Good morning and good afternoon, and welcome to Agenus' ESMO GI webcast. We're coming to you live from Barcelona, Spain, where we're excited to share with you the remarkable botensilimab balstilimab combination data we released earlier today, in which Dr. Anthony El-Khoueiry presented at ESMO GI's opening session. I am Ethan Lovell, Agenus' Chief Communications Officer, and I'm glad you've been able to join us today. Before we begin the formal presentation, however, I do need to provide our forward-looking statements disclosure. I'd like to remind you today that this webcast will include forward-looking statements, including statements regarding our clinical development, regulatory and commercial plans and timelines, including timelines for data release and partnership opportunities. These statements are subject to risks and uncertainties, and we refer you to our SEC filings for more details on these risks. With that housekeeping out of the way, I'd like to invite Dr. Steven O'Day, Agenus' Chief Medical Officer, to the podium to provide some opening commentary. Dr. O'Day. Thank you, Ethan. This is both a remarkable and an exciting day for Agenus. This morning we had the opportunity to present our combination data with botensilimab and balstilimab in cancer. The data is both remarkable and unprecedented in this advanced line of therapy, and it allows us to highlight one of our many deep pipeline jewels, botensilimab, which is a next-generation CTLA-4 that is much more than that. It's an engager of antigen-presenting cells, and it has been specifically designed to address the unmet need from first-generation CTLA-4s, where cold tumors did not respond. As a pioneer in CTLA-4 early therapy in melanoma, I saw both the great success and the great limitations of CTLA-4. The great success was in hot tumors. The great disappointment was in cold tumors. I've waited 20 years to find a molecule that could address this cold tumor phenotype, which is more than 70% of the solid tumor world. Today, we have some preliminary data that is very exciting. I'm gonna introduce our panel, and I'm going to then finish some opening statements, and then we'll have Dr. El-Khoueiry give the presentation from this morning. Then the exciting part beyond that will be a group discussion with three of the top global GI oncology leaders. I can't wait for that. The three panelists is Dr. Anthony El-Khoueiry, who's the Associate Director of Clinical Research and the Director of the phase I program at the USC Cancer Norris Center, my hometown of Los Angeles. Anthony is the PI on the trial and presented the data this morning. Dr. Heinz Lenz, his boss, the Deputy Director at the Norris Cancer Center in Los Angeles. Manuel Hidalgo, who is the Chief of Hem/Onc at Cornell Weill Cancer Institute in New York City and a GI expert. What's remarkable about botensilimab is its mechanism of action. It truly is about activating the front end of CTLA-4 molecule to engage these robust T cells that have memory and the ability to eradicate tumor. On the back end, it's been Fc-enhanced to bring the synapse between the antibody and the antigen presenting cells and bring it to the tumor microenvironment with the T cell so that the expansion of the T cell repertoire into colder tumor antigens can be brought forward and realized in the clinic. That was the hope. That was how it's designed, and now we have some real data. As you know, last year we presented at SITC the phase I trial that Dr. El-Khoueiry and Dr. Lenz were part of, showing activity of this single agent botensilimab or balstilimab in nine that we've tested. This has broad applicability. What we're presenting today is the most expanded cohort to date of that trial in MSS-stable colorectal patients. I just wanna highlight that this was a metastatic colorectal MSS-stable population that on median average, 50% had already had four prior lines of therapy, and a third of them had already seen an IO. We know IO has not had any deliverables in MSS-stable colorectal cancer. We've also looked at our responders, and there's absolutely no biomarker that's really suggesting why a traditional CTLA-4 should respond with a PD-1. For example, TMB was low at 10 or less. PD-L1 was only upregulated in one of the patients, and there were no POLE mutations or other genomic features that might predict from an IO response. This is taking it from a traditional CTLA-4 cold tumor with this new molecule and showing clinical activity. The responses were both impressive and durable, and the toxicity safety profile was excellent. I just wanna. We'll finish the session at the end and some of the Q&A about where do we go from here. As a company, we're very excited about putting this molecule front and center with high priority to move forward, not only in this trial, where we'll be delivering more data later in the year in other solid tumors, not just MSS colorectal, so other cold tumors, which with exciting activity. We're also then launching robust global phase II programs in colorectal, MSS stable, melanoma, and pancreatic cancer. We got a lot of work to do, but today is a remarkable day for the company, and I look forward to sharing this with these world-class experts. Thank you. Anthony's now gonna go ahead and give the presentation for this morning. Thank you, Steve. All right, we have the slides. Thank