Good morning, everyone. Very early good morning, everyone. It is 6:32 A.M. here at ASCO. My name is Yuval Cohen. Thank you so much to all of you for coming here so early. Thank you for those who are dialing in. We seem to have a tradition at Corbus of holding these events incredibly early in the morning, so I apologize for that. We're grateful that ASCO has given us the opportunity to be able to liaise with the conference itself and have this event so close to the conference center. Thank you to the organizers. They were here at 4:00 A.M. this morning, so we're immensely grateful. I'd also like to thank them for upgrading me through medical school, something that has always been my mother's dream. I always had terrible inferiority complexes about just being a PhD. Just for today, I'm going to bask in this MD. Thank you. I genuinely mean it. Thank you for your hard work. You guys are amazing. Thank you for the LifeSci team. Just incredible. A huge thank you to our panel. First of all, for being here so early. Secondly, for being here and giving your time to do this at a time at the most busiest conference on the oncology calendar. Thank you also for the hard work you've done to make these results magically appear on our screen and in our slide decks. I want to thank you and your teams, the other physicians and their teams who are a part of the study, and of course, the patients themselves. This really always has to go back to the patients who are facing such challenges and who made the decision that we're so grateful for, to take this experimental drug and be part of a journey of finding out what it is that it actually does. I'm going to start by introducing the panel, although a quick reminder, these are the three gentlemen that we also had so generously at ESMO as well. I think we're starting a roving band. I'm happy to do so. We have Dr. Ari Rosenberg, Dr. Glenn Hanna, and Dr. Cesar Perez. Very briefly, in no particular order, Dr. Rosenberg is Associate Professor of Medicine at University of Chicago. He focuses on developing novel therapeutic strategies, including immunotherapy for patients with head and neck cancer and thyroid cancer. In 2025, he was named in the prestigious list of 40 Under 40 in Cancer, an award that recognized him as one of the nation's most promising young oncology professional, and celebrated his contribution to lives of those affected by cancer. Dr. Glenn Hanna is Director of the Center for Cancer Therapeutic Innovation at Dana-Farber Cancer Institute. Dr. Hanna is Director of the CCTI Early Drug Development Project at DFCI, and his clinical and translational research efforts focus on precision medicine approaches to treat head and neck cancer. He has special interest in salivary gland cancers and rare head and neck malignancy, and molecular and immunological biomarker discovery. Last but absolutely not least is Dr. Cesar Perez Batista, Director of Drug Development Unit at the Sarah Cannon Research Institute at the Florida Cancer Specialists. Dr. Batista leads an early phase trial for solid tumors with focus on head and neck cancer, and serves as the Executive Chair of the Head and Neck Cancer Research Group for Sarah Cannon Cancer Network. He has served as several ASCO Head and Neck Committees and is an ASCO Ambassador. Dr. Perez is also an Affiliate Associate Professor of the University of Central Florida, and previously co-led the phase I Head and Neck Oncology Research at the University of Miami. Without further ado, what I thought we'd do is I'll start with some questions reflecting a lot of the questions that we've been getting in the last week, basically. Open it up for questions from the audience. Like ESMO, we're going to keep it very conversational and not particularly scripted. We absolutely welcome any questions you have here. I'd say let's start with the number one question I've gotten and my team has gotten since the data came out last Tuesday, which is how many patients are we talking about? If we can sort of deconstruct that question, let's start with before we even talk about the patient number is, what are we talking about? What is oropharyngeal cancer? What does it look like? How do we define it? How are these patients distinct from this umbrella term of head and neck cancer? Whoever wants to volunteer, please go ahead. Ari, there we go. Yeah. I'm happy to take that one. There we go. Thanks for the invitation to be here, and great to see everyone. Great to see you, Yuval, and my esteemed colleagues here on the stage. Head and neck squamous cell carcinoma. Squamous cell carcinoma represents the vast majority of head and neck cancers, about 95%. Of the different subtypes, the one that we certainly in the U.S. most commonly see in our clinic are those squamous cell carcinomas that start in the oral pharynx, which is the back part of the throat, usually representing tumors that start, for the most part, in the tonsil and base of tongue. This is unique compared to some of the other subsites in that these are often, particularly in the U.S., associated with HPV-associated disease, which we now know is a distinct biological type of head and neck cancer, different biology, different response to therapies, different prognosis. We take this into account with every patient that we assess. We also have in the oropharynx non-HPV related disease or HPV unrelated disease, often associated with smoking, alcohol. Certainly in the U.S. and in many of our practices, we're seeing more and more of the HPV-associated etiology of oropharyngeal squamous cell carcinoma, and I'm sure we'll talk more about that, but I think that's the distinctive characteristics of oropharynx as compared to some of the other head and neck cancer subtypes that we see. The only thing I would add is, people have asked, how do we make the distinction? How easy is it to discern if we're going to run a trial with oropharyngeal cancer and maybe not even HPV as sort of a marker of eligibility. Luckily, it's actually quite easy to discern. There's a few things, right? We can examine the oropharynx quite easily. We have fiber-optic nasal endoscopy that can visualize the area, and this is often a very classic clinical epidemiologic phenotype. These are often patients, there's a bimodal distribution, but between the ages of, say, 50 and 70, there's a 5:1 male to female predominance of HPV-associated oropharynx cancer. These patients often present with literally, cystic lymph nodes that they identify while shaving or didn't go away with an antibiotic or steroid. It's not difficult to discern these patients. Even if the clinical phenotype is identified and the primary site is small and there are enlarged neck nodes, you can biopsy and understand the HPV status of the lymph nodes. It's not hard, and this is very ingrained in our community globally. It's very clear that biologically, there's a unique feature related to carcinogen and HPV-negative cancer as related to oropharynx cancer and those that are HPV positive. I don't think there will be questions or concerns from the oncology community about identifying them. I think the only other thing I would say is about the increasing trend in epidemiology. Some of you may be thinking, "Hey, we introduced a vaccine for young kids, boys and