CytomX Therapeutics, Inc.

Good morning, everyone. Thank you for standing by. Welcome to the Cytomics Therapeutics 2025 Financial Results and Faceta Phase 1 Dose Expansion Data Call. Please be advised that today's conference is being recorded. I would now like to hand the conference call over to your host for today, Chris Ogden, Cytomics Chief Financial Officer. Please go ahead.

Thank you. Good morning, and thank you for joining us. Before we begin, I would like to remind everyone that during this call, we'll be making forward-looking statements. Because forward-looking statements relate to the future, they're subject to inherent uncertainties and risks that are difficult to predict, and many of which are outside of our control. Important risks and uncertainties are set forth in our most recent public filings with the SEC at sec.gov. We undertake no obligation to update any forward-looking statements, whether as a result of new information future developments, or otherwise. Earlier today, we issued a press release that includes a summary of our 2025 financial results and progress at Cytomix. Additionally, this morning, we are excited to announce positive phase one dose expansion data for Varsetta N in patients with late-line colorectal cancer. The focus of our call today will be the phase one expansion data update for Varsetta. For details on the company's 2025 financial results and other pipeline updates, we encourage everyone to read today's press releases and the associated materials which have been filed with the SEC. Additionally, the press releases, a recording of this call, and our SEC filings can be found under the investors and news section of our website. With me on the call today are Dr. Shawn McCarthy, Cytomix's Chief Executive Officer and Chairman, and Dr. Wayne Chiu, Cytomix's Chief Medical Officer. Shawn will provide introductory remarks regarding the clinical data and Varsetta program strategy, and Wayne will then walk through the clinical data. We will then wrap up with concluding remarks in a Q&A session. With that, I'll now turn the call over to Shawn for opening remarks.

