Corbus Pharmaceuticals Holdings, Inc. ($CRBP)

Greetings, and welcome to the Corbus Pharmaceuticals 2026 ASCO Data Update Conference Call and Webcast. [Operator Instructions] As a reminder, this conference is being recorded. [Operator Instructions] It's now my pleasure to turn the call over to [ Dan Ferry ], Managing Director with LifeSci Advisors.

Thank you, operator. Good morning, everyone, and welcome to the Corbus Pharmaceuticals 2026 ASCO Data update call. As a reminder, during this call, we will be making forward-looking statements, which are subject to various risks and uncertainties that could cause our actual results to differ materially from these statements. Any such statements should be considered in conjunction with cautionary statements in our press releases and risk factors discussed in our filings with the SEC, including our quarterly reports on Form 10-K reports -- on Form 10-Q and annual report on Form 10-K and cautionary statements made during this call. We assume no obligation to update any of these forward-looking statements or information. It is now my pleasure to turn the call over to your host, Dr. Yuval Cohen, CEO of Corbus.

Thank you, Dan, and good morning, everyone, for joining us. It's my pleasure to provide a detailed overview of the data we will be presenting at ASCO in just a few days' time. This data represents an April 1 data cut. I'm joined today by Dr. Glenn Hanna, Director of the Center for Cancer Therapeutic Innovation at Dana-Farber Cancer Institute. Dr. Hanna completed his fellowship training in hematology and medical oncology at Dana-Farber Cancer Institute in 2016, prior to this, you're on the medical degree from Georgetown University School of Medicine in 2010, we graduated Summa Cum Laude and was a recipient of the [ Culvert ] Medal for Academic Excellence. He is the Director of the Center for Cancer Therapeutic Innovation, CCTI the early drug development program at the DFCI is clinical and translational research efforts focused on precision medicine approaches to treat head and neck cancer. And you may remember Dr. Hanna from our KOL [indiscernible] event that we did last November. Following the presentation of the data, I'll have a brief Q&A with Dr. Hanna and then we will open up to questions from our audience. Just a reminder, we have three events coming up at ASCO, starting on Friday, our Cervical Data will be presented as an oral presentation on Friday afternoon. On a Saturday afternoon, our Head and Neck data will be part of the poster session for Head and Neck. And then lastly on Monday morning, we will have our KOL joined by the three KOLs who also were kind enough to join us in Berlin last November at ESMO, Dr. Hanna, Dr. [ Perez ] and Dr. [ Rosenberg ]. So with that, let me jump straight into the data, move at a pretty fast clip. The press release has been out now for about an hour. This deck can be found on our corporate website, and let me just go through the highlights quickly. In Slide 6, a reminder that everything we see data-wise around this ADC derived from the structure of this ADC. This is a very, very stable Neck in [ fort ] targeting [ MMAE-armed ] ADC that has the ability to hang on to its payload for much longer. It also means that it can be dosed far less frequently. And what we have seen both of ESMO and now at ASCO as well is that we continue to see level of MMAE related toxicology or toxicity that are certainly below everything that we've seen with other such ADCs. The data at ESMO was both our dose escalation and dose expansion. The ASCO data focuses now on two specific tumor types at the neck and cervical, at the two relevant doses, one of which is now moving forward. And we've seen -- it comprises of the patients you saw at ESMO as well as some additional patients that were not yet scanned at the time of the ESMO presentation. Our safety database has nearly doubled to 317 patients. This includes all the patients that we have dosed at all the doses, all the tumor types, including tumor types that we have yet to present, our head and neck population has gone from about 60 patients at ESMO to about 75 patients at ASCO and cervical has gone from about 50 patients or so of ESMO to 72 patients at ASCO. I'll start with the safety. On the safety side, what's been encouraging is that overall the picture is very similar to what we saw at ESMO despite the fact that we've doubled the number of patients in the safety population. We continue to see relatively few great [indiscernible] and very, very, very few great forwards. It's entire safety population has a sum total of just three grade 4 events and have been thanks for the no Grade 5 events. We continue to be best-in-class for peripheral neuropathy, all of it grade 1 or 2 none of it were grade 3 or above, and it continues to be well below 10%. We're also has a markedly better skin toxicity than other such ADCs, especially [indiscernible] with [ skin tox ] being mostly grade 1 and 2, and some of a single grade 3 [ skin tox ] with no Grade 4 or above. And ocular continues to be a feature of this ADC as we've seen with its class of ADCs. No big changes there. Again, the vast majority are grades 1 and 2, we have Grade 3 hovering at just above 10%, and there was just a single reversible Grade 4, which is the feature of this [ oculoplastends ] to be reversible. Most importantly for the ocular toxicity and in general for the overall toxicity, our rates of discontinuations continue to be very, very low and in fact, have improved since the ESMO data set. I can turn your attention to the next slide. We have, again, peripheral neuropathy well below 10%, none of it grade 3 or above in toxicity again markedly different than what we would see, for example, with an ADC such as [ Padsev ]. And last but not least, the ocular toxin. You're specifically looking at reductions and interruptions for [ ocular tox ]. They are part of the way in which the physicians manage these toxicities and the discontinuation rate specific to [ ocular tox ] is well -- is below 2%. Let's jump straight into the data starting with oral pharyngeal head and neck cancer. A very, very simple explanation about oral pharyngeal head and neck cancer is our locally throat cancer, it is basically the back of your teeth to the top of your throat, including the base of your tongue. What's interesting about this cancer type is that it is on the rise. If we look at the prevalence of this cancer, it is driven by HPV infections, and those are rising, frankly, at an alarming rate from about 11% 30 years ago to more than one in two patients for head and neck. We can also look at the incidents that has also risen at an alarming rate. while the incidence of HPV negative head in a cancer. And a reminder, that is the head and a cancer that is driven primarily in much older men with a history of smoking and/or excessive drinking. That patient population is not increasing. In fact, it is beginning to shrink as that generation of dies off sadly and is not replaced by younger drinkers for smokers. What would be the hypothesis for a Nectin-4 MMAE ADC working in oral pharyngeal cancer. And there are three elements to this. So one, it is a cancer that is driven by the HPV virus. And we have an example of a cancer driven by the HPV virus in which in Nectin-4 MMAE works very well, and that is cervical cancer, which is something that along the lines of 98% HPV positive whereas oral pharyngeal is not that far behind us, about 80% to 90% of those patients are HPV positive. The second fact to consider is it is a cancer type that's known to be associated with high levels of Nectin-4. Head and neck cancer specifically this type of head and neck cancer is one of the richest cancers in Nectin-4. Again, fitting into the same pattern as cervical cancer, another Nectin-4 rich cancer type. And last but not least, we actually have a precedent here, of a Nectin-4 targeting MMAE ADC in the form of [ passive ], specifically, as you'll see in a few slides from now, the frontline therapy of [ passive ] to pembro in Head and Neck and the breakdown that Pfizer