Good morning, everyone, and welcome to today's webcast. My name is Adam Levy, and I'm Chief Financial Officer and Head of Investor Relations at Acrivon Therapeutics. This morning, we are excited to host a key opinion leader panel to discuss our ongoing ACR-368 registrational intent phase II-B study in subjects with endometrial cancer. Before we begin, I'd like to remind you that certain statements made during this call, including those made by participants in the KOL panel, may constitute forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 and Section 21 E of the Securities Exchange Act of 1934, as amended. Joining the call today from Acrivon will be our Chief Executive Officer, President, and Co-founder, Peter Blume-Jensen, and our Chief Medical Officer, Mansoor Raza Mirza. Next slide, please. Following the discussion, we will have a brief Q&A session. Please submit questions on the text panel you see on your screen. With that, I'll now turn the call over to Peter. Thank you, Adam. A warm welcome to all participants calling in to join our exciting KOL panel discussion today. We are excited to have assembled a truly world-leading panel of gynecological clinical experts. By my account, they approved therapies over the past three decades, and many of them guideline-changing in gynecological cancers, including especially endometrial cancer. Some of them are joining live on site from the ongoing ASCO conference in Copenhagen, and some are calling in remotely. The agenda today includes Dr. Slomovitz presenting an overview of our data, which were presented just a little while ago in a late-breaking talk this morning at the ASCO conference by Dr. Panos Konstantinopoulos from the Dana-Farber Cancer Institute, and Dr. Slomovitz will also describe the unmet need in serous endometrial cancer. Dr. Mansoor Raza Mirza, our Chief Medical Officer, will moderate the Q&A panel section, after which we open up to the outside audience for questions. Next slide, please. The panelists are, from left to right, Dr. Robert L. Coleman, who is a special advisor to the President of the GOG Advisors. He's also a Vice President of the GOG Foundation, and with Texas Oncology, US Oncology Network, Chief Medical Officer at Vaniam Group. Dr. Ramez N. Eskander, Julie St. John Endowed Chair in Gynecologic Oncology. He's a professor and medical director at University of California, San Diego, and the Moores Cancer Center. From Italy, Domenica Lorusso. She's chair of MITO, which is a Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies group. She's a member of ENGOT. She is also a director and professor at Humanitas Research Hospital in Milano, Rozzano. Dr. Brian Slomovitz, member of the Board of Directors, GOG Foundation, and the Uterine Cancer Lead, GOG Partners. He's the Director of Gynecological Oncology and Co-chair of the Cancer Research Committee at Mount Sinai Medical Center and also a professor of obstetrics and gynecology at Florida International University. The goal of today's meeting is for this KOL panel to contextualize our maturing data from the ACR-368 registrational intent trial, including the recently disclosed promising results in serous endometrial cancer. Briefly, serous endometrial cancer is a very aggressive subtype. It's a vast majority of which contain P53 mutations and pMMR, and arguably the highest unmet need in endometrial cancer, with only very limited treatment options. It causes upwards of 50% of all mortality and has the shortest median overall survival of only about three years. With this, I will hand it over to Dr. Mansoor Mirza, who will moderate the panel. He and Dr. Eskander led the trials that led to the most recently introduced, and in some ways, game-changing new frontline therapy in endometrial cancer based on immune therapy and platinum-based chemotherapy. Mansoor, please take it from here. Everybody, it's my pleasure to have my Brian Slomovitz to discuss. He's the senior author of the trial, which was just presented by Panagiotis Konstantinopoulos. Brian, please, can you walk us through the data? Certainly. Peter, thank you for having me, and Mansoor, thanks for being here. For my colleagues, it's always a pleasure to work with you. Yeah, I'm really excited about presenting this data. I'm honored to present this data because, as Peter was alluding to, I think there are many unmet needs. I think the greatest unmet need that we have in treating our patients with endometrial cancer are these serous, these aggressive subtype patients, where treatment options are limited and, you know, the bottom line is we need to do better, and we need to come up with newer treatment options for these patients. It was great to be here. It's great to be here at the ESGO meeting, where we just did have our late-breaking session. I'll be reviewing the clinical activity of ACR-368 in patients with endometrial cancer, prospectively selected by OncoSignature, a phase II study of the ACR-368-201. I'm honored we were able to run this trial in partnership with the GOG Partners and working with the Acrivon team. ACR-368 OncoSignature, it's a proprietary tumor-agnostic functional biomarker test. What it does, it predicts benefit from ACR-368, which is a potent selective CHK1/2 inhibitor. The components is three protein biomarkers that measure the tumor's addiction to CHK1/2-mediated DNA repair independent of genetic alterations. Screening with this test across all tumor types found that endometrial cancer is most likely predicted to be sensitive to this agent. In this trial, subjects that were relapsed after prior platinum-based chemotherapy and one prior line of checkpoint or IO therapy, they were enrolled into the trial. The biomarker test was done, stratifying