CytomX Therapeutics, Inc. Aktie

Great. Well, welcome Sean McCarthy, CEO and Chairman of CytomX Therapeutics to Goldman Sachs Healthcare Conference.

First, welcome. Maybe to start things, for those in the audience and listening who may be newer to the CytomX story, can you give a brief overview of Probody therapeutic platform, masking technology and why you think it's differentiated?

Well, thanks so much for the invitation to be here. It's great to be at the conference. And this is a very exciting time for our company, CytomX Therapeutics. And the core technology that we have been working on now for a number of years is a platform we call the Probody therapeutic platform. It's a strategy for taking biologics such as antibody therapeutics and engineering them to be masked in a way that allows for unmasking in the tumor microenvironment.

And the unmasking happens specifically and selectively within tumor tissue due to the presence of active proteases. Protease biology is a phenomenon that's turned on in tumor tissue to enable tumor cells to invade, migrate and metastasize.

We take advantage of this differential between protease activity in normal tissue versus tumor tissue to unmask these mask biologics and improve or in some cases, as we're doing with our current drug, Varseta-M, EpCAM ADC; to actually create a therapeutic window for the first time.

Great. Before we get into Varseta-M, regarding the platform, you announced a pretty significant expansion of your existing collaboration with Regeneron. Can you talk a little bit about the scope of the agreement and what led to the expansion?

Well, one thing about the platform, the Probody platform that we realized very early on in the company's history was that it really offered opportunities to form broad-based partnerships to fully explore the potential of the technology and also quite importantly, over the years to act as a source of nondilutive funding for the company as well.

And the Regeneron deal, we're super excited to have expanded it recently. It's a deal that we first entered into in 2022. It's focused in the field of bispecific immunotherapies such as, for example, T-cell engagers, where there's enormous opportunity to improve therapeutic window for these highly potent immunotherapies by masking.

And in fact, we've shown previously with our own T-cell engager work in the clinic that masking can, for example, significantly reduce phenomena such as cytokine release syndrome. And so the strategy with Regeneron is aimed at in various bispecific constructs to improve tolerability, maximize antitumor efficacy and really make a new generation of immunotherapies to really push the whole field forward.

So it's a very natural application of our technology. And it's also one that since most of our work internally at the moment is focused in ADCs, which we'll come to in a moment, partnering on the immunotherapy side makes a lot of sense.

As you mentioned, we received a significant additional upfront payment from Regeneron, $37 million, for the selection of 2 additional targets. And they also have an additional 6 target picks over the next while, for which they'll pay additional upfront funds and, of course, substantial milestones and ultimately royalties and that doubled the size of the deal from a $2 billion deal to a $4 billion deal.

So just really excited -- really mostly excited about the science that we're doing with them. It's just really been terrific collaborating with their team and just doing some really cool stuff in the lab.

That's great. Turning to Varseta-M. As you mentioned earlier, targets EpCAM target that historically has been very difficult to target, given on-target off-tumor effects. Can you talk a little bit about how the Probody platform allowed you to potentially expand the therapeutic window and make it a viable drug?

Yes, we've had a long-standing interest in EpCAM at CytomX, and it has been a target that has been around quite a long time. In fact, the protein was first described as long ago, believe it or not, it was 1979. And I think that shows just how much of it there is on colorectal cancer cells. It was quite easy to find even with the tools that were available way back then.

So it's very highly expressed on colorectal cancer. Pretty much every patient expresses high-level EpCAM. It's also present on just about every other solid tumor. And for that reason, there have been multiple approaches, multiple attempts to turn EpCAM into a viable cancer drug target over the years. And none of them have worked with systemic therapeutics.

Why is that? Well, the first approaches that were naked antibodies encountered quite early in their development, a significant tox roadblock of acute pancreatitis. Subsequent approaches with higher affinity or empowered anti-EpCAM antibodies, for example, an EpCAM CD3 T-cell engager showed additional toxicities, including liver toxicity and some GI tox.

And these drugs were just -- they didn't get close to exposures in patients. They just could not achieve exposures in patients that resulted in significant antitumor activity. So the experiment was never really done until our masking strategy came along.

But what encouraged us to use masking to unlock EpCAM as a target with some really important clues from locally administered anti-EpCAM strategies, for example, a drug -- there's a drug, an anti-EpCAM CD3 T-cell engager that when given locally into the peritoneum, actually can do quite remarkable things in shrinking peritoneal growth that occur in patients with GI tumors. The growth they're called malignant ascites.

So anti-EpCAM CD3 can shrink malignant ascites in a very effective way, but the drug can only be given locally because it's too toxic systemically. Similarly, an anti-EpCAM bacterial tox infusion called obinutuzumab monotox several years ago was shown to have very robust activity in non-muscle invasive bladder cancer. But again, that drug has to be given locally into the bladder.

So what that told us was if you can get an empowered anti-EpCAM antibody to the right place in a cancer patient, it [Audio Gap] move. So we reason that well, with our masking strategy, really exactly what masking is designed to do. It's designed to diminish activity in normal tissues, allow for activity in tumor tissue where we see unmasking, and that's what led to the concept of Varseta-M.

We -- also reason that colorectal would be the place to start first because it's where the target is most consistently and abundantly expressed. It's where the unmet need is really, really high.

To do this experiment, we empowered our mask antibody with a Topo-1 inhibitor payload to treat CRC because we know that CRC is responsive to irinotecan, so it should be responsive to other Topo-1 inhibitors. And that set up the clinical experiment that we've been doing now for the last couple of years, evaluating what we now call Varseta-M in late-line colorectal.

And obviously, we're so excited at the company to have been able to report really unprecedented antitumor activity with this drug in late-line colorectal showing that we've really broken through on EpCAM as a target for the first time and in a very unique way, enabled by our platform.

Maybe let's dig in a little bit on the data. So you had shared encouraging Phase I dose expansion data in late-line metastatic CRC earlier this year. Can you go a little bit more detail on the data and importantly, contextualize these results versus current standard of care? And what patients are currently dealing with in late-line CRC?

Yes, absolutely. And maybe let's start with that last question in terms of what patients are currently dealing with in late-line CRC. The options available for patients after they've exhausted chemotherapy in the first and second line, the options available are dismal. And the prognosis for patients is dismal. And we have a 5-year survival in metastatic CRC of 13%. So we must do better.

And we reasoned that antibody drug conjugate could bring [Audio Gap] unique in the setting of colorectal because it's a very difficult disease to treat in no small part because it's a very heterogeneous disease. We have the colon, we have rectal cancer. So just there, you've got two different cancers.

We've got left-side and right-sided tumors that we know the biology of can be quite different and they behave in different ways or respond in different ways to therapy. We have patients with or without liver metastases and other remote metastases where CRC can move to. We have various mutational strategies, so BRAF-mutated tumors, KRAS-mutated tumors.

So it's become an increasingly complex landscape where -- and an increasingly fragmented landscape in terms of the treatment paradigm, but EpCAM is present on every tumor. So we took the view, well, we should be able to develop a drug for all of CRC. And that would -- wouldn't that be just amazing if we could do that?

That's really always been the vision for Varseta-M. And that's why in our Phase I study, we've enrolled all-comer CRC patients in the late line regardless of any of those clinical characteristics. And the activity that we've shown so far is independent of any of those clinical characteristics.

We've demonstrated our most recent update in March this year, we showed an overall response rate of 32% in fourth/fifth line colorectal. And that compares to the current standard of care in that setting where response rates, if indeed there is a response rate, are in the 1% to 2% range.

We showed progression-free survival at the 10-milligram per kilogram dose level of 7 months. that exceeds the overall survival of current standard of care in the fourth or fifth line setting, which is around 4 to 5 months.

So a very strong start with this drug. It's highly active. And that's across, again, all clinical characteristics. We have activity in patients with liver mets or without liver mets. We have activity in patients with KRAS wild-type or KRAS mutant left side or right side.

And that's one of the things that's been so exciting to our investigators, is -- and the pull from the clinical sites for the drug has been a function of the fact that it really can be a drug for all of late-line CRC. So really thrilled with what we're seeing so far in terms of the antitumor activity of Varseta-M.

Late-line CRC, obviously, a very rapidly evolving landscape with number of novel agents in the clinic right now, including different ADCs. How do you view Varseta-M -- mentioned maybe some of them, but how do you view the differentiation in this landscape?

So we're really excited to have Varseta-M as the first-in-class anti-EpCAM antibody drug conjugate being developed. And we are a long way ahead of the field.

And we got here by taking, if you like, calculated risks over many years in terms of how to explore the platform and how to apply the platform and how to get to this real killer experiment in colorectal with Varseta-M. So that is now putting us in a very advantaged place with the first-in-class anti-EpCAM ADC.

We also think Varseta-M has the potential to be the best-in-class ADC for colorectal. There are two others in development, ABBV-400, which is AbbVie's c-MET targeting ADC, is making solid progress in colorectal, as is M9140, the CEACAM5 5 targeting ADC being developed by Merck Serono.

They are a little ahead of us. They began their programs a couple of years before we did. They've both shown robust activity in late-line colorectal. They're both now in the early stages of their first pivotal studies in both cases.

But we believe Varseta-M has a very differentiated profile. First of all, we can treat all comers in the context of c-MET, c-MET is high only in about 25% to 30% of patients. And it remains to be seen with the AbbVie drug as to how important target selection may be in the long run. But with Varseta-M, there is no need to select target because every patient has high-level EpCAM as measured by [ IAC ].

We also -- with our drug, the safety profile, we think, is quite unique and very differentiated from the other agents. We see -- in addition to not seeing any of the classic EpCAM toxicities like pancreatitis because our masking is delivering, we see low rates of hematologic toxicity, actually really unusually low rates of heme tox for an ADC and particularly for a Topo-1 ADC.

And I want to underscore that this is a novel linker and payload that we're using. This is the first time this trialanine CAMP59 construct has been explored in the clinic. And so far, so good in terms of the heme tox profile, low rates of neutropenia, anemia and thrombocytopenia.

For some reason, the AbbVie and Merck drugs do show significantly higher rates of hematologic toxicity in the form of all three of those heme tox profiles, and that's clearly something to watch as those drugs develop. So we think -- and on top of that, it looks to us, I mean, a bit more work to do here, but we believe we may have the most active drug as well. So we do see Varseta-M as being intrinsically differentiated from the other ADCs.

There are, of course, other innovations coming in colorectal across immunotherapies. We're obviously watching closely the Exelixis TKI in combination with atezolizumab, which may come to the market before too long.

But again, we just feel like the intrinsic activity, quite honestly, the remarkable activity of Varseta-M in late-line colorectal is highly differentiated, and we're just really excited to get the drug into its first pivotal study beginning next year.

In that March update, you mentioned earlier showed activity across the two prioritized doses, the [ 0.6 ] mg per kg and the [ 10 ] mg per kg. You've completed enrollment in your dose optimization cohort. How should investors think about the overall clinical profile?

Yes. So we're progressively and systematically developing Varseta-M initially for late-line CRC. And that systematic development plan has involved, of course, initially dose escalation, dose expansion where we reported the results recently from the expansion of three doses, 7.6 -- excuse me, 7.2, 8.6 and 10 mg per kg given every 3 weeks.

And those expansions led to the efficacy data that we just reported, again, remarkable antitumor activity in late-line colorectal and also taught us a lot about the integrated safety profile of the drug and how to further optimize dose as we move towards that first pivotal study.

So what we elected to do and what we're in the middle of right now is we further narrowed the dose range to the top 2 doses from expansion, so 8.6 and 10 mg per kg, and we are now enrolling about 20 patients at each of those dose levels in the dose optimization phase, where we've also implemented a couple of additional measures to further refine and help us select the optimal dose where we've employed upfront prophylaxis at these 2 dose levels, treating patients with the antimotility agent, [ loperamide ] and the nonabsorbable corticosteroid budesonide.

And we're also evaluating the role of adjusted ideal body weight dosing to reduce the number of patients who -- when they come into clinic are -- have high body weights, particularly patients who may be obese, where under conventional actual body weight dosing, they probably get a little too much drug such that they can -- there's a risk of overexposure, and that can lead to increased toxicity.

So we're using -- I'd say, exploring AIBW dosing to decrease the number of patients who get this outlier exposure. And we believe all of these measures will go to further improving the safety profile of the drug and specifically the incidence of high-grade GI toxicity.

And that will allow us in the context of the activity that we're looking at for these 2 dose levels to then zero in on which of these two really great choices we've got actually for the pivotal study, which of these two doses we move forward into the first registrational design.

You've articulated publicly vision of expanding in CRC through combos and early line development. Can you talk a little bit about that strategy, the combinations that you're starting to explore in earlier line?

Yes. So there's -- I'd say there's a healthy debate out there right now in the investment community regarding -- which we think is great, regarding Varseta-M. There's a lot of interest in this drug, a lot of interest in what we're doing and a lot of questions being asked. And one of them is the -- our ability to bring Varseta-M earlier in the treatment paradigm. And let me tell you how we're going to progressively do that.

So obviously, we're beginning in the late line. That's where the unmet need is the highest. That's where we've conducted our clinical work to date, and that's where we have unquestionable activity and we believe a clear path to registering the drug in late-line colorectal. That doesn't seem to be much of a debate at the moment. I think everyone is on board with that, that, yes, this is an execution story now about getting the drug approved in late-line colorectal. And we're confident in our ability to do that.

In terms of putting the drug into the earlier lines, we're also confident there. We need to do the work. And so what are we doing? Well, first of all, as I said, we're working very hard to further characterize the safety profile and very specifically reduce the rate of grade 3 diarrhea that we see in patients treated with Varseta-M.

We showed a very strong start in our March 16 update with the first 20 patients treated in dose optimization, where we had reduced the incidence of Grade 3 diarrhea to 10%. And our goal over time is to keep that rate in the 10% to 20% range. That is going to be an acceptable range of grade 3 that everyone we talk to in the clinical community says that's going to -- that will be manageable, particularly in the context of the incredible benefit that the drug is bringing to these CRC patients.

So in the context of that dose optimization work, we're beginning combination work, and we've started to combine Varseta-M with bevacizumab. That's an obvious choice, of course, because bev is so frequently used in -- really across the treatment paradigm in colorectal from early lines into the late line. And so we want to get that experience because we absolutely anticipate that the combination of Varseta-M and bev will be in earlier lines of therapy.

We're also in the second half of the year, beginning combination work with chemotherapy. And the reason to do that is to -- it's a big step towards realizing our ultimate vision for Varseta-M, which is to replace irinotecan in the treatment paradigm. So irinotecan, Topo-1 inhibitor has been well established in the treatment of CRC for many years now, and it's used often in the front line, more typically in the second line in the context of FOLFIRI plus bevacizumab. And it's pretty effective in the second-line setting.

Our goal is to combine with the non-irinotecan components of the FOLFIRI regimen and of course, to evaluate it with bevacizumab as we gain experience with that combination as well.

So we're laying the foundation. We're bringing the drug earlier to the treatment paradigm by, number one, improving how to predict and manage the safety profile and optimize the safety profile; number two, pick the optimal dose for late-stage development; number three, gaining experience with bevacizumab and number four, gaining experience with other -- with chemotherapy.

So you can see in my comments how this program is broadening in real time. We are significantly broadening the scope of the Varseta-M program and really excited to see what we can deliver across the treatment paradigm for colorectal.

Talking about broadening in CRC, let's talk about broadening outside of CRC. EpCAM, as you mentioned, expressed in many other tumor types. As you think about the potential to move into other tumor types, how would you prioritize where to go first?

Well, with colorectal, we certainly feel like we've done the hardest experiment first. We really intentionally designed Varseta-M to be active in colorectal, and it is. It's highly active in colorectal. That was a big decision that we took as a company to focus our Phase I study entirely in metastatic late-line CRC. And that decision, we believe, has really paid off.

Because we've done the hardest experiment first, we are now very excited to move Varseta-M into other tumor types. And there's a long list of cancers that we can potentially address. EpCAM is expressed in many, many other solid tumors, and we do plan to start that work in the coming months.

We do like some of the other GI tumors, if you think -- if you like, franchise adjacent to colorectal as being areas of significant unmet medical need, tumors that are, in many cases, responsive to Topo-1 inhibition and where EpCAM is expressed at high levels. In some of those patients, it may require a patient selection strategy. We have a fully validated EpCAM selection IHC assay ready to go. So that's something that we're looking at right now.

We're working our way through a list of priorities, and we'll be sharing later in the year specifically what our non-CRC or what the first steps in our non-CRC strategy are going to be. Of course, our ultimate goal is to secure a pan-tumor label for EpCAM given its broad expression. That will take a while to get to, but these will be the first few steps along the way.

Shifting gears a little bit. There's a lot of, I think, very understandable investor focus on Varseta-M. But your second program, 801, is also in the clinic. You're advancing in dose escalation with pembro. Can you give a little bit of an overview of the program and what makes you excited about it?

Absolutely. We've already touched on some of the immunotherapy applications of the Probody platform in the context of our ongoing and now expanded work with Regeneron in bispecific immunotherapies. As I said, we absolutely see those types of strategies as being very natural places to go to leverage the power of masking to improve therapeutic window.

But the cytokine field is another whole universe of application of the Probody strategy. And we're working on a number of cytokines in the company, and the interferon program is the most advanced.

So CX-801 is a duly masked version of interferon alpha-2b. Interferon alpha actually was the first immunotherapy to ever be approved. It's a very powerful cytokine. It does multiple things in the tumor microenvironment to drive antigen presentation, T-cell activation. It actually has direct antitumor activity as well through interferon receptors expressed on the cell surface of tumor cells.

And for that reason, it's been utilized extensively in the clinic over many years and has been shown to have single-agent activity in a number of cancers, including in melanoma.

But interferon fell out of use because it's very poorly tolerated when given systemically. It causes a range of significant debilitating side effects. Patients have a very poor experience on systemic interferon alpha, including fever, including chills, including neuropsychiatric challenges. And so the risk benefit for unmasked interferon alpha has resulted in it falling out of use over the years.

