Thank you very much, everybody, for coming to this wonderful event. We have our experts in the field, who are our advisors and clinicians. We also have our internal experts and our internal team members. Thank you very much for being here, everybody. I hope that what we will present tonight is going to make an impression on everybody because we call it the Immuno-Oncology Revolution 2.0. What does that mean? It means that our mission statement, which is now, and it has been for the last 29 years, is to end the suffering of cancer patients. What that means to us is that cancer is plagued with medicines that have horrible side effects. I know that we pooh-pooh that sometimes, but when you ask patients, and we have in the last months and years, there is an unequivocal conviction of disdain for the types of medicines, and I'm sure that there are some exceptions, but types of medicines that provide the patient with a horrible quality of life. Of course, when we talk about quality of life, often, this is not something that's captured on a case report form in the context of clinical trials. When we talk about ending the suffering of cancer patients, it's number one, from a quality of life perspective, and number two, from the perspective of providing, increasingly providing, curative treatments that will increase in its frequency for the patient, and that's across all cancers. That is our ambition. That is why we have existed for the last 29 years, and that is why we will continue to press hard. Where we are today, if I may have the next slide, where we are today, and I have to give the disclaimer. The disclaimer simply says, we can say anything and everything under the sun, and don't blame us for it. Of course, we don't function that way in the real world. For full disclaimers, I suggest that you go through our SEC filings because we're a public company, and there are detailed disclosures of all the disclaimers. Next slide. Firstly, let me welcome everybody. We're going to change this order a little bit, but we have our Chief Medical Officer, we have our Chief Regulatory Advisor, and we have our Chief Strategic Advisor, who are all going to be here to talk about our data, facts, and those facts will be interpreted by our advisors. They are, Doctor, I'm just going in the order here, Dr. Manuel Hidalgo, next to our Chief Medical Officer, Dr. Bree Wilky, Dr. Alexander Eggermont, Dr. Marwan Fakih, and Dr. Pashtoon Kasi. Dr. Pashtoon Kasi is the newest member to join our team. When I say our team, I'm talking about our team of clinicians and advisors, and they will present to you amongst the most exciting outcomes that validate our mission statement. Next slide, please. This is a slide that's one of my favorites because it talks about why, starting with our lead program now, botensilimab, is really a new standard in immuno-oncology. We have now evidence that substantiates what you see on this slide. The evidence is our botensilimab, which is mistaken for a next-generation CTLA-4 antibody, but it is really a very powerful, multifunctional immune activator. That's what it is. It does, of course, bind to CTLA-4, which is something dear to the heart of my Chief Medical Officer, but it does so many other things that it should not be mistaken as a next-generation CTLA-4. This slide is a very simple slide. It depicts cancer in two dimensions. The bottom, the x-axis, is the stage of disease. On the left side is the early-stage cancer. On the right side, it is late-stage cancer. The y-axis is the type of tumor, cold tumors, and hot tumors. I've been in the immunology field for a long time. There was a time, and Lex remembers this, because there was a time when people said there are immunologically active tumors and there are immunologically inactive tumors. Today, what botensilimab does is take a so-called immunologically inactive tumor and make it active. This particular quadrant that you see here talks about botensilimab plus balstilimab, of course, being active in the right lower quadrant, which is the most challenging quadrant. Why? Because other immuno-oncology products have simply not worked in that quadrant. Of course, if you know a little bit of immunology, you would assume that if something works in the most difficult quadrant, it should work everywhere else. What's exciting about our program is that we now have evidence that it is doing exactly that. Dr. Pashtoon Kasi will talk about how it's active as you go from right to left in the cold tumor category. Many others will talk about how we're getting Doctor, of course, O'Day will talk about some of the most difficult tumors that have failed everything else, even if it's hot. For example, melanoma, which is a specialty that has failed every other treatment, which is mostly immuno-oncology combinations, is now responding to botensilimab plus balstilimab. With that, I would like to turn this over to our esteemed Chief Medical Officer, Doctor Steven O’Day. Thank you. Thank you, Garo. If I imagined that I would be standing in front of you 20 years ago saying that we are curing more than 50% of widespread melanoma, including brain metastases, people would say you're crazy. Even more importantly, five years ago, if I told you that I would have this slide, first slide up, let's put up the first slide, in MS stable colorectal cancer, showing deep durable responses in refractory setting that had failed prior chemo, antibodies, VEGF, experimental immunotherapy that were TMB low and didn't express PD-L1, people would say, this is five years ago, people would say, impossible. Yet tonight, we're going to update colorectal in the advanced setting. We're going to bring it back to untreated early-stage colorectal. We're going to pivot to pancreas, where we're combining it with chemotherapy. We're going to show melanoma data, where they failed IO and BRAF + MEK if appropriate. We're going to show sarcoma data that leiomyosarcoma and visceral angios that have not been part of the party, so to speak, are here to stay. We're going to show lung cancer data that PD-1 refractory and TKI refractory, the consistency is going to be there with botensilimab as a foundational agent. Now, the slide in front of you are 70 patients with this widespread refractory disease. Now that we have longer follow-up, the longest we've shown so far, starting tonight, with a median of 12 months. One of these patients at the very end is my patient in the clinic, who now is three and a half years disease-free, off treatment for a year and a half, and living her life. We have four patients that are approaching two years or beyond. This is unprecedented in this refractory setting. The duration of the response has not been reached with a median follow-up of 12 months, a hallmark of an effective IO, particularly CTLA-4 that generates memory. Let's go to the next slide. Remember, melanoma was a, ipilimumab was a 15% RECIST response. I just showed you 24% with deep durable response. Ipilimumab in melanoma, to start this revolution, was a 10%- 15% RECIST drug. The observations were that RECIST underappreciated the clinical benefit of stable disease and moderate reductions in tumor, where new tumors were not developing. To our surprise, survival was massively more than a 10% or 15%. In fact, the median survival increased substantially, and the cure rate was one in four, now with 15 years of follow-up on those patients. That's with a 10% drug. I'm showing you a 25% drug. Now I'm showing you survival data at 12 months, that is quite mature since the median follow-up is beyond 12 months, of over 70% in this cohort of refractory patients. What excites me even more is that the tail is starting to emerge, and it reminds me of 20 years ago when we started to see these first tails in melanoma. As you can see, the tail is just above 50%. The median has not been reached. Four months ago, when we presented this data with less follow-up, the median was 20.9 months. Now it's not reached because with continued follow-up, we're starting to see the impact of an effective therapy that doesn't need to be continuously given. We can just keep this slide up. I want to just return now again to the story. I experienced unmet need, and Dr. Tirini is in the audience who's a melanoma expert, for 15 years of my career. We had nothing to offer metastatic except our incredible surgical colleagues that understood the biology of the disease and were able to resect metastatic disease. We had no chemotherapy. We had no radiation. We had high doses of cytokines that cured a few patients, but we had nothing to offer other than a median survival of six months, a five-year survival of essentially zero. It's on that platform that I understand what that unmet need is. We then brought it up to 50% or more. My second half of my career is that what happened with the first revolution? The first revolution is a failure, not of ipilimumab toxicity or other issues. It was the fact that checkpoints did not prime against poorly immunogenic tumors. They didn't have the capacity to take a poorly immunogenic tumor and start the engine. What botensilimab is, Garo says, it's not a CTLA-4 classically. What it is is a CTLA-4 to release the brake, but on the back end with point mutations, it's bringing the immune synapse with other cells so that weak neoantigens can be seen and educated. That's