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. Thank you to the team that they've organized here on the ground to make sure that this is webcast and recorded. A reminder that you'll be able to listen in at your convenience. 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 am 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 for people who are listening in. I think you're here to listen to the panel. With that, Dominic, it's over to you. Thank you. Can you hear me? Am I using the microphone correctly? Yeah, 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. 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. Our panel, who essentially don't really need any introduction—oh, my slides are going—our panel here, who are very familiar with the moving slides on, and also probably many of whom are well known to you. They, I'm sure, today will be fantastic in providing that important patient-centered context, extra color. 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. 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. 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. Just a quick reminder, the poster, which is going to be shown at lunchtime 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 three weeks. I know that the physicians on the ground really value that. Yet we do have a differentiated pharmacokinetic profile. We have a drug antibody ratio of two, which means we can give a lot more total antibody. The fixed linker also means that we stay around in the circulation longer with lower levels of free MME. Our strategy, as we've said many times before, is we're not going after PADCEV. 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. Yeah, as we said, fixed link. I won't spend too much time on this slide. We're occupying and concentrating on the Nectin-rich tumors, principally cervical, head and neck, and bladder. This drug is an outlier in the ADCs. It's an outlier because we have much lower levels of free MME. I think that actually helps begin to focus on the differentiated safety profile and efficacy profile. I've already mentioned the dosing regime. 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. This is 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 MME activity that's gone on, particularly with Merus. We do think it's a really big market. Demographics, nothing too outstanding here, standard phase I. Many of you have already commented that we do have a median number of three prior lines of therapy. 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 had three prior lines of therapy as our median number. Treatment-emerging adverse events, the overall burden, and the gents will talk about this, is very low with the obvious differentiating feature that we've got [ITox]. That is a feature that's more prevalent with our drug. Compared to the ADCs, I won't dwell on this too much, but our grade 3 adverse event level is around 35%. I know from the feedback from these guys, that's really very much appreciated. Astonishingly low levels of peripheral neuropathy. I think that relates to the free MME, and that's true of our Chinese data as well. Low rates of skin adverse events. We've had three grade 3 adverse events, no grade 4 or grade 5. Really pleasing across 167 patients. We've got a slide in here for comparison with Tivdak, but I'll jump on to the waterfall. There are 1.8 patients in here as well. This waterfall is the lesional measurements, but we've also attached the RECIST measurements as well. The table includes both the overall confirmed rate. 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. We're starting to speak to the durability that we're seeing. Yeah, some other points. We're not seeing any real correlation with Nectin-4 status. We are seeing responses in both HPV-positive and HPV-negative patients. We're seeing responses in PD-L1 positive and PD-L1 negative patients as well. This is just a case study which Dr. Batista brought to us. I emailed you a couple of weeks back and said, what happened to that patient? Did they move on? Have they died yet? You said, no, no, they're just coming up. They just had their one-year birthday on trial. I think that speaks to some of the suggestions of durability that we've got as well. Just a fantastic patient. ECOG 2. Would you say nasal prong oxygen confined to their bed? Yeah, this is a very interesting case of this gentleman who is a dentist. He works helping people in Illinois. He contacted me himself because he was looking for trials. He was hoarse over the phone when I met him. I thought it was just because of the, you know, many of our patients are hoarse because of the local regional treatment. I told him, hey, we have a good trial for you. When I saw him in clinic, he was very sick looking. He was using supplementary oxygen. When patients like that show to my clinic, my research coordinators and my nurse practitioners tell me, Dr. P, this patient is too sick. My response to them was, I think maybe it's like he's having pneumonitis because he's coming from an immunotherapy, right? They opened the images. I saw those images you see on the left. I told them, this is all cancer. This is not pneumonitis. I have this protocol that says that we can put patients with an ECOG of 2, right? Most of the first in humans only allow ECOG of 1, right? I have asked in front, honestly, with a patient with an ECOG of 2 on oxygen, there were no contraindications. Many protocols that are top of 1 ADCs, right? They say contraindication patients on oxygen. You have to do PFTs and all. This protocol doesn't have any issues with that. His creatinine was not ideal. His creatinine clearance was less than 60. This protocol has a creatinine clearance of 30, the cutoff, right? This was a sick patient. When I met him, when I saw him, he