Thanks, Chris, and good morning, everyone. It's really a pleasure to be here with you all. The major focus of today's discussion will be an exciting update on Phase 1 data for our EPCAM-targeting antibody drug conjugate, Varsetatug-Mazatecan, otherwise known as VarsetaM or Varseta. There's been a very high level of interest in this program since our first data disclosure in May last year. in which we shared a strong start with the clinical development of this first-in-class ADC for colorectal cancer. We'll refer to colorectal cancer during this presentation as CRC. In today's update, we want to share the terrific progress we have continued to make over the past 10 months. We continue to be highly encouraged by what we're seeing, and we aim to develop Varsetta M aggressively for the benefit of patients with CRC and, over time, many other cancers. In this presentation, we aim to address key questions that relate to the next steps in the development of Varsetta, specifically the drug's efficacy profile across a larger patient dataset, improving our understanding and management of gastrointestinal adverse events, and how we are integrating all of this data into future dose selection as we lock in on plans for late-stage development and registration. Okay, let's get to it. Colorectal cancer remains one of the biggest unmet needs in oncology. 1.9 million patients per year are diagnosed around the world, and that's predicted to grow to more than 3 million patients by 2040. CRC is the second leading cause of cancer death worldwide and is growing in incidence in younger patients. Five-year survival in patients with metastatic CRC is a dismal 13%. We see colorectal cancer as one of the largest untapped solid tumor markers. This cancer type has been largely bypassed by the last 20 years of oncology innovation and progress. Antibody drug conjugates have transformed the treatment of many tumors, initially hematologic cancers and increasingly solid tumors. We're seeing ADCs coming earlier in the treatment paradigm, increasingly showing opportunities to replace systemic chemotherapy in a variety of tumor types. There is no approved ADC for the treatment of CRC. Varsetta M is bringing the potential and the power of antibody drug conjugates to colorectal cancer. CRC is a very large market opportunity. In the third line setting alone, there are projected to be 45,000 addressable patients in the US by 2040, creating a multi-billion dollar potential market opportunity. And while the unmet need is greatest in the later line setting, the entire treatment paradigm for this cancer could be changed by a pan-CRC ADC with the potential to move to earlier lines of therapy like Varsetta M. The current standard of care in late-line metastatic CRC is highly inadequate. The options available today for patients result in objective response rates in the low single digits and progression pre-survival of two to five months. These agents are unfortunately the best that are currently available for the treatment of patients after they have exhausted chemotherapy-based regimens. We must do better, and I'm pleased to say we are doing better by bringing Cytomix innovation to bear on this problem. Varsetta-M was intentionally designed to be active in CRC. We carefully selected the right target and the right payload, and we have uniquely unlocked this opportunity with our ProBody therapeutic platform. Varsetta-M targets EPCAM, epithelial cell adhesion molecule, It's been known a long time that EPCAM is present at very high levels on colorectal cancer. In fact, it was first identified as a CRC marker. EPCAM is uniformly and highly expressed across all stages of the disease. There have been many efforts to target EPCAM previously. The major challenge has been it's present on most normal epithelial structures. So, approaches to target EPCAM in the past have hit significant toxicity roadblocks very early in their development because of EPCAM expression in normal tissues. Based on these prior unsuccessful efforts and as also shown by our own preclinical experiments, a conventional ADC targeting EPCAM would not be expected to be developable. Farsetta-M is designed to unlock EPCAM as an ADC target and is based on a high affinity anti-EPCAM antibody which we have masked using Cytomix protease-dependent peptide masking pro-body strategy designed to minimize binding in normal tissues. The mask is removed by proteases within the tumor microenvironment, allowing binding and engagement with the target and delivery of the effector mechanism and anti-cancer activity. The anti-tumor effector in Varsetta M is a novel TOCYS1 payload called CAP59 that we licensed from Immunogen. The linker is also novel, a trialanine cleavable peptide linker optimized for bystander effect. We now refer to this TALCAMP59 linker payload as Mazatecan. Varsetta-M has a drug antibody ratio of eight. We really believe with this drug candidate, we have the right target and the right payload with this overall strategy being uniquely enabled by the Cytomix ProBody platform. So where are we with the phase one study? Shown here is the current enrollment status. As we reported in August last year, enrollment into the dose escalation and expansion phase at that time had reached a total of 73 patients. This included 60 patients treated at the prioritized expansion doses of 7.2, 8.6, and 10 milligrams per kilogram administered every three weeks. The updated efficacy data we're sharing today is focused on these expansion cohorts for which we now have meaningful follow-up and from which we expect our go-forward dose for the first registration study will be selected. In Q4 last year, we increased enrollment into the phase one study with the goal of further dose optimization. As of a data cutoff of January 16th, 2026, enrollment across the study had reached 93 patients. The additional 20 patients enrolled are the first 20 of a target of 40 patients being enrolled in dose optimization cohorts. Dose optimization is focused on the top two doses from the expansions, 8.6 and 10 mg per kg, and encompasses adjusted ideal body weight dosing and an updated prophylaxis strategy that Wayne will walk you through shortly. Today, we'll share safety data across the full 93 patients. showing the progress we're making in adverse event management and specifically the management of treatment-related diarrhea for which we believe we are making excellent progress. We are very excited today to share updated results from the ongoing phase one study of Varsetta M in late line CRC. This drug candidate continues to perform extraordinarily well. Antitumor activity continues to be very strong with a 32% confirmed overall response rate at 10 mg per kg and a 20% confirmed overall response rate at 8.6 mg per kg. Our current estimate of preliminary progression pre-survival has improved from 5.8 months in May of 2025 to 6.8 to 7.1 months. We've also made excellent progress in understanding and managing the safety profile of Varsetta M. We continue to see no evidence of the classic EPCAM toxicities that have limited previous efforts to drug this target. And importantly, through the use of further updated prophylactic strategies, we can report today a rate of grade three diarrhea of 10% in early dose optimization cohorts. Simply put, we believe we have an important potential new treatment for colorectal cancer that has been uniquely enabled by our core platform technology. This is a major landmark for our company, and most importantly, of course, a big step forward for patients. Our top company priority is now to move Varsetta forward aggressively into its first registration study. And with that, let me hand over to Wayne to talk you through the details of the data. Thanks, Sean.

