Good day, and thank you for standing by. Welcome to the ALX Oncology Post-SABCS 2024 with Dr. Alberto Montero conference call. At this time, all participants are on a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star 11 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 11 again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Jason Lettmann, Chief Executive Officer. Please go ahead. Great. Thank you. Good morning, everybody. Appreciate everyone making some time this morning. Would like to welcome you all. And today we're going to be walking through our data that was released last week at San Antonio, which is exploring the combination of evorpacept plus in breast cancer. We're excited about this data, excited to walk you all through it. And if you go to next, is our forward-looking statements. And then on slide three, just lays out the plan for today. I'm going to tee up the conversation here and just remind everybody where we are as a company, as well as where we are with our development plan. Next, we're going to have Dr. Alan Sandler, who is our new CMO, as well as Dr. Alberto Montero join us here for a walkthrough of the data. And Alan and Dr. Montero will go into a fireside chat and a Q&A. I'll also note we learned last week they're both Clevelanders, so please refrain from any Cleveland sports jokes when we get to the Q&A. And then I'm going to wrap it up with some closing remarks and then open it up for questions. So if you go to slide four here, just as a reminder here at ALX, we're working to transform cancer treatment by developing evorpacept. It's really the first in class and best in class CD47 blocker. We now have treated over 700 patients to date. We're excited about what we're seeing, as many of you know, we're in the midst of a rapid period of clinical data. And we are the first and only CD47 agent to demonstrate a strong efficacy profile and strong safety profile in a prospective randomized study, which was ASPEN-06. We feel coming off of a great year in 2024, we've demonstrated the mechanism here, and we have a clear biomarker to identify patients that respond best. This is building off of many clinical studies that we've executed to date, and we really have three big shots on goal here, combining with anticancer antibodies, checkpoints, and ADCs, and as we go into next year, we're going to talk about how that pipeline continues to build. This data at San Antonio is yet another demonstration of what we can do in combination with an anticancer antibody. We do feel like that story is certainly de-risked at this point from a mechanism perspective and excited to share the latest here today, so if you go to slide four, again, very quick reminder of what we're doing. We are blocking the don't eat me signal, which you see on the left. And then we're using an active, in this case, Fc active antibody to provide the eat-me signal. On the right is what evorpacept is. We are the only CD47 with an inactive or dead Fc. And this provides many features that are unique in the class. If you go to slide six here, I think what you see here is a quick summary, a quick snapshot of the clinical data that we've demonstrated to date. We've put up five positive clinical studies, again, the only CD47 blocker in development to show activity in a randomized setting, as well as across both hematologic malignancies and solid cancers. And feel that this is yet another dataset supportive of what this drug can do. At slide seven, again, a quick reminder of how this molecule was designed. Again, by intent, it does not have single-agent activity and works as a combination agent. It provides very potent CD47 blockade. Because of the way it's designed, we have less sync effect. We're able to dose higher because we have such a compelling safety profile. And we feel because of all of these things working together is why we're the only CD47 to have demonstrated activity in the solid tumor setting. If you flip to the next slide here on slide eight, this is a reminder of our development plan. We have several ongoing studies. As you know, this is one of them here with our combination and collaboration with Jazz to conduct this study with Zanny. Jazz conducted and sponsored the trial. We supplied the drug and are excited to be working with them here and sharing this data here today. So then on slide nine, quickly just wanted to introduce Alan. Alan has just joined us as our Chief Medical Officer. This is his first public call here. Absolutely thrilled to have Alan on board. Alan started his career as an academic. He's a well-renowned KOL in the lung cancer space. From there, he went over to industry to ultimately head up product development in late-stage oncology at Genentech. He then left Genentech to head up global development at Zai Lab. And then most recently, he was CMO at Mirati, which, of course, had a great ending there. So absolutely thrilled to have Alan. He brings a wealth of development expertise and late-stage development expertise at that and is a great fit for the team. So with that, I will turn it over to Alan. Great. Thanks, Jason. And thanks, everybody, for taking the time to be with us this morning. I've got two slides I'm going to speak to, and then I'll introduce Dr. Montero. Both of these slides relate to the mechanism of action of evorpacept. And specifically, in combination with zanidatamab, which is a Zymeworks created bispecific that binds to the HER2 extracellular domains of ECD2, which is pertuzumab's target, as well as ECD4, which is trastuzumab's. So it is an IgG1 antibody, and this will drive the antibody-dependent cellular phagocytosis, or ADCP. This combination is fundamentally different than any other HER2-targeted antibody alone. And the combo may and should drive responses where patients have progressed following HER2-targeted therapy, which we'll be discussing shortly. As Jason has noted, there's limited single-agent activity from evorpacept, of course, but also