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Okay. Good morning, everyone. Very early. Good morning, everyone. It is 6:32 a.m. here in 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 traditional Corbus of holding these events incredibly early in the morning. So I apologize for that. But 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 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. So just for today, I'm going to bask in this MD. So thank you. I genuinely mean it, but -- and thank you for your hard work. That was -- 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 deck. I want to thank you and your teams, the other physicians who and their teams are part of the study and of course, the patients themselves. This is 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 3 gentlemen that we also had so generously at ESMO as well. So I think we're just having starting a roving band, and 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 of the prestigious list of 40 under in cancer and award that recognized them as modern 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 its clinical and translational research efforts focused on precision medicine approaches to treat head and neck cancer. He has special interest in salivary gland cancers and rare head and neck malignancy, in particular, in molecular and immunological biomarker discovery. And 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 network. He has served 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 called the Phase I head and neck oncology research at the University of Miami. So without further ado, what I thought we do is I'll start with some questions, reflecting a lot of the questions that we've been getting in the last week basically, and then open it up for questions from the audience.

Like ESMO, we're going to keep it very conversational and not particularly scripted, and we absolutely welcome any questions you have here. I'd say, let's start with the member 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? And so 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? And how are these patients distinct from this umbrella term of head and neck cancer? So Ari wants to volunteer, please go ahead.

Yes, I'm happy to take that one. 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. So head and neck squamous cell carcinoma, squamous cell carcinoma presents the vast majority of head and neck cancers, about 95%. And of the different subtypes, the 1 that we -- certainly in the U.S., most commonly see in our clinic are those squamous cell carcinomas that start in the orophaynx, which is the back part of the throat, usually by presenting tumors that start for the most part in the tonsil and base of tongue. And 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, we -- different prognosis. We take this into account with every patient that we assess. And we also have an oropharynx non-HPV-related disease or HPV unrelated disease, often associated with smoking, alcohol. But certainly in the U.S., and 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. So 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 well shaving or didn't go away with an antibiotic or steroid. So it's not difficult to discern these patients. And then even if the clinical phenotype is identified and the primary site is small, and there are, in large neck nodes, you can biopsy and understand the HPV status of the lymph nodes. So it's not hard, and this is very ingrained in our community globally. So it's very clear that biologically, there's a unique feature related to carcinogen and HPV-negative cancer as related to oral faring cancer and those that are HPV positive. So I don't think there will be questions or concerns from the oncology community about identifying them. And I think the only other thing I would say is about the increasing trend in epidemiology. So 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. And so 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 incidents while smoking-related cancers decline well into 2040 and projected into 2060. And the reason is the lead time to diagnosis. It takes decades, right, after HPV oral infection, high-risk infection to develop these cancers. And so the population that got vaccinated today is not going to imprint on that decrease in epidemiologic trend for decades from now. So I think that's really important. Unfortunately, it's going to take us half a century sadly to see the improvements or shy of half a century to see improvements in epidemiologic trends. So 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. Yes, I just in case somebody is wondering, there go. I'll just add to what my dear friends here mentioning is -- we have to know that over the last 20 years, the incidence of sqaumous cell carcinoma of the head and neck hasn't changed much. And despite decreased rate of smoking and the main reason is what Glenn is mentioning, right, the smoking related cancers are trending down and oropharyngeal HPV-related is trending up, unfortunately, and that's what has kept the incidents 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 HBV on related, have been highlighted after we even changed the initial staging, right, several years ago. So we have even a different stage in upfront. So Glenn has mentioned is well recognized that this is a different site, right, with a different behavior and even a different staging for the HPV-related oropharyngeal. So it's well recognized in the community that these are different entities.

