Joining me today are Garo Armen, our Chairman and Chief Executive Officer; Dr. Steven O'Day, our Chief Medical Officer; and we will also hear from Dr. Benjamin Schlechter of the Dana-Farber Cancer Institute. Our discussion today will focus on the progress that we have made since our July webcast, including implementation of the ROBBIN phase III neoadjuvant program, continued physician interest in the access to BOT+BAL, and recent clinical and investigator-led activity that is helping inform the acceleration of BOT+BAL into the earlier disease settings. Following the prepared discussion, Agenus leadership, including Dr. O'Day, as well as Robin Taylor, Chief Commercial Officer, will join Garo for a live Q&A. Questions may be submitted at any time during the webcast using the Q&A function of the Zoom event below. Before we begin, just a brief reminder that today's discussion includes forward-looking statements, so please be sure to refer to our SEC filings for additional details also available on our website. With that, I am pleased to introduce our Founder, Chairman, and CEO, Garo Armen. Thank you very much, Stefanie, and thank you everyone for joining us today. When we had this session back in July, we spoke about the financing that was announced then, and we also spoke about the strategic shift into the neoadjuvant setting in terms of our approval strategy. At that time, of course, the concern was before that announcement. The concern was our path forward. I think very few people were questioning the high activity of our product or combination, but people were more interested in how were we going to take this to the finish line. And certainly, the financing played a major role in addressing that question. Since then, our stock has reacted favorably, by all standards, and we believe that some of the critically important risks associated with financing the company's future were at least removed for the time being. Now, we are not going to repeat that discussion today, but what matters now, and you are going to hear about this from Dr. O'Day, and if there are any questions, of course, Dr. Taylor, how are we doing since then? What are we doing to execute towards that strategic goal of initiating and completing our neoadjuvant trial? Now, over the last few weeks, there were two important bodies of BOT+BAL clinical evidence that moved into peer-reviewed journals for Clinical Cancer Research, which is the prestigious journal of the American Association for Cancer Research, and t he longer term for phase I-B study, which is in the refractory MSS metastatic colorectal setting published, shows longer-term follow-up and durability, and you will hear about this also from Dr. O'Day, durability of responses in patients that responded. These are, of course, important studies for us. The next one is the NEST neoadjuvant study, and that also talked about how we haven't had any recurrences since the study began. Now, we're also seeing increased investigator interest in studying BOT+BAL in the earlier disease setting. Of course, shifting to the neoadjuvant setting for our approval strategy helped, but we're seeing also additional investigator-sponsored proposals and studies for neoadjuvant. You're going to hear more about them, including the RECTIFY-1 study led by Dr. Ben Schlechter, and Dr. Schlechter is going to be joining us in just a bit. We interviewed him two days ago because of his patient schedule, and we're delighted that he had the time to discuss some very important points with us. Now, all of this is important because it gives patients the opportunity to be able to benefit from BOT+BAL. It doesn't change our course with the ROBBIN study. That is the strategic focus of the company, both from a financial allocation of resources and people allocation of resources. But it also reflects the broader clinical interest in asking what BOT+BAL may do before surgery and creates additional clinical trial access to patients. At the same time, physician interest in accessing BOT+BAL outside of clinical trials also continues. We've had geographic reach, and our access programs have expanded. We're seeing repeated interest coming from physicians. As you know, we have the French AAC program, and then outside of that, we have the paid Named Patient Program, and those requests are coming in, and that demand is growing. Now, at Agenus, our development priority, as I said before, remains very clearly advancing ROBBIN, our neoadjuvant CRC study in the colon cancer setting, forward. Steven will update you on how this program is moving forward. We've had some very exciting initial interactions. Well, they're not initial interactions anymore because I think we've covered the majority of the sites that will participate in this trial already. We'll also discuss what we're seeing through our access programs in addition to what I mentioned before. So, as I said, you'll hear from Dr. Ben Schlechter of Dana-Farber Cancer Institute, why the timing of immunotherapy may matter in colorectal cancer for the first time, why MSS disease has historically resisted first-generation immunotherapy while we're seeing responses in BOT+BAL patients, even in the late-stage setting where there's really no treatment options left for them. So, that's where I'd like to stop and turn this over to Stefanie to take the program forward. Great. Thank you so much, Garo. With that, Steven, let's actually start on a conversation here together and kind of take up where Garo left off. So, when we announced the ROBBIN phase III neoadjuvant study back in July, we had done a lot of work, you in particular, to define the study, the components that we received FDA feedback on on those key elements of this program to move forward and really establish the resources to move forward, including the financing that Garo just alluded to. So, I know it's only been about two months, but there's obviously been a tremendous amount of work and activity from you and the team and the organization towards opening up this global study. Can you share a little bit about what has changed operationally since July and where the team is focused today? Well, thank you, Garo and Stefanie. And boy, has it been a busy couple of months. Really unprecedented in my experience with excitement and enthusiasm. We obviously have a deep network of thought leaders and principal investigators around this very mature BOT+BAL program. But in July, we were focusing primarily on the design of ROBBIN, aligning with the FDA rationale for moving botensilimab and balstilimab into the neoadjuvant setting, a very important pivot that really optimizes the signal that we're getting with BOT+BAL with an intact tumor and draining primary lymph nodes. Since then, our focus in the last two months has been really increasingly and almost exclusively a shift to implementation and startup of this very important ROBBIN global study. This includes building and continuing to expand our global investigator and site network, advancing the regulatory and ethics work required in the countries where we intend to conduct the study, establishing pathology and translational infrastructure, and aligning our clinical, operational, and drug supply functions around the study initiation. There are a lot of individual work streams in the company right now involved with opening this global phase III trial, and we are moving in parallel with rapidity, and efficiency, and