... Okay. Hey, good morning, everyone. Welcome to day two of the Cantor Healthcare Conference. My name is Olivia Brayer. I'm one of the senior biotech analysts here at Cantor. And we have the pleasure of hosting Sean McCarthy, who's President and CEO of CytomX Therapeutics. Sean, thanks for making the trip. Happy to have you here. Thanks for having us, Olivia. Great to be here, and looking forward to our conversation. Yeah, really interesting time for your company. You guys just had some, some initial, you know, very positive data. You'll have some more coming up next year. So maybe give us the lay of the land of the company as it sits today, as we head into next year. You know, what, what are you most excited about as we get to the next phase one card flip for, for your EpCAM ADC? Yeah, well, it's been a really exciting year for us, for sure, and, obviously, very focused right now on the CX-2051 EpCAM ADC, which really integrates, you know, so much of the work that we've done over many years, with our Probody therapeutic masking platform, and in particular, applying it to, antibody drug conjugates. I'm sure we'll come back to other applications a bit later. But on twenty fifty-one, you know, the first look that we shared in May this year of, clinical data from our phase one study, is really showing that this drug is performing as we designed it, and it's been a very intentional design, leveraging our masking strategy to, address EpCAM with a systemic ADC for the first time. So we think we've really broken new ground. We've shown impressive clinical activity in the late-line metastatic CRC setting, which is a very hard place to show this kind of clinical benefit for patients, and it really unlocks EpCAM as a target, not just in CRC, but potentially in many other tumor types as well. So, yeah, we're currently expanding that study. We're gonna have additional data in Q1 of twenty twenty-six. We recently announced that enrollment into the expansion phase is complete. Actually, exceeded our expectations in terms of timing, and we're right on track to deliver what we've communicated previously, which is an update in Q1 of next year from more than 70 patients across three different dose levels. So, really excited about the drug candidate, about what it's doing for patients, and I think more than anything, just the fact that even in a really tough environment, particularly as it was earlier this year, even in a really tough environment, that investors have seen the potential in the drug and in the platform and in the company, allowing us to raise a $100 million round concurrent with the announcement of that data in May, setting us up to, you know, continue to do what we're here to do, which is to develop great drugs. Yeah, and EpCAM hasn't always historically been the easiest target. So maybe just talk about the antibody masking technology that you all have. I mean, what makes it unique, and what gives you confidence that you will be able to, you know, turn EpCAM into a druggable target, so to speak? Yeah. So the platform technology, the Probody therapeutic platform, is a masking strategy. We have, as you know, we've been in this space for a while. We've pioneered the space, actually, going back more than a decade, and in our particular case, our strategy for masking is peptide-based. So it's a peptide-based mask with a protease cleavable linker, and the whole system is designed to allow for mask removal in the tumor microenvironment by tumor-associated proteases. And we've achieved every first in this field over the years in terms of showing how this type of technology can function in patients. And we have been followed by others in the space, you know, several of whom are also doing quite well. And there are different strategies for masking. There's peptide masking, as we've pioneered. There are less specific masking domains being employed by others, and then there are even other approaches to conditional activation, including pH-dependent binding of antibodies to tumor targets, leveraging differences in pH between normal and tumor tissue. So different ways to potentially go about solving the challenge of getting the drug to the tumor and avoiding binding in normal tissues. We think our approach is the optimal one because it allows for a high degree of tunability in terms of getting the affinity of the mask right, the protease cleavability of the protease substrate right to deliver the appropriate therapeutic window. So why, why is ADC in particular the right approach, at least near term? Yeah, well, ADCs, I mean, we, we've always had the view that our platform should be applied in a multimodality way, and that continues to be the case. It's certainly the ADC that's in the news right now, given, you know, the impressive activity that we've shown in CRC. But we continue to be active in T-cell engagers, in cytokines, and other areas where improvement of therapeutic window could be really impactful. In terms of ADCs, we've done a lot of work with a couple of other programs that really led to the design of twenty fifty-one, and the thesis around applying masking to ADCs is to go after... it allows us to go after some of the most abundantly and broadly expressed tumor antigens- Mm ... even though they're expressed in normal tissue. And EpCAM is one of the best, if not the best, examples of this. And so, as you mentioned, EpCAM has been on the radar screen for all of us in oncology R&D for a long time. This target has been drugged successfully in the past, but only with systemic, with, locally administered therapeutics. There are drugs