the cohorts with prospective response prediction, subjects with high-grade endometrial cancer, less than or equal to three lines of therapy. In the biomarker positive group, they were treated with ACR-368, 105 mg per meter squared every two weeks, and in the biomarker negative group, they got the same dosage of the investigational agent but we also added ultra-low-dose gemcitabine, or ULDG sensitization to this group. The primary endpoint was a biomarker-positive population. Here are the baseline demographic characteristics, and really, across all different groups, it was very well balanced. I want to highlight a couple of things here. In arm one, there was a very high percentage of patients that had serous histologies, showing that there's a higher chance of being biomarker positive for these three proteins that we're looking for. In addition, about, in the, in the biomarker-positive group, about 60% of them were P53 mutated. Prior exposure to checkpoint inhibition were across all patients in both arms, over 95%. Prior exposure to the nivolumab pembrolizumab were really the standard of care after the first-line chemotherapy. About 47% in the biomarker-positive group and 42% in the biomarker-negative group had prior exposure to the nivolumab pembrolizumab. Let's dive right into the results. Here's in arm one, again, biomarker positive in the ITT intent to treat population, the overall response rate was 39%. Okay, the disease control rate was 81%, with a clinical benefit rate confirmed at 16 weeks to be 61%. Very encouraging data here. We looked at the subjects who had two lines or less of prior therapy in the biomarker-positive group, the overall response rate was 44%, and even the biomarker-negative group, the overall response rate we're seeing was 26%. Suggesting maybe better activity the earlier they were treated. Looking at the response rates of serous cancers, the uterine serous cancers, again, the ones that there's the greatest area of unmet need. Across the different arms, the biomarker negative or positive, less than two prior lines of therapy, we reached a response rate of 52%, with a disease control rate of 74% and a clinical benefit rate confirmed at 16 weeks of 65%. Here, again, when we're thinking about the encouraging next steps type of data, this is something that we're get particularly excited about. The non-serous patients, 22% response rate. Overall, I'd say it has a favorable safety profile. There were some limited and transient mechanism-based hematologic AEs, and most of them are shown here. Of note, especially when we're comparing it to some of the newer therapies, there was a really absence of GI toxicities, interstitial lung disease, stomatitis, ocular toxicities, and other peripheral neuropathies. Again, I'm suggesting that we can get this benefit without some of those serious AEs that we've seen with some of the other agents. In conclusion, ACR-368 is active in biomarker-positive endometrial cancer. In particular, the serous endometrial cancer subtype has a high overall response rate in both the biomarker positive and negative groups. The safety profile was favorable. Now what we're doing is in, like I'm introducing here arm 3, which is a biopsy-independent cohort, just of the serous histology, two or less lines of therapy. The biopsy, the biomarker panel doesn't matter. It's the treating patients up to 90 patients with ACR-368, which ultra-low-dose gemcitabine sensitization. Primary endpoint here is gonna be overall response rate. This is the study is being expanded throughout Europe as well to over 20 sites. Finally, before we go on with the discussion, I wanted to again re-highlight here the unmet need of serous cancers, serous endometrial cancers, and why we need to do better. We could see the incidence of endometrial cancer mortality on the top and the prevalence. You know, the way I see it, I like to refer to it as in uterine serous cancers, they make up about 10% of endometrial cancers, but they make up of over 50% of the deaths and recurrences due to this disease. Really highlighting the disproportionate mortality and morbidity shown with these agents. There's limited effective treatments, only really a moderate benefit from immunotherapy. Chemotherapy responses are short-lived, there's rapid resistance. The HER2 therapies are out there, but they're targeting smaller populations, and most of these patients are gonna progress after second-line therapy. With that, I'd like to turn it over back to the team. Thank you for allowing me to present. Thank you, Brian. This was a great start. Now we will start our panel discussion. Peter has already introduced us the whole panel. Yeah, my first question will be to Rob. Rob, how does efficacy, overall response rate, duration of response data compare to standard of care in second line and also in third line, specifically in serous endometrial cancer? Can you lead that, please? Yeah. Yeah, for sure. Thank you, and thanks for inviting me. Excellent job, Brian, in your presentation for some of this. The, thanks for asking the question. When we think about what we have available for patients who have gone through those index treatments that you just mentioned, we see response rates at a, at the top end around 15%. To see something like an asset that comes in either as a single agent or with this combination with low-dose gemcitabine to produce more than double that response rate, it gets us quite a bit excited. The other thing that Brian emphasized or mentioned, I want to emphasize here, is that when we think about how we treat patients, we treat patients. ... not necessarily to the attainment of a response, but we treat them as to the lack of progression when