Going into the data from the ongoing phase one trial. This slide summarizes key baseline characteristics among all 93 patients who are enrolled in the dose escalation, expansion, and dose optimization cohorts. Consistent with what was previously reported, The study population continues to be representative of a late-line metastatic CRC population, highlighted by the fact that most patients received at least three prior lines of anti-cancer therapy. Almost half received at least four lines of prior therapy, and over a quarter received prior Bevacizumab plus Lonserve. Three-quarters of patients had liver metastases at baseline, and the majority of patients had KRAS-mutated tumors. Finally, Most patients' tumors were microsatellite stable, with only one patient with known MSII disease. The following slides describe efficacy from the 60 patients treated in dose escalation and dose expansion cohorts at Varsetta M doses between 7.2 and 10 mg per kg administered on an every-three-week schedule. In the updated waterfall plot, Varsetta M continues to show striking anti-tumor activity and disease control across the three dose levels, highlighted by tumor reductions, including confirmed objective responses per RESIST 1.1 criteria. Objective responses were higher at the 8.6 and 10 mg per kg dose level, with confirmed objective responses observed in 20% and 32% of patients, respectively. The arrowheads indicate patients who were still on study treatment at the time of the data cut. And at the bottom of the slide is patient level information with respect to key baseline characteristics. As you can see, anti-tumor activity was observed in patients with KRAS mutated or KRAS wild type tumors and in patients with or without liver metastases. Finally, consistent with what was previously reported, EPCAM expression as assessed by immunohistochemistry on baseline tumor biopsies remains uniformly high, with an age score of 300 being the maximum value. All the valuable tumors had IHC age scores greater than 200, with the vast majority having age scores of at least 250. This is the updated spider plot characterizing changes in tumor burden over time. As previously reported and further substantiated with a longer median follow-up time of over eight months, Varsetta-M continues to provide impressive durable disease control. A total of 16 patients were continuing Varsetta-M treatment at the time of the data cutoff, with several patients having ongoing treatment in excess of 11 months. With the observed durable objective responses and disease control, We continue to observe progression-free survival at all three dose levels that compare very favorably with those of currently approved therapies in late-line CRC. Notably, the median PFS of Varsetta M treatment was 7.1 months at the 10 mg per kg dose level and 6.8 months at the 8.6 mg per kg dose level. Given the follow-up time and the proportion of patients who were censored at the time of the data cut, the PFS estimates will continue to mature with the potential for further improvement. Furthermore, the PFS estimates shown here are in the absence of dose optimization, which as we will now show, has the potential to improve the safety and tolerability of Varsetta M. Turning our attention to safety, to contextualize the safety data that will be presented in the upcoming slides, I wanted to summarize some of the key observations and learnings from the Phase I dose escalation, expansion, and dose optimization cohorts as the basis for late-phase dose selection. Key early observations during dose escalation indicated a manageable safety profile with Varsetta M in that no dose-limiting toxicities were observed. Importantly, dose-limiting toxicities observed with other EPCAM-directed therapies such as pancreatitis and severe liver toxicities were not observed with Varsetta M. Also of note, interstitial lung disease, which has been observed with other TOPAL1 ADCs, was not observed with Varsetta M. In addition, rates of hematologic toxicity were relatively low. Finally, consistent with the mechanism of action of TOPAL1 inhibitors, Diarrhea was the most frequently observed treatment-related adverse event and early on was identified as the main adverse event of interest. As we conducted dose expansion across the three dose levels from 7.2 to 10 mg per kg, the overall safety profile was consistent with what was observed during dose escalation in that no new safety signals were identified. We focused on understanding key drivers of treatment-related diarrhea and gaining important experience with diarrhea mitigation strategies, particularly with respect to grade three diarrhea as the highest grade observed to date. Initially, a strategy of recommending loperamide prophylaxis for patients at high risk of developing diarrhea was introduced. For reasons related to physician practice patterns, patient preferences, and the rapidity of enrollment into dose expansion, loperamide prophylaxis was not utilized extensively in the initial expansion phase. We nevertheless gained important insights regarding loperamide pretreatment to reduce rates of severe diarrhea. We also gained valuable experience with the oral corticosteroid budesonide as an additional approach to manage diarrhea, where 12 of 14 patients who had grade 2 or grade 3 diarrhea experienced at least a one-grade reduction in severity after budesonide was started. Finally, a thorough analysis of Varsetta M pharmacokinetic and exposure response supported dosing based on adjusted ideal body weight to reduce interpatient variability. The observations and learnings across dose escalation and dose expansion have been incorporated in the ongoing enrollment of patients into dose optimization cohorts where Varsetta-M is administered at 8.6 or 10 mg per kg based on adjusted ideal body weight, and mandatory dual prophylaxis with loperamide and vedesonide for all patients regardless of pre-existing risk factors has been implemented. As we will now show, early safety data from the dose optimization cohorts indicate meaningful reductions in severe diarrhea. From the dose escalation and expansion cohorts, We observed that treatment-related adverse events occurred early during Varsetta M treatment, exemplified by the observed median time to onset of grade 3 diarrhea of approximately five weeks. The tornado plot shows treatment-related adverse events in the first two months of Varsetta M treatment at the 8.6 and 10 mg per kg dose levels. comparing the 42 patients treated in dose escalation and expansion cohorts on the left with patients treated in dose optimization cohorts on the right. Patients with at least two months of on-treatment follow-up were included in this analysis. This ensures equal comparison between the two groups based on an identical follow-up observational period and is representative of the overall toxicity profile reflecting the relatively early onset of treatment-related adverse events. Treatment-related adverse events within the first two months of our SETM treatment among patients enrolled in dose escalation and expansion is highlighted by grade 3 diarrhea, which was observed in 29% of patients. In contrast, among patients enrolled into dose optimization cohorts, Grade three diarrhea was observed in only two of the 20 or 10% of treated patients. Notably, the decreased incidence of grade three diarrhea with dose optimization is paralleled by a similar reduction in the incidence of grade three hypokalemia, which is a known consequence of fluid and electrolyte balances caused by diarrhea. So overall, while early, the data to date indicate that dose optimization may lead to an improved overall safety profile, highlighted by reductions in the incidence of grade 3 diarrhea and grade 3 hypokalemia. Taking a step back from comparisons of the adverse event profiles between the dose escalation and expansion and dose optimization cohorts, the overall treatment-related adverse event profile across all cohorts and dose levels is summarized in this table. These data are consistent with the safety profile that was described previously and only partially reflects the safety profile with ongoing dose optimization. Across the safety data from these cohorts, dose escalation, expansion, and dose optimization, treatment discontinuations for related adverse events were low at 11%. With additional patient enrollment and longer follow-up, we are optimistic that measures incorporated into dose optimization will result in a more favorable Varsetta M safety and tolerability profile, maximizing clinical benefit for patients. Updated pharmacokinetic data of Varsetta M is summarized here. The data are from the 73 patients treated in dose escalation and expansion cohorts and does not include data from the dose optimization cohorts where Varsetta M was dosed based on adjusted ideal body weight. The data continues to support key characteristics from earlier observations in that, as shown in the figure, PK is dose proportional. We also observed interpatient variability, which we aim to reduce with adjusted ideal body weight-based dosing. Varsetta M circulates primarily in the masked form. The mean Varsetta M half-life of six to eight days is consistent with that of other in-class antibody drug conjugates. and unconjugated CAM59 concentrations in circulation are low, constituting approximately 1 to 3% of total of Varsetta M. Turning our attention to efficacy, the potential impact of Varsetta M dosing with adjusted ideal body weight on efficacy is illustrated in this figure, which shows the relationship between Varsetta M exposure and efficacy as measured by the clinically relevant metric of landmark six-month progression-free survival. The modeled exposure-response relationship based on clinical and PK data from dose escalation and dose expansion encompasses the exposure range for the 8.6 to 10 mcg per kg dose levels. Notably, observed Varsetta M concentrations at 8.6 and 10 mcg per kg with adjusted ideal body weight dosing fall within this exposure range. indicating that doses tested in the dose optimization codes are predicted to deliver similar efficacy to the corresponding non-optimized dose levels, where median PFS, as described earlier, has been shown to exceed six months. As you can see, as we gain an even deeper understanding of our CYTA-M efficacy and safety, this model gives us confidence in the range of dose levels as we work towards discussions with FDA, on dose selection based on project optimist principles, and finalizing registrational study plans. It has been a pleasure sharing this data with you today, and with that, I turn it back to Sean for concluding remarks. Thanks, Wayne.

