Fireside chat

Nov 5, 2026

Summary

BOT/BAL’s phase I and neoadjuvant data underpin the 850-patient ROBIN phase III trial in high-risk colorectal cancer. Management expects enrollment and response milestones before interim EFS analysis in H2 2029 and full readout in H2 2030.

All right. It looks like we've got the whole crowd here, so we're going to kick this off. Hello. Yeah. Good morning, everyone. Thanks for joining us here today to speak with the members of the management team of Agenus, symbols AGEN. It's a company that we've had a longstanding relationship with. With us today are Zack Armen, the VP of Corporate Development and Investor Relations, along with Robin Taylor, the Chief Commercial Officer. We're going to discuss the prospect for the company's immuno-oncology duo, known as BOT/BAL, and the imminent phase III study commencement of a phase III trial known as ROBIN. Before we get started, I just want to tell everybody that they were able to ask questions of our audience here by emailing me directly. I would not put them in the chat. I will ask your questions anonymously if you do that. My email address is mking@rodm.com. Just by way of background, we initiated coverage of AGEN at the end of September, rate the shares a buy with a $19 12-month price target. If you would like our report, please feel free to reach out. Full disclosure, neither I nor any member of my household owns the shares, neither are we officer or director of the company. One of the things I say in the report, and I'm quoting myself here, is, "We are hard-pressed to name any other clinical stage oncology asset that has created this large of a dataset prior to the commencement of a registration-directed study." This number may be obsolete now, Zack, you'll correct me, I'm sure, at 1,300 patients in clinical trials alone. I apologize if I stole your thunder here a little bit, but I think it's a remarkable achievement. I think it's unprecedented in the world of immuno-oncology. As such, we have a high degree of confidence in the ultimate outcome of ROBIN, as well as the commercial uptake of the BOT/BAL combination. The way we're going to do this is Zack and Robin will provide us with a slide presentation, and I will ask questions mainly at the end, although fair warning, I've been known to interject from time to time. Gentlemen, thanks for joining us. It's good to have you here. Zack, let me turn it over to you, and I think I need to just allow you to share. Yeah. Thank you, Mike. And there you go. Thanks, Mike. We appreciate you and the Rodman & Renshaw team inviting us to the chat. We are obviously very happy that you and your research team are now part of the story here with us as part of the coverage group for our stock. I will just do a quick intro, and Robin will as well, and then Mike, as far as format goes, we actually put together some publicly disseminated slides that go along with your questions. Okay. Just so this can be a flowing dialogue. Yeah. Go ahead and ask your questions. We are going to respond to them with voiceover, and we will have some slides to help enhance those responses. Okay, great. Did you want to introduce yourselves first? Yeah. Then we will. Sure. Okay, go ahead. My name is Zack Armen. I am the Head of Corporate Development here at Agenus, and Investor Relations. My role spans both IR, along with capital formation, internal and strategic finance, and business development. Robin and I work very closely across all of those fronts. Our story has drastically changed over the last few months, as we will get into with our July PIPE and our initiation of the new phase III ROBIN trial. To your earlier point, you are not stealing our thunder. We are still at around 1,300 patients treated, although we are planning to treat many more patients starting when we do our first enrollment for the ROBIN trial, which we anticipate in the next few months. Okay, great. I am Robin Taylor. I am the Chief Commercial Officer. I have been with Agenus for a little over three years. Spent the bulk of my career actually at Genentech and Roche, and had my start actually with colorectal cancer with the launch of AVASTIN over 20 years ago. The last four years I spent at I am old enough to remember Herb Hurwitz's presentation and the standing ovation that he got at ASCO. Indeed. I saw myself almost there. It was a momentous occasion. Still a foundational therapy, at least in metastatic disease. Yep. The last four years I spent at Genentech and Roche, I led the immuno-oncology franchise, not only the late-stage development with TECENTRIQ, but also working very closely with both the Roche and Genentech research groups. Immuno-oncology is very close to my heart. When I saw the data over three years ago coming out of Agenus, I was surprised. I was surprised to see this level of activity of an immunotherapy in a cold tumor, MSS colorectal cancer. That is what brought me to the company, looking forward to talking more about that today. Right. Obviously, I share that excitement because I recall that, I forgot what year it was, SITC in Boston, but a very compelling response rate as well as a very long tail on the event-free and overall survival curve. That was great. Excuse me. I do not know how many people know about the history of Agenus, but the company has quite a bit of expertise and experience with first-generation CTLA-4, zalifrelimab, and botensilimab is the successor to that. Maybe you can talk a little bit about the science there and what kind of scientific hypothesis were you trying to show there, and what does the Fc enhancement change about how the drug works? Great. Zack, we're still seeing present mode. the mode here. There you go. There you go. Perfect. If we go to the, yeah, here, the schema of the antibody. The secret