Welcome to this next session. My name is Paul Jeng. I'm a biotech analyst with Guggenheim, and I'm pleased to welcome our next presenting company, CytomX Therapeutics. With us today is Sean McCarthy, CEO. Sean, welcome.
Thanks, Paul. Thanks for having us. Pleasure to be here.
Maybe a good place to start is, for those that are maybe newer to the story, could you provide a quick overview of CytomX and your PROBODY masking platform and how the conditional activation is designed to widen the therapeutic window of your core assets?
Yeah, happy to. CytomX Therapeutics, we're an oncology-focused company based in the Bay Area, leveraging a very unique technology platform that we call the PROBODY therapeutic platform, which is a biologic masking strategy that allows us to engineer antibodies, cytokines, other biologics to be localized into the tumor microenvironment and less active in the periphery. The way we do that is through leveraging the protease-rich microenvironment of tumor tissue to cleave off peptide masks from the masked biologics. That creates a differential between normal and tumor tissue, which we are able to use to open therapeutic window, and either open therapeutic window where there hasn't been one previously, for example, with EpCAM that we'll talk about a lot in a moment, I'm sure, or improve and broaden therapeutic window where there's room for improvement. For example, our second program, which is a masked version of interferon alpha-2b.
This is a technology that we've really championed over more than a decade now, and it really just continues to allow us to do really interesting and unique things, which is really important at this moment in time where differentiation and staying ahead of the pack, I think, is particularly important.
Got it. As you mentioned, your lead asset, Varseta-M, is a masked ADC targeting EpCAM. Why is EpCAM such a compelling ADC target, and why does the conditional activation make it tractable, whereas other approaches may have not worked in the past?
Yeah, so EpCAM, epithelial cell adhesion molecule, it's a very highly expressed antigen that actually was first described as a colorectal cancer target many years ago. It's expressed also on most other solid tumors, so it's been of interest to the oncology field for many years. Many attempts have been made to try to drug EpCAM with different strategies, including antibodies, T-cell engaging bi-specifics, but they've all run into challenges very early in development because of the expression of EpCAM in normal tissues. One of the typical toxicities that was seen early in development of EpCAM therapies was acute pancreatitis due to expression of EpCAM in pancreatic epithelium.
That said, we have known for a few years now that if you can locally target EpCAM with an empowered antibody, whether it's a T-cell engager or certain drug conjugates, local delivery can be effective, for example, in bladder cancer, or in the treatment of malignant ascites, for which there's actually an approved product in Europe called KORJUNY. With the evidence that if you can get the drug to the target and you can shrink tumors, but with the lack of ability of others to have systemically engaged EpCAM, we reasoned that masking could be an ideal way to unlock a therapeutic window for this high potential target, not just in CRC, but potentially in many other cancers as well. We set about making a masked ADC with a topoisomerase I payload, and that's what we call CX-2051, now varsetatug masetecan.
We've just made terrific progress over the last couple of years in the clinic, initially in CRC.
Great. So maybe speaking on the CRC data, you had a clinical update earlier this year. Can you walk us through some of the key findings in a late-line colorectal setting that you showed at that update?
Absolutely. We decided a couple of years ago, as we entered the clinic with Varseta-M, to initially focus 100% in metastatic colorectal cancer for a number of reasons. First of all, that's where the target is most abundantly and most consistently expressed. It's also homogeneously expressed in every patient. We knew the target was there and that we wouldn't need to select patients into the study. We also, I mean, really had intentionally designed the drug to be active in late-line CRC. Thirdly, of course, there's just enormous unmet medical need. We felt that it was absolutely the right place to go first. A little bit risky, but certainly the right place to go first.
We've, as of our most recent update in March, our first update, first data disclosure was in May of 2025, where we showed that this appears to be an active drug. We showed significant evidence of anti-tumor reduction, and we clearly had opened a therapeutic window for EpCAM for the first time with an ADC. We updated that data in March this year. At that time, we were able to report response rates in fourth line or later colorectal of 20%-30%, progression-free survival of six to seven months. We didn't report OS at that time. That's something that's coming in our next update. But a really great start showing unequivocally that this is an active drug in late-line colorectal cancer, where the currently available therapies are highly inadequate.
Just to put our data into context, that 20%-30% response rate and six to seven months of PFS, that compares to. In the fourth-line setting, current standard of care drugs like fruquintinib or regorafenib have response rates of 1%-2%, progression-free survival of about three months. In fact, overall survival for those drugs is about five to six months. Our PFS in the most recent update actually exceeded overall survival in current standard of care in the fourth line. A very strong start for this ADC. Even in the third line, current standard of care is the combination of bevacizumab, the anti-VEGF antibody, with LONSURF, and their response rates are about 5%, PFS of about five months, and OS of about 9-10 months.
