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

[indiscernible] Meet the Expert series Part 2. I'd now like to turn the call over to your host, Rica Brock, Chief Scientific Officer at Corbus Pharmaceuticals. Please go ahead, Rachael Brake, Chief Scientific Offier at Corbus Pharmaceuticals. Please go ahead Rachael.

Thanks so much, Tara, and welcome to all of our remote participants today to our morning session, which is really our second session to Meet the Expert for Corbus Pharmaceuticals. And this particular session is really focused on the development of our next-generation Nectin-4 antibody drug conjugate known as CRB-701. We have some really exciting guests with us today that bring different disease specialties to the table. But before we dive into the Q&A, I thought it would be very, very helpful for our audience. If I spend a few minutes sharing with the audience exactly what is CRB-701 and the intention around design of this particular asset that would help set the frame as to why we have the diverse specialist that we do on the call today. So if we can just jump to the next slide. As a way of introducing Corbus Pharmaceuticals, some of you are very familiar with us, some of you may not be. But we're a microcap pharmaceutical company actually based in Norwood, Massachusetts. We have a couple of different assets in the pipeline. One of those assets is CRB-701, and we'll speak about that today. And then we also have an earlier asset in the pipeline, which is a blocking monoclonal antibody focused on the interface between an integrin that is known to regulate TGF-beta. And so this is an asset that will enter into the clinic in 2024. So as we move forward and we talk about CRB-701, not surprisingly, when you think about Nectin-4 targeting, the asset that comes to mind is the approved agent known as enfortumab vedotin or PADCEV. And so we often get asked questions with respect to how does 701 compare to PADCEV. And so this is a slide that we've prepared that speaks to some of those subtle differences. We recognize that PADCEV has been instrumental in changing the landscape in metastatic urothelial cancer patients. And so what we're trying to do here in the development of 701 is take some of the best advantages of PADCEV and to be able to hopefully solve some of the challenges. So relatively enfortumab CRB-701 has a novel monoclonal antibody. This antibody is thought to be able to internalize twice as fast as the enfortumab antibody can. We also have a novel third-generation site-specific cleavable linker -- this linker is conjugated at the free glutamines in the Fc portion of the antibody. And one of the features of this linker is the stability of that bond between linker payload and the antibody. It's probably one of the more advanced third-generation linkers that's in the clinic. Also because this is actually a conjugation event to free glutamines in the Fc portion, we have an MMAE drug antibody ratio of 2. The material and the incorporation of that payload is very, very homogeneous. We have greater than 95% of our material with the same drug antibody ratio. And we have a much longer half-life of our ADC. So we're actually dosing in the clinic right now on every 3-week schedule, so once every 21 days. And so there are some fundamental differences in the design of 701 relative to PADCEV. And so the implications of that for us as we think about our development strategy then is that we have increased hydrophilicity in the ADC. We have a longer half-life that's leading to less frequent dosing, faster internalization, a drug antibody ratio of 2, very homogeneous drug antibody ratio and linker stability that is tied to lower concentrations of free MMAE in circulation. So when we think about this asset and we think about the development strategy for CRB-701, we are mindful of the experience that PADCEV has brought to the table with respect to creating clinical precedent and proof of concept in metastatic urothelial cancer. But what I draw to your attention here on this particular slide is the potential opportunity for assets targeting Nectin-4, like CRB-701 that potentially have scope outside of metastatic urothelial cancer patients. And what you're looking at on the right-hand side, here is a graphical representation of gene expression data across a number of different tumors. Each individual dot is an individual primary patient sample, and each vertical is a disease indication. And you can see while metastatic urothelial cancers on the far right-hand side, you can see that there are a number of tumors that express elevated levels of Nectin-4, and we think that this creates an opportunity for development well outside of metastatic urothelial cancer. Hence, the distribution of experience that's coming to the conversation today with our resident experts on the oncology side and clinical development side. And so when we think then about the development strategy for CRB-701, we think about this through 3 different verticals. One is whether or not there is an opportunity for us to play in the metastatic urothelial cancer space and to address potentially some remaining unmet medical need despite the availability of PADCEV. We also recognize that there are emerging disease states where there is proof of concept around the biological validation for Nectin-4. And I draw your attention to some recent data that was made by -- presented by PADCEV -- on PADCEV I should say, at ASCO 2023, looking at squamous head and neck carcinoma. And then I also would mention that we believe that there are new indications where there's an opportunity for CRB-701 to consider even a first-in-class opportunity. And obviously, as we think about the broader distribution and the application of Nectin-4 biology, we recognize that there may be an opportunity and/or a need to apply a companion diagnostic to increase the probability of success of this asset as we move forward. So with that brief introduction, I will now turn the tables over to our speakers and our guests on the call today to maybe take an opportunity to just introduce yourself to our audience, your background with respect to your expertise, experience in developing ADCs, experiencing and focus on Nectin-4 targeting assets, just to set the stage with respect to the distribution of expertise that we have on the call today. So Dan, maybe we could start with you. And Tara, if you could help me pull the slides down, that would be great.