HER2-targeted therapy specifically in this particular setting. This is a chemotherapy-free regimen targeting the unmet need in breast cancer patients who have progressed on multiple HER2-targeted agents. And in this particular study, that includes prior therapy with HER2. Moving to the next slide, which should be slide 11, this is a cartoon that depicts the previous discussion that we had showing the binding of evorpacept to the CD47 domain and then the macrophage Fc receptor binding along with zanidatamab to the HER2 domain for establishing ADCP. With that introduction, I'm very pleased to present a Cleveland colleague, certainly who's at least there now recently, Dr. Alberto Montero, who is the Clinical Director of the Breast Cancer Medical Oncology Program, also Medical Director of the Oncology Clinical Trials Unit, and Professor of Medicine at Case Western Reserve University School of Medicine. And he will take on the next segment of this program. Alberto? All right. Thanks. Thanks, Alan. Thanks for the opportunity for being here. I'm very excited to talk about the data that was presented last week at San Antonio. If we can go to slide 13, which is my disclosure slide, and then moving on to slide 14 as sort of a background to the trial, so despite a lot of progress that's been made in breast cancer, as you can see on the bottom, if breast cancer is detected early, we have five-year survival rates for stage one and two or localized breast cancer, which are close to 100%. However, metastatic breast cancer still remains incurable. Although we've made progress, five-year relative survival for stage four breast cancer is around 32%, and that's really mainly driven by better drugs. So for breast cancer subtypes, here we're talking about HER2-positive breast cancer, which represents about 15%-20% of patients with metastatic breast cancer. And we've made a lot of progress because of the many new drugs that we have. If we go to slide 15, this shows the current landscape, which has been rapidly evolving. We've had many new drugs FDA approved. So right now, the current landscape is for metastatic HER2-positive breast cancer, the first line remains what was established by the CLEOPATRA trial many years ago, which is Trastuzumab and Pertuzumab, which Alan highlighted as monoclonal HER2 antibodies with a taxane. A second line more recently was established as T-DXd. There is an ongoing DESTINY-Breast09 trial that's looking at T-DXd in the first line with or without Pertuzumab. We don't have that data yet, but given the activity of T-DXd, it's very likely that that will be the first line and it'll shuffle and there'll be a realignment of sort of what to do beyond that. And we'll see that the dataset we have here in this trial is in patients that primarily had already received T-DXd. So it's going to be especially relevant for the future landscape. So if we go to slide 16, so this is the title of the abstract that was presented. So Zanidatamab in combination with evorpacept in patients with HER2-positive metastatic breast cancer and HER2-low breast cancer. And this was a phase 1B/2 trial. If you could go to slide 17. So this is the study design. The key eligibility criteria are on the left, but I wanted to highlight the fact that unlike some studies that really want to have a less heavily pretreated population, it's a testament to the credit of the Jazz and ALX Oncology team. And that was one of the reasons why I was excited about participating in this trial. They wanted a heavily pretreated population. So it was a requirement that patients must have had three or more prior regimens, including trastuzumab, pertuzumab, and either T-DM1, tucatinib, or T-DXd. Cohort two was a HER2-low population. And then cohort three, which is a smaller cohort, was non-HER2-expressing non-breast tumors. So it was a limited phase one trial because both of these compounds have been already evaluated independently. So there was really just two dose cohorts: evorpacept at 20 milligrams per kilogram or at 30 milligrams per kilogram Zanidatamab. Based on the pharmacokinetics, it was using a flat dose of 1,200 milligrams for less than 70 kilograms of body weight versus 1,600 for patients weighing more than 70 kilograms or more. Both drugs were dosed every two weeks on a 28-day cycle. As you can sort of see in part two, we had expansion cohorts, mainly HER2-positive metastatic breast cancer, which was the area of interest, and HER2-low, 15 patients, and then only eight patients in the HER2-positive non-breast tumors. As many phase one trials, the primary endpoint really was safety, and then with an eye towards overall response, with secondary endpoints such as PFS, OS, pharmacokinetics, and correlated markers as shown here. So if we can go to slide 18, so these are the patient demographics and baseline disease characteristics of the trial. So I just want to highlight the fact that this was a heavily pretreated population. So if you look at cohort one, which is the metastatic HER2-positive breast cancer, so there were 21 patients, all of which 100% had had T-DXd. In the cohort two, about a third had had T-DXd, and that's because through the course of the trial, the sort of landscape had changed. And so T-DXd became FDA approved in HER2-low metastatic breast cancer. But even the non-breast HER2-expressing had received prior T-DXd. So this cohort of patients is heavily pretreated, had had prior T-DXd, 100% of the HER2-positive patients. So HER2-positive assessment was based on local assessment of HER2 tumor. However, the trial required, if feasible, to get a biopsy, a repeat biopsy, and to send it for central review. And so this is something that we see in other trials where there is tumor heterogeneity because of evolution of the tumor. So of those 21 patients who had local HER2-positive assessment, 40% were confirmed by HER2 positivity. And again, there are many reasons for this, but I think one of the main reasons is just that the