the power of the next generation. The design was intentional. The unmet need I understand very well. 70%+ of tumors simply can't benefit because there's no key to turn the ignition. You can incrementally help T cells once they recognize a tumor as something they need to destroy. You can give them PD-1s and are exhausted. You can give them TIM-3. You can give them LAG-3. You can help generate hot tumors once the T cells recognize. The cold tumors, though, they need to start the engine. That's what we're doing with botensilimab. Tonight, I'm going to stop there and let you know that I have seen this drug in the clinic for two years as the principal investigator. I joined Agenus three years ago, and I have watched this data flourish. It's hitting both as a single agent in melanoma, refractory. It's a combination with chemo now. Tonight, you're going to see in pancreas, advanced disease like ovarian, sarcoma, MS stable. The point of tonight is to share this data, the most updated data we have, and to engage, not me, because you've heard it from me, to have a conversation with investigators who have seen it in their respective diseases, as well as understand this field more globally. I look forward to that, and we'll get started. Before we do that, though, we'll go ahead and bring Shefali Agarwal to the podium. Thank you, everyone. Thank you, Steve. I'm very excited to be here because I believe in this drug as a combination. I'm here because I believe it's a big unmet need, and we have an opportunity to do multiple successive BLAs with this combination. What I would like to walk you through in the next two slides is what's our plan. Our plan is very thoughtful, true, and tested. I believe that there is opportunity. We want to start with MSS CRC. Our indication is non-active liver mets. However, I believe that there are many other indications, as Steve talked about, in pancreatic, melanoma, and non-small cell, where we will be looking at unmet need and opportunities to file as quickly as possible in the next two years. Our plan is, as you already know, I'm going to go into CRC in detail in the next slide. That is our first BLA because it's the most mature data set. That's the furthest along, so we are starting with that. Believe me, we are not going to stop there. We're going to get this drug to every patient if possible in all these indications and many more where we have seen activity. Following CRC, we are planning to do a BLA in second-line pancreatic. We know it's a big unmet need, and there are experts here, so I'm not going to talk about the relevance and the unmet need. We have seen data where we saw biomarker reduction in the majority of the patients, along with tumor reduction. We are anticipating updated data by the second half of next year, and then a potential path by the end of 2024 or 2025. It's an impactful patient population. We believe this is going to be very important for these patients, as there's nothing in this patient population. The filing after that is second-line and beyond melanoma. As Steve mentioned, we are looking at patient populations that are Ipi/Nivo or even BRAF-native; there's nothing out there. We need to really get these patients this combo. Our plan is to really have this data by the second half of 2024, updated data, and then quickly go file in 2025. Lastly, we are also looking at non-small cell and a path in PD-1 refractory patient population. I want to end in all these indications with something exciting that Dr. Pashtoon Kasi is going to talk about, this neoadjuvant setting. This is very powerful because we are going in CRC in all lines of therapy. We are going from second-line where we are filing in a confirmatory study, possibly in front-line setting. Most activity, as we all know, is in early setting, in neoadjuvant setting. We are looking at the possibility if the data, with the way we see exciting, encouraging data today in the adjuvant setting, and when we expand, if that continues, which we really believe it would, we will try to look for a smaller study and look at clinical outcomes and endpoint. I know that in the adjuvant setting, normally people use endpoints that are bigger trials and long follow-up, but we are not going there. We are going to do something very different based on clinical outcomes because clinical outcomes matter to patients. Chemo free, surgery free is the future, and we need to go there. Let me move on to the next slide. That was our path for overall our registration strategy, but I'm going to go into detail on our first BLA path. Our first path is going into a patient population in second-line, third-line MSS CRC. We are looking at an indication in no active liver mets. Our plan submission is mid-year next year, 2024. The population that we are thinking, a lot of times we talk about this BLA, people say about phase I, but I'm talking about the big data set. We are talking about phase I, be approximately 150 patients in this indication that we are talking about. We also have an anonymized phase II study with approximately 230 patients. We are filing the totality of package, not one particular data set. The goal is to really look at this whole data set and file with that. The efficacy will be based on approximately 175 patients on one dose. This is a big number that we are talking about. The patient population, and there's a huge data set in terms of safety. We have tested more than 400 patients with this combination. We feel comfortable on our plan and on our strategy. I'm going to walk you through where we have reached already, but we feel comfortable with this package on our first BLA path in metastatic CRC. The results, the experts are going to talk about, and Steve is going to talk about. I'm just going to highlight high level that we have seen objective response rate when you compare to standard of care, really doubling or tripling, which is very important in this unmet need patient population. As Garo said, this is cold tumor. IO doesn't work here. We work here. We need to take this to the patients and make sure that it is in their hands, and that's our responsibility and ethically important. Our immunity survival is almost doubling, and we are very excited about that. This is really showing benefit in terms of stabilization. We talked about in terms of looking at stable disease and how it is important. We need to really make sure that these patients get this drug. Lastly, in the middle, what I'm showing is regulatory engagement. I think a lot of times people ask, well, are you just filing? It is not that easy. There's a process to file. We are doing all those things that are needed in terms of filing. We already have fast-track designation, and it's been given to us. We have completed our dose optimization. We know what our dose is based on this big data set of more than 400 patients. We have something that most of the people may not know is PSP, what we call a pediatric plan. It's required as a part of the BLA, and we've completed that. Now, what we are doing is next steps. What the next steps is, we need to align on a confirmatory study, which we hope is a front-line setting so we can expand the label, as that's in progress. We are on path to submit mid-2024. I'm excited about it and really want to get this patient with this great team and the help of these experts to patients as quickly as possible. We are also doing that in Europe. It is global, not just U.S. We have completed our advice with Denmark and Spain and also talked about this strategy already. We actually believe that if you work closely with regulatory authorities, they support you. We are working with them. We've brought up that strategy to them. Just like U.S., we also have the same thing about the pediatric plan in Europe. That's in progress. We plan to submit a set of advice, just like when you submit a submission to EMA, you basically have to get advice from them. Our plan submission to EMA is in the first half of 2025. Lastly, I just want to say highlight, this is something, again, I want to keep saying that it's a process. We are comfortable with it where we are. We are confident about the data, and there's precedence with this in metastatic CRC. We believe we have a path forward to get this drug to the patients, this combination, as quickly as possible. With that excitement, I'll pass it to my partner, Robin, who's going to get into the patients. Hi, everyone. I'm Robin Taylor. I'm the Chief Commercial Officer at Agenus. It's great to be here today to talk about bringing BOT/BAL to patients around the globe. Twenty years ago, I was privileged to be able to be part of the team that launched Avastin in metastatic colorectal cancer. While that was a significant advance at the time, we also know that the vast majority of patients ultimately succumb to their disease, despite the advances that have been made in the last few years. Most recently, when I was at Genentech and Roche, I spent four years with the immunotherapy portfolio. I could see the promise of immunotherapy. I could see that we were making a difference, but it was only in a subgroup of patients. Here in colorectal cancer, there's only a sliver of patients who really benefit from immunotherapy. That's why the promise of immunotherapy, the potential for cures, is so exciting as we think about bringing BOT/BAL