So good morning, everybody. My name is Dan Patrylak. I'm a Professor of Medicine and Neurology and the Division Chief of Genitourinary Cancer at the Smilow Cancer Center Yale University. I've had extensive experience in drug development and taxanes in addition to ADCs and worked extensively with enfortumab in fact, was involved with the original Phase I trials with both enfortumab as well as the second agent that was being looked at the AGS-15E antibody. I've also worked along with -- actually, it was -- the company originally [indiscernible] and also worked with [indiscernible] on the anti-PSMA antibodies in addition to AstraZeneca with their anti-PSMA antibodies as well. So I've had extensive experience in the field, both in prostate, bladder, and kidneys.

Great. Thanks so much, Dan. Alex, would you like to help us out?

Hey everybody. So I'm Alex Spira, I'm a medical oncologist. I'm currently a Virginia Cancer specialist while I run our research program there and mainly focused on thoracic oncology. I run our Phase I unit here in next Virginia as well as new Chair of the Research Executive Committee [indiscernible] titles there. Most of the time I spend doing lung cancer and Phase I drug development, a ton of experience with ADCs. We've helped develop the enfortumab, most notably somebody which is waiting anxiously to hear about the randomized data coming out soon, but also having developed numerous ADCs, and we have about 6 to 10 currently in clinical trial right now, and a lot of experience with Nectin-4, in particular, both in the bladder world. We had some trials around, but we also have some of others currently in development as well.

Great. Thanks so much, Alex. Ari?

Hi. Good morning, everyone. My name is Ari Rosenberg, I am a medical oncologist at the University of Chicago. I have expertise in head and neck cancer and across a couple of different interests have been involved in novel therapeutics across the advanced head and neck cancer space. I also have been involved in a number of different ADCs, including enfortumab vedotin in head and neck cancer, and I look forward to the discussion.

That's great. And Paraic, if you could introduce yourself...

Good morning, everybody. My name is Paraic Kenny. I'm a PhD cancer biologist and Director of a small Cancer Research Institute embedded within an integrated health care system in the Midwest. I'm also a faculty member in hematology and oncology at UW-Madison. On the translational side, I've developed an antibody drug conjugate against the cell surface protein called amphiregulin. And on the clinical side, I serve on a statewide molecular tumor board here in Wisconsin, where we frequently consider use of ADCs in patients with advanced cancer, sometimes on trial and sometimes off-label. Breast cancer has been my primary focus for the past 20 years, but my clinical involvement now spans a full spectrum of solid tumors.

That's great. Thank you so much for all of you for joining us. I think we've got a really broad distribution of expertise sitting at the table. So maybe just sort of a thoughtful question just to get us started, and maybe Paraic, we can stay with you. When you think about the evolution of ADCs and you think about sort of the disease sets that you focus on, help us understand how you think that those ADCs have affected your landscape today? Where have been the opportunities that you've leveraged from those ADCs? And where are the challenges that you're currently facing?

So I think we're really fortunate in breast cancer to have had a very solid, well-validated monoclonal antibody, trastuzumab Herceptin, which was first approved 25 years ago last month. With the emergence of ADCs as a potentially interesting modality over the past 5 to 10 years, trastuzumab was a really obvious low-hanging fruit to go after initially and I think looking back at the success of some of those agents as well as the challenges they face, I think we can look at it as a paradigm now for some of the challenges we're seeing going forward with perhaps some less validated targets. So some of the highlights, ADCs could work in solid tumors, which is great. They were initially developed in heme malignancies. We know trastuzumab emtansine, for example, is better than the bare bones antibody, trastuzumab itself. Also, we know that the first mover advantage isn't everything. So these antibodies can be -- these ADCs can be optimized and further improved. Trastuzumab deruxtecan is much more effective than trestuzumab emtansine, for example. And I think we've also seen the potential for tumor agnostic activities. So as I look more broadly outside the field of breast cancer, I see very nice efficacy for trastuzumab deruxtecan in lung cancer, for example, in situations where we can identify patients with biomarker. In that case, it's mutations of ERBB2. So I think we can look back at the history of ADC development in breast cancer and see a lot of optimism for the future. We can look back at a lot of the success and hope to translate that into other malignancies.