you. Okay. On behalf of my fellow investigators, I'm honored to present data from the ongoing study of botensilimab, a novel innate and adaptive immune activator, plus balstilimab, an anti-PD-1 antibody, in a cohort of patients with metastatic pretreated microsatellite stable colorectal cancer. There continues to be an unmet need for advanced refractory metastatic colorectal cancer in patients who are microsatellite stable. Standard of care options such as regorafenib or TAS-102 have low response rates and very modest survival improvement. Single-agent anti-PD-1 and PD-L1 antibodies are inactive in this setting. Responses with first generation CTLA-4 antibody combinations are quite rare. For example, in the CCTG study of durvalumab and tremelimumab, which was recently reported, there was only one objective response in 119 treated patients. There are several experimental PD-1 TKI combinations that have shown variable results and modest activity overall. You already heard from Dr. O'Day about botensilimab, but this is to show it schematically. This IgG1 antibody not only blocks CTLA-4 interaction with its ligands, but it has this Fc-enhanced portion that increases the binding to the Fc-gamma receptors on antigen-presenting cells and NK cells, thereby tightening the synapse, the immune synapse with T cells. This results in several unique properties relative to first generation CTLA-4 antibodies. This includes increased frequency of dendritic cell infiltration, expanded T cell priming expansion and memory T cell formation, enhanced Treg depletion. There's also a single point mutation designed to reduce complement fixation, which is hypothesized to also reduce complement-mediated toxicity such as hypophysitis. Balstilimab is an anti-PD-1 antibody that's been evaluated in over 650 patients with activity and safety similar to other anti-PD-1 agents. These are the baseline characteristics of the MSS cohort from this ongoing phase I study. Microsatellite stability was an eligibility requirement for this cohort, and it was determined by local assessment. Patients in this cohort were both from the dose escalation and expansion. This was a heavily pretreated population with a median of four prior lines of therapy. 50% of patients had four or more lines of therapy. 34% had prior immunotherapy. As per design, all patients were microsatellite stable, and the RAS and RAF mutation profile was as expected in this population. Now to be considered evaluable, patients must have had at least one restaging scan at six weeks. In the 41 evaluable patients, the objective response rate per RECIST 1.1 was 24%, with 10 partial responses, 20 patients with stable disease, resulting in a disease control rate of 73% at a median follow-up of 5.8 months. Eight of the responses are ongoing, three responses are beyond one year, and the median duration of response is not reached yet. Here is a waterfall plot showing the change in target lesion diameter. The plus signs reflect an ongoing response or ongoing stable disease. Of note, the responses occurred independent of RAS status. Only one of the responders was reported to have high PD-L1 expression, and all responders had a TMB of 10 or less. Two of the responders were IO refractory, had prior exposure to IO, and one of them was an IO, PD-1. Here's an overview of safety. These are treatment-related adverse events that occurred in 10% or greater of patients. 76% of patients had a treatment-related adverse event, but the majority of these were grade 1 and 2. Grade 3 events were limited to 24%. The most common adverse events were GI in nature, with 16 patients having diarrhea colitis, but only four of these were grade 3 in nature. There were no grade 4 or 5 treatment-related adverse events. The investigator-assessed immune-related adverse events occurred in 46% of patients. 17% had grade 3 IRAEs. 10% of patients discontinued treatment with botensilimab due to an adverse event, and another additional 10% discontinued both drugs. In summary, botensilimab + balstilimab is a novel Fc-enhanced CTLA-4 PD-1 combination. In heavily pre-treated patients with MSS colorectal cancer, we've seen deep objective responses with evidence of durability. The combination has a manageable safety profile with enriched responses in patients without active liver metastases. I guess we didn't have this slide at the moment, but in an exploratory analysis of patients with active versus without active liver metastases, the response rate in the patients without active liver metastases was actually above 40%, and the disease control rate was 96%. Based on the totality of this data, a global phase II trial in MSS colorectal cancer will launch later this year. Thank you. Anthony, for that nice presentation. Second time I've heard it today, so just keeps getting better. We're gonna take you off the hot seat right now and your colleagues, two world-class GI experts deeply in the field of unmet need of IO experience to date in GI. We'll talk about other GI malignancies because I really think this opens the door to a lot, but maybe start with Heinz as the colorectal guru of the world. What do you think? I mean, what's your reaction? How do you place this in the context of your personal experience with IO and just in this line of therapy, maybe that's. I think these data are incredibly impressive in a patient