excellence, and our goal continues to be enrolling the first patient in quarter one 2027. Well, that seems to be a huge undertaking, but very confident, particularly even, you are no novice to clinical studies, being an investigator yourself before coming here to Agenus. So, give us a little bit of a sense of the scale of that effort, Steven. How large of a clinical network are you building for ROBBIN, and what can you tell us about the geographic footprint particularly? I know we haven't. Yeah. Really shared much about that as of yet. So, this is a phase III global trial of approximately 850 patients. It will involve North America, Europe, South America, and Asia. We are extremely mindful, and I am in control with my team of selecting high- volume and high-quality sites, and t his is particularly important with a neoadjuvant study. It is really very different than studies in the late-stage metastatic setting. It is important these sites see the patients, which are high-risk stage II and III cancer. As you know, there is an epidemic worldwide, so these cancers are prevalent, particularly in the MS-stable, 90% of all colon cancer. And most importantly, though, that neoadjuvant studies require multidisciplinary teams to identify these patients, become aligned around neoadjuvant treatment. Now, this involves a medical oncologist, clearly. But what is different here is we need alignment and leadership from our surgical colleagues, but also our radiology colleagues, our pathology colleagues, our gastroenterologists, and our research teams. And this is no small chore, but our deep networks, my experience across 30 years in the clinic and networking with KOLs around the world has definitely been very helpful. But the data itself is what is most helpful and is really exciting people to participate in the trial. Most of the sites are major academic centers, but we are also selecting high-performing, high-quality community-based centers and networks, as long as they are integrated in terms of the multidisciplinary neoadjuvant setting. Interacting with medical oncologists alone is simply not enough. In order to be successful, we need to align and the enthusiasm from these multiple stakeholders. Thanks for that, Steven. Question. You just talked a little bit about the broad scope and your personal involvement in site selection as well, likely because of all of the relationships that are out there and the experience. Are these sites and some of the investigators, primarily investigators that are already familiar with BOT+BAL, or are you seeing that ROBBIN is also bringing in new investigators and institutions that do not have prior involvement or have not really been connected much more broadly with the program previously? It is a combination, but I will say, with over almost more than 1,200 patients treated in our Agenus-sponsored trials, as well as our investigator-initiated trials across the globe, we have an extensive network of investigators and thought leaders. What is interesting is there are also thought leaders and investigators that have been more concentrated in the neoadjuvant space, and we are leveraging this. So, we are bringing in additional new thought leaders and investigators with a particular experience in neoadjuvant setting. As you know, in MSI colon cancer, there is now an evolving experience in this neoadjuvant setting for GI oncologists. So, we are really piggybacking and really driving that experience. So, the short answer is it is a combination of our existing, but a whole new group of investigators are seeing this data, have done neoadjuvant trials, and want into this large global trial. Yeah. I think that we'll get to this a little bit later, but even more so recently, a lot more neoadjuvant investigator-sponsored studies are launching as well. In our July webcast, right, we had Dr. Pashtoon Kasi with the NEST-3 study and Dr. Benjamin Schlechter today, who started the RECTIFY-1 study at Dana-Farber, and then there's other neoadjuvant studies as well going on at Memorial Sloan Kettering Cancer Center and then also in the Netherlands. So, a lot of interest in the neoadjuvant setting, which I'm sure is a part of a lot of the excitement too around ROBBIN. Earlier, just getting back to something that you had mentioned, Steven, about the multidisciplinary nature of these sites. You started to allude to this a little bit, but what is operationally a bit different about a neoadjuvant study like ROBBIN compared to a traditional later line study, and why is that experience so important as we think about appropriately and efficiently getting ROBBIN off and opening it, enrolling, and that consistency that you alluded to earlier across all these different global sites? Can you talk a little bit about that? Yeah. Let me build on, I've obviously talked about the multidisciplinary alignment that's really critical. What people are very excited about is that this could be a paradigm-shifting study that will not only reduce recurrences and improve survival but deescalate chemotherapy in this very early-stage setting. That's really important. But there are other issues here. In addition to aligning the medical team, you're dealing with patients that are newly diagnosed. They're in healthcare systems expecting potential standard of care surgery and adjuvant chemo. Patients want more than that. Doctors want more than that. And ROBBIN trial inserts a defined treatment period before the surgery so that part of the process must fit within this established clinical pathway. I think patients are more than willing to delay their surgery a short period of time, given the data that we've shown that none of these patients have progressed during this period of time, and the opportunity to improve survival and reduce chemo is a win-win for doctors, surgeons, medical oncologists, and everyone involved. But you do have to identify the patient. You have to stage them. You have to identify their MS status, which is now routinely done in all colon cancer. Then, you move forward in a relatively short interval, and you need the teams to be ready and teed up, and that's what we're spending a lot of time talking to the teams and really being sure that they're set up for success. Success will require that patients be present, but also that the teams really function at a high level to get the treatment in and the surgery and the adjuvant therapy. Yeah. So, that's a lot of coordination across the different parties at the different sites. And you also mentioned pathology and the importance of that particular expertise within the multidisciplinary function, because it's also a very important feature of how we're going to begin learning about the impact of that within the ROBBIN study. Can you share with us a little bit about what needs to be in place to ensure that the pathologic response, the assessments, right, we know that this is a huge milestone for us, are consistent and rigorous across how it's going to be assessed across this large global study? Yeah. So, I think what's important is we're not starting from scratch here. The neoadjuvant setting with immune therapy has been established in melanoma. It's also prevalent in breast cancer now and lung cancer in terms of neoadjuvant perioperative. So, things are in place in terms of leveraging that history. But what's really exciting for everyone is that even though time to distant recurrence or metastasis