Earnings Call Transcript - CTMX Q4 2025

Operator, Operator

Good morning, everyone. Thank you for standing by. Welcome to the CytomX Therapeutics 2025 Financial Results and Varseta Phase I 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, CytomX's Chief Financial Officer. Please go ahead.

Chris Ogden, Chief Financial Officer

Thank you. Good morning, and thank you for joining us. Before we begin, I would like to remind everyone that during this call, we will be making forward-looking statements. Because forward-looking statements relate to the future, they are 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 CytomX. Additionally, this morning, we are excited to announce positive Phase I dose expansion data for Varseta-M in patients with late-line colorectal cancer. The focus of our call today will be the Phase I expansion data update for Varseta. 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. Sean McCarthy, CytomX's Chief Executive Officer and Chairman; and Dr. Wayne Chu, CytomX's Chief Medical Officer. Sean will provide introductory remarks regarding the clinical data and Varseta program strategy, and Wayne will then walk through the clinical data. We will then wrap up with concluding remarks and a Q&A session. With that, I'll now turn the call over to Sean for opening remarks.

Sean McCarthy, Chief Executive Officer and Chairman

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 I data for our EpCAM-targeting PROBODY antibody drug conjugate for varsetatug-masetecan, otherwise known as Varseta-M 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 Varseta-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 Varseta, specifically the drug's efficacy profile across a larger patient data set, 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 deaths worldwide and is growing in incidence in younger patients. 5-year survival in patients with metastatic CRC is a dismal 13%. We see colorectal cancer as one of the largest untapped solid tumor markets. 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 but 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. Varseta-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 U.S. by 2040, creating a multibillion-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 Varseta-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-free survival of 2 to 5 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 CytomX's innovation to bear on this problem. Varseta-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. Varseta-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 is 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. Varseta-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 CytomX's protease-dependent peptide masking PROBODY 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 effective mechanism and anticancer activity. The antitumor effector in Varseta-M is a novel topoisomerase-1 payload called CAMP59 that we licensed from ImmunoGen. The linker is also novel, a trialanine-cleavable peptide linker optimized for bystander effect. We now refer to this TAL CAMP59 linker payload as masetecan. Varseta-M has a drug antibody ratio of 8. 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 CytomX PROBODY platform. So where are we with the Phase I 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 3 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 registrational study will be selected. In Q4 last year, we increased enrollment into the Phase I study with the goal of further dose optimization. As of a data cutoff of January 16, 2026, enrollment across the study had reached 93 patients. The additional 20 patients enrolled at the first 20 of a target of 40 patients being enrolled in dose optimization cohorts. Dose optimization is focused on the top 2 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 I study of Varseta-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-free 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 Varseta-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 3 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 Varseta forward aggressively into its first registrational study. And with that, let me hand over to Wayne to talk you through the details of the data.