archival specimen, including several of my patients, had been done months or a couple of years prior to, and things can change and evolve over time. So that's something that we see in other trials. And then with the HER2-low cohort, 93% were confirmed HER2-low by central assessment. So if you go to the next slide, slide 19, this shows the safety profile. Again, that was the primary endpoint. So in all patients that were treated, it was well tolerated. There were no surprise toxicities. The main toxicity we saw were what we would expect, which were infusion reactions in about 4% of patients related to Zanidatamab, as well as diarrhea, which is again attributed to Zanidatamab. Of interest, if we look at heart failure, which is a known toxicity with HER2-targeting agents, there was only an asymptomatic ejection decrease, which was transient in one patient. If we can move on to slide 20, this shows the overall response rate by cohort. Cohort one and two are broken down by central confirmation. So of the 21 patients who were locally HER2 positive, nine were centrally confirmed to be positive. The overall response rate was 55% with a disease control rate of about 80%, and the median PFS was 7.4 months. The median duration of response has not been reached yet. As expected, because of the mechanism by which evorpacept enhances immune-mediated phagocytosis, it is not surprising that the tumors that have the highest HER2 expression had the highest response. But even those who there was heterogeneity in terms of the HER2 expression by central versus local lab still had a pretty impressive response rate and PFS, especially if we put that into context. On the right box, we have the SOPHIA trial. Again, intertrial comparisons is always challenging, but just to get a comparison. In the SOPHIA trial with margetuximab, which is a monoclonal antibody that has more of an immunogenic end of the antibody that interacts with FC receptors more readily, plus chemo, you see an overall response rate that compares this trial, the overall response rate without any chemo-free regimen compares quite favorably to that. And again, even in the cohort two, the HER2-low tumors, we still see not as good as the HER2-positive cohort confirmed by central review, but we still see a 20% overall response rate and a PFS that's in the ballpark of other trials such as the SOPHIA trial. And again, it's important to call out that all of these patients had had prior T-DXd and had had a median of six prior HER2 regimens. If we go to slide 21, so this is the waterfall plot. Cohort one, which is the HER2-positive cohort, is shown in the red bars. The bolded boxes on the bottom are the patients who had HER2 centrally confirmed tumors. So as you can see here, 71% of patients had a reduction in the target lesion size from the baseline. So in a very heavily pretreated 100% prior T-DXd, we see a very active regimen. Even in cohort two on the right, we see pretty good activity. If we move over to slide 22, this shows durability of response. We still have four patients in the HER2-positive cohort that are still on therapy. We can see again in the bolded boxes on the Y axis, we can see those are the patients who had local HER2-positive and centrally confirmed HER2-positive. Again, we see eight patients in cohort one who have been on treatment for six plus months and four for greater than 12 months. And then in cohort two, two patients were on treatment for six plus months, and one is still on therapy as of presentation of this abstract. If we go to slide 23, which will be my second to last slide. In conclusion, this trial is the first study that really reported data on the safety and efficacy of evorpacept in combination with Zanidatamab, which again is a HER2-targeted bispecific antibody in a very heavily pretreated cohort of patients with HER2-positive expressing cancers. This combination showed promising anti-activity in breast cancer patients who had had prior progression on T-DXd with an overall response rate in those that had HER2-positive confirmed breast cancer of 55% and a median PFS of 7.4 months. Even in those tumors that were HER2-expressing but didn't meet the threshold of HER2 positive, this regimen was active with an overall response rate of about 20%. As far as the toxicity profile for a chemotherapy-free, this is a chemotherapy-free regimen. It had a very well-tolerated safety profile. The infusion-related reactions were managed ultimately by reversing the order of the infusion and ensuring proper premedication, and the diarrhea was quite manageable. So in conclusion, further development of this chemotherapy-free regimen of evorpacept and Zanidatamab is definitely warranted. We can go to the slide 24, and that concludes my part of the talk. All right. Thanks, Dr. Montero. Now it's time for you and I to have a little bit of a Q&A. I've got several questions for you. I think I'd like to start sort of as an overview, if you would, to maybe provide just sort of a top-line view of the current treatment paradigm for patients with advanced and generally relatively heavily pretreated HER2-positive breast cancers, just to sort of set the stage for us. Yeah. So I think it's pretty, even though there are a lot of drugs, we can look at it in a pretty straightforward manner. So at this point, until we have new data, the standard of care for first-line is really a trastuzumab, pertuzumab, and a taxane for HER2-positive breast cancer. And then at progression, T-DXd would be second-line, and then you'd put sort of everything else in a bucket. Now, there was data presented at San Antonio looking at the hormone receptor positive, HER2-positive breast cancer, looking at endocrine therapy, sort of maintenance with CDK4/6 and HER2 therapy. But at this point, the standard of care, I think, would largely remain if somebody's chemotherapy can tolerate chemo, would be a taxane, pertuzumab, trastuzumab, and then T-DXd. Great. Thank you. And now maybe a little