girls. What's that going to do to the population?" Well, if you look at projections, and these are actually published now, sadly, vaccination rates uptake has actually been quite poor across the United States and elsewhere, even with mandates in countries like Australia. Unfortunately, the projection today, and this is very important for modeling, is that the rates of HPV-associated and oropharyngeal cancer will continue to rise in incidence while smoking-related cancers decline well into 2040 and projected into 2060. The reason is the lead time to diagnosis. It takes decades, right after HPV oral infection, high-risk infection, to develop these cancers. The population that got vaccinated today is not going to imprint on that decrease in epidemiologic trend for decades from now. I think that's really important. Unfortunately, it's going to take us half a century, sadly, to see the improvements, or shy of a half a century to see improvements in epidemiologic trends. This is not going anywhere in our careers. Maybe our children's children, but not in our careers. I should point out that our IP does not extend to 2050. Yeah, just in case somebody is wondering, there you go. Yeah. I'll just add to what my dear friend's here mentioning. We have to know that over the last 20 years, the incidence of squamous carcinoma of the head and neck hasn't changed much, despite decreased rate of smoking, the main reason is what Glenn is mentioning, right? The smoking-related cancers are trending down, oropharyngeal HPV-related is trending up, unfortunately. That's what has kept the incidence kind of fairly stable over time. I think it's important that we have to highlight that the difference between oropharynx, which is mostly HPV-related, although some can be HPV unrelated, has been highlighted after we even changed the initial staging, right, several years ago. We have even a different staging up front. As Glenn is mentioning, we'll recognize that this is a different site, right, with a different behavior and even a different staging for the HPV-related oropharyngeal. It's well recognized in the community that these are different entities. Dr. Perez, I want to follow up on that with you and the rest of the panel, because I think there is an interesting dynamic, right, between even geographically, if we think about different places in the world, we have, quote unquote, "The West," where, as you mentioned, Dr. Perez, those of you who've noticed the youth are no longer smoking or particularly drinking. We have places such as Asia or South America, where it's still very much a lot of nicotine consumption. Yeah. smoking consumption, and it seems to be sort of two dynamics between these two populations. Yeah. You touched upon that a little bit. Can you expand on that? Yeah. I think that's quite interesting. It's very nice because, for good or for bad, I have been traveling the country over the last 15 years, right? I started my practice at University of Louisville, where my HPV-related oropharyngeal, they were all smokers, right? When I came back to Florida and South Florida, then suddenly most of my squamous cell carcinomas are actually pure HPV basaloid just because of the geographic difference. There are geographical differences not only in countries, but within countries, about what patients actually present to our clinics. It depends a lot on smoking incidence and also in HPV prevalence between different populations. Yeah. We're all in geographic areas throughout the country. In Boston, we see a large catchment of HPV-positive patients, often just by nature, white collar, coming to academic centers in that age range, male, often limited or never smokers is sort of the population of interest. I would completely agree. I think when you go to Europe, there's a higher incidence of smoking. I was talking to Jean- Pascal from Brussels, and he mentions that many of his oropharynx cancer patients will be HPV negative. You go to Asia, and the rates of HPV positivity are quite low, and there are different epidemiologies, like EBV nasopharynx and things. I do think, and this is important when thinking about the trial, which is largely likely to launch in the U.S. and North America, there is a tremendous population. We'll get to it, but obviously the therapies that have been evaluated that are in phase III trials don't address this population at all. Just to illustrate and build on what Dr. Perez was saying a little bit as well, which is I trained on the north side of the city, and in that population for oropharynx, 90% were HPV positive, and it's probably even higher now than it was at that time. Where I practice now on the south side of Chicago, it's a bit of a more mixed population, and even there, the vast majority are now HPV positive. What we're seeing in our clinical practice, I think echoes what the epidemiological data is describing in terms of trends. We certainly, in retrospect, luckily saw the same phenomena. Our sites were initially activated in the U.S., then into Western Europe, and then further into parts of Europe that are much heavier smokers. We've seen that in our own data where those populations where we have a lot of smoking, we had very few oropharyngeal patients coming in there, and therefore relatively very, very few responses. In retrospect, that was actually a very helpful insight ahead of launching a registrational study. Let's dive in even deeper and start to put maybe some numbers on it. If we think about, again, North America, Western Europe, if we think about this late stage of the disease, think about head and neck patients who have failed their frontline and are moving or eligible to move to second line, how many of those patients are oropharyngeal? We've done some of our own third-party epidemiology, I say this in the context of a narrative that I think a lot of us have been exposed to from the EGFR bispecifics, where quite rightly, and in a very sensible manner, we're focusing on the other part of the population. I think that created a certain impression that we're talking about a small number of patients. Again, in no particular order, how many patients do you think there are out there? Even from your own practices, Dr. Rosen, you mentioned that a little bit, on a daily, weekly, monthly basis, what are you seeing walking through your doors? Yeah. This is the vast majority of patients that we see in our clinic. Of course, in head and neck cancer, we do cure most of our patients with multimodality treatment. That being said, even when we're talking about oropharynx or even the best prognostic patients of oropharynx, which are the HPV-associated patients, with our definitive treatments, it depends where you look, but 15% to even up to 25% of those patients will develop a recurrence. With the increasing incidence, we see more of that now than we used to, and we, I expect, will continue to see more of that. I think that's also reflected as you look through the phase III trials. A higher percentage of recurrent metastatic trials that are all comers in head and neck cancer are having higher percentages of patients that are oropharynx and HPV-positive oropharynx as well. I think some of the older phase IIIs were 20%, 25% HPV-positive. Many of the global trials are a third, and