they come in the clinic. To see this 50%, 60%, 70% lack of progression from those waterfall plots across these subgroups gives us a lot of hope for patients. Perfect. Well, Ketta, how big a deal is that ACR-368-induced adverse events are limited to transient hematological adverse events? I have to say that when I saw the data, I was really impressed about the manageable toxicity profile of the drug. 30%-40% grade 3/ 4 hematological toxicity is not a scaring toxicity for physician. This is much less than what we are used to manage with the vast majority of treatment that we have now in our clinical practice. Hematological toxicity is very easy for an oncologist, easy to prevent and easy to manage. I'm really impressed about the toxicity profile of the drug. To that, I would then continue to ask, ADCs are rapidly emerging. What are the main challenges we see there? Oh, for sure, we are waiting for this new class of agent, but we have a lot of problem right now with this new agent. Mm ... toxicity. We are seeing toxicity that oncologists were not prepared to manage, interstitial lung disease, ocular toxicity- Mm prolonged neurotoxicity, and this is not exactly easy to address. We have several problem about what is the dose, the optimal dose, and we are doing trial on that. What is the optimal sequencing ADC? Most of them have the same payload, and we cannot use ADC after ADC with the same payload. New drugs are greatly welcome in this setting. Thank you. That was That sets up the scene, I think, very well. Ramez, if approved, in what percentage, and that's a question I would like to ask you, from, as a USQL, in what percentage of your second-line serous patients would you use, ACR-368? Thank you. if it is third line, what about that? Thank you, Mansoor Raza Mirza, for the question. Congratulations to you, Adam and Peter, for the excellent shared data. Thank you for having me. I just wanna highlight two important points. Firstly, the efficacy data that was already shared by Dr. Slomovitz, which is, you know, the confirmed ORR, 52%, with a disease control rate as Robert L. Coleman alluded to, of 74%, significantly improves on existing standard of care treatment strategies. These patients, as was already alluded to, are patients that are not curative intent intervention in the recurrent setting. When you have an effective treatment strategy that manages the disease and that's tolerable, as Ketta just reviewed with us, this is going to be a treatment strategy that I would incorporate in every eligible patient who's dealing with recurrent serous endometrial cancer in the 2nd or 3rd line settings. could you allude, what percentage we are talking about where if it is serous histology? This would be, you know, over 75% of patients with recurrent serous cancer who have disease recurrence, who need effective treatment strategies. I would comfortably use this, if not more than that. Thank you. May I ask others, would you agree to what Ramez is saying, Ketta? Totally. This is the most aggressive among endometrial cancer subtypes. We need the drug for this patient. These results are really impressive. The toxicity profile, really manageable. I will incorporate this strategy in my algorithm for the vast majority of my patients. Rob, Brian? You know, I'll add to it. I mean, I think the value here, we don't know the great potential here, particularly we're talking about ADCs, but ADCs are currently also being evaluated in the first line. Maybe it'll improve a little, make some improvements in the first line. That'll leave the second line options wide open, a complete void of what we can do. An asset like this, I've had patients on this trial, okay? I've treated patients, and they do very well with this agent in general, and it's something that we need to continue to be excited about and further explore. Thank you. Ketta, how do you see the potential for global expansion? Now, we are opening also study in Europe, it especially it's the biopsy is not required. How do you see how it... We are so happy and so anxious to start the trial in Europe. The idea that the biopsy is not required is very comfortable to me. The vast majority of the patient has not a site of tumor easy to address for a new biopsy, so this will simplify a lot of the recruitment. This simplify in the future, potentially, the approval of this drug, because in Europe, we have a high IVDR regulation that makes much more difficult the approval of drug linked to a test, and I guess it is the same in US. This will simplify a lot. I would say that in U.S., the test is already clear, approved, and everything. May I come back to the same question in a different way, Rob? How big is the opportunity if you take U.S. and EU together? Yeah, thanks again. The idea of what is the opportunity, that speaks to a different number of patients than what we hear about, like, how many new patients that we see annually. What you're talking about is prevalence, and this is where to capitalize on what Brian also mentioned is, and Ketta had mentioned, is that if you think about the proportion of patients with new diagnosis in endometrial cancer, what proportion of those patients are serous? You know, it's, we know this is, like, 10%, 12%, right? You change the denominator, and you say: What is the proportion of patients prevalent, the prevalent population who have recurrent disease? That's a different denominator. In this particular setting, serous carcinomas account for half of that population. You've gone from a 10% incidence to a 50% prevalence, okay? This becomes a very big issue for us. Remember, prevalence is the sum total of all of these patients that are in that, hit that category. Second, third line, obviously, and