provided between their HPV positive population and their HPV negative population. If we look at our division in our head and had cancer, and a reminder that this was one of the seminal questions that were left unanswered at our ESMO presentation. it was do we split between HPV positive or oral pharyngeal and HPV negative or the nonoral pharyngeal heading. And what you'll see is that our breakdown in our U.S. and European sites fits nicely into the 50-50 breakdown with roughly half the patients being HPV-positive or oral pharyngeal and half of them being nonoral pharyngeal. This is another way of looking at our own data, and as you can see, unsurprisingly, our oral pharyngeal patients are overwhelmingly HPV positive, as you would expect. And the near image of that are our nonoral pharyngeal patients who are overwhelmingly a can be negative, as you would expect as well, again, from a population that's derived from the United States and Europe. A question again going back to ESMO was where would the efficacy lie in terms of bias or preference between these two very, very different types of subpopulations. And as you can see, the answer is markedly clear-cut in oral pharyngeal patients that represented 41% of our -- 41 of our patients. We have a pretty marked response. Their chances of responding were very high with a concerned objective response rate for the higher dose of nearly 43%. And then the exact near image effect in the nonoral pharyngeal patient, the HPV-negative patients where the response was very modest. What's particularly striking about this slide, is that it is the near image of what you would get with an EGFR bispecific. Those a reminder, have a strong bias in favor of the HPV negative patients, the nonoral pharyngeal patients. And in fact, two of the three EGFR bispecifics currently being explored explicitly exclude HPV positive cations. Another question we were asked at ESMO was durability. The ESMO data set was too immature to provide durability now for the first time, we can look at ongoing durability. And what we see here is the objective response rates. We have a durability in the 3.6 milligrams. That is already exceeding 6 months with a PFS that is catching up to it. In the non-oral pharyngeal, of course, this is a patient population that would not be sensible for a drug like fit. And again, a reminder, this is also a patient population where we would not expect Nectin-4 to be great express. And so as a summary, a question we've been asked often in the last several months, which of the 2 doses would be more sensible to move forward. And the answer is the 3.6 milligram per kilo dose, dosed at Q3 weekly. And as you can see in the summary, the confirmed overall response rate was nearly 43%, a DCR of nearly 86% and DOR at 6.3 months, a PFS of 5.6 months. Both of those are ongoing. And lastly, we do not exclude patients or do not mandate that patients be HPV positive, only that the oral pharyngeal patients. And in fact, eight out of our nine patients were also HPV-positive as you would expect from the demographics in this disease. Another key question that we were asked at ESMO is how would this fit in the landscape in second-line monotherapy compared to [ tosetimab ] previously [ Merus ] now [indiscernible]. And luckily, we can actually look at that data from the -- at the time [ Merus ] data set. The [ Merus ] data set a reminder showed a very nice response in the HPV negative, but your HPV-positive response was modest with only 2 out of 15 patients responding they look at oral pharyngeal patients who are also HPV-positive so there's a double restriction there. Luckily, we can actually look at the same thing in our data set. When we look at our oral pharyngeal bar confirmed to be HPV positive, we get a confirmed response rate of 8 out of 16. But as I've mentioned, our strong preference moving forward. would be to use the anatomical definition of oral pharyngeal and enroll patients regardless of their HPV status. Our durability whether it's median DOR or PFS already seems to be matching or exceeding those things seen in the [ Merus ] data set despite the fact that they did not break that down into HP positive or negative. And as you can see, our tolerability also seems to be superior to this. This is our path forward. [ PM1 ] is a single controlled registrational study that will launch this summer. It starts with 250 patients whether on half a monotherapy of CRB-701 and half on physicians' choice. It has an adaptive feature and the primary endpoint under accelerated approval, the ORR with a full approval based on OS. And as we've mentioned a few weeks or months ago, we have alignment with the FDA. We will provide more data on this, both at ASCO and a little bit after that as well. An intriguing view into what we could see in our front line study. We are currently dosing patients in frontline head and neck using CRB-701 plus pembro or [ KEYTRUDA ]. We will have our data we hope at the beginning of the year of next year. But in the meantime, there is precedent and intriguing precedent to that, and that's looking at positive. And this was the Pfizer now data at ESMO last year. And what we saw with [indiscernible] plus pembro in front line, was an overall response rate of 39%. That comprised of both HPV positive or negative or oral pharyngeal or non-oral pharyngeal. But passive showcase a very similar bias towards the HPV positive/oral pharyngeal that we do in second line monotherapy with a confirmed RR of 82% for HPV positive and a confirmed RR a far more modest 23% in the HPV negative. To just juxtapose it and again, the theme that this looks very much like the mirror image of the EGFR bispecifics for a very similar population in the front line we have to pembro at about 50% far less than what they're achieving in the HPV negative population, and then more recently, [ Vitera ] published their data in front line, including their efficacy with [ KEYTRUDA ] in HPV-positive patients coming in at a modest 27%. Very quickly, just to dive into cervical cancer. This will be our Friday oral presentation. A reminder that here is another HPV-positive or HPV-driven tumor type similar to oral pharyngeal head and neck? The bar to beat here is an existing drug. This is [indiscernible] previously from CGEN now at Pfizer, it is an MMAE armed ADC targeting tissue factor. And [ TTEC ] is limited by two things. It has a relatively modest efficacy at about -- or of about 17.8%. And it is hindered by a number of very challenging toxicities. Like [indiscernible], it has ocular toxicity. As you're a member of these agencies, as I've mentioned, ourselves, [ HDAC ], which, of course, is approved lager, which is approved. And of course, [ Blenrep ], which has similar toxicities but at much higher levels. [indiscernible] is also hindered by things that we don't have with CRB-701, high rates of [ prop of euopathy ], bleeding and skin toxicity. This is our waterfall plot for CRB-701 in cervical, again, a dose response as we saw in rig with a top dose delivery confirmed RR now of 34%. That's effectively twice the efficacy we have seen with [indiscernible]. And then a durability that again, like oral pharyngeal is still ongoing, but is already reached 8 months for the top dose with a PFS that is cashing up. And so just to put that into context on Slide 32, you can see where we line up versus tax. And for that matter, chemotherapy in second-line monotherapy, which will be one of the other physicians choices. And so far, we are certainly looking like a drug with a very attractive profile for this. So with that, I'm going to turn it over to Dr. Hanna. I've got a few questions for Dr. Hanna that I suspect many of you have already. And after that, we will turn it over to our audience. So that's now and good morning. Thank you for joining us early this morning. And I think my first question, which I'm sure is on people's mind is just a brief background on what is the oral pharyngeal cancer? How do you define it? How many patients are there? How do they differ from other head and neck patients, et cetera.