the U.S. trials that are enrolling now frontline recurrent metastatic are 40%, 50% HPV-positive oropharynx. I think it's a combination of the overall epidemiological trends, acknowledging that it's a favorable prognosis for that group, and a subset of those patients will recur. With the epidemiological trends as they are and the recurrence rates as they are, despite them being low, the absolute number will, I think, continue to trend up is what I expect. Yeah, certainly at our clinic, the vast majority of new multi-D cases, probably five to six a week, and we see about 700 patients a year at Dana-Farber in the head and neck program, are going to be HPV positive patients that need treatment. I think, again, if you take static numbers now, as Ari said, you increase projections over time. If you look back at SEER data, there's about anywhere around 43,000- 45,000 head and neck cases a year in the U.S. If you think about the larger percentage of HPV positive, and oropharynx as a subset, because they're actually teased out as oral and pharynx in the SEER data. You're talking about maybe 25,000, 30,000 patients, the vast majority of which would be HPV positive. As stated, if upwards of 25% of those patients in their lifetime will need recurrent metastatic treatment, you're now approaching greater than 10,000 or approaching 10,000 patients in an increasing trend. This is a large and growing population. I think the lower end of the estimates are well around 7,500- 8,000. The higher-end estimates approach 10,000 or higher patients. That, again, is continuing to rise. I think the other thing that's important and is even though the patient population may be that number, the motivation for these patients to come for trials is skyrocketing. I'm going to make a real but sad statement. Patients with HPV negative cancer who smoke are often older, marginalized, and not able to access clinical trials or willing to travel. I'll tell you right now, every 40- 50 year-old man or woman who gets HPV recurrent metastatic disease gets on a plane from wherever they are, makes their way to a center for the next best treatment. It is the patient I see most commonly in second, third referral, is patients who are post-immunotherapy, in fabulous shape, and in need of something. If they don't get a drug like these ADCs, they're getting basic chemotherapy that we know doesn't really work all that well. EGFR inhibitors are not an option, and it's game over. There is a tremendous need for antibody drug conjugates like this one in the armamentarium right now, and this trial will enroll incredibly well, probably ahead of projections. Again, it's not just about numbers. It's about how many patients are motivated to come for treatment. I'll make one last statement about this. I'll flip it and say the HPV negative EGFR novel agents, we're all involved with them. Some of them have struggled to enroll in the U.S. because those patients are not able to easily get to academic centers for these trials because of the socioeconomic and demographic realities of those populations. It is not the case. That is not the case for HPV disease. These patients are ready and willing to participate in new drug trials. Yeah, I 100% agree. One thing is just the deselection. All of us, we have treated patients with chemoradiation that have HPV-unrelated disease, and eventually, sometimes the patient, they don't make it to first-line recurrent metastatic treatment. Because of the comorbidities, because their disease is so aggressive or high bulk. Kudos to those companies that are addressing this population, even in the curative setting, because that's what they need. They need better therapies to be able to sustain a response. Now, I will ask my colleagues how many HPV-related oropharyngeal cancer patients you have seen that when they recur, they cannot get first line. It's very few. Almost none. Actually we have to treat them. It's true that as Ari has mentioned, we cure 80% of this population, but one out of six or so will recur, and all of them will actually go into recurrent metastatic therapy. Just because these are fit, motivated patients, usually highly educated, and all the social issues that Glenn is mentioning. The same token goes to second line. We lose a lot of HPV-unrelated patients after first-line therapy because of comorbidities, because they're sick, because the disease is very aggressive. When you see the KN-048 curves, those patients that drop on the first two months of the KN-048, they are mostly HPV unrelated. The patients that we lose with HPV-related squamous carcinoma in the first-line setting or second-line setting are also a very smaller number than the unrelated. These are motivated patients, healthier patients, and more fit for therapies. That's important. I think today in my clinic in the last six months, the number one advanced patient referral is a second, third-line motivated HPV positive patient post-IO who says, "I'm not getting chemo. This is not going to work. What do you have for me?" This is why we believe in and are sitting here now, six months, 12 months later, enrolling to ADC trials that have transformed other areas of oncology. Yeah. These are patients, just to echo, that they get immunotherapy wherever they are or chemoimmunotherapy wherever they are, and they come to academic centers in second line looking for a trial. Yep. That's where the referrals come from. That's where the vast majority of our referrals come from. That's where our colleagues who treat a lot of head and neck cancer are looking for trials, in dire need for trials because they have all these patients, and this is the type of trial that we're looking for this population in our clinic. I'm going to ask a loaded question because, again, thinking about this audience, we hear so many exciting things about head and neck and these EGFR bispecifics and see some incredible acquisition recently in that space and big pharma moving into that space. For an audience out there, or even a layperson listening in, how do you square the fact that what we're hearing here is, yes, there's some very exciting new modalities called EGFR bispecifics, and yet you're describing a patient population that has few to any options, and that represents, in this later stage of the disease, such a significant part of the patient. Help the audience understand, where is that paradox? I'll go first again. I think we've recognized the fact that in the recurrent metastatic setting, EGFR targeting is a strategy for the HPV-unrelated population. That's where we've seen the efficacy. I think for me, the big takeaway was when we saw the negative INTERLINK-1 results, which was the phase III that randomized cetuximab with or without monalizumab. [Cetu] monotherapy response rate in HPV-unrelated was 24%. If you back calculate, it's 5% or less in HPV positive. In my practice, that's not something that I think about. I don't think about EGFR targeting for HPV-associated disease. That's a strategy where we need a different therapeutic strategy, and that's also where we're seeing the signal for the ADCs. We can discuss all the different reasons why that might very well be the case, but it's a totally different population. Although historically, head and neck cancer has