Welcome to the ALX Oncology Conference Call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during that session, you will need to press star one on your telephone. If you require any further assistance, please press star zero for an operator. I will turn the call over to Jeanne Jew, Chief Business Officer of ALX Oncology. Jeanne? Good morning, and thank you for dialing in to today's conference call. I'm Jeanne Jew, Chief Business Officer of ALX Oncology. Today's call will focus on clinical data of evorpacept, a CD47 myeloid checkpoint inhibitor, and specifically data from our ASPEN-01 phase Ib trial in gastric cancer and head and neck cancer that will be presented at the Society for Immunotherapy of Cancer, or SITC, on November thirteenth. A slide deck for this webcast is available on our website in the Investors Events section. Dr. Sophia Randolph, our Chief Medical Officer, will discuss the updated phase Ib gastric cancer combination data. We are also privileged to be joined today by Dr. Dr. Kevin Harrington, Professor of Biological Cancer Therapies and Head of the Division of Radiotherapy and Imaging at the Institute of Cancer Research, who will discuss the clinical data in head and neck cancer in combination with pembrolizumab and chemotherapy. At the end of our remarks, we will open the line for questions. Dr. Jaume Pons, CEO, will also be available during the question-and-answer session. Before we begin, we would like to remind you that today's presentation will include forward-looking statements based on our current expectations and beliefs. Such statements represent our judgment as of today and involve substantial risks and uncertainties that may cause actual results to differ materially from the results discussed in the forward-looking statements. With that, I would like to introduce Dr. Sophia Randolph. Sophia? Thanks, Jeanne. Today, I will be highlighting data on evorpacept from the gastric cancer portion of the ASPEN-01 phase I trial from poster number 498 that will be presented at SITC 2021 this year. On slide number 1, you can see that gastric and gastroesophageal cancers are one of the more common cancers worldwide, with greatest incidence in Asia and poor survival in the advanced setting. By way of background on slide number 2, standard first-line therapy for patients with advanced HER2 positive gastric cancer is trastuzumab plus chemotherapy, most commonly a doublet of a fluoropyrimidine and a platinum. In the second-line setting, the combination of ramucirumab and paclitaxel, or ram-pac, is associated with the best outcome and is considered the global regulatory standard of care. Trastuzumab deruxtecan was evaluated in the third-line setting in patients with HER2 positive gastric cancer in the DESTINY-Gastric01 study. This randomized phase II study was positive based on objective response rate and overall survival and has been approved in the U.S. in the second-line and later setting and is a standard of care for patients as third-line therapy in Japan. However, trastuzumab deruxtecan's challenging safety profile may make its use in earlier lines of therapy challenging. Preliminary report at ASCO this past year of its use in patients with HER2-positive gastric cancer in a single-arm phase II study conducted in the United States and in the E.U. in the second-line setting had a similar objective response rate and PFS, but a shorter duration of response compared with that in DESTINY-Gastric01. Another second-line regimen, trastuzumab ramucirumab paclitaxel, was evaluated in a single-arm, predominantly single-institution phase II study, where an initial 52% objective response rate and median OS of just over a year were reported. Despite these recent advances, novel and tolerable regimens are still needed for the treatment of this aggressive cancer. As noted in slide three, tumors upregulate CD47 as a way to evade the innate immune response. Evorpacept is a high-affinity fusion protein that blocks the CD47 SIRPα myeloid checkpoint interaction. Because the molecule has an inactive Fc, it spares normal cells from CD47-targeted antibody-dependent cellular phagocytosis or ADCP activity. Evorpacept is designed to enhance the activity of anticancer-targeted antibodies and checkpoint inhibitors with minimal hematologic toxicity. By inhibiting the myeloid checkpoint, evorpacept in combination with trastuzumab, with its active Fc domain, maximizes the macrophage's HER2-targeted ADCP activity. Evorpacept also directly activates dendritic cells, enhancing their cross-priming of T cells, and so T-cell activity in combination with checkpoint inhibitors. Now, on behalf of the ASPEN-01 investigators, in slide 4, I will present the phase I data as of September 1, 2021, summarizing evorpacept for patients with advanced HER2-positive gastric or gastroesophageal cancer, presented at the annual meeting of SITC 2021. As you can see on slide 5, 18 patients with predominantly second-line HER2-positive gastric cancer received ALX-148, or evorpacept, at 10 or 15 mg/kg every week in combination with trastuzumab, ramucirumab, and paclitaxel. The study enrolled patients from the United States and South Korea, with more Asian subjects enrolled into this cohort. The majority of patients had distant visceral metastases, an ECOG score of 1, and all but one patient had disease that had progressed upon prior anti-HER2 therapy. On slide 6, evorpacept was well-tolerated in combination. The most common evorpacept-related adverse events in combination with trastuzumab, ramucirumab, and paclitaxel were low-grade rash, urticaria, and diarrhea. There were no dose-limiting toxicities or study deaths or evorpacept-related serious adverse events. The maximum evorpacept administered dose in combination was 15 mg per kg weekly. Here in the table on slide 7, we see that in 18 patients with second-line gastric cancer, a 72% objective response rate was seen, with a median duration of response