Happy to join the conversation. And it's exciting to see, again, drugs moving forward in the advanced head neck cancer space beyond the momentum that has been ongoing for the EGFR, the novel EGFR inhibitors I've been waiting patiently for the antibody drug conjugates to surface in sort of the next generation of advanced trials for these patients. So I think oral pharyngeal cancer, in general, as you outlined in the beginning of the discussion, is an anatomical distinction of sort of the back of the throat, we think of the consoles, the base of tongue, sometimes the lingual tonsil or the back of the tongue tonsil and soft pallet as making up this sort of area where HPV likes to hide a about 85% of oral pharyngeal cases, particularly in never smokers and in the United States would be attributable or causal related to HPV virus high-risk subtypes being 16, 18, 31, 33, 35, et cetera. And we define it largely by a clinical constellation of features. Generally, it's some -- often has a predilection for men as people know, five to one against women in terms of incidents, know these are often limited or never smokers, although that can be variable in some instances, they typically are people in their 40s to 60s, although there's some variation there, and that's based on the lead time that it takes for the HPV virus set up shop in the back of the throat and then lead to changes over time that result in cancer or neoplasia. And so all of that together sort of defines the HPV positive patient these patients, therefore, then compared to HPV-negative patients tend to be younger. They have less risk factors or carcinogen-based risk factors. And there is sort of a socioeconomic distinction between these patients. If you look at demographic and were in parts of the world where these patients are most present. Certainly, we have a large catchment in North America as well as in the United States, specifically. And so I think important, as you pointed out, the trends in the biology of this disease suggests that we're going to continue to see a rise in more of these cases an elegant question I often get is, how is current vaccination, preventative vaccination impacting these rates? These rates are still going to rise likely projected through 2040 all the way through and plateau in 2050. So that's another 25 years. And that's because of the lead time requirement for getting kids between 9 and 26 vaccinated and the time it will take to see epidemiologic shifts in cases. And so we're not going to see any slowing of cases at least through 2040 or 45 based on current predictions. And I think that's really important for thinking about who might benefit from a drug like CRB 701.