was so sick. He tells me, you know, my daughter is pregnant. The only thing I want to do is just meet my grandchild, right? He was due in January. He's in February, his grandchild. It was September. I'm like, wow. I went home and I told my wife that if this guy lives two weeks, he would live for a year, you know, but he might die within two weeks. I put him on and this would happen, right? He saw his grandchild. He's riding bikes. He's back to work. ECOG of 0 right now. He had some high toxicity, but we could manage that. His ctDNA is 0, right? What you see residual, it's just probably scarring. Obviously, they can still have measurable lesions in the lungs. We can call it 100%. Did you do a PET scan on that? A PET scan, yeah. He had a PET scan that was completely negative. No FDG lesions. DAPT was 0. This is one year after this. He emailed me like, hey, how is this patient doing? I said, oh, he had just had this one-year CT scan. That's what you see on the far right. It's an amazing case, just at the point of what we can do with good ADCs sometimes. Just remind everyone, when he shows up in the clinic, that this is what we can do when we find the right patient with the right agent. Obviously, this was the case. A very exceptional case, but something that we have seen with other patients too. Maybe not as remarkable, but he's like a case study of what this agent can do. Just one or two 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 onto our study. We had two patients who've had tisotumab 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 [tiso]. The patient that got a partial response had actually had previous stable disease on [tiso] That's not a comprehensive experience set, 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. 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, and say, could you perhaps help us by outlining the unmet need in head and neck cancer, particularly, you know, what is there for patients after they've had chemo or checkpoint inhibitor? Yeah, thanks. Huge unmet need. 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 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. After patients progress, we really have a paucity of options. Cetuximab, single-agent chemotherapy, none of which have truly remarkable activity. There is 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. We are 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. No, that's tremendous. You've reminded me, we had another question. Two local regionally recurrent patients, and we got one response there. I know local regionally recurrent disease, and thank you, Professor [Rosenberg], is a much harder-to-treat population. We're seeing it held up there as well. Yet, 85% of our patients had had both PD-1 and chemo. Some small subset of patients had tried monotherapy checkpoint inhibitors for a long time, and then they'd become too sick for chemo. They came onto our trial a bit earlier. Some of our patients had repeat bouts of checkpoint inhibitors, two lots of pembro followed by two lots of nivo. 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. Thank you for Precision Medicine, the CRA, doing a great job. This trial recruited way faster than anything I've seen in phase I before. I've done quite a lot of phase I over the last 22 years in industry. Could you speak to perhaps some of the reasons that, as we've already had elaborated by Professor Rosenberg, some of the reasons why you think it recruited well? Yeah, you know, the protocol, putting patients on clinical trial is not easy. I can tell you that. Dr. Rosenberg and Dr. Hanna are there. They obviously have high expertise on this subject. It's not easy to be a clinical trialist. Every day, the protocols become more restrictive. The population is smaller, more picked. 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- 1, and the creatinine clearance is more than 60, right? At the end, the population that are candidates for a trial decrease substantially with every single extra exclusion criteria that you put. It doesn't reflect the reality of the population. It doesn't, you know. You see all these results of phase I trials, but these are, in a way, picked. 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 treated heavily with platinum before. Some of them have a lot of comorbidities, the HPV-negative patients. Some of them have heavy burden of lung disease, like what I mentioned here. This protocol has no contraindication for heavy burden of lung disease, like we see here. Creatinine clearance was steady. There were no limitations with albumin, right? The protocol was written, which is very friendly for the patient enrollment, and in a protocol that actually could reflect, based on the criteria, what we see in clinic. You guys, when we see results, you guys don't know how hard some of these protocols, how selective and all these weird exclusions that they have. This protocol was very friendly in that sense. Because of that, and the inclusion that the patient had to be exposed to platinum and checkpoint inhibitors, it was fairly easy to just put most of our patients who were candidates for it. Most of the head and neck cancer patients that we had, cervical cancer patients also, they usually got carbo taxol up front. They have some local regional issues too, because of the previous surgery. Sometimes the creatinine clearance is not ideal either. 