Dr. Perz, 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 "the West" where as you mentioned, Dr. Perez, those of you who've noticed the youth are no longer smoking or particularly drinking and then we have places such as Asia or South America, where it's still very much a lot of nicotine consumption, smoking consumption. There seems to be sort of 2 dynamics between these 2 populations. You touched upon that a little bit. Can you expand on that, it'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? And then I started my practice at Universal Louisville, where my H2 related or offering, they were all smokers, right? And then I -- when I came back to Florida in South Florida, then suddenly most of my squamous cell carcinomas are actually pure HPV basally just because of the geographic difference, right? So there are geographical differences not only in countries, but within countries about how -- what patients actually present to our clinics, right? And it depends a lot on smoking incidents and also in HPV prevalence between different populations, right?

Yes, we would -- I mean we're all in geographic areas throughout the country. In Boston, we see a large catchment of HPV-positive patients often just by nature or like white collar coming to academic centers in that age range, mail, often limited or never smokers is sort of the population of interest. So I would completely agree. I think when you go to Europe, there's a higher incidence of smoking. So I was talking to Jean-Pascal from Brussels. And like he mentions that many of his oropharynx cancer patients will be HPV-negative. So and then you go to Asia and the rates of HPV positivity are quite low and there are different epidemiologists, right, like EBV, nasopharynx and things. So I do think -- and this is important when thinking about the trial, which has largely -- is largely likely to launch in the U.S. and sort of North America, there is a tremendous population, and 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.

And 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, I mean 90% were HBV 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 HV positive. So this is clearly the -- what we're seeing in our clinical practice, I think, echoes what the epidemiological data is describing in terms of trends.

And 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 and we've seen that in our own data, where those populations where we have a lot of smoking, we had very few oropharynx patients coming in there and therefore, very relatively very, very few responses. In retrospect, that was actually a very helpful insight ahead of launching a registrational study. Let's dive even deeper and start to put maybe some numbers on it. If we think about, again, North America, Western Europe, how many -- if we think about this late stage of the disease, think about head and neck patients who are -- have failed their front line and are moving or eligible to move to second line, how many of those patients are oropharynx? We've done some of our own third-party epidemiology and I say this in the context of a narrative that I think a lot of us have been exposed to from the EGFR bispecifics, we're quite right and in a very sensible manner, we're focusing on the other part of the population. And I think that created a certain impression that we're talking about a small number of patients. So again, in no particular order, how many patients do think they are out there and even from your own practices and Dr. Rosenberg, you mentioned that a little bit on a daily, weekly, monthly basis, what are you seeing walking through your doors?

Yes. I mean I think while this is the vast majority of patients that we've seen in our clinic. Of course, in head and neck cancer, we do care most of our patients with multimodality treatment. But 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. And with the increasing incidents, that is -- we see more of that now than we used to, and we -- I expect we'll continue to see more of that. And I think that's also reflected as you look through the Phase III trials, I mean, more 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 HV positive oropharynx as well. I think some of the older Phase IIIs were 20%, 25% HBV positive, now many of the global trials are 1/3 and the U.S. trials that are enrolling now frontline recurrent metastatic are 40%, 50% HPV-positive oropharynx. So 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. And 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 as what I expect.

Yes. I mean, certainly, in our clinic, the vast majority of new multi-D cases, probably 5 to 6 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, and then you increase projections over time. So if you look back at SEER data, there's about -- so anywhere around 43,000 to 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. And then 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. So -- this is a large and growing population. I think the lower end of the estimates are well around 7,500 to 8,000 the higher-end estimates approach 10,000 or higher patients. And that, again, is continuing to rise. So 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. But I'll tell you right now, every 40- to 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 as patients who are post immunotherapy in fabulous shape and in need of something. And 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. So 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. So again, it's not just about numbers, it's about how many patients are motivated to come for treatment. I'll make 1 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.