more specific. As you pointed out, this patient population was extremely heavily pretreated with a median of around five or six different therapies. Obviously, the options are quite limited for this group. In general, for seeing a patient like this outside of a clinical trial, what would you generally advise for patients in this setting at this time? Yeah. That's an excellent question. I think it's really an unmet need. T-DXd is really a very active drug, and so we really don't have a good answer of what to do after T-DXd, so I think this trial really addresses a really important unmet need. I think if there's no clinical trial, I think we just go down the list of drugs and we sort of see what a patient hasn't received, so that could be a lot of things. It could be tucatinib, capecitabine, and trastuzumab. If they didn't have T-DM1, they could have T-DM1, but really, none of the options in the post-T-DXd world has emerged to be superior than any other, so really, because these patients are incurable, quality of life is important, so you have to sort of balance the side effects. A lot of the decision-making on what to treat really is based on what they've been on before, what issues do the patient have, and sort of what is the toxicity profile of the potential options for that patient. Great. Thanks. And certainly, some of those options are limited to potentially chemotherapy in this setting as well. So certainly, it provides a setting where providing a chemo-free regimen might be advantageous. So let's talk specifically about this particular trial of which you put several patients on of your own. Anything about the data from this study, a phase 1B, phase 2 study? Did anything surprise you as a clinician? And in addition to that, if I may ask also, what was something that you found most interesting about this particular study as well? Yeah. So I think what I found most interesting about this study is that when it was designed, there was no cherry picking. You went straight for sort of the most heavily pretreated population. That was what got my attention and why, as my group, we decided to open the trial. As the trial was ongoing, I think what really surprised me most is I had a patient who had had a complete response, and this was a patient who didn't really respond to anything. She wasn't on anything for more than, say, six months. So she had gone through trastuzumab, pertuzumab, and a taxane. She had received T-DM1, T-DXd, tucatinib. And when she got on this trial, she not only had a complete response, but she sort of maintained a complete remission for over a year. Unfortunately, she then progressed. But I have really never seen anything like that. So that really was quite pleasantly surprising and also a testament to the importance of clinical trials. So it gave this patient really an extra year of very good quality of life because this is a chemotherapy-free regimen that controls her disease a lot longer than anything else would be expected to do. Right. That's obviously a very wonderful story to see a complete response in a setting such as that. Maybe you could provide us a little bit of background on your thoughts in cohort one and specifically those patients who were HER2-positive by central review and comment on how their response rate and median PFS looked better than when compared to the overall cohort. And I'll leave it at that. Yeah. I mean, several things. I think, first of all, it's because of the mechanism by which evorpacept works by enhancing antibody-dependent phagocytosis. The more target you have, the more antibody is going to be coating the cell and the more immunologic response you presumably have. So I would say it's expected that the more highly expressing a tumor is for the target of the monoclonal antibody, the more response you would see. In terms of why did we see this variability, I think, again, we assume that tumors are sort of static. We know that they're not, whether it's at a protein level or a gene expression or a DNA mutation level, tumors change, and so you have sort of temporal heterogeneity. So if at time X, a patient had a tumor that was biopsied in that area, happened to be highly HER2-expressing, and then at time Y, you biopsy a different area and a year has passed, it's not surprising that you would see that variability. And I think that's why a lot of registration phase three trials, Alan. I know you did a lot of late-stage drug development. That's why in late-stage trials, they require this sort of central confirmation to address this heterogeneity. Thanks very much, Alberto. A couple more questions. And now having evaluated and presented this data, how would you envision a path forward for evorpacept in combination with HER2-targeted agents in breast cancer? I'm really excited about the data, and I think it gives a very compelling signal that evorpacept really enhances the activity of monoclonal antibodies. So I would love to see evorpacept developed in this sort of post-T-DXd world where we really don't have any great options, none of which are non-toxic. They all have some sort of chemotherapy or antibody-targeted chemotherapy. So I would love to see evorpacept in combination with Zanidatamab or other HER2 antibodies in the metastatic breast cancer space in that post-T-DXd world, which might be as soon as if that becomes first line, that means then our box will be first line T-DXd and then second line will be everything else. And in that everything else category, there's again nothing that has emerged to be better, and we don't have many, if any, non-chemotherapy options. Great. Great. Thanks. I'm going to ask you to step outside your comfort zone for just a moment and understanding your comfort zone within as a breast cancer KOL, but understanding the mechanism of action of evorpacept and considering the data you've presented today along with the earlier top-line findings from ASPEN-06 in HER2-positive gastric cancer, how would you characterize