population who have very little treatment options, and the options available have very low response rate. I think this could be paradigm changing, showing for the first time that immunotherapies can be effective and can turn a cold tumor into an immune responsive tumor. I'm extremely excited it can change the way we look at these tumors because we have been frustrated with immunotherapy combinations in MSS colorectal cancer with very little efficacy, and this will change our view in how we move forward using immunotherapy in this patient population. Give the audience some perspective because you have pioneered the MSI high subgroup of colorectal with combination CTLA-4. Obviously, coming from you saying this is a cold tumor turning warm or hot says something. But do you wanna just relate that benefited from this approach? Yeah. There is no question about it. MSI-H tumors don't need chemo. They need i mmunotherapy. This is a big success. Now, saying that, the MSI-H tumors still have as best responders, 20%-30% progression of disease. What I thought would be how would they do. Uh. With your Fc-engineered antibody, would the rate of progression, which I think is really essential, 20%-30% do not respond, will they respond to a better-engineered antibody? I have no doubt they will. Yeah. To put that in perspective, in MSS, second line chemotherapy efficacy response rate are 10%-15%. To see 24 in all and 40 without liver lesions will change the spectrum completely and upside down treatment options in the different line of treatments. Yeah. I was just thinking of melanoma, where obviously ipi/nivo and CTLA-4 has produced great responses. To your point that there's still 20%, 30%, 40% that are left unmet by that. You can't help but wonder what a next gen CTLA-4 could add even to a hot tumor. The point is hot tumors, we've got room, but clearly the message today is cold tumor that has been just refractory to IO, basically. Yeah. I think, and I was always a believer in the CTLA-4 component with nivo, because when you look at all the data, it is more effective. You have an optimized CTLA-4 makes me even more happy, and that the duration of response has not been reached, is further a sign that this is really immune response which lasts. Yeah. That's the hallmark of CTLA-4 and these durable memory T cells that don't require continuous treatment. I agree. Manny, we'd love to hear your thoughts. You span the whole GI tract, but let's first start about the colorectal data. You're well-versed in this. Your reaction. Thank you, and great to be here today listening to the presentation twice as well. Well, I fully agree. The data is quite impressive. Certainly, patients in the third line and beyond for whom standard of care offers, as we have seen, extremely limited benefit in response rate and survival and progression-free survival. Other IO combinations or immunotherapy with other strategies is not there yet. A little bit better, but not substantial. This combination, which is a PD-1 with a, I think, a brand-new drug, a drug that targets CTLA-4 but has then an Fc segment that gives very different properties. You have a very clear overall response rate with a manageable toxicity profile. I fully agree that this is a very important data set. Let's I'm sorry we didn't have the slide that showed the enrichment for non-active liver mets. Just to reiterate, in patients who had prior liver mets that were treated either surgery or ablation or local techniques and then development tests, or patients who did not have active liver mets at all at any time, the response in that cohort was about half the patients, was over 40%, with disease control essentially near 100%. Now, this is a subgroup where IO should work in hot tumors the best. It's reassuring to see it working very well there. There is also activity in this 41 database. Although there's no objective responses in the active liver, we have stable disease at 24 weeks and some minor tumor regressions. We are not in any way conceding that we wouldn't potentially have an impact on active. Having said all of that, can you talk a little bit about obviously debulking liver, regional strategies to liver when you have a platform of an IO that's very effective systemically, will this reawaken sort of thoughts about combination directed and maybe encourage surgeons to be more aggressive debulking? Yeah. Before we implement? The other option, of course, is to tweak the tumor microenvironment. We have a pipeline that we think can really do that, and we're gonna work with others around the world. But let's first talk about Heinz and then maybe Anthony about rego, what do you think about the liver data and how do we maximize the active and not give up on that in any way? Yeah. The development of immunotherapy for MSS colorectal cancer really hit the wall with the liver metastases. It's still not clear what the tumor microenvironment does that it's so immune suppressive. I think this will be a really important challenge for the future to find options to overcome this immune suppressive environment. There are a lot of activities in this microenvironment which can play a role, including the endothelial cells, including the fibroblasts, including the dendritic cells, including the neurotransmitters. I think there will be a lot of things to learn in the future. Saying that, I