Corbus Pharmaceuticals Holdings Inc Aktie

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 and 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, 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 who 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 -- we're 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 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 the 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 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 co-led the Phase I Head and Neck Oncology Research at the University of Miami.

So 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, 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 #1 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 whoever wants to volunteer, please go ahead. Ari. There we go.

Yes, I'm happy to take that one. And 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 squamous cell carcinoma, squamous cell carcinoma represents the vast majority of head and neck cancers is about 95%. And of the different subtypes, the one that we -- certainly in the U.S., most commonly seen in our clinic are those squamous cell carcinomas that start in the oropharynx, which is the back part of the throat, usually representing 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 care 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 in the oropharynx non-HPV-related disease or HPV unrelated disease, often associated with smoking alcohol. But 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. 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 while 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, there are enlarge 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 oropharynx 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. Just in case somebody is wondering, there it goes.

I'll just add to what my dear friends here mentioning, it's -- we have to know that over the last 20 years, the incidence of squamous carcinoma to 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 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.

So we have even a different staging upfront. So as Glenn has mentioned, we are 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. 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 the West where, as you mentioned, Dr. Perez, those of you who have noticed the youth are no longer smoking or particularly drinking. And then we have places such as Asia, South America, where it's still very much a lot of nicotine consumption, smoking consumption. And 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've been traveling the country over the last 15 years, right? And then I started my practice at Universal [ Louvo ], where my HPV-related oropharyngeal, they were all smokers, right? And then 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, right? And 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, sort of like white collar coming to academic centers in that age range, male, 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 epidemiologies, 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 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. So this is clearly -- 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 oropharyngeal 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 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. 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 where quite rightly 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 you think there 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 Well, 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. 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 incidence, 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 HPV-positive oropharynx as well. I think some of the older Phase IIIs were 20%, 25% HPV 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 is 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 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 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 is 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 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.

Yes, I 100% agree. One thing is just the disease selection. We -- all of us, we have treated patients with chemo radiation that have HPV unrelated disease. And eventually, sometimes the patient, they don't make it to first-line recurrent metastatic treatment, right, because of the comorbidities, because the disease is so aggressive for [indiscernible] 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 -- and 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 recurrent or metastatic therapy just because these are motivated patients, usually highly educated and all the social issues that Glenn is mentioning. And the same token goes to second line. We lose a lot of HPV-related patients after first-line therapy because of comorbidities, because they're sick, because the disease is very aggressive.

When you see the KEYNOTE-048 curves, those patients that drop on the first 2 months of the KEYNOTE-048 that are mostly HPV unrelated, right? But 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. So these are motivated patients, healthier patients and more fit for therapies.

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 majority of our referrals come from. That's where our colleagues who treat a lot of head and neck cancer are looking for trials and 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.

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 EGFR bispecifics and see some incredible acquisition recently in that space and big pharma moving into that space. So for an audience out there or even a late person 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. So help us -- 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 [ INTERLINK ] result -- negative INTERLINK results, which was the Phase III that randomized to cetuximab with or without monalizumab and [indiscernible] monotherapy response rate in 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.

I would just keep adding. So remember, amivantamab , and we saw data yesterday from OrigAMI-4 in the second line as monotherapy and [indiscernible] 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 Wnt/ß-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 is petosemtamab, 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 HPV-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 [ FYSera ], [ Petosemtamab ] and, of course, [indiscernible] are largely HPV-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 oropharynx right? That's always a very special population, but it's 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 untapped 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 [ NCC ] 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.

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 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 -- second-line monotherapy study, I think that was 2023. And then 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? And 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?

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 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.

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 a [ vedotin ] right? We had Tivdak. We tried -- well, we tried with [indiscernible], but the response rate was too low.

We had EV, right? 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. Vedotin so far have proven efficacious, right, in patients with head and neck cancer. A big question is what will TOPO1 and [ exatecan ] 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 [indiscernible], 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 bit more than 2 years ago, remember, they sent us this trial and to our network. And then like, oh, that's a me to enfortumab and then nobody wanted it. And I like would they take head and neck? And they're like, well, it says that they take. Okay, I'll take it, right? And then we took it then back then based on the activity that PADCEV already demonstrated. It was already published, right? And then the interesting thing that it's very important what Ari is saying that it is very similar, Nectin-4 validated target. We have an [ MMA ] proven activity already with several different ADCs, but somewhat is not exactly the same, mainly because there's less free payload, right? The [indiscernible] 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 significant. It's not even a thing. And we haven't seen things that we have seen with other MMA-based ADCs, hyperglycemia. I treated with so many -- I probably have treated more than 80 patients with non-approved 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 problems mainly because we have more target engagement and less free payload. So yes, it's very similar than enfortamab, but it's not the same.

So following on that, there's no such thing as a free lunch, right? This is still a chemotherapy -- a targeted chemotherapeutic agent. Our good friends at [ CSBC ] 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 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 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 3 weeks. And importantly, as we've had more experience with it, if patients develop some of the [indiscernible] symptoms, 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, your patients doing their prophylaxis. And so this is toxicity management. This is what oncologists know how to do. This is what we have experience with, with any cancer therapeutic that we use. I think that's been my experience.

Yes. I think as we're all up here 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? It's 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 [indiscernible] 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 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. 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 your 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, 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, 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 cytopenias. 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 these better. Personally, now, I know that when somebody tells me that they have photophobia and lacrimation and they're sis fine. I like, okay, wait, let's take a break there because truly -- and the issue is that even when we hold the therapy, the biological half-life of 701, it's so long right? And the patients can just keep a dose altogether and the next scan, the 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 2 toxicity, then we have to stop therapy.

And 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 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 study because of adverse events, right? And in general, then I will dare you guys to look in all the data of 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 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 mean, I treat what [indiscernible], what, 34 patients, [indiscernible], something like that. I have to like 35 patients myself with this drug, 34, 35.

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 the fourth, 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 minuscule, right? That's the first. And the second thing is that when I was a fellow, 17 years ago and the [indiscernible] therapy came, and it was this testing issue, right, access to testing, access to testing. And they had a lot of things to overcome at that time. That is the same issue with ophthalmology when mirvetuximab, ELAHERE came to the market, right?

And then TIVDAK and then enfortumab and all the things we have now contact ophthalmologists. But guess what? Now most of the oncologists now they have access to ophthalmologists because we have 4 different ADCs that are approved that need some monitoring in ophthalmology. So we 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 ophthalmologists even outside this randomized 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 PADCEV plus pembro. Dr. Hanna, you've had experience in the [indiscernible] 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 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, that's -- I don't know if even they expected 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, that is important, right? The alternative is chemoimmunotherapy, 689 -- sorry, 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 [ Carbo-Taxol ], 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 tox in combination. So when we're talking about manageable eye issues, 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. So 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 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 2. 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 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, and it's no surprise that chemo immunotherapy 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 one of the things we learned from broader is that we don't have to select by PD-L1, right? And that's because of the high Nectin-4 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 that is usually HPV related, and this will be non-oropharyngeal mostly, but also because still, even when these agents are approved, the community 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?

So 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. 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. Oh, there we go.

Thanks. 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 -- 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 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 might dictate the accelerated approval would dictate the degree of use of this agent.

Maybe each of us could take one of that. I'll take the oropharynx's question. So there are some registrational and agency-related considerations here and realities about time and prediction. So 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 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 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.

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. I can 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 one of the earlier comments we were talking about the experience with the eye toxicity. It's actually been amazing.

And to Cesar'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 [indiscernible] to improve and patients see their scans and they say, no, I'm not going on chemotherapy. Don't give me a little more time. And I actually been amazed by that. So patients don't like chemotherapy is the point I'm trying to make. So I would say that's the response rate and the paradigm in 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 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 5 drugs in head and neck cancer. That's it. You got cetuximab, right? It doesn't work for any. You have 5FU that for -- it doesn't work for HPV related, [ 5FU ], which is not really great for HPV-related either. And then you have carbo-taxane, 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 are already born the 3 best agents upfront. So the responses that you see in the comparator arm for CheckMate 141 are mostly driven by the docetaxel, and that is the reality. So 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.

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 the trials are enrolling, the patients will 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 given 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 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 an HPV unrelated patient at the 1.8 milligrams 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 that doesn't mean it would be 0. So my point with this, I think that we're tapping in the right population, the oropharyngeal cancer population for the reasons Dr. Hanna mentioned, is the most practical thing to do not only in the trial 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 -- sort of 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? And could a trial that only enrolls oropharyngeal 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 HPV 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 AEs, 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 Yuval. You alluded to this during the discussion, but as you ramp towards the Phase III study starting up, are there any unique considerations in terms of sites and enrollment based on the or [indiscernible] 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 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. 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 populations. 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 HPV 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 oropharyngeal 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 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 chemo radiation. 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 population.

Yes. I'll also just add, I agree with all that. And I'll also just add that for this strategy, right, cetuximab remains one of 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 cetuximab with HPV-associated disease. And so you could also imagine that investigators' choice will have cetuximab, which will affect the comparator 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 taxination first line, I think that would probably go more between -- something between 15% to 20%, probably what we'll expect on the comparator arm.

So we have officially run out of time. I'm so sorry, there's -- 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.

Greetings, and welcome to the Corbus Pharmaceuticals 2026 ASCO Data Update Conference Call and Webcast. [Operator Instructions] As a reminder, this conference is being recorded. [Operator Instructions]

It's now my pleasure to turn the call over to Dan Ferry, Managing Director with LifeSci Advisors.

Thank you, operator. Good morning, everyone, and welcome to the Corbus Pharmaceuticals 2026 ASCO Data update call.

As a reminder, during this call, we will be making forward-looking statements, which are subject to various risks and uncertainties that could cause our actual results to differ materially from these statements. Any such statements should be considered in conjunction with cautionary statements in our press releases and risk factors discussed in our filings with the SEC, including our quarterly reports on Form 10-K -- reports on Form 10-Q and annual report on Form 10-K and cautionary statements made during this call. We assume no obligation to update any of these forward-looking statements or information.

It is now my pleasure to turn the call over to your host, Dr. Yuval Cohen, CEO of Corbus.

Thank you, Dan, and good morning, everyone, for joining us. It's my pleasure to provide a detailed overview of the data we will be presenting at ASCO in just a few days' time. This data represents an April 1 data cut.

I'm joined today by Dr. Glenn Hanna, Director of the Center for Cancer Therapeutic Innovation at Dana-Farber Cancer Institute. Dr. Hanna completed his fellowship training in hematology and medical oncology at Dana-Farber Cancer Institute in 2016. Prior to this, he earned a medical degree from Georgetown University School of Medicine in 2010, where he graduated summa cum laude and was a recipient of the Kober Medal for Academic Excellence. He's the Director of the Center for Cancer Therapeutic Innovation, CCTI, the early drug development program at DFCI. His clinical and translational research efforts focus on precision medicine approaches to treat head and neck cancer. And you may remember Dr. Hanna from our KOL ESMO event that we did last November.

Following the presentation of the data, I'll have a brief Q&A with Dr. Hanna, and then we will open it to questions from our audience.

Just a reminder, we have 3 events coming up at ASCO, starting on Friday. Our cervical data will be presented as an oral presentation on Friday afternoon. On Saturday afternoon, our head and neck data will be part of the poster session for head and neck. And then lastly, on Monday morning, we will have our KOL event joined by the 3 KOLs who also were kind enough to join us in Berlin last November at ESMO, Dr. Hanna, Dr. Perez, and Dr. Rosenberg.

So with that, let me jump straight into the data. I'll move at a pretty fast clip. The press release has been out now for about an hour. This deck can be found on our corporate website. And let me just go through the highlights quickly. In Slide 6, a reminder that everything we see data-wise around this ADC derives from the structure of this ADC. This is a very, very stable Nectin-4 targeting MMAE-armed ADC that has the ability to hang on to its payload for much longer. It also means that it can be dosed far less frequently. And what we have seen both at ESMO and now at ASCO as well is that we continue to see levels of MMAE-related toxicology or toxicity that are certainly below everything that we've seen with other such ADCs.

The data at ESMO was both our dose escalation and dose expansion. The ASCO data focuses now on 2 specific tumor types, head and neck and cervical at the 2 relevant doses, one of which is now moving forward. And we've seen -- it comprises of the patients you saw at ESMO as well as some additional patients that were not yet scanned at the time of the ESMO presentation.

Our safety database has nearly doubled to 317 patients. This includes all the patients that we have dosed at all the doses, all the tumor types, including tumor types that we have yet to present. Our head and neck population has gone from about 60 patients at ESMO to about 75 patients at ASCO, and cervical has gone from about 50 patients or so at ESMO to 72 patients at ASCO.

I'll start with the safety. On the safety side, what's been encouraging is that overall, the picture is very similar to what we saw at ESMO. Despite the fact that we've doubled the number of patients in the safety population, we continue to see relatively few grade 3s and very, very, very few grade 4s. This entire safety population has a sum total of just 3 grade 4 events, and there have been thankfully no grade 5 events. We continue to be best-in-class for peripheral neuropathy, all of it grade 1 or 2, none of it grade 3 or above, and it continues to be well below 10%. We also have a markedly better skin toxicity than other such ADCs, especially Padcev with skin tox being mostly grade 1 and 2 and the sum total of a single grade 3 skin tox with no grade 4 or above.

And ocular continues to be a feature of this ADC as we've seen with this class of ADCs. No big changes there. Again, the vast majority are grades 1 and 2. We have grade 3 hovering at just above 10%, and there was just a single reversible grade 4, which is a feature of this ocular tox that tends to be reversible. Most importantly for the ocular toxicity and in general, for the overall toxicity, our rates of discontinuations continue to be very, very low and in fact, have improved since the ESMO data set.

If I could turn your attention to the next slide. We have, again, peripheral neuropathy well below 10%, none of it grade 3 or above. Skin toxicity, again, markedly different than what we would see, for example, with an ADC such as Padcev. And last but not least, the ocular tox. And we're specifically looking at reductions and interruptions for ocular tox. They are part of the way in which the physicians manage these toxicities, and the discontinuation rate specific to eye tox is below 2%, in fact.

So let's jump straight into the data, starting with oropharyngeal head and neck cancer. A very, very simple explanation about oropharyngeal head and neck cancer or colloquially throat cancer, it is basically the back of your teeth to the top of your throat, including the base of your tongue. What's interesting about this cancer type is that it is on the rise. If we look at the prevalence of this cancer, it is driven by HPV infections, and those are rising, frankly, at an alarming rate from about 11% 30 years ago to more than 1 in 2 patients for head and neck. We can also look at the incidence that has also risen at an alarming rate, while the incidence of HPV-negative head and neck cancer, and a reminder, that is the head and neck cancer that is driven primarily in much older men with a history of smoking and/or excessive drinking, that patient population is not increasing. In fact, it is beginning to shrink as that generation dies off badly and is not replaced by younger drinkers or smokers.

What would be the hypothesis for a Nectin-4-MMAE ADC working in oropharyngeal cancer. And there are 3 elements to this. So one, it is a cancer that is driven by the HPV virus. And we have an example of a cancer driven by the HPV virus in which a Nectin-4-MMAE works very well, and that is cervical cancer, which is something along the lines of 98% HPV positive, whereas oropharyngeal is not that far behind it, about 80% to 90% of those patients are HPV positive. The second fact to consider is it is a cancer type that's known to be associated with high levels of Nectin-4. Head and neck cancer, specifically this type of head and neck cancer is one of the richest cancers in Nectin-4, again, fitting into the same pattern as cervical cancer, another Nectin-4-rich cancer type.

And last but not least, we actually have a precedent here of a Nectin-4 targeting MMAE ADC in the form of Padcev, specifically, as you'll see in a few slides from now, the frontline therapy of Padcev plus pembro in head and neck and the breakdown that Pfizer provided between their HPV-positive population and their HPV-negative population.

If we look at our division in our head and neck cancer and a reminder that this was one of the seminal questions that were left unanswered at our ESMO presentation, it was how do we split between HPV-positive or oropharyngeal and HPV negative or the non-oropharyngeal head and neck. And what you'll see is that our breakdown in our U.S. and European sites fits nicely into the 50-50 breakdown with roughly half the patients being HPV positive or oropharyngeal and half of them being non-oropharyngeal.

This is another way of looking at our own data. And as you can see, unsurprisingly, our oropharyngeal patients are overwhelmingly HPV positive, as you would expect. And the mirror image of that are our non-oropharyngeal patients who are overwhelmingly HPV negative, as you would expect as well, again, from a population that's derived from the United States and Europe.

A question, again, going back to ESMO was where would the efficacy lie in terms of bias or preference between these 2 very, very different types of subpopulations. And as you can see, the answer is markedly clearcut. In oropharyngeal patients that represented 41 of our patients, we have a pretty marked response. Their chances of responding were very high with a confirmed objective response rate for the higher dose of nearly 43%. And then the exact mirror image of that, in the non-oropharyngeal patients, the HPV-negative patients, where the response was very modest.

What's particularly striking about this slide is that it is the mirror image of what you would get with an EGFR bispecific. Those, as a reminder, have a strong bias in favor of the HPV-negative patients, the non-oropharyngeal patients. And in fact, 2 of the 3 EGFR bispecifics currently being explored explicitly exclude HPV-positive patients.

Another question we were asked at ESMO was durability. The ESMO data set was too immature to provide durability. Now for the first time, we can look at ongoing durability. And what we see mirrors the objective response rate. We have a durability in the 3.6 milligrams per kg that is already exceeding 6 months with a PFS that is catching up to it. In the non-oropharyngeal, of course, this is a patient population that would not be sensible for a drug like this. And again, a reminder, this is also a patient population where we would not expect Nectin-4 to be greatly expressed.

And so as a summary, a question we've been asked often in the last several months, which of the 2 doses would be more sensible to move forward? And the answer is the 3.6 milligram per kilo dose, dosed at Q3 weekly. And as you can see in its summary, the confirmed overall response rate was nearly 43%, a DCR of nearly 86%, a DoR of 6.3 months, a PFS of 5.6 months. Both of those are ongoing. And lastly, we do not exclude patients -- or do not mandate that patients be HPV positive, only that they be oropharyngeal patients. And in fact, 8 out of our 9 patients were also HPV positive, as you would expect from the demographics of this disease.

Another key question that we were asked at ESMO is how would this fit in the landscape in second-line monotherapy compared to petosemtamab, previously at Merus, now at Genmab. And luckily, we can actually look at that data at the time of Merus data set. The Merus data set, as a reminder, showed a very nice response in the HPV negative, but their HPV-positive response was modest with only 2 out of 15 patients responding. They look at oropharyngeal patients who are also HPV positive. So there's a double restriction there.

Luckily, we can actually look at the same thing in our data set. When we look at our oropharyngeal are confirmed to be HPV positive, we get a confirmed response rate of 8 out of 16. But as I've mentioned, our strong preference moving forward would be to use the anatomical definition of oropharyngeal and enroll patients regardless of their HPV status. Our durability, whether it's median DoR or PFS, already seems to be matching or exceeding those things seen in the Merus data sets despite the fact that they did not break that down into HPV positive or negative. And as you can see, our tolerability also seems to be superior to that.