evorpacept's potential across a broader range of malignancies? Yeah. I mean, I think biologically, all these other data, all these other trials outside of breast cancer just demonstrate that by blocking CD47, evorpacept can enhance antibody-dependent phagocytosis, which a lot of times we think about antibodies as sort of blocking signaling. In this case, there's a HER2 pathway or other, but equally important is really the immune-mediated mechanism. So by augmenting that, I think, is really important because then you can sort of get a synergistic sort of response where the antibody is blocking signaling, but at the same time, evorpacept is enhancing the other important mechanism of immune-mediated phagocytosis. So I mean, I think it's a rationale that resonates and could apply in any solid tumor setting where we use a monoclonal antibody that is immunogenic. Great. Well, thank you so much and really appreciate the time and your efforts, particularly in participating in clinical trials in general and taking care of these patients with metastatic breast cancer. So I'm going to turn the call back over to Jason. I believe he has a couple more slides before questions. Jason. Great. Thanks. Thanks, Alan. And a big thanks to you, Dr. Montero, for your leadership and participating in this. Great to hear of the patient stories, of course. That's core to why we do this. And appreciate all of your engagement here. So turning to slide 25, again, to just sort of paint the big picture here. We are very excited now about what we're seeing when combining evorpacept with an anticancer antibody. And we're particularly excited about what we're seeing Enhertu-positive tumors. This is now the third data set Enhertu-positive tumors. So we had the phase 1B in gastric followed by ASPEN- 06, which is our randomized study, and gastric followed by this data. And all three of those studies have a very, very strong signal. So there's really four things that we'd like to point to, again, to draw the parallels for you all across two different HER2-expressing cancers with gastric and breast. First is just the activity. On the left, as you can see in ASPEN-06, we demonstrated a 40% ORR when combining with TRAZ or Herceptin versus 26.6%. And very similar to what we saw here, encouraging durability of a DOR with close to 16 months. Again, here, what we showed with Zanny with an ORR of 33% in all of cohort one in this heavily pretreated population is similar to what we saw in ASPEN-06. The next bucket here is just this biomarker that we're seeing in ASPEN-06. As you'll recall, when we combined with TRP, we had a 59% ORR in patients with fresh biopsies versus 23% in control, which in some ways is similar to what you see on the bottom here with EVO plus Zany with an ORR of 55%, again, also in a heavily pretreated population where we confirm those patients via central lab. So we think we know now, of course, in quotes, but we think we know what patients benefit the most from EVO. The third is the safety profile. When designing and developing a combination agent, the safety profile is very important. And we continue to show that we are not adding anything to the backbone therapy. So certainly, it was the case in the gastric study with TRP. And now here, combining with Zany, we've demonstrated again that the safety profile really differentiates this drug and approach. And then last, but certainly not least, this drug is doing something different. It's bringing something different to the HER2-positive story that allows us to treat patients that have progressed on a wide range of HER2-directed therapies, including TRAZ, including Enhertu, etc. So again, on the gastric side, that was the design. All patients in the gastric study had progressed on a HER2-targeted agent. In that case, it was TRAZ. And then here, again, these patients had seen a whole lot of HER2-targeted agents, including Enhertu, and we were able to drive efficacy. So those are the four reasons why we're excited about this. Again, a consistent story. We've now delivered data in two different HER2-positive tumor types with two different FC-active antibodies, which we feel not only de-risk this program Enhertu-positive cancers, but also broadly when combining with an antibody. So just to wrap up here on slide 26, and then we'll go to questions. Again, this adds to the evidence now that we have. Again, this would be positive study number five for us. And again, what we're seeing here in patients that are heavily pretreated is very exciting. To see the responses that we are, I think, is a very strong signal. We feel importantly we know where the drug is working best. Again, that's very important in oncology broadly these days, but particularly in IO, as many IO mechanisms have stumbled when it comes to identifying the right patients. And then last, but certainly not least, we now very much are on our front foot in terms of advancing this program into breast. We're going to be sharing more soon as to what our launch plans are here and how we would take on this opportunity. But as a HER2 moves to the front line, it really does create an exciting opportunity for us to provide an option for these patients that have progressed on a HER2. So this is really the first of many updates. So the next update we're looking forward to sharing is our updated Aspen 06 data. We guided to first half, and we're refining that guidance here to say Q1. And we're going to be back in touch very, very soon as to what the medical meeting will be. We're going to be presenting more data on Aspen 06 in terms of durability, PFS, and then I think really importantly, looking more deeply at this HER2 story and other ways in which to measure HER2 expression to really refine our biomarker strategy. So with that, I'll close. Again, thank you again to Dr. Montero, the patients that participated in this study, certainly, and to the team. So with that, I will open up the line to questions from the analysts. Thank