We're super excited about our continued progress with Varsetta M. This drug candidate is working exactly as designed, and we believe we can make an enormous difference for many, many cancer patients. This is the first and only antibody drug conjugate targeting EPCAM, a target that many have tried to drug before and failed. Our data is truly a validation of our technology and a direct embodiment of our company vision statement of transforming lives with safer, more effective therapies. To restate, we believe we have an important potential new treatment for CRC, and this is just the start. We see Varsetta as a company building asset, a pipeline and a product, if you like, that puts cytomics on a value creation trajectory that we believe can be steep and sustained. We see three major layers of value creation being unlocked in the near, medium, and longer term. Firstly, we aim to rapidly bring this drug to its first approval in late-line CRC, where there are projected to be more than 45,000 addressable patients by 2040. This alone is a potential multibillion-dollar opportunity in the U.S. Secondly, we aim to bring Varsessa into early-aligned CRC. In fact, this has always been the vision for this program, to potentially replace Irinotecan. As we learn more about the overall profile of Varsessa, particularly the safety profile, we are feeling increasingly confident that we can penetrate into this very large market. Our third layer of value creation is to expand into other epcan-positive tumors, of which there are many. Given that we've broken through in CRC, we believe we've done the hardest experiment first. CRC is very difficult to treat cancer, and we're really excited to see what Varsetta M can do in other tumor types. In the long term, it's not a stretch to envisage Varsetta advancing towards a pan-tumor histology agnostic label like NHER2 has for HER2. Moving now to our upcoming milestones. With this updated data, we do believe we have put Barsetta and Cytomix on a very clear path to value creation through sustained execution. I hope you all see today's update as a highly meaningful step along the way in the development of this exciting drug. There's much opportunity and a lot of work ahead of us. Our top priority right now is the rapid advancement into registrational studies to start in the first half of 2027. We look forward to sharing additional data from the phase one study, including the dose optimization cohorts and registration study design in the second half of 2026. The strength of our data brings into sharper focus the opportunity to conduct our first registration study in the third line. We'll be continuing to assess this opportunity as our data matures. In terms of our earlier CRC strategy, we've already initiated phase one assessment of Varsetta in combination with Bevacizumab and we anticipate initial data late this year or early in 2027. Furthermore, today we're also announcing our intention to start combination work with bevacizumab plus chemo by the end of the year. The team is also working very hard to start our first clinical study outside of CRC later this year as well. So, really exciting times for cytomics. Thank you all for joining today, and before opening up the call for questions, I really want to thank the Cytomix team for doing just such an incredible job. Rosetta has been a long time in the making, and it takes so much dedication and perseverance to do this important work. My colleagues and I thank the patients who have trusted us and participated in this phase one clinical study, and we sincerely thank our investigators for their thoughtful guidance and diligent leadership. At Cytomix, we've never been more excited about what we're doing for patients, and we look forward to providing future updates. And with that, let's open up the call for questions.