Dr. Hanna, you -- on [ PRASM ], the data shows us that see North America and Europe is about one in two patients in these studies. But recently, you showed with me some interesting anecdotes around sort of real-world data you're seeing or experiencing in your practice around many of these patients are walking in for your door as well as some of the age distributions, we know they're younger and you refer to it, I think you shared in the anecdote that frankly surprised me around how young they can actually turn out to be.

Yes, that's the case. I actually just last week I met a gentleman from the south who's 31 years old with recurrent metastatic HPV positive head and neck cancer. So that just gives you a sense of the lower bound of the age range for some of these patients, and we see patients in their 70s and 80s. So while there are medians and averages, there are certainly patients that are on the edge of the bell curves and confidence intervals. I would say it's particularly at a place like ours at Dana-Farber in Boston, where we have a pretty large New England-based population in catchment. We do see a large percentage of patients with HPV-associated disease, as I was sharing with you, I would estimate that our group is probably seeing on average five to six new cases a week of curative or definitive head and neck disease related to HPV and perhaps if you take all of our patients over the course of several months, I would say that in some instances, it's almost 50% to 70% of patients that are in our clinics have HPV-associated disease. Now that is going to be -- there's going to be some regional and geographic variation and especially at our center, whereas maybe at our public hospital down at Boston Medical Center or across town at Mass General Brigham Cancer Institute, there might be some variation. But in general, we are seeing a large number of these patients, particularly in urban cities along the East and West Coast, which fits with how quickly the CRB-701 experience and trial has been able to recruit patients with oral variants in HPV-associated disease with a small number of sites. So I think a really important point as we think about enrolling a confirmatory registrational trial. There is no shortage of patients in need with HPV associated disease. And remember, about upwards of 20% or even 25% of all HPV head and neck cancer patients will eventually require advanced metastatic treatment and develop sadly either local regional recurrence, persistent disease, incurable or metastatic disease.