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. The first patient I put on the trial, he responded, right? It was an HPV-negative patient. Obviously, when I saw that, like if this worked for an HPV-negative on the lower dose cohort, I'm putting every single one of my patients here, right? That happens with all my other co-investigators, that it's easy to enroll. We saw responses and benefits from the beginning. I think that just prompted the fact that we were excited about putting patients on. The protocol was friendly to put patients on, and the medication was easy to get. When we discussed the durability, it's hard to offer a medication to patients that can put them in a hospital, you know, and that can have a severe adverse event. The patient asked me, so doc, how many patients have dropped dead from this medication? They ask me that. When you tell them none, that is very reassuring, right? When you see the adverse event profile, none of these AEs were life-threatening. There's no severe pneumonitis like with Deroxetican, right? There was no severe hyperglycemia to the point that was life-threatening, you know. They were not really life-threatening AEs. That initial efficacy that we saw and the friendliness of the protocol and the responses, that fed up with a profile that was very safe, at least for life-threatening AEs. We just continued to enroll. The momentum just kept until now. I think that's the reason why it continues to enroll so fast, right? Can I just add, I think the two other things that stand out to me, we have nine or ten ADCs in our portfolio at the moment. The schedule is actually a huge component. Many patients on PADCEV, either on or off trial in EV-202 cohorts nine and ten, or even in bladder, are not getting the day eight dosing. 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. Paired with what Cesar was saying, that made this trial enroll like wildfire, essentially. Thank you very much, sorry. I'm just going to add one more thing, which is, you know, I think that the payload as well, you know, is a payload that's very attractive to us in the head and neck cancer space. You know, microtubule inhibitors are very well validated as a cytotoxic mechanism as well in head and neck. I think that also complements what you already heard. That's tremendous. Professor Hani, 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. I've been amazed. I was expecting adverse events to come in of, you know, MOFs, multi-organ failure syndrome, like you say, deadly ILD, SJS, Stevens-Johnson's, none of it has been, very, very pleasing. 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? Yeah, I mean, I think, you know, number one is general, I know safety is sort of, but like let's be realistic. Number one is going to be the activity of the agent. You know, 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 enfortumab vedotin as sort of the first cluster of single-agent arms that were presented last year or in the last two years. They all sort of hovered around this 20-something, upwards of 40% with tisotumab vedotin, although the toxicity profile sort of shot that down, unfortunately, with tissue factor. That was sort of the benchmark. Many of them are this population, you know, maybe not as permissive as Cesar was mentioning in some of the earlier trials, a little more selection for healthier patients. Generally, if you look at the enfortumab vedotin data cohort nine from 202, it was patients who were largely sort of median three to five lines. 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. That said, you know, that's kind of the bar we were looking at when we bring in trials like this. You've got a validated target. You're not worried about, well, is this just, you know, like for ROAR 2 or some of the newer agents, you know, 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. 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 are subpopulation issues like HPV-positive, locoregional patients, patients who've been prior exposed to 5-FU versus taxanes, people who've had prior patritumab, given that that could change the field. I think those were all the efficacy concerns you would worry about and durability, right? People will say ADCs are another way to deliver chemo, right? ADC, a fancy, you know, chemo with a Gucci bag is what one investigator told me. Nonetheless, what I think of is they do have a toxicity profile. 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. 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. 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? All of those things are currently what people are thinking about when we're thinking about new drugs in this category and in the head and neck space. Summarizing, when you're seeing 30%, 40+% response, heavily pretreated, manageable AEs, permissive profile, a target that's already been validated, Q3 week schedule, you have my attention. It's easy to get patients engaged in that scenario. It's a slightly unfair question, but we're not necessarily going to be competing against Tivdak, but people will put us side by side. There's an obvious adjacency. How do we compare there? I mean, they've got grade 3, their monotherapy trial, grade 3 or greater adverse events was 59%, I think, and we're at 35%. I noticed all of you individually have spoken to me about how much things like fatigue are often ignored by companies. What do you think about, say, two parts there versus Tivdak and these things like fatigue? Yeah, I mean, I think, you know, and Tivdak 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. That's certainly a big one that we look at. 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. Neuropathy, which is a cumulative effect, and is oftentimes the toxic limiting maintenance. How long can you give the drug for? At what dose intensity? 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. At that point, they have to flip to a different strategy. 