you. As a reminder to ask a question, please press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. Our first question comes from the line of Michael Yee with Jefferies. Your line is now open. Hi, good morning. This is Jenna. I'm aligned for Mike. Thanks for taking our questions and congrats on the data. I have a quick one for Dr. Montero and a follow-up for management. So for Dr. Montero, given the strength of this data set with Zanidatamab, how do you envision what a combo withEnhertu could potentially look like since that data is coming next year? And to what extent does this data give you perhaps more confidence or more comfort that the combo could do even better withEnhertu? And the follow-up for management is putting together the Zanidatamab combo data today and what the evorpacept combo data could look like next year. Kind of how do you contextualize the two and how do you think about your overall opportunity and positioning in breast cancer? Thank you. Hi. Excellent question. I think to answer the first question of what would Zanny, sorry, what would evorpacept with T-DXd combination look like? And then the other part, I think, was how do you contextualize Zanny and evorpacept in a post-T-DXd world? So the first question, I think T-DXd certainly could be combined with evorpacept. I think there are reasons to do that. I think from a clinical trial perspective, though, I think one of the challenges if you envision a phase three trial is because T-DXd is so highly active, it would be hard to see a contribution of evorpacept even as active as evorpacept is. I wouldn't even know how big, if you look at the design, to see a difference in events. I think that might be a challenge. But I think that in a post-T-DXd world, which likely will be everything after first line, I think Zany with evorpacept or evorpacept with any other combination of monoclonal antibodies or with chemotherapy, whether or not it's an antibody-drug conjugate or not, I think makes a lot of sense. You could even envision an idea of could you rescue resistance to T-DXd or any other antibody by adding evorpacept as well? So I mean, I think there are a lot of possibilities for sure. Just to take your second part of your question there, Jenna, thanks for the question. I think, yeah, as Dr. Montero pointed out, I think we do feel like mechanistically this should work, if you will, withEnhertu. As you know, we have three shots on goal here with antibodies, checkpoints, and ADCs. All three of the mechanisms are slightly different. Of course, we love as a company to say each data point here that we share that's positive de-risk all three. I think the ADC story is different in terms of how we combine. But it's an intriguing question, and we're looking forward to sharing more data from the study withEnhertu that we're doing with I-SPY. And to see, frankly, if we're seeing a similar phenomenon here where patients that are truly HER2-expressing is that where we have our most benefit. So, I'd say hold that thought, and more to come soon. Got it. That's very helpful. Thank you so much. Thank you. Our next question comes from the line of Chris Raymond with Piper Sandler. Your line is now open. Hey, thanks. And thanks for this information. Maybe just a question on Zanidatamab. I'm just kind of curious if you guys had a sense as to how that drug would do in monotherapy in this setting. We were looking and can't really find a ton of data with that drug as a monotherapy. And then also just on cohort three, the ORR there was lower Enhertu-expressing cancers than in breast. Is this maybe sort of an indication that you're seeing a more active treatment in breast cancer or something else going on there? Thanks. Yeah. So the first question, again, I appreciate the question. Thanks, Chris. I think on what we're seeing in terms of activity, I think, as you know, we're by design built to not have single-agent activity. And I think what we're really excited here with this combination is just to see responses in a heavily pretreated population. I think what we know is that it's working, and we know it's working in a way that's different than other HER2-targeted agents. So then on your second question, I can weigh in and then have Alan as well. I think the beautiful thing about this mechanism is it shouldn't be tumor-dependent, right? CD47 signaling is a very common mode of evasion across almost every tumor type. And so what's exciting for us as we see this data in breast is that it's working here too. So certainly, there's a difference between gastric and breast. But again, I think from a mechanism perspective, we see a lot of parallels. And to see the data line up here so similar to 06, I think it's really encouraging. But Alan, do you want to add to that question? Yeah. Sure. Thanks, Jason. I'll actually double back on the initial question, which I believe also was referring to Zanidatamab as monotherapy and was there any data that was available. I think it was probably most appropriate to direct those questions to Jazz and any folks from ZymWorks to understand where that data might be. That was the one question. The other one, to build upon the tumor-agnostic cohort, yeah, I agree with what you stated. I would probably emphasize that the data that we have so number one, biologically, it makes absolute sense to consider that type of basket study looking at a tumor-agnostic approach. Second, the data that we have shows that it's feasible. There is some activity. And of course, as you know, small numbers of patients, lots of different tumor types that do differently respond differently to therapy regardless. Looking at outcomes is challenging in that setting with few patients, but I think is an opportunity to look as you build up the number of patients, then you can look at the different subsets and see how they do against their historical controls and have a better sense of that. But bottom line is agree with the concept that that's an