Yes. That's great. And I think you're right. The [indiscernible] story has been an evolution over 10 or 12 years, right, which has given us a depth of perception around how the evolution of an ADC can change. Thank you. Ari, I know you have a very different experience in head and neck. I wonder if you could speak to that.

Yes. Thanks, Rachael. In head and neck, we're much further behind breast cancer as it comes to ADCs. We don't currently have any approved ADCs in advanced head and neck cancer. That being said, there is certainly an unmet need within head and neck cancer. There are a number in development in hand and neck cancer. And Certainly, enfortumab vedotin is one of those that has indicated and an early signal that our folks in the head and neck cancer are enthuastic about, yet there's so much space for improvement and much opportunity in that space. So head and neck cancer is a disease where we know that cytotoxics are quite active, taxanes in particular, microtubular targeted agents. So there's certainly an unmet need and appetite in the head and neck cancer space. But again, currently, no approved ADCs in head and neck cancer.

Yes. Great. Alex, do you want to speak on lungs?

Sure. Lung cancer. Despite all the headway and targeted therapies, we're still really waiting for our first ADC approval. There's still a huge unmet need. Datopotamab, as I mentioned before, we are anxiously awaiting the results. It's a very active drug. However, it has a real toxicity, so we need a better drug with more activity and less toxicity. [indiscernible] trial verses [indiscernible] is supposed to be [indiscernible] next week with a lot of positive spin so far, but there's still a clear need there. So I think there's still a huge unmet need in the second-line non-small cell lung cancer setting as well as for a well-tolerated drug to try to move to the front line.

Yes. Okay. Great. And Dan, it would be great to hear your insights specifically related to, obviously, the relevance of enfortumab vedotin and the bladder cancer population. One of the impacts that you've shared with me in an off-line dialogue right is the role that these ADCs have played in managing visceral disease. And I think it would be great to hear that story. Dan, you want to unmute?

Enfortumab vedotin is a game changer in metastatic urothelial carcinoma, not only as a single agent, but as we'll see this week in combination with pembrolizumab. There's been a press release shown that there's a survival benefit too. So what are the things I think that's very, very impressive about the drug. We've seen this -- we've not seen this with cytotox therapy. We've have not seen this with simulation checkpoint therapy, is a response rate in visceral disease. It's generally low with those 2 different modalities and with enfortumab consistently, whether this is in the untreated patients in patients who got prior checkpoints and then the approval for those patients who had a checkpoint as well as having chemotherapy response rate 40%. And that's the same for nodal disease as well. This is an extremely active agent with long duration of responses. We have patients from our Phase I trial who had liver metastases who are live today, 8 or 9 years out, which is something which was unheard over this disease previously. So I think the real question is how much treatment is necessary for these patients? When do you stop? How do you monitor for neuropathy? How can you prevent the neuropathy that occurs in some patients. Was some of the risk factors and certainly, we've seen we're obviously developing in these patients over time. And particularly as we move these Nectin target agents up to the [indiscernible] setting, first-line therapy, and patients are living lock. This is going to become a more and more important problem in quality of life. So without question, this approach is a game changer in urothelial carcinoma and the question is how do we improve upon it, how do we modify it?

Yes. Right. So I think the point is right, across the distribution of these disease states, some are really very nascent and very -- still very much in the development space. And then in the bladder cancer setting, right, we have got an opportunity to actually take goods and hopefully make it better, right, in terms of improving that quality of life. So there's a really broad swath of experience with respect to kind of opportunity. So Dan, if we can say with you, talk to me a little bit about your Nectin-4 targeting experience to date and where are the opportunities and the challenges with those drugs mostly, I think it's important but just based on a depth of experience in the field, but anything that you can draw from with respect to where you see challenges for those drugs and an opportunity for something like 701 to potentially improve?

So I think that we really, at this point, don't understand the markers of response and resistance to enfortumab. We know that practically all specimens of urothelial carcinoma expressed Nectin-4. It's based upon the H score, which is basically some total of the overall stating. If we take an analogy to HER-2/neu, where HER-2/neu is based upon membrane study. You can see both cytoplasmic membranes with specimens in breast cancer. But the membrane setting is what's important because, of course, that's put on the cell surface and what's being targeted. That still has not been able to be distinguished yet and I think the best important area because we don't really understand whether the resistance is due to loss of Nectin over time. And the clone is not having it or it's due to the more heavy resistant, the chemotherapeutic target, and if it's a tubular-type resistance. So that has, I think, important implications to the types of drugs we're delivering. If we can get more binding or of a longer period of time of binding to the Nectin receptor or more exposure of the target to the drug, those are potentially ways of overcoming resistance in the situation. So we really need to understand more about this. And we've seen other Nectin targeted agents, other MME targeted agents that have different types of response patterns. You're getting a different target, but you're delivering the MMAE. So I think that we do have to understand this better. There is data in other tumor types. We know that there's been some data with enfortumab that's presented at ASCO last year with head and neck cancer. And then there was -- as part of the original bladder trial, that was a Phase I study that looked at other tumor types as well, I believe, including ovarian cancer. So again, I think the area with the landscape to investigate these drugs [indiscernible] is really there.