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. It's been a long time since I've practiced in the clinic, but grade 3 neuropathy specifically, what does that look like? Is that excessive tingling of the hands and feet, or is it something more sinister? Yeah, I mean, numbness, fingers and toes, paresthesias, pins and needles sensation. It can be painful, electric shock sensations. Those are some of the different descriptors. If it gets severe, 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. Buttoning, writing, typing, you know, everyone uses iPhones right nowadays, and you know, you need fine motor function to be able to live and do all the things that we all like to do. That makes a big thing. I'll mention just one of my patients that was on the study who'd gone through a number of lines, including taxanes, with recurrent disease in the neck. He was a horseback rider and taught horseback riding. 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. That just illustrates some of the things that we're thinking about when the patient's walking 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. I should just do a little sidebar on grade one, two, and three eye toxicity as well. Grade 1 is asymptomatic. We have induced a degree of artifact. It's not artifact. It's real. Because we have regular cadence of ophthalmological assessments in this study, the ophthalmologists come and they pick up an asymptomatic patient. They put fluorescein eye drops in them and they have a magnifying slit lamp and they see these little superficial punctate keratitis lesions. They get correctly grade one. 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 move in with them for a while because they couldn't use their iPhone. They couldn't see the TV. They couldn't use the remote for the TV. I think that's important. That patient got better. With the dose interruptions, the delays, they got better. They were still able to dose through whilst maintaining efficacy. 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. Of course, some patients just progress. We don't get to see the sort of the final end game with that improvement in eye. We are critically seeing improvements. The neuropathy is like a one-way ticket. Once you've got that, it ain't going away. I think the median time to resolution of a peripheral neuropathy is about one and a half years, which patients haven't really got. I just wanted to make sure I made that point. Maybe Professor Hanna, I'd ask you this horrible question, the 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? Yeah, I mean, I think the immediate unmet need we've alluded to is going to be the patient that we're going to be seeing and we're seeing now. If you step outside of some maybe one-year timelines 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 pedosentimab or ficerafusp alfa or both, is probably where we're headed in the next one to two years with pedosentimab as a potential monotherapy second-line agent. 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, and those drugs. You might use some 5-FU or capecitabine if you're reaching and you don't have a trial option. That for us becomes the immediate unmet need, 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. I think the immediate need for CRB-701 is, or an ADC, is going to be that patient population, as a better tolerated form of chemotherapy, so to speak, that has target engagement and a predictable safety profile. That puts you in the second line, potentially, or third line space, ideally. You sort of made this point, Dom, about how well pedo is looking in that line. For me, that doesn't actually matter a whole lot because there's a lot of people who, right after pedo, need something. Regardless of what that median OS is for pedo in second line, there's an immediate ADC monotherapy need or single agent need in that third line. People will say, how many people get to that third line? We're sitting up in here telling you we don't have enough slots and we're enrolling pretty well. It's not a low number of patients that get there. 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. pedo 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. Now in second line, it is six, eight, nine months on average, probably going to start getting out to 10 months, 12 months in second line. That's great. That's several years for an advanced metastatic head and neck patient. I think the third line is probably the low bar. You know, that's the unmet need in the moment. That's the patient I'd like to be able to consider this drug for. That's before you start thinking about, could we bring it into the neoadjuvant space? Should we add pembrolizumab and do it up front pre-surgery? That's a little bit right now where everyone's mind's going on the heels of 689. 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. I'm really grateful that you made that point about surviving through to later lines of therapy. I've seen that in my career. I think historically you look at the survivorship going through to second and third line with head and neck. It was kind of this sort of 15 years, 20 years ago, it was chemo and then more chemo. Then they're progressing, let's just try one last chemo. By that point, the patient was in trouble. The number of patients that bled through, if you pardon the phrase, to the latest stage was poor. Now these guys are in good shape. That's a tribute to Tivdak. It's a tribute to pembro and the patient selection. Like you say, as I often find, the recruitment rate to our trial tells us a lot about the commercial attractiveness of the drug. It's about efficacy and it's about unmet need. 