Thank you. To ask a question, please press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. Please stand by while we compile the Q&A roster. Our first question comes from the line of Edward Tenthoff with Piper Sandler. Your line is now open.

Great. Thank you very much, and congratulations. Very impressive. by these continued response rates and PFS from Vercetta. Really, really cool and I appreciate all the detail in both the dosing data and also the plans going forward. I guess when it comes to the pivotal trial, appreciating that you'll share design in the second half, how large are you anticipating from this study? And then secondly, could you share any in terms of what might be leading indications beyond CRC for the next EPCAM-positive tumor. Thanks a ton. Great. Thanks, Ted, for the questions.

With regards to the pivotal study, the first pivotal study, still a work in progress, of course, in thinking about sizing. We're obviously super encouraged and excited by the level of activity that Rosetta is bringing in late line CRC. And I want to emphasize, actually, this continues to be a very late line patient population, as you can see from the demographics that Wayne highlighted. We do see that with this updated data set, as I mentioned, and the PFS in particular continuing to improve, we do feel increasingly excited about the Pivotal being in the third line. We, of course, need to learn about OS, and we'll be sharing OS data as the program matures. That will be a key determinant of our decision-making on the Pivotal design. And too early to say what the size of that study would be, but we think it could be a manageable size and executed, we think, very quickly.

And do you want to comment on potential other indications outside of CRC?

Yeah, with regard to your second question, Ted, on non-CRC, as we've said for some time, we really are excited about the broader potential of EPCAM. It's expressed in many, if not all, of the solid tumors. We highlight in our presentation, have for some time, other GI tumors, including gastric and pancreatic. Of course, it's highly expressed in lung cancer. ovarian cancer, certain breast cancers, and so there's a wide range of opportunities here that we continue to work through. To this point, as you'll understand, we've been highly focused in CRC and bringing this drug to its first pivotal study, but we're excited to move into other tubotypes by the end of this year.

Excellent. Well, great work, and thanks for sharing all the details. You're welcome.

Our next question comes from the line of Roger Song with Jefferies. Your line is now open.

Thanks. And then a huge congrats for the data. Very impressive on the efficacy and the tolerability side. And thanks for taking the question. Maybe, Sean, so for the initial dose expansion, this diarrhea, kind of prophylactic protocol you say on the call it was not fully implemented or widely used and they're not using the dual so how should we think about you know the the implementation here and then also the real world use or what what is your advice feedback on this potential regimen for future and then in terms of the the pivot also a quick follow-up on that is that can comment on this, you know, you see the third line and then still looking at the OS, how likely this PFS will be the sole primary endpoint given the data is very impressive here compared to the standard tier. Thank you.

Thanks, Roger. Great questions. So, yeah, with regard to the expansion phase, one of the things that we've commented on quite frequently over the last six or so months is just how rapidly the expansions enrolled. The demand for the drug, as I think you can now see based on what it's doing, the demand for the drug was very high. We enrolled the expansions faster than anticipated. And for that and other reasons, the implementation of the original loperamide prophylaxis was not as extensive as we had perhaps anticipated. But there's also a clinical reason for that as well, which is these patients, particularly in the very late line, of course, they've experienced GI adverse events at various points in their treatment journey. They all have, for the most part, experience with loperamide. And it's a drug that, while bringing benefit, of course, to the treatment of diarrhea, it comes with its own challenges as well. So patients You know, they, in some cases, kind of make their own choices about how they manage that particular drug, unless it's really impressed upon them to use it. I would contrast that a little bit to the budesonide, which we've really demonstrated some key learnings in the expansion phase that budesonide is looking to be effective as well. And this is a drug that we've experienced that patients are very compliant with. So in terms of the prophylaxis overall and its use in the real world, we feel really good that it will be adhered to as we continue to refine and update and learn how to optimize the overall protocol. In terms of progression-free survival, being a primary endpoint. We're not guiding to that. There's no real precedent for that in the late-line CRC setting. We are planning for OS to be the primary. That is something we'll continue to talk to FDA about. And of course, we are looking at all and any ways to accelerate the development of Varsetta M. But for the time being, our assumption continues to be unchanged, that the first pivotal would be principally based on an OS primary. But given the unprecedented level of activity of this drug, we'll continue to look at all and any options.

Thank you so much. Congrats again.

Thank you. Our next question comes from the line of Matthew Beigler with Opco. Your line is now open.

Great. Thanks, guys, so much, and congrats from us as well. Could you comment on positioning relative to the other ADCs in development like PressMTCT especially now with diarrheal prophylaxis seeming to work well. What are the puts and takes from a physician's perspective in choosing one of the ADCs over the other? Thanks.