interesting approach. Thank you. Our next question comes from the line of Li Watsek with Cantor. Your line is now open. Good morning. This is Daniel Grund for Li. We have a question regarding the biomarker development, and we were curious if you were considering some of these more novel, more modern approaches looking at perhaps circulating tumor DNA by next-generation sequencing, which would alleviate the necessity for a biopsy. Thank you. Yeah, that's a really great question, Dan. We've been all over that one here for the last many, many months. I think one of the things we're curious about, particularly in our gastric data, is the question, does ctDNA, does circulating HER2 positivity show the same thing, right? Can we bring that to the table and, again, allow a patient to skip a biopsy in effect and use this as a way to help get the right patients on the drug? So I'd say that we're actively doing that. In our next ASPEN-06 data, we're planning to share more on that front. Then in this study, maybe we could have Dr. Montero just provide some thoughts on ctDNA and breast and kind of what you'd expect to see there. That might be helpful. Yeah. Happy to join the conversation. I think there are some interesting data, actually, in the same poster discussion of this trial showing in other data sets with T-DXd the correlation between circulating copy number of HER2 transcript as correlating with response and also prognosis. So patients that didn't have circulating HER2 mutations or DNA had a better prognosis. This has been seen in other settings. But so I think there is potential in the future to obviate the need for a biopsy. The challenge, though, is that all the trials that have been done until now are really all predicated on tumor biopsies. So we'll need some really robust data to help pivot the standard of care, which the standard of care really is, if possible, to do a biopsy and to do it close to the time of going on a HER2 therapy. Thank you. Thank you. Our next question comes from the line of Sam Slutsky with LifeSci. Your line is now open. Hey, good morning, everyone. Thanks for taking the questions. Thanks for the presentation as well. Two for me. I guess comparing and contrasting the gastric outcome with this breast cancer outcome, both show good response rates. Gastric also showed a really good duration of response. I guess with the swimmer plot that you showed today, do you feel that that's a more kind of pronounced swimmer plot than you would expect with Zanidatamab alone in this setting? And I have a follow-up question. Yeah. I think I can talk about the parallels to ASPEN-06 data, and then I'll ask Dr. Montero to weigh in on what he'd expect from a clinical perspective here in terms of the swimmers. I think we're developing an IO agent, as you know, Sam. So the tail and the durability, if you will, is super important. And we certainly saw that in ASPEN-06. Again, looking forward to sharing more there very soon. And so to see the tail here again, I think, is strong, right? And to hear some of the anecdotes around the durability of these responses is important. And when you're a patient faced with really refractory disease and looking at chemo as essentially your primary option, bringing IO to the table here is really a great option. So we're excited about that. And yeah, I'll let Dr. Montero talk to the specifics, though, here. Yeah. I think given how heavily pretreated this population is, I mean, I think the swimmer plot is quite impressive. That's not something I would expect in a chemotherapy-free regimen. That would be something I would expect more with an antibody-drug conjugate or combining HER2 antibody like Zanidatamab with chemotherapy. In fact, Zanidatamab is in a phase three trial. They're combining it with chemotherapy. So I think we would not expect that type of duration of response in a chemotherapy-free regimen in such a heavily pretreated population. Okay. And then just a quick follow-up. I guess between gastric and your breast cancer studies, you'll have data with Zanidatamab, trastuzumab, as well as Enhertu in combination. Obviously, all three of those agents are used in breast cancer across various different settings. I guess what's ultimately going to determine which setting in breast cancer you go with and which combination partner? And just how are you thinking on that? Yeah. I can speak to it at a high level, Sam. I think, again, this opportunity withEnhertu moving to the front line is going to be disruptive to many players. And the beautiful thing about this drug that I think we're seeing here is that if we have an Fc active antibody, we can drive activity. And so I think the opportunity for us is there. Again, we have a safe molecule. We know the dose. And so we have, I'd say, few limitations from a development perspective to move upline. So I think second line behind Enhertu would certainly be a compelling opportunity for us. But Alan, do you want to add more color to that? Yes. I agree with what was stated. And I think, again, key points to emphasize. We're going to be adding to what is considered standard of care. So I think that opens the door for lots of possibilities. We're not challenging those drugs that are already available. So I think partnerships to work with some of those other agents are available and will be opportunistic in that setting, always with a mind toward a registrational approach moving forward. How do we get this potentially lifesaving therapy to patients as quickly as possible? And so those agents that are already approved are in the mix. And then other agents such as Zanny that has a path forward is something we'll be watching with and can be worked with as well. Just trying to keep an eye on the ball to try and provide better cancer therapy for patients in this setting is the plan. Got it. Thanks. Thank you. Our next question comes from the line of Brad Canino with Stifel. Your line is now open. Hey, thank you for taking the