This is our path forward. TEMPO-1 is a single controlled registrational study that will launch this summer. It starts with 250 patients where they're on -- half on monotherapy of CRB-701 and half on physician's choice. It has an adaptive feature and the primary endpoint under accelerated approval, the ORR with a full approval based on OS. And as we've mentioned a few weeks or months ago, we have alignment with this with the FDA. We will provide more data on this, both at ASCO and a little bit after that as well.

Lastly, an intriguing view into what we could see in our frontline study. We are currently dosing patients in frontline head and neck using CRB-701 plus pembro or Keytruda. We will have our data, we hope, in the beginning of next year. But in the meantime, there is a precedent, an intriguing precedent to that, and that's looking at Padcev. And this was the Pfizer now data at ESMO last year.

And what we saw with Padcev plus pembro in frontline was an overall response rate of 39%. That comprised of both HPV-positive or negative or oropharyngeal and non-oropharyngeal. But Padcev showcased a very similar bias towards the HPV positive/oropharyngeal that we do in second-line monotherapy with a confirmed ORR of 82% for HPV positive and a confirmed ORR of far more modest 23% in the HPV negative.

To just juxtapose it, and again, this theme that this looks very much like the mirror image of the EGFR bispecifics. For a very similar population in the frontline, we have peto plus pembro at about 50% or less than what they're achieving in the HPV-negative population. And then more recently, Bicara published their data in frontline, including their efficacy with Keytruda in HPV-positive patients coming in at a modest 27%.

Very quickly, just to dive into cervical cancer. This will be our Friday oral presentation. A reminder that here is another HPV-positive or HPV-driven tumor type, similar to oropharyngeal head and neck. The bar to beat here is an existing drug. This is Tivdak, previously from Seagen, now at Pfizer. It is an MMAE-armed ADC targeting tissue factor. And Tivdak is limited by 2 things. It has a relatively modest efficacy at about ORR of about 17.8%. And it is hindered by a number of very challenging toxicities. Like us, it has ocular toxicity.

As to a number of these ADCs, as I've mentioned, ourselves; Tivdak, which, of course, is approved; Elahere, which is approved; and of course, Blenrep, which has similar toxicities, but at much higher levels. Tivdak is also hindered by things that we don't have with CRB-701, high rates of peripheral neuropathy, bleeding and skin toxicity.

This is our waterfall plot for CRB-701 in cervical. Again, a dose response as we saw in oropharyngeal with a top dose delivery confirmed ORR now of 34%. That's effectively twice the efficacy we have seen with Tivdak. And then a durability that, again, like oropharyngeal, is still ongoing, but is already reached 8 months for the top dose with a PFS that is catching up.

And so just to put that into context, on Slide 32, you can see where we line up versus Tivdak. And for that matter, chemotherapy and second-line monotherapy, which will be one of the other physicians' choices. And so far, we are certainly looking like a drug with a very attractive profile for this.

So with that, I'm going to turn it over to Dr. Hanna. I've got a few questions for Dr. Hanna that I suspect many of you have already. And after that, we will turn it over to our audience.

So Dr. Hanna, good morning. Thank you for joining us early this morning. And I think my first question, which I'm sure is on people's mind, is just a brief background on what is oropharyngeal cancer? How do you define it? How many patients are there? How do they differ from other head and neck patients, et cetera?

Thanks, Yuval. Happy to join the conversation. And it's exciting to see, again, drugs moving forward in the advanced head and neck cancer space beyond the momentum that has been ongoing for the EGFR, the novel EGFR inhibitors. I've been waiting patiently for the antibody drug conjugates to surface in sort of the next generation of advanced trials for these patients.

So I think oropharyngeal cancer in general, as you outlined in the beginning of the discussion, is an anatomical distinction of sort of the back of the throat. We think of the tonsils, the base of tongue, sometimes the lingual tonsil or the back of the tongue tonsil and soft palate as making up this sort of area where HPV likes to hide. As you said, about 85% of oropharyngeal cases, particularly in never smokers and in the United States would be attributable or causal related to HPV virus, the high-risk subtypes being 16, 18, 31, 33, 35, et cetera.

And so we define it largely by a clinical constellation of features. Generally, it often has a predilection for men, as people know, 5:1, against women in terms of incidence. We know that these are often limited or never smokers, although that can be variable in some instances. They typically are people in their 40s to 60s, although there's some variation there, and that's based on the lead time that it takes for the HPV virus to set up shop in the back of the throat and then lead to changes over time that result in cancer or neoplasia. And so all of that together sort of defines the HPV-positive patient.

These patients, therefore, then compared to HPV-negative patients tend to be younger. They have less risk factors or carcinogen-based risk factors. And there is sort of a socioeconomic distinction between these patients if you look at demographics and in parts of the world where these patients are most present. Certainly, we have a large catchment in North America as well as in the United States specifically. And so I think important, as you pointed out, the trends in the biology of this disease suggest that we're going to continue to see a rise in more of these cases.

An elegant question I often get is, how is current vaccination, preventative vaccination impacting these rates. These rates are still going to rise likely projected through 2040, all the way through and plateau in 2050. So that's another 25 years. And that's because of the lead time in requirement for getting kids between 9 and 26 vaccinated and the time it will take to see epidemiologic shifts in cases. And so we're not going to see any slowing of cases at least through 2040 or '45 based on current predictions. And I think that's really important for thinking about who might benefit from a drug like CRB-701.

Dr. Hanna, on [indiscernible], the data shows us that seemingly, in North America and Europe, it's about 1 in 2 patients in these settings. But recently, you shared maybe with me some interesting anecdotes around sort of real-world data you're seeing or experiencing in your practice around how many of these patients are walking into your door as well as some of the age distributions. We know they're younger, you referred to it. I think you shared with me an anecdote that frankly surprised me around how young they can actually turn out to be.

Yes, that's the case. I actually just last week met a gentleman from the South who's 31 years old with recurrent metastatic HPV-positive head and neck cancer. So that just gives you a sense of the lower bound of the age range for some of these patients, and we see patients in their 70s and 80s. So while there are medians and averages, there are certainly patients that are on the edge of these bell curves and confidence intervals.

I would say it's particularly at a place like ours at Dana-Farber in Boston, where we have a pretty large New England-based population catchment. We do see a large percentage of patients with HPV-associated disease. As I was sharing with you, I would estimate that our group is probably seeing on average 5 to 6 new cases a week of curative or definitive head and neck disease related to HPV. And perhaps if you take all of our patients over the course of several months, I would say that in some instances, it's almost 50% to 70% of patients that are in our clinics have HPV-associated disease.

Now that is going to be -- there's going to be some regional and geographic variation and especially at our center, whereas maybe at our public hospital down at Boston Medical Center or across town at Mass General Brigham Cancer Institute, there might be some variation. But in general, we are seeing a large number of these patients, particularly in urban cities along the East and West Coast, which fits with how quickly the CRB-701 experience and trial has been able to recruit patients with oropharynx and HPV-associated disease with a small number of sites. So I think a really important point as we think about enrolling a confirmatory registrational trial, there is no shortage of patients in need with HPV-associated disease. And remember, about upwards of 20% or even 25% of all HPV head and neck cancer patients will eventually require advanced metastatic treatment and develop sadly either locoregional recurrence, persistent disease, incurable or metastatic disease.

So one of the sort of paradoxes out there is there are these 2 competing notions. So one is there is a very meaningful population of these oropharyngeal HPV-positive patients, the other one is we have the rise now of these very exciting EGFR bispecifics and that are generating a lot of excitement and interest. And it looks as though the oropharyngeal or HPV-positive patients are being left out of that. So maybe help us understand what is the challenge here with the EGFR bispecifics? And then drawing from that, what is the unmet need if one is an oropharyngeal patient?

Yes. So I think you're highlighting what I have been thinking about over the last year as petosemtamab, which is an EGFR LGR5 bispecific, and ficerafusp alfa, as you know, the EGFR TGF-beta trap, have come into clinic. And now amivantamab sort of catching up quickly, this EGFR c-MET bispecific. Largely, the data is very clear that EGFR signaling is most critical in HPV-negative biology or carcinogen-driven biology. It is much less of a biological entity in HPV-associated disease, which is driven more by early proteins, E6, E7, and modulation of things like Rb and p53.

So I think you made an important point that if any of these trials or all of these trials in the first line, whether it's FORTIFY or the LiGeR trials or the OrigAMI studies, are all positive or some are positive, we're going to be looking at a new paradigm in treating HPV-negative disease with these novel EGFR therapies. So that leaves a wide open gap for the rising and increasing incidence of HPV-positive patients that we're seeing. And I can tell you, it's much easier to enroll HPV-positive patients just because there are so many less trial options for these folks. And as you highlighted, the need is growing. So if 20-plus percent of those patients develop advanced disease or incurable disease, you can see how the numbers are continuing to rise.

And I would just sort of focus on peto for a second because, as you said, while it's not confirmed and the trials, both the first and second peto studies -- sorry, monotherapy in second line and the combination IO plus peto trial in first line did enroll a percentage of patients with HPV-positive disease, their confirmatory studies, roughly 30%, it's not clear that they will observe a robust signal in that population for benefit. And it may be that the agency, the FDA decides in the end that there is not enough data or patients to justify a label that includes HPV-positive disease.

If that is the case, that will make even more of a wide open space beyond EGFR targeting for patients with HPV-positive disease, who right now have pretty limited options after the first line, our traditional pembro, pembro chemo option. That puts us in a position where second line, we're relying on garden-variety, old-school chemo, taxanes, 5-FU methotrexate-type drugs, but prioritizing clinical trials. So huge developing unmet need. This trial is coming. This Phase III trial, TEMPO-1 is coming at a very critical time.

We talked a little bit about or highlighted the unmet need here, the encouraging efficacy we're seeing, but there is a price to pay with this drug, and that is the ocular toxicity. Can you contextualize that, both in terms of how you're dealing with it, in terms of your familiarity with ocular tox as an oncologist, and contextualizing also the impact on the patient and what is that stake for the patient at that stage of their disease?

Yes. I think this is a really important point. I mean, first thing we have to acknowledge is who this patient is. And before we talk about the ocular toxicity, this is a patient with an incurable recurrent metastatic cancer, who is going to unfortunately succumb to that cancer at some point without meaningful cancer-directed therapy. And with that palliation comes the notion of what toxicities we're willing to accept to extend one's life and to minimize disruption of quality of life.

So let's just be clear about that when we're talking about, yes, there's ocular toxicity. And anything that mentions vision can be sort of a concern, but we need to realize that these are incurable patients who have already failed immunotherapy and/or chemoimmunotherapy, and we're trying to extend their life, hopefully by many months, if not years.

So having worked with this drug now for quite some time, I think the first thing to realize is that this does seem to be a reversible problem. So while we counsel patients that they may have some issue related to blurry vision or difficulty seeing while driving, for example, that may disrupt function for a period of time, with appropriate monitoring, holding of drug, intervention, and interception with certain eye drops, this is a reversible process. As you said, we thankfully have not seen significant persistent long-term effects that we're aware of at this point. So I think that's important.

I think the other thing to recognize is there are a number of other toxicities related to antibody drug conjugates as a class, which I've worked with many of them now over the last several years, as they've tried to move forward in head and neck. There's no free lunch here. I mean, these patients, there is some toxicity issue associated with a number of these drugs, and you highlighted some which are less of a concern for CRB-701, but extensive peripheral neuropathy, it's often irreversible and can result in significant mobility issues and daily activity or daily living disruption. That's something that patients need to be aware of. Significant skin toxicity can be an issue. Pneumonitis or lung inflammation resulting in discontinuation. So again, we're not seeing those things. And these vision issues tend to be manageable. They do mitigate with drug holds.

We have, thankfully, routine availability of Ophthalmology. I think that's the other important thing. We haven't run into issues with being able to refer patients to different venues throughout the city, for example, at our site, who can help to manage and monitor these ocular changes, because sometimes there's not even visual symptoms. It's just the beginning of monitoring changes on an eye exam, for example, where there might be mild corneal inflammation and we want to be vigilant with eye drops, for example. But again, with a few eye appointments and integrating eye drops, generally, patients are able to continue on drug, sometimes have to dose reduce, but able to maintain or resume dosing and demonstrate efficacy and benefit from the agent. And I think that's sort of the clear message I would make.

I think the other key point I would say about the ocular toxicity in general is that for most of these patients, when talking to them about pros and cons of different drug therapies, they seem to be very willing to participate in doing the eye care upfront and using eye drops sort of preventatively, keeping their eyes moist, et cetera. So I think patient engagement has been a positive signal for how we're able to handle this.

And the last thing I would say is, I would remind the investors and those listening, there are ADCs on the market that already have ocular toxicity warnings. I sometimes use off-label datopotamab. We just got another approval for datopotamab in the breast cancer setting. Now also in lung cancer. There's a required ocular exam prior to start. There is a well-established 25% rate of grade 1 to 2 ocular toxicity with that agent, and it seems to be something that patients can manage and that drug is on the market. So I do think we also want to contextualize the sort of placement of this drug outside of just head and neck cancer and in the broader ADC approved landscape.

Thank you. Very, very helpful. Let's turn it over to our audience. And operator, if you could go ahead and start the Q&A session, please.

[Operator Instructions] Our first question today is coming from Brian Abrahams from RBC Capital Markets.

Just 2 for me. I guess, first, it sounds like the ocular toxicity is pretty manageable, or continues to be pretty manageable overall. But I was wondering if you could elaborate a little bit more on the overall safety, including the ocular tox by dose at the 3.6 mg per kg dose and by the subpopulations.

And then secondly, just on the TEMPO-1 Phase III, can you maybe talk a little bit more about the mechanics of that study? Just how the interim analysis will work, when you think that might occur, what the bar would be for the primary accelerated approval endpoint on overall response, and just maybe a little bit more about that study design.

Brian, thank you. Let me start and then Dr. Hanna, if you have anything to add. On the dose by dose, we have that in the poster. So there are certain things that we're waiting for -- or we'll wait until the poster comes out. It is smaller numbers. I will say that overall, it's the same pattern. It also doesn't seem to be tumor-specific, which is encouraging. And I think on this deck already, Brian, we gave a breakdown specifically of the discontinuation and interruptions for the 3.6 mg per kg for ocular specifically as a dose.

And for TEMPO-1, we'll give you more updates at ASCO and shortly after. And again, we're just waiting for the final protocol approval from FDA. And once we have that, we will share that with you. We'll also share with you the specifics of what is the physician's choice, although I don't think it's particularly exotic. As you can imagine, for example, it's highly unlikely that it will be cetuximab in this population. But Dr. Hanna, is there anything you'd like to add at this stage?

Yes. I would just say to the first question, as you've all pointed out, without sort of saying too much, Table 2, which will be in the poster that's released this week, specifically addresses the question of dose-related ocular toxicity or keratitis. There is a sort of column that outlines the rates by dose level. So you'd be able to compare that to the total rate that was shown in the deck to you today.

And then I would say for the second question around the design of the trial, I will say this is a trial that's involved a number of key opinion leaders, including myself. And I think without saying much about the specifics, I would argue that the bar is probably generally pretty low, because you're thinking about a population where they've already been through chemo-immunotherapy. There's no standard agreement or preferred regimen in the second and third line, which the TEMPO-1 study would address as the comparator. And the traditional response rates, it's hard to know for HPV selected patients, because years ago, when these drugs were being defined as second, third-line options, we didn't tease out HPV-associated disease at that point in time.

I would argue that the response rate benchmark for most of us sits around 20-ish percent to even maybe a high end of 25%. So it's pretty low. So I mean that would be the bar in general for a second, third line recurrent metastatic head and neck trial. And so I think welcoming an ADC versus investigator choice design is very, very much on trend with what one would expect for a drug like this moving into registrational studies.

Next question today is coming from Paul Jeng from Guggenheim Partners.

Congrats on the nice update and providing all the helpful commentary. For the head and neck data, understanding it's early days, but is there anything you can say about how survival is trending? And specifically, have you seen enough durability on that front to finalize your powering assumptions for the Phase III? And related, how do you think about the control arm bar for survival in oropharyngeal patients? And then I have a follow-up.

It is, in that sense, early days, although what we're seeing in terms of DoR and PFS is certainly encouraging for that. Paul, I think we're just going to have to wait and see how that matures. The powering assumptions, again, Dr. Hanna has been very helpful with his comments. Remember, if I may, what we saw, for example, in -- and this is a little bit of speculation. What we see, for example, in peto second-line monotherapy is a larger study. But remember that they chose to address all comers. In other words, they have a population that is a mix of HPV negative, where they will see strong responses, and HPV positive, where we know that their responses are not as strong and that could create a certain amount of "drag".

We've chosen, philosophically, to do something that's much more similar to what Bicara and J&J are doing in their frontline setting, which is to focus exclusively on that 1/2 of the population where we see strong responses and not spend effort on another half of the population where we are very unlikely to bring benefit. Dr. Hanna, anything you'd like to add to that?

Yes. I mean I think what you're getting at is a great question. I would argue that early clues to the OS benefit is going to come from the durability and PFS, which you've all highlighted nicely that PFS for the second, third line plus median 3 line or more population with CRB-701 is around 6 months at the preferred 3.6 mg per kg dose. So that bodes well for an advanced population.

When you think about -- again, not necessarily for this particular drug, but in general, when we think about median OS for a second, third-line population, when we've looked at the follow-up data to KEYNOTE-048 from Dr. Harrington looking at second -- PFS-2, so to speak, and survival after exposure to chemo-immunotherapy or IO, trials are sort of hovering around median OS of 8 to 10 months. So I would say that's kind of the range we're interested in, in terms of recognizing that this is also going to be an oropharyngeal population where we need to maybe do a little bit better on the higher end just because these patients tend to do better with all treatments we give them as compared to an HPV-negative patient even in this setting.

So all of that's being accounted for and has been accounted for in the registrational design of TEMPO-1. But that just gives you sort of some numbers to start to chew on in terms of what we would project for median survival improvement -- or sorry, median survival and what we would need to improve upon with the CRB-701 experience.

Got it. So maybe a quick follow-up for Dr. Hanna. When you think about the provider base that may be treating patients with 701 in the real world, how attuned are you and your peers to a paradigm that sort of dissect by oropharyngeal versus non-oropharyngeal? And currently, is that already fully ingrained as a factor that might dictate, for example, EGFR use? Or is there some degree of education that's going to happen on that front?

No, I think that's pretty well established. I mean, the narrative around HPV causality linked to oropharynx has pretty much the entire head and neck community. And I would say the oncology community in general, even general oncologists who dabble in head and neck are comfortable with oropharynx versus not. So I actually don't think it will be an issue. This is not a new designation. This is not a new sort of way to separate apples and oranges. So I think that should be very clear for the oncology community.

Our next question is coming from Amin Makarem from Jefferies.

A couple of questions from us. First, I have a question for Dr. Hanna on patient selection. How straightforward is it to distinguish oropharyngeal patients versus other subtypes of head and neck? Are there clear boundaries there? Or are there gray areas when assigning patients? And then I have a follow-up.

Yes. And this sort of dovetails on the last question. It's actually pretty clear. I mean, when we see patients in clinic and we review scans and we look with an endoscope, a nasopharyngoscopy exam with a camera flexible scope, it's pretty clear that a patient is presenting with a base of tongue primary, which is exophytic and sort of sitting in the back of the tongue or arising from the tonsil, you can even feel this location if you palpate induration around the tonsil. So believe it or not, these anatomical distinctions are pretty straightforward and often correlate clinical exam on our endoscope and our physical exam with what we see on CT imaging.