beyond. Half of that patient population is made up of the serous population. That represents a very large opportunity. In the U.S., we're probably estimating 60,000-70,000 patient range of those who would classify under that under those conditions. It's a sizable population, and it's a huge need because this is a patient population already identified as having high-risk disease because they've recurred, and they have the most difficult characteristics for us to manage. Right. Yeah, it's certainly a very difficult disease to manage, so if we can take care of that would be a huge thing. Continuing with you, Rob, as you know... Mm-hmm both arm 1 and arm 3 are the registrational intent. Mm-hmm. Arm 1 enrolls all endometrial cancer subtypes that are bone biomarker positive. Positive. Yeah, and allows up to three prior lines of therapy. It has shown a very nice enrichment, with about 40% overall response rate. Can you comment on the unmet need this serves? I think it's been clear from what the discussion we've had already. We need assets in this range. What Dr. Slomovitz mentioned was that as we see these new agents identify efficacy, some activity in the recurrent setting, they're moved in early and earlier lines. We think about what the MMR population for which most of the our uterine serous cancer population have, is. These IOs and the exposure to ADCs and such are part of that development plan. When we think about what the unmet need is, it's the population we're talking about. It's the recurrent population, which is overrepresented by this high-risk histology and this group of patients. In my opinion, this arm three is actually very smartly designed because it's taking the elements of what we saw for the biomarker positive group as a single agent and the serous population, number of lines of therapy in the recurrent group with biomarker negative or biomarker unrestricted. It's a combination of the two efficacy signals that we saw from the arms one and two in the ongoing trial. I think it was very smartly done, and I think this is gonna be a great advance for our patients and a need for our clinical need to help our patients out. Both the high. Well, I think its recruitment should be going well because we have removed the biopsy-. Mm-hmm ... requirement. Definitely We have Europeans, too, coming in. Right. Ramez, a question to you. You, congratulations, you did the NRG-GY018 trial and led it, the approval of IO and chemotherapy for stage three and four or recurrent endometrial cancer. What do you think the potential is for ACR-368 in frontline maintenance therapy, switch maintenance therapy, both for serous and, more broadly, for pMMR population, where the efficacy of IO plus chemotherapy has been more modest than impressive activity of dMMR patients? Yeah. Thank you, Mansur, for the important question. I think, you know, firstly, it's important to remember that in the first line setting, the mismatch repair proficient population, there's still great opportunity to improve clinical outcomes, as you alluded to. We've made iterative progress- Mm-hmm. There remains an unmet need. I think what we've seen is there's been very strong preclinical data suggesting great synergy between ACR-368 and TOPO1 inhibitors, as well as synergy with immune checkpoint inhibition. As you can imagine, already was alluded to by Brian, this evolution of the antibody drug conjugates, some with TOPO1 containing payloads, and there's a beautiful rationale to think about how we can move this into the front line in a combinatorial strategy to try to continue to augment response and improve clinical outcomes and help these patients who, as we already alluded to, are dealing with a very aggressive malignancy. You know, I realized, Mansoor, in the earlier question that you asked me about the serous histology patients, in the recurrent setting, and I just wanted to emphasize, these patients almost invariably are non-curable. Universally, 100% of these patients are gonna deal with recurrent progressive disease. This 100% of patients need effective treatment strategies. That's why you're hearing this excitement around. Mm-hmm the data that was presented by Panos earlier today in person and then reviewed by Brian, for us so thoughtfully today. Mm-hmm. Thank you. I think this was a great discussion, and I would like to give it to Adam to continue the question and answers. Thank you, everyone. This was really inspiring discussion. It's great for your time and your thoughts. Thank you so much. Thanks, sir. Adam? Thank you, Mansoor. We'll give a moment for some questions to populate. Again, you may ask a question in the text box in your webcast screen. Our first question is from Marc Frahm from Cowen. Peter, the question is: What is known about the expression of the ADC's targets within serous subtype versus endometrial cancer more broadly? Are the same patients expressing leading ADC targets as Acrivon's biomarker, or are these different patients? How does the efficacy being seen with ACR-368 in serous disease compare to what has been shown with ADCs in that subtype? Peter? Thank you. There were a few questions there. Yeah ... on to the panel. Just a quick comment is I in as far as I know, there are actually still quite limited studies of specifically the serous subtype in the major studies, which include dMMR and pMMR. I think it's not known quantitatively very well. Mm-hmm ... what, the expression of the ADC targets are within the serous subtype. We do know, of course, that a small proportion are expressing HER2 3+, and, but beyond that, I think there's not specific studies, to my knowledge yet, that have surfaced around that. Maybe I can pass it on to the panel. I don't