Yes. Ari, any commentary from you with respect to sort of Nectin-4 and the [indiscernible] topic that Dan just raised with respect to the head and neck experience? Anything -- any insights you can share there?

Yes. I mean, as Dan referenced, we saw some data from the head and neck cohort for enfortumab vedotin that was presented at ASCO this past year. And this is a cohort of patients that had progressed on both immunotherapy and platinum-based chemotherapy. And so the -- really where the unmet need is basically as a single agent. And we saw actually a response rate of about 24%, which for this population is quite promising with progression-free survival of around 4 months for a highly refractory patient population, which, again, for head and neck is promising. But of course, yet much move for improvement. In terms of biomarkers for head and neck, -- there's a lot of more -- a lot more room for investigating biomarkers such as Nectin-4 staining, H score and other components in order to be predictive or enrichment for those patients that are more likely to benefit from a Nectin-4 targeted ADC strategy. And so we wait for more data -- more robust data to speak to that a bit more again. We're far behind the urothelial group, as you heard about, where most of this is much more developed than in the head and neck space, but the data is there, and we look forward to seeing more of it as it comes out.

Yes. So with respect to that 24% objective response rate, was there any correlation with Nectin-4 staining in the head and neck cancer experience?

We haven't seen an enrichment based on a biomarker in Nectin-4 targeted ADCs for head neck.

Okay. Okay. And Paraic, maybe I'll throw to you here because I know that you've done a lot of work looking at sort of the predictability of H score and not just Nectin-4, but I know you have some thoughts around this. What do you think around the value proposition of H score as a marker?

Yes. I mean I think I agree with you. [indiscernible] we clearly do need a biomarker, but what that will be. I'm really not sure. I mean, I think the intuitive idea is that the H-score would be a strong predictor. But when we look at a lot of the studies that have been done, we have responses and nonresponses across a full range of H scores. So that to me says a couple of things. So one, maybe there's some mechanism of intrinsic resistance in the tumor. Is there some patient-level resistance for some sort of mechanism we don't know about? Or the third option is maybe for a lot of these patients, we're not -- just not getting enough drug into the tumor. So perhaps where at least with PADCEV limited by the dose we can achieve with the dose-limiting toxicities that have been observed and maybe an agent that can be used at either a higher initial dose or with pharmacokinetics that allow the tumor to be exposed to a longer dose for a longer period of time, may be more efficacious and may at least help us start to tease out whether -- what kind of biomarker we should be looking for in this setting.

Yes. And so do you have thoughts around protein versus gene expression, like what -- how do you see the value of that with respect to sort of H score versus something that's much more genetically based?

Even though H score hasn't really worked out very well, I still think some kind of protein-based biomarker is probably going to be more useful unless there's some sort of broadly based genetic mechanism of resistance, which given the failures in response that we've seen at reasonably high levels in fairly treatment-naive patients or at least patients who haven't seen either in ADC or MMAE before, I think it's probably less likely to think that there will be a common mechanism of genetically encoded pretreatment resistance or de novo resistance.

Got it. Got it. And so Alex, can we just [indiscernible] that into the lung cancer experience. Obviously, you guys have a wealth of targeted therapies available to you now in lung cancer. And so what are your thoughts around sort of the adoption of protein expression and H score related to the lung cancer space and the opportunities and the challenges there?

