conference. My name is Roger Song, senior analyst cover small-cap biotech. It is my great pleasure to have the fireside chat with our next company, CytomX, and then we have our CEO, Sean McCarthy, with me. Sean, welcome. Thanks, Roger. Pleasure to be here. Thanks for having us. Excellent. Maybe Sean, give us a couple of minutes, a high-level state of our CytomX. You already give us a lot of exciting news. We're looking forward to more this year. Yeah. Once again, thanks for having us. It's a really exciting time for the company. Just to recap, CytomX is based on the concept of masking therapeutic antibodies and related biologics. This is a platform we call the Probody therapeutic platform. We've been leading this field for quite some time now, and I like to refer to CytomX as the original masking company. We've made a ton of progress over many years, but most recently we have advanced into the clinic our lead program, Varseta-M, formerly known as CX-2051, that we're developing initially in colorectal cancer. This is an anti-EpCAM antibody drug conjugate that we have uniquely enabled with our core technology, with our masking strategy, and we've just been so excited by what we've seen so far in the clinic. This is clearly a very active drug in late-line CRC and a drug that has potential, we believe, in many other tumor types because EpCAM, as I'm sure we'll discuss in a moment, is expressed in most solid tumors and actually has pan-tumor potential. I'm sure we'll discuss Varseta-M in a lot more detail. I wanted just to come back to the platform for a moment and discuss an announcement that we made yesterday, which shows that the Probody platform continues to deliver. We announced a major expansion of our collaboration with Regeneron in the field of immunotherapy bispecifics. This is a collaboration that we initially entered into in 2022. We've made terrific progress with Regeneron in research and early drug development. We've now expanded the deal to additional targets. That included the selection by Regeneron of two additional targets in the collaboration for which they're paying us an upfront amount of $37 million. That actually takes the total that we've raised over the last year in equity-based capital and non-dilutive to almost $400 million. We are continuing to finance the company in a very effective way to advance our pipeline, and in particular, move Vazetza-M towards its first registrational trial, which we plan to launch in the first half of 2027. Really exciting time for us. The company has never been in a stronger position and really looking forward to this discussion today. Excellent. All right. Before we talk about Varseta-M in details, for this is Regeneron. People look at the CytomX, obviously, you've been around for many, many years, and then you're the leader or pioneer for the masking technology, ADC, et cetera. How you think of this new expansion of the agreement with Regeneron really is about further validating the platform and how much economics associated with that? Give us a little bit more. Well, the economics of the deal have essentially been doubled. We now are eligible for up to $4 billion in integrated R&D funding, research, development, and commercial milestones. It is a major expansion of the deal. It encompasses now about 10 targets overall. Regeneron has the ability to come back for an additional six targets over the relatively near term and will need to pay additional upfront target access fees for those targets. This is just economically a deal that just continues to strengthen our financial position over the next few years. In terms of the science, they clearly are a high science company and a company that is very active in this space of oncology. Really, as we announced yesterday in our press release, they see the combination of our masking strategy with some of their bispecific strategies as really uniquely enabling a new wave of bispecific concepts, Where we're looking to improve the therapeutic window of bispecific strategies by localizing the activity of these drugs into the tumor microenvironment. That really is the core of our technology. We use the protease microenvironment of the tumor to activate the drugs by unmasking them specifically and selectively in tumor tissue. I think it's fair to say that the combination of terrific progress that we've made in the collaboration to date, together with the validation that we now have, and I really do think it's an unequivocal validation of the platform with the EpCAM work that we've done with Varseta-M, that has encouraged them to substantially expand our work together, and really, we couldn't be more excited about working with Regeneron now for the next several years. Excellent. All right. Let's zoom in for the Varseta-M because that's probably the current key value driver for CytomX, at least from the stock perspective. Maybe can you just recap at a very high level what you have seen and what you reported for the expansion cohort a couple of months ago? Because I've been having a lot of discussion with the investors that we can talk about the details. Maybe people are missing something there. Because you try to give us the picture of the activity and then improve the tolerability, and also you guiding us, you will give us an even fuller picture, the profile before you move into the pivotal. Maybe give me the high level, your take, and then we can discuss in detail. Yeah, absolutely. We've made terrific progress with Varseta-M over the last couple of years. We've been in the clinic now for about two years, we're still relatively early in our development of the drug. Over the course of that phase I work that we've done, we've been able to show really remarkable clinical activity in late-line colorectal. The drug was designed intentionally to be active in colorectal cancer. EpCAM, epithelial