know, Ramez, whether you would be wanting to answer that first or Brian? you know, I think it's a great question. You know. Mm-hmm which is better, ADCs or potentially this agent? You know, we're not seeing cures with ADCs. All right? Even though that some patient and we're looking at the activity, and we're not sure of a lot of the answer. Peter, you alluded to, we don't have the exact numbers in serous. Yes, there are serous patients can overexpress maybe slightly higher the HER2 antigen than others, but we're not getting cures. Whether the ADC goes first or this asset goes first, if there's promising frontline data, I'm quite sure that both are gonna be utilized, if that makes sense. And I think that's where further work's gonna need to be done. The other thing about ADCs, we haven't really explored ADC after ADC, specifically payload after payload. Many of these payloads are the TOPO1, so once they're used for a patient and they're resistant to that therapy, or maybe or the tolerability from other reason that they can't continue, again, we'll need another option, and that's where there's a potential here. Ramez? No, I agree with everything stated. The other nuanced part that we have yet to define is, even in the ADC development programs right now, what is the relevant expression level? What population are we looking at? Is there going to be a biomarker that's going to be required, and what is the cutoff? These are all unknown, so it makes it very difficult to give a concrete answer to the question that was posed, independent of the statements that were made by Dr. Slomovitz, which is, look, we view an opportunity for effective treatments which are required really in an urgent manner in this patient population, and that's why we're so excited by the promising data that was shared today. Thank you. Our next question is from Li Watsek of Cantor Fitzgerald, and she has a two-part question. Would you expect ACR-368 to remain efficacious in patients that have seen an ADC as an ACR-368 plus low-dose gemcitabine or biomarker positive? Yeah. I think Yeah I can start there. I think that was addressed a little bit by Ramez and Brian earlier, that we have seen a very significant synergy with TOPO1 isomerase inhibitors. They cause DDR stress, and you, in, the resistance to those actually includes the G2/ M checkpoint. The resistance mechanism is driven by the drug target for ACR-368. You kind of have a synthetic lethal opportunity. Once you have built up resistance to TOPO1, you now hit CHK1/2, which is where the vulnerability is, and you get the tumor cell death. I'd love to pass it on to the panel, but that's at least how we think about it at Acrivon. We have done phosphoproteomic AP3 profiling of these mechanisms and specifically pulled that out- Mm from what we see. Yeah, I can maybe add a little color to that. The question is asking, you know, it's kind of a two, there's two elements to it. One is, what is the sequential opportunity in patients who've been exposed to a TOPO1 ADC, TOPO1-based ADC, or even a DM, you know, an auristatin analog ADC? I think those are important elements to determine, you know, what is the sequential efficacy. The other element is, what is the opportunity for combination? Can these potentially be used in together to capitalize on, quote, "drug-drug synergy"? One is a resistance mechanism that's being amplified. ... and now is being a direct target of the drug. That's the single agent opportunity, of course, our drug development would be to look at ways that we would be able to do this, to combine these agents if in a synergistic way for combinatorial strategies. Both are on the table, which is actually quite nice. The other issue, we obviously we'll need to deal with is, like, how we can optimize the dosing for both of these agents, class of agents, if we're going to do those types of studies. The preclinical, and rationale for this is actually quite high, and it's very exciting for us because we know where these, as it was mentioned by the others, we know where these ADCs are focused in their development. Thank you, Rob. I would actually also like to ask the panel, which is relevant for this year. I think, Dr. Mansoor Raza Mirza told me that a big theme at ASCO amongst physicians was whether you would treat with pembro and nivolumab after frontline IO platinum. I think. Mm. Dr. Mansoor Raza Mirza, you can comment on that, but I think it was very clear that the data are emerging, showing that you can't come in a second round with IO. Now you have the ADCs there or an agent like ACR-368, but maybe Mansoor, you can comment. It's very clear message in ASCO in multiple sessions that IO after IO is not going to happen. We don't have data for that. We don't have any evidence for that. There is opportunistic in some centers they have been doing, as soon as we have more active agents available, there was a clear message that IO will be given once and move on to the others, either in combination with other agents or other novel agents. In addition, Mansur, if I can add, not only we have no data, but it's not reimbursed. In the vast majority of the world, you can use immunotherapy, just one in the natural history of disease in endometrial cancer. After that, you cannot reuse. The drug is not reimbursed, and this is a real limitation that came from the absence of data. Everybody agrees? Yeah. No, I. And, and- No, I was just gonna say we. Go ahead. got IO after IO with dMMR, a small case series, and it sort of exploded, right? Everyone- it's dMMR. dMMR. dMMR. Yeah. It exploded to everything. Correct. Right? Yeah. But I think that's, I mean, that reinforces the theme. There is an unmet need. We've been giving len/pemb in our