Plus you take into account the fact that usually the demographic and clinical characteristics of the patient align with those physical findings. So as we said, limited never smoker, often in their 40s to 60s, predilection for males. And just for you all, in initial stages, most men present with, or HPV patients or oropharynx patients in general present with a sort of cystic enlarged neck node, which is ipsilateral or on the same side of their primary. I mean that's sort of like a bread-and-butter classic presentation. So I don't see any concerns with delineating patients anatomically and clinically based on those findings. I think it should be quite straightforward for our community.

Helpful. And for the TEMPO-1 study design, it includes an adaptive feature for interim analysis and sample size potential re-estimation. Why do you think there could be a need for sample resizing?

Dr. Hanna, go ahead, you were very helpful in that protocol design.

Yes. So I think it's very prudent to have an interim analysis that's assessing response rate, I think, for garnering enthusiasm and making sure that we're seeing what we want to see in terms of the Phase III component of things as compared to our experience in this growing Phase I, which almost feels like a Phase II now with dose selection at 3.6 mg per kg. So I think we would, as I said before, sort of ideally look for response rates in the second-line advanced head and neck cancer setting for recurrent metastatic disease around that sort of 20% to 25% range. I think the details of the protocol are still being finalized. But if that were to be the case with an acceptable confidence interval, we would then also look at the PFS and OS signal for that first group of patients and then decide, do we need to increase the number of patients in the study to, therefore, tighten up the power or the signal for an improvement in OS.

So I think it's an opportunity, right? It's an opportunity to pause, make sure we're not seeing any new safety concerns, making sure that our Phase III experience is doling out what we were expecting in terms of hitting response rates as compared to that initial Phase I that we're doing, and then make sure that we feel like we have enough patients to adequately assess the power related to an improvement in OS. So this is fairly standard, as many of you know, for contemporary Phase III registrational studies. I know that FORTIFY is doing something similar around -- or it did around its dose selection. Certainly, peto is doing something similar and recently added patients to both their Phase II and Phase I.

Our next question is coming from Jeff Jones from Oppenheimer.

Really appreciate the additional detail here this morning. I guess 2 questions from us. Can you speak maybe mechanistically a little bit more to the difference in effect you're seeing in the HPV-positive patients? You mentioned Nectin-4 expression levels. And maybe then how you think about that impacting patient selection for the Phase III biomarkers and/or subgroup analyses?

And then curious how you're thinking about first line given, as you mentioned, the Padcev-Keytruda data, and how that might impact your thinking about second line down the road or moving ahead into first line?

Thank you, Jeff. Mechanistically, it fits nicely with a number of things. It's very similar conceptually to the dynamic of cervical cancer, right? We've known that this is one of the richest Nectin-4 tumor types out there as it's surgical. Remember that our very strong presence to date has been not to explore this ADC in bladder, simply for market reasons, commercial reasons.

The other thing, Jeff, that I think will be helpful for the audience to realize is, if possible, we would rather avoid a companion diagnostic approach. We would rather avoid having to do a biomarker selection in any of our tumor types. A reminder that, that is what Padcev managed to avoid doing in bladder, because bladder is so Nectin-4 enriched that there was really no rationale for having a specific CDx built into it.

In cervical, something like 98%, I think, of these women are HPV positive. And in head and neck or oropharyngeal cancer, as we heard today, and we've seen today, both our data set as well as the literature indicates something like 80-plus percent of these patients are positive. And so what we prefer to do is the anatomical selection and focus on that. What we've heard from Dr. Hanna and other of our clinicians and KOLs is that, that is also their strong preference. And as you can imagine, this was also a subject of discussions with FDA around that path forward. Dr. Hanna, anything to add to that?

Yes. I think I would just add a little bit more scientific color there. So Nectin-4 is a cell adhesion molecule. It belongs in the family sort of that allows epithelial cells to junction or sort of remain tight, and you think about that as being important at the intersection of cells breaking off and leading to metastases. So Nectin-4 does sort of play an important role, and there's biology that suggests that it's linked to viral transformation, how epithelial cells differentiate, and also that invasion metastasis question.

It's been shown to be able to activate things like PI3K signaling, which 30% of HPV-positive patients have, as well as Wnt/beta-catenin signaling, and it's also been important in promoting proliferation and motility and epithelial mesenchymal transition. I think all of that serves preclinically to strengthen the relationship between Nectin-4 and HPV. But fundamentally, the 2 points clinically I would comment on is that Nectin-4 is a validated target. Many of the patients enrolled for the initial Astellas/Pfizer study with EV were HPV positive, and there were response rates, as you all know, in combination with pembro, but also as a single agent as published in the JCO experience, and that's now in the guideline. So we know this is a validated target in this population. And then as you've all said, we have another candidate example of HPV-associated cancer in cervical that's showing nice response rates. So I think all of the totality of that data serves to strengthen its role for HPV cancer.

I would say for the second question around avoiding a companion biomarker, I think that is a smart move for a number of reasons, not just financial or from a regulatory standpoint. But there are a couple of arguments as to why you would not want to restrict. So when we're running this large TEMPO study, one of the things that could disrupt enrollment, dissuade enrollment, or complicate patients getting on is requiring central testing in real time for something like P16 or HPV. P16 testing is done at many labs, it's CLIA certified, but not every institution, outside of some of the major academic institutions, rely on HPV confirmatory ISH or PCR testing to show viral association. Remember, P16 is just a surrogate marker for HPV. It does not imply viral causality.

And so if you slow a trial down by requiring central testing, you're going to disadvantage patients, you're going to have drop out, you're going to have issues with delays to getting patients on when we can collect that data and check HPV and P16 status ad hoc or as a secondary analysis in the end. And we know that the vast majority of these patients, 85-plus percent, will have HPV-associated disease in the end, and we'd rather not slow that enrollment, and that would perhaps complicate a label.

And there's no preferred assay, right? People use whatever assay their institution prefers. P16 IHC can be done in a number of CLIA labs, but HPV testing is not unified or central. You can do ISH probes towards several probes, you can do PCR testing. So if we introduce that element of complexity, I think it would be a disservice to the patients and slow the trial down. So I think those were some of the fundamental reasons behind an anatomical designation for eligibility as opposed to a laboratory or biomarker companion.

And jeff, just to your second question on frontline, second line, and with that we're going to have to wrap up. But what we are emulating is both what Padcev did in bladder and what peto is doing in head and neck. We start with second line where we already have data, it's actionable. It seems like a very attractive commercial opportunity. We move forward with that, and that is the indication that will be first to market if all goes well. And then we also explore frontline, as Padcev did and as peto did. And in the frontline setting, we'll see what the data looks like early next year.

If the data looks encouraging, and again, we have this precedent of Padcev, then it will be very sensible to trigger that as well, knowing though that, that is a larger and more longer study than the second line, and it may actually eventually end up eclipsing the second-line indication in the same way that these days, for example, very few patients in bladder gets acted as monotherapy in second line. It really is all about now frontline plus pembro. But that takes time, and it's a much larger effort. And being able to plant the flag as peto is initially in second line will have some very important commercial ramifications.

Can I just add before you end, I just want to say that I would second everything you just said. To jump into first line with a combination right now, regardless of the HPV signal, would be not the appropriate place or the highest unmet need. The highest unmet need is beyond chemo-immunotherapy and IO where this single-agent drug by itself could become an established standard of care for these patients and replace sort of the outdated and historical controls of chemotherapy and less ideal agents. So we in the KOL community are very supportive of pursuing the second, third-line option first.

Thank you, Jeff. So with that, I'm going to wrap up. I'm sure there'll be lots of follow-on questions. I look forward to seeing, I hope, everybody, starting on Friday at ASCO. Again, a reminder, Friday sort of late afternoon is our cervical oral presentation. The next day, we have the poster. That poster should go live that morning. And of course, we'll put everything on our website as well. And then last but not least, our breakfast KOL event on the Monday morning, bright and early at 6:30 Chicago time with Dr. Hanna, Dr. Perez, and Dr. Rosenberg.

I'd like to thank Dr. Hanna for his time this morning and for all the hard work he's been putting into this program as well as, of course, thanks to the other clinicians, health care workers that have been part of the study, and the Corbus team, of course, and last but not least, of course, the patients themselves. Thank you, everyone. And operator, it's over to you.

Thank you. That does conclude today's teleconference and webcast. You may disconnect your line at this time, and have a wonderful day. We thank you for your participation today.

Thank you so much. Bye-bye.

Thank you. Take care.

Good morning, everyone. Welcome. We're excited to be continuing our 44th Annual JPMorgan Healthcare Conference. My name is Roland Ye. I'm associate on the health care investment banking team. And today, it's my pleasure to introduce Corbus Pharmaceuticals and CEO, Yuval Cohen. We'll have time for Q&A at the end. And with that, we'll hand it over to Yuval.

Good morning, everyone. Roland, thank you so much for that introduction. It's a delight to be here. We're very grateful to the JPMorgan team for hosting us again. I'm going to focus this morning on 2 of our assets. I'll start with important milestones coming up this year for our ADC. And then I'll talk a bit more about a refresher of our recent obesity data and the milestone there. I'm assuming everyone in this room and probably everyone listening knows the background of Corbus, understands our pipeline. So let's dive straight into it.

The key questions, I think, for CRB-701 in 2026 are the following, and I'll divide it into the 3 possible indications of this study -- of this drug. The first one revolves around our second-line monotherapy in head and neck. We presented updated data on that at ESMO. We have more and more patients. The duration is getting longer and longer, but it's still an earlier data set that we presented from this September data cut.

Later this year at a large oncology conference, our aim is to present the maturing data, where the key question revolves around the duration of response for these patients. I think we've established that CRB-701 is active in second-line head and neck. And now the question is how durable is that activity? How durable is that response.

Coinciding with that is on schedule this quarter, we're having discussions with FDA around what does the registrational pathway look like for this second-line monotherapy in head and neck for CRB-701. We don't anticipate that being a particularly dramatic discussion. There is a very clear and sensible precedent from [ PETO ] around second-line head and neck, and we will provide that update later this quarter.

And so between that update and the durability data, that would give us the informative data set that will enable us to move forward. At the same time, the second key combination of both registrational pathway and data revolves around our cervical data. And so here, again, at ESMO, we presented a young emerging data set in second-line cervical cancer. Again, clear signs of clinical efficacy. In cervical, it's a little bit easier to triangulate because our partners in China, CSBC already shared some of their cervical data.

And in fact, for that matter, their competitors in China, Mabwell, with a different construct of Nectin-4 MMAE ADC also shared data and all 3 data sets look remarkably similar. The question here, again, is durability. How durable is the response that we're seeing in these women in the second-line setting in cervical cancer.

And in an analogous fashion to what we just described for second-line head and neck, what is the registrational pathway. So also this quarter, parallel discussions with FDA around what does that look like. Here, the precedent is not helpful to us. The precedent would be TIVDAK in second-line head and neck -- second-line cervical apologies.

TIVDAK harks back to a time where FDA was probably a lot more open to single-arm accelerated approval stand-alone studies. Our assumption is that this FDA is less welcoming of that. And frankly, we wouldn't be particularly interested in that if that were a pathway. And so the discussion with FDA around second-line cervical is around a controlled study versus physician's choice.

The discussion will revolve around what is that physician's choice. TIVDAK is certainly one of those choices, but not the most common choice for physicians. And so we'll have that clarity from FDA. And again, in an analogous fashion to second-line head and neck, we will share that clarity. We will share the maturing data set, the durability data set this year.

And those 2 would allow us to really chart the path forward. The last milestone this year is around the data set that we don't actually have yet, but is increasingly being brought up in conversations we're having. And that is the -- our most recent study with CRB-701, which is frontline in combination with KEYTRUDA in head and neck. That study started relatively recently. It's a very young data set.

It should start to mature towards the end of the year. And that is a very, very different type of pathway unlike the second-line monotherapy head and neck, which is a pretty quiet swim lane for us. Frontline is seeing a lot of interest, a lot of competition, but with a very different mechanism of action.

The emerging frontline landscape in first-line head and neck is EGFR-dominated combinations that are either entirely biased or partially biased towards HPV-negative patients. And so that leaves us with an interesting possibility of positioning ourselves in combination with a checkpoint inhibitor, in our case, KEYTRUDA in that frontline setting. We don't know what that data would look like. We look forward to that data maturing and to sharing it with you later in the year.

What we do know is that Nectin-4 -- there is an example of a Nectin-4 MMAE working very, very well together with KEYTRUDA, and that is, of course, PADCEV plus KEYTRUDA in frontline bladder. It will be fascinating to see if we replicate some of that additivity in the frontline setting of head and neck.

And so just to summarize on our ADC front, 3 cards that are sort of flipping this year as it were, second-line head and neck durability and regulatory clarity, second-line cervical durability and regulatory clarity. And the last one, the most intriguing one perhaps, but a very unpredictable one is the emergence of the frontline head and neck in combination with KEYTRUDA.

So not a lot of drama, a pretty understandable, a pretty clear set of actions that are required from our perspective on CRB-701. And with that, to a field that could not be more different, which is obesity, of course, and our oral once-a-day small molecule CB1! inverse agonist.

Those of you who have been following the Corbus story know that we have a deep passion and expertise in this field and really have been championing the reemergence of these peripherally restricted CB1 inverse agonism. This is a mechanism that, as a reminder, was of great interest exactly 20 years ago.

This year is the 20th anniversary of rimonabant being approved in Europe and then had a really very significant setback to say the least, and that has come back. And it's come back with 2 parallel efforts. The one these days resides in Novo Nordisk, and that was or is Monlunabant. And the other one is CRB-913. A reminder, they are related. They're cousins, not very close cousins, but cousins.

We both share the same ancestor. Novo Nordisk, of course, reported their data in November of '24. That was a pretty memorable day. It wasn't a very pleasant day for us, and it was an extremely unpleasant day for them. And they recently published that data. That has not been picked up by many people. That was in the September issue of the Lancet diabetes.

CRB-913 finally got into patients, although we did it in a record time, but finally got into patients with a SAD/MAD data that we announced in December and is now in the dose range response data, the Phase Ib. A reminder that there is something fundamentally different about our 2 drugs. They are cousins. But while the Novo Nordisk, while Monlunabant is peripherally restricted, there is less of it in the brain than rimonabant, we are more than order of magnitude more restricted than they are. Our drug is very, very, very, very, very low levels in the brain.

And of course, there is a mirror slide to this slide, which could ask how much is in the brain and then how much is in the periphery. That's a bit more tricky for us to do because we don't know the exact levels of Monlunabant in obese individuals. But nevertheless, we can do some fancy modeling, and we reckon we are about 30% to 40% higher levels in circulation and obese fed individuals than Monlunabant.

So the differences are there's markedly less of us in the brain compared to Monlunabant and markedly more of us in circulation compared to Monlunabant at the same dose. This was the design of our SAD/MAD study. It's a pretty unremarkable design. We don't want to be particularly creative in the field of obesity. And so we have a ladder of SAD and a ladder of MAD.

All the blue cohorts are cohorts that were not selected for any BMI requirement and the 2 green cohorts are cohorts that were exclusively selected for high BMI. So these are individuals with obesity. And a reminder that the doses we gave in SAD/MAD, as is normal, are doses that are much, much higher than you would normally end up giving in the clinic.

So our 150-milligram a day dose is about 15x more than the clinical dose of Monlunabant, and we have every reason to believe that we are equally potent to Monlunabant. So what did we see? We'll start with safety. This is a Phase Ia. And in the case of CB1 inverse agonism, it really is all about the safety. CB1 inverse agonism is very, very likely to work in patients.

Every CB1 inverse agonist ever tested in the clinic has led to weight loss. I don't think there's a lot of controversy around that. The question is, have we solved the issues of safety surrounding that first generation. The first safety event, which was of interest to us and which frankly surprised us was GI toxicity or GI tolerability.

CB1 inverse agonism does not tend to affect gastric motility. If we go back to rimonabant's data, they have GI adverse events, but they tend to be pretty mild and at about 10%. It's not at all the same degree of GI tox that we would get with either an incretin analog or an incretin agonist.

One of the surprising data points in that Lancet diabetes paper on Monlunabant was the degree and magnitude of GI tox with Monlunabant. That is highly atypical of a CB1 inverse agonist. It is so atypical that we think that, that might be an off-target effect.

Monlunabant in some ways can be thought of as being almost a prodrug. It has a remarkably high degree of an accompanying metabolite. And CB1 inverse agonism has never shown these levels of GI tox. This looks a lot like an incretin analog.

What was very reassuring was to see in our data set on the right-hand side, a very, very mild profile of GI adverse events. It is in line, if not better, than the first generation, and that is typically what you would expect from a CB1 inverse agonist. The difference is remarkable. GI adverse events were the second most common reason for discontinuations with Monlunabant. These were not an inconvenience. These were a serious problem for these participants. So that is a case where the 2 safety profiles look markedly different.

But of course, if we think about that first-generation CB1 inverse agonism, we always think about the neuropsychiatric adverse events. After all, that was the issue around that first generation. We have a very, very granular view into the Monlunabant adverse events from their 4-month study, just like we had with GI adverse events. And what we see, there are a number of things. The one is very typical. Neuropsychiatric adverse events regardless of the mechanism of action, for that matter, regardless of indication, tend to appear very early on.

They tend to not be adverse events that occur much later in the study. And that is exactly what we see with monlunabant. It is dose responsive, which is also very reassuring in that sense.

The problem is there are a lot of them -- so in 180 participants, they had 111 events of neuropsychiatric adverse events. Now while the vast majority were mild, that's not great. That is problematic. And they were the member on cause of dropouts in the study. Again, that is a problem, especially in a study that is actually quite short, 4 months of dosing. And so despite monlunabant being at about 50% of the brain penetration or the brain levels of rimonabant, there's clearly a problem. There's clearly a problem there.

It was especially gratifying, especially as a scientist at heart, it was especially gratifying to see what our data looked like in terms of neuropsych. Remember, it's -- the whole premise here was keeping this drug as much as possible from the brain would lead to a differentiated neuropsychiatric adverse event profile.

It's wonderful on paper, but it's especially satisfying in our industry to actually see that happen in real human beings. And so to our delight, we had absolutely no clinical events of neuropsychiatric. So CSSRS, PHQ-9, GAD-7 were negative for all patients at all time points, time points were daily. And at all doses, remember, these individuals or some of these individuals are getting doses that are 15x higher than the Monlunabant doses. And so that was really, really wonderful.

We had, of course, no cases of suicidality, depression or dysphoria, which is delightful. Not even in the case of insomnia, which is remarkable given that this is a Phase I unit. These participants are not in their house or not in their home. So that was really, really nice to see.

We had the sum total of 3 cases of mild anxiety. This anxiety did not breach CAD-7 or PHQ-9. In other words, this is everyday human experience anxiety. One of which was situational. In other words, something happened to that participant that triggered them feeling anxious.

And the other two happened outside of the dosing window, one of which corresponded with gaining back weight once the drug was clearing out. So that's really encouraging. Now of course, this is a short amount of time, and we need to see more and for longer, but it is already so remarkably different than what we saw with Monlunabant, for that matter, with the first generation that we really are very, very excited about this.

