this next fireside chat. My name is Michael Schmidt, Senior Biotech Analyst with Guggenheim, and it's my great pleasure to welcome Chris Ogden, Chief Financial Officer of CytomX. So CytomX is a new coverage here, new research coverage at Guggenheim for us. It's a story we're really excited about, especially the lead program. But Chris, just to set the stage, I think many of us are familiar with CytomX to some degree, given the company's been around for a while, but just remind us of where the company is today in its life cycle and what the key biodrivers are. Yeah, and just before we start, thank you, Michael, and the Guggenheim team for having us at the conference. Excited to work with you and the team. Just a reminder, I will be making forward-looking statements, so I would refer you to our SEC filings. So yeah, CytomX has been around for some time, and we really invented the field of masked biologics. We've been working on this technology for more than 15 years, and we've really, you know, pioneered most of the firsts in this space. For those that aren't familiar, the idea is basically that you can put a mask on an antibody or a biologic format, and basically preferentially get binding and activation in tumor cells because of a dysregulated protease microenvironment that clips the masks, allows the drug to bind, drive potent activity, but the mask to stay on in healthy tissue in circulation. So that's really the idea behind the company. We've pioneered, you know, a multitude of formats over time. This can apply to antibody drug conjugates, T-cell engagers, we have a cytokine program. And really, the focus of the company today is on two clinical programs. We'll spend most of the time talking about the lead clinical program, a masked EpCAM ADC. Really, both of our clinical programs are the most focused application of our technology we ever have had in terms of the product concept and how we think about, you know, what's the right masking strategy, what's the right format for the clinical problem we're trying to solve? So what we'll talk about in terms of today, I'd expect is that application with our clinical pipeline. Great. Maybe then just jumping right into Varseta-M, which is your EpCAM ADC, as you mentioned. Yeah, maybe just about the target first, you know, what makes EpCAM a compelling target to address with an ADC, or more specifically, with a masked ADC? Yeah. So EpCAM, epithelial cell adhesion molecule, is a target that's been known about for some time. It's one of the broadest solid tumor targets that's been known for a number of years. It's expressed at high levels in most solid tumors, and was initially discovered as a CRC antigen because it's so highly expressed in colorectal cancer. So that's really where it was first discovered. Previous attempts to drug EpCAM, because it has been of high interest, have run into toxicities, so it's not been able to be drugged systemically. Prior high-affinity EpCAM antibodies ran into pancreatitis and liver tox at relatively low doses, and so that's limited the development. So the first thing is, it's a very attractive target from how abundant it is, but has had some dose-limiting toxicities, which is where masking comes in. We think the, the masking, and we'll talk about the clinical results later in the discussion, but we, we believe the masking can help open a therapeutic window. Now, why, why an ADC? It's something we, we gave a lot of thought, both in terms of format and the, the payload, the actual effector to kill the cancer. You know, first, ADCs, it's well established, that they're, you know, highly validated formats, so we think that that field is, you know, more de-risked. We chose to put a topo-1 payload on this ADC, in large part because irinotecan, which is a topo-1 inhibitor, is standard of care, big part of standard of care in multiple lines of CRC. And so, you know, the combination of this being a highly expressed CRC antigen that's been limited by toxicity, which masking, we think, can address, with an effector function that's truly de-risked in CRC and we know can help kill tumors, we really think was the right combination of, you know, leveraging our technology to, you know, do a very initially focused CRC development, and then, you know, beyond that, potentially other EpCAM expressing tumors. May you just remind us which tumor types rank highest on your list beyond CRC in terms of target expression and opportunity? Yeah. Well, there are a number of them. We have not, you know, specifically said which tumors we may go after next. We're giving that a lot of thought, but just as, you know, an example, it's expressed in most solid tumors, so gastric, pancreatic. It's also very high in tumors such as prostate cancer, triple-negative breast, lung cancer. So it's a plethora of opportunities. You know, as we. You know, our top priority is to progress this ADC in colorectal cancer, but as we, you know, learn about, you know, the path ahead there, we will start to give thought to other tumor types and would expect. to at least start focus work in some indications, in the second half of this year to really, you know, broad out the pan-tumor vision of Varseta-M. Right. You reported some very exciting early phase I data last year on Varseta-M in colorectal cancer. Just remind us of the key takeaways from that early data set and how it informed sort of the part two, the bigger expansion cohort