pMMR patient populations. We, I see patients in the second or third opinion, and they're coming in. They've been treated with len/pemb after failing a RUBY regimen or a GY018 regimen, where they already had IO. And we're not trying to do harm for the patients. There's no better options. That's where the. That's right. ... the, we're really looking to fill a void here. Mm-hmm. Mm-hmm. A follow-on question from Li Watsek, from Cantor Fitzgerald: "Also, can you confirm whether arm 3 allows prior ADC? Peter? The answer is, the answer is yes. We allow up to two prior lines of therapy, so that would typically include an AC consistent with what was just discussed about pembro and nivolumab. Mansur, please. Absolutely. Typically, what we would see is that patients will receive first-line therapy, either the RUBY regimen or GY018 regimen. In Europe, it can be the DUO- E because triplet is approved. Once they will progress, the PI has two options: either go on with our arm 3, or have another trial, which is because nobody's going to give the old standard of care, which is left-. Sure that was single-agent chemotherapy, which has absolutely inferior outcomes. Mm-hmm ... We will end up, either choose one of those, and in case, somebody chooses, ADC, the next progression will be obviously then this drug. This is both opportunity in after first progression and after second progression. One thing we maybe indirectly mentioned, but I think it's worth emphasizing, the frontline therapy is actually, in many ways, a revolution. Big, big, big step forward for dMMR patients, the 20-25% of patients recurrent there. Mm-hmm ... the frontline therapy introduced and published in The New England Journal of Medicine by Dr. Eskander and Mirza, has led to basically maybe cures for many of these. Mm-hmm DMMR patients. It's a fantastic revolution, the 75% that are pMMR overlaps almost perfectly with those that progress to second line. Pretty much all serous patients are not only P53 mutated, but also pMMR. It goes together. They progress, as Dr. Eskander said, to second, third line, because they will progress. I do think that's worth emphasizing. Great. Thank you, Peter. Our next question is from Silvan Tuerkcan at Citizens. Always good to have an AP3 question: "Did AP3 show that serous endometrial carcinoma is more sensitive to the drug versus all comers endometrial, Peter? Thank you for that question. That's a super important question. Interestingly, the way we found our way to serous was from the OncoSignature. We saw that or our biomarker lead noticed, as the study went on, that the biomarker levels for all three biomarkers were significantly elevated across serous patients. Given there is a threshold, a minimal threshold for positivity, that means the proportion of positive to negative now increases from the typical one to two to one to one. This prompted us to ask: who is it that contribute? What kind of patients is it that contribute to the response? The answer was, as you saw on Brian's slide, at the end in the serous all comer, that it's the contribution comes from the serous subtype. In hindsight, you can say it's pretty obvious. There's a strong biological rationale for that. They are pretty much all either P53 mutated or ARID1A deficient, meaning they have wild type P53 and are functionally deficient, they depend on the S G term checkpoint, which is where CHK1 and CHK2 operate. Now that becomes a vulnerability in the serous subgroup. You saw the difference. The all comer serous is about 50% versus the about 20% in non-serous. It's consistent with the biology. The OncoSignature biomarkers were the ones that led us to ask, why are they higher here, and are they contributing to the response? The answer was yes. Now the opportunity to not have the need for a pre-treatment tumor biopsy is obviously extremely attractive for us for rapid enrollment and ease of enrollment, hence the expansion to Europe. Ketta is on for that reason, Dr. Domenica Lorusso, for that reason, she's one of the four leading PIs there from four major countries in Europe that we are expanding into. Ketta, maybe you can comment again on the importance of this, but not having that biopsy, it's more involved in Europe for sure. It's absolutely much easier for us. Biopsy is not easy. Probably it's worth to mention that serous endometrial cancer has a rapid peritoneal spread. These patients are really symptomatic. When I saw 50% overall response rate, this means immediate tumor shrinkage, that means amelioration of symptom. This global spread in the peritoneum makes very difficult to approach the patient with a new biopsy. The possibility to participate to the trial in a cohort that does not require a biopsy will speed up the recruitment. It will be very fast. In addition to the unmet need for this patient, I do expect that Europe will be a great contribution to the recruitment of your trial. Mm-hmm. Very good. Our next question is from Roger Song at Jefferies. It's a 3-part question. The first part, Peter, if a single-arm study in second-line serous endometrial cancer showed ORR approximately 50%, like the 52% here, is there a minimum medium DOR you would want to see for this to be practice-changing? What ORR lower bound at interim would be compelling for accelerated approval? Should we take that first? I can take a quick answer and then, of course, give it to the panel. Mm-hmm. Dr. Slomovitz showed what the second-line standard of care is. That's from the KEYNOTE-775 control arm, where you basically in second-line have the chemo option. We just talked about the pembrolizumab and nivolumab now, where the new front-line include IO is something that physicians are becoming more resistant to use. That