So we have a plethora of targeted therapies, but to remind us all that still only about 30% to 40% of patients, depending on where you live here in the non-smoking belt. But if you go to Tennessee and West Virginia, there's still a ton of patients who don't have actual mutations, probably 90% to 95%. The datopotamab world was really kind of the first foray to look for [indiscernible] expression, and it failed miserably. I've heard several things that they're close to developing an assay and maybe people on this call know better than I do. But as of right now, we still don't have anything. And if data is approved, it's likely going to be in a tumor agnostic way. We are desperate to find a biomarker that works for everything that we treat. And we're so used to it, right? I mean we want these biomarkers to be done. It started with PD-L1. PD-L1 now is really obviously in the targeted world. It is not easy to do. The reason it's not easy to do is because it's not standardized yet. So the concept of doing the clinical study, where you have to figure out who's going to be able to enroll in the study with the marker is fraud with problems, right, between getting adequate tissue, having those patients waiting for those results to come back, not knowing if they're going to enroll is a huge logistical issue there. So they're in line the drug development issues. And I can use the example of CCAM 5, which is a very active drug, yet that study will be going on for years and never accrue because it's hard to identify those patients, at a very, very small number of patients. Nevertheless, we really are desperate to find a biomarker for whatever treatment that we do and then figure out how to operationalize in clinical studies. If the study is positive, it will be easy, right? [indiscernible] PD-L1.

Okay, good, good. So okay. So let's segue then, Dan, back to you and let's have this conversation about enfortumab vedotin. I think we've all agreed that I think it's been landscape changing with respect to the metastatic urothelial cancer population, both in the late line and obviously now emerging into that frontline setting. Help me understand where you see the challenges with that drug in practice for you and where there might be an opportunity for a second generation or a third-generation asset to sort of advance in the field. Some inputs there from you would be super helpful.

So I think a couple of areas that we certainly would have on their agents. Number one, of course, will be if we have an agent that would have less neurotoxicity and that would not have to be monitored carefully. So I think that, that's one area. The second area is what do you do when a patient progresses on enfortumab. And this would be in the metastatic state, if [indiscernible], and we see the same pattern in the muscle-invasive bladder cancer patients being treated [indiscernible]. There is a trial that is now looking at that particular question. The format of pembro. What do you do if a patient relapses within a year or after a year? Do they still retain sensitivity to the drug? Or are they resistant to the drug -- so that's the second area that we would also look into the resistant patients, both in somebody who's treated in the [indiscernible] setting as well as somebody who's treated in the metastatic set. So I think there are a lot of opportunities for developing new drugs from this disease.

Yes. So when you think about the safety profile of enfortumab vedotin as a monotherapy in the late line setting, versus what you're now observing as sort of the early tenders of clinical trial data coming out in the pembrolizumab combination with enfortumab vedotin, do you see similar adverse event profile? Do you see them at the same frequency, same intensity? And anything that you're seeing that's emerging that looks different across the combo versus the monotherapy?

No, it looks very similar. I mean, it looks like it's -- there's nothing that's synergistic in terms of side effects with the combination of enfortumab and pembro. Additive, I think that, that will probably be the best way to describe it. We've seen that in the Phase I trial that we published. So I don't think there's been anything that's been unique about the combination of the toxicity of the combination.

Yes. One question or 1 comment that I had heard previously is that the induction of peripheral neuropathy with enfortumab vedotin as a monotherapy was not surprising given the prior exposure that these patients typically have had to platinum-based chemotherapy is a sort of a pre-therapy. And so I think one of the things that I was surprised to see is that even in a [indiscernible] eligible population that maybe haven't seen prior platinum, we are seeing a similar frequency of peripheral neuropathy and skin toxicity. How do you account for that? What's the biological underpinnings of those data?

Well, I think the neuropathy that we see in patients who are second line is from platinum and also could be from diabetes as well as a preexisting condition. In reviewing the data that we have published with the EV-301 study, there didn't seem to be any increase in neuropathy in terms of prior platinum treatment. We saw that in the Phase I studies as well. It seems to be different mechanistically. In the EV-103 trial, we presented data at ASCO GU last year that looked in a [indiscernible], and the neuropathy what was seem to be about the same. Now granted this was on 3 cycles of treatment prior to cystectomy, but we still did see some neuropathy in patients. So it's a different mechanism. And we think it's way to the MMAE, of course, since that's a 2 [indiscernible] agent, but it seems to be different mechanistically.

Okay. That's a really good insight. Thank you. I don't think I had even heard that before. So okay. So let's turn our attention then to 701. So 701 is focused on several key features of differentiation. And I guess my question to each of you as you think about your release dates of interest, which is -- how do you think about these differences impacting the clinical observations and the utility of an agent like 701. So reducing the risk of deconvugation and therefore, reducing the concentration in this case of free MMAE. Obviously, a novel antibody that retains [indiscernible] C1Q binding as well as this increased internalization rate of the antibody, a reduced drug antibody ratio and an increase in hydrophilicity, and obviously, then the longer half life that Q3 weekly dosing and the homogeneity of that payload incorporation into the ADC. And so Paraic, maybe I'll start with you. I know that you come from the translational side. And so thinking about the sort of the technical aspects of an ADC build, I think, is [indiscernible] how you think about sort of the fundamental science here? What are your thoughts?