of 14.8 months. I'd like to remind you that the objective response rate with ramucirumab plus paclitaxel in the RAINBOW study was 28%, with a duration of response of 4.4 months. In the DESTINY-Gastric01 gastric study, the trastuzumab deruxtecan's ORR was 41%, with a duration of response of 11.3 months. The longer-reaching impact of evorpacept is especially seen in the preliminary median overall survival of 17 months, which compares favorably with the 9.6-month median OS seen with RAM+PTX in RAINBOW, as well as with trastuzumab deruxtecan's 12.5-month median OS in DESTINY-Gastric01. The waterfall and spider plots show the magnitude and deepening of response over time, in some cases well over a year, as well as the centrally determined HER2 scoring of archival tumor samples. In conclusion, on slide number 8, preliminary data suggests that evorpacept can be safely combined with no maximum tolerated dose reached in combination with trastuzumab, ramucirumab, and paclitaxel. In combination, evorpacept demonstrates a durable 72.2% objective response rate in HER2-positive second-line gastric patients with a 17.1-month median OS that suggests clinical activity beyond that expected from relevant historic controls. I'm now honored to introduce to you, on slide 9, Dr. Kevin Harrington, who will speak about evorpacept for patients with advanced checkpoint-naïve head and neck squamous cell carcinoma. Dr. Harrington is a professor of biological cancer therapies and the head of the Division of Radiotherapy and Imaging at the Institute of Cancer Research in London. He leads the targeted therapy section within the Royal Marsden, ICR Biomedical Research Center and is the national chair of the CRUK ART-NET Group. We are the beneficiaries of his deep experience in biologically targeted approaches to cancer therapy and especially head and neck squamous cell carcinoma. Kevin? Thank you, Sophia. Today, I'm really pleased to be able to speak on evorpacept for patients with advanced head and neck squamous cell carcinoma. On slide 10, you can see that head and neck squamous cell carcinoma is also one of the common global cancers. There is worsening prognosis once in the advanced setting. Its incidence rate is highest in Eastern Asia, but there are increasing frequencies of this disease in the United States and in North America. On slide 11, I show you that pembrolizumab was initially approved as a monotherapy in the second-line setting based upon the pivotal KEYNOTE-040 study. It was subsequently studied in the advanced first-line head and neck cancer setting in the KEYNOTE-048 pivotal study, and it is now considered the standard of care both in the first-line setting, where it can be used both as a monotherapy in patients with PD-L1 positive disease and in combination with 5-FU and platinum in patients with head and neck squamous cell carcinoma, irrespective of their PD-L1 status. One challenge that we encounter with immuno-oncology agents in this disease, and this is demonstrated in the table, has been the identification of phase II endpoints that are predictive of overall survival. That, of course, is the global standard of clinical benefit for patients with head and neck squamous cell carcinoma. As evidenced in both the KEYNOTE-040 and the KEYNOTE-048 studies, short-term response metrics such as initial overall response rate or even median progression-free survival have not always predicted the eventual clinical benefit as measured by the median overall survival seen with pembrolizumab monotherapy or in combination with a fluoropyrimidine and platinum in the first- and second-line settings. Indeed, in slide 12, the separation of the experimental arm from the control arm in the Kaplan-Meier plots of the total trial population for KEYNOTE-048 and for KEYNOTE-040 for both progression-free and overall survival does reflect the ultimate benefit of pembrolizumab-containing combination compared to the control arm. As you can see on slide 12, the benefit improves over time when looking at either progression-free or overall survival. However, in the case of the median progression-free survival in both studies, the improvement in clinical benefit is not yet seen between the test and the control arms at the median point. It is not until more progression-free survival or overall survival events have occurred, reflected at later time points, including the median overall survival, the overall survival rate at 12-month landmark analysis or the OS rate at the 24-month landmark analysis. This is where the clinical benefit is increasingly demonstrated. I am now pleased to present the updated results from ASPEN-01 on behalf of the study investigators. I will present phase I data as of September 1st, 2021, summarizing evorpacept for patients with advanced head and neck squamous cell carcinoma presented at the annual meeting of SITC 2021. On slide 14, I show you that evorpacept was administered with standard pembrolizumab, 5-FU and platinum in patients with first-line head and neck squamous cell carcinoma or with pembrolizumab alone in patients with checkpoint-naïve second line or greater head and neck squamous cell carcinoma. The primary study endpoint of this portion of the study was determination of the maximum tolerated dose of evorpacept in combination. The study enrolled patients from the United States and South Korea with more Asian subjects enrolled into this cohort. All patients enrolled into these two cohorts had had no prior treatment with a checkpoint inhibitor for their head and neck squamous cell carcinoma. As shown on slide 15, the most common evorpacept-related adverse events in combination with pembrolizumab and chemotherapy occurred in one patient each, and these were neutropenia, fatigue, pneumonitis, and anemia. The adverse event profile of patients receiving evorpacept and pembrolizumab has been reported elsewhere. There were no dose-limiting toxicities, no on-study deaths, nor