forward to not only this patient population, but many more. Now, as Shefali outlined, we're looking at not only a launch of BOT/BAL in colorectal cancer, but multiple tumors ranging from cold to hot. As an organization, we are embedded in preparing for the launch of BOT/BAL from our exceptional clinical and regulatory team who are actively engaged with investigators and health authorities around the world, to our highly experienced medical affairs team in the U.S. and in Europe, and I'm sure beyond that before too long, to our manufacturing organization that is fully prepared to ensure that we have the consistency and quality of the drug supply that we need to supply the world. Finally, to our robust commercial preparations to ensure that at approval, we make sure that everybody in the world is aware of this remarkable data with BOT/BAL, and that every patient has the opportunity to have access to these remarkable data and remarkable drugs. I will say I've been involved in many launches over the course of my career. Avastin was the first one, but there would be many more. Out of all of those drug launches, I truly believe this will be the most impactful because of the benefit and the promise that we are seeing here. With that, I would like to turn it over to Dr. O'Day. Let's put up the first colon slide again. I'm going to sit there. What I'd love to do is just engage this data as it is tonight, being updated with longer follow-up, both the deep durable responses and the survival. Maybe start with Lex, as somebody who's not a GI expert. We'll get to the GI experts very quickly. As somebody who's been a pioneer in the first revolution in hot tumors, how does this data impact you, seeing it? What you see here is a spider plot and a waterfall plot that strikes you in two ways because the title of the slide talks about refractory MSS, so colorectal cancer, CRC colorectal cancer, that has an intact DNA repair mechanism. The paradigm was that this was not very amenable to immunotherapy for a lack of antigens, neoantigens. Basically, we had almost written off colorectal cancer as a good target because of the experience both with the anti-CTLA-4s and the anti-PD-1s in MSS colorectal cancer, which is what? 96% of colorectal cancer? Right. We are struck by this type of activity. The bottom line behind that is that that's bizarre because we know about colorectal cancer that when you look at the primary tumor, you know there's tumor infiltrating lymphocytes there. You know by Jérôme Galon, Wolfe Friedman, that there is an immunoscore and that why would MSS colorectal cancer not be an immunotherapy amenable tumor, right? It makes no sense. One of the problems is, where do lymphocytes go to school? Lymphocytes go to school in the lymph nodal system, basically, in the body. What typifies a good school is good teachers and a good teaching program. In essence, the big step forward is that the molecule here provides a prolonged and a more intensified schooling system for lymphocytes that is prolonged because the macrophages cannot pick up the molecule from that learning process because of the FC modulation. It sticks. What you need in cancer and immunoprogramming is prolonged education and intensified education, which is what we actually need in all of society. What happens there is you get a whole cascade of positive events because you get better and a greater diversity of T cell clones. You get prolonged exposure and training, which means you get a further diversification of T cell clones because of also then being instructed to work against neoantigens that were not there yet, but now are there, and they're still instructing the system. Per T cell clone, you get a bigger amplitude of a T cell clone. You get more armies and a greater diversification of armies. What does that mean? That is a recipe for cure. It turns non-responsive tumors into responsive tumors because the threshold of activity is now overcome. If you see this in MSS colorectal cancer, it means this will be true for a whole number of other wishy-washy tumors that were not our prime objectives. If we send them all to a good school, this is what you can achieve. Thanks, Lex. We are seeing in the peripheral blood expansion of T cell clones and clonality to suggest that exactly what Lex said. Marwan, you may be the busiest clinical scientist in advanced colorectal in the world. Eric's here too. Eric, we have other PIs from Europe. You're from the U.S. You're one of our busiest. You're in the trenches. You've had extensive experience with lots of different agents, including TKIs and PD-1s. This survival curve is up in front of you now. I know you've treated a lot of these patients that are moving to the right. Maybe just give us, how do you look at this data? Yeah, I think from the clinical perspective, two things you have to focus on here. Number one, this is not a small study, right? The smaller the study is, the more your confidence interval is wide. That gives you uncertainty. The positive thing here is you have a 24% objective response rate that is wedded with a very good overall survival curve with flattening of the curve. You have to put it in perspective. You know, how does this compare to other immunotherapy in MSS CRC? There is no double checkpoint inhibitor that has shown this activity in MSS, right? If you look at a large Canadian trial that looked at tremelimumab plus durvalumab in MSS CRC patients, which was compared to best supportive care, to no treatment, two-to-one randomization, the study failed to meet the primary endpoint, there was one response only. That study was not all liver mets. There was at least 30% or so of those patients with non-liver mets. You're seeing something clinically different with botensilimab/balstilimab than you see with other CTLA-4/PD-1, PD-L1s. I think what is exciting for me looking at this data is that's what I see in my daily practice enrolling those patients on the study. We've enrolled about, I think, 25 patients on this study. I think the first patients, the first few patients I've treated, they're still in follow-up. We actually do have one CR on this study, and that patient is off treatment after only about four months, actually two months of therapy. What is exciting about this combination is that, for someone who's looked, for example, at other combinations of IO therapy in MSS CRC, I haven't seen mesenteric/peritoneal disease if isolated response to IO therapy. We have a patient who has mesenteric disease as well as serosal implants on the kidneys that is now coming up to her, I think, 18 months of therapy. The adverse events are actually manageable. You just have to be on the lookout. The beauty of this combination is that you may not need continuous botensilimab exposure. You just need maybe two doses, one dose. A lot of the patients that we are now following are maintained on balstilimab, and they're doing beautiful. I think definitely a very exciting combination. I have to put it in the context of what is the standard of care here. For these patients, arguably the best standard of care today is LONSURF/bevacizumab. If they haven't been exposed to LONSURF and went on this combination here, which many of them had, with LONSURF/bev, your response rate is about 5%. Your median PFS with b ev pre-exposed patients is probably around 4.5 months. The overall population was 5.6 months. The overall survival is still 10.6 months there. A huge unmet need and, you know, very exciting times to see this happen in colorectal cancer. About 40% of these patients have had either LONSURF or [regora]. This is even in that setting. It's wonderful to hear because it reminds us of the early melanoma days as we started to follow these patients over time, particularly with coming off treatment, the continued response, and the continuous therapy till death, which was sort of the motto for solid tumors, particularly in melanoma. All it can be broken. It's an amazing thing to witness as an investigator. Thank you. Manny, I know Pancreas is your sweet spot. Pashtoon, we're not going to forget you too. I know you've also been helping us lead this program with colorectal. Just some additional insights on just how this data is impacting you. It's very exciting. I think what is important is that these patients, all of them had failed the standard of care, many of them bevacizumab, LONSURF, regorafenib. Actually, the standard of care treatment for these patients would have been a clinical trial, phase I clinical trial, or supportive care for the majority of them. You see a consistent 24%, 25% PR rate, which are durable. Control rate is 80%. They last. Median survival non-breach, which is, I think, an unheard scenario in this particular population. That's fantastic. What I think is even more exciting is that now we will move this to earlier lines of the disease. You will talk about the preoperative. You will talk about, and actually, these are non-liver mets, but there is also activity in the liver metastases, which is a harder subgroup to treat. I think this is a combination that will be exploited with other interventions in that particular group. It's the beginning of IO in colorectal cancer, considering that MSS is the largest population. Very, very exciting data. Pashtoon and Bree, you have actually combined, because of the breadth of the phase I