Yeah, thanks, Matt. Really terrific question on the broader landscape. And as we've been saying, and this is just so exciting for patients, the ADCs are coming to colorectal cancer. And we think we've got a really good one, if not potentially better. potentially the best. So I want to emphasize again that Varsetta is a first-in-class anti-EPCAM ADC. It may very well be the best-in-class ADC for CRC based on this data that we're sharing today. This is a highly competitive data set. We believe a highly competitive drug. And I think of particular importance, as you mentioned, the safety profile that we continue to understand and learn how to manage. This is really important because it continues to open up, we think, the movement of Varsetta into earlier lines of treatment, into the first and second line setting based on its, we think, potential combinability and effective combinability with the other components of frontline treatment. So this is a very important data set that we're sharing today with big implications for where this drug can go. And as I said, we will continue to develop the drug aggressively and position, we think we've got a very competitive position against, for example, the AbbVie and Merck KGA drugs. Thanks, Ken.

Thank you. Our next question comes from the line of Michael Schmidt with Guggenheim. Your line is now open.

Hey, good morning. Thanks for taking my questions and congrats on the data from us as well. Obviously, the efficacy looks very compelling, despite the fact that you have a very high proportion of patients that are four prior lines, so fifth line plus population. And I'm just curious if you've looked at the data in third line only patients. Just curious if you see even further improved activity and something that could look closer to what you've been enrolling in phase three. And then a question on diarrhea. Just curious if you could just help us understand a bit more the duration of diarrhea, for example. Is this a first-dose effect or something that patients are having for a longer period of time? And obviously, PFS already looks very good despite the diarrhea. And I'm just curious when you think about the adjusted ideal body weight dosing cohorts, which is something that's not uncommon for ADCs in general. Just curious if there's an opportunity to further improve efficacy with that dose optimization that's ongoing. Thanks so much.

Thanks, Michael. A series of wonderful questions there, so appreciate that. So, first of all, in terms of parsing out the patient population and the data set, you know, I guess this just continues to be a late-line patient population that we think showing this level of activity is, you know, a great place to start. And so we're obviously very optimistic that as we move the drug earlier, the drug will continue to show similar, if not even more impressive activity. And we're not dissecting the data set really any more than that at this moment in time. We think it really speaks for itself. In terms of duration of diarrhea, I mean, we've been very focused on time to onset, as Wayne mentioned, About five weeks is the median time to onset for grade three when we see it. We're now in this position with this updated prophylaxis strategy to really get on top of that and get that number down, as you've seen in this preliminary data from dose optimization. And patients treated with this prophylactic regimen, obviously you're seeing a much reduced incidence of grade three. So that's really what we're focused on. In the earlier experience, in the expansion phase, we found that patients are responsive to the treatment with budesonide. And as Wayne pointed out, we saw 12 or 14 patients treated who we follow closely in the earlier stage of the study show at least one grade improvement in their diarrhea, giving us that initial clue that budesonide could be a terrific addition to the prophylactic strategy. You make another really important point, Michael, on PFS. These PFS numbers are from the expansion phase, and the expansion phase did not have optimized prophylaxis. So we do feel that this data can continue to improve. We do feel that this drug can continue to outperform over time as we learn more about it. And that also relates to your last question on adjusted ideal body weight dosing, which as you correctly point out, is something that has been used for a number of ADCs and shown to be effective. It's really aimed at decreasing the outliers, compressing the dose range so that we have more consistent dosing, and that should, we think, just add to our ability to manage the safety profile, keep patients on drug for the maximum period of time, maximizing the duration of their clinical benefit.

Thank you. Thank you. Our next question comes from the line of Olivia Breyer with Cantor Fitzgerald. Your line is now open.

Hi. Good morning, guys, and my congratulations as well on today's data. Shauna, I know you aren't necessarily breaking things out yet by individual treatment line, but anything you can tell us about how many lines of therapy, the confirmed partial responses that you had in that 8.6 and 10 mg per kg cohorts? And then wanted to ask a follow-up on your pivotal design. Any sense yet for what the comparator arm would need to be given that you guys are planning on going straight into the third line setting? And then just kind of final question, also wanted to ask about your plan for implementing a prophylaxis protocol as you think about a combination approach and moving this program into earlier treatment lines.

