our goal in this Phase Ia, Phase Ib trial is to identify the dose that optimizes safety and activity in tumor types, which we believe have the highest potential for success. These data will then set up the program well to advance into a future registration study.

With that, I turn the call back over to Jason.

Thanks, Barb, and thanks again to Dr. Schmidt for sharing his perspectives on the program as a KOL in the field. Again, Q3 was a strong quarter, both in terms of execution and new data. What we're most excited about now is driving a targeted IL breakthrough in a first-in-class drug with evo as well as are very encouraged by AOX2004's fast start in the clinic and building momentum.

In sum, our CD47 blocker has been successful where no other has, both in terms of its manageable toxicity profile as well as activity as we've now demonstrated efficacy in a randomized study, and we've identified an actionable and predictive biomarker for response to evo in our gastric cancer study. This further reinforces the benefit we have seen in terms of DOR, PFS and OS. And again, this biomarker is on mechanism.

Going forward, we're developing a CD47 biomarker, and therefore, it is really of no surprise to see that CD47 overexpression shows such a strong impact on our data. So what this allows us to use is CD47 to select for patients in both current and future trials with the goal of replicating the results we have seen here with gastric cancer and demonstrating the same significant and transformational benefit for patients in our HER2-positive breast study. Again, there are no approved therapies for patients overexpressing CD47 and no options in late development to address this known path of evasion. So we remain focused on delivering for them.

In 2004, there are also no approved EGFR-targeted ADCs. And although clearly a validated target, there remains a substantial unmet need for these patients as well. ALX2004 is off to a very strong start in the clinic, and we believe also has the potential to redefine standard of care across a range of EGFR-expressing cancers.

So with that, I'll open up the floor to Q&A. Again, thank you for the time this morning.[ id="-1" name="Operator" /> [Operator Instructions] And our first question will come from Lee Watsek with Cantor Fitzgerald.

This is Daniel Bronder on for Lee. This is an exciting update, and we're curious to hear your thoughts on how to correlate the CD47 positivity that you showed on Slide 30 with the kind of CD47 expression cutoffs that you showed in the gastric data on Slide 18. What would you say is CD47 high in this context? And how should we think about the patient population that would be matching that in your trial?

Thanks, Daniel. Appreciate the question. So 30, just thinking about what we saw in breast or what we've observed in the literature versus gastric, is that the question?

Yes, basically, yes.

Okay. Yes. Well, yes, it's a great question. I think it's one we've looked into. I think what's really -- what we're really fortunate to have is a strong scientific basis behind CD47. And so what we see is really promising concordance across the 2 indications. So if you look at gastric, it was roughly 50-50 in terms of the CD47 high group. And I think then if you turn to the benchmarks, and again, this is where the strength of the science comes in, it's -- we see we have 5 different publications looking at the question of CD47 in specifically HER2-positive cancer. And again, what we see is strong concordance there, too.

And if you add those numbers up, it's roughly half again. So 5 different studies supporting that around 50% of the patients will be CD47 high. And interestingly, those different publications use different clones, different methodologies, et cetera. And so yes, I think that's what gives us such conviction that this is translatable not only to breast, but frankly, a broad range of tumor types.

And if I may, can I ask a follow-up question?

Yes, sure.

How should we think about your companion diagnostic development? Are you doing that yourself in-house? Are you using the same kind of evorpacept construct? Or are you using an independent antibody? Can you shed any light on that?

Yes, sure. I mean I'll take it at a high level and then maybe ask Barb to weigh in on the path to a CDx. We've done the testing with a partner for the gastric study, plan to do the same in breast. And then, of course, as this data builds and I think as we continue to understand the right cutoff and how this translates, we'll pursue further work. But Barb, do you want to add to that?

I would just say that the assay is an IHC. It's a research use assay that was applied to the gastric data. our ongoing or our soon-to-be enrolling trial in breast cancer, the 80-patient single-arm trial will use the same research-based assay. And then we are working already with partners to think about the operationalization of the process prior to the initiation of a Phase III trial so that we will be ready for a companion diagnostic, but again, via a partner.

[ id="-1" name="Operator" /> And our next question comes from Roger Song with Jefferies.

Very interesting data. Maybe related to the efficacy in the CD47 high population, do you have any data in your breast cancer trials with Jazz and any new data you can maybe give some comments on the CD47 high versus low? And then in terms of historical breast cancer, do we have any evidence for the CD47 high population, the traditional or the standard of care is performing less than the CD47 low population? Have you done any retrospective study as well? Because I know the benchmark is using the SOPHIA or any other HER2 chemo combo, but that's in the broad HER2 positive, not the CD47 cutoff.