sauce in botensilimab is a couple of point mutations in the Fc region. What this does is it enhances the binding of the antibody to the Fc receptor, the FcγRIIIa receptor. That has a couple of effects. One is the binding to antigen-presenting cells, and so it provides an opportunity to create a tighter synapse with those antigen-presenting cells. That allows basically botensilimab to help the immune system to identify these weaker neoantigens. So we see expansion of T cell repertoire. We see priming, activation, and memory formation. We also see activation of myeloid cells. Additionally, what we see is a reduction in regulatory T cells, so a depletion of those intratumoral Tregs. We see that actually, we saw it preclinically, but we actually see it now in the clinic from the nice data we have from the neoantigen studies in colon cancer with both NEST and UNICORN. What you see here is a visual example of that. Basically, we're turning a cold tumor hot. You can see there are these CD4, CD8 positive T cells in the periphery of this tumor on the left. That's pre-treatment with BOT/BAL. Then after treatment, you see this flood of purple and green. Those are the CD4, CD8 positive T cells, and you don't see any red anymore. The red were the T regulatory cells that have disappeared. This is just one example of a number of the analysis that was done in both NEST and also in the UNICORN study. Robin, can you say what aspects of the cells you're seeing here? Are these the surface receptors? Are these internal proteins, or what are you actually measuring here in the slides on the right? Yeah. So we're measuring in green is CD4, purple CD8. Right. FOXP3 is the red, that is measuring the Tregs. Right. The tumor is- Which you don't want. Right. Yeah. Mike, this is an actual biopsy of a patient who was in the NEST trial. Okay who had MSS colon cancer. So, very similar profile of the patients we will be enrolling in the ROBIN phase III. As Robin Taylor just mentioned, you can see on the left, pre-BOT/BAL, the tumor is excluding that immune system. So, these cold tumors are broken down into just low immunogenicity. There is also tumor exclusion and tumor evasion. There are different sort of ways in which the tumor seems to be disallowing the immune system to do what it is naturally programmed to do. Right. BOT/BAL essentially unlocks or ignites that immune response and helps proliferate the army of killer cells, which you want to be entering the microenvironment, and then is kicking out the regulatory cells, which we need so that a cut that we get does not turn into a massive bleed-out. But in the case of fighting a tumor, we do not want those regulatory cells to be around Right to dampen that immune response. Yeah. Do you know, I do not want to put you on the spot here, but do you know sort of the case history of this patient? Was this third line plus kind of patient? Just trying to get a sense of Go ahead, Robin. Yeah. No, this is a patient with de novo colon cancer. De novo. Okay. This is from the NEST study. This patient had not had any treatment for their disease previously. Okay. Would you expect this kind of result if you were looking at a metastatic patient that had multiple prior rounds, or would it be less compelling? You may see something like this. There is a little bit more complexity, because the health of the immune system is a factor. Right. I think one of the reasons that we see potentially more robust results in early-stage disease is that individuals typically have healthier immune systems. The wear and tear of multiple rounds of chemotherapy and other treatments can kind of wear down people's immune system in late-line metastatic disease. Right. I still think from your metastatic setting, the C-800 study, you had- Yes you still had really good response rates. Yeah, exactly. So over 20% response rate. Response didn't tell the whole story in the metastatic setting, because patients with stable disease had stable disease sometimes for a couple, two to three years. Right. Here we're showing the overall results from our phase I-B study. This was over 411 patients enrolled across multiple different tumor types. Yep. These were highly refractory patients. Out of those that had efficacy evaluable tumors, you can see that there's this really nice consistent response rate across multiple different tumors in the range of 17%-20%, and 17% in the overall group in terms of tumor response. But you can see there's quite a large group that have stable disease here. You see that in the spider plot. You can see some of those going out quite a long ways. You've got patients out 120 weeks with stable disease. Right, weeks. response. Right. Not days. Yeah. Yeah. No, that is the part of the compelling story that I like here. Yeah. That translated in the phase I-B to a median OS of 17 months. But at two years, you still see 39% of patients alive, which is pretty remarkable for this late-line treatment setting in these patients. Right. We will get to the rationale why that, the flip to the frontline, the neoantigen setting. Let me just table that for a second. I just wanted to also, I do not know if you have the slide here, but I do not know if you had your translational work has shown that BOT lowers regulatory T cells inside the tumor, and even in patients who had stopped responding to earlier checkpoint drugs. Maybe you can tell us why that matters for cold tumors like MSS colorectal, and what does BAL add to that BOT alone does not generate? Yeah. Well, one of the challenges with immunotherapy is that we've seen either PD-1 or CTLA-4 plus PD-1 explored across almost every tumor you can imagine to try to see where the signal is. The signal has been in hot tumors. It's been where there's been typically enough or sufficient immune