cell adhesion molecule, is a very abundant CRC antigen. It's been known about for a long time. Many have tried to drug EpCAM. It is, if you like, a classic undruggable target until CytomX came along, in that it's present on not just CRC and other tumors at very high levels, but it's also present in normal tissues. Other sponsors and companies have had real difficulty in drugging EpCAM over the years because of toxicity in normal tissues, and most specifically in early drug development programs, the observation of acute pancreatitis, which was a roadblock to initial development. We made a masked anti-EpCAM antibody with a topoisomerase I payload on it. The reason for the topo I inhibitor payload is, again, a very intentional selection because we know that CRC responds to topo I inhibition, specifically irinotecan. Our strategy is to use masking to localize the anti-EpCAM ADC into tumor tissue, and we entered the clinic with a dose escalation. We dose escalated from 2.4 mg/ kg up to 12 mg/ kg, and we reported last May, the first look May of 2025, the first look at efficacy with very impressive activity across the dose range, significant confirmed overall response rates of above 30%, and a well-tolerated profile showing for the first time that we had opened a therapeutic window for EpCAM in CRC. More recently, in March, we presented an update on our data from the expansion phase of the program, where we had expanded three dose levels, 7.2, 8.6, and 10 mg/ kg. We enrolled 20 patients at each of those doses. We reported updated safety and efficacy, showing a response rate of 20%-32%. Just to put that in context, this is in patients who are fourth line or later. In fact, more than half of the patients treated in the study to that point had been actually fifth line or later, so very late-stage patient population, where current standard of care in that setting has response rates of around 1%-2%. We have made a substantial step forward in our ability to treat this disease. We also reported a median progression-free survival of seven months, which compares in that setting to progression-free survival of about two to three months. Again, a major step forward and a tolerability profile with some absolutely remarkable features. No evidence of EpCAM toxicities, very low incidence of hematologic toxicities, no interstitial lung disease, and really only one adverse event of note that we're learning more about, which is some level of GI toxicity, specifically Grade 3 diarrhea in about 20% of patients as of our first update last year, which we've now been able to reduce to 10% using a prophylaxis strategy of pre-treating patients with certain prophylactic agents that we can talk about, having reduced that Grade 3 rate of diarrhea to 10%. Very clearly, a big success in the early development program, and now we're working towards our third presentation on the phase I, which will come by the end of the year. That will be an update across the full 113-patient phase I, which is where enrollment is now reached, including data on a 40-patient dose optimization cohort, Where we've enrolled 20 patients each at the two doses that we're now focused on, which is 8.6 and 10 mg/kg administered every three weeks. We're using adjusted ideal body weight dosing to smooth some of the outliers in dosing, particularly in patients who are on the heavy side. We're also requiring upfront prophylaxis in every patient of loperamide and budesonide to manage the incidence of high-grade diarrhea. We're very optimistic that by the end of this year, we'll have sufficient data, and we'll have had discussions with FDA to be picking our dose and being able to share what our registrational strategy is in the late line. All right. That's a very good level set. Probably, I think people are a little bit confused by the efficacy you see from the expansion cohort and then also the tolerability side, and you just referred 10% Grade 3 diarrhea is coming from those optimization cohort. How should we reconcile that? Looking at the expansion cohort, the Grade 3 diarrhea is still relatively high, although you led them to do the loperamide prophylactic. That seems a lot of the patient or physician didn't use that. That's maybe the reason Grade 3 diarrhea is not necessarily lower. Later with the dose optimization, you mandated this dual prophylactic, and then very clearly, right? The Grade 3 diarrhea is dramatically improved. Let's take a few minutes to walk through the chronology here and, if you like, the natural history of this phase I program. As I mentioned, we began dose escalation, actually, at a pretty good starting dose, 2.4 MPK escalated to 12 MPK. That escalation went very quickly. We experienced no dose-limiting toxicities in the course of escalation. Very quickly realized that we have a very active drug on our hands and began to learn about the AE profile, which, of course, is the principal goal of a phase I dose escalation. It became very clear from that early escalation phase that the data was sufficiently clear to allow us to select three doses to expand in the course of 2025. Those doses were 7.2, 8.6, and 10 mgs/ kg administered every three weeks. Enthusiasm from the sites for the drug was so great that those expansions enrolled extremely quickly. We had been starting to observe, again, that the adverse event profile for this drug with no DLTs was really very attractive with this one observation of some GI toxicity that we were beginning to learn about during the expansions. We did provide some guidance to the sites during the expansion phase to begin using prophylactic loperamide where indicated, and that was used in some settings, and it did teach us certain things. It wasn't extensively used. The expansion phase really was a place where we learned even more about the intrinsic efficacy of the drug, and