But when we come back to its fundamental immunobiology and the way that interferon alpha modulates the tumor microenvironment and the inflammatory microenvironment, it does have all the hallmarks of a cytokine that can drive or if you like, restore sensitivity in the post-checkpoint inhibitor setting to a wide range of cancer types.

And in fact, it's been shown -- it was shown by Merck some years ago that the combination of interferon alpha-2b with PD-1 inhibition is highly active in melanoma. In fact, in frontline melanoma has a 60-plus percent overall response rate, but the challenge is that combination is poorly tolerated with, again, conventional systemic interferon.

So the experiment that we're doing in the clinic in real-time is focused on melanoma with our duly masked interferon alpha-2b, we call it CX-801. It has a peptide mask on the cytokine. It has an Fc mask, both of which are protease cleavable. The combined effect of those two masks shuts down the peripheral activity of the cytokine by about 5,000 fold. So it's very, very quiet in the periphery.

But the goal is when it gets to the tumor that those masks should be removed, and that should allow us to activate interferon biology in the tumor and then restore checkpoint sensitivity. And as you know, this is one of the biggest questions in immunotherapy today, how do we restore activity in patients who have been on checkpoint inhibition? Or how do we create activity in patients who are resistant or recalcitrant nonresponsive in the first place?

So we've been in the clinic now for about a year, and we have already reported some clinical data. Last year at SITC, we showed results in the first 5 patients treated with monotherapy CX-801. The data we shared was pharmacodynamic analysis of on-treatment tumor biopsies in the first 5 patients treated with CX-801. And it looks really exciting where clearly, the drug is activating multiple layers of interferon alpha-2b biology in the tumor.

We're activating interferon responsive genes. We're inducing checkpoint proteins, including PD-1 and PD-L1. And pretty dramatically, we see profound infiltration of cytotoxic T cells into the tumor bed in conjunction with the activation of local chemokines.

So mechanistically, the first few patients we've treated, the drug is working exactly as we've designed. It's also been very well tolerated. We haven't seen -- but we've already achieved dose levels in the clinic that have exceeded the clinically approved dose of interferon alpha.

And at those doses, we're seeing this powerful intratumoral modulation of the immune system, which really sets up the perfect foundation [Audio Gap] the real experiment that we're doing here in melanoma, which is to [Audio Gap] combine well into the combination escalation of 801 with KEYTRUDA.

We're enrolling at our third dose level, and we're on track to have initial clinical data for 801 in a handful of melanoma patients by the end of this year to look at what kind of activity and tolerability we're seeing with the combination in this late-line post-checkpoint inhibitor metastatic melanoma patient population.

In our closing time, maybe taking a step back, looking forward to the next several years for CytomX, how do you see the company evolving as Varseta-M 801 evolves or continues in the clinic as well as continuing to evolve the broader Probody platform?

Well, we're absolutely setting our sights on bringing Varseta-M to the market, building CytomX to commercial stage. Time will fly over the next few years, and we'll be there before we know it. We are well funded at the moment. We raised, as you know, in mid-March on the heels of our March 16 update.

We also, of course, had the cash infusion from the Regeneron expansion, which further strengthens the balance sheet and puts us in a robust position to continue to execute. So Varseta-M monotherapy driving that to its first approval. based on the first pivotal study that we'll initiate first half of next year.

Looking further down the road, bringing the drug into earlier line settings. And by the way, not just second line, we're also setting our sights on the potential of Varseta-M in the front line in colorectal. And this market is absolutely enormous and the unmet need is huge. So a lot of work ahead of us there.

And then continuing to broaden the pipeline, both ourselves with our collaborators, bringing 801 forward to clinical proof of concept, potentially bringing other ADCs into the clinic and just continuing to build the company around this very unique technology that we've been working on for a number of years, which is now absolutely delivering for us in this most remarkable way.

Fantastic. Well, thank you, Sean, for joining us today.

Thanks for having us.

Good afternoon, everyone. Thank you for standing by. Welcome to the CytomX Therapeutics First Quarter 2026 Financial Results Call. Please be advised that today's conference is being recorded.

I would now like to hand the call over to your host for today, Chris Ogden, CytomX's Chief Financial Officer. Please go ahead.

Thank you. Good afternoon 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 this afternoon, we issued a press release that includes a summary of our first quarter 2026 financial results and highlights recent progress at CytomX. We encourage everyone to read today's press release and the associated materials, which have been filed with the SEC. Additionally, the press release, 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 is Dr. Sean McCarthy, CytomX's Chief Executive Officer and Chairman. Sean will provide an update on our pipeline and company progress before I cover the financials for the quarter. We will then conclude with a Q&A session.

With that, I'll now turn the call over to Sean.

Thanks, Chris, and good afternoon, everyone. We're very pleased to be here today to provide an update on our first quarter developments and guidance for what's continuing to be a transformational year for CytomX. 2026 is off to a very exciting start, driven by our excellent clinical progress with Varseta-M in late line colorectal cancer. Varseta-M is a first-in-class EpCAM targeting antibody drug conjugate, or ADC, that was uniquely designed and enabled by our proprietary PROBODY therapeutic masking platform. Varseta-M is the only EpCAM-directed ADC in clinical development to our knowledge, affording us a strong lead and a powerful competitive advantage.

EpCAM is one of the most abundant solid tumor surface antigens and CytomX's breakthrough in unlocking EpCAM as an ADC target positions Varseta-M as a company-building asset over the near and long-term. We see multiple layers of value creation potential for CytomX through the advancement of Varseta-M.

In colorectal cancer, which I'll now refer to as CRC, our goal is for Varseta to become a core component of the standard of care, including in earlier line therapy. Metastatic CRC remains one of the largest areas of unmet need in oncology today, which really underscores the urgency we feel at CytomX to progress Varseta-M towards the market as rapidly as possible. Commercially, in the late line setting alone, this represents a multibillion-dollar market.

In addition to the very substantial opportunity in CRC, we also plan to capitalize on our leadership in EpCAM targeting by developing Varseta-M in other cancers and ultimately as a pan-tumor therapy. Varseta has the long-term potential to positively impact the lives of so many people with cancer, and we are focused on executing with urgency to rapidly progress this potential therapy to regulatory approval.

CytomX has made a very strong start in the clinic with Varseta-M. In our most recent Phase I data update in March this year, we shared updated efficacy data in late line metastatic CRC, showing a confirmed overall response rate between 20% and 32% and approximately 7 months of median progression-free survival. These data position Varseta as a potentially transformative step forward in the treatment of metastatic CRC, where currently available therapies offer overall response rates only in the low single digits and just a few months of PFS.

Varseta-M is working exactly as designed, and it's unlocking the true potential of EpCAM for the first time. With Varseta, CytomX is bringing the power of the ADC class to colorectal cancer.

I want to really underscore here that we've achieved something very significant with our PROBODY platform technology. In our view and based on our preclinical data and efforts of others over many years, we believe we can say with confidence that a conventional unmasked ADC targeting EpCAM would have no chance of achieving dose levels that deliver meaningful anticancer activity due to severe on-target toxicities. In contrast with Varseta-M, we have achieved remarkable anticancer activity in one of the hardest-to-treat cancer types. We firmly believe we have done the hardest experiment first by focusing initially in CRC and that the best is yet to come.

In terms of key near-term objectives for Varseta-M, we are currently in dose optimization with the goal of advancing into a registrational study in late line CRC in the first half of 2027. Today, we're very pleased to share that we have completed enrollment in the ongoing dose optimization cohorts with 40 total patients now enrolled across the 8.6 and 10 milligram per kilogram doses, taking total enrollment across the Phase I study to 113 patients. We remain well on track for an update before the end of this year as we work towards prioritizing 1 of these 2 doses of this highly active drug candidate for our first pivotal study.

In evaluating the potential registrational study dose, we're focused on optimizing the risk benefit of Varseta-M, building on the significant learnings in the dose escalation, expansion and optimization phases.

Regarding Varseta-M safety, we have been highly encouraged by the preliminary results we shared in March from dose optimization that show that updated patient management strategies have the potential to substantially reduce the rate of high-grade diarrhea we saw earlier in Phase I development. This is the principal adverse event of interest with Varseta, and it's something we feel confident we can get an increasingly well-developed understanding of as we move forward through the optimization cohorts and beyond. Typically, patients respond very well to management and our overall discontinuation rates are low, accounting for the impressive progression-free survival data we have shared to-date.

In terms of our next clinical communication, we expect to provide an overall Phase I data update, including safety and efficacy from the monotherapy dose optimization in the second half of this year. We expect these data, along with FDA interactions in 2026 to inform Varseta-M monotherapy dose selection and the first registrational study design.

Our primary goal with Varseta-M is initially to develop in the late line where we see this drug candidate as highly differentiated and frankly, as offering a highly impactful new option for CRC patients. Over time, our vision for Varseta in CRC is to replace systemic irinotecan in the treatment paradigm and potentially to displace chemotherapy entirely. Accordingly, and in parallel to its development as a monotherapy in CRC, we are aggressively advancing Varseta-M into combination studies to enable earlier line utilization.

Strategically, we see an enormous opportunity for Varseta in early line CRC. To access this opportunity, we have initiated a combination with bevacizumab as a first step to moving Varseta into earlier line therapy. Anti-VEGF antibodies, including bevacizumab are extensively utilized in early and late line CRC treatment. So this will be a foundational combination.

Varseta-M doses assessed in combination with bevacizumab will include both every 2 weeks and every 4 weeks schedules to align dosing with the approved 5 mg per kg every 2-week schedule standardly used in the clinic today. We expect initial clinical data for this combination by the first half of 2027. We're also accelerating plans to study Varseta in combination with chemotherapy, and we plan to begin a Phase I/II chemotherapy combination study in the second half of 2026, evaluating Varseta in combination with bevacizumab by fluorouracil and leucovorin with the potential to advance into the first and second lines.

In addition to our work in colorectal cancer, we are on track to begin Phase I expansion cohorts in additional EpCAM-expressing indications in the second half of 2026. We look forward to providing an update on the initial non-CRC indications later this year with the goal of generating clinical data supporting Varseta's ultimate pan-tumor potential.

Turning now to CX-801, our masked interferon alpha-2b program, which is currently in Phase I development for advanced checkpoint refractory melanoma. Our vision here is for CX-801 to become a new centerpiece for combination cancer immunotherapy as we harness and redirect the power of this cytokine to reprogram and activate antitumor immunity. We initially see CX-801 as well positioned to address the high unmet need in PD-1 refractory melanoma where response rates to approved standard of care remain in the single-digit percentages with limited treatment options available or in clinical development.

Interferon alpha-2b is a potent cytokine that has validated clinical activity in melanoma and other cancers and our initial translational data from Phase I suggests that CX-801's mechanism of action is working as designed in the tumor microenvironment. Importantly, our data shared at SITC in 2025 are highly supportive of our strategy for combining with the checkpoint inhibitor, KEYTRUDA.

Our ongoing CX-801 Phase I monotherapy dose escalation study has advanced to the fourth dose level, which exceeds the approved clinical dose of unmasked interferon alpha-2b. CX-801 has been well tolerated to-date, suggesting that our masking strategy is broadening the therapeutic window as designed. Combination dose escalation with KEYTRUDA is also progressing very well and is now actively enrolling in the third dose level. Overall, we view CX-801 as very well positioned to address a significant unmet need in advanced melanoma, and we look forward to sharing initial clinical data by the end of this year.

With that, I'll now transition back to Chris.

Thank you, Sean. Reinforcing Sean's earlier sentiment, we kicked off 2026 from a position of strength, not only with Varseta-M's encouraging data, but with the financing completed in March, a strong balance sheet that enables us to continue to execute against the significant value creation potential of Varseta and the PROBODY platform.

CytomX is in a strong financial position with projected cash runway to at least the second half of 2028 and the potential to achieve multiple milestones. Of note, our runway guidance does not include any supplemental milestones from existing collaborations or any new business development.

Importantly, we expect our current cash position will enable us to advance Varseta-M into a registrational study in late line CRC, also deliver safety and efficacy data for Varseta-M in combination with bevacizumab as well as Varseta-M data in combination with chemotherapy and deliver initial clinical data for Varseta-M in indications beyond CRC. Based on these opportunities, which have the potential to yield significant long-term commercial potential, we expect our capital allocation to be highly focused on Varseta-M over the near to medium term.

With that, I'll now walk through our first quarter financial results. As of March 31, 2026, we ended the quarter with $346.7 million in cash, cash equivalents and investments versus $137.1 million in cash as of December 31, 2025. Looking at revenue and operating expenses for the quarter, total revenue was $10.3 million compared to $50.9 million in the first quarter of 2025. The decrease in revenue was primarily attributed to the completion of obligations in 2025 under collaborations with Bristol Myers Squibb and Amgen.

Operating expenses for the first quarter were $29.8 million compared to $28.3 million in the first quarter of 2025. R&D expenses were $19.2 million during the first quarter, representing an increase of $0.4 million versus the first quarter of 2025, primarily due to increased manufacturing activities for Varseta-M, partially offset by $1.8 million in restructuring expense incurred in the first quarter of 2025.

G&A expenses increased by $1.1 million during the 3 months ended March 31, 2026, to $10.6 million compared to $9.4 million for the corresponding period in 2025, which included $1.1 million of one-time restructuring expenses.

As we move throughout the remainder of 2026, we will continue to be disciplined in our capital allocation and advancing the highest Varseta-M priorities for patients and CytomX stakeholders.

With that, I'll turn the call back to Sean for closing remarks.

Thanks, Chris, and thanks, everyone, for joining us today. We're very proud of the remarkable progress we've made with Varseta-M, and we're now in the privileged position of bringing the transformative potential of an EpCAM directed antibody drug conjugate to colorectal cancer patients. We look forward to providing additional updates as the year progresses and as the development program for Varseta-M broadens substantially. We also remain focused on the advancement of the clinical program for CX-801 with the initial goal of delivering a more effective treatment option for patients with advanced melanoma.

Before I conclude today's call, I want to sincerely thank and recognize the patients who join our studies, their families, our clinical investigators and our dedicated CytomX team.

With that, operator, let's go ahead and open up the call for Q&A.

[Operator Instructions] And our first question will come from Paul Jeng of Guggenheim.

So for Varseta-M, can you just talk a little bit about the scope of the clinical update you'll have in the second half? Will some or most of the dose optimization cohort patients have sufficient follow-up for PFS? Do you plan to break down responses by subgroup such as third line versus fourth line plus of therapy? And then how are you thinking about initial disclosures of overall survival from the study?

Yes. Thanks, Paul, for the questions. So we are expecting that the update in the second half will be fairly substantial. As we've mentioned today, we've now enrolled 113 patients across the dose escalation expansion and now optimization phases of the study. So this is a very rich data set that is emerging for our first evaluation of Varseta in CRC patients.

So in terms of the update, it will be across the entire study. It will include data from the full 40 patients optimization phase. And yes, we expect to have a reasonable follow-up in terms of safety and efficacy for the optimization patients, including, I would think an initial estimate of PFS. As you'll recall, last year, our guidance as we came through the second half of 2025 was that we wanted to communicate data this year when it was mature and meaningful, and that continues to be the case and continues to be our philosophy.

In terms of subgroups, yes, we'll certainly communicate the demographics of the patient population that we're enrolling. We do expect it to look quite similar to the patient population that we enrolled in the escalation and expansion phases. And I want to emphasize that one of the really differentiating and distinguishing features of Varseta-M as a drug for colorectal cancer is that we can treat every patient. We're not selecting patients. We don't need to select patients. This really is a drug for all-comer late line CRC. And we see this as potentially a huge competitive advantage as we move the drug toward the market.

In terms of the third component of your question and overall survival, yes, we absolutely anticipate having or providing, if you like, a first look at OS in this update in the second half of the year.

And our next question will be coming from the line of Edward Tenthoff of Piper Sandler.

Really excited for more data looking in the back half. I just had one quick clarification question on 1-2 chemo combo. Will that be triplet? So will you have -- or I guess, quadruple with the 2 chemos? And will that include Avastin? And do you need any of the Avastin combo data to start that chemo combo trial? I just want to make sure I understand that correctly.

Ted, thanks for the question. Taking the first question first in terms of the nature of the combination, yes, we absolutely will want to evaluate the Varseta-M plus chemo plus bev combination. We will want to look at that. Right now, we don't see the data from the ongoing -- sorry, Varseta-M plus bev as gating necessarily to starting that work in the second half. We do, of course, see that bev combination work -- the Varseta-M/bev combination is going to be really important to further down the road, considering from a registrational study perspective, the design of that study, if indeed we do, at some future point, decide to compare Varseta-M plus bev against other comparator arms. But we do plan to look at that triplet in the chemo combination later this year.

Yes. And then that's really helpful. And then when it comes to the new EpCAM positive tumors, I'm really excited to hear what you're thinking is. Maybe you can share with us now kind of what goes into some of that prioritization because there's a lot of different places you could go?

Yes, there are so many places we could go because EpCAM is such a broadly expressed cancer target on so many solid tumors. So we do have a lot of opportunities to work through and prioritize. It's not lost on us, of course, or really anybody else that there are some -- there's quite a number of, if you like, adjacent GI tumors that can make a lot of sense to evaluate with Varseta-M. There are also many others. So something that we continue to work through and prioritize, and we will communicate more specificity on exactly what we're planning to do in the second half.

[Audio Gap] line of Anupam Rama of JPMorgan.

This is [ Joyce ] on for Anupam. I think previously, you had said you were targeting midyear FDA interactions to start discussing the pivotal trial design. To what extent is reaching alignment on the trial design ultimately gated on seeing your dose optimization update later this year? I think you can start having those conversations with FDA now with your initial data in hand. So just how should we think about the update later this year in terms of solidifying your registrational strategy?