response already that you're able to unmask it with the addition of PD-1. Cold tumors are more challenging because you need something to ignite the immune response, and that's why botensilimab has this ability now to be able to broaden the range of immunotherapy to cold tumors, the classic being colorectal cancer. Zach, if you go to the next one, here's the example from the phase I-B, just looking at the 123 patients we enrolled with colorectal cancer without active liver mets. What you see is a 21% response rate and three-year survival of 33% in this patient population. So, a clear benefit. Yeah. This is sort of the conditioning that you want with the immune system, right? You want the immune system to continue this surveillance, be able to keep the tumor at bay, or ideally eliminate it. Right. Go ahead, Zach. Can we move on, Robin? We also have the ovarian cohort, Mike, that was just presented at the IGCS conference about a week ago. Sure. Let me just hold on one second because I just want to. The one thing that I do want to point out to people is that I think this kind of compelling data has sort of generated a bit of a renaissance in CTLA-4 assets in clinical trials. Now, you've got some fast followers that are putting activated Fc CTLA-4 antibodies or masked CTLA-4, sorry, Fc active CTLA-4 antibodies into the clinic. While we would like to have as little competition as possible, I like the fact that the scientific validation is coming along behind this. Obviously, you guys have a substantial clinical lead, but I won't name any of those companies. I'm happy to talk to people about them privately, but there's some significant developments in CTLA-4 antibody space, which had gone kind of fallow for a while after the launch of YERVOY. Anyway, go ahead, Zack. Why don't you show the ovarian data? Yeah. Here's the data that we recently presented in the update of our ovarian data from the phase I-B. You see a nice response rate here, but more impressively, what you see is these continual responses, so very consistent with what we see in colorectal cancer. Interestingly, one patient who had stable disease and then at 18 months, you see a response. It's really quite interesting sometimes how the effect of CTLA-4 can suddenly flip a switch with the immune system, and you actually get these late responses. Right. Ovarian is typically seen as a cold tumor. Yeah. What is really impressive is you see this plateau in terms of the overall survival. These long-term patients, we do not see any. You see this long plateau with about half of the patients alive at two years here. Yeah. Some made it to three. Yeah. No, it is interesting to me. P-ROC has gotten a lot of attention lately. There seems to be a flood of ADCs that have come into the space. I know you guys are pretty limited on what you can do right now with the development of BOT/BAL, but it definitely begs the question about what kind of benefit patients could get, P-ROC patients, or then, of course, move it earlier as well. Right with ovarian, combining BOT/BAL and an ADC. Yeah. I mean, expansion is certainly in our future plans, Mike. Yeah. Just what this data is also showing, which I think is important, and we see this consistently in other cold tumor types, MSS colorectal being obviously our largest data set, where patients who had a number of prior lines of therapy, whether it be one or two or greater than four, as we're showing in the right, or whether they had platinum resistance or sensitivity, those patients all had a similar survival benefit regardless of how many prior lines they had. Yeah. This is important, we think, obviously, because when you're going later in the metastatic treatment lines, patients are losing options that are going to help extend their lives. To have something that's going to benefit those patients as much as it benefits those earlier stage patients is really a great thing. It also speaks to the robustness of BOT/BAL, where it's able to mount, it's able to drive this durable response even in those sickest of sick patients at the same level of efficacy as those patients who are less sick and have had less courses of prior cytotoxic therapy. Right. Yeah, it also brings up the intriguing possibility of maintenance therapy, but we don't need to go there right now. I think it's a good pivot, Zack Armen, to go and talk about neoadjuvant and why untreated resectable colorectal cancer is the ideal place, at least initially, for BOT/BAL, versus the metastatic disease, despite the consistency of benefit. Maybe you can cover some of the immune system aspects of that and tell us about the pivot to Robin Taylor. Yeah, no, happy to. The reason we went to phase III in the neoadjuvant setting is because of the data that came out of two key studies, the NEST study run at Cornell, and the UNICORN study run by an Italian cooperative group, the GONO group. Here's an example of what we saw. This is a patient with an 8-centimeter mass, 40-year-old patient, lymph node positive. One dose of BOT, two doses of BAL, and seven weeks later, you can see that the tumor is not there. This patient, after this scope, went to surgery and pathologic complete response. It's one of several pathologic complete responses we observed across both studies. What this really demonstrates is that CTLA-4 in particular, when you have an intact tumor, and this has been seen not just in our data, but also with first-gen CTLA-4 in melanoma and hot tumors, you can see that you're providing the immune system with all of the neoantigens of the tumor at a stage when the disease has not spread. That's the most powerful thing you can do, because now you're educating the immune system, you're creating that surveillance. What we're doing here with neoadjuvant BOT/BAL is, in a sense, we're