The second question was, does it actually work? So in most of our SAD/MAD cohorts, we were not selecting for BMI, as I've mentioned. So we have a collection of people who are thin and overweight and obese. But we did have one cohort in the MAD that was exclusively high BMI. 12 individuals in total, they spend a week being dosed and then another week observed in the clinic.

So it's 2 weeks of them living effectively in a fish tank. And that allows us to have a very controlled environment in terms of what they're eating and what they're experiencing and what they're exposed to. And so we, at the end of the study, look back and asked the question, did anyone lose weight?

We were not expecting this degree of weight loss this quickly. And so what we saw were every single participant who was dosed with Monlunabant lost weight that in and of itself is unusual and delightful. And the weight loss was significant. These are not small fluctuations in weight in such a short period of time.

On average, it was nearly 3% weight loss after 1 week of dosing measured at the 2-week mark. To put that in context, if we look at sort of -- there's an interesting league of weight loss as it were in different mechanisms of action. And if we look at that league and the speed of weight loss and the depth of weight loss, we are in the top 4 mechanisms that have ever shown such a weight loss that quickly.

The other 3 are all incretin analogs. That were remarkable in their weight loss, but associated with a very high level of gastrointestinal adverse events. A reminder that you can lose a lot of weight if you have -- that's accompanied by a lot of vomiting and gastrointestinal intolerability.

We had no GI adverse events. We had one mild case of possibly related diarrhea. That's it. And so CRB-913 acted in a very robust manner to reduce weight. The other question we had was this graph shows that it is clearly not just driven by a single patient, but we wanted to know the temporal cadence of this. Did this all happen on the last day? Or was this gradual? And that's very easy data for us to pull out of the study as well. And so what you see in red are the placebo participants and nothing much happens to them, as you would expect.

And in blue is the cohort that are high BMI. And you can see that weight loss starts early, and it just keeps deepening as the study continues. A reminder that we dosed them only for the 7 first 7 days. The momentum of this compound is really, really satisfying to see. All CB1 inverse agonists have long half-lives measured in several days. That's not atypical. So that momentum makes sense.

Still, it was really quite remarkable to see this type of -- in this depth of weight loss. So we're really delighted with that. We have -- we did not have dose response cohorts that were exclusively high BMI, but we did have a dose response -- 3 dose response cohorts or dose escalation cohorts in the non-BMI selective cohorts.

And maybe it's a factor of just where the Phase I unit was in the United States, but our average participant in these 3 cohorts was already overweight to a certain extent and some of them were obese. And so what we see is a clear signal of weight loss even in the lower doses. The other thing you'll notice is that our 75 milligram a day dose and our 150 milligram a day dose in these 2 cohorts look really similar.

That's encouraging. We think the 150 dose is beyond the linear S curve. And so it means that 75, we would expect initially to be quite as efficacious as the 150 -- in other words, it means that we can afford to dose lower and still get the same efficacy.

Next 2 slides are cross-trial comparisons, which are comparisons that are very popular in the world of obesity with all the caveats, of course, that come with them. The first one is very easy to generate. We have so much data around rimonabant.

So it's very easy to generate a 16-week rimonabant weight loss curve that's placebo adjusted. And then the 3 curves that come out of the Phase IIa from Monlunabant. There is also the small curve that comes from the Phase Ib for Monlunabant. And then lastly, the very short green line is our high BMI 2-week dosing for CRB-913.

And so what you're seeing are a couple of things that I think are worth thinking about. Both Monlunabant and CRB-913 are clearly more potent than rimonabant. This is a very, very important observation.

One of the concerns with the emergence of this new peripherally restricted CB1 inverse agonist was that they would take a hit on efficacy. It seems to be exactly the opposite. The fact that they are so much more in the periphery than rimonabant was has translated into even better efficacy.

And remember, these are equi doses, especially around monlunabant, the doses are not dissimilar to rimonabant. And so what we're seeing here is a new class of CB1 inverse agonist that is markedly more potent than the first class that is unexpected and very, very welcome.

It opens the door to speculating what could this class show as monotherapy. A reminder that Novo Nordisk were guiding back in September of 2024, before September of 2024 to mid-teens to high teens eventual efficacy of Monlunabant, presumably at the 1-year mark.

They did generate open-label extension data that has yet to be published. But if we look at the Monlunabant curves from their RCT, it is not very hard to imagine that those do end up at the 1-year mark in the high -- in the mid- to high teens. It will be fascinating to see if they publish that. It makes us increasingly more and more confident that we may actually have a markedly more potent compound than we anticipated.

The other slide we can do is compare -- cross trial compare to a completely different compound, and that's Orforglipron. If Monlunabant is not a relevant competitor anymore, then what is a relevant at least benchmark. And that would be the easiest one is orfoglipron. Luckily, there is an Orforglipron publication, which is a very appropriate comparator, of course, with all the caveats. And what you see there in green is CRB-913. What you see in the other colors are orfoglipron.

And a couple of observations, CRB-913 does not look like orforglipron. It looks markedly more potent in at least a short period of time that this SAD/MAD provides, both for us and orfoglipron. A gentle reminder that orforglipron at a year is effectively sub-10%. Monlunabant at 4 months was at 8% already. And so we really are talking about something that could be not just similar to orfoglipron, but potentially really surprise us on the upside.

The other very big difference is this little table on this slide. Orforglipron is after an incretin agonist. And the gastrointestinal adverse events are as to be expected for the class. And again, a reminder of juxtaposing what was seen with orforglipron in a 4-week period versus what was seen with CRB-913 in a 2-week period, and they really are markedly, markedly different.

So what could you do with this compound? And then we'll talk maybe about upcoming milestone this year. In Slide 49, what we endeavor to do, and some of this is sort of back of the envelope, but I think it's pretty accurate. It's pretty robust, is we take the data set of approved incretin analogs, and we divide it into 3 slices. And the first one are responders and about 60% of patients are responding and do well and can tolerate them to various degrees.

For that slice of the pie, what would be intriguing to do with CRB-913 conceptually would be an induction maintenance usage. We have very, very, very good ways of losing weight for these 60% of patients with the injectable incretin analogs.

What is more challenging perhaps is lifelong weight maintenance and doing so with an injectable incretin analog is could be perhaps improved upon. And so conceptually, the idea would be you lose weight with an incretin injectable incretin analog and then you replace that with a daily oral pill that does absolutely nothing.

You don't lose further weight. That's not the point of the exercise. What it does is it prevents you from regaining the weight. It keeps your weight stable. And the key there will be tolerability, especially GI tolerability.

The other slice of the pie are the intolerant patients. So these are individuals who start incretin analogs and presumably the same thing will happen with incretin agonists and they just can't take it. The GI adverse events are just too much. There, an orthogonal mechanism of action is desirable. The chances of being intolerant to both seems to strike us as being unlikely. And so there, the idea would be to offer them a replacement, especially if that replacement alternative could be equipotent at least to an incretin agonist. That could be really, really disruptive.

The last ones are the nonresponders. So these are the individuals who can tolerate incretin analogs or agonists presumably, but it just doesn't do much or doesn't do anything. And so there, what we know is patients who are non-responsive for one of the incretin analogs tend to also be non-responsive for the other incretin analogs. There, an orthogonal mechanism is, again, intriguing, potentially either as a combination to try and kickstart the system perhaps or again, as a stand-alone with an orthogonal mechanism.

So what are we doing now? And what is the important milestone here this year for Corbus, apart from the ones we talked about for oncology, and that's CANYON-1.

That is our version of effectively what Novo Nordisk did with Monlunabant. There are some interesting tweaks. CANYON-1 is U.S. only. It's pretty similar doses. It's a pretty similar period of time. It's an identical number of patients. The one thing that is different is we are the first CB1 inverse agonist to ever implement titration, effectively because we can. Everybody else does it.

Titration is a very sensible thing when looking at anti-obesity medications, and we think it makes a ton of sense to do so also with CB1 inverse agonism. And so we will be titrating into the highest dose. And at the end of the study, figure late summer of this coming -- of this year of 2026, we'll have that data and that critical mass of data. This will be a highly informative data set.

It is more than enough patients for us to have a very granular idea of the safety, especially neuropsychiatric adverse events. And in addition to that, a very granular idea around dose response and being able to model what the weight loss is up to a year. So we very much look forward to that.

And I think with that, Roland, I'm pretty much ready for any questions you might have.

Well, thank you, Yuval, for that overview. Yes, we can open it up for questions, and I can start with the first question on my mind. So I think it's really interesting to see how CRB-701 is moving into first-line treatment for head and neck. And you mentioned an interesting kind of comparison with PADCEV. Can you talk about the similarities or differences between CRB-701 and PADCEV?

Certainly. And again, apologies for those who are less familiar with the story. So CRB-701 is a classic next-generation ADC. And like all of those, we're looking at a structure that looks like this for those of you watching here or -- there we go. Site-specific conjugation, so a precise DAR, that's pretty standard. It's using CLIQ technology. There's a bunch of those out there. A very, very, very, very stable linker, and this one is also very short. Again, it's a proprietary linker, but the approach has now become standard.

So it's a DAR of exactly 2 for MMAE and a very, very stable ADC. The mab here is not enfortumab. It's a proprietary mab for a different epitope of Nectin-4, and it has twice the rate of internalization as enfortumab. What does that all boil down to? It boils down to in humans to a markedly lower level of circulating MMAEs. That's really the big takeaway here, Roland. The ability to have less free MMAE means the ability to have fewer adverse events, especially when it comes to peripheral neuropathy and skin.

The other important differentiator is the ability to have a very stable ADC means that we can dose less frequently than PADCEV. But otherwise, conceptually, it's Nectin-4, highly validated with Nectin-4 MMAE, which is highly validated in bladder. And we've seen a bunch of Nectin-4 MMAEs now coming out primarily out of China, showing confirmatory data in bladder, which is not a focus for us; in cervical, which is a focus for us and in a bunch of other tumor types that are not the focus for us, at least not yet.

Thank you, Yuval. Any questions in the audience? Yes, please.

Trying to understand the mechanism of your weight loss.

Sure.

Have you studied whether these patients are eating less or drinking less because when you lose that much weight that quickly, we know for the GLP-1s, the concept is that they tend to eat less. So it takes some time for that to kick in and then it happens. You're seeing immediate weight loss starting day 1. How do you explain it?

Appetite suppression. So the patients are -- the participants are reporting a reduction in food craving, a reduction in food noise as it were, very positive. So it's -- we're not seeing something which is anhedonic. The case studies are interesting. The case report forms are -- I'm paraphrasing, but it's pretty accurate.

I'm no longer thinking about eating. I'm no longer obsessing about eating. What is intriguing, and I think I wonder if that's where you're going for was for 20 years, we've wondered what would happen if you took the site of activity of CB1 inverse agonism from the brain into the periphery, would you still get that because that was very typical of that first generation.

What is wonderful to see because we see the weight loss in mice very quickly, right? But it's very hard to interview a mouse about its eating habits. You can see the food consumption go down in mice almost instantaneously. But what's been really delightful from a scientific point of view is being able to actually interview and interact with humans.

How does it do it from the periphery into the brain is super intriguing. I don't think anyone has a very clear answer, but we know a bunch of things about CB1. And a gentle reminder, CB1 inverse agonism, there are over 9,000 papers on that with metabolism. It's 30 years' worth of research.

It's one of the most studied mechanisms or mechanisms of action in metabolism. So what do we know? We know a bunch of things. CB1 is heavily, heavily found in the organs of metabolism, not so much the digestive organs, but the organs of metabolism.

When you knock out CB1 in the whole animal, you get an animal that is obesity resistant. But Egan et al. at NIH did a series of marvelous selective organ knockouts in these mice. So they, for example, have a mouse that CB1 is knocked out only in muscles, right? And what you see is absolutely an effect on metabolism, on food consumption, et cetera.

And there is a slight analog here to -- or analogy to the incretin analogs at least, especially the really big one, where at least theoretically, it shouldn't be crossing into the brain or at least primarily crossing into the brain, and yet we have a very, very clear effect from the periphery into the brain that is not necessarily just GI toxicity mediated.

We have plenty of patients who have very mild to no GI adverse events, and they're reporting food noise reduction or craving reductions. So there's a lot more to explore there, but it is absolutely fascinating how that actually worked out.

So as you said, there are many ADC Nectin-4 in China. I had worked with some, right? So I don't know if your study were done in Asian population. If it was in just Caucasian, I want you to share a little bit the safety profile because what we have seen was a lot of SAEs around joint and also skin rash, very, very severe, very painful where the patient decided to discontinue on the study. So I would like you to share a little bit about that.

Wonderful question. So one of the advantages of where we find ourselves is we have a Chinese partner, that's CSPC. They run a completely independent program in China on ethnic Chinese everything I just showed today was our U.S. European clinical study.

And if we compare the 2, and we had that poster in 2020 -- at ASCO GU 2025, they're actually remarkably similar. A little bit more ocular tox in China, and I think that's maybe an environmental aspect as well.

But otherwise, remarkably similar, low, low levels of peripheral neuropathy. We have what seems to be the best-in-class peripheral neuropathy, low levels of skin and overall, a very tolerable safety profile that is echoed in the Chinese population. But you're so right, they're not always the same, and it's really important to compare.

We have time for maybe one more question, about 2 more minutes, if there's any questions from the audience.

Actually, before I forget Roland, I apologize, I'm looking at my CFO, who reminds me gently telepathically cash position. That's kind of important in our industry. So we had $172 million in the bank, and that gives us runway with both of these, both oncology and obesity into 2028.

Awesome. All right.

Thank you so much, everyone. Really appreciate it.

Thank you, Roland.

Good morning, and welcome to the Corbus Pharmaceuticals Investor Webinar. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be available on the Corbus website following the conclusion of the event. I will now turn the call over to Yuval Cohen, Chief Executive Officer and Director of Corbus Pharmaceuticals. Please go ahead, Yuval.

Thank you, Wilson. Good morning, everyone, and thank you for joining us on this call, this webinar, to discuss our results published this morning on our single-ascending and multiple-ascending dose. Very quickly, the forward-looking statement can be found on this slide, the second slide of our deck, and I'll remind you that we'll be making and as will some of the panelists, making forward-looking statements.

So I'm joined today by 2 distinguished guests that will help our discussions for the data that we announced this morning. First and foremost, Dr. Sarah Barenbaum. Dr. Barenbaum is Assistant Professor of Clinical Medicine at the Weill Cornell Medical College and an assistant attending physician at the New York Presbyterian Hospital. Dr. Barenbaum specializes in care of patients with obesity and weight-related medical complications. She sees patients at the Comprehensive Weight Control Center and also with the GI Metabolic and Bariatric Surgery Program, where she serves as the Obesity Medicine Director. Dr. Barenbaum received her BA from Yale University. She received her MD from Drexel University College of Medicine. Dr. Barenbaum completed both her residency and obesity medicine fellowship at the Weill Cornell Medicine, New York Presbyterian Hospital.

Our second distinguished panelist is Dr. Daniel Lee. Dr. Lee is a Board-certified psychiatrist with over 14 years of experience spanning clinical psychiatry, clinical pharmacology, medical monitoring, regulatory affairs and CNS drug development. He has extensive background in both clinical and industry setting, including direct patient care, psychiatric assessments and medical oversight in academic, military, FDA and pharmaceutical environments. Dr. Lee has supported Phase I to IV clinical studies, suicidality assessment, psychiatric drug safety monitoring and clinical pharmacological studies. He has deep expertise in trial design, medical monitoring, FDA regulatory reviews and industry-sponsored research, having been a psychiatrist in the U.S. Army and a regulator at FDA.

Dr. Lee received an MD from the Uniform Services University of Health Sciences, completed his residency in psychiatry at Walter Reed Medical Center and is a Board certified -- and is Board certified with the American Board of Psychiatry and Neurology.

Moderating today's discussion is my colleague, Dr. Dominic Smethurst, our Chief Medical Officer. So what we thought we would do is I'm going to go through the slides very, very quickly. You can find them on our website. You can find a link to them also in the press release. And I really want to spend most of this morning's session with Dom and myself, really having a dialogue, a discussion with Dr. Barenbaum and Dr. Lee around the data. So let me go quickly through the slides for those of you who have not seen them yet. And Wilson, if you could just cycle to the next slide, please.

Everyone on this call has heard us talk about the role that CB1 plays in metabolism, so we can skip to the next slide. Next slide, a reminder that both monlunabant and CRB-913 are offsprings. They share a common ancestor in ibipinabant, one of the first-generation CB1 inverse agonists and also a reminder that there were quite a few first-generation CB1 inverse agonists. Next.

A big distinguishing feature between our drug, CRB-913 and monlunabant is the degree of exclusion from the brain or peripheral restriction compared, for example, to rimonabant, the classic first-generation CB1 inverse agonist. Our brain to plasma ratio is 1/50 than rimonabant. So we are highly, highly excluded from the brain compared to rimonabant. And also compared to monlunabant, if we look at levels, and of course, these can only be done in mice. If we look at levels within the brain, we are 1/15 of the brain levels at the same dose compared to monlunabant. So we really do have a heightened best-in-class peripheral restriction.

Next slide, please. This is very quickly the schema of the SAD/MAD study, very, very typical. It's effectively patients or volunteers in this case, participants climbing a ladder where they receive higher and higher and higher doses. Often doses that are much higher than will be given in normal clinical study. And so we have on the left-hand side, the SAD with 64 participants. It went all the way up to 600 milligrams. So just to put that in perspective, that is 60x more drug than the effective dose of monlunabant. And on the right-hand side, we have the MAD or the MAD.

In this case, 7 days of dosing in-clinic, followed by an additional 7 days in the clinic for observation, so for a total of 14 days in the clinic. All the blue cohorts are healthy volunteers. They were not preselected for BMI. There are 2 green cohorts, one in SAD, one in MAD, and those were selected specifically for people with obesity, so for high BMI. And the primary reason we do a SAD/MAD study is to look at things like safety and PK. And the primary reason we have people with obesity in these cohorts is because PK may not necessarily be the same in someone who is suffering from obesity or metabolism may not necessarily be the same.

Next, starting with safety and again, juxtaposing with monlunabant. And here, again, kudos to the Novo team for their publication this past November. It was very informative and kudos to them for a very heightened degree of transparency. We know a lot about not only the adverse events that were experienced on monlunabant, but the cadence when they showed up and to what extent they showed up. There are two highlights that we want to mention here.

The first one is very surprising to us, and that is Gastrointestinal Adverse Events. We have seen so many of them, obviously, with other mechanisms of action, but they tend to not be associated that much with CB1 inverse agonist. Monlunabant is an outlier. There were very meaningful levels of GI adverse events. They happen very, very early. They typically happened in the first week. 90% of them were done in the first 2 weeks, and there are a lot more than we would expect. If we juxtapose that with CRB-913, CRB-913 is much more in line with first-generation CB1 inverse agonist. Maybe even more so, it has an unusually benign GI adverse event profile. We had the sum total of a single case of potentially or possibly related mild diarrhea, again, compared to monlunabant with markedly higher events.

It also tells us that when we do look at the weight loss in a few slides' time, the weight loss is not being driven by GI adverse events. They are simply effectively absent from this cohort. Next, please. This is a slide we were all waiting for in terms of the data, and that obviously is a neuropsychiatric adverse event, the sort of the problem associated with the first-generation CB1 inverse agonist, and surprisingly also found with monlunabant. Again, very helpful to have provided us with the cadence and the degree of neuropsychiatric adverse events in that Lancet Diabetes paper from September. And what we see is very typically, they happen early. That's pretty typical of neuropsychiatric adverse events. Most of them are gone by the time you get to 60 days. And again, that was seen with other first-generation CB1 inverse agonist. There is a surprisingly high number of them.