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

Yes. So I think you're highlighting what I have been thinking about over the last year as [ pidosymptomab ] as well as -- which is an [ EGFR LGR5 ] bispecific and [indiscernible], plus alpha, as you know, the EGFR TGF-beta trap have come into clinic and now [ amivantamab ], sort of catching up quickly this EGFR-cMET bispecific. Largely, the data is very clear that EGFR in is most critical in HPV-negative biology or carcinogen driven biology it is much less of a biological entity in HPV-associated disease, which is driven more by early proteins, E67 and modulation of things like RV and p53. So I think you made an important point that if any of these trials or all of these trials in the first line, whether it's FORTIFY or the LIGER trials or the ORIGAMI studies, are all positive or some are positive. We're going to be looking at a new paradigm in treating HPV-negative disease with these novel EGFR therapies, so that leaves a wide open gap and for the rising and increasing incidence of HPV-positive patients that we're seeing. And I can tell you it's much easier to enroll into positive patients just because there are so many less trial options for these folks. And as you highlighted, the need is growing. So if 20-plus percent of those patients develop advanced disease or incurable disease, you can see how the numbers are continuing to rise. And I would just sort of focus on [ PDO ] for a second because as you said, while it's not confirmed in the trials, both the first and second [ PDO ] studies -- sorry, monotherapy in second line and the combination [ I/O plus PDO ] trial in first line did enroll a percentage of patients with HPV-positive disease to their confirmatory studies, roughly 30%. It's not clear that they will observe a robust signal in that population for benefit. And it may be that the agency, the FDA decides in the end that there is not enough data or patients to justify a label that includes HPV-positive disease. If that is the case, that will make even more of a wide open space beyond EGFR targeting for patients with HPV-positive disease who right now have pretty limited options after the first line, our traditional pembro, pembro chemo option that puts us in a position where second line, we're relying on garden variety, old school chemo, taxanes, [indiscernible] methotrexate type drugs but prioritizing clinical trials. So huge developing unmet need. This trial is coming, this Phase III trial, TEMPO 1 is coming at a very critical time.

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

Yes. I think this is a really important point. I mean the first thing we have to acknowledge is who this patient is and before we talk about the ocular toxicity. This is a patient with an incurable recurrent metastatic cancer is going to unfortunately case to succumb to that cancer at some point without meaningful cancer directed therapy. And with that, palliation comes the notion of what toxicities we're willing to accept to extend one's life and to minimize disruption of quality of life. Let's just be clear about that when we're talking about, yes, there's ocular toxicity and anything that mentions vision can be sort of a concern. But we need to realize that these are incurable patients who have already failed immunotherapy and/or chemoimmunotherapy, and we're trying to extend their life, hopefully by many months, if not years. So having worked with this drug now for quite some time, I think the first thing to realize is that this does seem to be a reversible problem. So while we counsel patients that they may have some issue related to blurry vision or difficulty seeing while driving, for example, that may disrupt function for a period of time, with appropriate monitoring, holding of drug intervention and interception with certain eye drops this is a reversible process. As you said, we thankfully have not seen significant persistent long-term effects that we're aware of at this point. So I think that's important. I think the other thing to recognize is there are a number of other toxicities related to antibody drug conjugates as a class, which I've worked with many of them now over the last several years as they've tried to move forward in head and neck. There's no free lunch here. I mean, these patients, there is some toxicity issue associated with a number of these drugs, and you highlighted some which are less of a concern for CRB-701, but extensive peripheral neuropathy is often irreversible and can result in significant mobility issues and daily activity of daily living disruption. That's something that patients need to be aware of. Significant skin toxicity can be an issue, pneumonitis or lung inflammation resulting in discontinuation. So again, we're not seeing those things. And these vision issues tend to be manageable. They do mitigate with drug hold. We have, thankfully, routine availability of ophthalmology. I think that's the other important thing we haven't run into issues with being able to refer patients to different venues throughout the city, for example, at our site, who can help to manage and monitor these ocular changes because sometimes there's not even visual symptoms. It's just the beginning of monitoring changes on an eye exam, for example, where there might be mild corneal inflammation, and we want to be vigilant with eye drops, for example. But again, with a few eye appointments and integrating eye drops, generally, patients are able to continue on drug sometimes have to dose reduce, but able to maintain or resume dosing and demonstrate efficacy and benefit from the agent. And I think that's sort of the clear message I would make. I think the other key point I would say about the ocular toxicity in general is that for most of these patients, when talking to them about pros and cons of different drug therapies. They seem to be very willing to participate in doing the eye care upfront and using eye drops preventatively, keeping their eyes moist, et cetera. So I think patient engagement has been a positive signal for how we're able to handle this. And the last thing I would say is I would remind the investors and those listening, there are ADCs on the market that already have ocular toxicity warnings. I sometimes use off-label [ datapotumab ]. We just got another approval for [ datapotumab ] in the breast cancer setting. Now also in lung cancer, there is a required ocular exam prior to start there is a well-established 25% rate of grade 1 to 2 ocular toxicity with that agent, and it seems to be something that patients can manage, and that drug is on the market. So I do think we also want to contextualize the sort of placement of this drug outside of just head and neck cancer and in the broader ADC approved landscape.