Why do you use adjuvant chemo? You use adjuvant chemo because you're trying to get rid of- Manage that any remaining- Right residual disease. If you train the immune system to do that, we may actually be able to dispense with chemo. We won't be able to completely eliminate chemo in our phase III study, but we expect that actually we're going to see a de-escalation of some of the use of chemotherapy, which is also a patient benefit. Right. Zach, if you go to the next slide, I think we can show you that part of the reason for our pivot, because we were studying BOT/BAL in the metastatic setting, is really the size of the population here. We're looking at a very large patient population with MSS colon cancer. About 85% of patients are microsatellite stable as opposed to MSI-H. Obviously, MSI-H are very responsive to immunotherapy. But for those MSS patients, there really have been no advances in the last 20 years. The current- Yeah treatment is surgery followed by adjuvant chemo if the patients are high risk. About half of these patients in the early-stage disease setting are what we'd call high risk. These are high-risk stage 2, which is a large tumor, or stage 3, which is lymph node positive. Right. In terms of how we assess the addressable market here, we are looking at what we think would make sense in terms of a cost for a course of therapy of about $200,000 in the U.S., which is comparable to existing perioperative treatments. For example, KEYTRUDA in triple-negative breast cancer is in that range. That gets you to a total U.S. addressable market of over $7 billion, a very large market opportunity. Yeah, I do not think anybody would dispute the commercial potential for MSS stable colon. I just want to ask, just take one quick step back and sort of amplifying the point that Zack made earlier about the consistency of effect. Both NEST and UNICORN had sort of remarkably similar PCR and MPR rates. What did it tell you? Because I know you guys had explored, or your investigators had explored different doses, different regimens. I do not know if you have a slide on that, but I just wonder what you could tell us about the different doses of BOT that you looked at and the two doses of BAL versus four doses of BAL, and kind of what the learnings were from those studies. Yeah, so. Very good. That's the two different studies. NEST at Cornell, shown on the left here. Initially, the NEST study looked at about four weeks to surgery. It was a short window of opportunity. The surgeons wanted to make sure that they weren't seeing any progressions. But once they saw the results with a single dose of BOT, two doses of BAL, then they were encouraged, and Pashtoon was able to convince them to expand the study to eight weeks to surgery. With the additional time, we'll show you the results, you can see that, in fact, you're allowing more time for the immune system to really Right act on the tumor. The UNICORN study was similar in some ways, which was it was about five weeks to surgery. But in UNICORN, this was a platform study, they looked at both BOT monotherapy as well as the addition of BAL. So we get a nice look at the contribution of adding PD-1 to CTLA-4 in this setting, both in MSS and in MSI-high. So we show you the NEST results first. Here, what you see, on the left, NEST 1 is the four weeks to surgery. We do see a pathologic complete response, but it's really obvious that when you go to the longer time to surgery and potentially more additional doses of BAL, you're seeing more depth of response, more pathologic complete responses. That's the basis actually for why in the ROBIN study, we're going eight weeks between the initial dose and surgery. You also see great responses in the MSI-high, but that's what you expect. You see that with first-gen CTLA-4. Yeah. I know KEYTRUDA's approved in that setting, but you just wonder if you Again, we're talking blue sky here, but eventually, if you want to think about it as sort of like PD-1, first generation, then VEGFA post PD-1, that's taken the therapeutic benefit higher. Maybe eventually you guys could get into the MSI-high tumor setting, given these kind of compelling results, and really step up the magnitude of the benefit in those tumors. Particularly given the rapidity of the response. Yeah If you go to the next slide, it shows the UNICORN data. I will start on the right here this time. What you see in the MSI-H cohort, you can see that here we are seeing also what the addition of BAL to BOT does. BOT, we actually see monotherapy activity in MSI-H. We think this may be potentially the first monotherapy data people have seen with MSI-H in colon cancer with BOT, or with a CTLA-4. But clearly, the addition of PD-1 here, you get almost all pathologic complete response. So you have 100% major path response in a very short period of time. Within five weeks, you are seeing this result. So you think about how quickly the immune system is eliminating the tumor there. On the left, you see in a cold tumor, in an MSS, again, the contribution of PD-1 to CTLA-4, so the BOT/BAL combination, we see a 30% pathologic complete response rate, and 70% of these patients with over 50% tumor reduction. So very consistent with the NEST study. In fact, in some ways a little bit better, given the short time window to surgery. The UNICORN investigators are actually running an additional cohort now where they are expanding to eight weeks to surgery, encouraged, of course, by the NEST results. But very consistent results between these two studies. Importantly, what we see of every patient who was treated with the combination, none of them have recurred. So, BOT/BAL together in both MSI-H and in MSS, remarkably, we are seeing this median follow-up of anywhere from 19 to 32 months with no recurrences. Well, yeah, and