So in 180 patients that received monlunabant, there were 111 events. And that is surprising. That is markedly more than one would expect. There were cases of depression, both in their Phase I and their Phase II. And it was frustratingly the most common cause of dropout in the study. If we juxtapose that on the right-hand side with CRB-913 and again, with its very differentiated brain exclusion, it's really a very, very different picture.

As Dr. Lee will discuss in a second, CSSRS, PHQ-9 and GAD-7, the standard questionnaires, the validated questionnaires for suicidality, anxiety and depression and anxiety were negative. They were negative for all participants at all cohorts at all time points. There wasn't a single exception to that. No cases of suicidality or depression or even dysphoria. No cases of insomnia, which was really wonderful to see. We had 3 events of mild anxiety. They were associated with, again, negative GAD-7,PHQ-9 and CSSRS, and 1 event of mild irritability, again, associated with negative outcomes on the validated screens or questionnaires.

And to sort of give you a tiny bit of a preview. We saw weight loss even in cohorts where -- or circumstances where there were no neuropsychiatric events reported whatsoever. So a very differentiated profile, not only compared to that first generation, but really markedly differentiated compared to monlunabant.

Next. This is a slide when we saw this slide, we were delighted and honestly, wonderfully surprised. So a reminder, this is the cohort that dedicated to people with obesity. Their BMI on average was high, BMI of 36. They spent 7 days like all the other MAD cohorts, 7 days in the clinic being dosed on a daily basis and another 7 days being observed. The half-life of CRB-913 is very similar to the half-life of the other CB1 inverse agonist small molecules. It is long. It is measured in days, and that's very typical. CB1 inverse agonists tend to be very, very stable molecules.

And so what we saw first as an individual sort of waterfall plot, was reassuringly placebo did not lose weight. But every single participant on CRB-917 lost weight and sometimes quite a marked amount of weight loss in a period of just 2 weeks. If you want to convert for percentages to actual weight unit, the back of the envelope, typically, these patients are about 100 kilos each. So that's the individual participants weight loss at day 14 compared to where they started.

And if you do the placebo adjustment, you end up with just under 3% in 14 days, again, not being driven by GI adverse events. And we can look at it differently in the next slide, Wilson, where what we're seeing is the cohorts themselves on a daily basis. So every day, they get tested for everything, whether it's safety, including neuropsych, but also for their weight. And what we can see, which was really very reassuring was weight loss started early, very early, in fact, and then deepened as we were dosing them for more and more. And then you can see that momentum staying there again as a result, presumably of the long half-life, and we have the PK to correspond to that, whereas placebo do not, placebo behave very nicely. So that, again, was very reassuring.

Next slide. While we didn't have a dose response for cohorts that specifically enrolled people with obesity, we do have 3 cohorts that simply did not discriminate based on BMI. And they do have ever-increasing doses from 25 to 75 to 150 milligram a day, which corresponds to the cohort with -- that had selected for people with obesity. And what we see, albeit remember, with participants that have a lower BMI and average just 28, what we see is reassuring. We see weight loss in both the 75 and the 150. And in fact, it's very similar weight loss. And we see the indications of some sort of effect also starting to come up with the lowest dose, although again, it's much more subtle and neutralized by the placebo in that case.

It does tell us or give us an indication that the 150 may be beyond the linear range. And that's the case with not just CB1 inverse agonist. That's the case with -- we see that, for example, with incretin analogs as well. It's reassuring for us because if we want to dose lower, that means that we can dose within the linear range. And we have an indication for that in the next slide, please, which is a format that all of you are familiar, certainly from the incretin world, which is this cross-trial comparison, and it has all the usual caveats. But nevertheless, it can be wonderfully informative. And so what we have here is rimonabant, both at 1 month and 16 weeks.

And a reminder, rimonabant was back in the day, a promising drug, but the annual weight loss seen with rimonabant placebo adjusted was still only about 6.5%. In today's world, that's less exciting. We have the 3 doses of monlunabant. And what I want to draw your attention are to two things, which I think were lost a little bit in the initial press release from Novo, but really shined through in that Lancet Diabetes paper, monlunabant is a surprisingly potent CB1 inverse agonist. It is markedly more potent than rimonabant. And in fact, just to contextualize it, you can see where orfoglipron, an oral GLP-1 agonist would effectively fall on this graph. Monlunabant is within the same ballpark in terms of efficacy. It has the safety issues, of course, but its efficacy is pretty surprising for a CB1 inverse agonist.

And then what you can see also with monlunabant is as they dose higher from 10 to 20 to 50 milligrams a day, the weight loss is not linear. In other words, they're probably already beyond the linear range because the 50 milligrams a day is not that much more weight loss than their 10 milligrams a day. It's a relatively modest addition. Again, very reassuring for us in terms of finding that zone of linearity.

Lastly, on the very left-hand side, that tiny little green line, that's CRB-913. And again, early days, of course, in different doses, et cetera, but it does seem to fall within the ballpark of monlunabant. It seems to be markedly different than what we would have seen with the first-generation CB1 agonists. Next slide, please.

And where does that leave us in terms of next steps? And here, we look not only at our data, but also at monlunabant's data, again, very closely. Monlunabant has some very potentially painful lessons that we would very much like to learn from and avoid repeating, but also looking beyond CB1 inverse agonism to what are best practices these days in the world of other mechanisms of action of anti-obesity medication. And so we've launched or initiated CANYON-1 is a Phase Ib study. Its primary purpose is still safety and tolerability. That's very important. It shares many similarities to the study that Novo conducted with monlunabant. It's exactly the same number of patients. It's pretty much a similar dosing duration. Ours are 3 months, their's was 4 months. We are in U.S.-only sites. The Novo study took place in Canada. Our doses are very similar. We're doing 20, 40 and 60. They did 10, 20 and 50.

And we are titrating. We, I believe, are the first ever CB1 inverse agonist to titrate. And we're titrating because, again, we looked at the monlunabant data, and it's clear that when they started with higher doses, they were less tolerable. But we also look at things like the GLP-1s and the success that titration has had in terms of building tolerability for higher and higher doses. The last thing is very important. We will be much more vigilant and strict about screening criteria, much more in line, for example, with what others have done, and we will be excluding patients, for example, for participants that score high on the PHQ-9 at baseline.

So with that, just a final slide on conclusion, and then we'll open it up to our panel. And there really are four lessons that we can think of that we learned from this study of 112 participants. The one is that this very high, very unusually high best-in-class peripheral restriction really did seem to be associated with a favorable safety and tolerability. That hypothesis translated nicely from the pre-clinic to the clinic. We elicited weight loss early and it deepened. So that's encouraging as well. The weight loss was not driven by GI AEs, and that's very unusual, and we really want to highlight that fact. These participants were not losing weight because they're experiencing nausea or vomiting or diarrhea or constipation. The last thing about it is, maybe the most intriguing one, which is the weight loss is associated with restriction to the periphery. And this has been a very lively debate in academia for 20 years now, which organ system drives the weight loss with CB1 inverse agonist. Is it a centrally acting effect or peripheral effect.

Until now, what we've lacked as a community is a CB1 inverse agonist small molecule that just had this high degree of peripheral restriction. And now we have one, and what we see is that the weight loss is there. In fact, it's strikingly there. And so for the first time, we are able to start to really narrow down the hypothesis and point out to the fact that it does seem to be the effect on those peripheral organs of metabolism and their CB1. So with that, maybe first turning over to my colleague, Dr. Smethurst to Dom and say, Dom, any -- or ask any color, anything you want to add, you were so hands-on and involved in this study. What would you like to share with our audience that perhaps doesn't come across in these slides?

Yes. Thanks, Yuval. I mean it's a Phase I environment. It's very unusual. We've not seen this data shared in such an intimate way. The FDA asked us to do two things. They asked us to look at these three questionnaires every day that the patients were on the unit.

So it was a state -- a magnifying glass of hypervigilance. And they also asked us to bring in an independent psychiatrist to whom these patients could be referred. We had a discussion with the PI, just as if any of these instruments triggered a warning sign. And it's fantastic, they didn't. But I'd like to turn to Dr. Lee.

And specifically, given that you were a specialist psychiatrists on this study, and I know you have a wealth of relevant experience, specifically implementing these instruments, clearly top of mind is the neuropsych profile. We're seeing that in this study despite daily testing, no suicidality or depression, negative outcomes with those questionnaires, but we did have 3 mild cases of anxiety and one of those cases had mild irritability as well. Could you help contextualize this for our audience, please?

Sure. First off, good morning, everyone. So I spoke intensively with the investigator and kind of reviewed everything. The big take home is that it's not outside the realm of normal human experience. Based on the way everything went down, it essentially translates to, I am mildly uncomfortable right now. These were self-contained cases that resolved without need for alteration of dosing, usually resolved within 1 to 3 days at the very most. And they did not trigger on any of these scales, the GAD-7, the CSSRS or the PHQ-9, which is those scales are intended to quantify how much of a condition is present, be it depression, anxiety or what have you.

And so the fact that we never even got even remotely close to the mild cutoff on any of those scales tells you something. And honestly, if I was in a strange environment where I could leave and had to sit around all day and focus on myself, I'd probably feel a little bit uncomfortable too. And that seems to be what's happening.

Brilliant, I think that's really helpful. I did the PHQ-9 on myself a few weeks ago. 3, below normal threshold. But yes, it turns out jet lag can do that to you. Can you specifically just say, do these things all measure the same thing? Or does CSSRS, PHQ-9, GAD-7, do they measure something different or overlapping?

There's a little bit of overlap between the PHQ-9 and the GAD7, mostly because anxiety and depression are two very linked conditions. They're usually very, very high degree of comorbidity and the symptoms sometimes cross over. The CSSRS are completely different. It measures suicidality specifically.

That's really helpful. It sort of did occur to me reviewing that we test the suicidality twice. So they have 28 questions. It's almost enough to make one feel down, like you say, the introspection, the closed 4 walls, being stir crazy, et cetera. That's not to diminish the fact that they're looking for a signal, et cetera, and we have placebos, but it's incredibly helpful.

If I may, I'd just like to take a quick case study. One patient, a male who started the study. He was in the patients with obesity cohort or healthy volunteers with obesity cohort. He was in the multiple dose, 150 mg fed and had BMI of 32.3, weighed 106 kilograms on the day of dosing. He hit his nadir 3.3 kilograms down, so 2.9% on day 12. And then so it stopped dosing on day 7, dosing every day, building up, building up, building up and then gradually washing out, hit a nadir then and then started building back up, was discharged on day 14 after a week of observation and then came to the follow-up and had already regained half of these losses.

And I just want to take you through the GAD-7, the anxiety tests here, which were all 0 baseline. I mean not even 1s and 2s, which you'd expect in the normal population, but they were all 0, very well screened patients. And the patient's score was 0 every day for the first 14 days. Discharged to the community, come back on day 3 and a follow-up. I tell you the investigator spent the weekend trying to debate whether she felt it was restlessness or anxiety. And in the end, she spoke to the patient again on Monday and she came down on the side of anxiety. And so the patient scored 1 for anxiety and another 1 score because they had it for more than half a day since discharge.

And they also expressed concern about being easily annoyed or irritable once they've gone back out to the community. Now clearly, the drug has been involved and it is what it is. But I just thought it would be helpful to show how these things occur. And yes, I think the patients were really -- I'm not going to say happy, but they all wanted to know when this drug is going to be available. And I think that's a real testament. It's obviously still a long way away. It's 7 days dosing. We're amazed with anything. But yes, that's really helpful. I'll just hand it back to Yuval now.

Sure. Thank you, Don. Maybe turning to Dr. Barenbaum. Sort of a high-level question. And being slightly provocative is do we actually need alternative to incretin-based therapeutics? And one thing that occurred to me is we think about at the moment, the -- we think about these drugs being given as monotherapy. Do you find yourself actually combining drugs? And is there room for combinations with incretin therapies?

Absolutely. And hi, everybody. Good morning. I think this is a really great and really important question that is often overlooked. We definitely need so many more mechanisms than just the GLP-1 family. I think the media has really made it seem like these are miracle drugs. Everyone responds, they lose so much of their weight. But we know from the clinical trials, we know from clinical practice that they're not. At least 15% of people don't respond, being they lose less than 5% of their body weight on these drugs. A lot of people don't tolerate them. And obesity is a complex multifactorial disease that is driven by so many different pathways. We need drugs that treat different pathways.

I'll say there are more smaller, mostly retrospective studies that are coming out now, too, and that were just presented at Obesity Week recently showing that if people start on 1 GLP-1 and they don't respond to it and they switch to another, they often also don't respond to it. So creating more and more drugs in the same family don't necessarily lead to more help for people and at least 40% of American adults have obesity. So we just need more options.

And absolutely, thinking about monotherapy versus combinations of medications, I think this is also often overlooked and not fully understood. We often have patients on several different medications. This is not new to us. For years and years, we've been combining different drugs because, again, obesity is a multifactorial disease, we need to target different pathways, not just one. And combinations of different drugs target different pathways and can lead to an incredibly synergistic effect. Sometimes it allows us to use lower doses of any given drug, which can help improve efficacy and reduce side effects, too, if somebody is having tolerability issues. So I do think it is important.

And I will say, lastly, we think about people who might need more combination therapy. And right now, we do have a lot of people with higher BMIs. And in that population, if you're starting with a high BMI, 60, 70, 80, for example, say you do achieve optimal response with the GLP-1, you're probably still not going to lose enough weight to see resolution in all of the related conditions. Obesity is associated with over 200 conditions. It is the root of all metabolic disease. And this is why we treat obesity. It's not just to lose weight, it's to treat these diseases that are associated with it and improve cardiovascular mortality. And so I think that's another reason why having combinations of drugs that can be additive and lead to more weight loss can especially help that population.

Thank you for that. I think one of the things that I just find so scientifically fascinating is both we in 2023 and for that matter, Novo actually in a year earlier than that, published, of course, in mice because you can do everything in mice. Studies in DIO mice where we combine these two orthogonal mechanisms. So in our paper from obesity in '23, we looked at combining CRB-913 in DIO mice co-administered with either liraglutide, semaglutide and tirzepatide. And it was scientifically, very, very satisfying to see how these two completely orthogonal mechanisms, played nicely together and actually increased weight loss and the other outcomes that are easy in mice. It's always been something that I found really, really intriguing about this approach, especially today in where we are no longer like 2006 with very few options.

We have these wonderful options now and maybe it really is shifting to, as you said, the nonresponders and/or the combinatory approach. Dr. Barenbaum, if we can stay on this topic in a sense sort of from the macro to more specifically on our data, it's early days. It goes out saying. Again, these are relatively small number of patients. They're being observed for just 14 days. But I'm curious what you think of that weight loss, sort of the speed of it, the degree we've seen and especially your thoughts around what strikes me at least as a really differentiated GI adverse event sort of profile, again, because of your orthogonal mechanism of action.

Sure. In terms of the degree of weight loss, I think it's fantastic and really exciting. I think, of course, as you mentioned, it's early days. We need to see longer-term data. We need to see what happens.

But when we think about weight loss, as I mentioned before, we think about improvements in health. We don't -- it's not just numbers on a scale. We're not aiming for a "normal BMI." And our benchmarks, we start to see improvements of 2% to 5% weight loss, but we use these benchmarks to help determine whether or not a patient is responding and we're seeing improvements in health. And so that first benchmark at 14 days, it's there, and it's almost at that 5% benchmark. That 5% benchmark is what the FDA uses as criteria for approval for drugs. And it's also driven by our guidelines.

Our obesity guidelines recommend only continuing a drug at 5%, if at least a 5% weight loss, and that's at 3 months. And so technically, if something is at least 5% weight loss at 3 months, we can -- safe and tolerated, we continue it. So the fact that you're seeing 4% at 14 days is pretty remarkable. And I'm excited to see what comes in the longer-term study.

I think in terms of the GI side effects, I thought that was really interesting, too. I mean, clinically -- so I should mention I have -- I'm a full-time attending. I have a full panel of patients. And so I'm dealing with side effects of medications all the time. And looking at this versus monlunabant, which had so much GI toxicity and our GLP-1 family, which has so much GI toxicity, it is a common reason why we might have to take people off medications or make changes. So I think the overall profile, again, early days, but as you showed in the other studies, a lot of those GI issues happen early and quickly. And so I'm excited about the tolerability of this drug.

Maybe turning to actually to both of you. I'll start with Dr. Lee, but I do want to also hear from Dr Barenbaum. One of the interesting things, and Dom was mentioning this because it just came across in the reports in that cohort with the people with obesity was a very positively described by the participants reduction in food cravings or what's locally known as food noise. Would love to hear from, again, Dr. Lee and Dr. Barenbaum, first of all, how important is that in general in obesity?

And I think that I wonder if sometimes we underestimate the importance of that. And secondly, your thoughts around just the usefulness of seeing that with a CB1 inverse agonist. We know we've seen that with the incretin analogs. But just how important is it? How useful is it? How reassuring is it that we're seeing it? So Dr. Lee, maybe starting with you.

It's huge. The thing about kind of how our dopaminergic reward system works, it's not the joy of actually having the thing. It's the anticipation of think about it the kid, the Christmas present, the birthday present, it's not receiving the gift that is the most pleasurable part. It is looking forward to it and kind of the buildup to it.

And in many ways, it's similar to that with kind of food drive and obesity. The noise of the food and the anticipation of how pleasurable it will be when you consume it, is driving a lot of this kind of increased consumption. So the ability to short circuit that in some ways will make things so much easier for them to do all the other things that they need to do to lose weight.

Dr. Barenbaum?

Yes, I'd be happy to add to that. I think obesity, as we've been talking about, is really complex. And people don't just eat because they're hungry. People eat for a lot of other reasons, whether it's celebration or any other reason, boredom, habit. I will say something that people do talk about a lot is this kind of like pervasive thinking about food that is very intrusive. And that is kind of how I define food noise and how patients have defined it for me, this nonstop thinking about food, what am I going to eat in an hour? What am I going to eat for lunch? I know I have something in my fridge that I really want to eat. I'm working from home. I can't stop thinking about it. I'm going to go eat it.

And it can be so disruptive to people's lives on an hourly basis even. And I've had so many patients come in over the last couple of years and say, starting X medication has changed my life. I am no longer thinking about food all the time. I feel normal is what people say. This must be what it feels to be normal to not be thinking about food all the time. And it has such an impact on people's lives and I think their like psychological health, but it also allows them to then focus on weight loss, too. And removing that mechanism that drives people to eat can really, really help people achieve their weight loss goals.

Super helpful. Tara, I wonder if we can open it up to our audience and maybe take some questions from them?

[Operator Instructions] So our first question comes from Brian Abrahams at RBC Capital Markets.

Congrats on the data. Just a few for me. I guess, first, I was wondering if you could maybe talk a little bit more about the persistence of the weight loss out the additional week, whether this is all kind of related to that multi-day half-life or there's something else in the mechanism that leads to this persistence? And maybe if you can talk about maybe any of the PK or exposure curve relationships to weight loss?