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. Although in the upfront setting, we do cure the vast majority of those patients, there's 10%-15% that still recur. Because the increasing incidence overall, particularly in the U.S., is increasing for HPV-related disease, we see those patients that recur and metastasize and progress on immunotherapy and platinum-based chemotherapy. That's a group where we don't use very much cetuximab, right? Already that's also a particular line, right, where we're looking into that. That's another patient population. We talked a lot about performance status, but that's also a population 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. That's another patient population that I think is of interest that I've been interested in putting on this study. They live longer, right? This population lives longer. Very rarely a patient with HPV disease doesn't get to third line. It's very common they actually get to third line. The problem is that as of today, if you give carbo taxol, pembro to an HPV-positive patient in first line, you pretty much have nothing in second line. Nothing good. You have 5-FU that we think is okay, but maybe it's a little more active in HPV-negative, and cetuximab that we don't trust in HPV-positive. Obviously, those patients are in a great need right now. It's always a question of how much the EGFR bispecifics will contribute to the survival of this patient. We still don't know. Nobody's certain that it will. It might help. We're very 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? ficerafusp, BCA101 is not being studied in those patients, right? These patients have a big, big need. The HPV-negative patients also have a big need, but the HPV-positives certainly don't have a lot of options right now. One of my old Scottish physician colleagues used to call 5-FU, five fucking useless. It didn't say fucking either. There is a very impoverished set of therapies, single-agent chemotherapy that can be used after all these. Would any of you, all of you care to comment on what you think those are like? 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. In general, you're reaching for exactly as you said, some of the dose of Taxol 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 three or four times by several groups as an observation. In the follow-up data from the KEYNOTE 48 trial, there was a PFS2 assessment on second-line therapy. That's important to consider. They aren't inactive agents. They just come with all the plague toxicities that Ari and I were talking about: neuropathy, dose hold, cytopenias, 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. 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. I've never personally seen a response. 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 a carboplatin 5-FU weekly schedule with leucovorin just because patients are delicate at that point and I want to see them frequently. This is a European favorite too, oral capecitabine, which is the precursor to 5-FU. That has a little more potent. Someone who's healthy and doesn't have a trial option and wants an oral medication, I'll consider 5-FU as well. Outside of those, fluoropyrimidines, taxane recycling, a little bit of IO re-sprinkled in, that's it. Essentially, you don't really have, I don't personally use afatinib or the TKI that has a one-month PFS improvement historically in years gone by. I'm not sure if there are other agents that Ari and Cesar would use. I think that's why we're all trialists because that's pretty much all that's left. Yeah, I agree. Yeah, 100%. 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, it's a little bit early in the day. Question to Dom, to them, posed to the panel, Nectin-4 levels and what we're seeing and what we're thinking, et cetera. Let me go back. I think it's on the... It's in the waterfall plot on the bottom, right? Yeah. Right. H-score. Yeah. I mean, essentially, we don't see any actionable difference. You can see that the far right there, the most extreme response, Nectin score 55. We see that repeatedly. We've got some really great high scores over towards the left with patients that are progressing. This is no surprise. We're no stranger to this kind of thing. You think about immunohistochemistry. You get one small section, sometimes smaller than a grain of rice. It could have been from the patient's original head and neck tumor five years ago that's in archive. 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. Our drug is FC-optimized. We are internalized at twice the rates of many of, well, of PADCEV. 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 MAE, but you also reverse into it through the FC-mediated endocytosis as well. 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. Dom, 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, biomarker selection in this population would be not clear for the role. The point made about sticking the needle in the apple and assuming that you're getting the same thing out 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 three sites in the same tumor, you get different expression. I think these things may be somewhat dynamic. This is a cell-cell adhesion molecule, so it's likely somewhat steady over time, but can potentially change dynamically. 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. All of this tells you that the heterogeneity will, and reader operability on Nectin score is a score. It's a quantitative score that's calculated with some input from a pathologist. The last point I would make on that is the HER2 story. We're all humbled by the HER2 story. We're now talking about ultra-low expression, less than one. I don't even know what that means, like 0.1 plus. Yeah. But Deruxtecan in HER2 is working in HER2 ultra-low patients and changing the game on what these biomarkers actually mean in expression. 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 do or don't see benefit? It certainly doesn't look that way, which makes life easy. I think that's how you would easily explain this sort of swash of different values. Actually, I think I'm a big biomarker person. I love a biomarker selected option. 