that can be administered, for example, into the bladder, that can have impact, into the peritoneal cavity, that can have impact. But no one's broken through giving a systemic anti-EpCAM therapeutic, because EpCAM, epithelial cell adhesion molecule, as the name suggests, is expressed on most epithelial structures. Some of the early approaches to drugging, trying to drug EpCAM, quickly ran into toxicities, for example, acute pancreatitis, or liver toxicities, that limited their development. In the design of twenty fifty-one, you know, we've been very intentional in thinking about the three components that go into the design of an optimal drug using masking strategies. Number one, what's the target, and what's the validation that that target has, to show that if you can engage it, it will shrink tumors? EpCAM has that validation, as I've already said, from locally administered therapies. What's the tumor type that you're going to treat? Be very intentional about the tumor that you're going to go after, where the unmet need is high, and in this case, late-stage colorectal. And execute a clinical strategy specifically in that tumor type to get to an answer as quickly as you can. And then the third component of this three-component strategy for intentional drug design at CytomX is, of course, what's the effector? And in this case, we chose a TOPO1 inhibitor in the context of an ADC, because we know that colorectal cancer can respond... does respond in the early lines to TOPO1 inhibition, because, of course, irinotecan is such an embedded part of the standard of care. So that's kind of how we got to twenty fifty-one, and we think ADCs are just a terrific application of this technology. Yeah, and you mentioned safety, right? And just the importance of safety, especially around this EpCAM target. I mean, maybe just talk through the data you've seen to date. I know there was a disclosed patient death that did get some attention a couple of weeks ago. So maybe just walk us through what happened there. What are you all doing to actively manage for or mitigate some of those toxicities that have historically been seen with this target? Yeah, so beginning with the, you know, the activity of the drug, and just to summarize the data that we presented in, in May. So across eighteen efficacy-evaluable patients at that time, at doses of 7.2, 8.6, and 10 mg/kg, which are now our expansion doses, we demonstrated a 28% overall response rate, which, to put that in context, compares to, in the late-line, with drugs like fruquintinib, regorafenib, or Lonsurf, if you're looking at response rates in the 1-2% range. So this is really a big step forward in terms of showing clinical activity in the late-line CRC setting. And in fact, at 10 mg/kg, we saw three out of seven patients with confirmed PRs, which was really, really exciting. That's 42% ORR at the highest dose that we're currently expanding. So clearly, this is a very active drug in CRC. It's absolutely working as designed. In terms of AE profile, first of all, let's talk about what we didn't see. We saw, you know, low rates of hematologic toxicity, which is really important because, of course, our longer-term objective with twenty fifty-one is to bring it earlier into the early lines of the treatment paradigm, and so that will be, we think, a significant advantage in terms of combinations with chemotherapy in the earlier line setting. And as we look at some of the other competitive agents being developed in CRC, you know, we do see higher rates of heme tox compared to twenty fifty-one. We did see a GI signal, tox signal. We saw about a 20% incidence of Grade 3 diarrhea in the study. We know that TOPO1 inhibitors can induce diarrhea. It's a well-established toxicity seen with irinotecan. The payload CAM59, which we licensed from ImmunoGen, this is the first evaluation in patients of how CAM59 behaves, and so we're learning more all the time. You know, not surprised to have seen GI tox. John, can you contextualize that GI tox a little bit more for the audience? Just because we have seen high rates of GI and diarrhea with- Yeah ... a lot of other drugs in CRC, but also some later-line solid tumor indications. Absolutely. I mean, this is not an unusual toxicity to see. There are other agents with TOPO1 inhibitors, for example, Trodelvy, which has a significant rate of Grade 3 diarrhea. We also see other targeted agents, for example, HER2, HER2 bispecifics, HER2 small molecules, the Lilly CDK 4/6 inhibitor, Verzenio. So, you know, this is not an unusual toxicity for a TOPO1 ADC and something that we'll learn more about over time. In terms of the steps that we're taking, it's important to also note that first 25 patients of 25 safety evaluable patients in that first dataset in May, and we had not implemented up to that data cut any significant prophylactic measures to try to mitigate and decrease the incidence of Grade 3 diarrhea. In April this year, around the time that we decided to expand these three doses in the study, we did update our AE management plan. Mm-hmm ... to include, for example, prophylactic loperamide, the antimotility agent, which is, you know, a well-understood treatment for diarrhea, and that's something that is being utilized by our investigators in the context of the expansion phase. You know, certainly more to learn about this, the overall integrated AE profile. In terms of that Grade 5 event, it was a complicated situation. You know, we learned of that event, you know, some time ago. It was an event that was secondary, we believe, to GI toxicities, specifically nausea, vomiting, and