that's what's important about this. Zach Armen, do you mind just flipping back to the previous slide real quick? Because I want to stay on this for a minute. Again, a lot of the questions that typically come up with any drug in the oncology space, whether it's IO or precision oncology, whatever, is the durability. The follow-up here is substantial, which means that these are durable responses in both instances. The other question, or other point I want to just drill down on is, it looks like BOT on its own is quite active, but it clearly does a hell of a lot better when you add BAL to the equation. I think that's the strongest argument for why this is the pair that The combo that needs to be. Yeah, exactly. Also, another question I had, and it relates to the next slide, doesn't really matter, but if you didn't achieve a PCR or an MMR, are you included in these survival plots, or this is only Yeah. You are. This is all the patients. Okay. So that- This is- Yeah, Mike, regardless of response- Right this is every patient that received BOT. Right whether that is an MSS tumor. Yeah. Yeah. That is pretty remarkable. What you expect to see in this patient population if they are treated with surgery and chemo is Yeah somewhere between 20%-25% of patients would relapse by three years. By two years, you would expect to see about 20% relapse rate. We did see in UNICORN and in the BOT monotherapy treated, there were some relapses. This is a patient population who has a risk of relapse. The key thing here, I think, is that it is, again, it is sort of CTLA-4 conditioning the immune system for surveillance. That is how you can get rid of residual disease in a different manner to the treatment with adjuvant chemo. Right. You never say never, need sort of a top-up eventually, but you would think that these numbers Yeah. We get questions, Mike, from some investors about, we are going to get to the ROBIN trial, of course, but just one item that relates to this point on adjuvant chemo. We get questions from some folks that say, "Well, because your adjuvant chemo will be tumor-guided, tumor stage-guided, are you concerned that because patients in the control arm will get more chemo than patients in the BOT/BAL arm, that that may harm your efficacy numbers and your recurrence rates?" Our response is, "Well, no. We know how the control arm will likely perform. Right. Based on all the previously reported data, and we want patients to get less chemo in the BOT/BAL arm." That is a huge metric of QOL and what we know is going to matter to patients. We are confident that BOT/BAL will deliver a better recurrence rate with less of that chemo. That is part of the value proposition of our therapy. Right. Exactly. Okay. I know we are spending quite a bit of time on sort of the setup for ROBIN, but do you want to just take a quick look at NEOASIS? Because it is another sort of confirmatory, if you want to call it that, study that gives you very high MPR rates, and where you, I think, got a better sense of the BOT dose that you are going to use in ROBIN? Yep. I do not know if you had that slide in here. We have that in X, Mike, but we do think it's important to address safety. Okay. In this patient population, safety is really imperative. I think the tolerability profile that we're demonstrating here is going to be sufficient, and we're obviously really focused on the treatment protocols for the phase III being such that we're going to be able to show a similarly strong safety profile. Yeah, I would also point out that these are substantially below what you saw in C-800 because you've got patients with much more robust immune systems. Yeah, I also think that the other point here is that it's one dose of BOT as opposed to Right Two to four, which was difficult in the metastatic setting. Yeah. Okay. And Should we take a quick look at NEOASIS? Yeah, go. Yeah. NEOASIS is actually a fairly large neoadjuvant study looking at multiple different tumor types. This is being run by Myriam Chalabi at the Netherlands Cancer Institute. She's well known for the NICHE study, which examined ipi/nivo in both MSI-H and in MSS patients. NICHE was expanded in the MSI-H population, showing very nice data, and they recently showed very long-term follow-up in that study that's very impressive. So it shows the power of the immune system in a responsive tumor. But what's interesting here is that here we're looking at MSS tumor type, looking at two different doses. She was dose escalating 25 to 50 to evaluate safety. They're small cohorts, so five at 25 milligram, those are the striped, five at 50 milligram are the solid bar. What's interesting here is we see activity across a range of tumors. We see sarcoma, which is consistent with what we see in the metastatic setting. We see very nice responses in sarcoma. Also triple-negative breast cancer, both N and ER-positive breast cancer here. Then the MCC is one Merkel cell carcinoma, which is a warm tumor, so you kind of expect that to be a little bit more responsive. Was that an MCC that was previously treated with KEYTRUDA? That is indicated, so- No, these are de novo, so this is- These are de novo. Okay. untreated. Yeah. Okay. Yeah. I wistfully look at the sarcoma patient because I remember Bree Wilky's presentation a few years ago and the remarkable results she got there. Again, another cold tumor. Yeah, we continue to have a lot of interest in sarcoma as well, and maybe just a little digression on the metastatic setting. We have an access program in France. Yeah. The three approved indications there are metastatic colorectal cancer, ovarian cancer, and sarcoma. The ANSM, the French regulatory authority, recognized that there is unmet need for those patients and that BOT/BAL has data that makes sense to