Wayne Chu, Chief Medical Officer

Thanks, Sean. Going into the data from the ongoing Phase I 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 3 prior lines of anti-cancer therapy, almost half received at least 4 lines of prior therapy and over a quarter received prior bevacizumab plus Lonsurf. 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 MSI high disease. The following slides describe efficacy from the 60 patients treated in dose escalation and dose expansion cohorts at Varseta-M doses between 7.2 and 10 mg per kg administered on an every 3-week schedule. In the updated waterfall plot, Varseta-M continues to show striking antitumor activity and disease control across the 3 dose levels, highlighted by tumor reductions, including confirmed objective responses per RECIST 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, antitumor 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 H-score of 300 being the maximum value. All evaluable tumors had IHC H scores greater than 200 with the vast majority having H score 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 8 months, Varseta-M continues to provide impressive durable disease control. A total of 16 patients were continuing Varseta-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 3 dose levels that compare very favorably with those of currently approved therapies in late-line CRC. Notably, the median PFS of Varseta-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 Varseta-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 Varseta-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 Varseta-M. Also of note, interstitial lung disease, which has been observed with other topoisomerase I ADCs was not observed with Varseta-M. In addition, rates of hematologic toxicity were relatively low. Finally, consistent with the mechanism of action of topoisomerase-1 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 3 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 3 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 1 grade reduction in severity after budesonide was started. Finally, a thorough analysis of Varseta-M pharmacokinetic and exposure response supported dosing based on adjusted ideal body weight to reduce inter-patient 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 Varseta-M is administered at 8.6 or 10 mg per kg based on adjusted ideal body weight and mandatory dual prophylaxis with loperamide and budesonide 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 Varseta-M treatment, exemplified by the observed median time to onset of grade 3 diarrhea of approximately 5 weeks. The tornado plot shows treatment-related adverse events in the first 2 months of Varseta-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 2 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 2 months of Varseta-M 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 3 diarrhea was observed in only 2 of the 20 or 10% of treated patients. Notably, the decreased incidence of grade 3 diarrhea with dose optimization is paralleled by a similar reduction in the incidence of grade 3 hypokalemia, which is a known consequence of fluid and electrolyte imbalances 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 Varseta-M safety and tolerability profile, maximizing clinical benefit for patients. Updated pharmacokinetic data of Varseta-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 Varseta-M was dosed based on adjusted ideal body weight. The data continues to support key characteristics from earlier observations and 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. Varseta-M circulates primarily in the masked form. The mean Varseta-M half-life of 6 to 8 days is consistent with that of other in-class antibody drug conjugates, and unconjugated CAMP59 concentrations in circulation are low, constituting approximately 1% to 3% of total Varseta-M. Turning our attention to efficacy, the potential impact of Varseta-M dosing with adjusted ideal body weight on efficacy is illustrated in this figure, which shows the relationship between Varseta-M exposure and efficacy as measured by the clinically relevant metric of landmark 6-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 mg per kg dose levels. Notably, observed Varseta-M concentrations at 8.6 and 10 mg per kg with adjusted ideal body weight dosing fall within this exposure range, indicating that doses tested in the dose optimization cohorts are predicted to deliver similar efficacy to the corresponding nonoptimized dose levels where median PFS, as described earlier, has been shown to exceed 6 months. As you can see, as we gain an even deeper understanding of Varseta-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 Optimus 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.

Sean McCarthy, Chief Executive Officer and Chairman

Thanks, Wayne. We're super excited about our continued progress with Varseta-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 the 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 Varseta as a company-building asset, a pipeline and a product, if you like, that puts CytomX 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 Varseta into earlier line 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 Varseta, 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 EpCAM 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 a very difficult-to-treat cancer, and we're really excited to see what Varseta-M can do in other tumor types. In the long term, it's not a stretch to envisage Varseta advancing towards a pan-tumor histology agnostic label like Enhertu has for HER2. Moving now to our upcoming milestones. With this updated data, we do believe we have put Varseta and CytomX 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 I study, including the dose optimization cohorts and registrational study design in the second half of 2026. The strength of our data brings into sharper focus the opportunity to conduct our first registrational 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 I assessment of Varseta 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 CytomX. Thank you all for joining today, and before opening up the call for questions, I really want to thank the CytomX team for doing just such an incredible job. Varseta 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 I clinical study, and we sincerely thank our investigators for their thoughtful guidance and diligent leadership. At CytomX, 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.

Operator, Operator

Our first question comes from the line of Edward Tenthoff with Piper Sandler.

Edward Tenthoff, Analyst, Piper Sandler

Congratulations. Very impressed by these continued response rates and PFS from Varseta. 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 color in terms of what might be leading indications beyond CRC for the next EpCAM positive tumor?

Sean McCarthy, Chief Executive Officer and Chairman

Great. Thanks, Ted, for the questions. Regarding the pivotal study, the first pivotal study is still a work in progress, particularly in terms of sizing. We're obviously very encouraged and excited by the level of activity that Varseta is bringing in late-line CRC. I want to emphasize that this continues to be a very late-line patient population, as you can see from the demographics Wayne highlighted. With this updated data set, and PFS in particular continuing to improve, we feel increasingly excited about conducting the pivotal in the third line. We, of course, need to learn about OS and we'll be sharing OS data as the program matures. OS will be a key determiner of our decision-making on the pivotal design. It's too early to say what the size of that study would be, but we think it would be a manageable size and could be executed very quickly.