we learned a bit less about how to manage the toxicities. We did learn more about what the principal toxicities are, which again, are GI. We got some really important clues, though, also in the expansion phase from the clinical management of patients experiencing high-grade diarrhea, that not only was loperamide effective in certain patients, but really interestingly, the administration of the non-absorbable steroid budesonide was very quickly learned to be highly effective in the management of diarrhea induced by Varseta-M. Specifically, we've reported this before, of 14 patients who were treated with budesonide in the expansion phase, 12 of those 14 patients experienced at least a 1-grade improvement in their diarrhea, which began to give us clues as to how to manage this particular adverse event. Taken together, the data from the expansion phase showed us, confirmed that all three of those doses are highly active, that the combination of loperamide and budesonide could be effective in the management of the one AE that were of interest to us, which is Grade 3 diarrhea. That led us then to, together with, quite frankly, strong demand from the clinical sites, it led us to further increase enrollment in Q4 of last year into these optimization cohorts. Where we're now doing a very defined experiment in these 40 patients, taking the clues from the expansion phase to look at the ability of upfront prophylaxis to prevent patients from advancing into Grade 3 diarrhea, whilst maximizing the clinical benefit. As I mentioned early on, the update we gave in mid-March, together with the maintained dose-dependent tumor reduction and efficacy that we see with this drug in terms of ORR of 20%-32% and PFS of seven months, we've been able to manage that rate of Grade 3 diarrhea within the first couple of months to 10%. In terms of our goal for managing toxicity, all the work that we've done by talking to KOLs and doing our own calls would suggest that a rate of Grade 3 of 10%-20% is perfectly manageable in the context of the benefit that this drug brings to patients. Our treating physicians are observing that they've really got nothing else like it. This is a remarkable step forward in the treatment of late-line colorectal. We're absolutely on track now. Quite honestly, I don't think there should be any confusion at all out there in terms of what we've achieved and what we're doing and where we're headed with the drug. Our goal is to report more complete data from the phase I study, including the optimization cohorts, by the end of the year, and integrate all of that data into the design of our first registrational study to be launched in the first half of 2027. Awesome. That's very helpful context. The one thing is I keep hearing from the investor is the diarrhea profile. By the way, we don't want to lose the big picture because EpCAM is an undruggable target, at least systemically, and then you're not seeing any other EpCAM-mediated tox, only the diarrhea. We don't know if it's EpCAM-mediated or it's maybe also TPO-related. In terms of this diarrhea profile, how should we think about FU? The ultimate goal is to move Varseta-M to earlier line, right? Earlier line to potentially replace, Right. Irinotecan. How should we think about the combinability into the earlier line? What have you been hearing? What's the diarrhea profile will be suitable for the earlier line? Well, the first thing I'd say there, Roger, is that there is a lot of focus on this particular GI toxicity, but one of the reasons there's so much focus on it is because the only significant toxicity that we see. I want to just talk for a moment about some of the competitor ADCs being developed in colorectal, then I'll come directly to your question on combination strategies where we've already begun work. It's a really exciting time in colorectal cancer. Over such a long period of time, there's been such little innovation, but we can say, I think, very clearly that antibody-drug conjugates are coming to colorectal. With CytomX, not only do we have the first-in-class anti-EpCAM ADC, this is the only anti-EpCAM ADC in development in CRC or any tumor type, but we also believe we likely have the best-in-class ADC for colorectal. Why do I say that? There are two other drugs being developed. They're a little bit ahead of us in CRC. One is ABBV-400, the c-Met ADC with a Topoisomerase I payload. The other is M9140 from Merck Serono. They're both now moving into phase III or in phase III studies in colorectal. The overall profiles of these drugs are really quite different to our drug. We think our drug has highly competitive activity. In fact, it may be the most active of the three. The safety profile, one thing that's quite remarkable about our drug is the very low rate of hematologic toxicity. The other two ADCs are seeing significant rates of Grade 3 and above anemia, neutropenia, thrombocytopenia, and I think that is a problem for potential combination strategies in the future. That's something to watch. In our case, we have one toxicity to be aware of is GI. We've already shown that we can reduce the rate very substantially by using this prophylactic strategy, and our ongoing work is aimed at evaluating a number of combinations to move the drug into earlier lines of therapy. First of all, combination with bevacizumab, that work began several months ago. We'll have our first data for the combination in the first half of 2027, and that will be a foundational combination for moving into earlier lines, into third line and even further up front. Bevacizumab is now ingrained across multiple lines of treatment of colorectal cancer. We'll be starting in the second half of the year, chemotherapy combinations, and that is a first step towards realizing our ultimate vision for Varseta-M, which is to replace irinotecan in the second