We think a really significant step forward, potentially, in the treatment of colorectal with VARSETA-M really functioning as designed. In terms of safety, I should comment on the safety profile as well, of course. First of all, one of the most notable things that we learned in our early clinical experience is no evidence of the classic EpCAM toxicities. We haven't seen any evidence of acute pancreatitis. In fact, we haven't seen any evidence of even elevation of pancreatic enzymes like amylase or lipase. The masking clearly seems to be working and opening therapeutic window. We've seen no ILD, so no interstitial lung disease. This is a novel topoisomerase I payload on VARSETA-M, so masetecan, it's a topoisomerase I inhibitor that we licensed from ImmunoGen, formerly known as CAMP59. So, no ILD. Low rates of hematologic toxicity as well, which is really encouraging.
Across the board, neutropenia, thrombocytopenia, and anemia are all really low with VARSETA-M. The one safety signal that we have seen, that we continue to learn more about, is some level of GI tox, and specifically diarrhea, with a rate of Grade 3 diarrhea that in the escalation and expansion phase reached about 30%. As of our optimization data that we reported from the first 20 patients in March this year, we've been able to manage that down, at least in the first couple months of follow-up, to about 10%. We're getting an increasing handle on the GI toxicity over time, and just really excited about the overall profile of VARSETA-M that, as I've said, really now shows strong evidence that we've opened a therapeutic window for an EpCAM ADC for the first time.
Got it. As you mentioned, you've sort of implemented this dose optimization that will have some additional updates next year, and you've sort of set the target range in the past as roughly 10%-20%, Grade 3. I guess the question is, how did you arrive at this range? How likely do you think that it's achievable to fall in this range, and how does that actually translate to how clinicians think about diarrhea and managing the adverse event through dosing?
Yeah, just to take a step back and talk through the journey with the drug in terms of dose escalation and expansion, we expanded three doses initially, 7.2, 8.6, and 10 mg per kg. We give the drug on a Q3 week schedule, and we then selected the top two doses, 8.6 and 10 mg per kg, to move into further dose optimization, really with a strong view towards ultimately going to FDA to satisfy Project Optimus requirements as we began to steer the drug towards its first potential registrational trial, which I'm sure we'll come to in a moment. So, what we've been doing for the last nine, 10 months or so is looking at these top two doses, 8.6 and 10, Q3 week.
We enrolled 20 patients at each dose into optimization cohorts, and we also implemented a couple of other steps in terms of managing the toxicity. We've implemented adjusted ideal body weight dosing. The goal of AIBW is to flatten the exposure range across patients so that patients who have high BMI don't get overdosed, because we did see during dose expansion some correlation between patients that had high body weight just not tolerating the drug quite as well as patients who had more typical body weight. So, AIBW is a strategy that's been used very effectively in the past, for example, by ImmunoGen in the management of ocular toxicity with ELAHERE. So we're implementing AIBW in dose optimization. We also decided in optimization to use upfront prophylaxis of two drugs, loperamide and budesonide.
Loperamide is, of course, an anti-motility agent very broadly used in the treatment of diarrhea, and the use of budesonide is something that we learned during expansion. We learned that the administration of budesonide to patients who had Varseta-M-induced high-grade diarrhea could respond well to the drug. So, we do believe that the diarrhea that we see with Varseta-M, in some, not all patients, has an inflammatory component, and the use of budesonide, which is a locally acting, non-absorbable steroid, was effective in 14 patients that we studied in the expansion phase. 14 patients treated with budesonide, 12 of them showed at least a one-grade improvement in their diarrhea symptoms. So for that reason, we implemented budesonide prophylaxis, and all of these measures, as of the initial data update in March, appear to be working together to significantly improve the high-grade diarrhea burden, and we've continued to follow those patients.
We enrolled an additional 20 patients over the ensuing months, and in our next update, we'll have a more complete assessment of the safety and efficacy at both of those levels in both of those cohorts.
Okay. So maybe just to underline the upcoming update, which I think you recently refined to January of next year.
Yeah.
What kind of, for the patients that were reported back in March, what kind of sufficient follow-up for survival will you have for those patients? Then similarly for the new dose optimization patients, should we expect response rates, anything on PFS? So yeah, how do we think about those updates?