been a one size fits all disease where all the trials have enrolled all the different subtypes and that's been the strategy, we now know these are different diseases, and these are different populations, and there's actually very little overlap. I would just keep adding. Remember, amivantamab, and we saw data yesterday from OrigAMI-4 in the second line as monotherapy, and ficerafusp alfa are exclusively HPV negative trials. That's hard written in, and that makes sense biologically, as Ari just outlined with some of the results. We know that EGFR is not a critical pathway for modulation in HPV disease. It's E6, E7, modulation of Wnt/β-catenin signaling, Rb, p53, and then we know these surface expression markers like Nectin-4 and others are important. The other point to be made is you might say, well, there's petosemtamab, which based on its unique mechanism of EGFR LGR5, has been teasing that there is some interest and activity in HPV positive. If you look at the data very carefully, you'll all realize it's a very small subset of patients that have so far been presented, and it does look inferior in response rate in the HPV positive population. It's also public knowledge that despite them enrolling HPV positive in the first-line combo with pembro trial and the second-line LiGeR trial, they've paused enrollment and capped the HPV positive enrollment at 30% or so and increased enrollment by several hundred patients to both trials. I think, again, this is my opinion, I'm not informed in this, that tells me they're seeing something where they need to clarify the difference between signal. That's a long and complicated but important way of saying I think all three of these are going to be HPV negative drugs. I think ficera, petosemtamab, and of course ami are largely HPV negative. That leaves an entirely untapped, untouched, immediately in-need market and population for not only second and third-line HPV treatments as we're talking about with this trial, but even in the future, a combo first-line option for HPV positive patients with something like maybe a Nectin-4 ADC plus pembrolizumab. Yeah. I think we have to acknowledge there's a small overlap just in patients with HPV-negative oropharynx. That's always a very special population, but it's a fairly small population in general for everything that we treat. They might be that small overlap between these agents, and they all can work, and hopefully those patients will have more options. The PD-L1 of less than one, it's also an untapped population that hopefully we can address in the future. We have seen activity of 701 in patients with PD-L1 of less than one. I think that's another untapped population that will require novel therapies in the future. Certainly it's exciting for us to think that in five years, the NCCN guidelines maybe, and just maybe, will look completely different and will be a lot more elegant for our patients. That's what we're hoping with. Let's switch for a second from the EGFR bispecifics, et cetera, and talk about our mechanism. We have a Nectin-4 ADC targeting it armed with MMAE. We're not the first foray into head and neck with a Nectin-4 MMAE. There's a little-known drug called PADCEV that dipped its toes in there, and Dr. Rosenberg, you are certainly very involved in that. Maybe a little bit about what was seen in the first, the second line monotherapy study, I think that was 2023. This, I thought, a really remarkable poster last year at ESMO and the subsequent publication. What did we learn from it that's applicable to us? Adding to that, to yourself and to the panel, what are some of the challenges that may hinder PADCEV in moving forward into head and neck that perhaps are less of an issue for us? I'll start by the fact that obviously Nectin-4 expression is quite high in head and neck cancer broadly, close behind urothelial, and that does seem to be enriched in HPV-positive patients. There's been a number of papers that have described that as well. With enfortumab, both the second-line study and then in frontline, there was activity as you alluded to, and that activity across both studies was enriched for the HPV-positive population, which is what one would expect when looking at an ADC targeting a target that's overexpressed in a given biomarker-selected population. In the frontline study, it was a substantially higher response rate in the HPV and oropharynx in particular, even though it wasn't selected for a particular anatomic subsite. I think those were some of the key takeaways. The toxicity profile of enfortumab is now very well characterized, and much of it is driven by the free MMAE that leads to, I would say, most notably peripheral neuropathy. Patients with head and neck cancer have received platinum, they've received taxane oftentimes, and these are patients that already may be predisposed or have some predisposition to peripheral neuropathy, and that ends up being a dose-limiting toxicity in terms of optimization. We'll talk more about the mechanism of this particular agent, but I think any way to reduce some of that cumulative toxicity, which is dose-limiting in the clinic, not just by the way in our head and neck trials, but also my urothelial colleagues have this challenge as well, which is how do you keep an active agent going when you have this free MMAE-driven peripheral neuropathy toxicity? I think that's the one that I would say the most. A couple of additions. I think number one, Nectin-4 is a validated target. EV is an active drug in head and neck cancer. Let's put to rest that the target is important. It is important. I think that's the first thing we learn from the EV story. From both the first-line JCO publication, 20%+ response rate in a highly refractory population, and then the more recent combo data for head and neck. The second is, and I believe this is public because I've heard it from outside of closed doors, PADCEV has been deprioritized in head and neck cancer. That is public information. Astellas was toying with the idea of moving forward with a registrational study, but unfortunately, that was not a priority in the discussion with Pfizer, is my understanding. Again, that's public information that I've heard discussed. It's a moot point, and what I would say is if you have a Nectin-4 ADC and a validated target and the friend next door is not moving forward, you take advantage of that population, and that's why we're all sitting here. I think the next thing to think about is the schedule. The fact that it's a Q3-week schedule. PADCEV is day one, day eight. That's cumbersome for patients, even if an EV option was available. I think what have been the successful ADCs in head and neck oncology to date? Nothing's in phase III or approved. Every single thing is a vedotin. We had Tivdak. We tried with [SASI], but the response rate was too low. We had EV. There was data for the ROR2 bispecific from BioAtla. We're seeing data from micvotabart pelidotin from Pyxis that looks compelling for head and neck. Vedotins so far have proven efficacious in patients with head and neck cancer. A big question is what will TOPO1s and [exatecans] produce? While it's very rational biologically, those might be a little harder on head and neck patients who are otherwise a little bit fragile