Yes. I 100% agree. The 1 thing is just the disease, the selection, we -- all of us, we have treated patients with chemoradiation that have HPV-onrelated disease and eventually, sometimes the patient, they don't make it to first-line metastatic treatment, right? Because of the comorbilities, because the disease is so aggressive, high bulk, and 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 don't -- they cannot get first line. It's very few. Most of them get -- and actually, we have to treat them. And it's true that we -- as Ari mentioned, we cured 80% of this population, but 1 out of 6 or so will recur and all of them will actually go into recurring therapy just because these are motivated patients, usually highly educated and all the social issues that Glenn mentioning. And the same token goes to second line. We lose a lot of HPV related patients on after first-line therapy because the comorbidities, we got their disease is because the disease very aggressive. When you see the cancer,those patients that drop on the first 2 months, of the fat that's mostly HPV related, right? But the patients that we lose with HPV-related cacinoma in the first-line setting or second-line setting are a very smaller number than the unrelated. So these are motivated patients, healthier patients and more fit for therapy.

And that's important. I think today, in my clinic in the last 6 months, the #1 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? And this is why we believe in and are sitting here now 6 months, 12 months later, enrolling to ADC trials that have transformed other areas of oncology.

Yes, yes. And these are patients just to echo which -- 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. And that's where the referrals come from. That's where the vast 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, for this population in our clinic.

So 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 EGF bispecifics and seen some incredible acquisition recently in that space and big pharma moving into that space. So for an audience out there or even a lay person listening in, how do you square the fact that what we're hearing here is, yes, there are 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. So help the audience understand where is that paradox?

I'll go first again. I think we've recognized the fact that 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 Interlink result -- negative Interlink results, which was the Phase III that randomized cetuximab with or without monalizumab and therapy response rate and HPV unrelated was 24%. And then if you back calculate, it's 5% or less in HPV positive. So in my practice, that's not something that I think about. I mean I don't think about EGFR targeting for HPV-associated disease, that's a strategy where we need different therapeutic strategy and that's also where we're seeing the signal for the ADCs. And we can discuss all the different reasons why that might very well be the case, but it's a totally different population. And 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.

We just keep adding. So remember, amavantumab, and we saw data yesterday from OrigAMI IV in the second line is monotherapy. And alpha 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 beta-catenin signaling, RB2, P53 and then we know these surface expression markers like Nectin 4 and others are important. So the other point to be made is you might say, well, there's petosymptomab, which based on its unique mechanism of EGFR, LGR5, has been teasing that there is some interest and activity in HPV positive. But 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 HBV positive in the first-line combo with pembro trial and the second-line LiGeR trial, they've paused in enrollment and capped the HPV positive enrollment at 30-or-so percent and increased enrollment by several hundred patients to both trials. So I think, again, this is my opinion. I'm not informed in this, but that tells me they're seeing something where they need to clarify the difference between signal. A long -- that's a long and complicated but important way of saying, I think all 3 of these are going to be HPV negative drugs. I think petosemptomab and, of course, ami are largely HBV-negative. And 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.

Yes, I think we have to acknowledge there's a small overlap just in patients with HPV negative or firings, right? That's always a very special population, but it is a fairly small population in general for everything that we treat. So there 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 1, it's also an untapped population that hopefully we can address, right, in the future. And we have seen activity of 701 in patients with PD-L1 of less than 1, right? So I think that's another on-tap population that will require novel therapies in the future. But certainly, there's -- it's exciting for us to think that in 5 years, the NCCN guidelines may be and just maybe will look completely different and will be a lot more elegant for our patients. That's what we're hoping for.

So let's switch for a second from the EGFR bispecifics, et cetera, and talk about our mechanism. So we have a Nectin-4 ADC targeting it with armed with MMAE. We're not the first foray into head and neck within Nectin 4 MMAE. There's a little 1 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 -- and second-line monotherapy study? I think that was 2023. And then this -- I thought a really remarkable poster last year at ESMO in the subsequent publication. What did we learn from it that's applicable to us? And adding to that to yourself into 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?

Yes. 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 patients. And 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 1 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 subside. So I think that was -- those were some of the key takeaways. The toxicity profile of enfortumab is now very, 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 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. And so I mean, 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 our -- my urothelial colleagues have this challenge as well, which is how do you keep an active agent going when you have this MMAE -- free MMAE driven peripheral neuropathy, toxicity. I think that's the 1 that I would say the most.