provide them access. We are quite happy the French government is providing access to those patients in France. Do you find when you talk to investors, Zack, that people are aware of that? That there are docs out there that are getting real-world experience using BOT/BAL? We say it. Whether they prioritize it is really up to them. Whether they process it or not is another question. Okay. Yeah. Recently at ESMO this year, just a few weeks ago, Myriam Chalabi presented the dMMR colon cancer cohort from the NEOASIS study. Here you see some nice results. Yeah. They are at 83% major path response rate here. I think that it would be nice to see sort of pushing the dose a little higher. She is at 50. I think 75 would probably be, you know, maybe get a little bit better response in a couple of these patients. Yeah. Yeah. Very nice. Okay. Let us move on to, I think this is a good point then to transition to the discussion about ROBIN. So, it is your phase III trial, 850 patients, randomized one-to-one. Event-free survival is the primary endpoint. Talk a little bit about how FDA feedback shaped the design, including the control arm, standard care, and then also the inclusion of high-risk stage II and III disease. Yeah. So we modeled this study actually on a precedent, which was the FOxTROT study, which looked at neoadjuvant FOLFOX in same population, high-risk stage II and stage III patients. Here you are staging clinically. You are using CT scan to stage the patients to be able to try to climb the appropriate high-risk population. So we discussed with FDA the patient population, the study design where we would evaluate BOT/BAL versus basically standard of care. Standard of care here is going to surgery followed by adjuvant chemotherapy. One of the discussion points with the FDA was what adjuvant chemotherapy are patients going to get after surgery. What we agreed to with them was that the staging at surgery would determine what adjuvant chemo they would get, and that would be based on NCCN guidelines. That was consistent with what the FDA was looking for. They wanted basically investigators to have some guidance on how they would treat patients. What it means is that if we see a pathologic complete response and lymph node negative at the time of surgery in the neoadjuvant arm, then those patients would go to observation. So they would not get any chemo, which is consistent with what patients with a stage I tumor would get as a standard of care. Right. Here, we hope that we are going to see some de-escalation of chemo, particularly in the oxaliplatin, because in the oxaliplatin Yeah carries with it significant neurotoxicity. Right. Additionally, of course, the primary endpoint is important here, because primary endpoint is event-free survival. This is the standard in terms of neoadjuvant perioperative adjuvant studies. So there was no debate over the endpoint. The target hazard ratio of 0.65 was viewed as a significant benefit in this patient population. Right. Just for the record, Robin, the standard chemo, the adjuvant chemo is going to be FOLFOX, FOLFIRI, because it would be just five-FU, leucovorin? I mean Yeah, the standard adjuvant treatment is either five-FU, if it's a smaller tumor, or CAPOX or FOLFOX for larger tumors with lymph node positive disease. Typically, the staging will determine whether it's three or six months of treatment with CAPOX or FOLFOX. FOLFIRI is not used typically in this setting. Okay. And you're also trying to measure the oxaliplatin neuropathy as part of the benefit, correct? That's right. Yeah. Okay. And how you quantify that is just- It's one of the quality of life measures is- Okay. Yeah. Is that the QL36 or? It's not the QL36. There's a specific tool- I don't recall it right now. which we didn't list it specifically here, but there is a specific tool that kind of addresses that neuropathy associated with the oxaliplatin. Just curious, so what you'll be looking for, event-free survival, sorry, on an intent-to-treat basis, correct? Correct. What we expect in the control arm is that, at basically three years, you'd expect about a 25% relapse rate. So EFS would be 75%, who are event-free at three years in the control arm. We're looking to improve that by risk reduction of 35%. So we'd be up on this, an absolute basis, a significant improvement for these patients. That's if we hit the target hazard ratio. If we go better than the target hazard ratio, which if you look at other studies of neoadjuvant CTLA-4, we've actually seen even more impressive results in NADINA, for example, which was ipilimumab in stage 3 resectable melanoma. Ipi-nivo neoadjuvant versus adjuvant nivo had a hazard ratio well below 0.5. It was like 0.35, I think, so. Yeah. If you think about the triple-negative breast cancer setting as well, it's like some of the studies that were done by I-SPY with neoadjuvant pembro followed by either chemo or SAC-G. You've seen those PCR rates correlate really beautifully with event-free survival and overall survival, so. Yeah, and that should be. We took a look at that, looking at the delta in terms of pathologic complete response rates to see how well it correlates with event-free survival. You see actually a pretty good correlation in terms of this improvement in pathologic complete response rate. If you hit sort of where we saw in NEST and UNICORN at that 30% PCR rate delta, we predict a hazard ratio of around 0.5. For our target hazard ratio of 0.65, that would correlate with about a PCR of 17%. We think that would be reassuring. We don't think it's going to tell the whole story, because I think that when you look at the NICHE data, for example, and our own data, well, it's hard to correlate our own data because 100% of patients are recurrence-free with BOT and BAL, so Right that