And then I'm also curious on the safety side, if you saw any sort of lab changes, any changes to vitals such as changes in body temperature or patterns there? And then maybe just lastly, curious maybe if the panelists can talk about their views on how titration with this mechanism could potentially impact the safety profile and therapeutic window?

Thank you, Brian. I'll take the first one, Dom, maybe you'll take the safety, and then we'll open it for titration to the panel.

So Brian, yes, the half-life is several days, very, very typical. We see the PK curves. So they correspond with still a very meaningful amount of drug even in that second week. We've not presented the PK curves. As you can imagine, they're highly confidential because they offer such an important competitive advantage. So at some stage, we will, but not yet. But that's fairly typical. That was also seen, by the way, even back in the day with rimonabant studies. It takes -- there's a really nice momentum that's built into this mechanism.

Like I said, these are highly, highly stable compounds. They also tend to be hydrophobic, so they like to hide in fat, and so they slowly release out of it. And that's seen both preclinically and clinically and again, just across the class. Dom, maybe the question around any other AEs?

Well, I mean, we had -- very early on, we had one patient who had a little bit of arthralgia. We had a patient who got COVID with a sort of cluster of symptoms around there, but nothing too bad.

There's no manifest or extreme changes in any of the vitals and nothing really with great pleasure looking through all the labs, you look to sort of ALT, AST, et cetera, and there's nothing there. The obese -- patients with obesity, their cohort did yield a couple of patients who on some days had a blood pressure that would be diagnosed as hypertensive. But that was probably just subclinical hypertension in obese patients, and they probably haven't seen the doctor for a while. But there was nothing worrying at all. And then triglycerides were migrating down more rapidly in the obese patients in the fed cohort. But it was nowhere near as striking, just reassuring, it's nowhere near as striking as our weight loss was. But it really was a very clean study, subject to lots and lots of vigilance.

And Brian, just to add to that before I turn it to the titration question, Again, that will be the advantage of having several hundred patients over 90 days of dosing. We'll be able to get much more granularity around those.

Maybe on the titration, I wonder -- I'd love to start with Dr. Barenbaum because you have so much experience with titration. But I also want to hear from Dr. Lee thoughts around titration and just psychiatry. But Dr. Barenbaum, please, if you can start?

Sure. Yes. I think it's pretty much all of our medications that we use for obesity, not just the incretin agonist, we start at a low dose and we slowly increase. And what I always -- one of the main reasons we do that is that we slowly increase the dose, it really can improve tolerability.

And also, some people are very sensitive to medications. You might be able to use a lower dose and see weight loss without having to go up. So you might avoid having side effects by just using a lower dose that's effective. And so I think it's a brilliant idea to see what happens with titration. If people aren't losing weight, you can go up. And this is why you do these studies to see the safety and efficacy of it. And I think it's a great approach to try. And I'm excited about the titration aspect.

Dr. Lee?

I mean the nice thing that we observed is that the AEs appear to be dose dependent, but the efficacy, the weight loss does not. So even though we have an incredibly clean profile to begin with, we can mitigate against this even further by not taking the 150 further in development. So we're going to already be improving the already fantastic profile by going with this lower dose.

And then the titration is definitely something else that we will implement that should hopefully make this more tolerable as well. So we're hitting this from multiple angles. And I've definitely noticed that there are people that are very sensitive to lower doses that for some reason, have an easier time tolerating the drug when we get past that initial starting dose. Now granted this -- all of my experience here is with antidepressants and antipsychotics. But I can't say if this pertains to this particular mechanism, but it seems like it would be reasonable to assume it would.

That is true of obesity medications, too.

Our next question comes from Felicia Berben at Piper Sandler.

I was just hoping you could frame today's 2.9% placebo-adjusted weight loss at day 14 in the obesity cohorts against expectations for the upcoming Phase Ib doses, particularly given the titration plan and the lower daily doses being selected?

And also just a question for Dr. Barenbaum. I was hoping you could just elaborate a bit more on where you see this fitting into your treatment practice if 913 makes it to market in several years, If there are certain patient subgroups where this might be most ideal to use.

Thank you. If we can go, Tara, can you go to the slide where we show the different drugs and the weight loss across study, the cross-trial comparison. Thank you. So there we go.

A couple of thoughts, Felicia. We see from monlunabant, as I've mentioned, if you look at their different doses, it's clear that their higher doses are beyond linearity. In other words, you're really not getting that much more, even though you're dosing 5x more than your lowest dose. Our strong suspicion is that the 150 is in that zone. We'll find out, but it makes sense. Something similar was seen even with rimonabant in their earlier studies.

The other thing to think about is we have reason to believe that our efficacy is similar to monlunabant. We are after all sort of distant relatives and preclinically as well. And so we think that we can really dial it down and still get a very similar efficacy.

As Dr. Lee mentioned a second ago, it's really wonderfully reassuring that in the -- in the cohorts that did not select specifically for people with obesity or high BMI, but had patients or participants with a BMI average of 28, but some of them were higher than that. When we cut the dose from 150 to 75 or when we compare the 150 to 75, we take no penalty in terms of efficacy whatsoever.

Another thing to add, it goes back a little bit to Brian's question around the PK. We are not yet at steady state after 7 days of dosing. We're not nearly at steady state after 7 days of dosing. And so as we dose longer in those studies, and that's why that 90 days will be so informative. As we dose longer, our expectations are that we will see the levels rise. And that, of course, again, is very encouraging in terms of the potential to elicit efficacy.

They're not going to rise as high as 150, not even for our 60 dose. But for example, our lowest dose at 20 is going to rise meaningfully, and we've got the modeling for that. We know where that should end up. So we're really optimistic about it. Will we ever be able to reach those doses? Maybe the titration will tell us.

And as Dr. Barenbaum mentioned and Dr. Lee mentioned, even with, for example, the incretin analogs, we recently saw data with semaglutide, both injected and oral at doses that were higher than had previously been tried. And that's the wonderful thing about titration. It allows a process of adaptability.

And then there was a question for Dr. Barenbaum about where do you see this in your practice and subsets? How do you -- how might you contextualize it in years to come?

I think, Felicia, that's a great question and one that is so hard to answer right now because I think it's a little too early to know. I mean it's only 14 days of data. And this data is different from some of the data we've seen before. The weight loss is really remarkable. It's better tolerated. So it's hard to judge that based on just 14 days. I will say, I'll just kind of reiterate, I think just the need for so many different mechanisms of medications is so important.

But I need to see the Phase I, II, III trials have some clinical experience before I can really answer that. But I think it would serve a very important role to have a different mechanism. And I think the other really important part is it's not just my decision. I talk about it with my patients. It's a shared decision-making model about what they're comfortable with, what they're interested in. There isn't just a set like flow chart of how we think about medications, and we don't have like this is first line, this is second line. It's not how our field works because it's so complex and everybody has such different struggles.

So if it turns out that this medication ultimately has remarkable outcomes with food noise, then I would think about this as something to help treat food noise for patients. So I think, unfortunately, I can't answer it because it's just too early, but I'm excited to see the next trials and where the data goes that I can better answer that in a couple of years.

I think that's such a great point, Dr. Barenbaum. And again, going back to the wonderful world of mice for what it's worth. And the data we've published recently, again, in obesity, and we have another manuscript in, what we know from mice is there are 3 things we can do to mice with this mechanism. And the same would apply for that matter with monlunabant. We can show monotherapy, and that, of course, is what the first generation showed as well. We can show additivity, at least with the injectable incretin analogs. We haven't done it yet with the agonists, but it stands to reason that you could do that. And then we have a paper that's been submitted recently where what we do in a mouse in a DIO model is induction maintenance.

In other words, we induce the weight loss with semaglutide in the mouse and then take them off semaglutide and then switch them immediately to CRB-913. And unsurprisingly, it maintains that weight loss. But those are mice. And so we'll see what happens in people. We just need more patients, longer exposure. And we, of course, will start with monotherapy. The first thing we want to see, Felicia, and everyone is we first want to see what this looks like on its own to really understand and get a feel for the dynamics of this compound.

Our next question comes from Graig Suvannavejh at Mizuho.

Can you hear me okay now?

Yes.

Congrats on the data. I'm just wondering, we saw some differences in anxiety between obese and non-obese patients. I was wondering if there was an explanation? Is that just random chance? Any thoughts there?

A couple of thoughts on that. One is in the 150 -- and Wilson, I'm wondering if we can go back to the neuropsychiatric adverse events slide.

What's interesting is in the 150 so-called non-obese cohorts, that did not select for just high BMI, maybe a couple of more slides up. So in the non-obese 150 cohort, there were some -- there we go, there were some participants who actually had high BMI and actually lost weight. And we saw -- we didn't see anything reported from them. So that's sort of one piece of data.

I think on the whole, it's just too early. We need to really understand what this looks like in higher numbers. Some of these events happen post-dosing. So that's important to think about. What does that mean? Is that just the background noise? Is that patients perhaps regaining weight or not? We just -- the good news about having is that we have very, very few of them. The difficulty is we also have very, very few of them. So we just don't have enough to really call it out.

And Dr. Barenbaum or Dr. Lee want to come in with an opinion?

I mean I would basically echo everything that was just said. It's -- we -- at this point, we don't know if this is having any specific impact on neurotransmitters or anything. So it's really hard to tell at this point.

We do know that folks with obesity are at increased risk of depression and anxiety at baseline. So they may be more sensitive to some of the effects of the drug or they may just have a higher weight at baseline, and it's impossible to tell at this point.

This would just be purely speculative on my part because I wasn't a part of the study, of course, and I'm not a psychiatrist. But in clinical practice, I see a lot of patients who are struggling with anxiety and depression who have been trying to lose weight their entire life. And here in this study, you've given people a drug, they're losing weight on it, and they know this drug is about to end. They're about to go back into their regular life. And I would imagine that, that alone could cause some anxiety in people.

Dr. Barenbaum, that's really interesting. Again, the case study that Dom was referring to, for example, earlier on, the events occurred as the participants started to regain weight. And again, speculating, but that can be -- I can imagine that, that emotionally can be a difficult thing.

And then...

Graig, go ahead.

If I could just ask -- yes, if I could ask a follow-up maybe for Dr. Barenbaum. We are seeing across the industry, so many different new products, new mechanisms. I hear you on looking for additional mechanisms that go beyond perhaps GLP-1-based mechanisms. But if you look into the future or if you look into your crystal ball, is your current view that GLP-1s will be the go-to induction way of getting patients to start losing weight and then perhaps other mechanisms coming in as a more maintenance type of treatment or just overall thoughts on where novel mechanisms like a CB1 will fit? I know it's early days, as you mentioned, but is it still going to be GLP-1 based to start off and then maybe looking to switch or add something later on?

It's a great question. And we -- our guidelines are old, and there are some new guidelines coming out this year or next year where we might see that there is a recommendation of first line, second line.

But I will say one of the biggest barriers we currently face is access. Even if it's recommended to start first line with a GLP-1, so many patients can't afford them. A lot of insurance companies don't cover them, or don't cover them well enough. And out of pocket, as we all know, these are very expensive drugs and they're lifelong drugs. And so even if they were to become recommended as first line the incretin family as an induction medication, I don't know how many people would actually have access to them.

Hopefully, that will change. This is dynamic. It's changing all the time. We'll see. But based on what I know right now. And there's always going to be a need for different mechanisms, too. So I do think it's exciting thinking about perhaps having some medications as induction and then other medications going on to help with maintenance. We are seeing more trials like that going on right now. So I don't really -- again, it's a hard question to answer because I don't have a crystal ball, but I would say that even if it does become the case, who's going to have access to them.

Thank you for that. And just -- it's something I'm immensely passionate about. A reminder to everyone, this is a small molecule, synthetic like all the CB1 inverse agonists. Rimonabant at its height, I think, had 500,000 prescriptions. They were making literally metric tons of it, and it's doable. This is not the same as a peptide or other mechanisms. We have actually ran out of time. Believe it or not, I'm delighted. This was -- this went much faster than I thought.

So I just want to thank everybody. A reminder, CANYON-1 has been initiated. We should complete CANYON-1 by the middle of next year, summer of next year. And then looking forward to releasing that data. Again, that should be a really informative data set, both in terms of patient numbers and exposure and time. So I just want to thank our panelists for joining us this morning.

I want to thank Dom and his team for the incredibly hard work doing all this and LifeSci for organizing it and just thank our audience. I believe there are over 100 people listening in and more now, I think. So thank you, everyone, for taking the time in a very busy time of the year. And we really look forward to talking about this further and for CANYON-1 to read out. Thank you, everyone.

Good morning, everyone. Thank you so much for coming here this morning. We know how busy everybody is. So it's really wonderful to see. That's a wonderfully full room. So thank you for that.

I just want to start by some quick thank yous. First of all, thank you to the audience for coming here. Thank you to our panel for taking the time from their very busy schedule to spend an hour with us today talking about our data, especially around head and neck. Very big thank you to LifeSci, both Sarah here as well as the office back home for organizing this so smoothly. It takes an enormous amount of work more than I ever realized to actually get this all done, and thank you to the team that they have organized here on the ground to make sure that this is webcast and recorded. So a reminder that you'll be able to listen in at your convenience and also to the people who are listening in as we speak, especially those who are awake very early at the moment on the East and West Coast.

My name is Yuval Cohen. I'm the CEO of Corbus. I suspect most of you have met me before. It's a real pleasure to be here. I'm going to turn it over to my colleague, Dominic, who will introduce himself and the panel and moderate this conversation. If anyone at any stage has a question, if they can just raise their hand, Sarah will have a microphone. We will also be taking questions online from people who are listening in. But otherwise, I think you're here to listen to the panel.

So with that, Dominic, it's over to you.

Thank you. Can you hear me? Am I using the microphone correctly? Yes, I think I can hear a bit of. Again, lovely to see many familiar faces in the audience. Great attendance. Welcome to those online as well.

And I'll just whip through some important slides. This is the forward-looking statement, which I'm sure you're all familiar with, but still remains an important slide. And then our panel who essentially don't really need any introduction. My slides are going, our panel here who very familiar with moving slides on. And also probably many of whom are well known to you. And they, I'm sure today will be fantastic in providing that important patient-centered context extra color.

And I know and suspect they're going to be as honest with you as they are with me in dealing with the trial. They've all had this drug, CRB-701, go through their institutions. They've seen the patients. They've seen the reality. They've talked to the relatives. They've held the tissue boxes and they've seen the successes. I won't go through the detailed biographies. They are fantastic and a little bit intimidating for me as a physician, but well done. And I'll just take you through a few of the slides.

The slides I'm going to show you today, there's nothing new compared to what's on the corporate deck. What will be new today will be what these folks have to say. But just a quick reminder. The poster, which is going to be shown at lunch time today, which was released on the ESMO website yesterday morning, will show a markedly different safety level for our drug versus other reference ADCs. We also have a slightly more convenient dosing frequency. We can give it every 3 weeks. And I know that the physicians on the ground really value that.

Yes, the -- we do have a differentiated pharmacokinetic profile. We have a drug antibody ratio of 2, which means we can give a lot more total antibody. And the fixed linker also means that we stay around in the circulation longer with lower levels of free MMAE. And our strategy, as we've said many times before, is we're not going after PADCEV. And we've been very lucky in being able to define a differentiated product here today that has manifested itself as being very exciting in urothelial cancer, cervical cancer, but principally head and neck cancer will be the focus.

So yes, as we said, fixed linker, I won't spend too much time on this slide. We're occupying and concentrating on the next enriched tumors, principally cervical, head and neck and bladder. And we -- this drug is an outlier in the ADCs. It's an outlier because we have much lower levels of free MMAE. And I think that actually helps begin to focus on the differentiated safety profile and efficacy profile. I've already mentioned the dosing regime. And we've now finished dose escalation. We're heavily in the middle of dose optimization, Project Optimus, and we're starting to think about next steps as well.

So just a context to say that fortunately, a lot of people have really become aware of the market opportunities in head and neck cancer recently, thanks to some of the M&A activity that's gone on, particularly with Merus. But to say we do think it's a really big market. So demographics, nothing too outstanding here, standard Phase I. Many of you have already commented that we do have a median number of 3 prior lines of therapy. And when we compare ourselves to other head and neck cancer competitors, we think that looks very favorable. It's also the case that in the head and neck cancer patients, we also have 3 prior lines of therapy as our median number.

Treatment-emergent adverse events, the overall burden and the gents will talk about this, is very low with the obvious differentiating feature that we've got eye tox, and that is a feature that's more prevalent with our drug. Again, compared to the ADCs, I won't dwell on this too much, but our grade 3 adverse event level is around 35%. And I know from the feedback from these guys, that's really very much appreciated. Astonishingly low levels of peripheral neuropathy, and I think that relates to the free MMAE. And that's true of our Chinese data as well. Low rates of skin adverse events. We had 3 grade 3 adverse events and no grade 4 or 5, really pleasing across 167 patients.

Again, we've got a slide here for comparison with peto, but I'll jump on to the waterfall. There are 1.8 mg patients in here as well. This waterfall is the lesional measurements, but we've also attached the RECIST measurements as well. Then the table includes both the overall confirmed rate. And we've mentioned and outlined those patients, particularly in the 3.6 mg dose who have not yet confirmed. Two of them are still on trial, one of them subsequently progressed.

This is a swimmer plot, starting to speak to the durability that we're seeing. And yes, some other points. We're not seeing any real correlation with Nectin-4 status. We are seeing responses in both HPV positive and negative patients. And we're seeing responses in PD-L1 positive and PD-L1 negative patients as well.

And then this is just a case study which Dr. Batista brought to us. I e-mailed you a couple of weeks back and said, what happened to that patient? Did they move on, they died yet? And he said, "No, no, they're just coming up. They just had their 1-year birthday on trial." And I think that speaks to some of the suggestions of durability that we've got as well, just a fantastic patient. ECOG2, would you say nasal prong oxygen confined to their bed?

Yes, yes, it is a very interesting case of this gentleman who is a dentist and he worked helping people in Illinois, and he contacted me himself because he was looking for trials. And he was hoarse over the phone when I met him. And I thought it was just because of the -- many of our patients are hoarse because of the locoregional treatment. And I told, hey, we have a good trial for you. And when I saw him in clinic, he was very sick looking and he was using supplementary oxygen. And when patients like that show to my clinic, my research coordinators, my nurse practitioners tell me, Dr. P, this patient is too sick. And then my response to them was, well, I think maybe it's like he's having pneumonitis because he's coming from an immunotherapy, right? But then I opened -- so they opened the images and then I saw those images you see on the left. And I told them, this is all cancer. This is not pneumonitis. And I have this protocol that says that we can put patients with ECOG of 2, right?

And most of the first in humans, they only allow ECOG of 1, right? So I have in front honestly, when a patient with ECOG of 2 on oxygen, there was no contraindication many protocols that are TOPO1 ADCs, right? They say contraindication patients on oxygen and you have to do PFTs and all, but this protocol doesn't have any issues with that. His creatinine was not ideal. His creatinine clearance was less than 60, but this protocol has a creatinine clearance of 30 [ in the cutoff ], right? So this was a sick patient. And when I met him, when I saw him, he was so sick. He tells me my daughter is pregnant. And the only thing I want is just meet my grandchild, right? And it was due in January. He's in February, his grandchild, and it was September. So like, wow, and I went home and I told my wife that if this guy lives 2 weeks, he would live for a year, but he might die within 2 weeks. But I put him on and this what happened, right? He saw his grandchild. He's riding bikes, he's back to work. ECOG of 0 right now. And he had some high toxicity, but we could manage that. And his ctDNA is 0, right? And what you see residual, it's just probably scarring, but obviously, they can still have measurable lesions in the lung. So we can call it 100%...