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

[Operator Instructions] Our first question today is coming from Brian Abrahams from -- I'm sorry, from RBC Capital Markets.

Just two for me. I guess, first, it sounds like the ocular toxicity is pretty manageable over -- continues to be pretty manageable overall. But I was wondering if you could elaborate a little bit more on the overall safety, including the ocular tox by dose at the 3.6 mg per kg dose and by the subpopulations. And then secondly, just on the TEMPO 1 Phase III, can you maybe talk a little bit more about the mechanics of that study? Just what how the interim analysis will work when you think that might occur, what the bar would be for the primary accelerated approval endpoint on overall response and just maybe a little bit more about that study side.

Let me start and then Dr. Glenn, if you have anything to add. On the dose by dose, we have that in the poster. So there are certain things that we we're waiting for a wait until the poster comes out. It is smaller numbers. I will say that overall, it's the same pattern. It also doesn't seem to be tumor specific, which is encouraging. And I think on this stack already, Brian, we gave a breakdown of specifically of the discontinuation and interruption for the 3.6 or ocular specifically for a dose. And for TEMPO 1, we'll give you more updates at ASCO and shortly after -- and again, we're just waiting for the final protocol approval from FDA. And once we have that, we will share that with you. We'll also share with you the specifics of what is the physician's choice, although I don't think it's particularly exotic as you can imagine, for example, it's highly unlikely that will [ isatuximab ] in this population. Dr. Glenn, is there anything you'd like to add at this stage?

Yes. I would just say to the first question, as you've all pointed out, without sort of saying too much Table 2, which will be in the poster that's released this week, specifically addresses the question of dose-related ocular toxicity or [ keratitis ]. There is a sort of column that outlines the rates by dose levels. So you'd be able to compare that to the total rate that was shown in the deck to you today. And then I would say, for the second question around the design of the trial, I will say this is a trial that's involve a number of key opinion leaders, including myself. And I think without saying much about the specifics, I would argue that the bar is probably generally pretty low because you're thinking about a population where they've already been through chemoimmunotherapy, there's no standard agreement or preferred regimen in the second and third line, which the TEMPO 1 study would address as the comparator and the traditional response rates, it's hard to know for HPV selected patients because years ago when these drugs are being defined as second, third line options, we didn't tease out HPV-associated disease at that point in time. I would argue that the response rates benchmark for most of us around 20-ish percent to even maybe a high end of 25%. That -- it's pretty low. So I mean that would be the bar in general for a second, third-line recurrent metastatic head and neck trial. And so I think welcoming an ADC versus investigator choice design is very, very much on brand with what one would expect for a drug like this moving into a registration study.

Your next question today is coming from [ Paul Jeng from Guggenheim Partners ].

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

It is in that since early days, although what we're seeing in terms of [ DR and PSS ] is certainly urging for that. Paul, I think we're just going to have to wait and see how that matures. The powering assumptions, again, Dr. Hanna has been very helpful with his comments, remember, if I may, what we saw, for example, in -- and this is a little bit of speculation. What we see, for example, in [ picosecond ] line monotherapy is a larger study. But remember that they chose to address all comers. In other words, they have a population that is a mix of HPV negative where they will see strong responses and HPV positive where we know that their responses are not as strong and that could create a certain amount of drag. We've chosen philosophically to do something that's much more similar to what [ Bicara ] and J&J are doing in their frontline setting which is to focus exclusively on that 1/2 of the population where we see strong responses and not and efforts on another half of the population where we are very unlikely to bring benefit. Dr. Hanna, anything you'd like to add to that?

Yes. I mean I think what you're getting at is a great question. I would argue that early clues to the OS benefit is going to come from the durability and PFS, which you've all highlighted nicely that PFS for the second, third line plus median 3 line or more population with CRB 701 is around 6 months at the preferred 3.6 dose. So that bodes well for an advanced population. When you think about -- again, not necessarily for this particular drug, but in general, when we think about median OS for a second, third line population, when we've looked at the follow-up data to KEYNOTE-48 from [ Dr. Harrington ] looking at second PFS, so to speak, and survival after exposure to chemoimmunotherapy or I trials are sort of hovering around median OS of 8 to 10 months. So I would say that's kind of the range we're interested in, in terms of recognizing that this is also going to be an oropharyngeal population where we need to maybe do a little bit better on the higher end just because these patients tend to do better with all treatments we give them as compared to an HPV negative patient even in this setting. . So all of that's being accounted for and has been accounted for in the registrational design of Tempo 1. But that just gives you some sort of -- some numbers to start to chew on in terms of what we would project for median survival improvement -- or sorry, median survival and then what we would need to improve upon with the CRB 701 experience?