of this study. Yeah, yeah, great question. So first, before diving into the data, maybe just, you know, some contextual comments on colorectal cancer. So just, just to remind everyone, 1.9 million cases globally. Second leading cause of cancer death, globally, and in the metastatic setting, a five-year survival rate of 13%. That's, that's an overall CRC. It was just announced recently in the, in the U.S., colorectal cancer in patients under 50, leading cause of cancer death. You know, in the backdrop there hasn't been a lot of, innovation from a therapeutic perspective in CRC. We've seen innovation in other solid tumors like lung and breast, but CRC is largely still chemotherapy and some older generation monoclonal antibodies. So there really has not been, been breakthroughs. In terms of our specific data, we started in the last-line patients, so this is metastatic CRC, really the, you know, last line. So our, our patients had, an average of four prior, you know, therapies from a median's perspective, so it's actually, you know, fifth line, patient population. We aren't selecting for anything. We're not selecting for target because the target's so highly expressed. We're not selecting for other clinical characteristics like metastases to the liver or KRAS mutations, which often lead to poor prognosis. And so, you know, patients in this setting, you know, the options are really difficult. So, the standard of care for these types of patients right now, in terms of responses, so getting the tumors to shrink, are 1%-2%, and PFS, progression-free survival, of only a few months. Unfortunately, overall survival is six or seven months. So it's a very, very difficult situation. What we showed in our initial phase I data, kind of against that backdrop, was 28% objective response rate, so about you know, almost a third of patients responding. We had 94% disease control, so 17 out of 18 patients saw some clinical benefit from the drug in the key dose ranges. And an early estimate of PFS, progression-free survival, of 5.8 months. So, you know, from our perspective, a very strong start in a, you know, very difficult-to-treat patient population and, you know, what looks like to be an active drug. I'll just talk a little bit about also the safety profile, just to make sure we have the full context. So, as it relates to safety, you know, as I mentioned, this is a masked ADC against a target that really hasn't had a therapeutic window before. So first, we did not see, you know, the classic EpCAM toxicities that have limited other therapies. We didn't see pancreatitis. We didn't see signals of liver toxicity in the initial look. In terms of what we did see, you know, for an ADC, you'd typically expect to see some hematologic tox, cytopenias, some GI tox. Overall, I would say the heme tox, you know, looks very reasonable, manageable. And the one real toxicity we have, we has diarrhea, which was about 21% Grade 3 diarrhea, which is not unexpected from a topo-1 payload, including other ADCs and irinotecan. But that's really the key thing that we're learning more about as we get to the next steps, which you can talk more here in a few minutes. Right. And so this data you just described is on, I think, three active doses, right? Correct. Obviously, you enrolled many more patients now at those three doses, and with a very important update coming up later this quarter, we talked about it just earlier. So just remind us of, you know, what are you trying to achieve and how you approach dose selection based on this data? Yeah, so we, you know, post this encouraging initial data set, we decided to expand at three doses where we saw activity of the drug. We're literally looking at this as a range of doses. Those were 7.2 mg/kg, 8.6 mg/kg, and 10 mg/kg. So So our goal, as communicated at the time we presented the data, was to expand those three doses to about 20 patients per dose level to get a better understanding of the efficacy and safety across this range, you know, to better inform potential dose or doses to move towards later phase development. We have since, you know, in Q4, we announced that we expanded the enrollment to a target of about 100 patients, by the Q1 data update that we're planning for. And so, you know, really the overall goal is, you know, better understand the efficacy across this dose range, better understand the safety across this dose range, to really inform, you know, what's the optimal therapeutic window, you know, for the drug to inform next steps, you know, for the studies. And obviously, you know, the early phase I data, I think it was 18 patients, right? Evaluable patients- 18, yeah. In the phase I. Obviously, small n, but you're already in an area of great activity relative to historic data in this setting. So, you know, what metrics will you apply, or how do you think about selecting a dose or two doses to advance to, you know, in terms of balancing efficacy and tolerability? And what other key outcomes you'll be evaluating here? Yeah, I mean, it's hard to predefine, you know, the exact metrics, but, you know, some of the key ones, you know, we think about. So, you know, goal number one, in this larger data set is to, you know, see the overall profile of the drug, replicate, you know, within, you know, a certain range of the promising start we had in that that 18 patients, as you had mentioned. So, things we'll be looking at are response rate across