And you did a PET scan on that.

PET scan. Yes, he had a PET scan that was completely negative. Nor FDG-avid lesions, now [indiscernible] was 0. And yes, this is 1 year after this. So he went home, he e-mailed me like, hey, how is the patient doing? And I said, he just had his 1-year CT scan, and that's what you see on the far right. Yes, it's an amazing case, just at the point of what we can do with good ADCs sometimes. And just remind everyone when he shows up to the clinic that this -- this is what we can do when we find the right patient with the right agent. And obviously, this was the case, very exceptional case, but something that we have seen with other patients to maybe not as remarkable is like a case study of what this agent can do.

And just 1 or 2 more anecdotes and we'll launch into the panel discussion. This is a patient, just an example of how beat up and how many multiple therapies these folks have cycled through before they came on to our study.

We had 2 patients who had petosemtamab before. One of them got stable disease and one of them got a partial response. The patient that got stable disease had a previous partial response to peto. The patient that got a partial response and actually had previous stable disease on peto. So it's not a comprehensive experience, but it does at least speak to the fact that we're not intimidated or worried by the fact that there may be other agents coming before us when we come to consider our future pivotal studies. In fact, we would welcome it. We think it might even prime the patient.

So I think it's probably time for me to shut up, and I'll jump into the question session. I wonder if I could start with you, Professor Rosenberg. So could you perhaps help us by outlining the unmet need in head and neck cancer, particularly what is there for patients after they've had chemo or checkpoint inhibitor?

Yes. Thanks. Huge unmet need. And those of us on this panel see these patients all the time. Recurrent metastatic head and neck cancer is not only life-threatening, but can also have a substantial impact on quality of life, morbidity. Many patients have local regional disease, which in the context of the head and neck, where it's a very high-value real estate, pain impact on swallowing, speech can be very functionally debilitating in addition to some of the characterization of the patient you heard about already here.

Immunotherapy/chemotherapy, a subset of patients do quite well with that for a long time. But after patients progress, we really have a paucity of options. cetuximab, single-agent chemotherapy, none of which have truly remarkable activity. So there's a big unmet need for active agents in this particular setting that can improve survival, can lead to tumor regression that improves quality of life functionality. And so we're very eager. We're very eager for novel therapies with rational targets with a mechanism that makes sense for head and neck biology and can hopefully help the patients that we treat.

That's tremendous. And you've reminded me we had another question, 2 local regionally recurrent patients, and we got response there. So I know local regionally recurrent disease, and thank you, [ Professor Hanna ], is a much harder-to-treat population, and we're seeing it held up there as well. And yes, 85% of our patients have had both PD-1 and chemo. Some small subset of patients had tried monotherapy checkpoint inhibitors for a long time, and then they become too sick for chemo. So they came on to our trial a bit earlier. And some of our patients had repeat bouts of checkpoint inhibitors 2 lots of pembro followed by 2 lots of nivo. And I think that also sort of speaks to the desperation, the sort of wastelands of availability here in this sort of later-line therapy.

You talked about being eager to put patients on the trial. I wonder if I could ask you, Cesar. And this is a tribute to Ian, our operations team who are in the room today and listening at home potentially as well. Thank you all, and thank you for Precision Medicine, the CRO, you've done a great job. This trial recruited way faster than anything I've seen in Phase I before. And I I've done quite a lot of Phase I over the last 22 years in the industry. But could you speak to perhaps some of the reasons as we've already had elaborated by Professor Rosenberg, some of the reasons why you think it recruited well.

Yes. The protocol -- putting patients on clinical trial is not easy. I can tell you that and Dr. Rosenberg and Dr. Hanna here, they are obviously -- have high expertise on this subject. And it's not easy to be a clinical trialist. Every day, the protocols become more restrictive. The population is smaller and more [indiscernible] now you have to be dealing with exclusion from low albumin, exclusion from any lung disease. You have to be exclusion from untreated glucose. The ECOG has to be 0 to 1 and the creatinine clearance more than 60, right?

And at the end, the population that are candidates for a trial decreased substantially with every single extra exclusion criteria that you put that it doesn't reflect the reality of the population. It doesn't. So you see all these results of Phase I trials, but these are, in a way, they actually were picking very selected patients that are very healthy that they don't reflect the population that we are going to treat in the future. That is for some reason, when this protocol was written that I was not there when it was written, it was written to reflect the population that we're going to see in the clinic. Patients with head and neck cancer, they don't have a creatinine clearance more than 60 very commonly. That doesn't happen, right? They have been treating heavily with platinum before. Some of them have other comorbidities, the HPV-negative patients. Some of them have heavy burden of lung disease like what I mentioned here.

So this protocol has no contraindication for heavy burden of lung disease like we see here, creatine clearance study. There was no limitations with albumin, right? So the protocol was written, which is very friendly for the patient enrollment in a protocol that actually could reflect based on the criteria, what we see. And you guys -- when we see results, we -- you guys don't know how hard some of this protocol, how selective and all these weird exclusions that they have. This protocol was very friendly in that sense. So because of that -- and the inclusion of the patient had to be exposed to platinum and checkpoint inhibitors, both.

So because of that, it was fairly easy to just put most of our patients were candidates for it. And most of the head and neck cancer patients that we had, cervical cancer patients also, they usually get [indiscernible] upfront. They have some locoregional issues, too, because of the previous surgery, sometimes the creatinine clearance is not ideal either. So I think the design of the protocol was the main factor why this enrolled so fast and the fact that we saw responses from the first cohort.

So the first patient approved the trial, he responded, right? And it was an HPV-negative patient. So obviously, when I saw that, like if this work for an HPV negative on the lower dose cohort, I'm putting every single of my patients here, right? So -- and that happens with all the other -- my other investigators that it's easy to enroll, we saw responses and benefit from the beginning. So I think that just prompted the fact that we were excited about put patients on. The protocol was friendly to put patients on and the medication was easy to get.

And when we discuss the tolerability, it's hard to offer a medication to patients that can put them in a hospital and that can have a severe adverse event that can -- that the patient asked me, so Dom, how many patients have dropped death from this medication. They asked me that. And when you tell them none, and that is very reassuring, right? Because when you see the adverse event profile, none of these AEs were life-threatening. There's no severe pneumonitis like with oxytocin, right? There was no severe hypoglycemia that to the point that was to a life-threatening. So they were not really life-threatening AEs.

So then that initial efficacy that we saw and the friendliness of the protocol and the responses, then that fed up with a profile that was very safe, at least for life-threatening AEs. So we just continue to enroll. So we just keep the momentum just kept until now. And I think that's the reason why it continues to enroll so fast, right?

Can I just add, I think the 2 other things that stand out to me, we have 9 or 10 ADCs in our portfolio at the moment. The schedule is actually a huge component. So many patients on PADCEV either on or off trial in EV-202, cohorts 9 and 10 or even in bladder are not getting the day 8 dosing. And so in a head and neck population that's already a little bit stepped down in terms of frailty, a Q3-week dose for being able to get in and administer is actually quite important from the patient perspective.

The other is it's a validated target. It's a lot easier to tell someone, hey, why don't we think about this target delivery of chemotherapy when I can show you data that's published in JCO for an agent that has the same target engagement that has activity in an advanced head and neck cancer population. So paired with what Cesar was saying, that made this trial enroll like wildfire essentially.

So you very much -- sorry.

No, Dom, I'm just going to add one more thing, which is I think that the payload as well is a payload that's very attractive to us in the head and neck cancer space. Microtubule inhibitors are very well validated as a cytotoxic mechanism as well in head and neck. And so I think that also complements what you've already heard.

That's tremendous. And Professor Hanna, you've very nicely allowed me to segue on to my next question. It's a slightly complicated question, but you already highlighted some of the differentiating features. And I've been amazed. I was expecting adverse events to come in of MOFS, multi-organ failure syndrome, like you say, deadly ILD, SJS, Stevens-Johnson's none of it. It's been very, very pleasing. But with respect to both the safety and the efficacy, could you talk about what differentiation you see here versus the other ADCs and particularly what's important to you?

Yes. I mean I think number one is -- I know safety is sort of -- but like let's be realistic. Number one is going to be the activity of the agent. And so we have a landscape and a history here with antibody drug conjugates in head and neck. We were talking about this earlier. You had sacituzumab, tisotumab vedotin and EV as sort of the first cluster of single-agent arms that were presented last year -- or in the last 2 years. And they all sort of hovered around this 20-something upwards of 40% with TV, although the toxicity profile sort of shot that down, unfortunately, with tissue factor.

So that was sort of the benchmark. And many of them are this population, maybe not as permissive as Cesar was mentioning in some of the earlier trials, a little more selection for healthier patients. But generally, if you look at the EV data, Cohort 9 from 202, it was patients who were largely sort of median 3 to 5 lines. So I think for those of us who are working with ADCs, and it's not a surprise, as Ari pointed out, that these are all vedotins. It's a little bit easier to envision that benefit coming out of taxanes, but also tolerability. Whereas with topo, that's a tough bet on a head and neck cancer patient. We'll see those drugs come to clinic now, but I do have concerns about a head and neck population handling that kind of payload like exatecan, et cetera, or deruxtecan payloads.

So that said, that's kind of the bar we were looking at when we bring in trials like this. You've got a validated target. So you're not worried about, well, is this -- like for ROR2 or some of the newer agents, what's the validation? What's the spread with HPV positive/negative? You sort of had that answered with at least the signal you could see from the PADCEV monotherapy data.

So I think for me, that was some of the first things I think about. Of course, we want to see response rates potentially even higher than that and understand if there's subpopulation issues like HPV-positive, locoregional patients, patients who've been prior exposed to 5-FU versus taxanes, people who have had prior petosemtamab given that, that could change the field. So I think those were all the efficacy concerns you would worry about and durability, right? So people will say ADCs are another way to deliver chemo, right, ADC, a fancy chemo with a Gucci bag is what one investigator told me.

But nonetheless, what I think of is they do have a toxicity profile. But in general, to Dom's point, what we're looking for in that safety profile is if it's manageable and is it predictable, is there something we can do preventatively like eye drops or topical skin care, minimizing sun exposure, prophylaxis, those things sit well with us. But when we're talking about life-threatening long hold requiring or dictating toxicities that make it so that you can't dose over subsequent intervals and you start losing efficacy, you start losing durability, that is a major concern with some predecessor ADCs that sort of shoot things down.

So I think -- and what you've heard has been what we often ask, okay, in the vedotin class, I want to know, is this a cytotoxic agent? Is it going to have to require growth factor? Is there ocular toxicity? Is there an ILD or a lung inflammation signal? Are we seeing skin tox that's limiting chronic itching, pustular rash that's making us hold and talk to dermatology. So all of those things kind of are currently what people are thinking about when we're thinking about new drugs in this category and in the head and neck space.

So again, summarizing, when you're seeing 30%, 40-plus percent response, heavily pretreated, manageable AEs, permissive profile, a target that's already been validated Q 3-week schedule, you have my attention. And it's easy to get patients engaged in that scenario.

And it's a slightly unfair question, but we're not necessarily going to be competing against peto, but people will put us side by side. There's an obvious adjacency. How do we compare there? And I mean, they've got grade 3, the monotherapy trial, grade 3 or greater adverse was 59%, I think, and we're at 35%. And I noticed you -- all of you individually spoken to me about how much things like fatigue are often ignored by companies. What do you think about, say, well, 2 parts there. First is peto and these things like fatigue.

Yes. I mean I think -- and peto is not the only agent. I mean we use lots of agents, chemotherapy and lots of things that contribute to patient toxicities and morbidity. Fatigue is certainly one, right, sort of the overall decline in performance status with systemic therapy, which is something that makes us as medical oncologists that are trying to optimize quality and length for patients with really bad disease in terms of our selection of therapies. So that's certainly a big one that we look at and probably related to the lower free MMAE, we see less of that with this agent with the emerging data.

The other one that I agree with everything that Glenn said, one additional thing that is important to highlight is neuropathy. And neuropathy, which is a cumulative effect and is oftentimes the toxic limiting maintenance, how long can you give the drug for and at what dose intensity. With -- when I talk to my urothelial colleagues that use enfortumab vedotin all the time, they talk about the fact that everyone gets neuropathy eventually, and it's just a question of when. And at that point, they have to flip to a different strategy. So being able to manage those kinds of things, the fatigue, the things that drive decline in performance status, neuropathy, things that really limit the ability to maintain a dose level to keep that active agent and keep that response as long as possible is, I think, some of the other considerations that...

And it's been a long time since I practiced in the clinic, but Grade 3 neuropathy specifically, what does that look like? Is that tingling -- excessive tingling of the hands and feet? Or is it something more sinister?

Yes. I mean numbness in fingers and toes, paresthesias, pins and needles sensation, can be painful, electric shock sensations. Those are some of the different descriptors. I mean if it gets severe, I mean, patients feel like they can't walk properly, they can't balance because they can't feel their feet very well, have a very hard time with fine motor activities. So buttoning, writing, typing, everyone uses iPhones right nowadays, and you need fine motor function to be able to live and do all the things that we all like to do. And so that makes a big thing.

I'll mention just one of my patients that was on the study who had gone through a number of lines, including taxanes with recurrent disease in the neck, he was a horseback rider and talk horseback riding. And so for him, maintaining neuropathic proprioception, all those kinds of sensations to be able to function and do the things that he wants to do were very, very important to him. And so that just illustrates some of the things that we're thinking about when the patients walk into our clinic and trying to think about what are the toxicities that we're willing to take in order to achieve a response and help people live longer and better.

No, that's fantastic. Should just do a little side bar on Grade 1, 2 and 3 eye toxicity as well. Grade 1 is asymptomatic. And we have induced a degree of artifact. Well, it's not artifact, it's real. But because we have regular cadence of ophthalmological assessments in this study, the ophthalmologists come and they pick up an asymptomatic patient. They put fluorescent eye drops in and they're magnifying slit lamp and they see these little superficial punctate keratitis lesions, and they get correctly grade 1. But I think we have higher grade 1 than many of the other ADC studies historically, which didn't have this high frequency of eye events.

Grade 3, again, interfering with activities of daily living. We did have a patient who had to have their relatives moving with them for a while because they couldn't use their iPhone, they couldn't see the TV, they couldn't use remote for the TV. And I think that's important. And again, that patient got better with the dose interruptions, the delays, they got better, and they were still able to dose through whilst maintaining efficacy. So I think the reversibility of the eye, we're not mature enough in our data sets yet. We've not got enough volume to enumerate the degree to which we're seeing recovery. And of course, some patients just progress. So we don't get to see the sort of the final end game with that improvement in eye. But we are critically seeing improvements. And again, like the neuropathy is like a one-way ticket, yes. Once you've got that, it isn't going away.

I think the median time to resolution of the peripheral neuropathy is about 1.5 years, which patients haven't really got. So yes, I just wanted to make sure I made that point. And then maybe Professor Hanna, I'd ask you this horrible question, a crystal ball question. How do you foresee the drug being used in the clinic? Where would you -- and I'm not asking for a high acuity vision of where it's exactly going to land, but where just, for example, might you like to use it?

Yes. I mean I think the immediate unmet need we've alluded to is going to be the patients that we're going to be seeing and we're seeing now, but if you step outside of some maybe 1-year time lines and approvals, I think many of us think that immunotherapy with or without platinum plus a novel eGFR inhibitor in the mix, whether it's petosemtamab or ficerafusp alfa or both is probably where we're headed in the next 1 to 2 years with petosemtamab as a potential monotherapy second-line agent. But you still have chemotherapy, chemotherapy plus or like taxanes plus cetuximab in some instances. Most people are not using in clinic, particularly in the U.S. or North America, methotrexate, afatinib, those drugs. You might use some 5-FU or capecitabine. So if you're reaching and you don't have a trial option.

So that's really -- that for us becomes the immediate unmet need is the patient who's post platinum, post IO or PD-1 failure or progression and then may have had an eGFR modulating therapy of some kind. That is the growing patient that we see in our clinic ready to engage and go on trial, and that's HPV positive or negative. So I think the immediate need for CRB-701 is or an ADC is going to be that patient population is a better tolerated form of chemotherapy, so to speak, that has target engagement and a predictable safety profile. So that puts you in the second line potentially or third-line space ideally.

And you sort of made this point about how well peto is looking in that line. But for me, that doesn't actually matter a whole lot because there's a lot of people who right after peto need something. And regardless of what that median OS is for peto and second line, there's an immediate ADC monotherapy need or single-agent need in that third line. And people will say, well, how many people get to that third line? Well, we're sitting up in here telling you we don't have enough slots and we're enrolling pretty well. So it's not a low number of patients that get there.

And I think the reality is because things have changed. IO has made it more palpable for a patient to live longer with head and neck cancer with less toxicity and get to second line. Peto and these other drugs are making it feasible that people are going to get to third line. The median OS here is now extending. It's not amazing, but it's beyond 12, 15 months, even 18 months in first line all comers. And now in second line is 6, 8, 9 months on average, probably going to start getting out to 10, 12 months in second line. That's great. That's several years for an advanced metastatic head and neck patient. So I think the third line is probably the low bar, but that's the unmet need in the moment. That's the patient I'd like to be able to consider this drug for.

And that's before you start thinking about, well, could we bring it into the neoadjuvant space? Should we add pembrolizumab and do it upfront presurgery? That's a little bit right now where everyone's mind is going on the heels of 689, but that's a little cart before the horse. I think the immediate clinical need is that recurrent metastatic second or third-line patient needs a monotherapy ADC option.

And I'm really grateful that you made that point about surviving through to later lines of therapy because I've seen that in my career. I think historically, you look at the survivorship going through second and third line with head and neck. And it was kind of this sort of 15, 20 years ago, it was chemo and then more chemo and then we're progressing, well, let's just try one last chemo. And by that point, the patient was in trouble. And the number of patients that bled through, if you pardon the phrase, to later stage was poor. But now these guys are in good shape. That's a tribute to peto. It's a tribute to pembro and the patient selection. So like you say, as I often find, the recruitment rate to our trial tells us a lot about the commercial attractiveness of the drug, and it's about efficacy and it's about unmet need.

And then the other thing I just want to highlight as well is that in our clinic, we are seeing more and more recurrent metastatic HPV-related disease. And although in the upfront setting, we do cure the vast majority of those patients, there's 10%, 15% that still recur. And because the increasing incidence overall, particularly in the U.S. is increasing HPV-related disease, we see those patients that recur in metastasize and progress on immunotherapy and platinum-based chemotherapy. That's a group where we don't use very much cetuximab, right? And so already, that's also in particular line, right, where we're looking into that.

So that's another patient population. And then we talked a lot about performance status. That's also a population that at that -- in that setting, they still have a very good performance status. This is the marathon runner HPV-related recurrent metastatic disease, oftentimes where there's no active treatment option. And so that's another patient population that I think is of interest that I've been interested in putting on this study.