evorpacept-related serious adverse events in this cohort. The maximum administered dose in combination was 15 milligrams per kilogram every week. On slide 16, you can see that in patients with first-line head and neck squamous cell carcinoma receiving evorpacept in combination with pembrolizumab chemotherapy, a 38.5% overall response rate was observed in patients with both high and low PD-L1 expression. A median progression-free survival of 5.6 months, a median overall survival that was not reached, and 87.5% overall survival rate at 12 months compare favorably to the pembrolizumab chemotherapy arm of KEYNOTE-048 as a historical experience. In that situation, there was a 4.9-month median progression-free survival, a median overall survival of 13 months, and 53% estimated overall survival rate at the 12-month landmark point. Additional follow-up of enrolled patients with second-line checkpoint-naïve head and neck squamous cell carcinoma who received evorpacept and pembrolizumab showed that there was an overall response rate of 40%. Here, there is a 4.6-month median progression-free survival, a 24.5-month median overall survival, and 80% estimated overall survival rate at 12 months. These compare favorably to the pembrolizumab KEYNOTE-040 historical experience. In that situation, there was a 2.1-month median progression-free survival, a median overall survival of 8.7 months, and an estimated 40% overall survival rate at 12 months. Again, these data were reported in similar populations. In conclusion, on slide 17, I've shown you the preliminary data suggests that evorpacept can be safely combined with no maximum tolerated dose reached in combination with the regimens tested. Patients with checkpoint-naïve first line and second line or greater head and neck squamous cell carcinoma who were administered evorpacept in combination reported clinical benefit beyond historical landmarks, especially when looking at survival-based endpoints of median overall survival and overall survival at 12 months as measures of clinical benefit. I thank you for your attention, and I will now hand the presentation back to Jeanne. Jeanne. Thank you, Dr. Harrington. That concludes our prepared remarks. We'd like to open the line for questions. Operator? Thank you. As a reminder, to ask a question, simply press star one on your telephone. To withdraw the question, press the pound or hash key. That is star one to get in the queue. One moment while we compile the Q&A roster. Our first question is from Michael Yee with Jefferies. Your line is open. Hi, guys. Good morning. Thank you for the summary of the data. We had two questions. First, on head and neck data, appreciating, I think you sort of explained that you can't always look at overall response rate, and here there's often a tail for improved survival in immuno-oncology mechanisms. Can you just still attempt to put into context your 39% overall response rate versus the others and relate that to your mechanism of action, which is a don't eat me mechanism in which you would still think there's more cell killing? Maybe just put into context what you think is going on there, given the mechanism, and also in the context of small numbers for survival. That's my first question. The second question, if I may, I just have to sneak in an MDS question. If you could comment on the MDS ASH abstract, that would be helpful as well, as obviously investors are trying to put that into context as well. Please. Thank you. Yeah, this is Sophia Randolph from ALX. Thank you for your question. I think you know, first off, and then I'll ask Dr. Harrington to also speak again to the concept of response rates and how we think about that in this particular disease setting. First off, in terms of the data from our head and neck cohorts, we're actually you know, very encouraged with this data. Again, as you look at how immuno-oncology agents in general seem to be working in the head and neck space, it does seem as though the impact of immuno-oncology agents does take time for those clinical benefits to be seen. You know, while in the short term, very similar to the pembrolizumab experience in KEYNOTE, we do see objective response rates improvements. Although, again, you know, we see what we see, the 38.5% in the first line and the 40% in the second line. Certainly those responses do appear to deepen over time. And that impact of that durability and the impact of other patients even with stable diseases over time seems to be what's driving the longer PFS, and particularly overall survival. The drug itself as it works in combination with T-cell checkpoint inhibitors, it's really enhancing dendritic cell cross-priming of T-cells. That in and of itself leads to an increased activation of cytotoxic T-cells. When those are in the presence of its T-cell checkpoint inhibitor, namely pembrolizumab, we can see this increased activity. It may be a little bit different than the kinetics of what we see when we're combining with an anti-cancer targeted agent. Really, as we get into larger trials, and this speaks to the size that you had asked earlier, as we get into the larger randomized phase II setting, you know, we hope that we'll be able to learn more about how this drug works in that setting. I'm gonna turn it over to Dr. Harrington, if you wanna speak a little bit more to this concept of objective response rates in these diseases. Yeah. Thanks very much indeed, Sophia. I think you've given a really nice summary of the data. I guess, having been an investigator both in the KEYNOTE-040 and in the KEYNOTE-048 studies, we do recognize the fact that there are patients in whom you don't see a response, but in whom you subsequently see long-term survival. That is undoubtedly true, but also we see that patients who derive a response, especially, I remind you of the KEYNOTE-048 data with single agent pembrolizumab, the median duration of response of responding patients was nearly