A couple of addition. I think -- number one, Nectin 4 is a validated target. EV is an active drug in head and neck cancer. So let's put to rest that the target is important. It is important, right? So I think that's the first thing we learned from the EV story, right, from both the first-line JCO publication, right, 20-plus percent 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. And again, that's public information that I've heard discussed. So 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, right? The fact that it's a Q3-week schedule. Padcev is day 1, day 8, 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 is in Phase III or approved, every single thing is abedotin, right? We had Tivdak. We tried -- well, we tried with SAS, but the response rate was too low. We had EV, right? There was data for the RORI bispecific from BioAtla. We're seeing data from vodabartpeladotin from Pyxis that looks compelling for head and neck. Vedotin so far have proven efficacious, right, in patients with head and neck cancer. A big question is what will topo1 and exatecan will to 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. So I think for me, when I think about Nectin-4, MMAE or statin, vedotins and sort of moving that into a larger trial, it's very much makes sense, and I think this is an open space to run with.

Yes. It's nice to remember where we came from, right? A little more than 2 years ago, remember, they sent us this trial and to our network and then like, oh, that's a mid to enfortumab and then nobody wanted it. Al, would they take head and neck? They're like, well, it says a day take Okay. I'll take it, right? And then we took it then. Back then based on the activity that passive already demonstrated. It was already published, right? And then the interesting thing that is very important, what Ari saying that it is very similar Nectin-4, target. We have an MMA proven activity already with several different ADCs, but somewhat is not exactly the same, mainly because there's less prepaid load like the 2 instead of 4, right? So certainly, in my opinion, even though we have some toxicities that we addressed, a more elegant molecule, right? And more of the magic bullet concept better demonstrated. We don't -- the peripheral neuropathy that we have seen is honestly, it's not even -- it's not even significant. It's not even a thing. And we haven't seen things that we have seen with other MMA based ADCs, hyperglycemia. I treat it with so many -- I probably have treated more than 80 patients with nonapproved ADCs, MMA based ADCs and you deal with liver abnormalities, you deal with hyperglycemia, bad neuropathy, bad rashes and something. And we don't have those polyneuropathy because we have more targets engagement and less free payload. So yes, it's very similar than enfortumab, but I don't know, it's not the same, obviously.

So following on that is no such thing as a free lunch, right? This is still a chemotherapy -- a targeted chemotherapeutic agent. Our good friends at CSBC created 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 experienced, how does it compare to other ADCs with similar ocular toxicities and maybe also refer to this dichotomy we're seeing between the rates that we're seeing for especially Grade 1 and 2, but juxtapose with a discontinuation rate that seems to be very, very low.

For those of us that have been using the agent for a while now, it's become quite protocolized like many anticancer therapeutic. Patients see and ophthalmologists 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 3 weeks. And importantly, as we've had more experience with it, if patients develop some of the ophtho symptoms, where we've become quite comfortable with holding and it's reversible, right? So we -- it improves. We can usually restart. And it becomes a toxicity management, which, as oncologists, this is our bread and butter. And amazingly, it's not everyone also, right? Many of the patients, we caution them. We say this happens to some, not to others, and we get into it, and we don't see any of that. So 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. They're patients doing their prophylaxis. And so this is toxicity management. This is what oncologists know how to do is what we have experience with, with any cancer therapeutic that we use. So I think that's been my experience.

Yes. I think as we're all up her experience 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. So if we look at broad drug development, things -- 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, right, 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. So for me, ocular toxicity, let's just put it out there, it sounds scary, right, its vision. That said, Grade 1 is no symptoms. So that means you're just doing routine eye exams. And I would argue that patients after the age of 50, learning from the data 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. So that's 1 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. So then 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. So I know what like grainy inflammation feels like, and I know what irritation feels like. And the worst end of a grade 2 is maybe that you're driving is 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 and 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, what about access to ophthalmology and the exams that are needed? Again, I'll reference a fully approved drug, datapotumab, 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, but it's not that far off than what's been described in large data trials. So 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 sort of routinely to help follow these patients. And again, it's not all the time. These are baseline exams and then dictated as needed to follow up on any resolution. And 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 specialists, 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 cytopenia. So 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.