Yes. No, that's -- those are both great questions, Roger. So number one, in terms of the high versus low comparisons in the zani study and frankly, broadly, I think those are great questions. So this data and the way in which it's rippling through our development plan is relatively new, as you know, Roger. So I think we're really excited about what we're seeing. It's incredibly strong in terms of CD47 high in gastric. There's no question it's driving the effect in that study.

And so the natural question is where else is this working? And I think whether it's the study with Jazz or our work with Sanofi or the other studies we have going with anticancer antibodies, we're very keen to understand that. So I'd say what we know is we're seeing a 56% overall response rate in patients post ENHERTU that have seen a whole lot of HER2-directed therapy. And to your point around the margetuximab comparator, it's well north of what you'd expect.

And actually, there was recent data at ESMO that supports, again, a relatively low response rate. There was a real-world study that was sub-20% in patients in terms of ORR post ENHERTU. So to see 56% is very strong. And I think your question on CD47 high versus low is one we're in the process of understanding.

And then your second question on just benchmarking the data and what we see Barb had laid out the comparator with ENHERTU in the DESTINY-Gastric04 study. Certainly, if we were to line up the RAINBOW studies, to the best of our knowledge, the control arm is performing at par with benchmarks across a number of different studies. And to your question, which again is a good one, those benchmarks, we think are the best they're going to be, right? Because we know CD47 high is a negative prognostic and we know that those patients should do more poorly. And so to clear those benchmarks and compare well and then also be armed with the knowledge that those patients probably -- if we were to select from those studies, the CD47 high only patients, they would do even worse, certainly, I think, builds our conviction.

[ id="-1" name="Operator" /> [Operator Instructions] And we'll go next to Sam Slutsky with LifeSci Capital.

Just on the interims next year, both the EGFR ADC and the breast cancer program with evorpacept, curious on how many patients you're hoping to have in each of those data sets? And then just how you view a win as you think about safety on the EGFR side and then just delta efficacy on the evorpacept side?

Yes, both great questions. Thanks, Sam. I'll take 2004, and I'll ask Barb to weigh in on the breast front. I think 2004, as you know, targeting EGFR, one of the most well-validated Trode targets in oncology, there's just no question that EGFR is effective. So I think it's led to a natural question from investors and partners, and that's can you target this target with an ADC when you have a payload involved.

And as a reminder, again, I think we're very encouraged by what we see in the primate work. That tends to translate very well. And so far, so good, right, to clear 1 mg per kg quickly, I think, is a strong start at already a relatively high dose and now on to the next cohort, which, again, I think is moving fast is what you want to see. So as we go into the next year, early next year in terms of what we'll share, I think it's it depends, right, which is the reality of a dose escalation study.

I think our goal is to answer the safety question as best we can in a Phase I and then put up data that will answer that. And again, the study is marching very well here. And I think we feel real confident that if this continues, of course, we'll be able to share something going into early next year. And then on the breast front, in terms of benchmarks, Barb, do you want to weigh in on that one?

Yes. I think, Sam, thank you. I think you were asking what might our expectations be both for number of patients as well as the bar. The bar I'll start with. There's a lot of data with trastuzumab and chemotherapy, which really is the backbone upon which we add evorpacept in our trial. Chemotherapy, trastuzumab at best will have about a 20% response rate. Interestingly, there was new data coming out of ESMO looking at the post-ENHERTU setting and response rates continue to drop, not unexpectedly. And as we noted, our trial will enroll all patients post ENHERTU, where we do anticipate that CD47 overexpression becomes part of the mechanism of resistance, we attack that directly, and we anticipate having good outcome data in our evorpacept trial. So

I think the benchmark is going to be in the range of 15% response rates. Again, 20% might be the upper bound, but with the combination of the 2 things, the poor prognostic effect of CD47 as well as the evolving standard of care and the fact that there really isn't anything that has shown up well post ENHERTU really bodes well for us. What do we expect in our bar? I think doubling that would be nice, 35% to 40%. We certainly in our gastric data that I showed you in the gastric setting did even better, and we anticipate that the opportunity is there to do quite well, but I think we would be very happy with a 35% to 40% response rate in our breast trial.

[ id="-1" name="Operator" /> And this now concludes our question-and-answer session. I would like to turn the floor back over to Jason Lettmann for closing comments.

Great. Thanks, everybody. Really excited to share this data with you and continued good progress across both evo and 2004. So a real positive update today. And again, I appreciate the engagement and support and look forward to future updates. Thanks so much.

[ id="-1" name="Operator" /> Ladies and gentlemen, thank you for your participation. This does conclude today's teleconference. You may disconnect your lines, and have a wonderful day.