from the cancer is the primary endpoint of the study, we will get an early readout after the first eight weeks or so of treatment on the depth of this pathologic response. And more important than ever in immune-mediated therapy, more so than chemotherapy or targeted therapy, the depth of these responses are so highly predictive of eventual metastasis. So, we will be looking at complete and near-complete responses, and that will give us a lot of confidence as we go through, and this will be centrally reviewed by the trial, that we are consistent with our phase II data and highly set up to succeed in terms of the primary endpoint of the study. Now, this does require that we coordinate this, and we have leading centers around the world that have a lot of experience with pathologic response, and we're leveraging and identifying these centers to help us coordinate and make sure that this is a rigorous process of pathologic assessment. We're also collecting ctDNA and other biomarkers that will also be very helpful, not in real time in this study, but as important supplementary information as we wait for additional primary endpoint time to event. Great. Thank you, Steven. Certainly, once the sites begin opening and enrolling, that's really where I think the attention naturally will be, like how quickly are we actually enrolling patients. What do you see, from your perspective and your role, what will determine how efficiently ROBBIN moves from all of this build-up to the site activation into actual patient enrollment? As Garo and I often discuss, it's not, I mean, the first patient's very important, and we're on target, but we want to get really accrued quickly, and I think we're setting this up. So, it's not the number of sites ultimately, although we're well set up with a global trial, but it's the quality of these sites and their enthusiasm and alignment around identifying and treating the patient. Colon cancer is common, but ROBBIN is enrolling a defined population of stage high-risk II and III patients. So, ideally, we look forward to, in parallel, opening a number of early sites, and then obviously, as quickly as possible due to regulatory timelines, continue to open sites in early 2027. Great. Okay, so I have one last question for you, Steven, before the live Q&A at the end. But for all of our listeners and the stakeholders that are following ROBBIN, what are the most meaningful indicators of progress between now and that first patient in that you just alluded to, and then as the study begins enrolling more so? What are you looking for? Yeah. The first thing is the work we have done in the last two months, and we will do in the next two months, is really rigorously identifying sites that will succeed and produce rapid accrual and high-quality data. That is number one. Then, driving enrollment, and we have a plan for very active connection, and really staying very close to these centers as they ramp up. But I think in terms of ROBBIN, I think it is best to think of this in three stages. You build and activate the network. We are doing that with wholehearted enthusiasm, both from our team and our investigators around the world. You then drive enrollment, and as these responses become apparent, it will only increase the enthusiasm of the sites. Then, obviously, getting a readout of the surgical pathology results will be also very, very important. But we are on track to first patient enrolled in the first quarter of next year, and getting some pathologic data in the second half of next year as we have outlined previously. Ultimately, it is all about can we, through botensilimab and balstilimab and surgery, can we reduce recurrences and improve survival, and at the same time reduce the need for chemotherapy in a curative intent setting? This will be the paradigm-shifting feature of the study. Great. Thank you so much, Steven. Thank you for your time and walking us through that today. So, Garo, I am going to come back to something you mentioned earlier at the beginning of the call, because this is another area where the team has really focused and also seen some meaningful activity since our last discussion in July. ROBBIN, as you mentioned, is clearly the company's development priority and our focus. At the same time, as you have mentioned before, our kind of moral obligation that there are patients who need treatment today, and physicians who continue to approach yourself and Agenus seeking access to BOT+BAL. Can you give us an update on what has changed across the access program since we last spoke in July? Just to be clear, we have, as you know, two access programs in addition to any trials that are ongoing, that allow a patient to have BOT+BAL treatment. One clearly stated is the program that was approved in France, and we have not disclosed the number of patients treated, h owever, we have disclosed the reimbursement revenue that we get from the French government every quarter. We will be talking more about the progress that we are making there. So, that is a very important program, and French patients have been privileged enough to have access to this and have the government reimbursement. In addition to that, we also have the paid Named Patient Program. That is a program that allows a patient whose physician is seeing it appropriate to refer that patient to a country and a center where the treatment can take place. These include, of course, as we have talked about before, the U.K., Switzerland, France can treat patients with paid Named Patient Programs that are willing to pay out of pocket in addition to reimbursing their own patients. Belgium, Spain, Brazil, Argentina, and the number of countries are growing. Now, under this program, a patient can request, or the doctor can request to be treated for any indication that they seem to be fit for the patient. It does not have to be restricted by the AAC program indications or anything else, as long as there is data. As you know, we have data on over nine different kinds of cancers where we have shown consistent activity. In fact, at last year's ESMO in Berlin, there was an oral presentation where we showed the consistency of response rates in late-stage patients that have exhausted all other treatment options. So, this is quite exciting actually. It is exciting because we are seeing the momentum develop. In terms of the Named Patient Programs, for example, we have U.S. physicians referring patients to any country or any center where they can be treated with paid Named Patient Programs, and a s long as their physician sees it appropriate for the patient to undergo such a treatment, they can get it. Now, the unfortunate reality is that can you imagine a patient struck with cancer, they may not be in the best of health, they may not be in the best of shape to travel, but unfortunately, a U.S. patient has to travel to some other country, willing to pay out of pocket and be treated. We hope that that reality will change sometime soon, but t hat is the reality right now. One of the things that I wanted to also mention is that, as you know, Europe shuts down in the month of August, and in fact, increasingly, U.S. is also shutting down in the month of August, and we expected a slowdown in demand by doctors for August. In fact, we have seen a growth, n ot a slowdown, but a growth. So, those are very indicative of the fact that there is substantial enthusiasm by physicians and by patients