diarrhea. It was an unusual clinical case. The patient, as we subsequently learned, had donated a kidney to a sibling some time ago, decades ago. Met all the enrollment criteria to come onto the study in terms of renal function, but as the patient experienced GI toxicities, you know, the patient deteriorated and unfortunately didn't make it, for a whole host of other complicated reasons relating to that patient's medical history, so you know, we did report that, of course, to FDA, and we decided to communicate press release that event because of this somewhat new phenomenon that we're all dealing with in our companies, which is how to manage inbound interest and requests from patient blogging. So we're seeing a lot more activity, I would say over the last couple of years, running clinical studies, seeing patients, sharing information, which of course they want to do, and is their right with each other as they're on clinical studies. And I'd say that it feels like investors are paying a bit more attention to this information. Yeah ... these days, than perhaps they did, and there's more information making its way to the public domain, and we saw some very specific posting relating to this adverse event, some of which was accurate, a lot of which was not, and we received a significant number of inbounds from our investors, and we decided pretty quickly, actually, to just communicate and set the record straight in terms of what we did know, what had happened with that patient, and also what was inaccurate. For example, that there was an investigation with FDA or that the study was on hold, and so on and so forth. So we felt it was better to get out in front of that, and I'd say that, you know, our conversations with investors in the ensuing days and since then have been very constructive, and I think people are appreciative of how we effectively managed a, you know, a complicated situation. Yeah. I mean, we always appreciate the transparency, so thank you for that and for staying in front of it. You mentioned, you know, dialogue with the FDA or that you all disclosed it to the FDA, and I know there was a safety review committee that was also involved. What's been the feedback from both of those entities? I mean, obviously, your trial is continuing as planned, so- Yeah I guess what I'm trying to ask, right, is one, what's been the feedback? And two, why shouldn't investors be concerned about this event going forward? Several reasons. I first of all, although this was a Grade 5, very unfortunate event, the actual clinical case is not overall inconsistent with what we've seen previously with twenty fifty-one, right? This patient was particularly unique, but the patient experienced GI toxicities that we've seen and reported previously, even in our first update in May this year. You know, as we met with our SRC, which is comprised of our clinical investigators, very quickly after learning of that event, you know, their view was, yeah, this is something that looks like an outlier case, not inconsistent with the overall AE profile that we're seeing for twenty fifty-one, and the study should absolutely continue. And that decision was made very, very quickly. In terms of FDA, obviously can't comment on any, you know, specific dialogue with FDA, but we fulfilled our obligation in terms of reporting in a timely manner, and that was, gosh, more than six weeks ago, and the study continues, and everything remains on track. We are, as I said earlier, we're fully enrolled with the expansion phase. We can certainly enroll additional patients as and when we need to or decide to. The study is open and ongoing, and I think that we again. I think we've very effectively navigated that situation. The event in and of itself was not something that we needed to disclose. These things happen in clinical trials. These things particularly happen in late-stage studies, such as this patient population that we're studying, a fifth line, fourth, fifth line, or even later, CRC. But again, we decided to be transparent just to stay ahead of it. So that's kind of our assessment. Have you guys disclosed whether the patient was in a dose escalation group or which dose the patient was in? This was an escalation patient, I mean, an expansion patient, rather- Expansion ... but we haven't shared those. Okay, okay. And then how does this change how you're thinking about, like, eligibility or enrollment criteria going forward? Or are there any tweaks that you can make just to try to mitigate for any one-off, you know, events? It really hasn't, really hasn't changed very much at all. You know, this patient was eligible for the study in terms of renal function at the time, entry to the study, and the time of screening, and you know, obviously, we will be paying even closer attention to whether or not patients have you know, donated kidneys. It's so not something that you see very, very typically, so again, this looks to us like an outlier case, but no, we're confident about our enrollment criteria. We think that we're doing all the right things there. Okay, great. Can you-- You can hear us both now? Okay, great. So let's fast forward. You've got data coming in 1Q. Right. Maybe just set the stage. How many patients? You know, what should we be looking for? I assume ORR, probably an update on DCR, safety. What else can we expect to learn? Yeah, so it should be a pretty robust update across those three dose levels. So again, we've enrolled across those three dose levels. We've expanded to about 20 patients in each dose level, and the update in Q1 will be, of course, an update