Yes. Thanks. Great question. Really important question. And I'll start by saying that we're just really excited to have this dialogue with FDA as we progress through the year. We anticipate multiple interactions. And we do expect that the data from the optimization cohorts will be central to those conversations in relation to dose selection for the first pivotal study. That's, of course, a large part of the reason we're doing these additional 2n equals 20 cohorts at the 8.6 and 10 mg per kg doses is to generate data to satisfy Project Optimus and have a highly productive a conversation with FDA as we can.

So yes, that data will be important, and that's why we're guiding that really towards the end of the year or by the end of the year, the next comprehensive update that we plan to provide will not only include, of course, data across the 113-patient Phase I study, but will also include guidance as to where we're going next in terms of design of the first pivotal study, what the patient population is, what the comparator arm is and of course, what the dose is.

And our next question will be coming from the line of Roger Song of Jefferies.

Congrats on the progress. This is Nabeel on for Roger. Maybe one for me first. So just on the 8.6 versus 10 mg per kg, just a little bit curious if you could maybe give some color on the dose decision logic because we saw the headline ORR of 32% versus 20%. But what is the framework that you guys would apply to finally lock in on a dose? Or is it related to tolerability at this point? Because we noticed in the exposure response model, it looks like there's pretty similar efficacy. So are you weighing depth and durability? Are you weighing safety more?

Yes. Thanks, Nabeel. That's obviously -- there's a lot in that question in terms of the work that we are doing in real time, and we'll be continuing to do as we move through the year to lock in on the go-forward dose. And first thing I'll say is we think we've got 2 great choices here in terms of the 8.6 and 10 mg per kg doses, both of which, as you'll recall, we're currently evaluating on an adjusted ideal body weight basis in the context of the dose optimization cohort.

So we're going to learn a lot as the year goes by as to the performance of these 2 doses, of course, in terms of efficacy, also in terms of safety. And on efficacy specifically, as we've been discussing for quite some time now, we do anticipate that at least our base case for our first registrational study, we do anticipate that overall survival will be our primary endpoint. And that, of course, means that ORR is really an important metric here for how the drug is performing, and this drug is performing extraordinarily well, as you said, 20% ORR at 8.6%, 32% at 10 MPK, that is remarkable activity.

But we also have remarkable progression-free survival of 7 months as reported on March 16, and we are very keen to see how that translates into OS as the data matures with OS, of course, as I just mentioned, being our primary and most likely primary in the go-forward pivotal study. So we'll see. We'll see how these 2 doses deliver in terms of all of these different metrics, and we'll choose accordingly.

And our next question will come from the line of Olivia Brayer of Cantor Fitzgerald.

For that second half data disclosure, can I just clarify that you guys plan to break out tolerability and efficacy for those 40 patients specifically in the optimization cohort? And if so, will we still get PFS and potentially even an early look at some OS data from those patients specifically? And then from a timing perspective, top line second half of this year, does that mean you'll likely follow it up with a presentation at a medical conference sometime in early 2027? And then I've got one quick follow-up on the new formulation with bev.

Yes. Thanks, Olivia. So yes, obviously, the 40 patients optimization cohorts is of high interest to us and others. And so we absolutely plan to report the full safety picture, which we gave an early look at in the March 16 disclosure. We gave an early look at the first 2 months of experience, which is very encouraging. So we plan to give a similar look for the full 40 patients by the end of the year, together with efficacy. And as I've already mentioned, PFS would certainly be a goal there to have PFS for those 40 patients.

I think OS is going to be too early. We're just -- as we've reported today, we've completed enrollment, but that's been relatively recent. So I think OS is going to be immature. But we do anticipate having OS from the escalation and expansion phases, which I think will be particularly telling because remember that in those patients, those first escalation and expansion patients, we have not optimized our adverse event management plan, but we were still able to deliver 7 months of PFS, and we're optimistic that we'll have an encouraging OS number as we get to report that later in the year.

In terms of venue for data updates, we do think a medical meeting this year is on the cards. Certainly, as we move into 2027, additional medical meetings, we're, of course, keeping our options open.

Okay. Very helpful. And then for the combination with bev, is there anything you guys can tell us at this point about the formulation work that you've done to get Varseta-M administered as an every 2 and 4-week dosing schedule instead of every 3 weeks? Or is there any data that you'll be sharing there at some point?

Well, there's no real formulation work that needs to be done. It's simply an adjustment of the schedule from Q3 to Q2 and then accordingly to Q4. And that's to match the -- as I just mentioned on the call, that's to match the established clinical use of bev in the FOLFOX/FOLFIRI setting on a 2-week schedule. So there's no additional formulation. It's simply a question of adjusting the frequency of dosing to match the use of bevacizumab in the marketplace today.

And our next question will come from the line of Matt Biegler of OpCo.

Just kind of curious how you're seeing the emerging competitive profile here of Varseta-M versus the other ADCs that are also in development, Precem-TcT being one of them. And then I guess more importantly, do you think this is like a winner takes all, zero-sum game here with the Topo-1-based ADCs? Or do you think different patients might get different ADCs depending on certain health status, et cetera?

Thanks, Matt. Well, we certainly don't see this as winner takes all by any means. And I think that would be a very unusual scenario for an oncology drug in this class in an area of unmet need like this. I mean, our thinking is very different on that question. So first of all, with regard to Varseta-M, we have a first-in-class anti-EpCAM antibody drug conjugate. And again, I really can't emphasize how important it is to realize that we've done something really, really -- I'll use the word special with our technology to unlock the potential of EpCAM for the first time with our PROBODY therapeutic platform.

Secondly, we really do believe that Varseta-M has the potential to be the best-in-class ADC for colorectal cancer. This drug is highly active. It's highly active in terms of its response rate. It's highly active in terms of its progression-free survival, and we'll see what it can deliver in terms of overall survival as we move forward. This is a very active drug, and we believe does have the potential to be best-in-class.

So we're going all out with this drug to get it to the market as quickly as we can. We think it's highly competitive. And we think there's a ton of value to build in our company with this drug, most importantly, an enormous amount of benefit to bring to these patients.

[Operator Instructions] Our next question will be coming from the line of Mitchell Kapoor of H.C. Wainwright.

This is [ Yan Zi ] sitting in for Mitchell. I was wondering, could you break -- so actually, with the enrollment now complete in the 40 patients dose optimization cohort, can you give any update on whether Grade 3 or higher diarrhea in the optimized adjusted ideal body weight plus prophylaxis population is still tracking closer to that initial 10% rate that was seen in the first 20 patients or whether it moves closer to something like the historical 25% to 30% range at the 8.6 and 10 mg per kg as follow-up has occurred?

Well, no new data today. That data will be coming. We're obviously -- we're highly encouraged by the initial data we presented on March 16 from the first couple of months of follow-up of the first 20 patients enrolled into the optimization cohorts with a rate of Grade 3 diarrhea of 10%. I think we commented at the time, and we've been very consistent about this over the last few months that our objective is, of course, to manage the rate of Grade 3 to the best of our ability with this updated AE management strategy that includes upfront use of loperamide and budesonide. It appears to be performing very well as of that first data update, and we're encouraged to see additional data now from the full 40 patients. That data will be shared later in the year.

Our goal overall is to manage the Grade 3s into the 10% to 20% range. That we think is really the target. And that's based on our own research. It's based on a lot of conversations we've had. And quite honestly, a lot of work that's been published and presented by others over the last 6 or so months. So we're -- we feel we're very much on track, as I said in my prepared remarks, to get a strong handle on that particular aspect of the Varseta-M program.

I see. Curious also, so for an optimized regimen, how standardized is prophylaxis practice? Do you see any implementation friction that could matter in a community oncology setting if, for example, Varseta-M moves earlier in late line CRC?

We really don't. The upfront work that we're doing right now with these optimization cohorts is absolutely intended to pin down a prophylaxis strategy that will be readily translated into the community setting as we move into our first pivotal study and of course, as we bring the drug to the market. So it's a good question. It's an important question, and it's one that we've asked ourselves, and that is, again, just to restate a big part of why we're doing this upfront optimization work right now. But we -- right now, we don't see any challenges with the translation, if you like, of this updated AE management plan into a larger number of sites and ultimately into the commercial marketplace.

I'm not showing any further questions in the queue. I would now like to turn the call back to Dr. Sean McCarthy, Chairman and CEO, for closing remarks.

Thank you. And again, I'd just like to thank everyone for joining us today. We're very excited about our progress here. I hope that comes across. And we really look forward to providing additional updates as the year progresses.

And this concludes today's program. Thank you for participating. You may now disconnect.

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' 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 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 or 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' Chief Executive Officer and Chairman; and Dr. Yu-Waye Chu, CytomX' Chief Medical Officer. Sean will provide introductory remarks regarding the clinical data and Varseta program strategy, and Yu-Waye 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.

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 incidents 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 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. 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 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 market. 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 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 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 license from ImmunoGen. The linker is also novel a trialanine-clevable 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 Waye 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 Waye to talk you through the details of the data.

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 these 4 lines of prior therapy and over a quarter received prior bevacizumab plus Lonsurf.

3/4 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 a 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 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/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 TOPO 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 managed diarrhea, where 12 of 14 patients who had Grade 2 or Grade 3 diarrhea experienced at least a 1 grade reduction 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-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 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, Waye. 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 in 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 in HER2 has for HER2.

Moving now to our upcoming milestones. With this updated data, we do believe we have put Varseta-M 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 Instructions] Our first question comes from the line of Edward Tenthoff with Piper Sandler.

Congratulations. Very impressed by the continued response rate 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 larger 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.

Great. Thanks, Ted, for the questions. With regards to the pivotal study or the first pivotal study, still work in progress, of course, in thinking about sizing. We're obviously super encouraged and excited by the level of activity that Varseta is bringing in late-line CRC. And I want to emphasize, actually, this is -- continues to be a very late-line patient population, as you can see from the demographics that Waye highlighted. We do see that with the -- 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 determiner of our decision-making on the pivotal design. But too early to say what the size of that study would be, but we think it would be a manageable size and executed, we think, very quickly.

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

Yes. With regard to your second question, Ted, on non-CRC, as we've said for some time, we really are we're really 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 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.

Excellent. Well, great work, and thanks for sharing all the details.

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

Then 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 duals. 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 care?

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 6 or so months is just how rapidly the expansion is enrolled. The demand for the drug, as I think you can now see, based on this -- what it's doing. The demand for the drug was very high. We enrolled the expansions faster than anticipated. And so 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, they, in some cases, going to 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 demonstrate some key learnings in the expansion phase that budesonide is looking to be affected as well. And this is a drug that is -- 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 what -- how to optimize the overall protocol.

In terms of progression-free survival being a primary endpoint, we -- 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 Varseta-M, but for the time being, our assumption continues to be unchanged. 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.

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

Congrats from us as well. Could you comment on positioning relative to the other ADCs in development like PresenTCT, especially now with diarrhea prophylaxis seeming to work well? Kind of what are like the puts and takes from a physician's perspective in choosing 1 of the ADCs over the other?

Yes. 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 divest. So I want to emphasize again that Varseta 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 Varseta 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 showing today with big implications to 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.

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

Thanks, Michael. A series of wonderful questions there. So I appreciate that. So first of all, in terms of parsing out the patient population in the data set, I guess this is -- just continues to be a late-line patient population that we think showing this level of activity is 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 Waye mentioned, about 5 weeks is the median time to onset for grade 3 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 Patients treated with this prophylactic regimen, obviously, you're seeing a much reduced incidence of grade 3. 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 Waye pointed out, we saw 12 or 14 patients treated who we followed closely in the earlier stage of the study show at least 1 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, key patients on drug for the maximum period of time, maximizing the duration of their clinical benefit.

Our next question comes from the line of Olivia Brayer with 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?

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 I 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 on to Varseta-M without a whole lot of workup necessary because we're not selecting for KRAS or BRAF or liver mets.

And you could 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 3/4 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 in that -- it 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 Waye to comment on that in terms of the extrapolation of what we've seen so far into the combination setting.

Yes. So I mean as we highlighted today, I mean we really believe that we have a very effective prophylactic strategy with the dual use of low loperamide and budesonide. 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 many of the chemotherapy agents used in early line settings themselves cause diarrhea. So management of diarrhea with the standard agents will formally involve some form of anti-GI-motility agents such as loperamide.

So the adaptation of loperamide in the 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, it's 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 we don't -- 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.

Our next question comes from the line of Etzer Darout with 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 [indiscernible] in an earlier line setting based again on the data that you're disclosing today?

Thanks, Etzer. With regard to -- great questions. With regard to dose selection for the bed combo and other tumors, work in progress. So 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 thinking about where we are now compared to where we were 10 or so months ago, we've narrowed the field from 3 active doses 7.2, 8.6 and 10, so the 2 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 with 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, there is patient selection that relates to the signaling mechanism of the EGF receptor and RAS signaling and such like. In our case, this is one of the beauties of Varseta, 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 we -- 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 Varseta is that this is a drug for all-comer CRC.

Our next question comes from the line of Anupam Rama with 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?

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 Waye 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 set. 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 Waye also mentioned, will be very helpful as we go to FDA and discuss considerations around project Optimis.

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

Congrats again on the data update today. Just kind of given the reduction in GI AEs with a prophylaxis regimen, and a lot of things kind of in the optimized dosing. Just wondered if you're considering reevaluating the higher dose cohorts here, the 11 or 12? And then second question, just could you just remind us of the focused indications here for the broadening study for [indiscernible] positive tumor types and how big those calls might be?

Thanks, Robert. So with regard to the question on reducing tops 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 Instructions] Our next question comes from the line of Mitchell Kapoor with 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 in 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.

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...

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?

Yes. So the -- our focus -- Mitch, it's a good question. Our focus is 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 again, I'd like to really emphasize and really commend Waye 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 dosing strategy.

So in terms of -- on that note, in terms of the role or the contribution of adjusted ideal body weight to the improved safety profile, hard to tell, obviously, right now, we're using loperamide, budesonide and AIBW. And it looks like it's working. So we'll take it. And I think over time, we'll learn more. But it would be expected I guess, said slightly differently, I 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...

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 kind onset of diarrhea, so we can understand kind of the context of that 10%, right?

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.

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.

Welcome, everyone, to the 44th Annual JPMorgan Healthcare Conference. My name is Anupam Rama. I am one of the senior biotech analysts here at JPMorgan. I'm joined by my squad, [ Rathi Pinhe ], Joyce Zhou and Priyanka Grover. Our next presenting company is CytomX and presenting on behalf of the company, we have CEO, Sean McCarthy. Sean?

Thank you, Anupam, and thanks to the JPMorgan team for the invitation to present. It really is a privilege to be here. I'm also joined by the squad. Chris Ogden, CFO; Rachael Lester, Chief Business Officer, and I see at the back, Wayne Chu, Chief Medical Officer.

So once again, real pleasure to be here. Last year 2025 was a super exciting year for CytomX. We don't expect 2026 to be any different. We're working hard on building a highly differentiated pipeline, and the theme of what I'll talk about today is unmasking advances in oncology. The clicker doesn't seem to be working.

While, we're doing that, I'll say that in the course of my presentation, I will be making certain forward-looking statements, and I refer you to our SEC filings. Thank you so much.

So CytomX is a South San Francisco-based oncology-focused biotech company. And for the last 15-plus years, we have been developing, optimizing and applying our highly unique Probody therapeutic platform which is a novel strategy for masking antibodies and improving therapeutic window. We are the leader in this field. We have been for a long time, and we continue to lead this entire strategy.

We currently are highly focused on 2 clinical programs for Varsetatug masetecan, which is our EpCAM-targeting Probody Topo-1 ADC, which we're developing in colorectal cancer and CX-801, which is our Probody version of interferon alpha-2b which we're currently developing in melanoma.

We're in a robust cash position. We're funded well into Q2 2027. We completed our most recent financing last May that runway excludes any potential milestones or new business development. And we have been very active in business development over many years, resulting in a number of very high-quality partners, including BMS, Amgen, Astellas, Regeneron and Moderna. And I am privileged to work every day with 70 outstanding employees, and we have integrated R&D capabilities again at our South San Francisco HQ.

So over the years, we have learned a lot about how to mask antibodies and other therapeutic modalities. And as I said, we've really CytomX has achieved every first in this field. And over the years, we have built the foundation of knowledge to allow us today to really have the most focused strategy for product development that we ever have. We are leveraging the technology to really think deeply about the right combination of what's the clinical problem you're setting out to solve? What is the target on the tumor that you're going to go after? And then what's the effective mechanism? What's the best way to actually affect cell killing in the context of that therapeutic challenge that we're taking on.

And in the context of our 2 lead programs, they're both really great illustrations of this focused strategy. So first of all, the EpCAM Probody, which we now refer to as Varseta-M or Varseta that's how you'll hear me refer to it as I go through my presentation. This is a very focused strategy. colorectal cancer, EpCAM is the target. It's an antibody drug conjugate and the payload is a Topo-1 inhibitor. I'll have a lot more to say about that in a moment.

The second program, CX-801 interferon alpha-2b, tightly masked to enable opening a therapeutic window for this highly potent cytokine, which really is 1 of the most powerful modulators of the tumor microenvironment, and we're developing it in a very focused way in melanoma. I'm not going to say a lot more about the platform from here on other than we really have figured out how to mask antibodies in a protease-dependent way.

And the way the platform works, involves masks being removed in the tumor microenvironment, specifically and selectively by tumor-associated proteases. And we've gone very deep into this technology over more than a decade. Our platform has driven a highly differentiated pipeline.

Let me just briefly lay out what we are highly focused on today as a company. With regards to Varseta-M, our EpCAM targeting Topo-1 ADC, we are expanding the Phase I study to encompass more than 100 patients. We are on track for a data update by the end of Q1 of this year. Our first data was presented, as you probably know, in May, of last year, which I'll recap briefly in a moment.

And in the context of that 100-patient expansion, we're looking, of course, to further substantiate the very strong efficacy that we saw in late-line colorectal cancer with Varseta also further understand the safety profile, how to understand and manage the safety profile, how to model go-forward doses, how to plan for our first registrational study in late-line colorectal cancer, begin to move the drug into earlier lines of therapy. And in that regard, we have commenced a combination with bevacizumab. We are commencing that during Q1 and also to explore additional tumor types because EpCAM is present in many, if not all, solid tumors and really represents a remarkably large opportunity in oncology.