after chemoradiation. We don't know yet, but those trials are ongoing. I think for me, when I think about Nectin-4, MMAE, auristatin, vedotins, and sort of moving that into a larger trial, it very much makes sense, and I think this is an open space to run with. Yeah. It's nice to remember where we came from. A little more than two years ago, I remember they sent us this trial and to our network and then like, "Oh, that's [AMID] to enfortumab," and then nobody wanted it. I was like, "Would they take head and neck?" They're like, "Well, it says that they take head and neck." "Okay, I'll take it." Then we took it then back then based on the activity that PADCEV already demonstrated. Right. It was already published. The interesting that it's very important what Ari's saying, that it is very similar, Nectin-4 validated target. We have an MMAE proven activity already with several different ADCs. Somewhat is not exactly the same, mainly because there's less free payload. The DAR is two instead of four. Certainly in my opinion, even though we have some toxicities that we addressed, a more elegant molecule and more of the magic bullet concept better demonstrated. The peripheral neuropathy that we have seen is honestly not even significant. It's not even a thing. We haven't seen things that we have seen with other MMAE-based ADCs, hyperglycemias. I probably have treated more than 80 patients with non-approved ADCs, MMAE-based ADCs, and you deal with liver abnormalities. You deal with hyperglycemias, bad neuropathy, bad rashes and something. We don't have those problems mainly because we have more target engagement and less free payload. Yes, it's very similar to enfortumab, no, it's not the same. Following on that, there's no such thing as a free lunch. Yeah, correct. Mm-hmm. Right? This is still a targeted chemotherapeutic agent. Our good friends at CSPC created this very novel ADC that seems to have engineered out issues such as peripheral neuropathy and skin, but there's a price to be paid, which is the surface of the eye toxicity. Maybe contextualize how you're dealing with that with your patients. For those of you who have experience, how does it compare to other ADCs with similar ocular toxicities? Maybe also refer to this dichotomy we're seeing between the rates that we're seeing for especially Grade 1 and 2, but juxtaposed with a discontinuation rate that seems to be very low. For those of us that have been using the agent for a while now, it's become quite protocolized, like many anti-cancer therapeutics. Patients see an ophthalmologist to take a look at their eyes before we start. We talk to patients about it and let them know, just like we do for every drug that we use in cancer, about what to watch out for and what to let us know about, and ask them when they come in for their treatment every three weeks. Importantly, as we've had more experience with it, if patients develop some of the ophthal symptoms we've become quite comfortable withholding, and it's reversible. It improves. We can usually restart, and it becomes a toxicity management, which as oncologists, this is our bread and butter. Amazingly, it's not everyone also. Many of the patients, we caution them. We say this happens to some, not to others. We get into it, and we don't see any of that. I think it's become something relatively routine, and it's something that we look for, patients look for, we manage. Patients are good about their eye drops and their prophylaxis, and we tell them that that's important, and these are motivated patients that take it to heart, so they're going to let us know if they notice something. These are very adherent patients. These are patients doing their prophylaxis. This is toxicity management. This is what oncologists know how to do. This is what we have experience with any cancer therapeutic that we use. I think that's been my experience at least. I think as we're all up here experienced with ADC novel therapy, but let's step back. Antibody drug conjugates are essentially another way to deliver chemotherapy in a payload or warhead mechanism. If we look at broad drug development, I often think about what will take patients off of drugs. If you develop intractable and unrelenting neuropathy that's not going to reverse, you're going to come off a drug. If you develop severe mucositis and you've already had head and neck radiation and you're nutritionally compromised, you're going to come off a drug. Cytopenias that are uncontrollable with growth factor, et cetera, or limiting pneumonitis or inflammatory lung disease, all of which we just discussed just now are not major issues with this drug. For me, ocular toxicity, let's just put it out there. It sounds scary. It's vision. That said, Grade 1 is no symptoms. That means you're just doing routine eye exams, and I would argue that patients after the age of 50, learning from the dato experience, if I took all of you in the room and did an eye exam, I would put money down that half of you have some mild inflammatory changes on your eye. I'm almost certain of it. That's one thing. How many people are just walking around with this that would never have otherwise been identified, but we needed to be careful and cautious in screening? The Grade 2 question is symptoms. These are patients who have maybe dry eyes. I wear contacts. I can justify that I know what these symptoms probably are like, and I've had keratitis when I was younger. I know what grainy inflammation feels like, and I know what irritation feels like. The worst end of a Grade 2 is maybe that your driving's a little impaired and you're not going to night drive because your eyes are feeling a little bit off. As Ari said, there's been a nice mitigation strategy, quickly adopting by giving patients upfront eye drops. Here in the registrational study, the plan will actually be to provide a kit so that there's no issues with access to drops or picking them up so that the patient is informed upfront. The other question is, well, what about access to ophthalmology and the exams that are needed? Again, I'll reference a fully approved drug, datopotamab, which requires eye exam at baseline, eye drops, and follow-up exam, and there doesn't seem to be any issue there. There are slightly higher rates of Grade 1 to 2 AEs related to ocular toxicity with CRB-701, it's not that far off than what's been described in large dato trials. Again, we already have comfort and principle, and ophthalmologists are comfortable with managing and seeing patients who have ADC as a potential therapy. I think there are plenty of optometrists and ophthalmologists available routinely to help follow these patients. Again, it's not all the time. These are baseline exams dictated as needed to follow up on any resolution. As Ari said, this is not taking patients off trial. It's not taking their vision permanently when they discontinue. This is you notice symptoms, you address them, and see an eye specialist. You're more vigilant. You might reduce the dose, and you stay on the therapy, and it becomes manageable. It's not an intractable neuropathy. It's not ILD that almost kills you with hypoxemia. It's not intractable mucositis or cytopenias. Again, no free lunch, but I do think as we've gotten more comfortable and