two years. Responding per se is important, because it is associated potentially with a durable remission, and therefore that can read out into durable and long-term overall survival. Taking that context, I think the data that we see here, and I'll do it in reverse order. In the second line setting with an overall response rate of 40%, well, that's albeit with small numbers. You asked me to comment on the small numbers. We can't get away from that. Nonetheless, as you know, the best response that we saw in single agent pembrolizumab in KEYNOTE-048 was 23% for the CPS greater than or equal to 20. If this were replicated in the randomized trial, this would be far and away above what was witnessed in the KEYNOTE-048 study. In the first line setting of course, those response rates look a little bit closer to what we saw, for instance, in the patients receiving chemotherapy plus pembrolizumab in KEYNOTE-048. Again, I think the survival rate at 12 months at five out of six patients, 87%, is really very compelling and is very interesting, and is certainly what's driving me to be interested in being an investigator in this trial. I think the mechanism of action has been covered by Sophia, and I think the combination with chemotherapy, of course, gives us that additional benefit of potentially triggering immunogenic cell death at the same time as having an anti don't eat me signal on board or a blocker of the don't eat me signal, which of course can promote greater degrees of ADCP. Then, of course, that cross-priming event, which leads to T-cell activation, which in the presence of the anti-PD-1 antibody, hopefully will translate into better responses and subsequently into more durable responses and subsequently into improved overall survival. I think those are the really key points that I would take from these data while recognizing N is small in each of the components of this analysis. That's very helpful. Sophia, you're gonna get the question anyway. The question around interpreting the MDS ASH abstract, which the market seemed to digest in a negative way. Could you just put some color around that and how to compare that to magrolimab? Thank you. Sure. Yeah. Just very briefly, the ALX-148 updated data in looking at evorpacept plus azacitidine in patients with first-line MDS and relapsed/refractory MDS was reported out in abstract form a couple of days ago. I think in that case, we also put out a press release, and I think there was a little bit of a mix up between folks who were looking at the abstract and perhaps not taking into account the press release. In the abstract, we reported 2 out of 5 patients with first-line treatment-naive MDS who had had cytogenetic responses. As we got the complete data set on those patients after the abstract was submitted, those two patients also met criteria for CRs. That updated data was presented in the press release that went out with the accompanying abstract. Overall, in the five evaluable patients who received first-line treatment in the untreated MDS population, we had two out of five patients with CRs, which is, you know, it's small numbers, but if you wanna put the percentage to it, that's 40%, which is in our minds certainly demonstrating clinical activity and on par with some of magrolimab's earlier data. Certainly an improvement upon the backbone of azacitidine, where in that population you would anticipate about or somewhere around 17%-20% objective response rate. These patients just by chance were all TP53 positive, TP53 mutation positive, including the two responders. The trial does enroll an all-comers population, and we'll be presenting additional data at ASH in approximately 20 patients overall. On the relapse-refractory side, we also had 5 evaluable patients who were described in that abstract. In this population, one might expect to see really anything in the relapse-refractory setting is considered significant. Here, 2 out of the 5 patients had CRs. Again, very encouraging and we'll be presenting the fuller data set at ASH in a matter of a few weeks. Thank you. Thank you. Our next question comes from Chris Raymond with Piper Sandler. Your line is open. Good morning. This is Nicole Gabreski on for Chris. Thanks for taking the question. Maybe just kind of touching on ASPEN-03 and ASPEN-04. It looks like per your updated corporate deck that you've shifted the endpoints to now include a 12-month OS rate as well as response rate. I guess maybe we just had a couple questions based on this. First, how should we be thinking about what success looks like given the co-primary endpoints? And on the response rate portion, do those rates need to be in line with other comps? Or what kind of benefit will you need to show in your phase II studies to be meaningful? Secondly, can you just kind of talk about any regulatory interactions you've had in regards to modifying the primary endpoint and what the feedback has been? Okay. Before I get to the details of the study design, I'm gonna ask Dr. Harrington if you wanna speak to just the concept of why we incorporated the 12-month OS rate into those studies. Yeah. I mean, I think as a key secondary endpoint in each of those studies, I think overall survival, of course, is what people are looking for and clearly what those that register drugs, the FDA and outside of America, the EMA are looking at. I think it's important that we get a sense of how active these regimens are and look in terms of overall survival. I think we get a very clear indication. If you look at the data from CheckMate 141, you look at CheckMate, KEYNOTE-040, and then at KEYNOTE-048 in the first-line setting, we see that even in situations where curves cross one another for OS, and we do see that in the first-line setting in KEYNOTE-048. We see that early on, especially in those tumors that are PD-L1 on the low side, we see crossing of the curves. Those curves have crossed really no later than 7 months, and that