We're also working hard to advance CX-801 to proof of concept in combination with KEYTRUDA by the end of this year. So I'll turn now to Varseta, our EpCAM-directed Topo-1 ADC, which we're developing in CRC. I don't need to tell you that antibody drug conjugates have transformed the treatment of many tumors initially hematologic tumors increasingly solid tumors. And we're seeing ADCs come earlier and earlier in the treatment paradigm and increasingly show opportunities to actually replace systemic chemotherapy in a wide variety of regimens across a wide variety of tumor types.

Varseta-M is bringing the potential and the power of antibody drug conjugates to colorectal cancer. Colorectal cancer remains 1 of the biggest unmet needs in oncology, 1.9 million patients per year diagnosed around the world, that's going to grow to more than 3 million patients by 2040. It's the second leading cause of cancer death worldwide, and 5-year survival in patients with metastatic CRC is a dismal 13%. This is an enormous market. And in fact, colorectal can be considered the largest by far, untapped, solid tumor market after the last 20 years of innovation in many other tumor types, including, of course, the immunotherapy wave, which is really yet to make impact in colorectal. In the third line alone, we have 45,000 treatable patients in the United States, resulting in more than a $5 billion market opportunity.

These numbers are very big. It's a very large untapped market. And I would say it's also an untapped market that is beginning to attract attention from large pharma after many years of really very little innovation, we are starting to see innovation and CytomX is at the leading edge of that innovation wave with Varseta. Varseta targets, EpCAM epithelial cell adhesion molecule. This is one of the most broadly and abundantly expressed tumor antigens that we know of. 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. It's uniformly and highly expressed across CRC across all stages of CRC and the challenge with EpCAM has been, it's present on most, if not all, 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.

For example, the T-cell engager solitomab developed by Micromet and Amgen ran into significant GI and liver toxicities at very low doses and was discontinued early in development, was unable to get to therapeutically active levels of the drug. We do know, though, that if you can get an empowered EpCAM antibody to the target in a patient with local delivery, it actually can be effective, and this is illustrated very well by a drug called Korjuny, which has recently been relaunched in Europe for the treatment of intraperitoneal malignant ascites but the drug has to be given locally because systemically, it's too toxic.

This is really important because it shows that engaging EpCAM can result with the appropriate empowered antibody in potent antitumor activity. So we designed and developed Varseta, a novel EpCAM targeting Probody ADC to target EpCAM systemically ultimately across a wide range of tumor types. So the molecular design is shown here. The -- this is Varseta is based on a high affinity anti-EpCAM antibody which we have masked using our protease-dependent peptide masking Probody strategy designed to minimize binding in normal tissues. The mask is removed within the tumor, allowing binding and engagement with target and delivery of the effector mechanism.

The effector in Varseta being a novel topoisomerase-1 payload called CAMP59 that we licensed from ImmunoGen, it's a novel linker as well, a tri alanine cleavable peptide linker optimized for bystander effect. We have a drug antibody ratio of 8. We really believe with this drug candidate, we have the right target, the right indication and the right payload. The current standard of care in late-line metastatic CRC is highly inadequate.

The options available to patients result in objective response rates in the low single digits, progression-free survival of 2 to 5 months. And these agents are really the best that's currently available for the treatment of patients after they've exhausted chemotherapy strategies. We must do better. And we are doing better. So our data that we shared last year, May 12, 2025, was a very strong start with the development of Varseta.

We showed in a patient population with 4 -- median of 4 prior lines of therapy, a 28% confirmed overall response rate, 94% disease control of 5.8 months of preliminary progression-free survival, showing us very early in the development of this drug after just 12 months in the clinic that we have the potential for Varseta to become a new standard of care in the treatment of late-line CRC.

We also were able to treat every patient enrolled in the study or enroll patients regardless of clinical characteristics, as I'll show you on the next slide, because EpCAM is indeed expressed at very high levels in every patient. We also demonstrated a favorable safety profile with no EpCAM toxicities, the types of toxicities that have limited EpCAM in the past. So a really exciting start. And I have to show you the waterfall plot from last May because this has excited us and a lot of other people in the oncology community and in the investment community because this is the type of waterfall that you just don't see in late-line CRC. This is essentially a fifth line CRC patient population. And you can see the depth of these responses across multiple doses.

And also, I want to point out here, if you look at the bottom of this chart, we've enrolled patients, as I said, just now independent of their clinical characteristics. Over the years, CRC has become an indication where patient selection based on specific pathways or specific mutations or specific targets has become fairly typical, for example, whether or not a patient has liver metastases, whether or not a patient has a left sided or a right-sided tumor whether or not a patient has a KRAS mutation. But you can see that we have activity across the board, and this is a huge advantage for this drug once it reaches the market because it means that no patient selection should be required for the selection of patients to treat with Varseta so a really exciting start, and to position that activity relative to the current standard of care in the late line that I just showed you, we have a wide window in terms of comparing to the existing benchmarks. 28% overall response rate, 94% disease control, 5.8 months of PFS. Of course, too early to comment on overall survival that will come over time but a highly competitive profile for further development in late-line CRC.

On the safety side, the safety profile that we presented is encouraging, the -- rather remarkably, we have not seen any evidence of the classic EpCAM toxicities of pancreatitis and liver enzyme elevation, strongly suggesting that masking is delivering. This is the first time that a systemic anti-EpCAM antibody therapeutic has successfully demonstrated antitumor activity and it's an ADC to that. So we're a long way ahead now in terms of being the only -- not only the only anti-EpCAM therapeutic antibody but also the only anti-EpCAM ADC.

So we've really broken through, we believe, on the target. In terms of the safety profile, we're encouraged so far. AEs generally manageable and reversible most grade 1, grade 2. As I said, no signs of pancreatitis or serious liver tox. No evidence of ILD, which has been a challenge for a number of Topo-1 ADCs, as you know. An attractive hematologic profile, low rates of high-grade anemia and neutropenia, which may be attractive for future combinations.

The most common treatment-related adverse event we saw in the Phase I study so far is diarrhea with a 21% to 22% rate of grade 3 diarrhea. That is something that we're laser-focused on understanding more of as we expand to this 100 patient data set, including evaluating prophylaxis of patients to try to prevent or reduce the incidence of high-grade diarrhea in these patients.

And that's really the 1 safety signal that we have with this drug to really learn more about. In terms of where we are and where we're going, we're currently expanding the Phase I at 3 dose levels, 7.2, 8.6 and 10 mg/kg. Those together, those expansions will reach 100-plus patients by the end of Q1. Our goals with the expansion update, which we'll give by the end of Q1 will be, of course, First question, does that level of efficacy replicate in a larger patient population across these different dose levels? And secondly, how much more have we learned about the AE profile and specifically the GI toxicities and the role that prophylaxis can play in managing patients through their course of treatment.

I also anticipate that in this upcoming update, we'll have a preliminary assessment of progression-free survival at each of the 3 doses, which will be very important in helping us pick our doses or dose for moving into a potential registrational study, which is our -- really our top goal as a company today is to move Varseta as quickly as we possibly can into a late-line colorectal registrational study.

There's a very broad development opportunity for Varseta in metastatic CRC. Of course, we're beginning in late line, and that's where we believe this drug can first be registered and where it makes the most sense to run that first registrational trial. But we're very motivated to bring the drug into earlier lines. And as I said, we've already initiated the combination with bevacizumab with the goal of bringing the drug into the third line, potentially even into the second line, where our vision is to replace the irinotecan component of combination chemotherapy. This is very consistent with what we're seeing across the board with ADCs and solid tumors coming earlier and earlier in the treatment paradigm and beginning to replace components of chemotherapy in earlier lines.

Beyond colorectal, EpCAM is expressed in just about every other solid tumor. This is why there have been so many attempts to drug EpCAM in the past that unfortunately have failed. Given that we've broken through in CRC, in a way, I think you can argue fairly strongly that we've done the hardest experiment first. It's a very, very difficult-to-treat tumor type, and we have remarkable levels of activity in that patient population.

But shown here is just a few examples of solid tumors where EpCAM is highly expressed. And in the second half of this year, we aim to start work in non-CRC indications. And over time, you could see how an anti-EpCAM ADC could potentially move towards a pan tumor agnostic label, a little bit like ENHERTU has, for HER2. It's going to take a little bit of time to get there. But it absolutely is on the horizon. So the multiple layers of value creation that we see for CytomX that are unlocked by Varseta are shown here.

First of all, get the drug approved in late-line CRC, get the drug launched. And in third line plus more than 35,000 patients in the U.S. alone, this is a significant, as I said earlier, more than $5 billion market opportunity that we can tap into by getting the drug registered in that late line. Move to combinations to replace chemotherapy in the first and second line and then expand into additional EpCAM indications. And the patient numbers get very large, as you go from left to right on the slide.

And accordingly, the commercial potential is really very, very big. So quickly, mindful of time, I'll move to our interferon alpha program, which is a novel immunotherapy focused in melanoma. A little bit like EpCAM, interferon alpha-2b is an old friend. It's been around a long time. It actually was the first immunotherapy to be approved in 1986. It's fallen out of use because it's severely toxic, patients do not tolerate interferon alpha very well at all. It does have single-agent activity in multiple tumor types but it really has receded into the background in the context of clinical oncology because it's just so difficult to use. But interferon alpha is a very potent and multifaceted modulator of the tumor microenvironment, the immune microenvironment, it does a lot of different things to the immune system.

It can activate antigen presentation, can modulate NK stromal cells and vascular cells and also has direct antitumor cell killing ability as well. So it's a very differentiated cytokine from IL-2, IL-12, IL-15, very potent. And if we can harness its activity. We were very encouraged a number of years ago by the data with the gene therapy Adstiladrin that showed that local delivery of interferon alpha-2b in nonmuscle invasive bladder cancer can be very effective in shrinking that particular tumor type. That gave us the impetus and the rationale for making a masked version of interferon alpha that by localizing into the tumor could potentially unlock the potential of using interferon alpha as a centerpiece of immunotherapy to turn cold tumors hot. That's essentially what we're trying to do with this drug.

So we've applied our protein engineering strategies and our masking strategies to make a very tightly masked version of interferon alpha-2b. It actually has 2 different masking strategies that we're leveraging. First of all, protease-dependent peptide masking on the cytokine domain at the top of this cartoon. And then an Fc domain, which is a steric mask, which serves to not only lock down the systemic activity of the drug but also increase the half-life to more antibody-like which we think could be a big advantage. Both of these masks are protease cleavable.

We are focused in melanoma and our dose escalation, and the reason for that is that there is still significant unmet need in the late-line melanoma setting. Obviously, immunotherapy and checkpoint inhibitors, specifically have made a huge impact in the treatment of melanoma. But once patients progress on checkpoint inhibitors, they have very few options available to them. So we're initially evaluating 801 in the post checkpoint inhibitor setting, where rechallenge of these patients results in single-digit response rates. So there's a real opportunity here to bring the power of interferon alpha to melanoma and specifically in combination with KEYTRUDA. So we're in the clinic.

We are currently escalating with KEYTRUDA. We presented at SITC last year data from the first 5 patients treated with CX-801 monotherapy, and that initial dose escalation experience in monotherapy allowed us to open up the combination last year. The combination will be the drug the drug here will be 801 plus KEYTRUDA, at least initially in melanoma. That's what we're very focused on. But I do want to show you some of the data from the SITC presentation, which we think is really quite honestly, super cool.

So what we did with these first 5 patients, we were able to get on treatment patient biopsies, so we have pre- and post-treatment biopsies, really looking within the microenvironment that how this powerful cytokine is modulating the immune microenvironment. Shown here are 2 single cell images showing potent induction of interferon-regulated genes within the tumor microenvironment by 801. So this is strong evidence that the drug is being unmasked in the tumor, and that it is engaging with interferon receptors and inducing interferon regulated gene expression.

And importantly, some of those interferon-regulated genes are indeed checkpoint inhibitors like PD-1, PD-L1 and LAG-3, setting the stage for the combination with KEYTRUDA. I should also say that we were very encouraged in dose escalation to have not seen any dose-limiting toxicities across the first several doses that we've evaluated monotherapy and we've already exceeded the clinically approved dose of Peginterferon alfa. So far, so good on safety. It looks like the masking in the periphery is really working to shut down the systemic toxicity.

And in the tumor, we're seeing exactly what we want to see, which is activation of gene expression. And that actually extends the activation of an inflammatory microenvironment within the tumor. And this is one of my favorite slides as my team knows, showing here the dynamic induction of cytotoxic T cells into the tumor bed, you can see in the top right hand of this panel, you can see a blood vessel. And you can see that T cells have been extravasating from the vasculature into the tumor. And that's been driven by the induction of a potent T-cell recruiting cytokine CXCL10, which is in and of itself, at interferon-regulated genes. This is just 1 example of the powerful immunobiology that interferon can stimulate if you can get it to the right place at the right time.

So very excited about that, and our goal for the program is now to really study the combination as we move through 2026.

So let me wrap up on milestones and outlook, and then we'll go to some Q&A. So first of all, with Varseta-M laser-focused on this 100-patient Phase I study. We are on track for an update by the end of Q1. And we also anticipate presenting additional updates as that 100-patient study matures over the course of the year at major medical meetings, of course, focused in CRC.

As that data matures, we will be going to the FDA to discuss our registrational design, including, of course, dose selection for that study and really looking forward to those discussions. Also with Varseta-M we're initiating Phase I with the bevacizumab combination to enable earlier lines of treatment, and we anticipate initial safety and efficacy data early -- in the early part of 2027.

We're also planning to initiate other tumor types with Varseta-M where there's a multitude of choices, we'll have more to say about that in the second half of this year. Right now, we are continuing to be very focused in CRC because we really want to pin down this huge opportunity in colorectal, where this drug is behaving exactly as we have designed it. 801 with that foundational work done over the last 18 months, including this really exciting PD data that I just showed you, we're now highly focused on executing dose escalation with KEYTRUDA in melanoma, and we plan to have initial data for the combination also by the end of 2026. So an action packed year ahead, not that 2025 wasn't action packed.

I really want to thank the CytomX team for doing just such an incredible job. Well, I thank the patients and our investigators for participating in our studies, and we've never been more excited about what we're doing at CytomX for patients and would like to thank you all for your interest and support of the company. Thank you very much.

Thank you, Sean. I'm going to ask the first couple of questions, but to the extent there are any questions on the audience, I'll prompt you and just raise your hand, and we'll get your question answered.

Sean, I was wondering if you could expand a little bit on the Varseta-M Phase I dose expansion data that we're going to be getting here in 1Q. I mean I got to ask if you can give more granular time lines, which you'll probably just reiterate 1Q. But if I could just hear that from you. And then the size and scope of the data, I was interested because you said you'll give us a PFS update as well, right?

Q1, yes. In terms of size and scope, we gave a couple of updates last year on how enrollment was progressing in August. Our update was that we reached 73 patients and achieved our initial target of 20 patients at each of the dose levels. And then in our -- at our earnings call in November, we further updated that we had decided to further expand the Phase I study to 100 patients with the goal of having 100 patients enrolled by the end of Q1. So the data update in Q1 will be somewhere between 70 to 100 patients. And we do think that there'll be sufficient data at each of those dose levels that have at least a preliminary assessment of PFS.

And then how are you defining a win scenario on ORR specifically, the dose escalation part that we got last time was around 28%, but the high dose was had a 4 handle on it. like what's the win scenario there on ORR?

Well, we've got a lot of room to maneuver, we believe, when you look at the benchmarks with current standard of care in the late line setting, having very, very low single-digit response rates. So we've really broken through 28% is a great number. I think that there's a lot of room to maneuver around that number. and have a very, very competitive drug. So we'll see where it lands.

I would also emphasize that as we get deeper and deeper into the development of Varseta, it's really PFS and OS that will be the most meaningful endpoints. And that's why these preliminary assessments of PFS in this upcoming data release, I think will be very helpful for investors.

And then maybe if we could dig into the safety side, specifically on that diarrhea AE, and you talked about the use of prophylaxis now in the study. the prior data was all grade 78%, grade 3 was 22%. So with prophylaxis, what does that diarrhea profile look like that would get you excited?

Yes. So at the end of the day, with Varseta the balance between the efficacy and the safety profile will be evaluated in the context of overall risk benefit in this patient population. And this is a patient population with very few options that progresses incredibly quickly for which new treatments are desperately needed.

So the initial assessment of grade 3 diarrhea in the low 20s is something that we're coming to understand a lot more about and it's hard to put a number on it really at this point. It's really too early. I think we have to understand a lot more about the clinical benefit. And that, again, will be reflected in this next update in terms of ORR and PFS. We are working very hard to understand more about the etiology of the diarrhea in these patients.

We have a lot of discussion with investors around where does it come from? Does it come from the payload? Is there a target-mediated component. And our view on that is to the extent that we know, which we don't, is that the fact that masking has allowed us to avoid the classic on target EpCAM toxicities like pancreatitis. It suggests very strongly that masking is working. And masking has to be working for us to get to this remarkable level of antitumor activity.

So in the context of the masking delivering, it tends to, we think, tip the balance towards the GI toxicity being more payload driven, and we know that irinotecan, SN-38 or the Topo-1 inhibitors. In fact, even on the Topo-1 ADCs do induce GI toxicities. All that said, the most important thing, we believe, is to really understand the clinical course of the GI tox in patients and evaluate strategies for continuing to get ahead of it, so that we can deliver the maximum risk benefit for our patients.

Questions from the audience? Sean, I was interested in if you could expand a little bit more on in the back half of the year, you're going to be talking about additional EpCAM indications. Like when you look at the whiteboard of indications that you could possibly choose, like what are the push/pull levers in choosing? And maybe you could walk us through how you got to CRC, maybe that might help us as well.