knowing the landscape of ADCs, there are other drugs on the market where this is an important toxicity that's already being addressed in the community. Yeah, I think we have learned over the last two years on how to address this better. Personally, now I know that when somebody tells me that they have photophobia and lacrimation and their sight is fine, I'm like, "Oh, okay. Wait, let's just take a break there." Truly, the issue is that even when we hold the therapy, the biological half-life of 701, it's so long, right? That patients can just skip a dose altogether, and the next scan, the tumor will continue to be shrinking. That's what we learned, to be proactive and making sure that the minimal symptoms that the patient had, that as Glenn's mentioning, then that will translate to a Grade 2 toxicity, then we have to stop therapy. Now that we do that and we hold the therapy, we don't stop, we hold the therapy, and eventually it will just come back to normal and patient's back to baseline, we can always resume. Because of the reversibility of this issue, then there's so few patients that have actually had to come off study because of adverse events. In general then, I will dare you guys to look in all the data of all the ADCs, all the TOPO1s, and see the amount of discontinuation because of adverse events, and you compare to the data that we have, and our amount of discontinuations is very, very low. Mainly because when I present this trial to my patients, I tell them, "You can have this issue," but I treated, what, Yuval? What, 34 patients, Yuval? Something like that. I have treated 35 patients myself with this drug, 34, 35, none of them had end up in the hospital because of an adverse event. That's a big thing. That's a big thing, because these are patients that obviously some of them are delicate. Some of these patients have been in fourth, fifth line, for HPV-related or for anti-angiogenic therapy cancer. It's very, at least fulfilling for the oncologist that we are giving you something that at least I know the chances of a life-threatening event are minuscule. That's the first. The second thing is that when I was a fellow, 17 years ago, the CAR-T therapy came, it was this testing issue. Access to testing. They had a lot of things to overcome at that time. That is same issue with ophthalmology, with rituximab. [Elahere] came to the market. Tivdak. [rovoltuma], and all these things. Now we have no contact ophthalmologists. Guess what? Now most of the oncologists now they have access to ophthalmologists because we have four different ADCs that are approved that need some monitoring, ophthalmology. We usually now have access to that, and that's very different than six years ago. In practice, most of us, in practice, have access to ophthalmologists even outside this random trial. It's not that much of a limitation. It's a real AE. It is important for quality of life, but it's something that we can manage and the community oncologists now is getting more used to deal with. Last question from me before we open it to the audience. We talked a lot about the current study and reminder, we'll be launching our registrational study in second-line monotherapy setting this summer. There is another study happening in the background at your centers, which is a study looking at combining CRB-701 with pembro, in the frontline setting. Again, Dr. Rosenberg, you've had experience in PADCEV plus pembro. Dr. Hanna, you've had experience in the Bicara settings. We've had petosemtamab also plus pembro. Pure speculation, of course. We have no idea what the data looks like. We're hoping to start to get the first flavor of efficacy early next year. What could we look at? What could we seeing? What is the unmet need, again, in those patients that's starting their late-stage journey? Do these mechanisms like to play together? I guess that's my question. Yeah, I think we've seen most of the data's initially been from the bladder space, where we've seen incredible synergy between Nectin-4 ADCs and immunotherapy. I remember seeing those curves from my colleagues in the GU space and saying, "Oh, my gosh." Right? I don't know if even they expected to see that kind of efficacy when you combine immunotherapy with Nectin-4 ADCs. In head neck, this is an immunogenic disease. Oftentimes, there's parallels between urothelial and head neck cross drug development. I think that is important. The alternative is chemoimmunotherapy, [KEYNOTE]-048 chemoimmunotherapy, Grade 3 tox over 85% in that study. Obviously, we use a lot of pembrolizumab monotherapy, but that's suboptimal in terms of its efficacy alone for many of us. We use some carboplatin, but that also has neuropathy as a major dose-limiting toxicity. A lot of opportunity in that space as well, in my opinion. I'll just add to the idea of existing tox in combination. When we're talking about manageable eye issues, that's a pretty rare event actually with pembrolizumab to see an immune-mediated ophthalmologic issue. It's less than a few percentage points across global studies. I think it's really nice in lending to a partner. I think we've learned, as Ari said, we've already validated the potential synergy from urothelial with EV plus pembro, and there is, as you may know, data now accepted and published. The manuscript I think is out now. EV plus pembro in head and neck, the response rate for us looks quite good. There's clearly, it was around 43%-44%. Again, validated target, nice possibility for combination. This is where the field is going. Everyone is excited about ADC plus IO as a new way to replace traditional cytotoxic agents. That paradigm has got years to go. I think all of that really makes sense, and you could imagine a first-line trial, maybe not today. I think we all agree that this is the right study to do now, but let's say there's an approval for this agent, bringing this forward to a oropharyngeal or HPV-positive population in first-line with CRB-701 pembro is a very contemporary option, which doesn't overlap at all with the largely HPV-negative drugs that are hopefully going to be on the market and changing lives in the next year or two. I think this is a very clear registrational path, not just for the current study, but actually for a future study, and even taking it one last step further, we have KEYNOTE-689 with pembro neoadjuvant. Everyone and their brother, including all of us, is looking at what's the next partner for pembro to modulate upfront path response and event-free survival in resectable head and neck cancer. It's no surprise that chemoimmunotherapy ADC-IO is where everyone is looking. You could see that this drug could move forward very nicely to multiple phase III trials and registrational opportunities across the disease spectrum. Yeah, I think one of the things we learned from bladder is that we don't have to select by PD-L1, right? That's because of the high Nectin-4 expression, and that's a good thing. Right. One of the limitations of the current trials, not only that this probably for a different population as Dr. Hanna is mentioning, but that is usually HPV-related, and this will be non-oropharyngeal mostly. Also because still, even when these agents are approved, the committee will continue to use chemo in some patients