question and for hosting the event. Maybe to the physician on the call, you mentioned after T-DXd, you can create this bucket of all the other therapies that are available. But I want to know which one do you generally focus on as your third-line therapy for patients in your practice? And what level of activity do you generally notice in that post-T-DXd therapy? Just trying to get a sense for some comparison, knowing that there are few, if really any, post-anti-HER2 benchmarks from clinical studies given the recent change in the paradigm. Thank you. Yeah. Excellent question. Thank you for that. I would say in a post-T-DXd, well, my preferred regimen actually for the last two years has been this trial. So if I don't have an exciting trial, then typically I probably would bring into tucatinib with capecitabine and trastuzumab. And somewhere in the ballpark of 20-ish, 20%-30% response rate is sort of what I anecdotally would expect. But the issue is that you do get significant toxicity. So I think it's almost an apples-to-oranges comparison because here you have very good response. The numbers are small, but very impressive signal and without any sort of chemotherapy and little in the way of toxicity. But yeah, so generally, it would be something like tucatinib or T-DM1. But again, even that, after T-DXd, T-DM1 doesn't really work so great, at least in my experience. And then you have a lot of neuropathy and a lot of issues, LFT elevation. So a lot of toxicity and response rates that are not really that great. That's helpful, and then maybe on the biopsy, how onerous is that, particularly in community settings, to keep doing sequential biopsies for HER2 status? I would think with the introduction of Enhertu in second line, there's at least several stainings and biopsies that are done. Can you just provide some comments on that? Thank you. Yeah. I think with just the proliferation of targeted therapy options, and sometimes we do a ctD NA in the blood, and you may or may not see anything, and it might just be a sample issue, so I think especially for HER2-positive breast cancer, because things can change and patients tend to have visceral disease, it's usually not super onerous, and if you have a good interventional radiologist, it can be safely done. I think it's more of a problem in ER-positive breast cancer because you have more bone metastases, and bone is sort of problematic and testing by immunohistochemistry or DNA, so for HER2-positive, patients tend to be younger, more aggressive disease, more visceral. So I think it's a little easier to get a biopsy. Appreciate it. Thank you. Thank you. Our next question comes from the line of Ting Liu with UBS. Your line is now open. Oh, hi. Good morning, everyone. And thanks for hosting this event. So maybe to follow up Chris's question and also echoing some of the earlier questions that we're looking at the swimmer plot, the fact that there is a clear association of HER2 expression and response does seem to us it's mostly Zanny taking action here in this patient pool. So can you yeah, you mentioned you cannot really comment on Zanny's monotherapy activity, but are there any other commentary you could make that you see in this data set that you can highlight and make us feel more comfortable that evorpacept has provided additional efficacy on top of Zanny? Thanks. Yeah. Sure. Thanks, Ting. Appreciate the question. I mean, again, I think what gives us such high conviction is this is not a well-known study, right? We now have several with anticancer antibodies across both heme and solid, right? If you think about our data of NHL, gastric, this, I mean, it's a growing body of evidence that supports that when patients have progressed on prior HER2 therapy, we're able to do something and add a very different mechanism to the equation. So again, I think for us, that's what gives us conviction. So we would yeah, it's not our question to answer in terms of activity, but again, really have a lot of confidence in this combination. So Alan, I don't know if you want to add to that, but go ahead. Yeah. Jason, thanks. Again, agree with what you said. Won't speak specifically to Zanny. That's their data. But I think it's fair to say that in the setting that we've described with patients with five or six or more prior lines of therapy, there really isn't much single-agent data that would suggest a response rate that would be anywhere near what we saw, five responses out of nine patients, including the one CR that Dr. Montero had mentioned as well. We know it's small numbers, but these were all centrally pathologically confirmed patients to be HER2-positive, five responses out of nine patients in a setting where I would venture to say one response out of nine would probably, if not, and be generous even with two in that particular setting with monotherapy of any agent whatsoever. So to see five responses, we're really excited about it and looking forward to further development here. Yeah. Thank you much, Jason and Alan. I have a quick follow-up. So for the central assessment, were patients sample collected before or after they started the treatment? I can start with that. All patients had biopsies and tissue procurement before starting treatment. That had to be evaluated before the treatment started. Okay. Yeah. Thank you. That's all my questions. Thank you, Alan. You're welcome. Thank you. I'm currently showing no further questions at this time. I'd like to turn the call back over to Jason Lettman for closing remarks. Sorry. I was talking to my mute button. But appreciate the engagement here. Really excited about this data. Again, another data set here that certainly builds our confidence. Very much looking forward to the ASPEN-0 6 update, which is coming soon, and looking forward to talking to everyone again then. So thanks again, and I hope everyone has a great holiday. This concludes today's conference call. Thank you for your participation. You may now disconnect.