would be great to see. But in NICHE, in the MSS cohort, this is ipi/nivo here, you can see that any patient who had at least a 50% tumor reduction was recurrence-free. Right. Yeah. No, it's a beautiful thing. All right. Well, maybe this might be a good time to talk about kind of the event horizon, if you want to call it that. If you want to maybe walk through sort of the. Yeah, here we go. Why don't you walk us through sort of the near-term milestones that people should be mindful of, and then what's going to come with time? Sure. Why don't I start, Mike, and I'll frame this timeline in the context of the transaction that we did back in July. Yes. Because I think that the timeline that we have for the ROBIN trial is very much aligned with that transaction. Yeah. Just to remind everyone, the transaction we are referring to, we closed on July 13 of this year. It was a PIPE, it was a private placement, which was oversubscribed for up to $340 million of financing, $85 million of which was done upfront at the time of closing, and the remaining $255 million of potential proceeds are part of two warrant tranches, the Series A Warrant tranche and the Series B Warrant tranche. We'll talk through the mechanics of those as well. All three tranches, the upfront, the Series A Warrants, and the Series B Warrants were priced at premiums to the then market price, which was $3.35 on the date of closing. We're obviously focused, and investors are focused on the sort of economic value of those warrants, but also the critical milestones that relate to those warrants are part of the ROBIN trial. Just to go through it, the Series A Warrants will have an expiration date that is 30 days after we publicly disclose that 50 patients have been enrolled in the ROBIN phase III trial. We expect that event to occur in Q2 of 2027. As we've alluded to before, our anticipated first patient enrolled is expected for Q1 of this year. Based upon the sort of expectation of enrollment ramp, that's how we get to those time points. We can obviously talk a little bit about the excitement that we're feeling among the oncology community and the sites that we've been engaging with for the trial. We did talk a bit about that in our earnings announcement earlier today. Just to stick to the timeline, the Series A warrants would result in $85 million of gross proceeds into the company if all of those warrants are exercised. Those warrants are priced at $4.02 per share. Once we trigger those warrants, and if those proceeds come into the company, that obviously extends our cash runway, and we project that to be a cash runway extension through Q1 of 2029. The next big inflection point is the interim readout on pathologic response rate in the first 100 patients enrolled in the trial, 50 on the BOT/BAL arm and 50 on the control arm. That we expect to happen in Q4 of next year, rather. That will trigger the 30-day expiration of the Series B warrants, which, if all are exercised, would result in an additional $170 million of proceeds into our balance sheet, and those are priced at $5.03 per share. An important mechanic, which I am not sure people appreciate, but it is part of the filed terms of the transaction, is that if Series A warrants are not exercised by investors, they will lose their Series B warrant. Right. There is an expectation that these warrants will be exercised. We, of course, know that investors will be looking to the response rate data as part of that Series B tranche as a true clinical de-risking outcome. As Robin alluded to earlier, we know that pathologic complete response rate is an important correlate, but we also believe strongly that major path response is an important correlate as well to long-term EFS benefit, and we will be announcing both of those metrics along with just the pathologic response rate, which is anything above 50% tumor shrinkage. We anticipate LPI in the trial to be second half of 2028, and that would then lead to our projected timelines for the readouts for the primary endpoint of EFS, the interim analysis in the second half of 2029. That is at a 75% information fraction, meaning 75% of the EFS events are anticipated to have occurred at the time of that data cutoff for the interim readout. The full readout, which is, of course, 100% of the anticipated EFS events, would occur roughly one year thereafter, in second half of 2030. Hmm. Will you be following people, patients ultimately for OS, or once they Yeah. Okay. OS is a key secondary endpoint. Okay. Zach, can you talk about operationally, in the early part of the study, for the first 60, is the site enroll initiation ramp going to be gated in any way, or are you going to basically just start ramping as if, assuming that the warrants are exercised and you're just going to plow forward with the target number of sites? Does that make sense? Yeah, I understand your question. No, we don't have any gating. We're anticipating that we're basically trying to activate every site that we can as quickly as we can. We expect U.S., South America, Australia potentially to be the earliest sites to be open, and then Europe takes a little bit longer in terms of the clinical trial application. We expect them to come in at not too much later, about a quarter later maybe. Asia as well, we're opening the study. It takes time around the world, but we definitely expect to have the full study open by mid-year next year. And ultimately, how many sites, Robin? We haven't said specifically, and we're still sort of in that phase where we're kind of validating a number of sites. So we'll hold off on saying that for the moment, but- Okay yeah. It's going to be a big number. Well, we're focused on high-volume sites because we're- Yeah and we are doing something unusual, which is that typically, a lot