Yes. I mean, I think for me, out of your list, the reduced risk of deconjugation is very appealing. So the amount of MMAE that comes off other ADCs really seems to be a major driver of toxicity. It seems to be a class effect of these MMAEs. So we have overlapping toxicities observed in a lot of cases. The more stable linkage that MMAE has as part of this CRB-701 ADC is a really a positive feature. So that may allow us to get higher dosing of the agent in patients because they're protected from some of the MMAE release for the antibody. And ultimately, I think of doses being the amount of active agents that the tumor is exposed to over the course of treatment rather than the amount of dose that's infused into the patient initially. And when you have that combination of the more stable linker and the defined DAR, which favors more hydrophilic antibody and less clearance from the circulation. I think you've got an interlocking set of advantages there that are quite attractive to me.

Yes. Thanks. Alex, any thoughts from you on the lung cancer space with respect to sort of the features of differentiation here?

I mean a little to add other than that, that's all relevant to what we do. I mean, the neuropathy is a challenge in our patients just because of the platinum therapy they've gotten before [indiscernible] a little bit older. So a little to add other than that I would agree whole hardly with an aspect that is important as.

Yes. Ari, your thoughts?

Yes. I would just -- I agree with what's been said about some of the potential advantages. I would just add that in the head and neck space, many of our patients, in addition to receiving prior platinum also taxane, both of which can result in neuropathies, but a great limiter of the ability to continue therapy when that's a cumulative toxicity challenge, the dosing difference. So weekly versus Q3 weekly dosing potentially in terms of some of the longer half-life, also represents advantages in terms of patient convenience and feasibility as some of these things rolled out. And then, of course, some of the opportunities that you were -- that were well described in terms of potential advantages in terms of efficacy, in terms of increased and faster internalization to other components, we have to do better in terms of both response rate progression-free survival in order to get that translation to a survival advantage in the head and neck cancer space.

Yes. Dan maybe we'll finish up with you in the bladder cancer space.

I mean, certainly, one of the things I think is important again is, as we've talked about before, the structure of this drug has is going to different bladder cancer. But when you see -- with this particular drug, there may be a reduction in free MMAE, which in all of our other studies, in the prostate cancer, remember, we had a lot of problems with that particular issue. That can cause more toxicity and MMAE, given by itself as a drug is completely feasible because of the known toxicity -- neurotoxicity as well as the immunologic toxicity. So the thing I think is going to be important is getting the drug -- more drug, intensifying the dose and seeing if we can overcome some of the issues that we've talked about previously.

Yes. Very good, very good. So Alex, maybe I'm going to start this 1 to you, right? So thinking about the development strategy for CRB-701 and thinking about the lung cancer space, where do you see the remaining areas of greatest unmet medical need in lung cancer? And where would you think about sort of developing a paradigm for 701?

So I mean the second line lung cancer is wide open. And even if datopotamab gets approved, I think we're all going to be a little disappointed on the results right now. Obviously, we're hoping despite another ADC that peers is better. And if it doesn't get approved, will then it's still really wide open. So that's clearly the motion to get anything going down there. I think nobody would have any issues putting anybody on a study even the absence there. And the bar, as we will find out, is going to be pretty darn low because it's still being compared to [indiscernible], which still has minimal efficacy as well. So to me, it's very easy to look at the second-line patients right now in terms of operationalizing a clinical study. Clearly, just to get patients on starting with any lines of therapy as long as they have any lapping toxicities, but then rapidly move into the backfills or an expansion go looking at that pure second line.

That's great. And Ari, maybe we'll start with you and talk about that in the head and neck. I know there's a different set of challenges there.

Yes. I mean head neck, we haven't had as much success as breast or urothelial or even lung in terms of some of our strategies. I -- similar to what Alex described, I think second line and beyond still remains the biggest area of unmet need in head and neck. This is a space where single-agent chemotherapy or cetuximab response rates only in the 8% to 10% range, really some optimal after immunotherapy platinum-based failure. So again, a very low bar opportunity. The other is in the frontline recorded metastatic setting, where for PD-L1 positive, pembrol alone is one of the approved agents, but the response rates there are only around 15% to 20%. So there also, there's an opportunity to combine, to try to boost the -- ultimately the survival advantage from the frontline recurrent metastatic. And then I think moving beyond that, for head and neck, the majority of patients still get diagnosed in the local regionally advanced [indiscernible] setting, yet we see recurrences and development metastases and about half of those patients that are treated with curative intent. And so ultimately, bringing it into the local regionally advanced setting and even the neoadjuvant setting for head and neck would be exciting. But I think the second line frontline of current metastatic is probably the place to start.