Chris Ogden, Chief Financial Officer

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

Sean McCarthy, Chief Executive Officer and Chairman

Yes. With regard to your second question, Ted, on non-CRC, as we've said for some time, we are really excited about the broader potential of EpCAM. It's expressed in many, if not all, solid tumors. We have highlighted other GI tumors in our presentation for some time, including gastric and pancreatic. Of course, it's highly expressed in lung cancer, ovarian cancer, and certain breast cancers. So there is 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 on bringing this drug to its first pivotal study, but we're excited to move into other tumor types by the end of this year.

Operator, Operator

Our next question comes from the line of Roger Song with Jefferies.

Jiale Song, Analyst, Jefferies

Huge congrats for the data, very impressive on the efficacy and the tolerability side. 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 then now using the dual. So how should we think about the implementation here and then also the real-world use? What is your advice, feedback on this potential regimen for future? And then in terms of the pivotal also a quick follow-up on that is, can you comment on this, you say, 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 of care?

Sean McCarthy, Chief Executive Officer and Chairman

Thanks, Roger. Great questions. So yes, 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 expansion enrolled. The demand for the drug, as I think you can now see based on what it's doing, was very high. We enrolled the expansions faster than anticipated. Another reason the implementation of the original loperamide prophylaxis was not as extensive as we had perhaps anticipated is that, clinically, these patients, particularly in the very late line, have experienced GI adverse events at various points in their treatment journey. They all have, for the most part, experience with loperamide. And while it brings benefit in treating diarrhea, it also comes with its own challenges. So patients, in some cases, are going to make their own choices about how they manage that drug unless it is really impressed upon them to use it. I would contrast that a little bit to budesonide, where we've demonstrated some key learnings in the expansion phase showing budesonide appears to be effective and patients are very compliant with it. In terms of prophylaxis overall and its use in the real world, we feel really good that it will be adhered to as we continue to refine, update, and learn how to optimize the overall protocol. Regarding 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 overall survival to be the primary endpoint. That is something we'll continue to discuss with the FDA. Of course, we are looking at all ways to accelerate the development of Varseta-M, but for the time being, our assumption remains unchanged: the first pivotal would be principally based on an overall survival primary, though given the unprecedented level of activity of this drug, we'll continue to consider all options.

Operator, Operator

Our next question comes from the line of Matthew Biegler with OpCo.

Matthew Biegler, Analyst, OpCo

Congrats from us as well. Could you comment on positioning relative to the other ADCs in development like Precem-TcT, especially now with diarrheal prophylaxis seeming to work well? Kind of what are like the puts and takes from a physician's perspective in choosing one of the ADCs over the other?

Sean McCarthy, Chief Executive Officer and Chairman

Yes. Thanks, Matt. That's a terrific question about the broader landscape. As we've been saying, and this is really exciting for patients, ADCs are coming to colorectal cancer, and we believe we have a really strong candidate, possibly the best. Varseta is a first-in-class anti-EpCAM ADC and may well be the best-in-class ADC for CRC based on the data we're sharing today. We view this as a highly competitive data set and a highly competitive drug. Importantly, the safety profile, which we continue to understand and learn to manage, is key because it supports moving Varseta into earlier lines of treatment, including first and second line, given its potential to be combined effectively with other components of frontline therapy. This is a very important data set with significant implications for where the drug can go, and we will continue to develop it aggressively. We believe we are very well positioned competitively against, for example, the AbbVie and Merck KGaA programs.

Operator, Operator

Our next question comes from the line of Michael Schmidt with Guggenheim.

Michael Schmidt, Analyst, Guggenheim

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 4 prior lines, the 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 rolling in Phase III? 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?