Yes. That's a great question. Beginning with CRC, it was an interesting decision that we had to -- a very important decision that we had to take in focusing Phase I dose escalation entirely in metastatic CRC. It was a decision we discussed that with investors going back a couple of years. I think it was viewed as bit of a risky strategy because of the large number of drugs that have just failed in that setting. But we really had conviction that the drug -- the target is so abundant in colorectal and we were confident in our preclinical data.

And we really felt that it was the right time to do the absolute killer experiment to demonstrate once and for all that this technology can deliver. And so we committed and we generated this data set, and we're obviously super excited about that decision. I mean, the other way to go would have been to do a more typical multi-tumor solid tumor all-comer study go looking for signals and then pursue those signals and expansions. That's the more conventional strategy, but we decided not to do that. And I'm very glad that we did.

In terms of other tumor types, I mean, there really is a multitude of opportunity. We look at some of the other GI tumors as being great opportunities, but the target is so broadly expressed. I think for us, it's taking -- going to take a bit more analysis including thinking about potential combination strategies as well because in every solid tumor field, now including colorectal, nothing stands still, right? I mean these fields are evolving very, very quickly. There's so much innovation, so we've got a bit more work to do before we settle in on exactly where we go next.

Questions from the audience? Maybe just switching gears in the last few minutes here. When you think about the SITC update for 801, what do you think the Street is missing here? And then just walk us through for the combo later this year, what's going to be the size and scope and what would get you excited?

I'm not sure, the Street is missing a whole lot at the moment. I think that there's so much focus on Varseta understandably that we do need to remind, we do need to remind investors and quite frankly, sometimes we need to remind ourselves about our second child. And -- but the second child is growing up. And that's why we put that data out in November. We intentionally wanted to get some early results out there to provide a foundation for conversations with investors about what's coming down the road.

And I mean, 801 has the potential to be just as big as Varseta, I mean really, the number of tumor types that interferon has been shown to be active in and the unmet need in post immunotherapy -- the post-immunotherapy solid tumor setting is enormous, and we really see 801 as potentially becoming a new centerpiece of combination immunotherapy and everything that we showed in that SITC update demonstrates in our view that we're just right on track with that biology.

Again, back to the T cell recruitment, I think about on the -- as an example, one of the biggest challenges with developing a wide range of immunotherapies, including T cell engagers, is that you're dependent upon a T cell effective function to actually bring about the tumor cell killing that you need.

And that's a very -- that's complicated pharmacology to be dependent upon T cell biology as your effector and a subset of T cells at that will be reactive to the appropriate neoantigens in the context of each tumor cell, it's asking a lot. So an agent like 801 that has this ability to dramatically stimulate the tumor microenvironment and bring T cells into it offers terrific opportunities for combinations, we think, with a wide range of mechanisms.

We're focused initially, just like we are with Varseta, we're focused in melanoma. We're focused on the PD-1 combination, to get to an initial proof of concept but that really is just the beginning. So I don't really think investors are missing a whole lot. I think they'll -- we'll certainly be talking more about it as the year goes on. And I'm sure that it will continue to grow in their minds, as an important part of our story.

Okay. Thank you, Sean.

Thank you very much.

Good afternoon, everyone. Thank you for standing by. Welcome to the CytomX Therapeutics Third Quarter 2025 Financial Results Call. Please be advised that today's call is being recorded.

I would now like to hand the call over to your host for today, Chris Ogden, CytomX's Chief Financial Officer. Please go ahead.

Thank you. Good afternoon, and thank you for joining us. Before we begin, I'd 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 this afternoon, we issued a press release that includes a summary of our third quarter 2025 financial results and highlights recent progress at CytomX. We encourage everyone to read today's press release and the associated materials, which have been filed with the SEC. Additionally, the press release, 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 is Dr. Sean McCarthy, CytomX' Chief Executive Officer and Chairman. Sean will provide an update on our pipeline and company progress before I cover the financials for the quarter. We will then conclude with a Q&A session.

With that, I'll now turn the call over to Sean.

Thanks, Chris, and good afternoon, everyone. We're very pleased to be here today to provide an update on our third quarter developments and our strong continued company momentum at CytomX. I'd like to start by welcoming Rachael Lester to the team as Chief Business Officer. Rachael's broad strategic planning and business development experience will be highly valuable as we shape our pipeline and corporate development strategy towards realizing our ambition of building CytomX to commercial stage.

Rachael is a terrific addition to a wonderful team that I'm privileged to work with every day. Our goal at CytomX is to make innovative medicines for people with cancer that are substantially more effective than currently available treatments. Our most advanced drug candidate, CX-2051, is currently focused in colorectal cancer, one of the biggest unmet needs in oncology today with more than 1.9 million new cases annually worldwide, expected to exceed 3 million by 2040. I'll refer to colorectal cancer as CRC from here on.

CRC is also increasing in younger patients and is the second leading cause of cancer death. 5-year survival for metastatic CRC is only 13%. At CytomX, we have used our proprietary PROBODY therapeutic platform to attack this problem in a new and different way. The PROBODY approach is a masking technology that allows us to hit cancer cells hard and with stealth, sparing normal tissues, opening up therapeutic strategies that were previously impossible. Specifically, with CX-2051, we have deployed our platform to bring the power of an antibody drug conjugate to the treatment of CRC.

ADCs are transforming the treatment of many cancers. There are currently more than a dozen approved in the United States, but thus far, ADCs have not broken through in CRC, a notoriously difficult cancer to treat. There's an enormous opportunity here to meaningfully impact patient lives and access a global multibillion-dollar market, and our ambition at CytomX is to build an integrated commercial stage organization around this exciting opportunity. CX-2051 is a masked PROBODY ADC targeting EpCAM.

This drug candidate has been intentionally designed by selecting the optimal target, tumor type and cell killing mechanism to deliver potent anticancer activity. CX-2051 is, we believe, a truly differentiated molecule being the first and only EpCAM-directed ADC in development. EpCAM is a very highly and consistently expressed target in CRC. While certain locally administered EpCAM strategies have shown promise in cancer treatment, systemic approaches have consistently failed due to toxicities in normal tissues where EpCAM is also expressed.

To solve this problem and realize the potential of EpCAM, CX-2051 leverages our masking strategy to reduce normal tissue binding and maximize activity within tumor tissue. The CX-2051 payload is a topoisomerase-1 inhibitor known as CAMP59, selected because of the well-established responsiveness of CRC to this mechanism of cell killing, underscored by the widespread use of irinotecan in CRC therapy. Our CX-2051 product design strategy was quickly validated with our positive interim Phase I data reported in May this year from a highly focused dose escalation study in late-stage unselected metastatic CRC.

This first look at data from our Phase I study demonstrated robust clinical activity and the potential, we believe, for CX-2051 to become a new standard of care in this setting. To briefly recap the data, CX-2051 demonstrated meaningful tumor reductions, including confirmed objective responses or disease control in nearly every patient as well as preliminary median progression-free survival of 5.8 months, a potentially substantial improvement over currently available treatments for late-stage CRC that provide only 2 to 3 months of benefit.

Patients included in this initial data set had a median of 4 prior lines of therapy with all patients previously having been treated with irinotecan. Encouragingly, anticancer activity was observed across a wide range of clinical characteristics, including in patients with liver metastases and KRAS mutations. The activity we've seen across this broad late-stage patient population, together with the fact that we don't need to select the EpCAM expression in CRC suggests that CX-2051 could become a pan-CRC drug.

CX-2051 was generally well tolerated, including a notable absence of safety events such as pancreatitis and liver toxicity that have limited prior EpCAM therapies, strongly suggesting that our masking technology is working as designed. We were encouraged with the hematologic safety profile of CX-2051, which could be favorable for future chemotherapy combinations.

The most common adverse event in early Phase I was diarrhea, a known side effect of TOPO I-based therapies such as irinotecan. We're currently focused on better characterizing and managing gastrointestinal adverse events as part of our ongoing development program. Based on these very promising initial results, we're now well into the expansion phase of the Phase I study with our next data update planned for Q1 2026.

With that, let's review our progress with CX-2051 this quarter as well as next steps. In August, we announced that the CX-2051 dose expansion cohorts at the 7.2, 8.6 and 10 mg/kg doses had reached our enrollment goal of approximately 20 patients each. Since August, we've continued enrollment in the dose expansion cohorts, and we now expect total enrollment in the CX-2051 Phase I study to be about 100 patients by our planned data update in the first quarter next year. As we work towards our goal of initiating a potential registrational study for CX-2051 monotherapy in late-line CRC, we expect this expanded Phase I patient enrollment will further inform dose selection, including FDA dialogue regarding Project Optimus.

Additionally, given the momentum within the program, we expect to initiate a Phase Ib study with the anti-VEGF antibody, bevacizumab in the first quarter of 2026. Bevacizumab is a core component of CRC therapy across multiple lines of treatment, and we anticipate this combination data will unlock broad additional potential. Beyond CRC, we continue to see potential for CX-2051 across many other cancers where EpCAM is also expressed. Given our compelling initial results in CRC, we're currently assessing additional indications for future development, and we expect to provide an update on non-CRC indications in 2026.

Now turning to CX-801, our masked interferon alpha-2b program currently being developed in combination with KEYTRUDA in advanced melanoma. The metastatic melanoma landscape continues to evolve rapidly as checkpoint inhibition moves to earlier-stage treatment, leaving considerable unmet need in later-stage settings. Advances are being made, for example, with cell therapy and oncolytic virus strategies, but new approaches are urgently needed. We are very excited about the potential for CX-801 in melanoma as illustrated by the positive initial biomarker data we will present at SITC this weekend.

In designing CX-801, we have applied a similarly focused set of design principles as we did with CX-2051 by selecting a validated pathway, a potent effector mechanism and a focused initial clinical development path centered on clear unmet medical need. Interferon alpha-2b is a well-validated powerful immune system modulator that has previously been approved for cancer therapy, but that has been limited in use due to poor tolerability. Our masking strategy for CX-801 is highly novel and includes masks on both the cytokine domain and an Fc masking domain to really minimize activity in the periphery while directing activity towards the tumor microenvironment.

Conceptually, what we're aiming for here is to harness the potent ability of interferon alpha to selectively activate the tumor immune microenvironment, allowing for synergistic antitumor activity in combination with checkpoint inhibition. We treated our first patient in the CX-801 Phase I study in September last year, and we've made excellent progress thus far in the clinic. Monotherapy dose escalation has reached the fourth dose level, including multiple dose levels that exceed the approved clinical dose of unmasked interferon alpha-2b.

Now this is important since it already suggests that masking is working as designed. Our SITC presentation this weekend encompasses biomarker data from 5 melanoma patients treated with monotherapy. CX-801 has been generally well tolerated through the first 3 dose levels and is inducing robust interferon signaling within the tumor microenvironment. Specifically, our initial data includes gene expression analysis of pre- and post-treatment patient tumor biopsies, demonstrating consistently increased expression of interferon-stimulated genes, evidence of T-cell activation and upregulation of immune checkpoint inhibitors such as -- checkpoint genes, including PD-1 and PD-L1.

We also observed evidence of sustained chemokine elevation in the tumor microenvironment with stable chemokine levels in the blood, suggesting preferential 801 activation in the tumor. Furthermore, CX-801 is activating cell populations of both the innate and adaptive immune systems as anticipated and consistent with interferon alpha's broad mechanism of action. This initial progress with CX-801 is exactly what we aim for in assessing the initial monotherapy performance, and it lays a strong foundation for the potential of the combination with KEYTRUDA, which we initiated in May of this year.

We currently expect initial data for the CX-801-KEYTRUDA combination by the end of 2026, and we look forward to sharing those results. Before handing over to Chris for financials, I'd like to also briefly highlight a second poster presentation we have at SITC this weekend, introducing a new program at CytomX, CX-908, a masked T-cell Engager targeting CDH3, also known as P-cadherin. In addition to our work on masked ADCs and cytokines, we continue to be active in the T-cell Engager space, and this preclinical data highlights the power of masking to substantially widen therapeutic window for this modality. We also continue to be active in T-cell Engagers and bispecifics in our collaborations, including with Astellas and with Regeneron.

With that, let me hand over to Chris.

Thank you, Sean. Reiterating Sean's earlier sentiment, our third quarter was characterized by continued momentum with our clinical development programs, and we continue to drive towards our key milestones in a capital-efficient manner. Having completed a $100 million financing earlier this year with a strong group of investors, we are positioned to rapidly advance 2051 towards later phase development and build value in CytomX over the near and long term.

As Sean mentioned earlier, we are on track to provide a CX-2051 data update in Q1 of next year, and investing behind a potential first approval will continue to be our top capital allocation priority. We also will begin focused investments to drive additional value in CX-2051, including initiating a combination study with bevacizumab in the first quarter of next year. And we are also in the process of evaluating additional EpCAM-expressing indications for CX-2051 development.

With that, I'll now walk through our third quarter financial results. As of September 30, 2025, we ended the quarter with $143.6 million in cash, cash equivalents and investments versus $158.1 million in cash at the end of the second quarter of 2025. We continue to project that our cash balance, will be able to fund CytomX operations to at least the second quarter of 2027. As a reminder, our cash guidance does not account for any additional milestones from existing collaborations or any new business development, and we continue to make progress with our partners and expect to remain active in business development to extend the reach of our technology.

Looking at revenue and operating expenses for the quarter. Total revenue was $6 million compared to $33.4 million in the third quarter of 2024. The decreased revenue was primarily attributed to the completion of our performance obligations in our Bristol Myers Squibb collaboration. Operating expenses for the third quarter were $21.7 million compared to $29.3 million in the third quarter of 2024. R&D expenses were $15.3 million during the third quarter, representing a decrease of $6.1 million versus the third quarter of 2024, primarily due to a reduction in CX-904 expenses as well as reduced research expenses.

G&A expenses decreased by $1.5 million during the 3 months ending September 30, 2025, to $6.4 million, driven by lower personnel costs as well as patent and legal expenses. As we look ahead to 2026, we will continue to employ a disciplined approach to capital allocation, focused on delivering on our key program milestones for CX-2051 and CX-801 and advancing the pipeline towards later-stage development.

With that, I'll turn the call back to Sean for closing remarks.

Thanks, Chris, and thanks, everyone, for joining us today. 2025 certainly continues to be a highly productive year for CytomX. Our PROBODY masking platform is really coming into its own with 2 exciting programs in the clinic that build on everything we have learned over more than a decade about how to optimally deploy this strategy that we have pioneered. CX-2051 and CX-801 both utilize validated mechanisms. And in both cases, the clinical problems we're addressing and the potential value we can create are very clear.

We remain focused on our objective of building CytomX around these and future innovative programs and moving them further into development and ultimately to commercialization. Regarding CX-2051, our planned Q1 2026 update will encompass broad progress with the program as we look to position the initial registrational path while initiating combination strategies to support use in earlier lines of CRC therapy. This is a major opportunity. CX-801 is also off to a promising start, and we're excited to see KEYTRUDA combination data in 2026 in melanoma.

Before I wrap up today's call, I wanted to sincerely thank all CytomX stakeholders for your support. We are here to make the biggest difference we possibly can. With that, operator, let's go ahead and open up the call for Q&A.

[Operator Instructions] And your first question today comes from the line of Edward Tenthoff from Piper Sandler.

And really great update. I'm excited to hear all the progress with 2051 and looking forward to the 801 and the new program at SITC this weekend. My question really has to do with respect to expectations for the 2051 readout, and I appreciate that you're up to around 100 patients. What should we be expecting from an ORR? Is there a chance for that to deepen? And I know that the PFS was immature at 5.8 months, what do you guys sort of see as a win here for PFS in the late-line pieces?

Yes. Thanks for the questions. So just to recap our data in May, which we were super excited about. As you know, across the 3 relevant dose levels that we're currently expanding, the 7.2, 8.6 and 10 mg/kg doses, we saw an integrated confirmed response rate of 28%, which very substantially beats the current standard of care in the late-line setting, where, as you know, response rates are in the single digits.

So that gives us a lot of room to maneuver. Similarly with progression-free survival, the 5.8-month preliminary estimate based on that early data set compares to 2 to 3 months in the late-line setting for current standard of care. So our feeling is a lot of room to maneuver on the data set as it continues to mature from this larger expansion phase, and we're excited to have the update in Q1.

Yes. And I totally agree with all that. And a quick follow-up question. Will you break out dose -- or will you break out efficacy by dose? And do you think you'll have enough data at that point to really select the dose or doses in [indiscernible]?

Yes. We absolutely would expect to be breaking the data out by dose in this next update. I think that's going to be very important from an efficacy and safety standpoint as we continue to work towards dose selection for the next studies. Absolutely.

Your next question comes from the line of Roger Song from Jefferies.

This is Nabeel on for Roger. Maybe 2 from us. Excited to hear about the enrollment picking up. What do you attribute that to? And is there any more feedback you have maybe from your trial partners in terms of what you're hearing from them and anything regarding the prophylaxis and how that's going? And then another follow-up would be just regarding the ESMO data that we saw from some other competitors that did not differentiate from standard of care, if you had any thoughts on that as well?

Yes. Great. Thanks for the questions. In terms of enrollment, I'd take you back to the comments we made during our August updates where we were able to rapidly increase enrollment during Q2 and Q3 after the initial May disclosure to 73 patients. And that really was a reflection of the high interest from our investigators and patients to come on to the study. And that's been continued in Q4. We continue to see a lot of demand for 2051, and we felt as we moved through this quarter that it will be helpful to continue to enroll patients and continue to gain additional experience with this drug as we work towards dose selection for our next stages of development in 2026.

Regarding prophylaxis, that continues to be an important area of investigation. We are highly focused on really the one adverse event that we need to actively manage with the drug, which, as you know, is the diarrhea. We have implemented prophylactic measures at the early stages of the expansion phase, and we would anticipate that we will continue to learn about the AE management protocols over time. And we feel that we'll have a much better understanding of many aspects of this adverse event as we move into 2026. And I can assure you that we're very much on it.