And they live longer, right? The population live longer. And those very rarely a patient with HPV disease doesn't get to third line. I mean it's very commonly they actually get to third line. But the problem is that as of today, if you give carbo-taxol, pembro to an HPV-positive patients in first line, you pretty much have nothing in second line. I mean nothing good. You have 5-FU that we think that it's okay, but maybe has a little more active in HPV negative and cetuximab that we don't trust in HPV positive. So obviously, those patients are in a great need right now.

And it's always a question how much the eGFR bispecifics will contribute to the survival of the patients. We still don't know. But nobody is certain that it will -- it might certain -- we're pretty sure that it will help the whole population of head and neck cancer patients, but how much it will contribute to the HPV is still kind of in question, right? And, obviously, BCA-101 is not being studied those patients. So yes, these patients have a big, big need. And obviously, the HPV-negative patients also have a big need, but the HPV positive certainly don't have a lot of options right now.

One of my old Scottish physician colleagues used to call 5-FU 5 freaking useless. We didn't say freaking either. But yes, there is a very impoverished set of therapies, single-agent chemotherapy that can be used after all these. Would any of you or all of you care to comment on what you think those are like because we're potentially staring at that as a comparator arm in our future registrational studies?

I mean I think -- I'm sure we have slight variations. But in general, you're reaching for exactly, as you said, some of the docetaxel in some instances, which does have activity. I would argue it's cautious to interpret the data of the past because chemotherapeutics do actually seem to work better after IO exposure in the advanced head and neck population. That's actually published 3 or 4 times by several groups as an observation. And in the follow-up data from the KEYNOTE-048 trial, there was a PFS 2 assessment on second-line therapy.

So that's important to consider. So they aren't inactive agents. They just come with all the plagued toxicities that Ari and I were talking about, neuropathy, dose hold, cytopenias, et cetera, hair loss and all of the like. Some people will combine taxanes with cetuximab. That's an effective regimen. That's a European favorite, I'm told, for HPV negative. But again, you're adding all of that chemo tox on top of now skin rash and serious dermatitis issues. That's a pretty potent but pretty difficult combination to maintain. I don't use methotrexate. I had a lymphoma physician tell me once that the dose that's used in head and neck cancer is not even therapeutic essentially compared to what's given in lymphoma treatments. So -- and I've never personally seen a response, and it feels like a last ditch effort, frankly. I would always prioritize a clinical trial.

I do use 5-FU. I'll often do it in like a carboplatin 5-FU weekly schedule with leucovorin just because the patients are delicate at that point, and I want to see them frequently or -- and this is a European favorite, too, oral capecitabine, which is the precursor to 5-FU. That is a little more potent, but someone who's healthy and doesn't have a trial option and wants an oral medication, I'll consider 5-FU as well. But outside of those, fluoropyrimidines, taxane recycling, a little bit of IO resprinkled in, that's it. I mean essentially that you don't really have -- I don't personally use afatinib or the TKI that has a 1-month PFS improvement historically in years gone by. So I'm not sure if there are other agents that Ari and Cesar would use, but I think that's why we're all trialists because that's pretty much all that's left.

Yes.

So a question from our virtual audience. Believe it or not, there are over 30 people watching this live in the U.S. I'm delighted, but also a little bit concerned for them. On a Sunday morning coffee. It's a little bit early in the day. Question to Dom to then pose to the panel. Nectin-4 levels and what we're seeing and what we're thinking.

May go back. I think it's...

It's in the waterfall plot on the bottom, right?

Yes. H-score. Yes. I mean, essentially, we don't see any actionable difference. You can see the far right there, the most extreme response, Nectin score of 55, and we see that repeatedly. And then we've got some really great high scores over towards the left with patients are progressing. And this is no surprise or no stranger to this kind of thing. You think about immunohistochemistry, you get one small section, sometimes smaller than a grain of rice. And it could have been from the patient's original head and neck tumor 5 years ago, that's an archive. And then you come up and you try and correlate that with what a radiologist is looking at on a Thursday morning in 2025 in a patient's liver lesion and wonder why it doesn't correspond. That's true of any IHC.

But then also, our drug is Fc optimized. We are internalized at twice the rates of many of -- well of PADCEV. And one of the potential mechanisms of action that we have here is not only that you go in through the front end through Nectin-mediated endocytosis or Nectin-mediated bystander killing, dropping off the MMAE, but you also reverse into it through the Fc-mediated endocytosis as well. And that, therefore, speaks to how it may well not be the case that there's no requirement for Nectin staining because some of our mechanism of action doesn't require Nectin to be there at all.

So I would say that heterogeneity is the answer here for most cases, right? I mean this is actually good from a commercial standpoint that on brand with most ADCs that biomarker selection in this population would be not clear for the role. I mean the point made about sticking the needle in the apple and assuming that you're getting the same thing throughout the whole apple is a little bit naive in 2025. We know that every metastasis is different. You biopsy the same site in the same tumor -- or 3 sites in the same tumor, you get different expression.

So I think -- and these things may be somewhat dynamic. This is a cell adhesion molecule. So it's likely somewhat steady over time, but can potentially change, right, dynamically. And primary tumors versus metastatic tumors. Some of these are older archival specimens within a year that came from the prior resection. And then some of them are new fresh biopsies. So all of this tells you that heterogeneity will and reader operability, right, on Nectin score is a score. It's a quantitative score that's calculated with some input from a pathologist.

I would also -- the last point I would make on that is the HER2 story. I mean we're all humbled by the HER2 story. I mean we're now talking about ultra-low expression less than 1. I don't even know what that means, like 0.1 plus. But deruxtecan and in HER2 is working in HER2 ultra-low patients and changing the game on what these biomarkers actually mean in expression. So it's nice to see that I think the key here for the Corbus team and in the trials is to figure out, is there a lower level at which a cutoff exists below that point, you don't -- you do or don't see benefit. It certainly doesn't look that way, which makes life easy. But I think that's how you would easily explain this sort of [ swash ] of different values.

But actually, I think I'm a big biomarker person. I love a biomarker-selected option. But in this case, for commercial viability and patient selection, it's actually good because one of the headaches, not so much for us, but in the community is if I have to wait to use this drug because I have to get a biopsy slide from Kentucky or outside hospital or I got to rebiopsy and get my pathologist to stain for Nectin-4 and I got to develop a companion diagnostic, that's a delay, a headache and a disruption for generalizability. So I actually think this is a positive.

Ari, did you want to?

Yes. No, I agree. I was just going to add that in parallel, we should keep working and trying to figure out for these -- for a Nectin-4 targeted ADC like CRB-701, what is the right way to figure out what the right biomarker is. And it's not H-score, right? It's not quantification of expression of Nectin-4 in a particular tumor for all the reasons that Glenn talked about, and that's consistent with what we've seen across other ADCs as well. But it doesn't mean we shouldn't stop trying and trying to figure out what those predictors are.

Right. And certainly, if other ADCs do come to fruition in head and neck cancer, to Ari's point, if there is ultimately a biomarker -- like, let's say, it's an agnostic population, but above a certain cutoff, there's an even enrichment for success we might be more inclined to use this drug as opposed to reaching for something else. And Dom, this circles back to, let's say, in a world someday peto and CRB-701 are options in the second line, perhaps expression levels at certain cadence will tell you or at certain level cutoff, I'm going to go with the Corbus drug because I'm likely to get this enriched response benefit, whereas I'll save peto for later.

So to Ari's point, I don't want to discredit biomarker selection. I think it isn't -- for us, it's very important later. These are still drugs with toxicity profiles. So that's a nice place to be agnostically, but then you can learn as you get more data for who's the enriched population to focus on.

Yes. I think just to add that to the -- because how friendly the protocol was the fact that the limitation of how friendly it was is that we didn't have to do mandatory biopsies to put the patients on. So we could use archival tissues, but then we end up -- obviously, the downside is that we end up with some tissue that does might not reflect what we're treating at this time, right? So I think that's the main limitation that we had. I was a little surprised initially because this is such a clean ADC in terms of where it lands and having so little free MMAE.

But in the same token, you will expect that you will have relationship with expression, but then I think just the fact that the tissue was not just before starting therapy. That's probably why -- one of the potential reasons why we might not have actually a correlation.

And I know you want to come in ask a question, but there's one question absolutely must ask and it's behoove and upon me. Are we seeing durable responses? Or are they kind of responses that are here today gone next month?

I feel that they are as durable as we expect for a good vedotin-based ADC to work. I don't see anything else. If anything less, obviously, we have exceptional cases that stay on therapy for long. This is not the only patient. We have other patients that have stayed on therapy for long. The only issue is that this trial is not -- we have been going on this trial with like something like 18 months only, right? So we don't have enough time to just look back and analyze for how long the patients have stayed on trial.

For now, what we've seen is that these patients are staying in therapy for a good amount of time, right? It's not just that they get one scan, they respond and they progress on the other. That's not how it is. The responses and they have -- some of them, as you have described before, have been deepening as time passes, right? So yes, I think it's encouraging, definitely, the duration of response. Hopefully, we'll have it next year, the duration response. But what we have seen so far it seems to be very encouraging.

Fantastic. Yuval?

Yes. We are approaching time, so we have about 10 minutes. A reminder, if anybody does have a question in the audience, we have a microphone here with Sarah. And if you could just identify yourself, thank you.

This is [ Pasquale from Cendrum ]. A couple of questions to management and also the doctors. So if peto makes it in frontline, right, with pembro, would you like treat patients in second line with peto monotherapy? So this is the first question.

Second question, is there like any rationale for Nectin-4 amplification being probably get better biomarker to enrich for responders? And what is the role of like Nectin expression going from front line to third line? Is there like any studies like suggesting that you like enrich for expressors as you go on in the therapeutic algorithm?

And then another question on keratitis. So this grade 3 keratitis that you saw so far, what is the basically the logic beyond discontinuation, dose delays and so on. What do you need to see? And how do you decide what patients need to like drop the therapy?

Maybe we should split this -- maybe I'll do the peto question. Someone can do the expression question and someone can do -- so mine will be quicker. So yes, there will be a role for peto in the first and second line. And you can envision, for example, just based on different patients, different needs and adoption of use that someone could get chemo IO, they could get pembrolizumab alone, they could get pembro-peto, ficera-peto. But if someone got any of those -- I would say we are not going to recycle eGFR targeting likely. That needs to be figured out, but it does -- I don't yet see a rationale to go from a ficera combo to peto second line, maybe because LGR5 is distinct, but I think we want to see data before we would do that. We would want to use -- I would want to use an ADC.

But there are going to be people who even in the face of a potential approval for first and second-line peto, people may get only the second line. They might just come out the gate with pembro only for whatever reason the doctor decides or chemo IO for whatever reason, right? We love to split the hairs of the data. So there may be subpopulations that we feel benefit from one. So the short answer is I think there's room for both. There's a market in a space and a clinical need for peto and even ficera in the first and then peto second line.

Yes. And for the second question about the Nectin-4. So most of the data that I'm aware of actually is from urothelial, where it's a much more validated target. And so for example, there's been data from urothelial about membranous expression as opposed to overall expression as being a key thing. Differences in terms of Nectin-4 expression at the primary versus the metastatic site as well. So again, we have to do that work for head and neck. I don't think we're -- from a Nectin-4 targeted perspective, we're still, I think, in the process, we have to do that work in head and neck.

The other thing just to highlight as well is that there are some studies suggestive that it's enriched in HPV positive, right? In this study, we see responses, both HPV-positive, HPV-negative. HPV-positive is the population where -- we're less -- we don't use -- I don't use a lot of cetuximab in that setting or eGFR inhibitors are -- as a target is less -- we're less enthusiastic about eGFR as a target for HPV positive. And that's also where Nectin-4 happens to be enriched and things like that. So we have to do more work. We have to figure out which component is most important to the efficacy of the Nectin-4 targeted ADC and we have to do that work and hand back.

And Cesar, do you want to do Nectin-4 degradation? Or do you want to do keratitis?

So let's just briefly talk -- I think the question is very valid and the data actually here from Germany of Nectin-4 amplification as a single agent patient with urothelial carcinoma where there was a 96% response rate. It's only in 25% or so of the bladder cancer patients. It seems to be less in head and neck and it hasn't been well studied, but obviously, it will be great if it will be a small population. But then you will be missing out a couple of patients -- a good amount of patients that might respond despite having amplification, right? But we don't have that data, unfortunately, in head and neck. It seems to be very impressive for bladder cancer patients, but we don't have that data for amplification.

And in terms of the keratitis, so I think the main point is that as soon as the patients have symptoms, eye symptoms, the grade 1 is asymptomatic, right? As soon as the patients are having symptoms for the full, et cetera, we learned that we have to hold drug, right, and give them a little bit week. So it will actually stabilize and improve. If we don't, that it can actually fall into Grade 3. And that's -- it's significant in terms of quality of life when it goes to grade 3. And there's many flavors of grade 2. Some patients says, I'm fine. I have a little bit of -- the light bothers me, but don't dare to stop my drug, please. I need to get better. And some patients will say, "Oh, I'm afraid that if I drive, I can go into crash. You have to stop this. And everyone is a little bit different.

But certainly, grade 3, we have to immediately hold as soon as the patient is asymptomatic, sorry, and sometimes do a dose decrease if it doesn't get better in a short -- in a couple of weeks. We have patients that we had to skip a whole cycle, in general. But despite that, the good thing is that it's all universally reversible. And the patients usually are able to be redosed later on either at the same dose if we think it's safe or at a lower dose. Usually, when we grade to grade 2, you have dose decrease. But for grade 2, we can redose it at the same dose after dose delay.

And ophthalmologists are becoming more comfortable with this class of drug and the payloads. And so they're being more proactive about helping with eye drops and stimulant drops that will -- and refreshing and wetting drops that will help maintain the patients minimizes the keratitis or irritation to the eyes.

And we are looking actively at Nectin-4 amplification. It is, as Cesar says, it's relatively infrequent, but it's kind of doing exactly what you'd expect it to do. But it's not actionable because there are so many patients responding who are not amplified.

One second. I think Andy had a question here in the front, and then Amin.

Andy Hsieh, William Blair. Congratulations on the team and good efficacy really stepping in the right direction. I have a question about the skin toxicity. So is it -- if you look at some of the skin toxicity that's showing up, do you see a correlation between prior eGFR? In other words, are these eGFR agents exacerbating some of the skin tox that you're seeing? And then the frequencies, I think if you calculate, there's like one across a variety of different descriptions of skin. Is that just from one patient? Or is it actually dispersed throughout?

Yes, I really wanted to get the data on skin tox out there because I know it's important, and I know that our skin tox profile is good. The higher term, the higher term addictionary includes alopecia, of which we've got about 40%. So it would have looked ridiculously high. But if you take that down, in the end, we -- I spent a long time with Paola, our clinical scientists said, let's just give them the laundry list of what there is. It's not -- most -- there's 3 grade 3s, no discontinuations, except the one bullous dermatitis. It's good.

So we just need to give -- and that's what some people call a rash a rash, some people call it dermatitis, acne form, some people call it whatever you know. But it's a great question about eGFR. I don't know anecdotally, if you've known anything about that.

I haven't seen that. I haven't seen exacerbation because of prior eGFR.

And frankly, mechanistically, it's not -- this is not an immune stimulant that would recall eGFR-mediated rash. And so generally, it's actually myelosuppressive or cytotoxic in its payload. So that will actually help with rash management.

And maybe a quick one about dosing, just how you think about dosing going forward?

I think the position from us is we really can't comment until we talk to the regulatory authorities. Amin, please.

Amin Makarem from Jefferies. I had a couple of questions. One on the number of patients that you have so far, how long follow-up do you think you need to feel comfortable about the profile of this drug? And how many more patients or more follow-up you need to move on basically to a registrational phase?

And for our panel, I just wanted to ask about if we can get more granular on your personal experiences with keratitis, when do you usually see it the first time? Is it at the beginning of the dosing or it can happen anytime during the treatment? It would be great if you can add some color there.

I mean I can -- I think we did 5 weeks, 6 weeks, the median time to indicate the eye toxicity, right? I think it was around 6 weeks around the time when they are getting the third dose is the median time where sometimes we actually reported that we have to do a fall. And that's around the time they're having the scans. Sometimes they respond were like, okay, you know what, you're responding right now. Let's just make sure that your eyes are okay, and let's just delay a week. And that's kind of the typical scenario. Hey, I have a little bit of photophobia and lacrimation or you have to see the eye doctor now. You have Grade 2 keratitis, let's give you a week or 2 weeks delay. And that's kind of a typical scenario.

So like tearing issues, feeling of like a little grittiness or dryness in the eye, I'm a contact lens wearer. So like that feeling that there's something there, needing to rewet, you've got the drops. So that's kind of the grade 2 category. Grade 1, as we heard, is not really any symptoms. It's just that the eye specialists saw the punctate keratitis. And then I mean, grade 3 would be pretty substantial, right? It's really interrupting activities of daily living to a substantial degree, whether it's no longer operating cars or needing assistance with balance, et cetera, or symptoms that are really disrupting vision or vision quality.

So I would say for our experience at DFCI, we've kind of hung around that grade 1 to 2 range. But it does require eye drop commitment and engagement from the patient. So that's important.

Yes. And we've also observed the reversibility of the symptoms with holding and oftentimes a lack of recurrence of symptoms when the drug is be introduced in some cases as well. So that's also been something that from the patients that we've enrolled as well that I think is important to mention where they have these symptoms and the dose is held and then when they're ready for the next dose or the next cycle, in some cases, their symptoms have substantially improved back to baseline in some cases.

But the Corbus team was probably asked about the size of the signal needed to move forward and the time line and the number -- you asked about the follow-up required for the current trial as we heard, it's been ongoing for 18 months. I think that's more something you guys would.

Yes. We're talking to various stakeholders. We've all been incredibly encouraging, and they do say that we do need more follow-up to answer the questions more enumerate the reversibility, properly get some confidence intervals around duration of response look at disease control rates, relative dose intensity, all of these extra metrics that just take time.

But perhaps in the next few months, you're talking about 60 head and neck patients treated. We're already in expansion at focused dose levels. That's pretty sizable compared to what other contemporary companies have decided to move on. I mean I sort of chuckle to myself, there are some recent ADC decisions that on a 14-patient denominator decided they might launch a global Phase III, which was an interesting move. But nonetheless, we're already approaching 60 patients with almost 2 years of data. I would say that's starting to get into a range where you feel healthy about making a decision.

Yes. I don't think -- and you correct me if I'm wrong because you guys are a lot better than me with numbers. But I don't think that based on Phase I data, ficera, peto, the other couple of ADCs we had, I don't think nobody has reached 60 on the first report that we have. Peto moved forward with a lot less patients. These were 40-something...

40-something in ficera. Ficera already...

Enfortumab 30-something. So usually, they are in between the 30 and the 40 range. I don't think nobody has reached that 60 number. So I think we'll have a very good data in a year or so.

Or like mid-'26 is probably a healthy time to assume that the loose ends will be clearly sorted.

You hit the nail on the head.

We are unfortunately really out of time, and there's a driver waiting for us to take us to the conference because we do have at some stage to be there. I just want to thank, first of all, the panel, you've been really tremendous and generous with your time. Thank you for the audience. Thank you for the 35 people who are awake in the United States at the moment. Please go back to bed. It's Sunday morning.

Thank you for the LifeSci team again and the audiovisual team. We are around at some stage, find us, but thank you again and just immensely grateful. Thank you.