just because they want a fast response, and this will be only approved for PD-L1-positive disease, right? My hopes will be that somewhat we can demonstrate a strong signal on oropharyngeal cancers in the first-line setting with pembro unselected by PD-L1 because that is the only way we're going to replace chemo as it happened in bladder cancer. That's my hope. That's how it should be. Fingers and toes crossed. Okay, we have a few minutes for questions from the audience. I'm not sure Wilson, do you have a microphone? I'm going to start with Brian Abrahams, if I may, here in the front. Oh, there we go. Thank you. Thanks. Thanks, Yuval. Thanks to you and the team for putting this together, and thanks to the KOLs. Maybe just a few questions for the physicians on the panel. I guess first off, as we think about the registrational study being focused on oropharyngeal rather than necessarily honing in on HPV positive, are there any considerations that the company should think about in conducting the study just to ensure that the vast majority of those patients are indeed HPV positive? What will you guys be looking for from the overall response rate here and that could warrant accelerated approval to be kind of excited about using this? Is it 30%, 40%, 50%? Lastly, of the 7,500 - 10,000 recurrent patients that you talked about, I guess, in what proportion could you envision using 701 versus chemo or an experimental agent or another ADC on or off label? What are some of the sensitivities around how the response rate that might dictate the accelerated approval would dictate the degree of use of this agent? Maybe each of us could take one of them. Yeah. I'll take the oropharynx question. There's some registrational and agency-related considerations here and realities about time and prediction. Oropharyngeal cancer in the United States, 85% and probably at our centers it may even be higher, are HPV-associated or causal. That being said, even in patients who have mild or moderate smoking history, HPV may still be causal when those two overlap. That is certainly a little bit less, maybe closer to 60% in Europe. You have to balance that out. I think we have communicated with the company about what site selection makes the most sense. This trial, I imagine, will open in the United States and North America very quickly and enroll that dominant HPV-positive population. I think the realities are that despite P16 being widely available as a surrogate marker for HPV and HPV-ish testing and RNA testing and PCR testing available at many centers, there is not one standardized assay, and the FDA would absolutely require companion diagnostic evaluation, which is cumbersome, costly, and completely unnecessary for our field, where we already use these tests routinely in practice to make prognostic and treatment decisions. We agree, pros and cons balanced, that approaching an oropharynx population will enrich heavily at the sites of interest, and that was where we worked closely with the team to decide and identify colleagues across the country who treat patients similar to ours, who would enrich for this population, and then collect that information retrospectively, account for it in stratification between both arms, and go back and look and ensure that you have a strong, robust signal of P16 and true HPV causality across the trial. The interim analysis will also lend to assessing that, and I do believe that that will be a moot issue. I think for those reasons and largely the registrational component of avoiding a CDx, it makes the most sense to pursue the anatomical definition. Which, by the way, there were other companies thinking about a similar strategy. This is not unique to the Corbus drug. Yeah. I could take the response rate one. I think we've seen in the post-IO era that chemotherapy has around a 20% response rate in head and neck cancer. I think if we're looking at response rates in the arena of 30%, 40%, that's kind of a no-brainer, right? If you're a patient in that setting, the response is important to you. I think the other thing to think about is that patients don't like chemotherapy. They don't like chemotherapy. They're looking for alternative strategies. I was going to mention on one of the earlier comments, we were talking about the experience with the eye toxicity. It's actually been amazing. To Cesar's point about some of these patients on the study have this durable response because of the half-life. I have a conversation sometimes if we have to hold the drug for a bit to allow the eye tox to improve, and patients see their scans and they say, "No, I'm not going on chemotherapy. Give me a little more time." I actually have been amazed by that. Patients don't like chemotherapy is the point I'm trying to make. I would say that's the response rate and the paradigm in the post-IO era. Okay. of what we're thinking about, looking at, and what patients care about. Yeah. I think to answer your question about what happens in second-line, the reality that is going on in U.S. is the following. We have the KEYNOTE-048 as the Category 1 recommendation, but it's very commonly physicians are using carbo, TAXOL, pembro in the first-line setting. There are five drugs in head and neck cancer. That's it. You got cetuximab, right? Doesn't work for head and neck cancer. You have 5-FU that doesn't work for HPV-related. 5-FU, which is not really great for HPV-related either. You have carbo, taxanes, checkpoint inhibitors. When the most common regimen is used for an HPV-positive patient, which is carbo, TAXOL, pembro, and they come to us looking for options, guess what? They already burned the three best agents up front. The responses that you see in the comparator arm for CheckMate 141 are mostly driven by the docetaxel, and that is the reality. In the reality, when these patients will come into a second-line trial and they already got carbo, TAXOL, and pembro, most of us will be a little bit stuck with the other comparators that are actually inferior. You can say that second-line therapy for head and neck cancer brings a response rate of 15%, but the reality is that nowadays when these trials are enrolling, the patient will already have been exposed to taxanes probably, platinum, pembro, the physician that will have this patient will face the reality that we face every day. Recycling taxanes, right? Just giving another regimen that is not ideal. That is the problem for oropharyngeal cancer patients. There's no good second line. There's none, right? That is the reality that we face. Should we cap it to 20% HPV unrelated? Should we just leave it, just run, just based on the epidemiology? I think Corbus will make that decision later on, but I just want to remind you guys that my first responder on this trial was a HPV-unrelated patient at the 1.8 milligrams per kilogram dose. It's not that it doesn't work, right? It's just that there's a little lower response rate, and thus we have to focus where the responses are. Even though it might bring it down, right? That doesn't mean it will be zero. My point with this, I think that we're tapping in the right population, the oropharyngeal cancer population for the reasons that Hanna mentioned, is the most practical thing to do, not only in a trial, but also in