of times you will work with a CRO. The CRO will recommend a bunch of sites, and you end up with 300 sites, but a third Right will never enroll anyone. Right. Here, we are doing something different, which is we are actually getting on a meeting with every single site that we are going to include in this study. We are having a discussion with them. We are understanding if they are going to have any challenges, and we are selecting. We are being very selective about who can participate in this study. Is China going to be part of it or no? We are evaluating China. Cannot say for certain yet, but it is possible. Yeah. Certainly all the major markets, Mike, will be a part of the trial. Well, the thing about China, I mean, is you just can enroll so many patients. It is just they are incredible. And operationally, I think they are as good as anything you get elsewhere, but Yeah, no, we have been thinking of I don't want to make words we don't need either. with some key sites in China. You're right. The volume of patients they see dwarfs anything we see anywhere else. Yeah. It's remarkable. In terms of volume, is there any qualification that the surgeons need to have as far as how many patients per year they see or Yeah their experience with the surgery, et cetera? Yeah. No, definitely adequate volume in terms of the number of surgeries that a site sees is part of the screener that we have. Yeah. Also, it is a plus if the surgeons have had experience with other neoadjuvant colon studies. So there is the MSI-H is the obvious ones. Some of the AZUR studies, for example. I think that is where we are seeing there are some surgeons who already have experience, so they are kind of used to it. And very much, I think the standard now across the world is that sites are evaluating first whether a tumor is dMMR or pMMR prior to deciding whether to go to surgery or not. Right. Yeah. Okay. I think we are coming up on time fairly soon. I just was curious, here is the ROBIN timelines. I am just curious, are we going to see any further updates, little gumdrops, little breadcrumbs that your investigators might drop on NEOASIS? Is Myriam Chalabi going to be I know you cannot speak for her, but would you imagine that there would be data drops throughout the course of 2027 and so investors can get comfort that- Yeah. Yeah, for sure. No, we have a number of ISTs that are ongoing. Myriam's NEOASIS study is obviously one of the key ones, and we are anticipating that she is going to present data next year. We also have a number of rectal cancer studies that are ongoing. Andrea Cercek at Memorial Sloan Kettering is running a study with BOT and BAL. Rectal's really interesting. Yeah. Yeah. Yeah, especially if they can increase the level of sphincter preservation. Organ preservation. You had that. for sure is a key one, and ability to de-escalate radiation in particular Yeah but also chemo and radiation. I mean, there's such a bigger need in that setting, Mike. Not to compare need, I mean, every patient has a need, but it's very clear in rectal that there's a sense of urgency among oncologists and among regulators to find a better solution for these de novo patients. To Rob's point, we do have multiple ongoing ISTs in that neoadjuvant MSS rectal disease area. We do believe that there will be some data from those coming out next year. We can't speak to specifics on that. But that is certainly our second focus beyond the ROBIN phase III, when it makes good sense for our company to potentially start to think about sponsor trial expansion. That is very likely where we will go. Yeah. Okay. Well, look, I'm looking in the chat and I'm looking on my email. I don't have questions here, so I don't know if you want to wrap up with anything before we give you back your time. I'm just going to wrap up with the fact that I'm super excited that we're evaluating BOT and BAL in a curative intent setting. When you look at MSS colorectal cancer, there have been no improvements in the treatment of these patients in over 20 years. I mean, the last therapy to come into this space was oxaliplatin, and that was in 2004. Yeah. Yep. Yeah, remarkable. I'll just frame it, Mike, a little bit in the sort of investor frame, which is we think we presented now a very clear pathway of how we get this therapy to its first full approval, and we've established what we think are the fair market metrics to understand what that means from a value creation perspective. We've also sort of solidified, at least for the time being, our capital needs through this PIPE transaction and how many shares will be out there. So for investors who are taking a first principles approach to valuing our business and establishing a view on whether the price is undervalued or overvalued, I think we've given them all of the key parameters to do that. Right. We, of course, are always looking to help investors and refine that, and we do a lot of that through our sell-side analysts like you and your team. But we do think that that story has very much crystallized over the last few months. And obviously, our view is that there's a whole lot more value in our stock price than what our stock price is reflecting today. Our jobs are to continue to execute. But for those out there who are looking for a fundamentally oriented deep value story, we think that we represent that. Yeah. And if you're looking for validated mechanism of action and de-risked assets, I don't know how you can get much better than BOT and BAL. Anyway. All right. Well, listen, I want to thank you guys for joining me here today. It was a pleasure. We'll keep our close watch on your progress. Want to thank everybody for joining us here today, and enjoy the rest of your day. Yeah. Thank you. All right. Thank you, Mike. Take care. Thanks, Mike.