to be treated with BOT+BAL because it can offer them a hope and a reality of survival for an extended period of time. Dr. O'Day always says the durability of responses with immuno-oncology combinations is really very notable. So, that is what we are seeing, and we are very excited that the roster of physicians who are familiar with the data and are willing to treat patients is growing. Great. Thank you. I know that the team anticipates this, share more specifics during our Q3 earnings update. Again, very positive that the interest still continues to grow, even over these periods where we are expecting and anticipating maybe some leveling. You have mentioned in the past, Garo, too, that not just the expansion of additional countries and making the access to BOT+BAL available for their patients, but you are starting to see physicians, repeat physicians, treating multiple patients at their centers. What do you think is driving the physicians to come back and seek access for additional patients after they have initiated treatment? Stefanie, this is a very important point, of course. One very important aspect of this, and we have heard this from physicians that most recently have shown very high enthusiasm in participating in our trials, particularly the ROBBIN trial, o ne very notable reason is that, as I talked about a little while ago, for example, in the last few weeks, we had two publications discussing long-term outcomes for patients, one in the late-stage disease and one in the neoadjuvant setting. We expect more to come between now and the end of the year, of course. These are very important drivers, the credibility of the data and their own personal experience. If you treat one patient and you see something happening, you want to treat another patient. That does not mean that every single patient is going to respond, particularly in the late-line setting, that is not going to happen. But it is encouraging because it is the last hope for patients, and hope is a very important element here. Very important element because how could you tell a patient that we have exhausted all treatments and there is nothing else we can do for you? We offer that last hope for the patients who have exhausted all treatments, and that is clear based on the data that has been published and presented. We also hope for patients in the neoadjuvant setting to be treated less, I should say, less in a punishing way, more in a sustainable benefit. Dr. O'Day explained this beautifully. It is a very important point for patients. In some cases, what we hope is that patients will be able to benefit from lesser surgery. Lesser surgery, meaning, some of these surgeries are quite radical, debilitating for the patient. For example, if you have rectal cancer or colon cancer that is near the rectum, you have a life-changing surgery. We have some patients, including relatives of our colleagues, where they have been treated with radical surgery, and life is never the same for them. What we hope to do with the ROBBIN trial is to change that reality for patients. I think this is going to be a very, very, as Dr. O'Day said, potentially life-changing outcome for patients. Thank you, Garo. I know that you had just mentioned, certainly because of the different pathways of these different access programs, both being the French AAC as well as the paid Named Patient Program, which is available across various countries around the world, that offers a lot of accessibility to patients, but that also comes with the responsibility that you have mentioned before. So, as physician interest grows, right, and these programs continue to expand, how are you thinking about Agenus' ability to support them and our infrastructure and our personnel? Can you maybe share a little bit about, with our audience here, what we are doing to ensure safety, and our efficiency, and then also our response time to support these patients and physicians around the world? Of course. Let me step back for a moment and recount the fact that the last two and a half years for the company have been one of the most trying periods in the company's existence. What's confused us and our colleagues, our scientific, clinical, and other colleagues, is that we've seen some absolutely remarkable clinical outcomes, both in the late-stage setting and in the neoadjuvant setting across multiple tumors. I may want to remind you that we had another webcast a little while ago on December 3rd, where Dr. Christopher Lieu of Colorado, he said there was a patient he treated, it's in the webcast, and this patient has exhausted all treatment options, and h e said our choice was either sending her to hospice or treating her with BOT+BAL. And this patient was treated with BOT+BAL, and the patient is now alive after two years, essentially free of disease and conducting a regular life. Of course, this doesn't happen to every patient. But for the patient that this happens, it's a miracle. Nobody can deny that. Now, we have been of the mindset, Stefanie, that our responsibility as a company was to take the product to patients on a mass scale as expeditiously as possible. One of the very important cornerstones of this strategy was to make sure that we have commercial product ready for patients when the product is approved. Unfortunately, for reasons that everybody pretty much knows, unfortunate for the patients, unfortunate for our company, and unfortunate for our investors, that that didn't happen as we expected. However, we have lined up a significant amount of commercial product, commercial-grade product, ready. This product, by the way, has a very long shelf life. So, if we play it right, which we are, of course, this product is good for essentially the next 10 years. So, from a product perspective, we have plenty of product, both botensilimab and somewhat lesser balstilimab, but we have the pathway to make more balstilimab, commercial balstilimab, very, very quickly. So, we have no product shortage. That's one part of the answer to your question. The second piece is, well, we have product, and it may be sitting in a distribution center or two. How do we get it to patients in hospitals, or hospitals and patients? That's where we, a little while ago, announced a collaboration with a company called BAP Pharma. I am skeptical any outsider, but BAP Pharma has been an absolute delight to deal with because they have the same focus on benefit for patients as we do. So, if a patient under any of our programs, paid Named Patient Programs in countries where this is allowed to be administered, or the French AAC program, or any of the ongoing clinical trial programs, we can get product to patients at a lightning speed, at a cost that is very modest, very modest, and with an infrastructure of professionals, which we're starting to expand both in Europe and South America, where education is properly provided for physicians such that we can monitor patients' progress with treatment, we can monitor any safety issues carefully and record them. So, these are very important elements of our sense of responsibility in making sure that patients are well-served. Great. Thank you so much for that, Garo. Thank you for that very thorough review and description of the preparations of the organization. Let's switch gears a little bit. We talked a lot about ROBBIN and how we're moving forward to implementation with Steven, t hank you, Steven, and what we're