think that the liver-directed treatments or surgical local regional treatments may become differently looked at when you have a treatment efficacy of 40% outside. Outside. I think that could challenge a little bit the lines of treatment segments we usually consider. If I have liver lesions which I can go easily after and have multiple lung lesions, you may want to consider a liver-directed treatment surgery, SBRT, or and then have a treatment option. In fact, we have already done that in some patients where we know that treatment options open up for patients like this. So- I think it may challenge. Yeah. I hate to bring it back to melanoma, but that's exactly as we had more active systemic treatments, both IO combinations and BRAF mechanisms. The approach, which was always more surgical and debulking when we had nothing, also increased further when we had more Yes. For that very reason. I would expect that possibility. Anthony, you're in hepatocellular and in addition to colorectal, but you focus a lot on cholangiocarcinoma, hepatocellular where regional therapy is just the same question to you that I had. What do you think about this data and how we might optimize combination? I fully agree with Heinz that this is something that absolutely needs to be explored. You know, the optimal liver-directed modality is not clear. Yeah. The extent of debulking that needs to happen is not clear. There's a lot of unknowns. I'll refer to actually a very important proof of concept study that was done at NCI by Tim Greten's group in HCC, where they actually gave patients who were refractory to treatment with HCC just tremelimumab and just partial ablation of single lesions in the liver. I'm not talking about the clinical efficacy, I'm talking about a biologic proof of concept where they showed that with this partial ablative therapy, they had a definite positive immune modulation, like increase in CD4, cytotoxic T cells, etc. The impact on the micro and immuno-microenvironment could be positive, and I think it's worth exploring. Disrupting the tumor, releasing antigen, and disrupting the myeloid and other suppressive group. So this also begs the question, you know, let's talk about this was a median of four prior lines, you know, and extraordinary activity. Obviously, it begs the question of, first line, earlier lines where liver mets may be less dominant, but even adjuvant and neoadjuvant where liver is not even present if you truly have a systemic treatment that is this active. Do you, Manny, you wanna just. Sure. I think this is the beginning of a developmental potential which is way beyond the second and third line. You could envision strategies to move this into first line. Certainly first line patients, you reduce then the tumor with chemotherapy, with antibodies, and then maybe the liver disease is less prominent. Exactly. At that time. Those sort of local treatments that we alluded to before, we already made some of that. You can start thinking of maintenance strategies. Then going to earlier lines of disease, we have seen some very recent examples or in rectal cancer, MSI rectal cancer, how effective immunotherapy is. If we have now a regimen that is effective in MSS, can we think on development in rectal cancer and in situations where surgery will be mutilating or there will be very large, high toxicity of treatments? I think it's gonna be a fascinating spectrum of possibilities down the road. Heinz, you've obviously pioneered both the metastatic MSI-H and also the neoadjuvant approach. Correct me if I'm wrong, but in the neoadjuvant MSI-H, obviously the response rate is over the top. Even in the stable with ipi/nivo, weren't there some pathologic response which correlates with the melanoma data that clinical size change in lymph nodes has radiographically underestimates the path. If there was already a hint with 1st- gen ipi/nivo in MSS stable where liver is not involved. Couldn't this really be a platform to study it further? Yes. I think, there is a difference between local disease versus metastatic disease. The inflammatory response in these tumors are completely different, which is one of the argument when you do nivo-ipi in MSI rectal localized, you have 100% pathological response. With the same argument, you would think that an MSS local tumor would also respond better to an optimized treatment regimen like you presented today. I have no doubt. Will it be 100%? I don't know. But certainly, that window of opportunity should be really evaluated. For metastatic disease, I think you have now a really effective backbone. I think the challenge will be, can you further optimize it? Can you find an optimization and combination which targets liver metastases? I think you have now a pool of data and preclinical models where you can play around and further optimize. In the meantime, you can treat the extrahepatic disease very effective. Yeah. It should go to second line, there is no doubt in my mind. Yeah. Because in second line, we have really no effective treatment. First line, I think I would do more homework and optimize the combination. Well, we look forward to engaging you and your center around that as well as others. We have an ILT2 that's about to hit first in human any day now that is sort of really a myeloid drug that will really not only affect myeloids but also lymphoid cells and