Yes. I think we learned, right, we have learned over the last 2 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, okay, wait, let's pick up -- break there because truly, and the issue is that when -- even when we hold the therapy, the biological half-life of 701, it's so long, right? And the patients can just keep at those all together, and the next can, this tumor will continue to be shrinking, right? So that's what we learned to be proactive and making sure that the minimal symptoms that the patient had that, as Glenn mentioned then that will translate to a grade to it, then we have to stop therapy. And now that we do that and we hold the therapy, we don't -- we hold the therapy. And eventually, it will just come back to normal, patients back to baseline. We can always resume and because of the reversibility of this issue, then there's so few patients that have actually had to come off story because of adverse events, right? And in general, then I will dare, you guys to look in all the data, all the ADCs, all the top ones and see the amount of discontinuation because of adverse events, and you compare to the data that we have. And we -- our amount of discontinuation is very, very low. Mainly because when I present this trial to my patients, I tell them, you can have this issue, but I mean, to treat what, 34 patients event, something like that, I have to like 35 patients myself with this drug, 34, day 5. And none of them had end up in the hospital because of an adverse event. And 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 fifth line for HPV-related oropharyngeal therapy -- cancer. And it's very at least for feeling for the oncologist that we are giving you something that, at least I know the chances of a life-threatening event are miniscule, right? That's the first. And the second thing is that when I was a fellow, 7 years ago and the ARC therapy came, and it was this testing issue, right, access to testing, access testing, and they had a lot of things to overcome at that time. That is same issue with a tool with Elahi came to the market, right? And then Tivdak and then enfortumab. And all this in no, we have no contact of ophthalmologist. But guess what, -- now most of the oncologies, now they have access to ophthalmologist because we have 4 different ADCs that are approved that need some monitoring of them. So you usually now have access to that, and that's very different than 6 years ago. So in practice, most of us in practice have access to ophthalmologist even outside this round trial. So 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 at the community oncologists now is getting more used to deal with.

So last question for me before we open up 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. But 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. And again, Dr. Rosenberg, you've had experience in pads plus pembro. Dr. Hanna, you've had experience in the Bicara settings. We've had petosentimab, 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 be seeing? How -- what is the unmet need, again, in those patients that starting their late-stage journey? Do these mechanisms like to play together? I guess that's my question.

Yes. I mean I think we've seen most of the data has initially been from the bladder space where we've seen incredible synergy between Nectin-4 ADCs and immunotherapy. And that 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 expect it to see that kind of efficacy when you combine immunotherapy with Nectin-4 ADCs and in head and neck, right, this is an immunogenic disease. Oftentimes, there's parallels between urothelial and head and neck across drug development. And I think that is important, right? The alternative is chemoimmunotherapy, 689 -- or sorry, Ki chemoimmunotherapy, Grade 3 to over 85% in that study. Obviously, we use a lot of pembro monotherapy, but that's suboptimal in terms of its efficacy alone for many of us. We use some carbotaxol, but that also has neuropathy as a major dose-limiting toxicity. So a lot of opportunity in that space as well, in my opinion.

Yes. And I mean I'll just add to the idea of existing toxin combination. So 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. So 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 should, I think, is out now, but EV plus pembro in head and neck, and the response rate for us looks quite good. I mean there's -- clearly it was around 43%, 44%. So again, validated target, nice possibility for combination and this is where the field is going. Everyone is excited about ADC plus IO as a new way to replace traditional cytotoxic agents. So that paradigm has got years to go. I think all of that really makes sense. And you can 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 is an approval for this agent bringing this forward to an oral fringile 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. So 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 there, including all of us, is looking at what's the next partner for pembro modulate upfront, path response and event-free survival in resectable head and neck cancer, and it's no surprise that chemoimmunotherapy ADC IO is where everyone is looking. So you could see that this drug could move forward very nicely to multiple Phase III trials and registrational opportunities across the disease spectrum.