we see that the shape and the direction of travel of the overall survival curves that establishes itself at about 12 months is then feeding into what we see as the longer-term tail on the curve as it emerges. I think the earliest that you get a clear indication of direction of travel and what the likely benefit and the separation between curves is going to be is around that 12-month point. To try to look any earlier, I think will give you potentially a false view of how things are going to emerge. Clearly, the longer you leave it, the clearer the picture becomes, and that's the reason why we publish long-term data from these trials. But I think when you're looking for a signal with a view to deciding on powering a phase III study or making strategic decisions about how to develop an asset, I think overall survival at 12 months really is a very key and powerful endpoint. I hope that addresses the question that you had. Thanks, Kevin. This is Sophia, and I can also speak a little bit to the statistical design. With what Kevin has said, how we've incorporated this into both ASPEN-03 and into ASPEN-04 is to create a statistical design where we have co-primary endpoints. We start by looking at that 12-month OS rate first. The trial is increased a little bit in size due to the powering around now incorporating both a 12-month OS rate and the co-primary objective, response rate. Now our the size of our trial is around 177 patients, and we'll be evaluating these different co-primaries in a fixed sequential design. The overall structure of the trial is the exact same as what it was before. It's still a 2-to-1 randomization. ALX is being given as 45 mg per kg every 3 weeks, to make it more convenient to be combining. Because of our safety profile we can do this, to be combined with standard of care Keytruda in terms of ASPEN-03 and in terms of ASPEN-04, in combination with Keytruda plus 5-FU and cisplatin. In terms of, you know, what does success look like for that 12-month OS rate, in the KEYNOTE-048 first-line head and neck, 12-month OS rate was around 51%. We'd be looking for an improvement there, to somewhere, you know, in the mid-60s, is what we've powered the study to look for. In terms of the ORR, as a fixed sequential design, if that OS rate is positive, then we go on to look at the ORR. Certainly for the OS rate, that's going to be really the key of those two endpoints, the first one that'll be evaluated. In terms of the ALX KEYTRUDA chemo combination in ASPEN-04, there in the KEYNOTE series, 12-month OS rate backbone is around 63%, so fairly similar. Again, looking to improve upon that into the around 66% or the higher 60s%, you know, a surrogate of what we believe it will be a surrogate of clinical benefit, as measured by overall survival, which would be a key secondary endpoint as Kevin mentioned. Hopefully that addresses your question. Some additional detail around that will be provided in the trials in progress posters that we have for both ASPEN-03 and ASPEN-04, that'll be presented at SITC as well. Okay. Yep, that's very helpful. Thank you. Thank you. Our next question comes from Brad Canino with Stifel. Your line is open. Morning, thanks for hosting this presentation. For Dr. Harrington, it looks like only two patients progressed rapidly in the frontline head and neck quad. Can you comment at all about how that compares to the KEYTRUDA chemo combo? Would you expect more rapid progressors without evorpacept? Then I have a follow-up. Thank you. Thank you for the question. The marked difference in the KEYNOTE-048 data sets between the single-agent pembro and the pembro chemo combo is really the shape of that early part of the curve, as you correctly, I guess, suggest in your question. The reality is that for the pembro chemo combination there isn't a clear detriment early on from OS, which is what we see with the single-agent pembro. What would I expect, I guess, is difficult to know, but we would expect relatively small numbers of patients if they are covered with the combination of chemotherapy. That, to me, is one of the main attractions of using chemotherapy, pembrolizumab combination regimens, especially in patients with bulky disease, with symptomatic disease, where even relatively small volume progression before you evolve a response can be associated with a significant detriment in terms of quality of life, or indeed even pose risks, to the patient in terms of getting pneumonia or something like that from swallowing dysfunction that could lead to an early mortality event. I don't think there's enough data for us to make a clear comparison here. What we can say is that evorpacept is certainly not performing any worse than this, and one would hope that it would indeed guard against any of those early progressions and hopefully would mitigate the risk of that. I don't really have enough data to say conclusively that that's happening. Great. Thank you. Then for Jaume or Sophia, a strategy question for you, because now that you're moving away from the ORR endpoint from the ongoing frontline randomized phase II trial, are you more likely to now need a phase III trial for approval? Because I can't really think of any precedents for surrogate approvals on a 12-month OS. I guess, can you talk through any updates to the data readout timing, which I think you previously suggested might have been in 2023? Thanks. This is Dr. Sophia Randolph. I'll start, and then Jaume can, you know, we can speak together on the milestones. I think in terms of the strategy for our evorpacept combinations in head and neck, yeah, I mean, you know, as we have discussed before, the original design of this study was potentially registrational with the ORR. We certainly haven't taken the ORR out of the design. We've only added in an additional co-primary endpoint. I think, you know, in terms of the design of this study, ultimately it will be a review issue, as it always is, with the