seeing through the access programs. But to really put the clinical rationale for moving earlier in the disease into context, you yourself, Garo, recently sat down with Dr. Benjamin Schlechter, who's treated patients with both BOT+BAL in the advanced colorectal setting. But he as well is also now leading the RECTIFY-1 study, which is a neoadjuvant study in rectal cancer, in MSS rectal cancer. So, it really gives him a direct investigator perspective on using immunotherapy before surgery. So, your discussion ranged from what neoadjuvant treatment means and why the timing matters to why MSS colorectal cancer has historically not responded to first-generation immunotherapies, and really what the long-term BOT+BAL experience has shown, a nd as you mentioned earlier, why the NEST neoadjuvant findings have really prompted investigators to explore the combination earlier in this disease. So, why don't we go ahead and take a look at that discussion from earlier this week. Hello, Ben. We're joined today with Dr. Ben Schlechter, who is a senior physician at Dana-Farber Cancer Institute. We've had the privilege of working with Dr. Schlechter for a number of years now, particularly in the context of our lead programs with BOT+BAL. So, maybe you can start with defining what the neoadjuvant setting is and what is typically different about those patients in the neoadjuvant setting versus the typical patients in the late-stage setting who are in a much more desperate predicament. Yeah. So, in colon cancer and in a lot of solid tumors, we're talking about solid tumors here, not, for example, blood cancers, but i n solid tumors, everything rotates around the axis of surgery. Surgery is sort of this very important point. Traditionally, we did surgery, and then chemotherapy was given after surgery as a helper to prevent recurrence. That's the term adjuvant. Adjuvant is a helper. That was the role of chemotherapy, and we used risk factors at surgery. So, the surgery is done. We look at the pathology and the biology, all the specimens under the microscope. We make a guess about how high likelihood it is of recurrence. Then, if the likelihood is high enough of recurrence, we give chemotherapy to prevent that recurrence. Neoadjuvant just means the exact same chemotherapy or immunotherapy or other targeted therapies before surgery, and that can be used in a number of ways. Number one is if a tumor is big and scary and just can't come out, you can use neoadjuvant therapy to shrink it. It's actually relatively uncommon. For the most part, that's not the case, at least in colon cancer. But another way to think of it is that surgery is hard on patients in a number of ways. Sometimes, if chemotherapy is challenging and surgery is challenging, chemotherapy is critical, but it can become too challenging after surgery. So, increasingly in certain diseases, it's moved to before surgery as a way of getting it in, letting someone heal, and then go to surgery. It's a little bit different when we talk about immune therapy, because immune therapy is fundamentally different from chemotherapy, and that's what's really important for the discussion today really is not just what is neoadjuvant therapy, but why is immune therapy so different from chemotherapy and why it's probably better in the neoadjuvant setting, the preoperative setting, than the postoperative setting. So, based on what you're saying, patients, when they're first diagnosed with cancer, I'm assuming then that their initial reaction is, "Let's get the cancer out of our body." So, w hen you are trying to explain why certain treatments prior to surgery, including chemotherapy for that matter, but particularly with immunotherapy, makes sense, how do you convince them? What is their reaction typically? Also, what is the interaction between, for example, your discipline as an oncologist and the surgeon who is typically accustomed to getting the tumor out, provided that, as you said, the tumor is operable? They want to do surgery at the moment that is best for the patient. So, if a patient is sick in some way, they want us to get them healthier, but t hey also want this to set the patient up for success. The goal of surgery is to cure patients of cancer. If you say to a surgeon, "This is a patient with cancer. Your job is cure, my job is cure, and I think there may be an advantage to doing a treatment before surgery rather than after surgery," they are going to sign up for that. We are not taking away surgery. We are simply changing the time of surgery so that we can sort of boost the benefit to patients. So, in terms of the surgeons, surgeons can work with this. Surgeons know how to work with this. We have many paradigms within colorectal cancer to do this. Within the time that I have been a doctor, we went from, before I was a doctor, surgery first in rectal cancer, and then all these treatments afterwards, t hen there was an era of radiation first in rectal cancer, and then surgery, and then chemotherapy. Now, we have moved to all the chemo, all the radiation, everything before surgery, and we finish with surgery. So, these are not novel concepts for surgeons, and they are not novel concepts for oncologists. The benefit of treatment before surgery, with immune therapy in particular, is that surgery does something. Surgery does something good. It removes a big tumor, but surgery also removes things that are there for a reason. Your lymph nodes play a role in your immune system. Your lymph nodes are the surrounding immune tissue in your colon and every organ, really. There are immune cells in there that are learning how to fight infection, and cancer, and viruses, and all these things. You have to remove those with surgery, because by removing those, you remove lymph nodes that may be contaminated with cancer. But by removing them, you also sort of remove the university system of the immune system. The immune system needs to learn how to fight cancer, and so we have to get those lymph nodes out. But by doing that, we actually handicap the immune system a little. So, immune therapy, in particular, after surgery is uneducated immune therapy. So, giving immune therapy before surgery is where you have the most infrastructure to teach the immune system how to fight cancer. By giving these treatments earlier and the same surgery you are going to do anyway, you actually end up with a more vigorous immune response, because you have not yet removed those lymph nodes, which play such an important role in fighting cancer, even though they have to come out because they could be contaminated by cancer. So, it's interesting because even though chemotherapy also works systemically, what you're saying, Dr. Schlechter, is that immunotherapy seems to have a longer-term potential memory sort of response. So, you're training the body to remember, so that if there's a residual emergence of disease, that the immune system will remember and shut it down. Exactly. Whereas chemotherapy may not do that exactly the same way. Yeah. Chemotherapy is sort of agnostic to when you do it. If you do it's the same. I see. Immune therapy is quite different. It's like a vaccine, right? You don't get the flu and then get your flu shot. You get your flu shot so you don't get the flu. It's not a vaccine, it's a different biology, but there's a lot of things in common. Activating the immune response when the immune system's at its best is really what