Yeah. So the next update, and we've been saying for some time that we want the next update that we give on the Varseta-M program to be obviously very meaningful for investors in terms of showing where we're headed in terms of the next stage of development of this drug. We are highly motivated to get Varseta-M into its first pivotal study as quickly as we can. We'll come to the competitive landscape in a moment. That's certainly influencing us. So we want to share directionally where we're headed with the drug and the data that underpin that strategy, including the outcome of our interactions with FDA, particularly in the context of dose optimization. So, we've now got 113 patients enrolled into the phase I study, 73 in escalation and expansion, 40 in dose optimization.
Very importantly, this next update from CytomX will include the first disclosure of an overall survival number for Varseta-M. That's particularly important because we do anticipate that the primary endpoint in our first pivotal study in metastatic CRC will be OS. So, this will be the first opportunity to share and discuss OS and the implications of what we're seeing in terms of study design. We'll also share from the optimization cohorts, safety, and ORR and PFS. It'll be too early to share OS from the optimization cohorts, but we will have ORR and PFS. So taken together, across the 113-patient phase I study, including where we're at with FDA at that time, we anticipate this will be an important update to really show where we're going next with this really exciting drug.
Okay. And then, I guess, how do you think about a phase III design at this moment? Would this more likely be a third-line plus versus LONSURF/Bev or a later line versus fruquintinib or even regorafenib, or is it going to be informed mostly by that survival update coming up in January?
Well, let me say at the outset that we see an enormous amount of opportunity in CRC, initially in third-line plus. By the time patients have been through usually a couple rounds of chemotherapy with metastatic CRC and they become eligible to be treated with current third-line standard of care, which is bevacizumab/LONSURF, they really need better options. Bev/LONSURF is obviously becoming the standard of care in third line, but they really need better options from third line and beyond. We are evaluating, we continue to evaluate study designs in third line or potentially later, and it really comes down to, of course, patient population and comparators. We see two really very attractive options for the company in terms of moving the program to the next level in the context of the first, and I'll emphasize first, pivotal study.
One design would be to compare to a physician's choice of fruquintinib or regorafenib in, let's call it fourth line. There, we've already discussed the bar. You've got a response rate in this patient population of 1%-2%. It could be even lower, and just a few months of progression-free survival. And we've already shown PFS that is similar to or exceeds OS in that particular setting. So that's a very compelling place to go. We also, though, have not ruled out doing a study where we go head-to-head against Bev/LONSURF. That is a higher bar. There you've got overall survival of nine to 10 months. And so we'll have to see where our OS number comes out and how competitive we think the monotherapy for VARSETA-M could be up against that combination.
I should say that our competition that are a little ahead of us, AbbVie and Merck Serono. AbbVie is running a third-line study in combination with Bev against Bev/LONSURF. They actually dropped their monotherapy arm a few months ago. Merck Serono is still keeping their options open. They're running a three-arm study looking at monotherapy, precemtabart tocentecan, which is their CEACAM5 targeting ADC, combination with Bev, also against Bev/LONSURF in the third line. But we see both designs for CytomX being highly attractive. We'll make a data-driven decision. The third line plus market in the U.S. we see about 35,000 patients annually treatable. So, this is a very substantial market opportunity in the late line. Obviously, on a global basis, metastatic CRC is a huge and largely untapped market that we could access, we think, through either one of these initial designs.
This would just be the start for where we could go in the future, potentially with combination strategies, bringing the drug progressively into the earlier line setting.
That is right. We do get a lot of questions, as you alluded to, on the competition, especially given different targets, but usually using similar mechanisms of payloads. Would love to get your thoughts on ultimately what the positioning for Varseta-M might be relative to these other assets, and maybe your thoughts on emergent targets as well, like CDH17.
Yeah. We think we are very well positioned. Relative to the AbbVie and Merck drugs, AbbVie, c-Met targeting ABBV-400, otherwise known as Temab-A. I have just mentioned they are in a phase III trial comparing to Bev/Lonsurf in combination with Bev. Merck is running the study I just described. Then we have CytomX, then we have coming up quite a bit earlier, but not something that we need to pay attention to, a large number of CDH17 ADCs. These are all topoisomerase I ADCs. I think we can say that the ADCs are certainly coming to colorectal. It is a really exciting time for CRC patients, where there has been a real dearth of innovation for the longest time. Antibody drug conjugates coming to CRC, into really the largest untapped solid tumor market on a global basis.