repolarize them to activated [TAM 1] cells. The liver, of course, is a microenvironment that's particularly myeloid hostile, so to speak. Again, that's just one pipeline-type approach, but agree. I have another question here about. Let's take this out of colorectal and right now. Obviously, we have evidence in gynecologic cold tumors, cold sarcomas, even the warmer sarcomas like angiosarcoma. There's visceral, angio, and cutaneous, and BRAF and traditional generation ipi/nivo type regimens have not really managed to show response in these visceral low TMB tumors. We have evidence of other diseases that we're gonna be very interested in exploring further. We haven't really gone much outside of the colon and the GI tract. Some comments about pancreas is gonna be a focus based on some preclinical data with our botensilimab in mouse models, very high-level mouse models showing curative potential with botensilimab and chemotherapy. Dan Von Hoff has been pioneering that work with us, and Manny has also. We sort of wanna engage that study in the phase II in the coming months. Manny, why don't you talk about pancreas maybe, and then what about these warmer GI tumors in the upper tract, and even the liver? What's the potential where chemo-IO is already established in itself? As you mentioned, the mechanism is designed to warm up these cold tumors, and the coldest is probably a pancreatic cancer for which really there has not been any hint of activity. Even the MSI patients, they respond, but they don't do that well. Yeah Compared to colon or endometrial. Very different biology. Testing this in pancreas cancer, I think it's necessary. The preclinical data you mentioned is very strong in the KPC. Some of the strongest data I have actually seen. I think would be very important to do these studies. There are some other tumors in the GI tract that, you know, are perhaps not so cold, but not that warm. Cholangiocarcinoma, liver cancer. Maybe Anthony, you wanna comment on those. I can see a broader spectrum of development in GI. Anthony. Yeah, sure. Thank you for the handoff there. I think, you know, I would say hepatobiliary cancers are very heterogeneous, right? There is a subset in both HCC and cholangiocarcinoma that is probably more immunogenic and then a majority that's not. There is an opportunity here to expand the benefit of immunotherapy more broadly in these two areas. I think the combinability of botensilimab is outstanding because of the safety profile. You could add it to first-line regimens, you could explore it in second-line combinations. Certainly nowadays with cholangiocarcinoma, first-line therapies really largely mirror pancreas, right? With gemcitabine-based combinations plus durvalumab b ased on the TOPAZ study. Adding there is another opportunity. I think there's definitely excitement there. I think in the sort of warm tumors, PD-1 chemo combinations have been quite, I mean, Merck has obviously, it's been a huge platform in lung and maybe upper GI. In the cold tumors, PD-1 chemo combinations have really not done well, ovarian, pancreas. It's my sort of thoughts that the partner shouldn't always be PD-1. If you don't have any engagement of the tumor by T cells, there's no exhaustion to sort of recover from. I see a great opportunity in particularly colder tumors, where not just reflexing to PD-1/ CTLA-4 combinations, but actually using next- gen CTLA-4 as a foundational partner with chemo, for example, in pancreas, but other diseases, PARP and other opportunities. I think there's gonna be a lot of opportunity to position this with PD-1 when the biology and the immunology makes sense. Not necessarily waste PD-1 on cold tumors that aren't recognized. Now, you could argue that once they're recognized, you can drive them and prevent exhaustion. There may always be some additive role. I think the proof of concept in the cold tumors may be to really look at a CTLA-4 that's active in cold tumors and then combine without PD-1. Thoughts on just that kind of thinking. I think this makes sense. I think a very unique opportunity for this combination would be gastric cancer. Mm. It is immune responsive, but not great. There are these subsets where you have a high CPS score, where immuno is better than chemo. I think the combination showed better when you have a CPS of 5. There is a lot of fluctuation in the gastric field, where you have some immune responsiveness. If you optimize this, you may get rid of the chemo, and I think that would be really a paradigm-changing approach. Yeah. I think there are unique opportunities where you have the cold and then some immune responsive and then the very immune responsive tumors. I think it makes sense to do cold tumors like you have shown with the MSS colorectal cancer. Look at the ones which have some efficacy where it is limited or where you can really change the picture and the treatment strategy completely. Yeah. My fantasy is, of course, to have, you know, a platform of a next-gen CTLA-4 that's active in cold tumors, and then to use brief bursts of cytotoxicities, whether with short couple cycles of ADC or radioablate, you know. Really let the magic of these memory T cells do their work. You may not need it. I- I mean. Yeah. Look at the atezo-bev [audio distortion] treatment. I think for some tumors. Yeah. You will probably need some combination, and