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

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

Your next question is coming from Amin Makarem from Jefferies.

A couple of questions from us. First, I have a question for Dr. Hanna on patient selection. How straightforward is it to distinguish oral pharyngeal patients versus other subtypes of head and neck clear boundaries there or other great areas in signing patients? And then I have a follow-up. .

Yes, and this sort of dovetails on the last question. It's actually pretty clear. I mean when we see patients in clinic, and we review scans and we look with an endoscope nasal endoscopy exam with a camera flexible scope. It's pretty clear that a patient is presenting with a base of tongue primary, which is exophytic and sort of sitting in the back of the tongue or arising from the console, you can even steal this location if you play in duration around the tonsil. So believe it or not, these anatomical distinctions are it straightforward and often our correlate clinical exam on our endoscope and our physical exam with what we see on CT imaging. Plus you take into account the fact that usually the demographic and clinical characteristics of the patient aligned with those physical findings. So as we said, limited number smoker, often in their 40s to 60s preelection for males. So -- and just for you all, in initial stages, most men present with or HPV patients or faring patients in general, present with a sort of cystic in large neck node, which is ipsilateral or on the same side of their primary. I mean, that's sort of like a bread-and-butter classic presentation. So I don't see any concerns with delineating patients anatomically and clinically based on those findings. I think it should be quite straightforward for our community.

Helpful. And for the TEMPO 1 first design, it includes an adaptive feature for interim analysis. And sample size potential reestimation, what do you think there could be a need for sample resizing?

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

Yes. So I think it's very prudent to have an interim analysis that's assessing response rate, I think, for garnering enthusiasm and making sure that we're seeing want to see in terms of the Phase III component of things as compared to our experience in this growing Phase I, which almost feels like a Phase II now with dose selection at 3.6%. So I think we would as I said before, sort of ideally look for response rates in the second-line advanced head and neck cancer setting for recurrent metastatic disease around that sort of 20% to 25% range. I think the details of the protocol are still being finalized. But if that were to be the case with an acceptable confidence interval, we would then also look at the PFS and OS signal for that first group of patients and then decide do we need to increase the number of patients study to, therefore, tighten up the power or the signal for an improvement in OS. So I think it's just -- it's an opportunity, right? It's an opportunity to pause, make sure we're not seeing any new safety concerns, making sure that our Phase III experience is doling out what we were expecting in terms of hitting response rates as compared to that initial Phase I that we're doing and then make sure that we feel like we have enough patients adequately assess the power related to an improvement in OS. So this is fairly as many of you know, for contemporary Phase III registrational studies. I know that Fortify is doing something similar around -- or it did around its dose selection. Certainly, [ PDO ] is doing something similar and recently added patients to both their Phase II and Phase I.

Our next question is coming from Jeff Jones from Oppenheimer.

I really appreciate the additional detail here this morning. I guess two questions from us. Can you speak maybe mechanistically a little bit more to the difference in effect you're seeing in the HPV-positive patients you mentioned Nectin-4 expression levels. And maybe then how you think about that impacting patient selection for the Phase III biomarkers and/or subgroup analyses. And then curious how you're thinking about first line given, as you mentioned, the [ PAD KEYTRUDA ] data and how that might impact your thinking about second line down the road or moving ahead into first line?

Mechanistically, it fits nicely with a number of things. It's very similar to concentrate the dynamic of cervical cancer, right? It's we've known that this is one of the richest Nectin-4 tumor types out there as is surgical. Remember that our very strong preference to date has been not to explore this ADC in bladder for -- simply for market reasons, commercial reasons. The other thing, Jeff, that I think will be helpful fees for the audience to realize is, if possible, we would rather avoid a companion diagnostic approach. We would rather avoid having to do a biomarker selection in any of our tumor types. So a reminder that, that is what has managed to avoid doing in bladder. Because bladder is so n[ Nectin-4 ] enriched that there was really no rationale for having a specific [ CDx ] built into it. In cervical, something like 98, I think, percent of these women are HPV-positive and in head and neck oral pharyngeal cancer as we heard today, and we've seen today, both our data set as well as the literature indicates something like 80-plus percent of these patients are positive. And so what we prefer to do is the anatomical selection and focus on that. What we've heard from Dr. Hanna and other of our acquisitions and KOLs is that, that is also their strong preference. And as you can imagine, this was also the subject of discussions with FDA around that path forward. Dr. Hanna, anything to add to that?