the doses, so response rate by dose. We also are increasingly focused on progression-free survival, and are hoping to have an estimate at each dose. You know, we think PFS is important for a number of reasons. One, it does integrate efficacy and safety in terms of that patient experience, and would be increasingly important as we think about, you know, later phase studies. You know, ultimately, progression-free survival and ultimately overall survival will be the key outcomes. And so, we think that, you know, PFS by dose will be important in terms of, you know, an important metric to inform our thinking in this dose range. And then really all that's in the context of the risk-benefit of the safety profile and, you know, how those things, you know, fit together. I mentioned the GI tox, the diarrhea, we're, you know, focused on understanding the etiology of that, strategies to, you know, mitigate and manage that. We did implement some prophylactic measures, prophylactic loperamide, at the time of our expansion in Q2 of 2025, and so we'll get an understanding of how that's working as well, you know, in this larger data set. Right. So it sounds like you think the diarrhea was off target. Is that correct, or maybe payload related? And, just remind us, so in phase I, there was no prophylaxis or anything implemented to mitigate diarrhea. Is that correct? So let me start with the second question. So in terms of phase I, we were not giving guidance to use prophylaxis at that time. We're trying to understand the safety profile, you know, early in dose escalation. So that's really something that was implemented after dose escalation. In terms of where it comes from, you know, the short answer is, you know, we don't know. We certainly think that if you look topo-1 inhibitors, including ADCs and irinotecan, that it certainly could be explained by the payload. This is a novel linker payload that we licensed from ImmunoGen. So certainly could be explained by the payload. That said, EpCAM, the target, is expressed in the GI tract in healthy tissues. In our masking technology, you know, the way to think about it is it shifts the binding curve, we think by about a hundredfold. So, you know, there can be low level, potentially of binding. So the short answer is we don't know. You know, our focus is trying to understand it, mitigate, manage it, and really, you know, optimize the risk-benefit for patients in terms of how to best use the drug clinically. Right. So what proportion of patients in our study will have had the opportunity to use prophylaxis? Yeah, I can't really comment on that. We'll have to see in terms of, you know, what the data and experience was and, you know, what we learned from that. Right. The investigators do have some discretion. Yeah. You know, as you can imagine, colorectal cancer patients in terms of the GI toxicity can be complicated. Yeah. They've often seen, you know, therapies in prior lines, where diarrhea is a side effect. And so the investigators do need that discretion to manage those things. But, you know, they're well-suited to do that. Makes sense. And, remind us, did you see a dose response in phase one in the early look, or do you expect a dose response in this larger sample size? Yeah, in the first data set, you know, it's really the numbers are too small to draw any definitive conclusions on dose response, either for efficacy or safety. We did see numerically higher response rates at the highest expansion dose, but we're really focused on the range of activity and, you know, that overall disease control and response rate of 28% across those doses is the way we think about the totality of the drug. And then the same thing on safety in that set. You know, in a larger data set, it is typical for ADCs to show some dose response. And so in a larger sample, we would expect that. In terms of how that plays out, in terms of dose response for efficacy and safety, is essentially what we're trying to understand, and where is the sweet spot in terms of finding the therapeutic window and the right risk-benefit for patients. Right. So, so what is the ideal outcome for you? I mean, you, you're already in the ballpark of a promising drug, in my opinion, in colorectal cancer. Is the goal to reproduce the phase I data, or are there more nuances to that in the larger sample? You know, I think at a high level, goal number one is, yeah, the profile holds up in a larger sample size. You know, that would be, you know, very encouraging, you know, given the unmet need in CRC and, you know, the lack of innovation that's been there, and patients need new therapies. You know, I would say beyond that, we really have an eye towards what's the next step for development of the drug. So we do wanna learn more, as I mentioned, about the dose range and starting to narrow, you know, where those doses, you know, dose or doses could be for the next phase of development. So we would expect, you know, data dependent that, you know, by mid-year, with some additional follow-up from this study, to, you know, potentially have some discussions with FDA, to really start to align on what does a next study look like, and we hope that that could be a registrational study. We'd have a goal to start that no later than the first half of 2027. Makes sense. Yeah, that's a good segue for my next question then. Yeah, how do you think about path to market, obviously, you know, in terms of