We see our drug as being highly differentiated from really all of the other players, specifically with regard to the c-Met and CEACAM5 ADCs. As I have already mentioned, we see very low rates of hematologic toxicity, which we think could be very advantageous in the post-chemo setting. By the time patients come to third or fourth line, their bone marrow is not in great shape, they are sensitive to cytopenias, and our drug is very well tolerated from a hematologic point of view. As I have already mentioned, no evidence to date of interstitial lung disease, and we are feeling pretty confident that over time, we are getting and will continue to get an increasing handle on managing the one toxicity of interest, which is GI toxicity, using prophylactic strategies and dose optimization.
With regard to the CDH17s, I think it's really interesting that yet another highly abundant cell surface molecule that's in the class of transporters, adhesion molecules, is beginning to show itself as a target through which you can achieve objective tumor shrinkage with Topo1 ADCs. But boy, it's a very crowded field, and I don't think yet you can point to any of the three drugs that have shown data so far as being particularly differentiated from each other. The safety profiles, I think, are really early, and we know very little about depth and duration of response. And with at least 15, if not 20 CDH17s in development, we feel really great about where we are with EpCAM, because as a function of our really unique platform technology, we are the only company, to our knowledge, with a clinical EpCAM ADC program with an intrinsically differentiated profile.
As we fast-forward a few years to, fingers crossed, the approval of several of these drugs, and let's say, for example, that the first three that are approved are CytomX, AbbVie, and Merck, we think we've got a very competitive value proposition with varsetatug masetecan that will be a terrific choice for GI oncologists to use for their patients.
Great. Then, there's also a lot of development ongoing for yourselves in combinations, including with bevacizumab, which will have data next year, as well as a bevacizumab chemo combo. Can you talk about the status of those respective combinations and what we should expect from the bevacizumab combo data next year?
Absolutely. Happy to, and it allows me to emphasize that everything that we've talked about so far with regards to varsetatug masetecan relates to monotherapy, which is the leading edge of the program right now, and our goal of getting this drug into its first registrational trial as quickly as we can. But this is just the beginning of what we can do with this program. Our goal is to. We are actively exploring combinations with bevacizumab. We aim to start work in combination with five-FU by the end of the year, which is, of course, a critical component of second-line metastatic CRC treatment. And over time, our goal is to march this drug earlier and earlier into the treatment paradigm in CRC, whilst also moving into other cancer types.
We've also recently initiated and broadened the program into three other GI tumors, into gastric, gastroesophageal cancer, pancreatic, and also biliary tract tumors. These are the GI tumors that are adjacent to CRC from a franchise perspective, and all areas where there's still significant unmet need. The pancreatic landscape is obviously shifting in real time, but we don't anticipate the long-term unmet need in pancreatic to diminish as patients go through their journey on RAS inhibitors. These are all indications that are known to be responsive to topoisomerase I inhibition. We think it's a really exciting time to go. We're going deeper with varsetatug masetecan in CRC, and we're going to go broader into other tumor types. Then there's a large number of other EpCAM-positive cancers we could go to over time as well.
Okay, great. With our last two minutes, quickly on CX-801. You've got a data update for the KEYTRUDA combo next year. Can you set some expectations? How many patients, which dose levels, and what should we expect to see?
Yeah. CX-801 is our masked version of interferon alpha-2b. We think another terrific application of the power of masking. We've used our masking strategy to create this drug, CX-801, that has 5,000-fold lower affinity for interferon receptors than unmasked interferon. The reason we've masked it so tightly is to really shut down the peripheral activity of the interferon, because that's been the main limitation on the widespread use of interferon, really over the last decade or two, because it has significant systemic toxicities in the form of immune-related adverse events, neuropsychiatric events, flu-like symptoms, that in the context of its anti-tumor benefit, it just don't offer a value proposition for the use of this drug, and it's really fallen into disuse. However, interferon is a very powerful activator of the immune system across multiple parameters.
It induces interferon-responsive genes, it modulates multiple immune cell types, T cells, NK cells, dendritic cells, and can be used to reprogram the immune system. Our strategy with 801 is to initially evaluate in melanoma and essentially turn cold tumors hot again by reprogramming the tumor microenvironment to be competent to respond again to checkpoint inhibition. We have demonstrated, as recently as SITC last year, a really powerful pharmacodynamic modulation of the immune microenvironment by CX-801 in the context of great tolerability at doses that exceed the clinically approved dose of interferon alpha-2b. We're now escalating with pembro under license from Merck, and our goal is to present initial data in late-line metastatic melanoma in the first half of 2027.
All right. A lot to look forward to in 2027, but I think we'll have to wrap it up there. Thanks so much, Sean, for joining us. Really appreciate it.
Thanks, Paul. Thanks again for having us. It's been a pleasure.