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 re-biopsy 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. I actually think this is a positive. Ari, did you want to? Yeah, 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? 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. That's consistent with what we've seen across other ADCs as well. It doesn't mean we shouldn't stop trying and trying to figure out what those predictors are. Right. 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. Dom, this circles back to, let's say, in a world someday pedo 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 pedo for later. 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. 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. Yeah. I think we 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. We could use archival tissues, but the downside is that we end up with some tissue that might not reflect what we're treating at this time, right? I think that's the main limitation that we had. I was a little surprised initially because this is such a clean, you know, ADC in terms of where it lands and having so little free MMAE. In the same token, you will expect that you will have a relationship with expression, but 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 actual correlation. I know you've now once come in and asked a question, but there's one question I absolutely must ask, and it's beholden 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, anything less. Obviously, we have exceptional cases that stay on therapy for a long time. This is not the only patient. We have other patients that have stayed in therapy for a long time. The only issue is that this trial is not, you know, we have been going on this trial with something like 18 months only, right? We don't have enough time to just look back and analyze for how long the patient has 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 to the progression of the other. That's not how it is. The responses, and they have, some of them, as you have described before, have been dependent as time passes, right? I think it's encouraging, definitely, the duration of response. Hopefully, we'll have it next year, the meaning of the short response. What we have seen so far seems to be very encouraging. Fantastic. Eva. Yeah, 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. If you could just identify yourself, thank you. Hi. Yeah. Hi, this is Pasquale from Kanjarum. A couple of questions to management and also the doctors. If Tivdak makes it in front line, right, with pembro, would you like to treat patients in second line with Tivdak monotherapy? This is the first question. Second question, is there like any rationale for Nectin-4 amplification being probably a better biomarker to enrich for responders? What is the role of Nectin expression going from front line to third line? Is there any studies suggesting that you enrich for expressors as you go on in the therapeutic algorithm? Another question on keratitis. This grade 3 keratitis that you saw so far, what is 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 drop the therapy? Maybe we should split this. I've got. So PITO. Maybe I'll do the Tivdak question. Someone can do the expression question, and then someone can do the higher one. Right, right. Mine will be quicker. Yes, there will be a role for pedo in the first and second line. 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 pedo, ficera pedo. 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 I don't yet see a rationale to go from a ficera combo to Tivdak 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. There are going to be people who, even in the face of a potential approval for first and second line pedo, 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. There may be subpopulations that we feel benefit from one. The short answer is I think there's room for both. There's a market and a space and a clinical need for pedo and even ficera in the first and then Tivdak second line. Yeah. For the second question about the Nectin-4, most of the data that I'm aware of actually is from urothelial, where it's a much more validated target. For example, there's been data from urothelial about membranous expression as opposed to overall expression as being a key thing. There are differences in terms of Nectin-4 expression at the primary versus the metastatic site as well. 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 and HPV-negative. HPV-positive is the population where we're less, we don't use it, I don't use a lot of cetuximab in that setting, or EGFR inhibitors are as a target, as a less of, we're less enthusiastic about EGFR as a target for HPV-positive. That's also where Nectin-4 happens to be enriched and things like that. 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. We'll have to do that work in head and neck. Cesar, do you want to do Nectin-4 degradation, or do you want to do? 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, you know, 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 not having amplification, right? 