trial, the colorectal, the pancreas, all of the, have seen this across not just one disease, but broad cold tumors. I've seen it from within and above, but you guys have really stayed with it. We'll get to the individual cancer types, but just a quick comment about how this data impacts you to see this MSS, which is our largest and most durable cohort. I think building on what Dr. Fakih was mentioning, you know, we work closely with patients and ad hoc groups. Even when you start talking about regorafenib or TAS-102, pretty much patients are under the impression that you're pretty much writing them off. These are patients who actually got exposed to this, so they're in really, you know, limited options position. Now, phase I trials also are not necessarily the best home. This is, you know, very provocative and reassuring. Bree, you said. I think we've all experienced patients coming to us and being like, I want immunotherapy. I remember sitting there as a fellow or a junior attending and talking to a newly diagnosed metastatic colorectal patient and being like, immunotherapy doesn't work for you. That's what people said. Same thing for prostate, same thing for these other tumors that were cold. Sarcomas too, you know, sarcoma is always neglected. That's a whole other thing. We'll talk about that. The point is when you can look at someone and say, you know what? It can. All of a sudden now these rules, these things that we've been preaching as dogma for years, that's not exactly true. There's hope for you to have the same sort of transformative, life-changing responses that people with melanoma and lung cancer and bladder cancer and kidney cancer are all over the news and all over the internet talking about how they've got their lives back. I think that's what you see when you see these patients that have been told they have no hope. Suddenly, you do. Yeah, I remember as a clinician, you have to look someone in the eye. When they say, I want IO, we had to say it won't work in 70%. I had the advantage of knowing what it could do in melanoma and kidney, and it was devastating. Now we don't have to say that anymore. It's not based on one tumor. It's based on multiple. This is representative of a broad cold tumor turning the ignition to initiate the education that Lex is talking about with T cells. The program is broad and reproducible across these cold tumors. The real breakout for me, and tonight we're going to start talking about it, is what about, to Garo's initial slide, bringing it to tumors that haven't yet metastasized, haven't had the resistance develop, the environment become hostile? What about BOT as a foundational partner with PD-1 when appropriate, but other cytotoxics, ADCs, vaccines, the world is at? Let's also talk about, obviously we're going to talk about pancreas and chemo. Let's first move to stick with colorectal and move to this data that you, Pashtoon, in your IST, have really given us an amazing glimpse of the future. You know, we have had the privilege of, as they say, standing on the shoulder of giants and foundational work that was already done by colleagues, but also colleagues here in Europe, in terms of the NICHE study earlier, a few hours ago, they talked about the NICHE- 3 study. There were parallel observations being made about the neoadjuvant setting as a conducive platform with the whole paradigm shift across multiple tumors. Also, the data in BOT/BAL with metastatic setting, those things in parallel prompted us to consider an investigator-initiated trial, bringing those two observations together in terms of, even if you look at the original Nature of Medicine paper, looking at APNEVO, Dr. Chalabi and colleagues had argued that they were going to take off with the MSI high boat, but for the MSS, this platform could be a window of opportunity for other novel agents. We haven't had more activity in that space since the publication several years ago. This was, we called it NEST. This was our neoadjuvant platform to nurture these novel agents and see what else we can do. For proof principle, kept MSI high, but that was limited to no more than three patients. Then, treat another nine patients with MSS at record pace within May to August in three months. The study was already complete, actually overflowing. We had to stop the referrals because we are now expanding the study to other cohorts. The waterfall plot is something that we were hoping for some activity. In fact, on purpose, I asked as my statistician, there will be no interim analysis because he did not want to undoubtedly stop the study midway if there wasn't activity. Thursday night, we have tumor boards. Every tumor board, it's almost like a drum roll. Where's the last patient? Where's the next patient? What did the path show? The comments from the pathologists were also very intriguing in terms of the pattern of responses. Now, for those who are familiar with the NICHE- 1 design, these were resectable colon cancer. These were also resectable colon cancer, but to the eye of the surgeon and Cornell, there's a lot of things that are resectable. These were bulky tumors, often T3, T4, N1, N2 disease. Compared to the European colleagues in the United States, there's no such thing as neoadjuvant therapy for colon. We were seeing almost all these patients with a surgical date already on the books. I'm here to talk to you about this trial that you may have, but my surgery is already set for the 30th of October. During that time, if the patient agreed, we were pushing the surgery to the patient or caregiver who wants the tumor out of their body, the surgeon who already has an operative date to say, cancel this and let's move it to. This was only three weeks into therapy, so one dose of botensilimab/balstilimab. Just one dose of botensilimab. The last thing you want to do is colitis in somebody who's about to get colon surgery. This was compared to the metastatic setting; this was half the dose. Not just one dose, but one half of the effective dose, so to speak. A person could go for surgery three weeks later, and most patients did. The surgeon told them one day you could operate. They already had the date booked. The few extra days we got for immunotherapy brewing was because of scheduling issues. Otherwise, almost every single patient got their surgery within four weeks of starting therapy. The robustness, the rapidity, and also we published about the pattern response. It was kind of like a cirrhosa to mucosa response. Even the tumors that were like T4 and T2, what they were left with was like T2 and N0 or T1 and N0. Even the barely some tumors that had some floating pools around, they were all kind of simplistically, the trash was already ready for pickup for the surgeon. It's not necessarily 100% responsive, but I think what we also questioned, the response as a measure of what the drug is doing is the true downstaging that's happening within just a few weeks. Despite just a short interval, six out of these nine MS stables had at least 50% shrinkage, and two were complete. Do you want to talk about these complete responses? As the field in Sloan with the data regarding selective emission radiation was evolving, four out of these 12 were actually rectal cancer patients too. If a rectal cancer patient can also go straight for surgery, we allowed them the opportunity of participating in the trial. For that one patient, it would have meant an ultra low LAR with a possible chance of maybe even getting an ostomy. That was somebody who had one of the first patients who had the 100% response. To kind of ironically seal the cohort, the last patient who just had surgery last Thursday is somebody who is an informed scientist who was like, if I can get surgery in three weeks, the surgeon already gave me a date. What if I waited a little longer? Can I wait? Does your trial allow? I was like, the trial allows for as long as you want to wait. He allowed the immunotherapy to brew a little bit more. Just a couple of weeks. Just a couple of more weeks. That was a person, again, with bulky disease. In fact, the day I enrolled him, the next day, one of my other colleagues in our division, you know, we have clinics together, kind of in passing said, you know, I probably won't have enrolled that patient onto your trial because that was a pretty bulky tumor. Just throwing it out there. I was like, I think we would agree to disagree here. He ended up being another 100%. That's true. These were very profound stories. I remember Dr. Chalabi mentioning that she remembers every single person who had, I think we've had some really interesting stories of young onset colon cancer, as early as 26 years old, enrolling in the trial and getting. These patients early will be seared in your memory as you watch. Obviously, it's a disease of young. It's a huge help. The other thing that's interesting is the earlier point made by Dr. Garo about the chemotoxicity. One good problem we've had post-op is between the oncologists and the patients and caregivers. They are saying, my tumor is T1 and N0. You're saying I still need chemo because we're kind of, we don't know what to do. You know, because you often start the treatment based on the stage you started off with. A stage 3C colon cancer should get three to six months of some sort of doublet chemo. The patient doesn't want chemo. We