Yes. Okay. That makes sense. And Paraic, what are your thoughts around breast cancer and specifically sort of MMAE as a payload and HER2 as a precedent and breast cancers, I think, are a space where the tolerability profile of an agent start to become very, very meaningful.

Yes, that's right. I mean our standard of care options in breast cancer developed at great pains over many years. We're actually working reasonably quite well now and are reasonably well tolerated. So that puts a barrier there in front of bringing in one of these agents and advancing it to earlier lines of treatment due to the potential toxicity concerns. So I think there's always a trade-off, right? Trading potentially more toxicity for potentially greater efficacy. And I think the rate of movement in that direction is a little bit slow. So I think like we've talked about trastuzumab based agents have turned out to be very positive so far. But in endocrine-resistant breast cancer, I think we still have a tremendous unmet need. I think in triple negative breast cancer despite the approval of sacituzumab govitecan, we still have a pretty significant unmet need. So I think there's lots of room for improvement here. And then look at agents like Nectin-4 and the Nectin-4 is expressed in about half of breast cancer patients. And I think we've done a pretty good job in breast cancer and taking advantage of the hard work that's been done elsewhere. So I'm hoping that the folks who are developing these agents and head and neck cancer and bladder cancer will come up maybe with some suitable biomarker that we can then take advantage of in breast cancer, so that rather than trying to evaluate whether these ADCs are effective in all comers, we may have a better ability to select a subgroup of patients that may be more likely to achieve the benefit.

Yes. Very good. Dan, your thoughts around bladder cancer and the remaining greatest areas of unmet medical need? And we talked a little bit right offline, you and I about the evolution in the landscape right now, and how that shift of thinking about enfortumab vedotin in the frontline setting? And what does that do in a later-line population? What are your thoughts there?

I mean I think that there is the opportunity and a weighted a lot of population to develop new drugs. And the field of shifting, as we've seen, as we've talked about previously. In the first line, enfortumab vedotin turns up to be the standard of care not only for neoadjuvant but for metastatic disease, then the question, of course, is what are you going to do in the next situation. We do have targeted agents such as [indiscernible] for the small percentage of patients that have more positivity. Sactuzumab is a different epitope that's recognized by the antibody as well as a different warhead. And there is about a 30% response rate in patients who received sacituzumab and enfortumab or vice versa. So they are non-cross-resistant but still 70% of patients are not responding in that particular situation. So we have that opportunity to look at now. We have the opportunity, of course, again, when is the check point going to be administered -- and then, of course, can you rechallenge patients in a combination steroid-therapy study to receive the checkpoints. So markers, new drugs, 20% complete response rate. We're not yet curing everybody and we'd like to cure patients -- to have these patients live longer, but also have them live well and have fewer side effects.

And so just related to that, when we think about the evolution of the landscape in pembrolizumab moving earlier, both in first line and then potentially also in the neoadjuvant setting, what have you thought -- I know that there's sort of a conversation, I think, in the field broadly, right, around the idea of retreatment with a similar payload. And I think my question to you is really centered around the thoughts around sort of the retreatment hypothesis, if you were failing monotherapy late line PADCEV or enfortumab vedotin versus if you failed neoadjuvant PADCEV in the earliest of line? And how does that time away from MMAE exposure potentially influence that retreatment hypothesis?

This is a fascinating question. And I can answer that from 2 different angles. So years ago, one of the thoughts about the chemotherapeutic rate from MBAC was that the dose wasn't high enough. And so there were these dose intensification schemes for MBAC doubling the methotrexate doubling the adriamycin giving a higher dose cisplatin. And honestly look at that question, and they found that they had secondary responses in the metastatic setting. But the patients who responded were the ones who had a longer time from the original treatment with conventional unpack. And so some of the drug resistance was lost over time. Same thing with prostate cancer. When we first were looking at taxanes in prostate cancer with docetaxel. There was one anecdote we had of a patient who had a great response in the Phase I trial of 40 milligrams per meter squared. When other Phase I studies after he progressed and his wife actually was the one who came with the idea of retreating with docetaxel. And he re-responded. I was kind of resistant to that, but then the time off treatment was about 1 year, 1.5 years. And we've seen that where we've been able to cycle patients on docetaxel as well a small percentage. But we really still don't understand why these patients are resistant. We don't have a great market. And if we can change the kinetics of the drugs or change the way the drug is exposed to the -- the patient is exposed to the drug, that may be an advantage and maybe a way of rekindling, a response to a particular class agents.