means that the bar right there, right now approved, is about 15% based on that, and 3.4 months of PFS. I would say when if you are having a lower bound that starts moving up to 25%, 30%, you should already have something very meaningful based on the current standard of care, excluding the 8%-10%, where you can use the HER2-targeted ADC, where it's approved. I would also say that in terms of duration, obviously, if you separate well from the 3.4 months, maybe towards five months, which our data indicate, then I would think that makes a lot of sense. Obviously, we just discussed pembrolizumab and nivolumab, and that is gonna be very difficult to use after the front line in these patients. You are either having ACR-368 or an ADC if the data hold out. I think that, but I would like to hear what the panel think, but it's all about beating standard of care in a meaningful way. Bob? I mean, I can Yeah, yeah, I can definitely add to that. I chuckled a little bit in the question because at least for the U.S. FDA, the accelerated approval standard is a moving target. I think what you ended on with your statement there, Peter, is exactly right. If we're in a domain where the expectation of the comparator arm is standard chemotherapy, the numbers that we saw in KEYNOTE-775 are very apropos because they reflect the efficacy of those particular two agents as single agents. The FDA, you know, wants to see several factors in consideration for accelerated approval. It's not just objective responses, as the question asked, it was also about duration of response, and it's also the sum total of the safety profile. All three of those are under consideration. In the past, all we had to do was to show that the lower limit of confidence at 95% could exclude the median or mean anticipated objective response rate. In this case, it would be that the sample size has to be large enough to have a 95% confidence interval that eliminates 15%. I think we're still in that, in that range, but again, the confidence interval is gonna be predicated by the sample size. Part of the nuance in accelerated approval is to have a large enough sample size so that you can provide enough efficacy and safety information. It's both those are under consideration. If you have 100 patients, and you have a 35% or 30%-35% response rate, your lower limit of confidence will be around 20%. That is kind of like where the marriage of the sample size and the targets for sample size have come into fruition. The duration response is more difficult to understand exactly because it's also predicated on how frequently you assess for progression. In general, what we've used as a guiding principle is that the DOR needs to be two assessment cycles. That if you're using imaging as a way to identify progression, you would have to go through two assessment cycles to show that you have a sufficient duration of response. Of course, then it's predicated also on the toxicity profile. That's what I say. I chuckle a little bit because it is difficult. It requires negotiation with FDA, these are kind of the general parameters that are around the accelerated approval strategy. Of course, the last thing I'll just mention, I forgot to mention, is that the confirmatory trial needs to be substantially enrolled. That's another component which we haven't really talked about here, but that would be the other component of this. Super helpful, and obviously, the AE profile is very differentiated, as you saw. Mm-hmm. Brian shared the lower bound of the confidence interval is already now 33%, right? Exactly. As you said, and then the duration we have is approaching five months. I think Dr. Domenica Lorusso have to go and chair a session. I'm so sorry, Peter. I have another session to chair and to talk. She's so popular. Thank you so much for inviting me. Thank you so much for inviting. Very nice discussion. Very interesting. Bye. Bye-bye. Thanks, Kira. Thanks. Thanks. Thank you. Thanks, Kira. See you later, Kira. Thank you so much. Maybe that was super helpful. Thank you, Rob. Any other comments from anyone? Otherwise, maybe question number two, Adam, from. Yes. Yes. Roger's second question: Is in post-pembrolizumab and lenvatinib patients, what ORR/DOR bar would make this your preferred option? I think based on the discussion we had, and I think it was mentioned pretty much by everyone, and Mansur emphasized it based on the meeting, right? It might be that that one is becoming less and less frequently used. I think that's clearly the trend now. I think it's more the ADCs that could come in in second line. We know they're there for HER2 3+, and many use it for 2+ as well, which is an additional 15%-20%. It is a fraction, a smaller fraction of the series. We think there's not specific series analysis. We're doing some in-house ourselves of HER2 3+ and 2+. With that said, I think it's more a matter of the ADCs if they come in before. If one is going single agent, we can move fast. I think that changes that. I don't know if Roger had more. To answer the question, there's a cohort of patients that may receive adjuvant carboplatin and paclitaxel, potentially. Mm-hmm. In that patient population at recurrence, there may be an opportunity for lenvatinib and pembrolizumab. If I am interpreting the question, which is in that recurrent setting, post-lenvatinib- Yeah Pembro in that patient population, what is the expectation? We fall back at least relatively ineffective standard of care, cytotoxic chemotherapy strategies. The bar, if anything, will probably be lower than what we've quoted. Mm-hmm ... from the KEYNOTE-775 control arm, because that population was only one prior line of therapy. Here you're seeing patients getting sequential