Thanks, Olivia. Great questions. In terms of treatment line, I think we just emphasized that, again, late line patient population, we haven't broken that out. But I would say that across the study, it's very consistent with what we saw in the phase one disclosure in May of last year, where we did break out at that time the specific number of priors for each patient. And you could see one patient, we do like to point out, who had actually 10 prior lines of therapy who had actually the deepest response. So this drug is active in patients who are heavily pretreated really across the board. I should also emphasize something we haven't really focused on too much today. I can't underscore how important this is, but this is an unselected patient population. So we're not selecting for Epcam. We're not selecting for Target. It really is an all-comer, late-stage patient population. This is incredibly valuable and attractive in the context of the use of this drug, ultimately, we think, in its uptake because patients can be rapidly brought onto Varsetta M without a whole lot of workup necessary because we're not selecting for KRAS or BRAF or liver mets. And you can see, actually, the percentage of patients in the study with liver mets and KRAS mutations is higher than it was last year. It's almost, it's about three-quarters of patients. I think this gives some important insights into how oncologists are using this drug at this early stage in its development. In terms of the pivotal comparator, I mean, in the third line, if you look at studies being conducted by others, that's Bevacizumab plus Lonsurf. That is currently the standard of care in the third line setting. So that's something that we'll look at. As we've said, we do believe this data points us increasingly in that direction. No decisions made yet, but we are actively considering that as the data continues to mature, and in particular as we get a read on OS later in the year. And then in terms of prophylactic strategies, let me ask Wayne to comment on that in terms of the extrapolation of what we've seen so far into the combination setting.

Yeah, so as we highlighted today, I mean, we really believe that we have a very effective prophylactic strategy with the dual use of loperamide and bedesonide. And we don't foresee significant challenges to move into the front line simply for multiple reasons. One, we should remind everyone that both medications are oral, so there's a convenience factor for patients that make this relatively easy to take. Secondly, even in the early-line setting, remember that, you know, many of the chemotherapy agents used in early-line settings themselves cause diarrhea. So management of diarrhea with the standard agents will uniformly involve some form of anti-GI motility agents such as loperamide. So the adaptation of loperamide in a prophylactic sense in the early line should not be a significant barrier. Finally, I'll just point out that the use of combination prophylactic agents is not just restricted to diarrhea. For example, nausea and vomiting, for example, typically utilize multiple agents for prophylaxis, including that that's administered intravenously. So again, I think in total, we don't see this as a significant barrier in any way of implementing prophylaxis in early-line settings.

Great. Thank you, guys. Very helpful.

Thank you. Our next question comes from the line of with Barclays. Your line is now open.

Thanks for taking the question and congrats as well on this data update. A couple of questions for me. First, just curious about maybe dose selection for the BEV combination studies as well as the other tumor types based on the data we're seeing today. And also, the KRAS activity was interesting. Just wondering, If you would consider KRAS wild type as well as muon in an earlier line setting, based again on the data that you're disclosing today. Thank you.

Thanks, Ed, sir. With regard to, well, great questions. With regard to dose selection for the BEV combo and other tumors, work in progress. We are doing some dose ranging with BEV, as you might imagine. That work has been kicked off. And we'll have more to say about that later this year or early next year. I should also say that in thinking about dose optimization overall, just think about where we are now compared to where we were 10 or so months ago. We've narrowed the field from three active doses, 7.2, 8.6, and 10, to the two highest doses, 8.6 and 10. And these are both great options, and we're learning more about them to pick the go-forward dose for the first pivotal. So we've really learned an enormous amount about how to use this drug and how to optimize dosing in a very short space of time. And we'll be porting that, of course, over to our experience as we begin work in other tumor types as well. So terrific progress. In terms of KRAS mutational status, That's an interesting question because, of course, in the context of EGFR therapies, you know, there is patient selection that relates to the signaling mechanism of the EGFR receptor and RAS signaling and such like. So in our case, this is one of the beauties of Varsetta, is it doesn't really matter, we don't think. The target is present at high levels on every patient, and we've shown activity in KRAS wild type and KRAS mutant. So I think it just emphasizes that right now we don't need to select patients. Now, that doesn't mean that we're not looking at our data for clues as to where the drug may be perhaps even more active. But right now, the main message with Varsetta is that this is a drug for all-comer CRC.

Thank you.

Thank you. Our next question comes from the line of Anupam Rama with JP Morgan. Your line is now open.

Hey, guys. Thanks so much for taking the question, and congrats on the update. Sean, just wanted to follow up on your comments about, hey, we're learning a lot more here about the 8.6 and 10 mg doses that were used in the dose optimization. So any difference there? I know it's only 20 patients, but any difference there in terms of what you're seeing on diarrhea, as well as on the efficacy side, ORR in particular, anything in the dose optimization portion that you can comment on in the 20 or so patients? Thanks so much.

Yeah, thanks, Anif. With regard to the diarrhea, too early to comment on that. And obviously the data as it stands, we think is very exciting, but it is early. And the dose optimization cohorts as we enroll up to the full 40 patients will continue to mature over time. So with regard to activity, the exposure efficacy model that Wayne walked you through is, we think, really important and integrates so much of the work that we've done over the last year or so in understanding the pharmacokinetic and pharmacodynamic profile of Varsetta, and we feel very optimistic that we're in the right dose range with adjusted ideal body weight dosing, so the drug will continue to show robust activity as we move forward. So that data will be forthcoming, but what we've really tried to convey with that model that's based on data from the expansion cohorts itself This is really important. The PK exposure efficacy model is built on our actual experience in the expansion phase. We think it's highly predictive of what we'll see with the optimization cohorts. And that data, as Wayne also mentioned, will be very helpful as we go to FDA and discuss considerations around Project Optimus.