line. Irinotecan is, of course, an embedded component of FOLFIRI. It's a Topoisomerase I inhibitor. That's what motivated us to make this drug in the first place. Remember that irinotecan itself, when it was first developed, has a high rate of high-grade diarrhea. We're simply planning to switch out irinotecan for Varseta-M, and as we continue to understand the safety profile of our drug, we're very optimistic that that will be a very effective combination. Just back to the bevacizumab combination for a moment. We do not anticipate any overlapping toxicities there. The toxicities of bev are typically cardiovascular in nature, changes in blood pressure. There are very low incidents of gastrointestinal perforations. That's a very different toxicity to what we've been seeing. We're very optimistic that the combinability with Varseta-M will be very effective. We're doing all the right things in developing this drug. It's still a phase I drug, and our combination strategy is very intentional to move the drug into earlier lines. This point about we're not combining with irinotecan in the second line. We're replacing it with a drug that we think is far superior as an ADC with a Topoisomerase I warhead. Yeah. Got it. Okay. Just last point really to tolerability. You're using the budesonide as a dual with the loperamide. How you think that in real-world adoption for that regimen and then why in the expansion cohort you don't have many people using loperamide, rather they use the budesonide? The prophylactic regimen is very straightforward. It's upfront loperamide, which is a drug that's very familiar to CRC patients that they will all have experienced before in their treatment histories. The budesonide is also a very straightforward drug to take. It's a daily oral medication, and the prophylaxis is administered for the first week of every cycle on the drug. What we're hearing is that compliance with this prophylactic strategy is very high. Again, I want to come back to maybe a bit of a misconception about the expansion phase where because the study enrolled so quickly and because we gave investigators quite a bit of discretion in terms of how to use loperamide only in that setting as prophylaxis, we just didn't do the experiment. We are now doing the right experiment in the optimization phase of requiring that patients get loperamide and budesonide up front. We don't anticipate any challenges with translating that regimen into the community setting. Again, it's a very straightforward, very well-precedented schedule for loperamide. Budesonide is an easy drug to take. We hear from patients that they feel benefit, and it's because they feel that benefit, and it's a very easy medication to take that they're highly compliant. We really don't see any significant challenges in that regard as we move into the registrational study. Of course, this is why we're doing this upfront work right now in the context of the phase I to really optimize the dose, optimize the prophylactic strategy, optimize the AE management plan to maximize our success in this first registrational strategy and trial to begin next year. Got it. You mentioned the 14 patients on the budesonide, and then 13 on the one, at least a 1-grade improvement. That's only with the budesonide, not with the loperamide. That's right. It was easier to quantify. The quantification of the loperamide experience in the expansion phase is a little bit more challenging, so we don't have quite such hard numbers on it. There's quite a bit of anecdotal evidence, and as you would expect, loperamide does offer benefit in a number of settings for a number of patients. The budesonide treatment is something that we've been able to more readily quantify. I think that's really important because it tells us that it actually is one of those really critical and important clinical observations in terms of the early management of these patients that we've been able to translate now into a go-forward strategy for the management of patients on Varseta-M. Got it. Two more quick questions, maybe we can move on to the next step, is the dose optimization cohort. You give us a two-month follow-up for the tolerability side, and which is you refer to 10% Grade 3 diarrhea, which is a very good number. We preview this at in 10% across the entire CRC and renal cell TKI is very good. How should we think about beyond two months? That's number one. Number two is people asking, okay, understand two months is too short follow-up for efficacy, but at least qualitatively can you comment on the activity side? Do we see difference compared to the expansion? Seven months PFS for the 5th+ line, that's impressive. Well, as you wrote yourself this morning in a report that you put out coming out of ASCO, the thesis for Varseta-M is, let's just say strongly intact coming out of ASCO. We saw nothing at ASCO in this space other than confirmation of the dearth of opportunities for patients in the late line setting and reaffirming just how remarkable our anti-tumor activity is in this fourth/fifth-line patient population. This is a highly active drug. It's acting exactly as we designed it. It's been very intentionally designed to be active in late-line CRC. We are just so excited to move this drug forward into late-line development. I guess I would say there is, of course, quite a lot of debate around Varseta-M out there in the investment community. We've had really terrific conversations all day today with investors about the drug and where it's headed. Debate is good. Debate shows there's a lot of. It just did, yep. There's a lot of interest. Yep. There's off-the-charts interest in the work that we're doing. Everyone's trying to look around corners as to where is this program going, and we totally understand that from an investment perspective. The question around the two-month follow-up of the safety that we shared in March, I do want to address that directly. First of all, the two-month follow-up on safety is a very meaningful number because we know that median time to onset of Grade 3 diarrhea in the study up to that point is 4.8 weeks. Over two months, we would predict that we have seen about 80% of the Grade 3 events that would have occurred. We did a time-match comparison. It was a very carefully thought out apples-to-apples comparison of what we'd seen in the first 20 patients in the optimization cohorts, compared to a time-matched analysis of patients in escalation and expansion, where we saw about a 30% incidence of Grade 3 diarrhea in the absence of significant prophylaxis. 