Yes. I think I would just take a little bit more -- add a little bit more scientific color there. So Nectin-4 is a cell adhesion molecule, it the lungs in the family sort of that allows epithelial cells to junction or sort of remained tight and you think about that as being important at the intersection of cells breaking off and leading to metastases. So Nectin-4 does sort of play an important role and there's biology that suggests that it's linked to viral transformation, how epithelial cells differentiate and also that invasion metastasis question. It's been shown to be able to activate things like [ PI3K ] signaling, which 30% of HPV-positive patients have as well as [ beta-catenin ] signaling and has also been important in promoting proliferation and motility and epithelial mesenchymal transition. I think all of that serves preclinically to strengthen the relationship between neck and [indiscernible]. But fundamentally, the two points clinically, I would comment on is that Nectin-4 is a validated target, many of the patients enrolled to the initial [ Astellas ] Pfizer study with EV were HPV-positive and there were response rates, as you all know, in combination with pembro, but also as a single agent as published in the JCO experience. and that's now in the guidelines. So we know this is a validated target in this population. And then as you've all said, we have another candidate example of HPV-associated cancer and cervical that's showing nice response rates. So I think all of the totality of that data serves to strengthen its role for HPV cancer. I would say for the second question around avoiding a companion biomarker. I think that is a smart move for a number of reasons, not just financial or from a regulatory standpoint. But -- there are a couple of arguments as to why you would not want to restrict. So if -- when we're running this large Tempo study, one of the things that could disrupt enrollment to said enrollment or complicate patients getting on is requiring central testing in real time for something like P16 or HPV. P16 testing is done at many labs. It's CLIA certified, but not every institution outside of some of the major academic institutions rely on HPV confirmatory ish or PCR testing to show viral association. Remember, P16 is just a surrogate marker for HPV. It does not imply viral causality. And so if you slow a trial down by requiring central testing, you're going to disadvantage patients, you're going to have drop out, you're going to have issues with delays to getting patients on when we can collect that data and check HPV and p16 status ad hoc or as a secondary analysis in the end. And we know that the vast majority of these patients, 85-plus percent will have HPV-associated disease in the end, and we'd rather not slow that enrollment and that would perhaps complicate a label. So -- and there's no preferred assay, right? People use whatever assay their institution prefers. P16 IHG can be done in a number of CLIA labs, but HPV testing is not unified or central. You can do ish probes towards several probes you can do PCR testing. So if we introduce that element of complexity, I think it would be a disservice to the patients and slow the trial down. So I think -- that was -- those were some of the fundamental reasons behind an anatomical designation for eligibility as opposed to a laboratory or biomarker companion.

And Jeff, just to your second question on frontline second line. And with that, we're going to have to wrap up. But what we are emulating is both what passive did in bladder and what PDO is doing in head and neck. We start with second line where we already have data. It's actionable. It seems like a very attractive commercial opportunity. We move forward with that. and that is the indication that will be first to market if all goes well. And then we also explore frontline as [ passive ] did and as PDO did. And in the frontline setting, we'll see what the data looks like early next year. If the data looks encouraging, and again, we have this precedent of [ passive ] then it will be very sensible to trigger that as well, knowing though that, that is a larger and more longer study than the second line, and it may actually eventually end up eclipsing the second-line indication the same way that these days, for example, very few patients and bladder gets passed as monotherapy in second line, it medias all about now frontline plus pembro. But that takes time, and it's a much larger effort and being able to plant the flag as PDO is initially in second line will have some very important commercial ramifications.

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

So with that, I'm going to wrap up. I'm sure there'll be lots of follow-up questions. I look forward to seeing -- I hope everybody starting on Friday at ASCO, again, a reminder, Friday sort of late afternoon is our cervical oral presentation. The next day, we have the poster that poster should go live that morning. And of course, we'll put everything on our website as well. And then last but not least, our breakfast [indiscernible] all event on the Monday morning, bright and early at 6:30 Chicago time. and with Dr. Hanna, Dr. Pres and Dr. Rosenberg. I'd like to thank Dr. Hanna for his time this morning and for all the hard work he's been putting into this program as well as, of course, thank the other clinicians, health care workers that have been part of the study and the core of the scheme, of course, and last but not least, of course, the patients themselves. Thank you, everyone. And operator, it's over to you.

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

Thank you so much. Bye-bye.

Thank you. Take care.