Thanks so much for taking our questions.

Thank you. Our next question comes from the line of Robert Driscoll with Wedbush. Your line is now open.

Hey, guys. Thanks for taking the question, and congrats again on the data update today. Just kind of given the reduction in GIAs here with the prophylaxis regimen and other things, kind of, and the optimized dosing, just wondered if you were considering re-evaluating the higher dose cohorts here, the 11 of 12, And then second question, could you just remind us of the focus indications here for the broadening study for the webcam-positive tumor types and how big those cohorts might be? Thanks.

Thanks, Robert. So with regard to the question on reducing tox and increasing dose, we're very, very pleased with where we are right now with these two doses. We think they integrate really all of the learning so far. They continue to give us a lot of room to maneuver, as we've always said, with Varsetta. And so we don't really see a need to push the dose higher. Now, that said, this drug's going to have a long life cycle ahead of it. So there's a lot of work that remains to be done to maximize that opportunity. But right now, we feel really good about where we are In terms of non-CRC, again, there are so many opportunities there. It is so exciting to think about how many patients we could benefit with this drug over time. And nothing really more to say there in terms of exactly where we're going or size of study, but we will provide additional details as the year goes on. It is important to strike a balance, and it's one of the hardest things to do, really, at the moment. It's striking the balance between going as fast as we can in CRC and getting going elsewhere, but we're going to try and do it all.

Great. Thanks so much, guys.

Thank you. As a reminder, to ask a question at this time, please press star 11 on your touch-tone telephone. Our next question comes from the line of Mitchell Kapoor with HC Wainwright. Your line is now open.

Hey, guys. Congrats on the impressive data. A couple of questions from us. Firstly, can you comment on the frequency of grade 3 diarrhea events at the 8.6 and 10 mg per tig dose levels? Our work with KOLS was suggesting that the number of events was maybe more important than the headline of the rates of grade 3 diarrhea. And then separately, on the optimized safety regimen, how much of the grade 3 diarrhea improvement to 10% do you attribute to the adjusted body weight dosing versus the updated prophylaxis. And then if you can just help us on the median time on therapy for these optimized safety cohort patients just in light of the median time to onset of the diarrhea events.

Hey, Mitch. This is Chris. I think your first question relates to does grade 3 diarrhea tend to recur? Is that my understanding of the question versus just happening... Okay.

Right. Like, are there patients in the hospital once a month or, you know, kind of like how does the grade three diarrhea manifest itself over time?

Yeah. So, you know, our focus, Mitch, it's a good question. Our focus in these optimization cohorts, of course, is to prevent patients getting into it in the first place. And that's really what we're focused on right now. So, and we're just really encouraged by these initial data. and i again i'd like to really emphasize and really commend wayne and the team for doing some terrific work here really listening to our investigators really understanding the patient experience and keying into some of these key clinical observations particularly with budesonide and seeing that evidence that given some of these pk outliers that aibw dosing could be a significant addition to the overall to the overall dosing strategy so um In terms of, on that note, in terms of the role or the contribution of adjusted ideal body weight to the improved safety profile, you know, hard to tell, obviously. Right now, we're using loperamide, budesonide, and AIBW, and it looks like it's working. So, you know, we'll take it. And I think over time, we'll learn more. But it would be expected, I guess, said slightly differently, wouldn't be a surprise, of course, if AIBW was having a significant impact because we did see, as you can see in the PK curves, we wanted to be very transparent about this and show the per patient PK. You can see that in the non-AIBW, there is a fair amount of variability, some of which is driven by BMI, for example. So we'll learn more over time. And I'm sorry, I think your last question?

Yeah, the last part of it was just trying to understand how long these patients have been on therapy on the optimized safety dose, just in light of the median time to onset of diarrhea, so we can understand the context of that 10% rate.

Yeah, so as we presented in today's update, this is the two-month cutoff, and that's very relevant because the median time to onset of grade 3 In our experience, the date is about five weeks. So we do think this is a meaningful time point, and we will continue to follow these patients. And we're continuing to enroll, right? We're going to increase enrollment from 20 to 40 patients. This will be a much more mature data set as we move into mid-year and into the second half of 2026. So work in progress, but we think a very good start. Congrats again.

Thank you.

Thanks so much.

That concludes our question and answer session. I will now turn the call back over to Dr. Sean McCarthy for closing remarks.

Well, thank you again, everyone, for joining us today. We are delighted to have given this update, and we appreciate your interest, and we very much look forward to providing additional updates as the year goes on and following up with you all. Take care.

This concludes today's conference. Thank you for your participation. You may now disconnect.