you can further enhance the efficacy. Yes. That the chemo need may be not as high as we still think when you find the right partner. I think this is a very good start in order to have an effective combination for cold tumors, and it will go potentially in different combinations depending on the site of metastasis or the primary tumor. Very unique opportunities and options. Great. Great. I could do this for hours, but with this panel. Let's introduce Dr. Garo Armen, our Chairman and CEO of Agenus, who's in the room, and Dr. Joe Grossman, our Vice President of Early Clinical Development and a GI oncologist who has pioneered this program. Kudos to Dr. Grossman, who I've sort of been his wingman, but he has really driven this MSS-stable colorectal. Both are in the room. I think we can take some questions. Okay. I'm gonna move this thing out of the way here first. All right. It's now time to move to the Q&A portion, where we can take some questions from the online participants. First, I'd just like to thank all of our panel members. I mean, it's a fascinating discussion and it's always really enlightening to hear true experts opine on these various fields because you really understand that there's, you know, such complexity to the management of patients and introducing various therapies that, you know, make a tremendous difference in their future. So I just do have a few housekeeping comments to make about asking and having answered questions. In order to ask the question on the webcast, you'll see a line that says, "Click here to ask your question by audio." You're gonna need to click on that and then open Zoom meetings, which will be the next prompt that you receive if you're participating online. One other important point, if you are in the queue to ask a question, and you are prompted to ask that question, please mute the audio of the presentation that we're giving here in order to avoid feedback on the webcast presentation. With that, maybe we'll turn it over to the operator to take our first questions. We will now begin the question- and- answer session. Please allow a moment while we open the queue. The first question will come from Matthew Phipps from William Blair. Mr. Phipps, your line is now open. Take our first questions. Oh, boy. Hopefully you can hear me. Okay, sorry. Thanks, guys, so much. Good afternoon, and congrats on this update. Just curious if you had what the response rate was in patients who had prior immunotherapy. I was kind of surprised that so many people had prior immunotherapy in this trial. Dr. O'Day, just wanted to confirm, you said only one patient had elevated PD-L1 expression? Yes. The answer is yes to that. The first part of the question was what? Just if you had responses in people who had prior immunotherapy. Yeah. There were responses in prior immunotherapy. I think there were two responses. Anthony knows the data, yeah. Two responses out of the 10 were in prior immunotherapy. About 1/3 of the 41 patients had seen some form of. That includes single-agent PD-1, PD-1/ CTLA-4 combinations, or PD-1 TKI. The two responders in the IO group were a PD-1 monotherapy progressor and a PD-1 TKI progressor. Great. Okay. Thanks. Thanks for that. The TMB was low, 10 or less in all of our responding patients. Thanks, Dr. O'Day. The slide did mention that pneumonitis was rare. Can you give any more details? I guess maybe just general thoughts from the panel on the safety profile here versus, you know, what they might expect from other IO combinations or IO TKI combinations. Sure. Yes. There was no pneumonitis in this. Oh, there was actually one pneumonitis in this cohort. As a matter of fact, in the investigator brochure, there are two cases, I think, of pneumonitis mentioned in total. To date, 203 patients have been treated. Of course, it's an ongoing trial, the data is still evolving, but it's a very rare phenomenon within a large number of patients. As we had mentioned earlier, no cases of hepatitis or colitis kind of consistent with the design to reduce complement fixation. Great. Okay. Thanks, Matt. Thank you. Can I ask one more question? Just on as far as, if these responses were confirmed? Can we take the next question if it's queued up? The next question will now come from Mayank Mamtani with B. Riley Securities. Mayank, your line is now open. Mayank, perhaps your line is muted. Yes. Can you hear me now? Yes. We can. Okay. There's a little bit of a lag, I think, when I come on versus the web cache. But yeah, regardless, congrats on the data, and thanks for taking our questions. Just maybe two follow-up for Dr. El-Khoueiry about the data set presented today. The liver mets versus non-liver met 50/50 proportion in fourth line plus setting, is that kind of consistent with sort of prior studies we have seen, you know, from IO drugs and other sort of studies that you referenced initially? And then the second question was that, is there monotherapy data that is accumulated here? Because you do point to in your AE in your safety table there was some monotherapy data also referenced and you also talk about the combination that you know it's all 10% discontinuation. Do you have any information on the efficacy side for monotherapy? I think the first question, if I heard it correctly, related to a comparison of the activity that's been seen with other therapies in