treatments and progressing, we already know that the expectation with standard of care is gonna be compromised with each iterative recurrence and cytotoxic drug exposure. That would even, in my impression, right, add greater confidence to the data that's emerging from this specific therapeutic strategy based on the numbers that were shared and discussed in Brian's presentation. Remember, half of these patients had received Pembro lenvatinib, so these data-. Mm-hmm are very solid for that, to answer that question. Right. Remember, just in simple terms, the control arm is still gonna be the same. Exactly the weekly paclitaxel and Adriamycin. To what the point of Rob and to Ramas and others, it may be lower. These are another line of therapy for this patient, the response to those agents is gonna be lower than it was, and they're really not perceived to be active agents. Yeah. Very, very, very helpful. Thank you. Did Roger have more questions, or is there a question more, Adam? Roger had one more. Could you comment, Peter, on the current enrollment in EU sites and feedback from the site? We have initiated more than 20 sites or are initiating more than 20 sites in Europe. It's Italy, Germany, France, and Spain, with major PIs and KOLs, including Dr. Domenica Lorusso. We are in the midst of completing that right now, there's a lot of documents with so many countries. We anticipate an extremely, or I do at least, efficient enrollment, based on both enthusiasm and also the absence of a need for a pre-treatment tumor biopsy, which is. We are seeing already an accelerated enrollment in the U.S. for that same reason. In Europe, I think, if anything, they might be even more excited about the avoiding a lot of AEs with its current. Mansoor, you should add comments first on the enrollment. CTIS has made it possible that all four countries will be starting, all sites will be getting approval at the same time, and they have very strict timelines. Timelines, their timelines to approve will be by end of March. We would see patients coming in. All sites, we had a very nice meeting today, this morning, with the EU colleagues. All sites are extremely tuned in. They've already started setting the dates themselves for SIV. We would be seeing patients coming in just early Q2. The enrollment, as it would seem like, will go pretty fast. As we know, the statistics from these sites, some of the best recruiting sites. I'm pretty confident that together with the U.S. EU together, we will be able to get an answer pretty fast. Mansoor, you've led a lot of trials out of, out of Europe with the U.S., so you also know all of these people and the enrollment speed. We have a target and publicly declared that of completing enrollment of up to 90 patients by end of Q3. We anticipate it to go very fast, that's already going well in the U.S. I guess we are getting maybe at the end of the hour. Peter, we had one additional question, if we have time. Yeah. From Emily Bodnar at HCW. Emily asked, "You mentioned that both arm 1 and arm 3 are of registrational intent. Can you walk us through your current strategy for potential approval in second line/third line patients, and when you plan to have discussions with FDA? That's a great question. Thank you, Emily. The insights on the serous subgroup are more recent, obviously. We've just actually disclosed that data, and it's based on analysis over the last couple of months. We have continuously ongoing active interactions with the FDA, and at the end of the day, it's a matter of data. We've talked about the unmet need, we've talked about the response rate, the duration of responses, the AE profile, as Rob Coleman so eloquently described. It's a multifactorial analysis, but at the end of the day, it's a subject of review of the data at the time of filing. If the current data hold up, obviously you will. We are doing a prospective enrollment now. That's for the simple reason that the current data are based on a retrospective analysis of the ongoing trial. We want to see that the prospective enrollment will show us that the activity holds up there. If it does, even close, maybe we have done some internal modeling, but around 30 patients and looking at confidence intervals and duration, et cetera, we would obviously come with that data and discuss with the FDA to assess that with potential for other regulatory opportunities to accelerate to get this drug towards market in this high unmet need group. That's the best I can answer now. We haven't publicly disclosed anything more in detail, but it's a recent insight. We are in active dialogue with the FDA, and they have, at our face-to-face meeting, obviously said that at the end of the day, it's a matter of review at the time of filing. That's why we're doing this prospective enrollment to see it holds up. I don't know if anyone wants to add. I see you're nodding, Brian, but- Mm-hmm. Nothing. No, I agree completely. Okay. well, we are getting at the top of the hour, maybe we should start thinking of. Are there more questions, Adam? No, that concluded the questions, Peter. Okay. We are at the top of the hour, I guess, and I want to wholeheartedly thank the KOL panel, the panelists for participation today. I think it was very informative. Less is actually known about the serous subtype. I think you've helped really educate myself and others, hopefully, on the unmet need here, how much it contributes to mortality, how aggressive it is. A big thank you for participation to the panelists and also for everyone calling in today. Thank you so much. Yeah, thank you. we. Thank you. ... look forward to keep you updated later this year. Thank you. Great. Thank you. Thank you. Appreciate you. Thank you.