Yes. I think 1 of the things we learned from Broder is that we don't have to select by PD-L1, right? And that's because of the high necking for expression. And that's a good thing. One of the limitations of the current trials, not only that is probably for a different population, as Dr. Hanna is mentioning, but -- and that is usually and this will be non-offer mostly but also because still, even when these agents are approved, the community will continue to use chemo in some patients just because they on a fast response, and this will be only approved for positive disease, right? So my hopes will be that somewhat, we can demonstrate a strong signal on oropharyngeal cancers in the first-line set with pembro on selected by PD-L1 because that is the only way we're going to replace chemo as it happened in bladder cancer. But that's my hope, so we have to shoot for the stars, right, and that's what it should be.

Fingers and toes crossed. Okay. We have a few minutes for questions from the audience. I'm not sure who's Wilson, do you have a microphone? I'm going to start with Brian Abrahams, if I may, here in the front, there. Thank you.

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 -- just any considerations that the company should think about in conducting the study, just to ensure that the vast, vast majority of those patients are indeed HPV positive? Secondarily, 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%? And then lastly, of the 7,500 to 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? And what are some of the sensitivities around how the response rate that that might dictate the accelerated approval would dictate the degree of use of this agent?

Maybe each of us could take one of them. I'll take the oropharynx question. So there's some registrational and agency-related considerations here and realities about time and prediction. So oropharyngeal cancer in the United States 5% and probably at our centers, it may even be higher or HPV-associated or causal. That being said, even in patients who have mild or moderate smoking history, HPV may still be causal when those 2 overlap. That is certainly a little bit less, maybe closer to 60% in Europe. And so 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 is 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 recently in practice to make prognostic and treatment decisions. So 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 sort of 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. But 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. So this is not unique to the Corbus drug.

Yes, exactly to get the response rate one. I mean I think we've seen in the post IO era that chemotherapy is around a 20% response rate in head and neck cancer. So 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, that's -- 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. And 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 into Caesar's point about some of these patients on the study have these durable response because of the half-life. And 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, "I'm not going on chemotherapy. Don't -- give me a little more time". And I actually have been amazed by that. So patients don't like chemotherapy is what I'm trying to make. So I would say that's the response rate and the paradigm and the post IO era of what we're thinking about looking at and what patients care about.

Yes. So I think to answer your question about what happens in second line, the reality that is going on in the U.S. is the following. We have the KEYNOTE-48 as the Cat-1 recommendation. But it's very commonly physicians are using Carbo, Taxol, pembro in the first-line setting. There are 5 drugs in head and neck cancer. That's it. You got cetuximab, right? It doesn't work for icons. You have 5-FU that for -- it doesn't work for HPV-related review, which is not really great for HPV-related either. And then you have carbo, taxanes, check inhibitors. When the most common regimen is used for an HPB positive patient, which is carbo/Taxol, pembro, and they come to us looking for options, guess what? They already burned the 3 best agents upfront. So the responses that you see in the comparator arm for CheckMate 141 are mostly driven by those attacks. And that is the reality. So in the reality, when these patients will come into a second-line trial and carbo, taxol, and pembro, most of us will be a little bit stuck with the other compactors that are actually here. So 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 patients who already have been exposed to taxanes, probably, platinum, pembro and then the physician that is -- we have this patient will face the reality that we face every day. Recycling taxanes, right, or just giving another regimen that is not ideal. So that is the problem for oropharyngeal cancer patients, there's no good second line. There's none, right? And that is the reality that we face. Now should we cap it to 20% HPV on related, should we just leave it, just run just based on the pilot. 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 HPV unrelated patient at the 1.8 million per kilogram dose. So it's not that it doesn't work, right? It's just that there's a little lower response rate and that we have to focus where the responses are. But even though it might bring it down, if I put it, that doesn't mean it would be 0. So my point with is, I think that we are tapping in the right population, the roaring population for the reasons that Dr. Hanna mentioned, is the most practical thing to do not only in trouble, but also in practice. And 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.