agency in terms of looking at the data. They'll have to take into account the landmark analysis of OS. To your point, in this field, median overall survival has always been the benchmark for full approval. It will have to be an evaluation of the 12-month OS rate. However, the original ORR is still there. As we had discussed before, depending on the data, that trial design was still considered as potentially registrational from the agency standpoint. I think regardless, we're gonna have to do a phase III, whether you know regardless of whether or not something meets criteria for accelerated approval or not. We certainly are moving forward with that in mind and are working on phase III development plans as we would anyway in the development of this agent in head and neck. Hopefully that addresses your question. Yeah, in terms of completing. Oh, milestones. You asked about milestones. Yeah. I mean, exactly. I think yeah, go ahead. Complete understanding. For the milestones for this, you know, they're all slightly larger studies. I think we've gone from a size of 105 with the ASPEN-03 study to 177. And then from the ASPEN-04 chemo combo study, going from 106 up to 162. The actual overall timelines aren't any different because we can operationally address that with just additional sites. There is an added follow-up period just with the 12-month OS rate. However, with, you know, an operational approach, we don't anticipate the overall timelines for these phase IIs to change. Okay. It sounds like you get accrual or at least are targeting to get accrual by the end of next year to kind of get the 12-month follow-up and then have data by the end of 2023. Is that fair? I think what we've said externally is just when we anticipate getting a readout from this study, and those timelines have not shifted. Yes. The only thing I would add is that, we should actually look at these two studies in a different way. I think the strong debulking effect of chemotherapy is, masking a little bit the ORR, effect of evorpacept. In the case that we do not have chemotherapy, in the case of the pembro combination only, I think that would be easier to see, ORR, as we're seeing now the small number of patients we have. Okay. Thank you for the comments. I appreciate it. Thank you. Our next question comes from Colin Bristow with UBS. Your line is open. Good morning. Thanks for taking the questions. On the head and neck data, is there any meaningful difference in the baseline characteristics or dose exposure of the additional 9 patients that you would highlight or believe drove the 22% ORR versus the 75% in the first 4? Second, just with regards to OS rate, is it reasonable to be opining on this and making changes to the phase II trials at this stage, just given the immaturity of the data? You know, I think the median follow-up was 6.2 months. Just one final question. Have you thought about potentially enriching for even higher CPS scores in 3 and 4, just given it looks like, you know, that there is a correlation here? Is there a concern that you'd then be operating at the thin end of the wedge in terms of the incremental efficacy you could demonstrate on top of KEYTRUDA? Thanks. I can start with talking a little bit about the ASPEN-01 data itself. As you asked about the additional patients who have been enrolled, honestly, you know, the overall patient population hasn't changed that much. We still have, as I look through here, we still have about, in both cases, about somewhere around 54%-60% of patients who've had visceral distant metastases, which is a mark of the aggressiveness of the disease. The relative enrollments of male versus female, the predominance of Asian enrollment from our South Korea colleagues, those are fairly similar to what we had presented in the second-line setting, what we're seeing now in the first-line setting. I don't think there's anything totally new there. In terms of CPS scores, you know, for the current data set, it's a very small data set, so it is an all comers. You can see which is consistent with pembrolizumab's label where in combination with chemotherapy it is based upon a CPS-agnostic population. Here when we look at the total population, we actually are seeing a nice mix of both CPS low as well as CPS high in the ASPEN-01 data set. Although with small numbers, we have seen a complete response with a patient with that on the waterfall plots, as you can go back and look, with CPS score of 50 and a very deep response in a patient with a CPS score of 0. You know, both at high and low CPS scores, we're seeing responses, but again, small numbers. As we go into the ASPEN-03 and ASPEN-04, larger randomized phase II, CPS is certainly important. As part of the randomization, we'll be taking into account certain sort of stratification like factors. One of those will be CPS score. You know, patients with different CPS, you know, as they fall into different CPS buckets, had slightly different characteristics in terms of their responses in the KEYNOTE-048. CPS score is important. We will be stratifying for that. We'll be stratifying by region, so Asia versus ex-Asia, as well as looking at a few other stratification factors as well. I'm gonna hold off there. Dr. Harrington, I don't know if you wanna speak to just in general the concept of some of the characteristics of a population that can have an impact upon response, at least from the KEYNOTE-048 series. Yeah. I mean, I think it's a very interesting conceptual question about would we a priori expect that patients who are CPS high or those who are CPS low might derive the greater benefit from the addition of evorpacept to pembrolizumab with or without chemotherapy. The honest truth is, I think you could probably construct a line of sight theoretically to either of those groups being likely to derive the greater degree of benefit. Honest truth is we don't yet know. I think I'm attracted to the idea that the addition