you want to do with cancer immune therapy. So, giving patients the opportunity to derive the most possible benefit from their own native immunity is really important when you think about the best application of immune therapy. Let me switch gears for a bit. Now, of course, when immune therapy came to existence with some of the leading targets like CTLA-4 and PD-1, the first emphasis was melanoma, which is typically known as a cancer that is visible to the immune system. Then, that was followed by, to some extent, with lung cancers as well. Not quite the same level of success, perhaps, but still very successful. Now, when we look at colorectal cancer, we have heard, of course, some very striking developments in colorectal cancer with a minority of patients that comprise the colorectal cancer population known as MSI-high patients. But the majority don't benefit from immune therapy. Can you explain a little bit more about what is the difference between the two different types of colon cancers, and what has changed based on your experience over the last few years? So, when you say colon cancer, you really just mean the typical colon cancer, not MSI-high, because that is actually quite uncommon. In an advanced disease, it is rare. It is like 3%. It is probably a little bit more in earlier stage disease. MSI-high cancer, the term is genomically unstable. Its DNA is wet and wild. Its DNA is profoundly different from the normal colon, so there is a lot of stuff for the immune system to recognize. The immune system's job is to find differences, and when you have something which is radically different than normal, it is easier for it to do its job. There is a lot of stuff for the immune system to latch onto and generate inflammation against and attack. It does not take too much to push the immune system from the off state to the on state. The cancer is fighting back. That is what all those drugs are doing. They are fighting back against the immune system. We interfere with that, giving these drugs. But dMMR cancers or MSI-high cancers, those are wet and wild. They are weird looking. They are really strange genetically, so the immune system has something to work with. More typical colon cancer is actually quite different. More typical colon cancer is profoundly similar to the normal colon, so there is not a lot of things to latch onto, and so you need to kind of coax the immune system more. The other thing is more typical colon cancer has a profound kind of immune-suppressive desert around it. It produces things that suppress the immune system, so the immune therapies that work in other cancers need to be kind of jiggered a little differently. Not just to take T cells that are sort of asleep, but know there is a cancer there, but instead get rid of the guardrails. Different drugs do different things, and some of those drugs had early successes in melanoma, but honestly, they were overkill in melanoma. They were not necessary. But in colon cancer, they are not overkill, so you need to think differently about immune therapy. The experience of the last 10 years has been beginning to understand that averaging all cancers was a mistake, and t hinking much more nuanced about cancers and averaging all immune therapies was a mistake and thinking much more nuancedly about the different drugs and using the right drug with the right disease. I am the first to say that I had become a pessimist for these classes of drugs. We had 10 years of failure, something like that. We also know more about the immune system. We can think less simplistically and more complexly about where these different things are operating, in particular CTLA-4. So, botensilimab is that sort of like rationally designed CTLA-4. The first-generation CTLA-4s are good drugs in the right disease, but they did not work in colon cancer. With some careful work, really, it is your work, I am not going to take credit for it, c areful work, things were identified that could be done to alter CTLA-4 drugs to push them a little bit harder, make them behave a little bit better in ways that are relevant in colon cancer. Colon cancer has a ton of these T cells that are bad actors. We want to get rid of those. We want to get rid of bad T cells. Okay? But we want good T cells. Botensilimab is good at kind of doing that nuanced approach. Balstilimab, the thing that works with it, is also important because there are different components to the immune response. There are regulatory T cells. We can get rid of those with botensilimab. Those are bad T cells. There are good T cells, but cancer fights back. Cancer delivers a knockout punch to those T cells, just really, like, wounds them. Balstilimab and similar drugs like nivolumab, for example, and pembrolizumab, those work on that more chronic wounding of the immune system. So, you need different components. You have to turn on the immune response with botensilimab by removing regulation, by taking off the brakes. You need to prevent the immune system from some sort of tumbling down into sleep by using balstilimab or those other PD-1 drugs to keep that active. Yeah, so I will brag a little about our Clinical Cancer Research paper that just came out. How about that? Excellent. It is yours as well. Excellent. So, that was from the C-800-01 study. That was the original trial of BOT and BAL in colorectal cancer, among other cancers. There was an initial presentation a couple of years ago in Nature Medicine. This is a follow-up paper in Clinical Cancer Research looking at, Nature Medicine was 77 patients with colon cancer, t his is 123 patients. Nature Medicine was short-term follow-up. This is long-term follow-up, three years of follow-up. There are a couple of really important findings. The first thing is that who it worked in is relevant. It works really best outside of the liver, and there is some interesting biology about that, and we could talk about that for hours. It is not the most relevant point today. But the further from the liver you get, the better things get. Okay? That is very clearly demonstrated in the paper that we just put out. The other thing that we noticed is that a subset of individuals derives deep benefits, like major responses. Some of them, as far as we could tell, like all visible cancer disappeared, which is called a clinical complete response, and that is a great thing. We do not know what that means in the long run because it is just too new, but certainly, no patient is sad if all their cancer is gone from a scan. That is right. The other important point from C-800-01 was that a significant number of patients, and this was a really, really sick population, t hese were not early stage, these were not first and second line, these were late-line patients, a significant number of patients just kept living. They failed to get sicker from their cancer. And that is an important point. Something like 1/3 of patients in this very, very advanced disease population are alive three years out, which is quite remarkable when you think about how bad colon cancer is. And 17% of patients, so around half of those alive, have never gone on to need other therapy for their cancer. There is something called the tail of the curve in immune therapy, and that is different than chemotherapy. Chemotherapy works, then does not work. You get a deep response for a period of time, and then it fails, and eventually it stops working in everyone. Chemotherapy