For the doctors, I think Dr. Hanna, you made a comment that HPV-patients tend to be fragile, but also that HPV-positive patients are younger, perhaps with better fitness. Just wondering how does that impact how you adjudicate or manage adverse events for these patients versus perhaps a non-oropharyngeal? And could a trial that only enrolls or print have a greater prioritization perhaps for dose intensity versus managing adverse events? And then I have a follow-up.

Yes. I mean we talked a little bit about this. I mean these patients come out of first line as stated. They're still fit. They're still working. They're ready to go. And so 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 HBV patients because of their fitness and because of their protoplasm, but you could flip that argument and also say that if a drug worked really well, but was very, very toxic, on many multiple organ systems, people would discontinue it because they're still working and living their lives. They're sort of that balance of what they're willing to tolerate and what you're willing to tolerate as a physician. So 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 -- as this is a tolerable drug that patients can stay on and have reasonable quality of life. So I don't think there'll be any issue enrolling to the study. And 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. So your recycling old drugs. So I think this is a no-brainer, and that's why the trial has enrolled so well.

Great. So then second question is for you all. You alluded to this during the discussion, but as you ramp towards the Phase III study starting up, are there any considerations in terms of sites and enrollment based on the inferential focus? For example, do you expect a different distribution of centers or pace of enrollment compared to your EGFR peers perhaps? And how does that factor into ex U.S. enrollment as well, given the different rates of HPB 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. But panel, any thoughts on that?

I mean 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 population. So -- but I would agree. I think my prediction is this trial will open in a largely North American population first, and they will have to -- they will be going very, very quickly and hopefully open some sites in Europe and perhaps in Asia. But 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. But I don't think that will be an issue. And I think the population that's being investigated here will be representative if it is able to achieve a label.

And ex U.S. is also seeing increases in oropharynx cancer and HBV associated as well.

Andy?

Thanks for the session, super informative. So I think during the last call last week, you mentioned about oropharyngeal subtype having a higher response to other therapies, including chemotherapy. So 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 or faring subtype, what is the comparator arm going to look like in 2026?

Well, I mean, so 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. But 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. So we have to benchmark against what would be the historical response rate, and we already sort of outlined, it's not well known because there haven't been any readouts of HPV-only second, third-line trials in this space. But from what we can tell from subset analyses, and we're talking about 15%, best-case scenario, 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. But I don't think that's a very high bar to beat. I mean I have said to them in designing the study. What you for me need to beat is probably what do we think docetaxel or paclitaxel would do in this population? And I don't think that the objective blinded central review, not investigator, blinded central review response rate is going to exceed 20% or 1 in 5 for docetaxel in an HPV-positive refractory.

I'll also just add, I agree with all that. And I'll just just add that for this strategy, right, cituximab remains one the options. And 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 or patients that have already received rituximab with HPV associated disease. And so you could also imagine that investigators choice will have cetuximab, which will affect the competitor also.

Yes. And in Europe, patterns of use are actually -- I mean there's more methotrexate use, there's more sort of tighter label use as opposed to novel combination or sort of off label, so to speak, guideline combination, much more stringent. So 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.

Yes. I also don't expect more than 15%. I probably will just because of the tax in first line, I think that would probably go more between something between 15% to 20%, probably what we expect on the comparator arm great.

So we have officially run out of time. I'm so sorry if there's a very selfishly, there's a head and neck event happening at ASCO at 8:00 this morning. Hence, our need to be here at 6:30. 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. and enjoy the -- what's left of ASCO. It's been an incredible conference for us. Thank you so much.