of chemotherapy with triggering cell death and enhancing phagocytosis and cross-presentation is a good way of going. I think also for those patients in whom you have the absence of chemotherapy and whereby you're relying upon evorpacept to add something else to pembrolizumab, where pembrolizumab itself may be insufficient, again, is an attractive hypothesis. I think we'll see this from the data, and I think the trial is designed in such a way that we'll get a good indication from that. In terms of the distribution of the patients that were in the original ASPEN-01 study, I think it's difficult to draw any conclusions. I think certainly this isn't what we're used to seeing in registrational studies, certainly in terms of the distribution and the predominance of patients coming from Asian jurisdictions. That's not something we normally see in registration studies, at least not those that we take part in with our European and North American colleagues. I don't think necessarily we can conclude that the data are invalid for that reason, and I certainly would not come to that conclusion. More generally, in terms of the distribution of patients in KEYNOTE-048 and how that can impact and of course, irrespective of PD-L1 CPS value, and that does have an impact on response rates and overall survival. I think the other things that we do need to be aware of course, are patient performance status, which is really very important and obviously also p16 status, HPV status of the patients. In terms of the performance status, I mean, that gives us a clue as to the disease burden and the likelihood of symptoms arising from that disease. We know that patients with bulkier disease, most likely, and most investigators would probably agree with this will derive greater degrees of benefit from regimens containing chemotherapy because it gives them that debulking of disease that you don't necessarily get early on with single agent immunotherapy. I guess those are the only additional comments I'd make, Sophia. Yeah, thanks. Those other factors that you mentioned, p16, and performance status are also part of the stratification design for ASPEN-03 and ASPEN-04. Thanks. Just on the idea of opining on and making changes just based on relatively immature OS rate data. I'm sorry, say that question one more time. I just, we're obviously talking about OS rates and making changes to the phase II trials on the back of a 6.2 median follow-up in the head and neck cohort. I'm just curious how you guys feel about that. I see. No change has been made to the ASPEN-01 study, but based upon where we're seeing that follow-up, based upon the information that is coming in, and appropriately so, based upon the information coming out of this first-in-human, we have modified the two randomized phase II studies that have just begun. For each of those randomized phase II studies, there is a safety lead-in portion, which is the initial portion of those studies, which is a non-randomized safety lead-in and confirmation cohort because we're looking at this 45 mg per kg Q3W dosing of ALX for the first time in these studies. The changes to the randomized portion of the study, we have not entered into the randomized portion of the study yet. That's an important point, which I'm glad you raised that. We are not changing the design of the study after having started the randomized portion. This is a prospective change that will go into effect after we complete the safety lead-in portion of the study. Just to make that clear. Thank you. Thanks. Our next question comes from Alethia Young with Cantor Fitzgerald. Your line is open. Hey, guys. Thanks for taking my questions. A lot have been asked. I guess maybe one is just talking a little bit about kinda how if these data, you know, kinda continue to hold up both in gastric and head and neck, how do you think it consolidates kind of, you know, second line and beyond since they're like, you know, kind of many treatments used there? And then also just, you know, looking at the safety, it continues to look, you know, obviously differentiated. I just wanted to kinda just get any perspective that you have there and how does that, you know, does it further kind of increase your conviction across, you know, other solid tumors? Thanks. Thanks, Alethia. For the gastric cancer, we haven't had a chance to speak much about the gastric cancer. The gastric cancer data coming out of the ASPEN-01 continues to improve and continues to remain strong. The last time we presented this data was at ESMO GI not too long ago, about six months ago. The update that we're providing at SITC, we see even still, you know, further improvements in the overall response rates, but particularly in 72.2%, particularly in the duration of response where we're seeing our 14.8%. Starting to see the impact dragging out those median PFSs and median overall survival endpoints, which are, of course, the gold standard in this aggressive disease. In terms of the question around how does this fit with the other second-line agents that are being used in the field, I think comparatively very well. You know, RAM+PTX is still the global standard. In the U.S., trastuzumab deruxtecan is being used in the second-line setting, based off of the third-line data. The preliminary data that we're showing here really shows a very nice improvement, you know, over both of those backbones of therapy. For us, we're very, you know, again, very excited to move this forward in the second-line setting. There has been a smaller study that I mentioned before, a single-arm, predominantly single-institution looking at trastuzumab and paclitaxel. And that in and of itself, with an objective response rate of 52% and median PFS of 7.4, we're seeing an improvement over that with the contribution of evorpacept on top of that triplet backbone. Again, you know, as much as you can compare between two different studies and single arms and single