have the perfect person to actually weigh in on this. I mean, Dr. Eggermont, like no one else, I think, in the world has seen what's happened in melanoma, has pioneered neoadjuvant as the optimal curative model, and spoken a lot about drug development of the future. Lex, your reaction to this, obviously, these T cells are getting educated very quickly in their school because, you know, historically, people thought in melanoma that neoadjuvant IO, unlike chemo or targeted, would take too long to be relevant and we'd lose control of tumors. In fact, just the opposite. This is further. Lex, comment on this data, put it in perspective for us. There are a couple of elements. If I go and refer back to the school system, the neoadjuvant system is introducing already a fantastic primary school because you really optimize the educational situation and you use the primary tumor as a source of a rich educational program. Instead of trying to do innovation at the back door of the school or at the back door of all the schools, once you have seen multiple lines of therapy and you have widespread disease, what is there to educate? You are in a fundamentally immune-suppressed status, in an inflammatory status, and actually, lymph cells don't know where to go anymore. They can't find their teachers, and it's too late to do anything. There is a fundamental problem with how we utilize our innovation because you cannot do the best innovation at the back door after college, where you didn't go, but you should bring your innovation up front where you can achieve just uncharted opportunities. You would be surprised how many good people and pupils there are in this world, right? That leads not only then to a better society, I'm sure, it leads to an optimized functional and diversified functional immune system that achieves then three things in neoadjuvant in melanoma. The model, the easiest model to understand is if you have palpable lymph nodes. The relapse rate after surgery for the palpable lymph nodes is local regionally more than 40%, but distant relapses is actually above 90% relapses. Basically, they're all destined to die. Do not start your innovation when you're almost there. This was the moment to use your neoadjuvant approach and you work with all the T cells, all the pupils, right, in those lymph nodes, and you optimize and you provide a perfect schooling model. You get a diversification of T- cell clones that is so rich and an amplitude of T- cell clones that is so large that you will see in melanoma within this patient population in two-thirds of pathologic complete response. You will see in the upper 80s a major pathologic response, including the near pathologic responses, etc. What leads that to? That leads to very rare relapses. In that two-thirds of the patient population, you see two relapses in about 80 patients over the next three years. We have never ever seen this ever in the history of melanoma. Secondly, you achieved it by short treatment cycles before doing the surgery. That was less systemic exposure. Thirdly, if you have a pathologic complete or near complete response of the lymph nodes, you do not need to do the lymph node dissection. It's a triple effect: more cures, shorter systemic treatment exposure, less surgery. This is the first proof in melanoma. In MSI colorectal cancer, it is unbelievable. Everybody has seen the picture in The New York Times with the 16 young patients who all had a pathologic complete response for their MSI rectal cancer because that's the richest one in terms of antigens. It will translate into all these neoadjuvant programs in bladder, also rich in mutations, and in head and neck, and so forth. If it works in one, it's going to be a transversal effect that you can optimize in combo with chemo, yes or no, where necessary. It's not just the immunotherapy revolution 2.0; that's even too modest. It's immunotherapy revolution 4+, right? That's how big the jump can be in completely changing patient management in what I think across two tumor types within the next three to five years. I think Dr. Pashtoon has really dreamt big. He's worked with his surgeons. I think the next stage of this trial is to allow for a longer run-in, which will hopefully really produce deeper durable responses. Clearly, in melanoma, when they're deep, just like in the metastatic setting, deep responses are very durable. In the neoadjuvant setting, those deep responses have led to very, very, very few event-free distant recurrence. To the word that was mentioned several times, diversification, because the surgical setting is you have the generous amount of tissue from a right hemicolectomy specimen. We were able to visualize, through immunofluorescence, the true diversification that was happening pre and post. There's always a good generous colon biopsy in anybody who's diagnosed with colon cancer. As opposed to some other tumor types where lack of tissue can be a problem, we were in a situation where we were real-time seeing these analyses supporting and even mechanisms of action beyond T cells and macrophages and other cells that were beyond just what we know about the drug was also refreshing to see. That gets to the multifunctional immune activator. This is so much more than a front-end CTLA-4. The CD4s, the priming cells, were heavily infiltrated in your two cases. It was so fascinating. Even in the same patient, if there was a part of the room that still wasn't cleaned up and the part of the room that was almost dead, you could see a difference in the activity of the T cells, even within the same patient, just in different parts of the tumor that were about to be killed, where there was still a wave of highly active Ki67 positive T cells. In the part where the job was done, it was kind of like your office after 5:00 P.M. This window, though, of just three or four weeks, for most of the neo, we wait longer. We haven't really understood what's happening so soon, but it sounds like. A comment our pathologist even made for the tumors that, for example, had only 25% viability based on the scoring system. The repeated comment that we were hearing from our pathologist was it was all just on the mucosa. Barely a few cells made it to beyond the submucosa, so I had to call it P3. By the books, if we had waited a little longer, which is going to be the expansion, and to the last MSI patient that got surgery, surgeons are very comfortable in not operating and being out of business for this particular subset of patients for organ preservation. Sounds like you have a lot of buy-in, and we can't wait to see this continue with longer. Bree and Marwan or Manny, I mean, we want to move to pancreas, but any sort of quick comments about neoadjuvant and what you're seeing here? No, I think this is a wave of the future. I think I'm glad that you jumped in in the MSS. There's a lot of questions to answer, whether it's rectal cancer or colon cancer. Congratulations on your work. I think you should move forward. Yeah, OK. Just one additional comment that, of course, this was a great experiment. We learned a lot, safety, the biology, all the school system, all the teaching. That went very well. One could say, well, these patients get cured with chemotherapy and with surgery and chemotherapy. That's not correct. 30% of the patients still fail despite surgery and chemotherapy. Many of them, particularly the rectal cancer patients, need mutilating surgeries, which could be avoided. It's a very important clinical endpoint. Basically, most of the patients get three to six months of chemotherapy with oxaliplatin and 5-fluorouracil. We know that oxaliplatin contributes very little, maybe 5%, 8% to the overall outcome. It's very toxic, right? They develop neuropathy and then it stays there forever. Even if you could just avoid the oxaliplatin in the adjuvant setting and reduce chemotherapy to, let's say, three months instead of six in all patients, that would be a major clinical outcome. This is a very nice experiment. I think it has a tremendous future. Of course, we'll need to do the proper studies to move it forward. There is a significant need. These patients don't die, or most of them do not, but this is still a very significant clinical problem. To Pashtoon's point, you know, a lot of the colorectal neoadjuvant has been in sort of a diversity of earlier or later stages. These patients seem to be selected for very T3, T4, and nodal disease, which makes it very impressive in the short interval. It also has the lack of ability of imaging to underestimate. We're good about telling bulky tumors, but in terms of early-stage tumors, there's no consensus, and it's not as good as rectal. A lot of these patients, now that we're using CTD and some of the other methodologies, it is humbling to see how many patients are not cured, as Dr. Hidalgo was mentioning, after curative intent surgery and chemotherapy. Every time we get a T4 and T2 before even chemo begins, we, as the tumor board, know that this is something that's unfortunately not going to be well in the long run. It's good to have an option. Increase the number of patients who are able to get laparoscopic surgery versus open surgery is a huge difference. The time of hospitalization, pain, issues after surgery. We, you know, because the field is so all over the place, the question asked by