Corbus Pharmaceuticals Holdings, Inc. (CRBP) Earnings Call Transcript

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.