colorectal cancer, initially? Yeah, well, I mean, I would say the first thing is, we're thinking about speed, and because patients do need new therapies. And, you know, based on what we know today from the first update that we presented, you know, as I mentioned, based on that profile, we think a late-line study versus a single-agent TKI, for example, fruquintinib, which has, you know, really 1%-2% response rate, 3.7 months of progression-free survival, we think that that would be, again, if things hold up, a highly derisk study, and we could execute it quite quickly. And so that could be an important value creation, fast-to-market pathway for the drug. That said, we're not ruling out running potentially a head-to-head study versus the combination of LONSURF and bevacizumab, which is, you know, the most common drug used in third line. It's highly fragmented, but that's the most common drug used in third line. The PFS of that drug is about 5.6 months, and so we do wanna see our data mature, you know, and if it mature positively on PFS, we would consider that. Longer term, you know, the vision of the drug is to really replace chemotherapy, specifically around irinotecan. So, you know, the late line is goal number one, pin that down, but we really wanna start to get experience in combinations, and we're starting with bevacizumab in Q1, this quarter, to understand the combination profile, eventually chemo combinations to move it earlier line, in particular second line to replace irinotecan. Yeah, makes sense. We get asked sometimes about just the landscape. Obviously, there is potentially cabo, PD-1 combo coming into the market, TBD. Yep. And then obviously there are a couple of ADCs, CEACAM5 ADC from Merck, and then the cMet ADC from AbbVie. Yeah. How do you think your position, perhaps relative to the other ADCs, you think? Yeah, well, I would say the first thing... You're right, there's been, you know, the Exelixis drug, you know, I think had a positive study. There's been a couple other readouts in CRC. I mean, our view, big picture, is that, you know, of everything, I would say, across the CRC field, you know, the ADC data is by far the most compelling. So, you know, we can just say that the ADCs are coming to CRC, and that's a pretty exciting opportunity, and, you know, we think we have a really good one, and as I mentioned, you know, potentially an ideal target, given how broadly it's expressed, you know, we think across all lines of therapy. So we think we're in a, I would say, a really strong position from a competitive landscape standpoint. As you mentioned, there are a couple of other competitor ADCs from larger pharmas, AbbVie, which targets cMet, which we estimate is expressed in about a third of CRC patients, so it's, you know, a less broadly expressed target within CRC. And then CEACAM5 ADC from Merck KGaA, who's presented data, which, you know, it's encouraging initial results. And, and we think, you know, both of those drugs, you know, the data they presented is, is compelling and, you know, de-risking for us. In terms of how it shakes out, in terms of, you know, ultimate positioning, I think that'll be, you know, determined in larger studies. The way we view it is it's a really big market, a lot of unmet need, and we've got, you know, a compelling drug in this space, really on the leading edge of ADC innovation for CRC. Right. And you mentioned your planned bev combo study. Are you considering other combinations as well, either, for example, with PD-1s or other therapies that are approved for colorectal cancer? We're thinking about all those things. In terms of critical path, we're gonna start with bevacizumab, based on how broadly that's used within CRC, and, you know, I think there's probably direct, you know, pathways to grow the addressable market in third line and potentially unlock second line. In second line, we're likely to need chemo combination, and so that's. You know, we haven't determined the exact timing of that, but we'd like to get going on the full FOLFIRI replacement strategy, as soon as we can. In terms of, you know, other combinations with either, you know, newer novel therapies or, you know, things like that, I think we're watching the field, and no decisions are made, but I would say, you know, one important criteria would be, you know, does it allow us to move upstream in terms of the treatment paradigm, which is, you know, a big consideration for us. Right. Okay, so then looking forward to the data update this quarter, and then in the last 26 seconds - maybe just touching on 801, which is your other phase I asset, and what to expect this year from that product candidate. Yeah, I'll go quickly, but similar to EpCAM, interferon alpha-2b, we think is highly validated. It's just been limited by toxicity. And it is a broad and potent stimulator of the immune system, and we think the thesis here is to turn cold tumors hot. We're starting in a very focused way, as we have with the epcam program, exclusively in late-line melanoma, PD-1 refractory melanoma, and we think the drug is initially gonna be in combination with KEYTRUDA. So we're in that dose escalation. We're gaining that experience, and working towards, you know, initial clinical update in the second half of this year. Awesome. Well, with that, we have to wrap up, so really appreciate the time. Thank you. Appreciate the time. For presenting. Thanks, Michael. Yeah.