practice. I don't foresee how this could go wrong. I think this is the right thing to do. Okay. We got about 10 minutes. Paul Jeng, please. Oh, there we go. Hey, thanks. Paul Jeng, Guggenheim. For the doctors, I think Dr. Hanna, you made a comment that head and neck patients tend to be fragile, but also that HPV-positive patients are younger and perhaps with better fitness. Just wondering, how does that impact how you adjudicate or manage adverse events for these patients versus perhaps non-oropharyngeal? Could a trial that only enrolls oropharyngeal have a greater prioritization perhaps for dose intensity versus managing adverse events? I have a follow-up. Yeah. We talked a little bit about this. These patients come out of first line as stated. They're still fit, they're still working, they're ready to go. Giving them an ADC that has a manageable toxicity profile where we're just talking about maybe eye drops is not going to likely hinder their ability to continue to work and live their lives. I do think that the benchmark for being able to tolerate some toxicity on a physical level is higher for HPV patients because of their fitness and because of their protoplasm. You could flip that argument and also say that if a drug worked really well but was very toxic on many multiple organ systems, people would discontinue it because they're still working and living their lives. There's that balance of what they're willing to tolerate and what you're willing to tolerate as a physician. I think the nice thing about this ADC, again, as highlighted previously in our discussion, is that other than managing eye drops and monitoring for occasional other AEs, this is a tolerable drug that patients can stay on and have reasonable quality of life. I don't think there'll be any issue enrolling to the study. Frankly, as highlighted by Cesar, there are no other good options. It's this or methotrexate, which some people think is actually unjust to give patients because it's so inferior in its activity level, or oral capecitabine because they got a taxane, and that's a 5-FU-like agent, or cetuximab, even though we know it doesn't do anything, frankly, in HPV positive head and neck cancer as a monotherapy. You're recycling old drugs. I think this is a no-brainer, and that's why the trial has enrolled so well. Great. Second question is for Yuval. You alluded to this during the discussion, as you ramp towards the phase III study starting up, are there any unique considerations in terms of sites and enrollment based on the oropharyngeal focus? For example, do you expect a different distribution of centers or pace of enrollment compared to your EGFR peers perhaps? How does that factor into ex-US enrollment as well, given the different rates of HPV positivity around the world? I'd say as a rule of thumb, you want to avoid countries with very high level of cigarette smoking and focus, as Dr. Hanna mentioned and others, on North America and Western Europe. Panel, any thoughts on that? I think there should be some involvement globally. That's the right thing to do. I think the FDA will want to see a largely U.S.-based population. We've already seen drugs that have had to redo entire trials because they come out of Asia, and there are changes in the epidemiology and how drugs are processed across populations. I would agree. My prediction is this trial will open in a largely North American population first, and they will be going very quickly and hopefully open some sites in Europe and perhaps in Asia. I think there are other studies that with HPV negative focus prioritize countries like India, where there's tremendous unmet need and maybe more Asian sites, et cetera. I don't think that will be an issue. I think the population that's being investigated here will be representative if it is able to achieve a label. Ex-U.S. is also seeing increases in oropharynx cancer. Sure. HPV associated as well. Andy? Speak loud, please. Thanks for this session. Super informative. I think during the last call last week, you mentioned about oropharyngeal subtype having a higher response to other therapies, including chemotherapy. I guess from a powering assumption perspective, as we go into the registrational trial, how do you think about the comparator arm? Do we have epidemiology data or clinical data that would suggest within the oropharyngeal subtype, what is the comparator arm going to look like in 2026? HPV-positive patients, you'll hear some of us say in blanket that they do better, quote, "with almost everything", EGFR inhibitors aside. They have a different biology, and they tend to, for whatever reason, respond well to platinum agents, et cetera. That being said, think about the context of the disease state we're talking about. This is post-IO. This is now post likely platinum or 5-FU. We're already out of chemoradiation. We have to benchmark against what would be the historical response rate. We already outlined it's not well-known because there haven't been any readouts of HPV-only second-line, third-line trials in this space. From what we can tell from subset analyses, we're talking about 15%-20% response rates in well-selected studies. Acknowledging that post-IO drugs seem to work a little bit better in all of head and neck cancer, I don't think that's a very high bar to beat. I have said to them in designing this study, what you for me need to beat is probably what do we think docetaxel or paclitaxel would do in this population. I don't think that the objective, blinded central review, not investigator, blinded central review response rate is going to exceed 20% or one in five for docetaxel in an HPV positive refractory population. I'll also just add, I agree with all that, and I also just add that for this strategy, cetuximab remains one of the options. Yeah. In the community, and many places that do large phase III trials at community sites are still using a lot of cetuximab for HPV-associated disease. Many referrals I get for trials are patients that have already received cetuximab with HPV-associated disease. You could also imagine that investigator's choice will have cetuximab, which will affect the comparator also. Yes. In Europe, patterns of use are actually, there's more methotrexate used. There's more tighter label use as opposed to novel combination or off-label, so to speak, guideline combination, much more stringent. Our European colleagues would welcome a study like this because it would give access not only to the drug, but also uses agents they're comfortable with. Yeah. I also don't expect more than 15%. Just because of the taxane issue in first line, I think that would probably go something between 15%-20%, probably what we'll expect on the comparator arm. Agreed. We have officially run out of time. I'm so sorry. Very selfishly, there's a head and neck event happening at ASCO at 8:00 A.M. this morning, hence our need to be here at 6:30 A.M. Having said that, first of all, a huge thank you to our panel. Huge thanks to our audience, again, coming here so early in the morning. The room is full, for those of you who are not here in person. We're here for plenty of follow-up questions. You know where to find us. Enjoy what's left of ASCO. It's been an incredible conference for us. Thank you so much.