on the activity that we're seeing. I do anticipate that we'll have pretty significant follow-up on the majority of patients, which obviously is important. So we should have a pretty good look at how PFS is shaping up across those three doses. And of course, where the AE profile is at that point, the impact of prophylactic measures, as well. But most importantly, of course, the work that we're doing in the expansion phase is principally designed to pick our dose or doses for the next study, and it would be great. Maybe we should talk a little bit about where we're going next- Yeah ... in terms of, you know, what do the next studies for twenty fifty-one look like as we move into twenty twenty-six? Yeah. Are there higher doses that you plan to study? We have evaluated two additional dose levels in the study, in the dose escalation. We reported in the May disclosure, you know, we had the view that those upper dose levels, dose levels six and seven, were getting into the territory of maximum administered dose. We're not currently expanding at those dose levels. You, of course, want to get there in a dose escalation to get a sense of what the upper bound is, but we think we've got what we need at the three dose levels of 7.2, 8.6, and 10, where there's a lot of room to maneuver, we think, in terms of the activity that we've seen for the drug, not just in terms of ORR, but also in terms of disease control rate and also PFS. So what do your next steps look like at this point? I mean, I assume there'll be some engagement with FDA around what a regulatory path forward looks like or a registrational study. Yeah. What are you guys thinking about just in terms of trial design, potential dose moving forward? I mean, I guess we'll wait to see what the first quarter update looks like. But what can you tell us at this stage? Yeah. So obviously, we'll be data-driven based on what we see in this next data set, but we're, I mean, our main goal as a company right now is to get this drug into the next stage of development and push it to registration as quickly as we possibly can. And given the scope of the unmet need in the late-line CRC setting, we've got, we believe, a very competitive drug candidate here. So, yeah, we haven't locked in to any specific design yet in that next study, but, one example would be to go into the fourth line, compare to current standard of care. Maybe, you know, one specific component of standard of care, like, for example, Regorafenib, which is approved in the fourth line, which, as I've already mentioned, has a overall response rate of 1-2% and median PFS of 2-3 months. So we think that twenty fifty-one would be very competitive in that setting, and that's a study that, again, depending upon what we see, the expansions could be run with one dose. Maybe we're still evaluating two doses in phase 2, depending upon how quickly we get there, and that's a study that we think could be designed with potential registrational intent. We're also keeping a close eye on the third line setting as well. So in the third line, of course, Bev/Lonsurf has become standard of care. You know, low single-digit response rate, five-ish months of PFS. Our understanding is that in the actual real-world setting, it's not performing quite as well as indicated by those numbers. And so, you know, we'll be evaluating our data very carefully over the next few months to figure out whether we see an opportunity for monotherapy in the third line- Mm-hmm ... as well. And then, of course, as we move into 2026, another key objective will be to start combination studies, and the most obvious combination to start is bev- Sure ... to bring, to allow us to bring twenty fifty-one into earlier lines of therapy, including, but not limited to, the third line. So you would consider doing, you know, for a potential third-line study, would you do a monotherapy arm and a combo arm with bev? Or is the bev combo really more of a second line and moving further upstream? I think it's gonna be, yeah, very, very, very data-driven, right? In terms of what we see, particularly in terms of what we see with PFS. So I think everything is still on the table, for sure. And then, as you think about endpoints, what's your expectation there around ORR versus PFS versus, you know, maybe not overall survival, but curious to hear your thoughts? Yeah. I think we need to be a little cautious there in the CRC setting. So of course, you know, there's little precedent in the colorectal, in late-stage metastatic colorectal for ORR-driven endpoints for accelerated approval. It's not unprecedented. It has been seen with certain targeted therapies, but that's not an expectation that we're setting just yet. It's more likely that an approval endpoint in a potential accelerated approval would be PFS driven, potentially with an early look at OS. But you know, in this setting, the disease moves so quickly and PFS is so short for current standard of care, that's a study that could be executed very rapidly. So we don't think that's an impediment to getting the drug, you know, to a potential registration very, very quickly. Obviously, we're gonna be data-driven and depend upon our dialogue with FDA, at the appropriate time. Sure. And then, so let's assume you move forward with a randomized control fourth line study. Anything you can tell us at this point around how you're thinking about... You know, I assume there'll be a superiority analysis. Anything you can tell us about statistical design, or is it too early? Not just yet, but I think, again, given the space between standard of care and what we think