In terms of ESMO, it was a busy conference, wasn't it? And there was quite a lot of news in CRC after such a long time of very little innovation in this space. It's really exciting to see multiple mechanisms, pathways, targets strategies being used to try to make inroads into this very difficult-to-treat cancer. We didn't really see anything that gave us any concern. We continue to believe strongly that 2051 is a highly differentiated molecule and approach. Of course, as an antibody drug conjugate is bringing the concept of the ADC into CRC, which we think is going to be really, really important. So we are as excited about 2051 as we have ever been.

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

Congrats on all the great progress here. What is the strategy for the combination approach with bev? Are you looking at enrolling third-line patients? Or is it really more about exploring second line? And would you wait until the next CX-2051 monotherapy update to actually inform a dose escalation strategy for the combo? And then I've got one follow-up.

Yes. Thanks, Olivia. Thanks for the question. So the strategy initially, of course, we will be beginning by looking at a few doses of 2051 to explore the combination with bev as we -- because we're beginning this study in Q1. We think it's important to get this study going. It's a crucial part of the development plan as we broaden out the 2051 strategy to bring the drug into earlier lines of therapy.

So -- but starting in Q1, it will be concurrent with continued evaluation of dose selection for monotherapy. So I anticipate that we'll be looking at more than 1 dose of 2051 with bev. Obviously, the goal ultimately is to get into the second-line setting. Specifically, which patients we enroll into the very earliest phases of the combination, that remains to be determined. In terms of the data update on the combo, too early to tell. We want to get the study going, and we'll see how it's -- timing-wise, we'll see how it aligns with future updates on the monotherapy.

Okay. That's helpful. And then what can you tell us at this point just around the percentage of patients who you actually expect to receive loperamide in the dose expansion phase for the monotherapy? Are there any parameters that you guys have put in place in terms of which patients can or can't receive it? Or is it really truly at the investigator's discretion? And then just to kind of sneak in a point of clarification on that. Can that loperamide regimen, can it actually be used both proactively for prevention, but also reactively at first onset of diarrhea?

I'll take the second question first. And the answer there is yes. I mean loperamide is used -- it's a common drug to be used to manage diarrhea for any medicine that has that adverse event. So that's a very normal thing to do. But it's also been shown to be effective, as you know, for example, in the PRIME study with TRODELVY, where upfront treatment of patients with loperamide was effective in reducing the rates of Grade 3 diarrhea in patients treated with that particular TOPO I ADC.

In terms of our study, as we've said previously multiple times, we instituted loperamide prophylaxis in the protocol concurrent with initiating the expansions in April. We did leave the investigators some level of discretion there. Loperamide, as we've commented before, does not come without its own side effects. And so that has to be used thoughtfully and deployed thoughtfully. And so we felt it was important to give investigators the flexibility because, of course, they're managing their patients on the ground as it were.

Over time, and again, just to really emphasize, we are laser-focused on this question of learning more about the onset, the timing, the overall etiology of diarrhea in these patients and learning how to get ahead of it with loperamide. And over time, as we learn more, I would anticipate that our AE management plan will continue to evolve and continue to be refined as we move into 2026 and towards discussions with FDA relating to dose selection and, of course, navigating Project Optimus.

Your next question comes from the line of Matthew Biegler from Oppenheimer.

Thank you so much for the update here. I just wanted to ask a follow-up one on your current thinking of the regulatory strategy, particularly as a monotherapy. Do you think you can go head-to-head against bev-Lonsurf in the third line? Or are you thinking monotherapy would more likely be a fourth-line trial against, I guess, physicians' choice?

Yes. Thanks, Matt. Look, I think everything is still on the table. So we're generating now an even more substantial data set with the continued enrollment into the Phase I. And I think we feel, as we commented previously, pretty confident that the very first look at the profile of 2051 showed us that this drug has the potential to comprehensively beat standard of care in the fourth line. So that seems clear from the very early data set.

In the third line, of course, we know that bev-Lonsurf has a PFS of 5.5-ish months. And we need to see our data mature to have a better handle and understanding of how competitive monotherapy 2051 can be in the third-line setting. So that remains to be determined, but it's very much still on the table as we collect more data, we follow our patients for longer. And by the time we get to Q1 of 2026, just to further build on one of the earlier questions asked, we do anticipate that we'll have estimates of PFS at all 3 of the expansion doses. So that will be, I think, very helpful and informative in helping us lay out what our thinking is at that time about the go-forward potential registrational path.

Your next question comes from the line of Anupam Rama from JPMorgan.

This is Joyce on for Anupam. I understand there's a host of other tumor types outside of colorectal where 2051 could have potentially meaningful benefit. What are your thoughts on which tumor types you're most excited for? And then what should we expect in terms of timing or cadence next year of new proof-of-concept studies in these other tumors? And just how are you balancing that with your development plans in CRC?

Yes. Thanks. Great question. And in a similar way to how we like to refer to 2051 as potentially being a pan-CRC drug. It really has pan-tumor potential given the widespread expression of EpCAM on so many solid tumor types. We're eager to get going in additional cancers, and there are many of them, gastric, endometrial, uterine, pancreatic, lung, it's a long list. And so we're enthusiastic to get going. At the same time, we've got so much work to do in colorectal that we need to be thoughtful of timing. But I do anticipate that we'll have updates on the initiation of additional cohorts and additional tumor types in 2026. We are working towards that.

Your next question comes from the line of Etzer Darout from Barclays.

Just a couple of ones for me. On the over enrollment that you're seeing, just wondered if any of the additional enrollment is skewed to any of the 3 doses that you're exploring? And then of sort of this 100 patients or so, are we going to get a breakout maybe of maybe less pretreated patients versus sort of the 4 median prior therapy patients we got in the initial update?

Yes. Thanks, Etzer. So in terms of enrollment, I mean, I can say that we're enrolling patients at similar dose levels or within the same dose ranges that we've been expanding. Not quite ready to comment on specifically which doses that we're adding additional patients, but we're really thrilled that with the speed and rate of continued enrollment during Q4, it's going to give us a lot of additional information, important information as we move towards dose selection in the early part of next year.

In terms of breaking out less or -- it's a really interesting question, less heavily pretreated or more heavily pretreated. We may look at that, but I can say that the patient population that we're continuing to enroll is pretty consistent with what we saw in the first 20 to 25 patients that we shared in May. So still pretty late-line CRC.

So if you're wondering whether we'd have, for example, some initial suggestions of maybe some second-line patients that may have squeezed into the study or a large number of third line. I don't anticipate that to be the case. I think we're really still going to be, at least for now, in the pretty late-line setting. That said, of course, we're -- we always want to try to analyze and squeeze as much information out of every patient and data set as we can.

[Operator Instructions] And the next question comes from the line of Mitchell Kapoor from H.C. Wainwright.

Congrats on the progress to date. Just wanted to ask if you could elaborate on your interactions with the FDA so far and what they have indicated their feelings are about what would be registrational or positive in the fourth-line setting. Would that -- have they said anything like 20%, 25% ORR and 6 months PFS would be impressive to them? Anything that you could say about what their alignment has been like with you all to date? And what was the last time you spoke with them about the registrational plans? Obviously, there's been a lot of changes with the FDA, but I just want to know when the last communication was and when you plan to meet with them again?

Yes. Thanks, Mitch. So obviously, regulatory strategy is something we're going to be super focused on as we move into 2026. We anticipate those discussions to happen next year.

Okay. Great. And then just secondly, if you could talk about your updated thoughts on BioAtla's EpCAM bispecific. What are the puts and takes there in terms of read-through, but also differentiation where we should think about your strategy in a different way?

Yes. We think that it's an interesting strategy as the EpCAM CD3 conditional activation approach. We obviously know that -- all know there's a lot of EpCAM in colorectal cancer and leveraging that particular effective strategy, I think, could make some sense. We feel like -- at CytomX, we really feel like the ADC strategy is the right one.

I'm not showing any further questions in the queue. I would now like to turn it back over to Dr. Sean McCarthy, Chairman and CEO, for closing remarks.

Thanks very much, and thanks, everyone, for tuning in today. It's been great to give an update. We're super excited about our progress in 2025 and the direction that CytomX is headed with our clinical programs and our platform overall and our collaboration. So thanks for your time and look forward to following up.

Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.

So really quickly on disclosures. So for important disclosures, please see the Morgan Stanley research disclosure website. And if you have any questions, please reach out to a Morgan Stanley sales representative. So thank you all for joining. Welcome to the Morgan Stanley Healthcare Conference. I'm delighted to be sitting with Sean McCarthy, the CEO of CytomX. Thank you for joining us, Sean.

Thank you.

And I'm Ross Cohen, and I'm an Executive Director within the healthcare investment banking team.

So maybe just kicking off, Sean, why don't you give us a quick overview in terms of history around CytomX for those of us who maybe more -- less familiar with the story.

Yes. Thanks, Ross, and thanks for having us at the conference today. Real pleasure to be here. So CytomX is an oncology-focused biologics company, developing a platform technology and a pipeline around that platform called the Probody therapeutic platform. And this is a unique antibody masking strategy that we pioneered. In fact, I refer to CytomX as the original masking company. We got this whole field going really going back as long as 15 years. And the concept of antibody masking is to improve therapeutic window for highly potent anticancer agents like antibody drug conjugates or T-cell engagers, for example, we are currently in the clinic with 2 very exciting programs, EpCAM-targeted masked ADC, we call CX-2051 and a masked version of interferon alpha-2b, we call CX-801. And just making a ton of progress. So happy to be here today and talking about our platform and pipeline.

Yes. No, great to have you in a super exciting time. So maybe just double clicking on the masking technology for a minute. Can you maybe just walk into a little bit more detail around that? And also how do you think about ADCs as being one of the better applications of that technology?

Yes, absolutely. So the way the technology works and was originally conceived of is to take an antibody or indeed other biologics, for example, cytokines, and engineer them such that they are masked with short highly specific peptides. And the mask is designed to block the ability of the biologic to bind to its target until the mask is removed. And mask removal is achieved specifically and selectively in disease tissue and in our case, specifically in cancer tissue, by tumor-associated proteases. We've known for a long time that protease biology is dysregulated in tumors. Proteases are involved in tumor cell migration, invasion and metastasis. And we take advantage of that difference in protease levels in tumor tissue compared to normal tissue where proteases are very tightly controlled to allow us to activate the drug locally.

So why is this useful? Well, it allows us to go after really innovative novel targets, tumor targets that are very abundant in tumor tissue but have been difficult to drug historically because they may also be a normal tissue. So for these targets and EpCAM is a great example of this, we're able to open a therapeutic window by using the masking strategy to bias towards tumor tissue and away from normal tissues. ADCs, absolutely one of the killer applications for the technology. There are a number of proteins, including EpCAM that are very abundantly expressed in tumor tissue that would be great targets for anticancer therapy except for the fact there are many normal tissues. And so enter CytomX and that's why ADCs have become such an important focus for us.

Yes. It makes a ton of sense. And maybe on the lead ADC program, the EpCAM ADC, maybe can you just describe the design of that molecule specifically and then the unmet need within colorectal cancer that it's looking to address and maybe beyond?

Absolutely. So EpCAM is a target that's been around for a long time. It was actually first described, believe it or not, in 1979 as a highly expressed protein on the surface of colorectal cancer cells. And it's very, very abundant in CRC. It's expressed at essentially HER2-like levels. So there are millions of copies per cell. It's expressed consistently and homogeneously as far as we can tell in every CRC, just about every CRC patient. However, as the name suggests, EpCAM is epithelial cell adhesion molecule and it's present on all epithelial structures in the body. So it's present on many normal tissues throughout the body. So many have tried to target EpCAM over the years but have not succeeded because of that expression in normal tissues.

And toxicities have been observed at low doses with different strategies, including pancreatitis, liver toxicity, certain GI toxicities, and that's limited the ability of anyone to bring a systemically administered anti-EpCAM drug into the clinic successfully. But there are clues from other locally administered EpCAM strategies that if you can get an empowered potent antibody to EpCAM with local delivery, it can actually be very effective. There are 2 examples of this. One drug, a toxin fusion that has been shown to be quite effective in non-muscle invasive bladder cancer, but that drug had to be given intravescicularly into the bladder.

And then the second example is actually a T-cell engager, a CD3 EpCAM bispecific which has just been reapproved in Europe actually for the treatment of a condition called malignant ascites. These are epithelial structures that form in the peritoneal cavity of patients with certain GI and gynecologic tumors. This EpCAM CD3, when given into the peritoneal cavity, it's quite effective at shrinking these tumors and treating these patients who have a very difficult experience with these growths. So -- so we know that if you can get an EpCAM antibody with some kind of payload on it, if you can get it to the tumor, it could be effective. The question is how do you do that with a systemic drug, and that's what we've done with our masking strategy.

Yes. No, that's actually a very interesting point you make on the peritoneal piece of it as well because these are not uncommon in colorectal mets, right? And those tend to be some of the more challenging tumor types or...

Correct, in many tumors actually, yes.

Yes. And so do you think that EpCAM can actually have a potentially differentiated role within that specific area as well?

I think that certainly could be something else to look at with 2051 over time for sure.

Yes, that's interesting. And then maybe you guys have showed some super interesting data back in May. Can you walk us through what the data looks like on some of the early patients? And then what are the expectations going forward there?

Yes, we're just super excited about the progress we've made with 2051 so far. So first of all, let me just recap the very intentional design of this drug. So obviously, EpCAM as we've discussed, is the target, very abundant in CRC. The masking strategy essential to localizing the drug into tumor tissue and mitigating the previously seen systemic toxicities with EpCAM therapies. And then thirdly, and really importantly, the effector on CX-2051. Of course, it's an ADC, and the effector mechanism is a topoisomerase-1 inhibitor payload. And the reason that we selected topo-1 inhibitor is, of course, because topo-1 inhibition is a central component of standard of care in earlier line settings in the treatment of colorectal cancer and specifically irinotecan.

So we designed this drug very intentionally, the right target, the right payload, the right tumor type, using our masking strategy to really deliver in -- initially in late-line colorectal where the unmet need is just enormous. I mean it just -- and we can talk more about that later. But there's so much need in this field. So the Phase I study that we conducted, we focused entirely in CRC which was, I think, a bold move. It's a tough patient population for sure. But we decided to be -- we designed the drug to be evaluated first in CRC, so that's what we did. And in May this year, we reported our first clinical experience from the first year in the clinic, but only a year, the program has actually moved really very quickly.

We had 18 efficacy-evaluable patients across 5 dose levels beginning at 2.4 milligrams per kilogram up to 10 mg per kg, the drug administered every 3 weeks. A late-line patient population, median number of prior therapies of 4. So this is essentially a fifth line CRC patient population. So very heavily pretreated. And we were just delighted to see really robust clinical activity in this very-difficult-to-treat patient population. First of all, confirmed objective responses in 28% of those 18 patients. And to put that in perspective, the current standard of care in the fourth line has a response rate of between 1% to 2%.

So a huge step forward, we think, for the field, a very active drug, but in addition to the objective responses, most patients, in fact, just about all patients benefited from drug with a 94% disease control rate which translated into an initial assessment of progression-free survival of 5.8 months. Again, to put that number in perspective, the current standard of care in the fourth line has a PFS of 3.5 months. So a very competitive profile emerging for the drug in this first dose escalation. The drug looks to be performing exactly as we designed it. It's translated very effectively from our preclinical studies into the clinic. And on the safety side, we're very encouraged there as well in terms of what we've seen so far.

This is the first in-human evaluation of the payload, we call it CAMP59. It's a payload that we licensed from ImmunoGen. So we are learning as we go with this particular topo-1 inhibitor, but we've seen an attractive safety profile with actually no dose-limiting toxicities during dose escalation, manageable hematologic tox with low rates of Grade 3 anemia and neutropenia. And in terms of other toxicities, generally well tolerated with perhaps the AE to watch going forward being GI. We've seen a little bit of GI tox, upper GI in the form of nausea and vomiting, which is fairly typical for topo-1 inhibitors, particularly topo-1 ADCs. And we saw a reasonable amount of Grade 3 diarrhea in patients about 20% across the 25 safety-evaluable patients. And that's something that we continue to learn about as we move forward, and we'll continue to understand and look to take steps to manage and mitigate. But overall, we're just so thrilled with this first look, the first year of development and just so excited now to push this drug forward as fast as we can.

Yes. No, really, really exciting data, and it's great to see. And so -- and then you briefly touched on that in terms of what comparator data could look like per se. But I guess, when you think about what a comparator in late-line CRC looks like, what are you really comparing to? And what are the typical results in the efficacy side? What are the things that they're also focused on from a safety perspective?

Yes. So in the fourth line, I mean the field has evolved a little bit over the last few years. We've seen approval of the tyrosine kinase inhibitor fruquintinib, specifically in the fourth line. That is now 1 component of standard of care, is 1 option for patients. And as I mentioned, fruquintinib was approved based on 2 placebo-controlled studies with a PFS of 3.7 months, an ORR of low-single digit, 1% to 2%. So fruquintinib doesn't really efficiently shrink tumors, but it does give a modest PFS benefit. Other options in the late line include LONSURF, which is trifluridine and tipiracil, monotherapy or in combination with bevacizumab, the anti-VEGF antibody, that's typically used in the third line.

So by the time patients get to the fourth line, fruquintinib or maybe the other TKI regorafenib are options for patients. Our additional data with 2051 really has the potential to transform this field because we're so far our ORR and our PFS are so much better than current standard of care. We think that a potential fourth-line study that will compare ourselves to the current options in the fourth line could be executed very quickly, could be enrolled very fast, would have a, we think, a very high degree of probability of technical success based on what we already know about 2051. We're going to know a lot more by Q1 of 2026. We've already completed enrollment into expansions of 3 dose levels, 7.2, 8.6 and 10 milligrams per kilogram. Each of those 3 dose levels showed activity in the dose escalation with confirmed PRs at each of those levels and an impressive disease control.