Dr. Jing is, are we giving the option of skipping adjuvant therapy in the trial? This trial, the way we structured it, because there's so much variation in terms of adjuvant therapy, and also we weren't sure what we were going to expect with the trial, we limited the trial till the surgery and then the MRD period of post-op to collect ctDNA as a measure of seeing if somebody's cured or not. What they could get, we left it open because we had patients from Brooklyn, Queens, Manhattan, from different surgeons, 12 different medical oncologists. I think the pro and the con about the study was we left that part flexible. The expansion. Even for the expansion, because the other thing that we wanted to keep practical was a patient from, even if they are from a different state, if they could just come in for, we had actually three patients who flew from California, from Carolina to Vegas, and just were here for two visits and surgery, and then they could return for whatever chemo, three to six months of whatever they want to do. We can still capture their recurrence and other outcome variables. We wanted to design a trial keeping the practicality in mind. I think while it's an important question, we would probably still err on the side of making it as patient-friendly as possible. Also, to your point about chemotherapy, we could also see, you know, from a patient and physician standpoint, if, for example, as Dr. Hidalgo was mentioning, could, let's say, a dose or two of immunotherapy obliterate or decrease the duration or intensity of chemo, that could be something that could be escalated or de-escalated as a measure that I think in a probably like a large registration study. This has been a great discussion. I want to give Bree the last comment on neoadjuvant. We will move. This is amazing, and we've got so much great data to share. Bree, do you have some. Five seconds. Yeah, no, we love it. Grade 3 sarcoma, adjuvant chemotherapy, which is doxorubicin and ifosfamide, possibly one of the most evil regimens we put anyone through. This has been the greatest debate for the last 50 years about whether to adjuvant or not because you only get 5%- 10% improvement in overall survival with this horribly toxic chemotherapy. If there is any shot that you could dose a patient with a sarcoma, which apparently kindergarten's the time to go in, everything we need to know, we learned in kindergarten, right? In kindergarten, you dose this patient, you take that tumor out, which you're going to take anyway, and it's full of pills. Like that, knowing that is possible in a cold tumor, if there is any shot that would avoid the need for putting patients through this for marginal benefit. We don't have the colorectal data for the benefit of adjuvant therapy. We just don't. To be able to do that in that group of tumors would be transformative. Six months ago, we hadn't imagined it. They got 12 patients on, so we need to move it forward with other malignancies. All right. Quick, then we got to move on. I've wondered if it's profound because of the question. Do you still. To repeat the question. Yeah, I'm repeating the question. OK. The question was, do you still offer adjuvant therapy? The proof of that concept already has been produced. In melanoma, with palpable nodes, if you have a pathologic complete or near complete response in the largest node, you don't need the lymph node dissection, less surgery, and you do not need adjuvant therapy. None of those patients treated in Amsterdam had adjuvant therapy if they had a pathologic complete or near complete response. That's exactly my concern because guess what? We give people with FOLFOX a lot of steroids. Yeah, and oxaliplatin is not so good. Yeah. That was the part, less systemic treatment. OK? Don't forget it. The last point is, how do I talk to my Surgical Oncologist? Yeah, because the audience is mostly Medical Oncologists, and you all have this problem. How do you talk to your Surgical Oncologist? I happen to be a Surgical Oncologist, and I know how difficult that is. One of the arguments that you must bring into the discussion is that we did not realize how quick the pathologic complete responses and near responses are achieved. They're all basically achieved in the time frame of six to eight weeks. That must be initially inserted in the discussion to show that the surgeon opens up to your discussion, right? Very important. Talk to your surgeon. That's a great way to end neoadjuvant. We could talk about this forever. The good news is we have a lot more exciting data. Let's move to pancreas now. You know, pancreas was built on a preclinical model with Dan Van Hoff, one of the pioneers in pancreas, with a very resistant, poorly immunogenic pancreas model, where the addition of BOT to chemo was curative in the mice. Remember, in the clinic, this gets to turning the key for cold tumors. PD-1s have been tried and many other IO agents with chemotherapy in advanced pancreas have failed because there's no switch. The T cells have simply not been educated that there's something wrong. The mouse model suggested that this was transformative in a mouse model, and he encouraged us to quickly go big in very refractory pancreas, pancreas that Gemma Braxton's been using the second-line metastatic with a 10% or 15% response rate. We designed a randomized trial, which has now started. As a run-in to that trial, for safety purposes, we treated two doses of BOT, three patients at just a very small dose of BOT, and then moved to our definitive dose that we think is the best, 150, and treated six patients. These are patients who had failed FOLFIRINOX in the first line. They had rising tumor markers, and they all had liver metastasis. It doesn't get much worse in pancreas than that. We saw four of these patients have already two are PRs, and two are moving quickly towards that. One patient has not yet been scanned. One patient has progressed. Manny, you're the guru in pancreas among the world's experts. How do you react to this data? It's early, but it's quite amazing. I'm very, in my mind, I think it's important that it's very consistent because the KPC model, the model you were referring to, is intrinsically resistant to chemotherapy. Chemotherapy does nothing, and all of a sudden, those mice got cured, which we have never seen before. As simple as that. Never before. Agenus did some internal work with that model as well. Perfectly consistent. Similar results across the two labs. Here you have the. Responses, four out of six, one is still pending. The response rate in this group with the standard of care is around 5% to 7%, as you said. Tumor markers going in the right direction, so very predictive as well of what the responses are. These are truly FOLFIRINOX-resistant patients. They have received FOLFIRINOX for metastatic disease, or just in the adjuvant setting, and then they progress. Many of these patients actually, you could argue, were third line because they have got adjuvant, then FOLFIRINOX, and then the combination. The final point is that the concept that there is a dose response is quite interesting and also consistent with the idea that the drug is doing something very, very unique. Early, but I think this is already the university, not the school anymore. Yeah. Pashtoon and Marwan, and we'll get to Bree, who's also looked at chemo with our botensilimab now in sarcomas. It opens up this notion that everything doesn't have to be tied to a PD-1. If you can turn the key and drive cytotoxicity briefly for a period of time, can the memory response, and we need to watch these patients over time. You also have treated a pancreas patient, one of these six. Do you want to just tell us about that experience? Yeah, no, to your point, I think there are parallels in other tumor types, including liver cancer, where the PD-1 story has been up and down, but the CTLA-4, even if it's just one dose, does change the outcome and the tail. In pancreas cancer, the patient that we've had the opportunity of treating, again, this is second line patients post-FOLFIRINOX. It's more of a stabilizing disease control kind of situation. You don't see much of a response, but to see a tumor marker go from 20,000 down to 4,000 and still ongoing. I think it's usually rare when you're a patient with pancreatic cancer with ascites or other issues, second line therapy after four to six weeks reports to your nurse practitioner that this was the best week that they've had in a while. Usually, it's not the case. Those things that are not tangibly seen in these responses, like the cyst doesn't even capture the ascites that dries up. I think those are huge clinical nightmares to have a patient with pancreatic cancer with malignant ascites start, need for biweekly drains or that become more frequent. It's a very morbid decline. This is early on, but again, to Dr. Hidalgo's comment, a consistent theme, which is encouraging. Yeah, and the nice thing with gemabraxine, it is a standard first line regimen, also with a higher cytotoxicity, you know, 30% response rate. Second line, it drops precipitously. Obviously, you can imagine more activity as we move forward. Of course, neoadjuvant is wide open. Such a big need in pancreas in these locally advanced tumors. Marwan, yeah, your thoughts as a GI specialist about this early data? Yeah, I think the fact that