institutions. I think that the buffer that we're seeing in all of these endpoints compared to the current second-line therapies that are in play right now. The quadruplet of evorpacept plus trastuzumab, ramucirumab and paclitaxel, preliminary data suggests that we're seeing superior activity. The proof of that, of course, won't come until we go into a randomized setting, and that is our next step. To directly address the contribution of evorpacept to a trastuzumab, ramucirumab and paclitaxel backbone, the next step in ASPEN-06 will be a phase II study randomized to look at the quadruplet, evorpacept, trastuzumab, ramucirumab and paclitaxel versus trastuzumab, ramucirumab and paclitaxel, and that'll be the next step. After that, we'll do the phase III, which will be comparing the evorpacept, trastuzumab PAC to the regulatory comparator, which would be ramucirumab paclitaxel. I think I answered your questions. The safety profile I think that was the other. Yeah. For safety profile across, you know, honestly, across the program, it continues to be rock solid. I mean, we've treated now cross-program over 185 patients. We're starting to get into new combinations in the myeloid space, combining with azacitidine. And we've just initiated dosing in our AML study looking at evorpacept plus azacitidine. So whether there or whether on the solid tumor side here with multi-agent chemotherapy regimens, you know, checkpoints, antibodies, the safety profile has been, continues to be unremarkable. That's, I think, one clear differentiator for evorpacept versus other CD47 targeted agents. It does allow us to be able to combine with these chemotherapy-based or other cytotoxic-based therapies and move this drug up earlier in line of therapy where we can potentially have the greatest benefit upon a patient's course of their disease. The safety profile allows us to do that in a way that I think other CD47 targeted agents will be challenged. That's definitely from a development standpoint, that safety profile is something that you know we believe makes this drug a best-in-class molecule. Maybe one follow-up, and I get this question every so often, even sometimes from physicians, just that, you know, maybe the safety means more in solid tumor versus in some of the hematologic malignancies like MDS, for example. I mean, do you guys believe that to be true? Or, like, how would you, what's your perspective on that? You know, yeah, that is interesting. Even in the myeloid space, people die from complications of cytopenia. I guess I would argue if you have a drug that doesn't exacerbate the cytopenias associated not only with the disease itself, but also with current treatments out there, backbones of azacitidine and venetoclax, that would be a good thing. You know, on the solid tumor side, I think that you know, benefit is very clear. On the heme side, again, anything that can decrease you know, potential complications due to cytopenias can not put you at risk for having to have multiple transfusions. You know, I think that that's a good thing and something that the patients have benefited for. You just don't want it to come at the expense of efficacy. Certainly to date, we are not seeing that with the, you know, very preliminary data. Awesome. Thank you. Thank you. Our next question comes from Adam Evertts with LifeSci Capital. Your line is open. Great. Thanks for the data update. Gastric data in particular, quite impressive. I just wanna go back to the combination of evorpacept and anti-PD-1. On the topic of dendritic cell priming and T-cell activation, do you have or will you have any translational data to support or outline that piece of the mechanism in head and neck? In terms of the, I'll speak to what we're doing in the clinical space. Then, Jaume, maybe you can speak to just what we've learned through our non-clinical evaluations with checkpoint inhibitors. In the clinical space, the pharmacodynamic endpoints that we have been focusing on have been looking at CD47 receptor occupancy. We'll be looking at the ability of the drug to access its target not only in the peripheral blood but ultimately into the bone marrow itself. That's data that we will be evaluating in the phase II setting, where we'll have a much more homogeneous population of patients to evaluate. Doing some characterization of the immune cells that we see in these different compartments. Different ways of looking at T-cell activation and tumor infiltrating lymphocytes or tumor infiltrating macrophages into these different compartments. In the clinical setting, those are some of the things that we'll be looking at. In terms of the general mechanism of action, Jaume, do you wanna speak to that? Yeah. From the preclinical setting, we have published. We have seen that the blockade of CD47 in dendritic cells, dendritic cells as expressed in SIRPα, and therefore they are constantly inhibited by interaction with CD47 on cancer cells. We have seen that evorpacept alone by itself does activate dendritic cells, and these dendritic cells can activate T-cells that are cancer specific. These T-cells, obviously in combination with our PD-1, can be even more active against tumors. Another mechanism that we have shown in the preclinical setting, we and others have shown in the preclinical setting for CD47 blockade is the conversion of M2 macrophages into M1 macrophages, therefore making them less immunosuppressive and more anticancer in the tumor microenvironment. This data has been published and can be found in our website. Great. Thank you. All right, and I'm not showing any further questions in the queue. You may continue with any final remarks. Thank you. If there are no more questions, we'd like to extend our appreciation to Dr. Harrington for his valuable insights today. Thank you for your participation. Have a good day. Thanks. Thank you. With that, we end our program for today. Thank you for your participation. Have a great day.