30% comparing to 10% over a two-month period. It's a very meaningful data set, but it's an early look, but we would anticipate that over time, of course, we're going to follow those patients up, and the next update will be across 40 patients followed for several months. It will be an even more meaningful update. Regarding efficacy, we've been very consistent, really going back to last August when we announced that we had completed enrollment, our initial enrollment goal. We have met our original enrollment goal of 20 patients at those three expanded dose levels, because enrollment went really fast last summer. We suddenly had all these patients enrolled. Of course, we began to get questions, "Well, when are you going to show us the efficacy from the expansion cohorts?" Our answer was, we will share efficacy when we have PFS at each of the dose levels, because we believe that will be most important, most helpful to investors. It will be the most meaningful data to really build on the impressive first look at efficacy that we shared last May, which was principally about ORR. We're very consistent on our messaging, and I think everybody appreciated that. When we did share efficacy, we were able to share PFS, including PFS at the doses of 8.6 and 10 mg/kg of 6.8 in seven months. Very impressive, very meaningful numbers that basically blow out the standard of care by a long way. To answer the question about sharing efficacy data from two months of follow-up in an optimization phase, it's way too early. We know that it takes the median time to response for Varseta-M is three months. It takes a couple of scans. In some cases, it takes three scans, very typical for an ADC. We will share efficacy data when the data is mature. We'll share efficacy data from the full 40 patients, and that's what we believe will be most helpful to investors. We'd like everyone just to be a little bit patient with us. We'll continue to do what we're doing, which is develop this drug, and the next time we come forward with an update, it will be not just data in terms of follow-up on escalation, expansion, and optimization. We'll have an OS number for the first time from the escalation and expansion phase. We'll have efficacy from the optimization cohorts, and of course, we'll have a lot more follow-up on the role that prophylaxis is playing in managing the one toxicity that we have to be thinking about, which is GI toxicity. All of that data will be integrated into what we plan at that time, which is to announce what our go-forward phase registrational strategy is going to be, reading out the several interactions that I anticipate we'll be having with the regulatory authorities as the year goes by. We're on track. We're very confident in what we're doing. We're developing this really exciting drug for these patients that need it so badly, and we look forward to keeping the investment community fully updated as the year goes on. Excellent. I think this second half, this update is going to have a long year. The update will be extremely meaningful. You give us everything, all the data, even OS, and then also the tolerability, and then the regulatory next step into the pivotal. Right now, the base case is going to be later line, and then as a control study. What's the base case for the registrational pass? Yeah. There are a few ways we can go and a few options that we have that we're continuing to really intensively pressure test in terms of what that first registrational study could look like. One option is, of course, to go into the late line, fourth line, compared to standard of care, something like fruquintinib or regorafenib, or maybe the two of them, or physician's choice. Our data so far beats those benchmarks by such a long way. I can't overemphasize that study would have a very high chance of technical success. That's one way to go. Of course, the fourth-line market is smaller than third line. We're interested in potentially going into the third line for our registrational study. The fourth line study could be executed faster. It clearly would be the fastest-to-market strategy. Third-line options are also very much on the table. Monotherapy against padeliporfin is a trial design that we continue to look at and/or combining with bevacizumab against padeliporfin. That study would take a little bit longer to initiate because it's only recently that we began to combine with Bev, but that work is ongoing. These are all terrific options for developing the drug in the late line. Of course, in parallel, we're beginning that combination work with chemo to begin to jump into the second line as quickly as we can. The tiers of value creation for this drug at our company right now. They should be very clear to everybody. We're well-financed to work our way through them, like I said, having raised $400 million of capital over the last 12 months. We look forward to continued, and I'm sure, robust dialogue with investors over the coming months. Excellent. Thank you so much, Sean. I think it's a great dialogue, and we learn a lot, a couple of things, and thank you so much. Thank you, everyone. Thanks.