So we've expanded. We now have about 20 patients at each of those dose levels enrolled into the study. We'll have that data moving into Q1. And that's going to be really helpful to us and essential to understanding dose response, dose relationships as it pertains to adverse events, the degree to which adverse event management strategies that we've implemented in the expansion phase are helping us with the overall AE profile and integrating all of that into selecting our doses for this go-forward study that we plan to initiate in 2026.

Yes, no, makes a ton of sense. And I guess just shifting back to maybe the EpCAM point, you mentioned kind of the rationale for why EpCAM makes so much sense in CRC and the expression. But I guess as you look across the different lines of therapy within CRC, do you expect to see consistently high levels of EpCAM expression?

Yes, we do. We've done some work on this actually. So if you look in the public databases, there's a lot of information on EpCAM out there. It's been -- the target has been worked on by so many people for so many years. You can see in the expression data that EpCAM is highly expressed in all stages of CRC and it doesn't change as colorectal cancer advances. It's expressed in sort of stage 1 through 4. It's expressed at similar levels in primary tumors and metastatic tumors. And we've also begun to do some work within our Phase I study, looking at the kinetics, if you like, of how EpCAM expression looks over the course of treatment. And our data is still quite preliminary, but we're encouraged to see that so far that EpCAM levels are maintained as patients are maintained on drug.

So it's a very stable antigen, we believe, which I think makes it another reason why it's such an attractive target. One other thing that I should mention about why we think EpCAM is such a great target for CRC is that in our Phase I study to date, we've confirmed that in every patient for whom we have an evaluable sample, EpCAM expression is indeed very high. So we haven't selected patients coming into the study for EpCAM expression. We don't think any selection will be necessary. This really does have the potential to be an all-comer drug. We also observed in this first data set in May that the activity that we've seen is across all clinical characteristics.

It's independent of some of the typical clinical characteristics that can be used to segment the CRC population. So for example, whether patients have left or right-sided tumors or whether they have liver mets or not or whether they have KRAS mutations or wild-type KRAS. We see activity across the spectrum. And again, this has the potential to be an enormous advantage for this drug candidate because -- and this is how our investigators are seeing that they can bring any patient onto the study without having to spend time sub-categorizing them into specific clinical subsets. So we think that ultimately, commercially, this will be a great advantage and it's one of the great hallmarks of EpCAM as a target for CRC.

Yes. No, it makes a lot of sense. And so -- and then on 2051 on safety specifically, maybe -- and you walked through a bit of the initial safety profile, but if you can touch on that again and also focus more so on what -- how are those indicators in the masking technology might be working on your EpCAM ADC versus what you've seen in another situations?

Yes. Well, any time you take a new ADC into the clinic, you hold your breath a little bit. I think in particular with this one, given how broadly and widely EpCAM is expressed and what's been seen before with serious toxicities with previous approaches. So what were we on the lookout for? We were on the lookout in particular, for pancreatic toxicity because, as I mentioned, that was the roadblock that the first EpCAM strategies ran into. I'm very pleased to say that not only have we not seen any pancreatitis to date, we haven't seen any modulation of pancreatic enzyme levels either.

So that, I think, is strong evidence that masking is delivering and keeping the drug masked and quiet, if you like, in systemic normal tissues. I think additional evidence that masking is working comes from the liver toxicity profile. So we've seen EpCAM agents in the past have significant liver tox in terms of elevating liver enzymes. We haven't seen a signal there either. And so I think the evidence that masking is working, I think, is really quite strong.

Yes. And I guess, how is that GI tox compared to irinotecan and other topo-1 ADCs?

Well, when irinotecan was first studied many years ago, it was first being used, it had a very high incidence of high-grade diarrhea. It was a very difficult drug to use. That's been optimized with different dosing strategies and regimens over the years, as you know. And is -- I mean, there still is significant GI toxicity with irinotecan, but it's -- oncologists have learned a lot about how to use it and how to dose it over the years. But it's a really important point that topo-1 inhibitors in general, whether the chemotherapy itself or in the context of antibody drug conjugates, they do induce significant GI toxicity.

So we were on the lookout for this in our Phase I study and the fact that we've seen some GI tox is not a surprise at all. So the -- and as I mentioned, this is the first human experience with this particular payload, and one topo-1 inhibitor is not same as the next. They all have their own unique profiles in terms of how the toxicity emerges. Some have significantly more heme tox, for example, than ours does. But overall, I would say we've not been surprised by the tox profile, and we continue to take steps to learn more about it.

Yes. And then what have been some of the learnings maybe from most of the -- probably the oncology community as well and clinicians, but around mitigating some of those GI tox with other ways, too?

Yes. So this, of course, is not the first drug to have GI toxicity and specifically diarrhea as a signal. And there is a lot of precedent of strategies being used to manage and mitigate and in some cases, even use prophylaxis to treat patients early in their treatment cycle to minimize these types of adverse events. The types of strategies that have been used previously include anti-motility agents, like loperamide, steroid approaches like budesonide. And I'm thinking of drugs like neratinib, the HER2 inhibitor, which has a fairly high rate of Grade 3 diarrhea, those are some strategies used there.

There's a study called the PRIME study, which was performed on TRODELVY, looking specifically at the ability of prophylactic loperamide to reduce Grade 3 diarrhea. And that actually was quite successful. It reduced by about 40% to 50%, the incidence of Grade 3 diarrhea for that particular topo-1 ADC. In terms of what we're doing in April this year, as we initiated our expansion cohorts or the expansion phase of the study, we decided to implement loperamide prophylaxis. So we asked our investigators still with a level of discretion because it's really up to them to manage every patient, to use loperamide where indicated upfront, to try to, yet again, get ahead of this fairly predictable AE of diarrhea.

Yes. And then final question on safety, I promise. But I think for last month, there was the Grade 5 event that you announced and so maybe can you just walk us through some of the details that you can share?

Yes, it was a complicated situation that we had seen a Grade 5 treatment-related adverse event going back a couple of months. This was a patient who experienced some GI toxicity and unfortunately, advanced to acute kidney injury and for various reasons, including other confounding clinical factors, including the fact that patient had donated a kidney earlier in their life, so had a solitary kidney, the patient ended up unfortunately not making it. And in reviewing the patient's clinical history with our Safety Review Committee very quickly after learning of this event, the Safety Review Committee felt that while this was likely an outlier event, the kidney injury, most likely secondary to the GI toxicities that we're seeing, and this can happen that patients with nausea, vomiting, diarrhea can become dehydrated that could put pressure on the renal system, and in this particular case, this patient having a solitary kidney, that renal pressure -- the pressure on the renal system was -- ended up just being too much.

And again, other confounding features unfortunately contributed to this patient situation. So our investigators were of the view that, okay, this looks like an outlier case, study continues, no changes, except to more proactively monitor patients to ensure that we don't enroll patients that have donated kidneys previously, but no other significant changes to enrollment criteria. We felt that they were all fine.

The challenging situation we found ourselves in was receiving or being notified by a few of our investors that there was a patient blog that they had come across that actually included some very specific details of this particular case at one of our clinical sites and so we -- which quite honestly, shouldn't really have happened, but we don't need to get into the details there. But it put us in a tough situation where we were getting a lot of inbound questions from investors. There were a number of other comments made in this blog that quite frankly, were inaccurate relating to study being paused, study being on hold, investigation with FDA.

And so we quickly -- we quickly decided to issue a press release to lay out exactly what happened with this particular patient case and also set the record straight that the study was ongoing, that everything had been reported appropriately to FDA in a timely manner. And we had a lot of very constructive conversations and follow up with our investors over the following 24 to 48 hours, and I think everybody appreciated that transparency. It does I think, highlight in a way, kind of a new challenge that we all have to deal with as drug developers running public companies, which is that this public narrative that can appear in blog posts could be very, very difficult to deal with.

And we're, of course, not in the business of responding to these comments. Typically, in this case, we felt that it was important to because there were just some real specific details shared and we were getting a lot of inbound inquiries. I think we made -- I'm 100% confident we made the right decision to disclose at that time. So in totality, though, as unfortunate as this case was with this particular patient, this adverse event is not out of -- it's not completely out of scope in terms of what we've seen with the drug already in terms of originating from some lower grade GI toxicities. And we know that's something we need to learn more about and manage with 2051 moving forward.

Yes. No. It makes a lot of sense. And so now that you've basically fully enrolled all 3 expansion doses, what is -- what do you view as the key criteria for now selecting a dose and next steps?

Yes. So really very interested to see a number of things from this -- what will be at least a 70-patient update. So we've enrolled 73 patients as of the last update. And that's consistent with guidance we've given since our May disclosure that we would have 70-plus patients of data in Q1, and we're absolutely on track, because enrollment went so well in Q2. And by the way, one of the other things you can see from these patient blogs is that people want to come on our study. These patients have very few options and they want to be on 2051. And even the patients who put all these details out there was frustrated and disappointed that they haven't been able to get on the study themselves. So enrollment went great. By Q1, we're going to have, I think, pretty significant follow-up on the majority of those patients in terms of follow-up on clinical activity.

We'll have obviously an update on the response rate across the 3 dose levels of 7.2, 8.6 and 10. We'll have, I think, preliminary estimates at a dose by dose of PFS, which I think will be really important in helping guide us to the go-forward doses. And we'll also have an analysis of exposure dose response and exposure dose AE relationships. And I think that will all go into an analysis then of which dose or doses we're taking into our next study that, again, we hope to launch in 2026.

Yes. And just a quick follow-up to that point is how many patients do you expect there? And maybe how much follow-up do you anticipate to have?

Yes. So the expansions have all been enrolled to about 20 patients at each of the dose levels. And given that enrollment was complete as of August 13, our last update, we're going to have I would think 6 months of follow-up on the majority of patients which I think will be great. So we'll see -- we haven't decided exactly when in Q1 we'll disclose. We're keeping our options open at this point. But I think we're of the view that communicating data that's more mature rather than less mature will be most helpful for everybody. But we're still working through exactly when that communication will be.

Yes. And in terms of the benchmark that you're looking to hit as a driver for success there, how do you think about that when you're presenting?

Well, we think the numbers that we delivered in May were a great starting point. And obviously, we're -- we'll be very excited if those numbers remain in that ballpark. I think the 28% overall response rate across the first 18 evaluable patients, efficacy evaluable patients is a terrific start. I think there's room -- there's quite a lot of room on either side of that number, quite frankly, for this to be a very competitive drug. So we'll see how it shapes up. I think the 5.8 months of PFS again, if that is maintained, we'll be very happy, if it happened to improve a little bit, we'd be even happier.

Yes. And then do you expect the registrational pathway to require a randomized controlled study? Or could a single-arm study suffice? And maybe walk us through how you're thinking about the next set of studies?

Well, I think in the CRC space, we're not setting any expectations at this point for a single-arm accelerated approval. That's been a really tough bar with FDA in colorectal for a multitude of reasons. But we also feel that the time line to execute a randomized study, given the -- unfortunately, given the speed with which patients advance in this late-line setting, that study could be executed very, very swiftly. So one way that we're thinking, no decisions made yet, is that the next study could be absolutely a randomized study against physicians' choice or against fruquintinib, for example, in the fourth line, maybe 2 doses initially of 2051 because we really don't want to rush dose selection. I think it's an ADC, we need to be thoughtful. Perhaps we take 2 doses forward. Depends on what we learn from the expansions. If the expansions give us the answer, then we'll be taking 1 dose forward, but probably 2 or leaving our options open for 2.

And that would be -- I think that study could very well have a basis for accelerated approval based on a PFS endpoint. That's how our current thinking has evolved. So -- but again, all these decisions about the design and structure of our next study will be highly informed by our data and will be data driven.

And then as you think about combinations such as bev, how do you fold those in over time?

So obviously, the late line is just the place to start with 2051 and represents, by the way, a major commercial opportunity. Even in the fourth line, we can see this being a multibillion-dollar drug. There are 12,000 patients at least in the U.S. treated every year in the fourth-line setting. And fruquintinib actually has done quite well in its first couple of years on the market with those numbers that I mentioned with 3.7 months of PFS. So we see the late line is a terrific opportunity, but we're highly motivated to bring 2051 into earlier lines of therapy where the numbers get very big very quickly.

Yes. So third line, we will want to do some initial combination work with bevacizumab bringing the drug into the second line. We'll want to do some combination work with chemotherapy because the vision of the drug ultimately is to use 2051 in place of irinotecan to make a superior second-line therapy to currently the irinotecan containing chemo strategies. So it will be a progressive build over time. with combinations really being very, very important. And as we learn more about the safety profile, I think we'll learn more and more about the combinability of the drug in the earlier lines.

And then maybe more broadly, how do you -- what other indications do you think 2051 could work in beyond CRC?

Well, EpCAM has got so much potential. It's present in just about every solid tumor at some level including many tumors that are known to be topo-1 sensitive. So multiple places to go, including other GI tumors, certain gynecologic tumors, lung cancer. And so really, the ultimate vision for the drug is for 2051 to become a pan-tumor treatment. And so we look at the way that ENHERTU gained its pan-tumor label in HER2-positive solid tumors. In our mind, there's no reason why we couldn't go there with 2051 over time.

Yes. And then maybe shifting gears a little bit to CX-801, interferon alpha-2b, what should investors expect to see in the preliminary mono data update in the fourth quarter?

Yes. So we're really excited about 801. It's obviously, a different concept altogether. It's an immunotherapy, and it's designed to turn cold tumors hot and to restore responsiveness to checkpoint inhibition. We're conducting a very focused Phase I study in melanoma with 801. And again, just to remind everyone, it's a masked version of interferon alpha-2b which we know has some monotherapy activity in melanoma. So we're making good progress. We've advanced through several monotherapy escalation cohorts. The drug has been well tolerated. That's all gone fine. That allowed us to open up the combination arm with KEYTRUDA. We dosed our first patient with KEYTRUDA in Q2. And our goal for this year is to share some translational biomarker data on paired biopsies in the monotherapy arm, looking at regulation of interferon responsive genes, modulation of different cell populations in the tumor microenvironment by the masked interferon.

So looking at -- our goal is to demonstrate that the drug is mechanistically doing what it should be doing, getting unmasked, activating the right cell types, inducing interferon responsive genes, really setting the stage for the combination to be effective, combination data, clinical data we'll plan to present sometime in 2026. So this update this year will be very translational biomarker, not planning any response data or safety data from the study. It will be very, if you like, sort of molecular evidence of performance of the drug in the early stages of dose escalation.

Yes. No, makes a ton of sense and that's super exciting. And so maybe we probably have time for 1 more question. And so maybe just taking a very quick step back. How are you kind of thinking about the next 12, 18 months? You obviously have a number of catalysts coming up as you kind of think about your financing strategy around that, as you think about nondilutive options around that. Maybe just walk us through a little bit your thinking.

Well, we've got a lot of work to do, that's for sure. We've got a really, really exciting drug on our hands in 2051. Top priority is now to get this expansion data and use it to formulate our next steps in clinical development in CRC to begin combination work to get the drug ready to come earlier in the treatment paradigm for CRC to evaluate which tumor types to potentially initiate additional work in other tumor types in the not-too-distant future. And all the way along, carefully consider our financing strategy.

We were very, very pleased to be able to finance in May this year in conjunction with our data disclosure. But we've got a big program here that's going to have significant capital requirements. And so we're thinking carefully about what that future capital formation strategy will be. And of course, also thinking about when might the right time be to consider a partnership for 2051 because it does have the potential to become a very broad program very quickly. And I do feel confident that there will be a lot of interest from strategic parties in potentially collaborating with us. So a lot of work ahead of us. It's been an exciting year so far. And again, thanks for having us today.

No, of course, not. And thank you for joining, Sean. Congratulations on all the success. And we're looking forward to the next several months here, as always.

Thanks a lot, Ross.

Thank you.

Good afternoon, everyone. Thank you for standing by. Welcome to the CytomX Therapeutics Second Quarter 2025 Financial Results Call. Please be advised that today's call is being recorded.

I would now like to hand the call over to your host for today, Chris Ogden, CytomX' Chief Financial Officer. Please go ahead.

Thank you. Good afternoon, 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 this afternoon, we issued a press release that includes a summary of our second quarter 2025 financial results and highlights recent progress at CytomX. We encourage everyone to read today's press release and the associated materials, which have been filed with the SEC. Additionally, the press release, 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 is Dr. Sean McCarthy, CytomX' Chief Executive Officer and Chairman. Sean will provide an update on our pipeline and company progress before I cover the financials for the quarter. We will then conclude with a Q&A session.

With that, I'll now turn the call over to Sean.

Thanks, Chris, and good afternoon, everyone. We're thrilled to be here today to review our progress for the second quarter, highlighted by the exciting clinical data we announced in May for CX-2051, our PROBODY antibody drug conjugate targeting EpCAM, which we view as having significant potential in colorectal cancer and potentially many other tumor types. We're also making great progress with our second current clinical program, CX-801, that I'll come to a little later.

I'll focus initially today on CX-2051 and our work in colorectal cancer, which I'll refer to from here on as CRC. CRC remains one of the biggest unmet needs in oncology with approximately 1.9 million patients diagnosed per year on a global basis. This disease burden is expected to increase considerably over the next couple of decades to more than 3 million, and is currently the second leading cause of death by cancer worldwide. Despite many advances across many other cancer types in recent years, CRC has seen little impact from innovation over this period of time, resulting in current 5-year survival rates in metastatic CRC of about 13%. New treatments like antibody drug conjugates are urgently needed to treat this cancer.

In other solid tumor types, ADCs such as ENHERTU, TRODELVY and ELAHERE have made a big difference for patients, but ADCs have yet to break through in CRC, representing a major scientific, clinical and commercial opportunity. At CytomX, we have intentionally designed CX-2051 to address this opportunity, building on years of experience in how to optimally leverage our PROBODY technology for the maximum benefit of cancer patients.

Let me recap the key design elements of CX-2051. EpCAM is a very highly expressed target in CRC, making it very attractive for an ADC. The payload on CX-2051 is a topoisomerase-1 inhibitor, which is ideally matched to CRC, where the Topo-1 inhibitor, irinotecan, has been a core component of the standard of care for many years. And thirdly, critically, CX-2051 uses CytomX PROBODY masking technology to limit binding in normal tissues, something that has thwarted previous attempts to drug EpCAM.