Yes. I think that's right, right? I think there are 2 parts to that component. One is we don't really understand the mechanisms of resistance. And then I think relatedly, right, we don't really understand the premise of resensitization either, right? Time away from drug seems to be the biggest predictor just based on sort of the underlying science of dependency for the tumor, but we don't really know that definitively. And so I think there are 2 aspects to that question around retreatment, right? And that hopefully, assets like 701 and also like the bicycle drug, give us an opportunity to try and test that hypothesis.

Exactly.

Yes. Yes. Very good. So I'm going to throw this one to you. So -- and this is maybe more supposition and hypothesis driven and data driven at this point in time. But 701 is testing this idea, right, that a really highly potent hydrophobic warhead like vedotin or MMAE could potentially afford to be dosed at a lower concentration, right? And it gets back to a sort of [indiscernible] talking about this constellation of not so much the dose that you're giving, but rather the exposure of MMAE that's actually making it to the tumor face and therefore, subsequently internalization. But on the face of it, 701 has a lower drug antibody ratio. And so from a stoichiometric standpoint, we get a lot of questions around low DAR versus high DAR and what's a desire of state for a payload and an ADC. What are your thoughts around that? And how do you -- when you think about the constellation of an antibody, a linker and payload. How do you think about that?

Yes. I mean I think from a preclinical and mechanistic perspective, that number one, with the ADC development, at least have had neck cancer, toxicity remains dose-limiting and efficacy limiting and so the opportunities to improve upon that with longer half-life with increased linker stability with some of the increased hydrophilic components all seem to be more favorable and are promising at least in terms of being more favorable in terms of reducing toxicity. And the other piece is as you sort of described, which is bringing more of the MMAE cytotoxic component to the cancer cell itself to be internalized and ultimately lead to increased cytotoxicity. Because at the end of the day, we're talking about patients with a poor survival, with poor quality of life, with a lack of efficacious agents to help both of those kinds of components. And so what we're really looking for is a drug antibody ratio that's going to bring more cytotoxic component to the malignant cells lead to increased cytotoxicity without toxicity limiting dosing prohibition. So we're able to improve survival for these patients.

Yes. [indiscernible], how do you see the low DAR, high DAR, how do you see that equation? I often hear, and I speak to a lot of people about this, and I think that being -- having a low DAR, we attract a lot of criticism that more is always better. And I think that, that's typically the cancer way, right, when we think about oncology medicines. What are your thoughts?

Yes. I mean, I'm not surprised that you get those questions. I think it's entirely intuitive and simple to suspect that the more drug you can pack onto these antibodies the better. And I think some of our perspective in that in breast cancer comes from the experience with trastuzumab emtansine and trastuzumab DM1, where DM1 sorry, trastuzumab emtansine and trastuzumab DXT where DXT turned out to be much better, surprisingly to many people than the first agent. So there was a lot of hand waving and tried to explain why that is. And one of the most simple distinctions between those antibodies is that the DXT has twice the DAR as the other agent. And I think that's led people to become quite bullish on this idea that high DAR is always better. I think you guys have done a good job of really trying to explain the different trade-offs that you get with increasing or decreasing DAR. And I think your rationale for having a low DAR and the advantages that, that potentially gives you and the ability to dose higher and expose these tumors to larger amounts of the drug over time is really, really meaningful. So I'm not surprised you get those questions, but I think you've got some pretty persuasive responses, and I look forward to seeing the data that emerged when this hypothesis will be really tested by you guys.

Yes. Thank you. I appreciate the feedback. Alex, any thoughts there for you on low versus high, like how do you think about that hypothesis in the lung cancer space.

Very similarly, I mean, not much of a difference than what you've heard. I mean I think we're all still trying to learn how that fits in. So similar to before, I don't have much to add. I think I'm pretty much on board with everybody else. I don't know [indiscernible] any different than the other tumor types.

And so there's a lot of openness, I think, in your mind, I guess, if I can put words in your mouth, that sort of high or low DAR is really not the predictive thing, but rather sort of proof is in the pudding as it relates to what does the data tell you?

Exactly. We've also learned over time that there's a wide dosing interval as well. So the therapeutic range is very wide. So yes, sometimes a nice thing at a high DAR. But at the end of the day, you can do something to 2 to 3 patients respond at 1/3 to 1/2 the dose that we actually end up being at, so that it really not matter of the year.

And then I get back to the biomarker, right? How do you predict that response? What does that look like?

Correct.

Yes. Dan, any other thoughts from you?