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. In terms of the keratitis, I think the main point is that as soon as the patient has symptoms, eye symptoms, you know, the grade one, it's asymptomatic, right? As soon as the patients are having eye symptoms, photophobia, et cetera, we learn that we have to hold the drug, right, and give them a little bit of weight, so it will actually stabilize and improve. If we don't, it can actually fall into grade three, and that's significant in terms of quality of life when it goes to grade three. There are many flavors of grade two. Some patient says, "I'm fine, you know, I have a little bit of, the light bothers me, but don't dare to stop my drug, please. You know, I need to get better." Some patients will say, "Oh, I'm afraid that if I drive, I can go into a crash. You know, you have to stop this." Everyone is a little bit different, but certainly grade three, we have to immediately hold as soon as the patient is asymptomatic, and sometimes do a dose decrease if it doesn't get better in a short, you know, in a couple of weeks. We had patients that, you know, we had to skip a whole cycle in general, but despite that, the good thing is that it's all universally reversible, you know, and the patients usually are able to be re-dosed later on, either at the same dose if we think it's safe or at a lower dose. Usually, when we grade to grade three, you add dose decrease. For grade two, we can re-dose it at the same dose after a dose delay. Ophthalmologists are becoming more comfortable with this class of drug and the payloads, and they're being more proactive about helping with eye drops, stimulant drops, and refreshing and wetting drops that will help maintain the patient's, you know, minimize the keratitis or irritation to the eyes. 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. 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. Yeah, thanks. Andy Shea, William Blair. Congratulations on the team. Good efficacy, really stepping in the right direction. I have a question about the skin toxicity. 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 toxicity you're seeing? 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? Yeah, 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 in the dictionary includes alopecia, of which we've got about 40%. It would have looked ridiculously high. If you take that down, in the end, I spent a long time with Paola, our clinical scientist, who said, let's just give them the laundry list of what there is. It's not most, there's three grade threes, no discontinuations except the one bullous dermatitis. It's good. We just need to give, and that's what some people call a rash. A rash, some people call it dermatitis acneiform, some people call it whatever, you know. It's a great question about EGFR. I don't know anecdotally if you've known anything about EGFR. I haven't seen that. We need to look at. Yeah, I haven't seen exacerbation because of prior EGFR. Frankly, mechanistically, it's not, this is not an immune stimulant that would recall EGFR-mediated rash. Generally, it's actually myelosuppressive or cytotoxic in its payload. That would actually help with rash management. 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. Hey, 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? How many more patients or more follow-up do you need to move on basically to a registrational phase? 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 dosings or can it happen anytime during the treatment? It would be great if you can add some color there. I mean, I think it's five weeks, six weeks, the median time to when the eye toxicity, right? I think it was around six 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 hold. That's around the time they're having a scan. Sometimes they're responding 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. That's kind of the typical scenario. You know, hey, I have a little bit of photophobia and lacrimation, or you have to see the eye doctor now. You know, you have grade 2 keratitis. Let's give you a week or two weeks delay. That's kind of the typical scenario. Tearing issues, feeling of a little grittiness or dryness in the eye. I'm a contact lens wearer, so that feeling that there's something there, needing to re-wet, you've got the drops. That's kind of the grade 2 category. Grade 1, as we heard, is not really any symptoms. It's just that the eye specialist saw the punctate keratitis. Grade 3 would be pretty substantial. 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. I would say for our experience at DFCI, we've kind of hung around that grade 1 to grade 2 range. It does require eye drop commitment and engagement from the patient. That's important. Yeah, we've also observed the reversibility of the symptoms with holding and oftentimes a lack of recurrence of symptoms when the drug is being produced in some cases as well. That's also been something that, from the patients that we've enrolled as well, 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. The Corbus team was probably asked about the size of the signal needed to move forward, the timeline, 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. Yeah, we're talking to various stakeholders. They've all been incredibly encouraging. 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. 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 sort of chuckled 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. Nonetheless, we're already approaching 60 patients with almost two years of data. I would say that's starting to get into a range where you feel healthy about making a decision. Yeah, 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, Tivdak, the other couple of ADCs, we have. don't think nobody has reached 60 on the first report that we have. You know, people move forward with a lot less patients, right? Yeah, 30 or so. These are what, 40-something? Forty something in Pfizer. Yeah, so they're already. Thirty to forty something. You know, so usually they are in between the 30 and the 40 range. I don't think nobody has reached that 60 number. Right. I think we'll have very good data in a year or so. Yeah, like mid-2026 is probably a healthy time to assume that the loose ends will be clearly sorted. Yeah, 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 center 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're around at some stage, find us. Thank you again and just immensely grateful. Thank you.