Our initial experience with CX-2051 in the clinic announced in May is very encouraging. We have focused our Phase I clinical evaluation exclusively in CRC with the goal of delivering clear clinical proof of concept in this high area of unmet need. I'd like to briefly recap the CX-2051 initial Phase I data from May. For context, CX-2051 has initially been studied in a fifth-line CRC patient population where approved standard of care therapies are typically associated with 1% to 2% response rates and progression-free survival of only 2 to 3 months. In comparison to these benchmarks, CX-2051 has demonstrated robust clinical activity with a 28% confirmed overall response rate, 94% disease control, and 5.8 months of preliminary progression-free survival in the first 18 efficacy evaluable patients at relevant dose levels.

We're also encouraged to have observed clinical activity, including confirmed objective responses across a relatively wide range of doses. Our initial data has also validated that EpCAM expression is abundant in late-line CRC with every evaluable patient having high target levels. This is important because it suggests that CX-2051 may broadly address CRC and may not require patient selection, potentially a significant commercial advantage. Furthermore, our CX-2051 masking strategy has succeeded in avoiding classic EpCAM toxicities such as pancreatitis that have impeded the successful development of drugs against this target previously.

In terms of next steps, we have initiated dose expansions at doses of 7.2, 8.6 and 10 milligrams per kilogram administered every 3 weeks, and we are targeting enrollment of approximately 20 patients at each dose level. Enrollment is going well, and we remain on track for an updated data set from a total of about 70 patients in Q1 2026. Our goals for the dose expansions are to more fully characterize the dose response of CX-2051, both in terms of clinical activity and safety with the goal to inform dose selection for Phase II.

In terms of safety, the most common adverse events in the interim Phase I data were diarrhea, nausea, vomiting and anemia. In the expansion phase, we're paying particular attention to management of diarrhea using prophylactic medications, and we'll continue to iterate and refine our AE management strategies to best position CX-2051 for Phase II and beyond.

In parallel to enrolling the expansion cohorts, we are in the process of developing our Phase II strategy in late-line CRC and planning for potential initiation during the first half of 2026. While detailed next steps will, of course, be data dependent, our current view is that the next study would likely evaluate CX-2051 monotherapy in fourth-line CRC based on the high unmet need, the potential speed to market and the multibillion-dollar market opportunity we see in this treatment setting.

Looking out to the longer term, CX-2051 is also anticipated to have potential in earlier lines of CRC therapy and ultimately may be positioned, we believe, to replace irinotecan as a foundational component of CRC treatment. In support of this strategy, we anticipate starting combination studies in CRC in 2026.

Now turning to CX-801, our masked interferon alpha-2b program that we're developing in combination with the PD-1 inhibitor, KEYTRUDA. Interferon alpha is a powerful immune system modulator with known anticancer activity across multiple tumor types, including renal cancer, bladder cancer and melanoma. But it's fallen out of clinical use in oncology due to its poor tolerability. We designed CX-801 to really clamp down on the undesired broad systemic activity of interferon and localized activity to the tumor microenvironment. In May of 2025, during Q2, we dosed the first patient in the combination arm of our Phase I study with KEYTRUDA. This study is focused in metastatic melanoma, and we're targeting initial data for the combination in 2026.

In the fourth quarter of this year, we anticipate providing a first look at translational data for monotherapy CX-801 impaired tumor biopsies and specifically how it's modulating the tumor microenvironment, including potential upregulation of interferon stimulated genes like PD-L1. Positive early results here would provide evidence that the mechanism of action is working as designed, underpinning our rationale for the KEYTRUDA combination and supporting our vision of turning cold tumors hot with this novel immunotherapy. We look forward to providing this initial CX-801 translational update in Q4 this year.

With that, let me turn the call over to Chris for updates on our finances.

Thank you, Sean. Echoing Sean's earlier comments, the second quarter was important as we presented initial CX-2051 Phase I data that informed clear next steps for the program. From a capital formation standpoint, we are pleased to have completed a $100 million follow-on offering with a top-tier group of shareholders, further underscoring CX-2051's potential. Following the execution of the financing, CytomX is in a strong financial position with projected cash runway to the second quarter of 2027. Of note, our cash guidance does not assume any additional milestones from existing collaborations or any new business development. Outside of CX-2051, we will continue to employ a focused capital allocation approach, including for CX-801, where we are aiming to deliver initial proof of concept in combination with KEYTRUDA in melanoma.

In terms of our research collaborations, we continue to view partnering as a capital-efficient way to extend the reach of our technology and drive increased long-term value. A key current focus in our collaborations is T-cell engagers, where, for example, we have momentum with partners, Regeneron and Astellas and have the potential to earn milestones over the next 1 to 2 years.

With that, I'll walk through our second quarter financial results. As of June 30, 2025, we ended the quarter with $158.1 million in cash, cash equivalents and investments versus $79.9 million in cash at the end of the first quarter of 2025. Total revenue was $18.7 million compared to $25.1 million in the second quarter of 2024. The lower revenue was driven by the completion of our performance obligations in the BMS and Amgen collaborations as well as decreased activity with Moderna.

Operating expenses for the second quarter were $19.9 million compared to $33.6 million in the second quarter of 2024. R&D expenses were $13.3 million during the second quarter, representing a decrease of $11.9 million versus the second quarter of 2024. General and administrative expenses also decreased by $1.8 million during the 3 months ending June 30, 2025, to $6.6 million compared to $8.4 million for the corresponding period in 2024, driven by lower personnel costs and lower legal and patent expenses. Overall, we will continue to maintain a disciplined data-driven capital allocation approach in order to advance the most promising opportunities in our pipeline.

With that, I'll turn the call back to Sean for closing remarks.

Thanks, Chris, and thanks, everyone, for joining us today. CytomX made tremendous progress during Q2, and we look forward to the second half as we set our sights on 2026 and in particular, next steps for the CX-2051 program. With EpCAM, we believe we have unlocked a new approach to the treatment of late-stage CRC, leveraging our proprietary platform technology and prior experience with masked ADCs. We view CX-2051 as a first-in-class and highly differentiated asset with broad scope for value creation.

Based on the interim Phase I dose escalation results disclosed to date, we see a clear path forward to develop CX-2051 in late-line CRC, and we plan to execute against this opportunity as our top near-term priority. We're excited to see Phase I results in Q1 of 2026, together with our next steps for the program.

Regarding CX-801, we're executing a similarly focused strategy to CX-2051 in melanoma in order to generate proof of concept for the KEYTRUDA combination. Positive data here would reestablish interferon as a potential new centerpiece of combination immunotherapy with broad potential across many immunologically cold tumors or for patients who become refractory to checkpoint inhibition. We look forward to advancing CX-801 towards this vision.

Before I wrap up today's call, I want to sincerely thank and honor the patients who joined our studies, their families, our clinical investigators and our dedicated team here at CytomX. Your collective contributions are responsible for our advancements, and we're grateful for your help in getting us to where we are today.

With that, operator, please go ahead and open up the call for Q&A.

[Operator Instructions] Our first question comes from the line of Edward Tenthoff with Piper Sandler.

Congrats on all the progress here. So my question has to do with the potential to move into earlier lines of colorectal therapy. What's going into those decisions? And how do you envision sort of announcing those trials?

Ted, thanks for the question. So as I mentioned, first of all -- first and foremost, we're super focused on executing towards the late-line opportunity. We see a terrific opportunity there to move really quickly in fourth line. Coming into the earlier lines, obviously, is a key -- will be a key focus for us over time to really broaden the opportunity. That will require combination studies to assess the doses that we ultimately select for the Phase II for the monotherapy in the context of certain combinations to come into -- well, into third line and then, of course, into second line, where the vision would be to replace irinotecan.

So one, clear opportunity there in terms of combinations, given the extent of its use in treatment of CRC is to evaluate the combination with bevacizumab. And that's something that we're looking at carefully. And we will be doing -- I'm pretty sure in the future, we need to obviously round out the Phase I study and select our doses.

Our next question comes from the line of Nabeel Nissar with Jefferies.

This is Nabeel on for Roger. Thanks for the updates. Quick question regarding the rationale for value creation of EpCAM beyond CRC. Are we approaching this with partnerships? And what is the strategy? Are we looking for a particular TAM? Or is there a particular tumor indication that would fit better with your technology?

Thanks for the question. It's a terrific opportunity to broaden the 2051 development program outside of CRC. We do, of course, currently have our hands rather full with the scope and scale of the opportunity in colorectal alone. But just to restate, EpCAM is expressed in most solid tumors and in many of them at high levels. So for example, lung, pancreatic, gastric, endometrial breast cancer. So there's an enormous opportunity here now that we have initial proof of concept in colorectal.

So it is the kind of drug or the kind of profile of drug that over time, could very well benefit from a partnership. We'll get there when the time is right. As I've said many times on these calls, we'll do the right deal or right deals at the right time. But that could certainly make sense in the future for value creation. But again, right now, over the next few months, we're -- I think it's important for us to be laser focused on really building value initially through the CRC opportunity.

Our next question comes from the line of Matt Biegler with Opco.

What do you think is the bar for accelerated approval in CRC right now, assuming you do go forward with like a monotherapy fourth line? I think obviously, like the rule of thumb that the buy side loves to point to is a 30% ORR, but we've recently seen an ESMO working group come out advocating as low as 20%, I think, like given how poor salvage therapies work in this setting. So I'm just kind of curious if you had any thoughts on that or whether you think ORR is even the most relevant outcome versus PFS or OS or something like that?

Yes. Thanks, Matt. Great question. And of course, an exceedingly difficult one to answer at the moment. But given the activity that we've seen so far and the performance of 2051 in this area of such enormous unmet medical need, we, of course, have to be thinking about strategies that could lead to an accelerated approval. We want to get this drug to patients as quickly as we possibly can.

That said, there are two major considerations as we develop that strategy. One, there's not precedent for accelerated approval in the CRC setting based on ORR, as you know, that would be breaking new ground. More typically, we're looking at a patient population in a clinical setting where we're relying on PFS and of course, ultimately OS endpoints.

That said, the scope of the unmet need, the nature of the unmet need here is so high and our activity is so encouraging that we are considering it, and we will, at the right time, have discussions with FDA. The second thing, of course, is just the overall regulatory uncertainty at the moment, which none of us can ignore. But just to reiterate, of course, we're all aligned here and wanting to get this drug to patients by the fastest possible means.

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

So on the preliminary 801 monotherapy data here in the fourth quarter, what are you looking for that might give you confidence in sort of the combination potential of this product with KEYTRUDA and melanoma? And I guess, any thoughts on any risks of overlapping tox that you're going to be monitoring for?

Anupam, great question. I'm happy to talk about 801 a little bit more. So first of all, there's actually a very good precedent for -- mechanistically for PD-1, specifically KEYTRUDA and interferon alpha-2b having very powerful combination activity in melanoma. That's been shown by Merck in a somewhat earlier setting -- patient setting than we're currently working in. But nonetheless, they showed robust activity, but it was limited by significant incidence of Grade 3 adverse events of various kinds, particularly immune adverse events. So we do know that this combination can be very effective in melanoma as a starting point.

In terms of the progression of our development plan for 801, we're being very deliberate about it. We have escalated through several cohorts already of monotherapy just in a handful of patients to get initial experience with the drug. In that escalation, we've reported previously, we've already exceeded the clinically approved dose and clinically utilized dose of interferon alpha. So we've already made progress, which is consistent with masking showing an overall tolerability benefit.

Most importantly, though, that initial experience with just a few monotherapy patients ungated our ability to start the combination, which we did during Q2, as we just mentioned. And that really is the drug here. So we see the drug ultimately as being 801 plus KEYTRUDA, and we're now going to aggressively enroll that arm of the study, and that data will be reported next year. So the safety and efficacy data from the combination will come in 2026.

In the meantime, with this handful of monotherapy patients that we've treated, we have been studying and we'll continue to study a series of paired tumor biopsies to interrogate the immune tumor microenvironment to look at how in the microenvironment, the unmasked interferon is modulating immune cells and also inducing what we would expect it to do, which is to induce interferon regulated genes, which include PD-L1, which really underscores the rationale for the combination with a checkpoint inhibitor like KEYTRUDA.

So the data that we're planning to share in Q4 will be from a handful of patients. It will be biopsy data initially. We're not expecting in this initial small number of patients to have any kind of initial ORR assessment. It's going to be translational data, but very important and hopefully very informative data that shows us that at the molecular level, the drug is behaving as we've designed it.

Our next question comes from the line of Peter Lawson with Barclays.

I apologize if this has been asked, I joined late. On the EpCAM ADC, so we got the Phase I update in Q1. Kind of just if you could talk through the size of the data set we see and the scope of it, and kind of if we should expect to see durability and also biomarker data.

Yes. Thanks, Peter. Thanks for giving me the opportunity to recap some of our earlier comments on the call. It's very important. So as we said, we're super focused on generating this next data set for 2051. We anticipate that in Q1 2026, we'll have 70 and maybe a few more patients have experience with the drug compared to the update, the initial disclosure in May, which was 25 safety evaluable patients and 18 efficacy evaluable. So by the time we get to Q1, that data set should be quite a bit larger and predominantly across three dose levels, 7.2, 8.6 and 10 mg per kg. Each of which were doses that we saw clinical activity for in that initial disclosure, right?

So by then, yes, we would expect to have reasonable follow-up on the majority of those patients. And the other element of that update will be integration of that data into our go-forward plan for Phase II. So that's our current plan is that the Q1 update will be a rounded out Phase I data set plus our strategy for moving forward into Phase II. That's the current plan.

And that Phase II, would that have a randomized component to it?

I think that's most likely. Yes, we're still obviously collecting data from the Phase I. So no decisions made yet, but we are of the general view that the next study would be randomized to a component or components of current standard of care in the fourth line where, unfortunately, for patients today, the bar is very low. So we think that 2051 is very well positioned against those comparators. And we'll also be thinking through in the context of Project Optimus and also, of course, based on the full Phase I data set that we analyzed later this year and into Q1, whether that's a one dose of 2051 or maybe two, that remains to be decided.

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

You mentioned that there's quite a low bar for 2051. That makes a lot of sense. But thinking about what triggers a go/no-go move into the Phase II and fourth line as a monotherapy, can you just speak to what we should be looking for that would be indicative of a positive outcome that would immediately trigger looking to move into Phase II?

Yes. Mitch, thanks for the question. Well, again, just to recap our experience with the first 18 efficacy evaluable patients where across the three dose levels of 7.2, 8.6 and 10, we saw a confirmed ORR of 28%. So I think we all agree that that's very exciting and would set up a very clear go-forward decision into the fourth-line study. Number doesn't, of course, need to be as high as that to go forward. I don't think we're going to put a number on it today, but we've got a lot of room to maneuver, we think, with the data that we've already presented with CX-2051 as our data continues to mature.

Okay, great. And just one more on the CRC combos in earlier lines, would you potentially advance multiple combinations? And have any plans been discussed with the FDA on the combination strategy so far?

Multiple combinations are certainly on the table. We need to be mindful of our resources at this point in time. And as I mentioned, the place to start most likely would be the combination with bev. We have yet to have significant conversations with FDA relating to few go-forward study design. That will come, of course, as our Phase I data continues to mature.

Our next question comes from the line of Mayank Mamtani with B. Riley.

This is Jeff from B. Riley for Mayank. My first question is given that CX-2051's Grade 3 diarrhea rates exceeded those of other Topo-1 inhibitor ADCs. Will you explore alternative mitigation strategies such as specific protease inhibitors or microbial modulation rather than relying solely on loperamide. My second question is how much median follow-up are you expecting to have at 1Q update? And are you planning to present data at ASCO GI in January 2026?

Great. Thanks for the questions. So taking the first one relating to diarrhea. Yes, so as I mentioned on the call, that is one of the AEs that we're most focused on in this Phase I study. We've learned a lot about it in the context of the data that we initially disclosed. Just to recap what we're doing, as we've discussed before. In the earlier part of this study, of course, as we wanted to understand the overall AE profile of this drug, we have not implemented any prophylactic measures for management of diarrhea. But we did earlier this year around the March time -- March, April time frame around the time that we were beginning to gear up some of these expansion studies.

And so we continue to be focused on the use of loperamide as a prophylactic measure. We're going to learn a lot about that as we continue to execute on the expansions. And in terms of the incidence of Grade 3 diarrhea in the study, about 20%. I want to remind everyone that in the early days of irinotecan development, that number was closer to 30% to 40%. And we do know that Topo-1 inhibitors in the context of ADCs can also induce significant levels of Grade 3 and higher diarrhea. So it's something we need to understand more about, something we need to manage. We're really exploring loperamide as a starting point.

Your question on protease inhibitors, I think is an interesting one. At this point, that will be very exploratory, and we don't really have any evidence right now that protease biology is playing any role in the AE profile. So that may be something for future exploration. But thanks for the question.

I think you had two more questions in terms of median follow-up. I guess there, what I would say is that, as I mentioned earlier, enrollment of the expansions has gone well. We're midway through 2025. So by the time we get to Q2 -- sorry, Q1 of next year, we'll have a pretty decent follow-up, we think, on the majority of these patients. So I can't give you a number. The study is still in progress. And of course, I can't comment on the ASCO GI 2026. We will plan to keep all of our options open in terms of where and exactly when we present data as is customary. But thanks for the questions.

Ladies and gentlemen, I'm showing no further questions in the queue. I would now like to turn the call back over to Dr. Sean McCarthy, Chairman and CEO, for closing remarks.

Thanks, everyone, for joining us today. It's been a pleasure to recap our tremendous progress during Q2 of 2025. We look forward to providing additional updates as we move through the second half of the year. So enjoy the rest of your day.

Ladies and gentlemen, that concludes today's conference call. Thank you for your participation. You may now disconnect.