does not cure colon cancer in the advanced disease setting. In an immune therapy, there is going to be a subset of individuals who just keep doing well, and they keep living in spite of their cancer. They may be disease-free, they may be disease managed, it might be the immune system just kind of knows what it is doing here. And those tails of the curve are really important because they are not accounted for in averages. So, you have to look different. You have to look at these landmark points. Like how many people are alive at one year? How many at two years? And now, we can say, how many at three years? And three years is a big number in advanced colon cancer. So, I am very proud of this work. A lot of people put a lot of effort into getting these patients on at a really tough time in the world, and we got them through treatment, and they did well, and there are patients still alive today who I see in my practice because they received those drugs. So, f irst of all, pretty much every trial of immune therapy before surgery or radiation, immune therapy is better than if you do it after. Immune therapy gets better the better the patient fitness, the better the patient anatomy. That is point number one. Point number two, investigators in Italy, in the Fondazione GONO group, the UNICORN study, and investigators in the United States did a clinical trial called NEST-1 and then NEST-2, a nd they took patients with colon cancer, not rectal cancer, and they gave them botensilimab and a few doses of balstilimab, and then they did surgery. And they did it as a test. They gave botensilimab, they gave balstilimab, they did immediate surgery, and, like, wow, the cancer was already reducing even in a few weeks compared to what we would have expected to see at surgery. Okay? So, that was pretty cool. And then it was botensilimab and a little bit more balstilimab, and wait a little bit longer, and the longer you waited, the better it got. The NEST study showed that we could majorly reduce the amount of cancer in a subset of patients, and that is very important because maybe we could reduce it so much we could avoid chemo. And that is a big deal. We have done a lot of work to try and reduce chemotherapy in colon cancer. That is where NEST lies. So, this could be a game changer, of course, for patients who would benefit from it, because I am assuming, Ben, that there are competing priorities here, meaning a surgeon may indulge in taking as much of the organ out as possible so that they can be sure of not leaving cancer behind. Yeah. I mean, colorectal surgeons, I think, are a particular breed. They have led the research on not doing surgery, and that tells you a lot about how these surgeries go. So, I think colorectal surgeons really have weighed in on understanding that a good cancer surgery can have a bad functional outcome. So, I want to give a lot of credit to the colorectal surgeons who've led this field. They deserve a lot of credit for that. Yeah, the problem is the right surgery is rough on patients. We don't want to jeopardize the chance of cure because of a functional issue, but we don't want to jeopardize function if we can cure people anyway. Thank you very much for all of this, by the way. I know that you're a physician who cares about patients because we have referred some patients to you that were in desperate need. Unfortunately, some of these patients, Ben, are very young. Yeah, I mean, it's pretty scary, right? The leading cause of cancer-related death under the age of 50 is now colon cancer. In women, it's going to surpass breast cancer pretty soon, within the next couple of years. That is new. That did not exist 30 years ago. Something is happening that colon cancer is the disease that is getting worse over time. And honestly, we don't know what it is. There's really not a major genetic hallmark. These are just average colon cancers that generally don't respond to conventional therapies, and the younger the patients are, the worse they do. This is, as far as I'm concerned, this is a medical crisis. There should be alarms going off that I've treated a 16-year-old, that like 20s and 30-year-olds are dying of colon cancer. Right. That's not acceptable, and we need to sort that, and we're working on it. But boy, is it painfully slow, and y eah, boy, do we need new drugs. So, Garo, I wanted to thank you and Dr. Schlechter for taking the time to have that discussion. I think you brought up a lot of really important elements and components. Given the time, I know that we have a lot of really important questions that have been submitted, so we are actually going to jump through to answer some of these questions. I am going to start off, Steven, there is a couple of questions here about the ROBBIN design that I think would be helpful to clarify. One question here is, this is a randomized study, it is a phase III program, but given the control arm in ROBBIN does not include a neoadjuvant treatment, how do we ensure that patients randomized to that control arm are going to complete their treatment and not drop out of the trial? I know that is always kind of a consideration, and that was something that we had thought about for the late line setting. Can you comment on that, Steven? Yeah. Well, I mean, the standard of care, this is surgery and adjuvant chemotherapy. There is not an opportunity to get botensilimab and balstilimab in this study, except by participating in the study. We have done this multiple times in phase III trials. It is pretty simple. Patients will get standard of care if randomized to standard of care, or they will have botensilimab and balstilimab, but we do not anticipate that there will be a large number of dropouts because this is the standard treatment. Okay. In a curative setting. So, obviously, patients are not going to jeopardize curative potential. Thank you. I do have one other question for you related to the pathologic response data that we are anticipating in the second half of 2027. The question here is, you touched upon this slightly, but is there a minimum pathologic complete response rate that we believe we would need to ensure confidence in the EFS primary endpoint? I know when we're looking at it, it's on a very small component of patients, considering how many we are going to be treated in the full study. But is there kind of a guidance there, even though it's not the? I'm not going to speculate on that. Yeah. In this setting. I will say that in the neoadjuvant FOxTROT chemo trial, 3% or 4% complete response rate produced a mildly positive study that has not been adopted worldwide because of the toxicity. But let's just look at our data in phase II, obviously, where we're approaching 35%-40% in two independent trials with pathologic complete. So, you can imagine and do the math regarding that. Yeah. Thank you. Thanks for that commentary, Steven. So, Robin, there's some questions here related to the commercial opportunity. We had communicated that the patient population is approximately 30,000 addressable patients within the U.S. that are diagnosed. The question here is how many of those patients get treated in some of these academic centers that have the multidisciplinary teams in place to essentially ensure that if approved and the trial is successful, that we won't lose patients to surgery before they actually have the opportunity to get treated in a neoadjuvant setting? Can you maybe talk