there's liver metastases here and you're seeing some responses with chemo is very reassuring. This is a highly refractory tumor in general. It brings up the question that sometimes more is not better, but there are instances where you combine with chemotherapy. We know that the tumor microenvironment is different in different organs and in the primary tumor. Back to colorectal, we've shown that lung and colon primaries are different than liver as far as metastases. It doesn't mean that liver may not respond. It just means it may need a nudge with chemotherapy. It may need to be controlled a little bit longer until you traffic yourself into the tumor. Exactly. I think these are situations where, when you have extensive metastatic disease, when you have liver metastases, the door is not closed on botensilimab. I do think that is an area that is of prime interest when you combine with chemo in that setting, whether it's pancreas or other GI malignancies. Yeah, just one more comment, you know, it's somewhat discouraging when you have an approval that gets withdrawn in stomach cancer. You know, Pembro was withdrawn in the third line approval, but now you have first line chemo plus IO across the board approved. The idea of chemo IO in this scenario, I think there are some parallels. Yeah. Was this all at the same time? Like, was the botensilimab and the gemabraxine all on day one? No, it was all simultaneous to the patient's visits. There wasn't a separate visit. Just come in on your cycle one, day one, and then six weeks later, you're back on your six-week annuation. There were no extra visits. I'll just say I think this is so intriguing because again, we've combined botensilimab and balstilimab, and this is all ongoing work with doxorubicin, which is our go-to immunogenic booster in sarcomas. I think so much that we don't understand is when the right time is to intervene with the chemo versus the botensilimab. To keep with your analogy, should we prep the students before they're about to get, you know, the pop quiz, or should we just throw it at them and see what they know all at once? I think clinically here, the issue was second-line pancreatic cancer. They decline before you even enrolled them. What about a week or two, right? Can you do it? It's so challenging. We've had three fails doing just that. In fact, it's a bad situation. Okay, yes, [Eric]. Manuel or Pashtoon or somebody else, I'm really impressed with this data in pancreas, but can you explain or speculate a little bit on the mechanism? All we know is that it works very well. Yeah, we're all impressed. We're all impressed. Why Dan did that experiment, who knows, but he has always very good sort of insight. I don't think we have done any more sophisticated study in the mouse model of why. We also know that PD-1 didn't work and actually doesn't work. Across all pancreas cancer preclinical studies, usually CTLA-4 for some reason is better. The answer is that I don't think we know. I don't know. I don't think it's known, but obviously it's a very important question to try to understand because it's looking quite intriguing. In the colorectal cohort that we have both pre and post biopsy as well as surgical tissue, we're almost halfway through, but there are new patterns and things that we just want to make sure that they solidify. It's more than just, as narrated earlier, the diversity of not just the CD8, but also T-Rex going up in the ratio and macrophages. There's a lot of things that we're seeing. It would be nice to see if there's a consistency, but it seems like there's more than one mechanism at play. In the mouse model, the chemo had a temporary effect like the clinic in humans. Both botensilimab and balstilimab had a longer effect, but not curative, the combination was curative. Something about how the chemo, even in a 10% cytotoxic situation, it's making the tumor vulnerable to a T-cell attack. Yeah, this is the KPC, the KRAS. I wouldn't know that yet. The question was, are the patients on the pancreatic cancer RAS mutant? The ones at our institution are all RAS mutant because once we had response and safety calls, this is open at six or seven centers. On our weekly safety calls, when we have the discussions, we always are intrigued by, is anything TMB or BRCA or something else that explains the response? These are all just plain RAS mutant low TMB for that to have a response. Fifth, that's the cyst is pending and one progression. Is three RAS mutant? I would say all. When we're on the calls, we discuss the other centers too. There's nothing unique immunologic-wise. Our patient is the run-of-the-mil KRAS G12B mutant, CDK53, all the classic triad. We have a little bit of a time limit here. It's a great discussion. Let's move to melanoma. Obviously a hot tumor that has failed IO. Remember, we've cured approximately 50% of melanoma with checkpoint inhibitors plus minus BRAF drugs when appropriate. The next experiment we wanted to do is look at single-agent botensilimab in a refractory melanoma setting. What we're showing in this slide is that in our phase I trial, we saw responses. We only treated a small group of refractory melanoma. We saw single-agent activity. We've now enrolled a phase II trial in BRAF and Ipi/Nivo mutant patients that have failed Ipi/Nivo. The trial is maturing, but we're already seeing proof of concept with the single agent. Remember, we've shown you botensilimab data in advanced colorectal. We've shown you botensilimab data in neoadjuvant colorectal MS stable. We've shown you botensilimab plus chemo data in refractory pancreas. In melanoma, we're going to show you single-agent botensilimab in Ipi/Nivo failures. Are we a differentiated CTLA-4 inhibitor? We are combining our balstilimab with our botensilimab in refractory melanoma, and that's actively accruing. What's interesting about four patients we're showing, there's actually five here, is that if they were BRAF mutant, they'd already failed BRAF + MEK. If they were not, either way, they've also failed single-agent PD-1, PD-1, CTLA-4, combos, even a PD-1 LAG3 combo. Yet we're seeing deep responses in these representative patients that gives us great confidence that as we expand this cohort and then add our PD-1, we're going to see continued strength in this resistant setting. Just your thoughts on what you're seeing here in melanoma. This actually demonstrates how different botensilimab is. Yeah. We should not underestimate that, we should accentuate that because botensilimab is a much better teacher than the teachers who have been acting before. Even after having failed everything that you can throw at these patients, and then you come back with a monotherapy, which is an anti-CTLA-4, but it's a very different one, that shows what the difference makes, makes how good a teacher can be. Otherwise they think, it's just another anti-CTLA-4. No, it's not just another anti-CTLA-4. There's something very essential about the fact that this teacher is not removed from the lesson from the school by endomicrophagy, by the FC gamma receptor 2, and so on, because it sticks. It's a teacher that stays in front of the classroom until they're all educated. That's why it's such an effective model. Yeah. You're not surprised that both my parents are teachers. Obviously we're starting in the refractory setting. We would love to move earlier in first line. Neoadjuvant is wide open, where more than 50% of patients with neoadjuvant are the deep or complete responses with Ipi/Nivo. We can imagine the future in melanoma if we can increase that deep pathologic response, not just in the refractory, but early stage. Huge unmet need. Hot tumors are not off our radar. Early treatment is where we're going. Any other thoughts from other panels? I want to show you some lung cancer data briefly, and then Garo's going to close us out. I want to, anything? One thing I just want to reiterate, and Dr. Kier alluded to it earlier. We've had Ipi/Ni vo as well as durvalumab data, and combined with radiation, even for pancreas. One of the studies from NGH looked at Ipi/Nivo in MSS colon and pancreas plus radiation to see if that would help. Other than quality of data, there wasn't any kind of activity. There are some parallels to this; it's not necessarily the same class of drugs. Yeah. I think our design has been to use PD-1 broadly to show that we can make cold tumors hot. Do we have a single agent that's different? Melanoma is telling us that. Can it be combined with non-PD-1 drugs? Obviously, cytotoxics like chemo, ADCs, vaccines now are coming back with mRNA vaccines. There's a real priming potential that has been absent in the field. A lot of excitement. Lung, let's put it. We have publicly described this initial cohort of eight patients. This is now nine patients that we're showing tonight. These are PD-1 refractory patients who have failed frontline metastatic lung cancer. We've seen five responses in these first nine. Again, it's consistent. It's not surprising anymore because it's consistent across these solid tumors. This cohort has been rapidly expanded. We're now up to about 40 patients. The data is maturing and we will show more of this data in the first half of next year. What's equally important about this cohort is we started with just PD-1 refractory. Because of this strong signal, we wanted to expand a