Sean McCarthy, Chief Executive Officer and Chairman

Thanks, Michael. A series of wonderful questions there, I appreciate that. First of all, in terms of parsing out the patient population in the data set, this continues to be a late-line patient population and we think showing this level of activity is a great place to start. We are obviously very optimistic that as we move the drug earlier, it will continue to show similar, if not more impressive, activity. We are not dissecting the data set any further at this time; we think it really speaks for itself. In terms of duration of diarrhea, we've been very focused on time to onset. As Wayne mentioned, about five weeks is the median time to onset for grade 3 when we see it. With this updated prophylaxis strategy, we are now in a position to really get on top of that and reduce that number, as you’ve seen in the preliminary data from dose optimization. Patients treated with this prophylactic regimen are showing a much reduced incidence of grade 3, so that is our focus. In the earlier experience in the expansion phase, we found that patients are responsive to treatment with budesonide. As Wayne pointed out, 12 of 14 patients treated and followed closely in the earlier stage of the study showed at least a one-grade improvement in their diarrhea, which gave us the initial clue that budesonide could be a terrific addition to the prophylactic strategy. You made another important point on PFS. These PFS numbers are from the expansion phase, and the expansion phase did not have optimized prophylaxis, so we do feel this data can continue to improve. We believe the drug can continue to outperform over time as we learn more about it. That also relates to your question on adjusted ideal body weight dosing, which, as you correctly noted, has been used for a number of ADCs and shown to be effective. It is aimed at decreasing the outliers and compressing the dose range so we have more consistent dosing, and we think that should add to our ability to manage the safety profile, keep patients on drug for the maximum period, and maximize the duration of their clinical benefit.

Operator, Operator

Our next question comes from the line of Olivia Brayer with Cantor Fitzgerald.

Olivia Brayer, Analyst, Cantor Fitzgerald

My congratulations as well on today's data. Sean, 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 I 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 a final question. I 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?

Sean McCarthy, Chief Executive Officer and Chairman

Thanks, Olivia. Great questions. Regarding treatment line, I should emphasize again that this is a late-line patient population; we haven't broken that out further. Across the study, results are very consistent with what we reported in the Phase I disclosure in May of last year, when we did break out the specific number of prior therapies for each patient. One patient had 10 prior lines of therapy and actually had the deepest response, which shows this drug is active in heavily pretreated patients across the board. I should also emphasize something we haven't focused on much today: this is an unselected patient population. We are not selecting for EpCAM or any specific target. It really is an all-comer late-stage population. That is incredibly valuable and attractive for uptake of the drug because patients can be rapidly brought onto Varseta-M without extensive workup, since we are not selecting for KRAS or BRAF mutations or liver metastases. In fact, the percentage of patients in the study with liver mets and KRAS mutations is higher than it was last year; it's about three quarters of patients. I think this gives important insight into how oncologists are using this drug at this early stage. Regarding the pivotal comparator, in the third-line setting the standard of care used by others is bevacizumab plus Lonsurf, so that is something we will consider. As we've said, the data increasingly points in that direction. No decisions have been made yet, but we are actively considering it as the data matures, particularly as we get a read on overall survival later in the year. In terms of prophylactic strategies, let me ask Wayne to comment on extrapolating what we've seen so far into the combination setting.

Wayne Chu, Chief Medical Officer

Yes. As we highlighted today, we believe we have a very effective prophylactic strategy using low-dose loperamide and budesonide, and we don't foresee significant challenges moving into the front line for several reasons. First, both medications are oral, so they are convenient and easy for patients to take. Second, many chemotherapies used in earlier lines cause diarrhea, and standard management typically involves anti-GI-motility agents such as loperamide, so adopting loperamide prophylactically in earlier lines should not be a significant barrier. Finally, combination prophylactic regimens are common for other toxicities as well; for example, nausea and vomiting are typically prevented with multiple agents, some administered intravenously. Overall, we do not see significant barriers to implementing prophylaxis in early-line settings.