active and non-active liver mets. Okay. If you think about some of the waterfall charts that we have with regards to that. Sure. Look, it's always difficult to do cross trial comparisons and cross study comparisons. In a nutshell, if we look at IO/IO combinations, meaning PD-1/CTLA-4 combinations, the biggest study is the 119 patients from Canada with durvalumab, tremelimumab, with one objective response out of 119 patients. You put this side by side with this, it's obvious that this has a much higher objective response rate. When you look at PD-1 TKI combinations, even though that's a completely different concept, right? Let's look at that. The response rates are anywhere from 0% to maybe low teens to 15%. When we look at lung mets only, in a few studies, it gets up a little bit higher, but on average in the low 20%s. Even then, side by side comparison, this appears more active overall as far as objective response rate and in the non-liver mets patients. I hope I answered that question. Yeah. Uh... I'm not sure what the second question was. Mayank, would you? I understood. Do you mind? It's asking about single agent. Mm-hmm. Single agent. Activity. Yeah. Thank you. Yeah. Go ahead. From the phase I data that we've shown, and Steven, you can bail me out here if I forget something. There's definitely single agent activity in cold tumors. We did see responders with cold tumors. If I try to remember off the top of my head, I believe a pancreas response and an MSS endometrial may have been in single agent botensilimab. Yeah. I'm getting nods from Joe. Yes. Yeah. That's correct. Cervical. I was asking colorectal because I believe the plan is to look at you know, monotherapy activity and combination and then compare it to standard of care regorafenib. Is that sort of Dr. O'Day, maybe for you, is that sort of a trial design, sort of an update on that you're thinking for going forward? Or is this data gonna inform you to do things differently? 'Cause it definitely looks much better than what we saw in the prior update. Commenting on the plans going forward around combination potential with regorafenib and phase II study design. Yeah. You know, we're committed to moving forward quickly in melanoma, pancreas, and MSS colorectal. We have not publicly disclosed the details of those trials. We're in active discussion with the FDA on multiple levels. We clearly, in colorectal, the combination is very active and safe, and so we're excited about that. We are obviously gonna go into melanoma, and we have had single-agent activity in PD-1 resistant CTLA-4 naive melanoma and in CTLA-4 refractory melanoma, again, suggesting that we have something different than a me-too CTLA-4, even a slightly modified CTLA-4. We're seeing single-agent activity in hot tumors, PD-1 resistant tumors, cold tumors, and even, you know, we've reported a response in a CTLA-4 refractory hot tumor. Very exciting on the single agent activity approach, and then, obviously, the combinations seem well-tolerated, and the unmet need is huge. Thank you. Thank you [crosstalk]. If I could pre-leave a final one, if that's okay. Go ahead, Mayank. Thank you. This is for the, you know, the GI expert. You know, as you think about earlier line settings and also thinking, you know, chemo-free regimen, you know, as a lot of other indications are benefiting from, what would you think is that of the combination partner of choice, you know? Both from a legacy kind of targeted therapies, but also, you know, you guys are excited about some of these emerging pipeline molecules also. Just curious if you guys could comment on that would be helpful. I think, you know, obviously, we've commented on our company strategy around clinical experiments in melanoma, colorectal, and pancreas. But we're really, you know, you can imagine the engagement from the GI community, from the sarcoma community, from the GYN, and even my melanoma colleagues who haven't got a lot of melanoma data are incredibly impressed with the concept of a cold tumor turning warm. We are gonna be engaging Joe and his colleagues at the company are obviously an investigator-initiated. We're gonna take the best minds of academia around the world, global leaders, and show them this data as we have, and we're gonna have them help us, you know, develop proofs of concepts and earlier lines of treatment so that we can rapidly get this drug by itself and in combination to approval. It's gonna be an exciting year or two here as we move this forward. The first step is you've got to get a cold tumor warm or hot. I wanna reemphasize, that is not an easy task. It has been the plateau of the second revolution of immunotherapy. First revolution, CTLA-4. Second, PD-1. We have been flat in cold tumors. You know, these are early days, but this to me excites me to see something start to transition a cold to warm and hot. The future is wide open, but we're gonna need help. We're gonna need our academic and KOLs worldwide, our investigators. I can say that all of our investigators in these diseases that we're sponsoring trials in the coming months are really excited to join, and it's been a pleasure to introduce this drug to them. That is all the time we have for questions today. This will now conclude our webcast. Thank you for your participation. Thanks everyone for joining. We appreciate it. Have a wonderful day.