cohort of patients who are TKI refractory in the metastatic. It's a large population of lung cancer. As you may know, it's been incredibly refractory to IO. It's really serial sort of generation TKIs and then chemo and then nothing. We've already seen two responses in this small expanded cohort in the TKI. Again, it gives us more confidence that we can expand both the PD-1 refractory and the TKI refractory. The panel hasn't, this is new data to the panel, I think, but thoughts to sort of how we're approaching this and what does the lung cancer data tell us? I think in general, when we see patients where they've already failed IO, the leaning is not to try another IO because the outcomes are, it's not a gift that gives you as much if you just failed something. To see that you can go from an IO-based strategy to another IO in somebody who truly failed IO, I think it's encouraging. Yeah. I think you're seeing parallels across all tumor types, right? Which is encouraging. You know, the same story with melanoma, non-small cell lung cancers, the differences with CRC, and it's only giving you more and more confidence that this is clinically different, clinically more effective. I think this is an unmet need. Definitely looking at this population makes a lot of sense. As PD-1 is moving in front line and now in the neoadjuvant setting in earlier disease, there are going to be more patients who are PD-1 refractory. I think the opportunity to develop a drug that has a completely different mechanism of action and for that reason works is very out loud. You've seen the neoadjuvant lung data now with chemo plus IO with about 20% deep pathologic responses. BMS presented at this conference a chemo-sparing ipi/NeVo regimen also showing 20%. Imagine the possibilities of weakening either with chemo or an IO-IO alone sparing chemo produced much higher neoadjuvant deep pathology. It's pretty exciting. Bree, I want you to give, before Garo ends here, I want you to present an oral session in sarcoma. Maybe just give us the highlights of what you've learned in sarcoma from your presentation. Yeah, real quick. Again, sarcoma is a group of over 100 different diseases. It's really a microcosm of cancer in general. I think what we can say is that we found our hot tumors. There's a couple of signals in diseases like cutaneous angiosarcomas that have very high mutational burden, look very similar to melanoma with a UV signature, thanks to this woman who did the sentinel work who's sitting here with us tonight. Yes, there are tumors that you can throw PD-1 at them and they'll respond. The vast majority of sarcomas are cold as can be, and they don't have lymph node involvement, and they have no schooling. There's nothing out there to tell them at all that there is a serious problem that these tumors are foreign. That's what you see when you look. Clueless immune cells. They have no idea what they're supposed to be fighting. I think when you add leiomyosarcoma, which, if you look at Pembro monotherapy, zero out of 10 responses in our tumors, uterine leiomyosarcoma, zero out of 40 to PD-1 or Nivo or Ipi/Nivo, there's just not that signal. We presented 16 patients with leiomyosarcoma, which is one of the coldest tumors. Again, it's early. We're still tweaking things. The data is very, very early. You're seeing waterfall plots where half the tumors are shrinking. That does not happen with the chemotherapies we have. That doesn't happen with targeted therapy. Just to add, the worst tumors out there, no one wants to deal with sarcoma. They don't follow any rules. They're awful. We can actually see signals. The dose may also be, there was quite a dose response here, wasn't there? There really was. We need to sort through everything, but that's a compelling observation. It really takes us back to the drawing board. The biggest question across all of this is what is it doing? What is that? How is botensilimab teaching so effectively? I think once we really understand that across these tumors, we're going to be able to customize even further. I think it's unlocking that the backend stickiness of the FC is allowing the education. It's allowing that synapse to drive a more durable, long-term teaching effect in antigens that are just not available with, I think that's, yeah. Do you want to just talk about that visceral patient who has the long-term survival? It was quite illustrative in terms of a minor early progression and then this deep, long response. Yeah, visceral angiosarcoma is not the same thing as cutaneous. We don't have the UV signatures typically. This particular patient, 45 years old, prime of his life, low tumor mutational burden. He had already had a primary in his bone, which is a really unusual site, had had cisplatin, doxorubicin, and they had taken care of that, but then rapidly progressed with metastatic disease in the pleura. Pleural sarcoma is bad because there's no walls, and that stuff just sticks on everything. It's like a mesothelioma that just crawls all over everything. He had progressed through our standard chemotherapies. He'd had dox, he'd had paclitaxel, he'd had gemcitabine, and tetanus toxin, nothing touched this tumor. By the time he went on this study, he had pleural studding. You could just see the disease creeping everywhere. Within weeks to months, he was going to have a malignant pleural effusion and he was going to be dead. That's what happens in this disease. He progressed initially. That six-week scan, with that horrible decision, you sit there with the patient, you're like, I don't know what to tell you. The stats would say sarcoma is not going to respond and this is not going to work for you. We can keep going and roll the dice and have that faith. By the next scan, he dropped by 50%. He kept marching down. By three months on study, he was at essentially a CR. No PET avid disease. Pleura's clean. Developed his toxicities, had his colitis, had his pancreatitis, got some room stuff. We had to take him off of treatment. This is at least probably a year and three months ago. He's been off of everything completely. Visceral angio, cured of his disease, living his life. That doesn't happen. That's cheating. Yeah, it's cheating. Thank you. That's quite a story. That's how we learned in melanoma because we had nothing else to give the patients. We saw these early responders. We sent them to hospice. Progressors, yeah. The hospice would call us and say, your patient's doing particularly well. We did see the kinetics in the metastatic setting. We've seen very early responses with botensilimab and balstilimab. Occasionally, we will see this delayed response, which is almost certainly inflammatory. Garo. Thank you very much. I hope that you have gotten a good sense tonight that we don't have an active drug. What we have is an immunological agent, which is doing things that nothing else is doing. This is true in nearly 700 patients, not in one indication, not in two indications, not in three, but nine indications, nine different cancers. You have heard a number of them tonight. There is no ambiguity about that. Now I'm going to touch on a subject very briefly, which is an uncomfortable subject. Of course, money could be very important if you're trying to do something good with it. It also could be very evil if you're just trying to do something for personal profit. Of course, now we're in a situation right now in the world that some have described as the most difficult biotechnology market in the history of our business. Why is that? It's because there was irrational exuberance in our business. A lot of companies came about just to make profits for people. I can't fault them for it because some of these people are good people and so are our Agenus shareholders. They're very good people. What I can tell you is that in spite of all of these difficulties, in spite of the difficult marketplace, we have embarked on a path as a company that is going about, in fact, we've ignited multiple pathways, ignited it. It's underway as we speak that will bring about monies into the company so that we can continue on this good work, multiple pathways without or with very little contribution from issuing stock. Investors don't like companies issuing stock because it's dilutive. Their ownership goes down and we're respectful of that. That's why we have ignited these multiple pathways to make sure that we have alternative means of doing it. With all of this, there's a presidential dinner and unfortunately, our esteemed Dr. Todd Yancey sacrificed his wonderful ending comments as well so that we can pay respect to the president of ASCO at this dinner. Thank God it's only ESMO, sorry. Wow, that's a Freudian slip there. Of course, the president's presidential dinner of ESMO, thank goodness that it's only about 15 minutes from here. That makes it easier for a number of our guests to get there. Starting with Dr. Kasi, thank you very much for your wonderful work. Dr. Marwan Fakih, Dr. Eggermont, Dr. Wilky, and Dr. Hidalgo, thank you very much for your time. This is really a very special occasion for us and it has been a wonderful event for us to have you here. Dr. O'Day, our team, of course, Dr. Robin Taylor, even though she didn't say very much, she's been the engine behind all of this. Dr. Buell, Dr. Agarwal, and Dr. Yancey, thank you very much for your time.