the performance of twenty fifty-one could be, we do think that the study, these next studies, would not need to be too large. and then as you think about the unmet need in fourth line, maybe just frame the revenue opportunity there. Yeah. I mean, patient numbers, how big of a market realistically could fourth line be? Yeah. Where do you think it would slot in? I mean, is it as simple as it would become the new standard of care, fourth line therapy, or, you know, does it get a little bit more nuanced than that as you consider orals and other things like that in the space? Yeah. So the fourth line opportunity is significant. In the US alone, we're looking at about 12,000 patients on an annual basis. In the third line, 30,000-plus patients. And so you know, it's not hard to get to a multi-billion-dollar drug here, even in the late line setting, so in the US alone. So we really think the opportunity with twenty fifty-one is huge. Of course, thinking about then modeling in earlier lines, coming into second line, and then outside of CRC in other tumor types. Right now, we're pretty focused in colorectal because we see that as a massive opportunity, but we are highly interested in moving into other tumor types. To facilitate that, we, of course, are mindful that a partner for the drug could be helpful at the right time. That's... You know, we've always said with our robust deal making over the years, it's all about doing the right deal at the right time, but it's not lost on us that a partnership on twenty fifty-one could make sense, and it probably won't surprise you to hear that there's been robust interest in our data from you know, from external parties over the last few months. Would a potential partnership be something where you would maintain, you know, control in the US, but commercialize it ex-US with a partner? Or at that point, would it become, you know, there would maybe be an opt-in period where a partner could move that into a registrational study? I mean, I know it's a little bit early to comment on without actually having any agreements in place, but what would be an ideal partnership for you all as you think about this program? Our corporate and strategic goal continues to be to build CytomX to a commercial stage company, and twenty fifty-one, we believe, gives us an incredible opportunity to do that. Any partnership that we explore will be structured in the context of our commercial ambitions. Okay, understood. And then maybe remind us on, just on capital allocation and cash runway. Yeah. Ended Q2 with $158 million on the balance sheet, so strong, strong cash position, and that provides runway into Q2 of 2027. So, you know, in a great place, having financed on the heels of the really exciting twenty fifty-one data earlier in the year. We continue to be active in business development. Probably won't surprise you that based on the really, you know, clear proof of concept for the technology platform that we've now demonstrated, in our view with twenty fifty-one, we're now, you know, active in BD again- Mm-hmm ... and a lot of interest in the CytomX ProBody therapeutic platform. And so, you know, potential, as there always has been, for non-dilutive capital over the course of that runway. So, we feel like the company's in a very strong place from a financial perspective. You have talked about the potential for your Probody technology and other modalities right outside of ADC. Yeah. So maybe just talk about, you know, are there modalities at this point that you all have identified or that you feel like maybe have a higher probability of success with your technology platform? We continue to be really interested in T-cell engagers. We're doing a lot of work with our partners, with Regeneron, with Astellas, as two examples, and the field has made some progress in terms of masking, you know, that overall modality. It's a more complex modality, I would say, than ADCs. The field is probably ten years less advanced than antibody-drug conjugates, but nonetheless, we've made significant progress. We demonstrated with our EGFR CD3 CX-904 program that masking on CD3 can substantially reduce cytokine release syndrome, masking on EGFR substantially reduced EGFR toxicities, and you know, so we're optimistic about T-cell engagers, and then in maybe our last minute, I can just give a quick summary of where we are with our other clinical program. Please ... which is our masked version of interferon alpha, the cytokine interferon alpha. So we're in the clinic with CX-801, a dually masked interferon alpha-2b. We're running a very focused clinical study in metastatic melanoma, looking for initial proof of concept, in combination with Keytruda. We do anticipate having initial biomarker data by the end of this year, looking at the molecular performance of eight oh one in melanoma patients, and our guidance is clinical data for the combination in twenty twenty-six. So, another exciting program. So we think ADCs, T-cell engagers and cytokines continue to be important applications of masking, and I think you'll continue to see us active in all of those areas, whether it's with our own internal proprietary programs or in our partnerships. That biomarker data, is that an internal readout, or will you all be presenting that at some medical congress by the end of the year or sometime next year? Yeah, to be determined, but certainly by the end of the year. Okay. Yeah. Okay, great. Well, clearly a lot going on. We're looking forward to all the updates. A lot going on, yeah. Well, thanks for the time. Thanks, Sean. Congratulations. Thank you very much.