a little bit about that and what you're already thinking down the road for when and if the combination is approved in this setting? Yeah. Well, we actually have a nice example in colon cancer already because patients who are MSI-high or dMMR, and that is now a standard test that is performed for all of these early-stage colon cancer patients for whom neoadjuvant immunotherapy may be an option, t hose patients are already tested, whether it's community or an academic center, and a majority of them are going to be referred to get immunotherapy prior to surgery. If you look at the NCCN guidelines, that's the recommendation. So, practice changes when there is data that supports that change of practice. That's what we're intending to do with the ROBBIN study. Our goal here is to be able to generate data that will support a change in practice. If that data is as robust as we anticipate based on what we're targeting for our hazard ratio, or if we see something better, then I fully expect that we're going to see a change in practice. Right. Thank you, Robin. This next question here could be a little bit of a combination, maybe. Dhan Chand, for those that don't know Dhan, he's Head of Research here at Agenus, but this is kind of a combination question. So, there was a question about the recent adjuvant vaccine discontinuation in resectable colon cancer. How do we think about the difference between treating molecular relapse after surgery and priming immunity before it? Does the other product's failure change any assumptions about how we view the competitive window? Thank you, Stefanie. That's an excellent question. In fact, it raises a point that Dr. Schlechter made earlier as well. The best time to prime is when there is a tumor present so that the immune system can recognize the tumor-associated or tumor antigens. When you remove the tumor, you have very little to recognize, very little to prime again. So, that is why in the neoadjuvant setting, BOT+BAL works so efficiently, versus giving it, say, after surgery. And w hat was the second part of that question again, Stefanie? This might be a little bit more for Robin, but essentially, given what you just said, then thinking about what has happened in the competitive setting, does this recent failure of another investigational product change our assumptions or our view of what that competitive window and the differentiation of BOT+BAL? Yeah, no, I think you have got it. Steven is. Yeah. I think Robin can certainly add to what I have to say, but I want to be very clear, that was a vaccine monotherapy in a cold tumor in an MRD setting. In melanoma, there is no PD-1. They do have a PD-1 combo that is still under study. But I think what it says, we have known this for a long time, vaccines, when the tumor is removed in cold tumors, have never been effective. Now, in melanoma, we actually in SWOG S1801 did the proper experiment. We gave a limited number of cycles of, this is hot tumor, where PD-1 works after surgery, and we gave several doses before with an intact tumor followed by after, versus only after. There was a 20% survival benefit in just giving a couple doses of a PD-1 in a hot tumor. In cold tumors, you need better priming CTLA-4s before you can add the PD-1. So, it does not surprise me at all that a vaccine in a cold tumor alone would not work. So, botensilimab is really set up in a neoadjuvant, but potentially in an MRD setting, and we are testing that in combination in cold tumors. Thank you, Steven. Robin, was there anything that you wanted to add to that before we moved on to the next question? No, I think it was an interesting contrast, right? Because recently, Moderna had announced positive data in melanoma with basically a new antigen vaccine. A similar vaccine in colon cancer was negative. Is that a commentary on the vaccines or is it a commentary on the disease setting? Hard to say, but clearly those are very different disease settings in terms of the immunological environment, as Dhan can tell you as well. Yeah. Great. Thank you. This is going to be, I think, a joint question, too, probably for Robin and Steven, and Garo, I am sure you might have some comments. But as you guys know that there has been some additional news this week within the space of MSS colorectal cancer and looking at other neoadjuvant studies. Certainly, the question here, or maybe more of a comment, is what can we do to speed up ROBBIN? I know that everyone is working diligently, v ery large study, robust. The work up front is going to make a difference. But some of this question here is kind of just related to comment on competitors. I do not know if I would say similar to BOT+BAL, but maybe similar mechanism in a certain way, but partnering with other PD-1s in the same setting. Can you guys maybe provide some commentary of that or more importantly, comment on BOT+BAL, the program, and the differentiation, and where we are within the program, particularly in MSS disease? Robin, I don't know what you, y eah, maybe you. I'll start with, [crosstalk]. Yeah, you start, Robin. Dhan and Steven. Yeah. I think part of that question was, what about partnering with a different PD-1? I would say, why would we do that when we have a perfectly good PD-1, thanks to what Dhan Chand designed in terms of a PD-1 that is comparable to existing PD-1s already in the market. There is no reason for us to do that. Secondly, I think the question was approaching, where are we from a competitive perspective? Well, clearly, we are ahead. We are starting a phase III study. We have data. The only other CTLA-4 with data in the neoadjuvant MSS colon setting was ipilimumab. That was actually helpful data for us, but none of the next-gen CTLA-4 presented any data in this setting, and we are off and running into starting up our phase III study. Perfect. Yeah. I might just add that I agree. We are well on our way with 1,200 patients treated across multiple tumor types at a phase III trial. What encourages me about this whole field now is it is coming back to CTLA-4, right? We have failed with TIGIT, we have failed with multiple other targets in cold tumors, thinking that adding PD-1 to a new target or chemo is going to be the solution. The solution is a better CTLA-4 that not only primes and activates memory, it depletes Tregs and it repolarizes myeloid and dendritic cells. Our neoadjuvant data that you will see in the publication already and a soon-to-be publication really reinforces that we have a differentiated CTLA-4 that makes cold tumors hot, and honestly, it reminds me of, it looks like melanoma. So, that is the difference. CTLA-4 is the target that matters the most in broad tumor types. We just need a better CTLA-4, and we have that in botensilimab. All right. Well, thank you. We are a little over time, but I think it was really important to be able to answer some of these questions that were submitted. So, thank you for everyone who stayed a little bit over. With that, Garo, do you want to make any just closing comments before we close out the call for today? Well, thank you, everybody. My colleagues have done such a fantastic job in describing our strategy, the data, the next steps. I think that we're focused on what we need to deliver over the next months, not next year or two. I feel confident that with the team we have right now, we're going to be able to achieve these targets. Thanks again, and we'll see you next time.