Operator, Operator

Our next question comes from the line of Etzer Darout with Barclays.

Etzer Darout, Analyst, Barclays

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 mutant in an earlier line setting based again on the data that you're disclosing today?

Sean McCarthy, Chief Executive Officer and Chairman

Thanks, Etzer. Great questions. Regarding dose selection for the bev combo in other tumors, work is in progress. We are doing some dose ranging with bev, that work has been kicked off, and we'll have more to say about that later this year or early next year. In thinking about dose optimization overall, and where we are now compared to about 10 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. These are both strong options, and we're learning more about them to pick the go-forward dose for the first pivotal. We've 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 apply that experience as we begin work in other tumor types as well. So terrific progress. On KRAS mutational status, that's an interesting question because in the context of EGFR therapies there is patient selection related to EGF receptor and RAS signaling. In our case, one of the strengths of Varseta is that 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 both KRAS wild-type and KRAS mutant. So the main message is that right now we do not need to select patients. That doesn't mean we're not looking at the data for clues about where the drug may be even more active, but currently Varseta is positioned as a drug for all-comer CRC.

Operator, Operator

Our next question comes from the line of Anupam Rama with JPMorgan.

Anupam Rama, Analyst, JPMorgan

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?

Sean McCarthy, Chief Executive Officer and Chairman

Yes, thanks, Anupam. With regards 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 cohort 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 it integrates so much of the work that we've done over the last year or so in understanding the pharmacokinetic and pharmacodynamic profile of Varseta, 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.

Operator, Operator

Our next question comes from the line of Robert Driscoll with Wedbush.

Robert Driscoll, Analyst, Wedbush

Congratulations again on the data update today. Given the reduction in gastrointestinal adverse events with a prophylaxis regimen and the optimized dosing, are you considering reevaluating the higher dose cohorts, specifically cohorts 11 and 12? And second, could you remind us of the focused indications for the broadening study in EpCAM-positive tumor types and how large those cohorts are expected to be?

Sean McCarthy, Chief Executive Officer and Chairman

Thanks, Robert. So with regard to the question on reducing tox and increasing dose, we're very pleased with where we are right now with these 2 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 Varseta. And so we don't really see a need to push the dose higher. Now that said, this drug is 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.

Operator, Operator

Our next question comes from the line of Mitchell Kapoor with H.C. Wainwright.

Mitchell Kapoor, Analyst, H.C. Wainwright

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 kg 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?

Chris Ogden, Chief Financial Officer

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...?

Mitchell Kapoor, Analyst, H.C. Wainwright

Yes, right. Like are there patients in the hospital once a month or kind of like how does the grade 3 diarrhea manifest itself over time?

Sean McCarthy, Chief Executive Officer and Chairman

Yes. So 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. We're really encouraged by these initial data. I'd like to emphasize and commend Wayne and the team for doing terrific work here — listening to our investigators, understanding the patient experience, and keying into some of these clinical observations, particularly with budesonide, and seeing evidence that given some of these PK outliers, adjusted ideal body weight dosing could be a significant addition to the overall dosing strategy. On that note, regarding the role or contribution of adjusted ideal body weight to the improved safety profile, it's hard to tell right now. We're using loperamide, budesonide, and adjusted ideal body weight, and it looks like it's working, so we'll take it. Over time we'll learn more. It wouldn't be a surprise if adjusted ideal body weight is having a significant impact because, as you can see in the PK curves, we wanted to be transparent and show the per-patient PK. In the non-adjusted ideal body weight group 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...

Mitchell Kapoor, Analyst, H.C. Wainwright

Yes. 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 kind of the context of that 10%, right?

Sean McCarthy, Chief Executive Officer and Chairman

Yes. So as we presented in today's update, this is the 2-month cutoff, and that's very relevant because the median time to onset of grade 3 in our experience to date is about 5 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 midyear and into the second half of 2026. So work in progress, but we think a very good start.

Operator, Operator

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

Sean McCarthy, Chief Executive Officer and Chairman

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.

Operator, Operator

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