All right. All right. Welcome, everyone, to Jefferies 2025 Global Healthcare Conference. My name is Roger Song, one of the senior analysts covering Simcha Biotech in the U.S. It is my pleasure to have the next fireside chat with CytomX Therapeutics CEO, Sean. Good. Yeah, good to see you.
Pleasure to be here, Roger.
Awesome. Maybe before we start, we know you just announced very exciting data from your lead clinical program for EpCAM ADC. Maybe just give us a high-level recap, and then we'll have a conversation.
Yeah, once again, great to be here. Thanks very much for the invitation. We are super excited about the data set we presented on May 12th this year regarding CX-2051, our Probody ADC targeting epithelial cell adhesion molecule, EpCAM. This is a drug that we believe has disruptive potential in the treatment of metastatic colorectal cancer and potentially many other cancer types. In addition to CRC, EpCAM is a target that actually was first described as a colorectal cancer antigen many decades ago. It's been of high interest to many in the oncology field for a very long time. It's been a challenging target to drug because of its presence on normal tissue. It's been, as I said, of high interest because it's very highly expressed on many solid tumors, including CRC.
We have always believed that it had the profile to uniquely benefit from our technology, our Probody masking platform. This first 25 patients of data that we presented just a couple of weeks ago have, we think, shown that we have not only broken through on EpCAM for the first time with a systemic therapy, but we are able, with this drug, we are making a very big difference for a very tough area of oncology to treat, which is late-line metastatic CRC. Really happy to be here today, Roger, to talk more about the data, what we have seen so far, what it means, and where we are headed with this drug candidate.
All right, let's drill down this. When I look at the data, obviously, it's positive on the top line. If you look into the details, swimming plot, and then the disease control and the durability, all looks very good. Maybe just give us what are the key data points when you look at this data, say, wow, this gives me the confidence we should move forward this program, even we only have relatively small n and then still in early stage.
Yeah, absolutely. The drug has been very intentionally designed for the treatment of colorectal cancer. The target is broadly and highly expressed in just about every patient, if not all patients, as far as we can tell. It is a terrific target for CRC. The payload that we have selected for this drug very intentionally is a topoisomerase I inhibitor. Of course, we know that CRC responds to topo I inhibition in earlier lines of treatment. It is standard of care, irinotecan, in various regimens. We have applied our masking strategy in a very intentional way. The fourth aspect, a very intentional aspect of our strategy, has been to focus our phase I study entirely in metastatic CRC, which was a big decision for us about a year ago. It is really, we think, paid off.
The data set that we've shared so far, 25 patients treated through dose levels one to five in our dose escalation, beginning at a dose of 2.4 mg per kg administered every three weeks, up to and including the dose of 10 mg per kg, which was dose level five, also a Q3 week. 25 safety evaluable patients across those five dose levels, 23 safety evaluable at dose levels three, four, and five of 7.2 mg, 8.6 mg, and 10 mg per kg. And within that dose range, 18 efficacy evaluable patients as of our April 7th data cutoff, with a very impressive response rate, 28% confirmed ORR across those 18 efficacy evaluable patients, including three out of seven patients treated at the top dose of 10 mg per kg, accounting for an overall confirmed response rate at that dose level of 43%.
Just to put that in context, these patients had a median number of prior lines of therapy of four. This is essentially a fifth line metastatic CRC patient population. We know that in the fourth line, current standard of care response rates are in the 1%-2% range, with PFS of about 2 months-3 months. We also had a very encouraging preliminary assessment of PFS in this initial 25 patient data set of 5.8 months, which is a great start. Combined with disease control, a disease control rate of 94%. Across all measures, ORR, disease control, PFS, this drug really has had a very strong start in the clinic.
I think our strategy of deciding very intentionally to not only design this drug for CRC initially, but do the right experiment first and really take on the challenge of late-line CRC has really delivered. The response that we've had from investors and others in recent weeks has been really, really exciting, including, as we'll probably talk about in a moment, a very successful $100 million financing that we closed on the cusp of the data around May 12th as well.
Excellent. Yeah, those dependence, very long duration of the response, and then the disease control translates to the PFS is way higher than standard of care. The safety, right? Because we look at the top one related to safety and then also EpCAM related to safety, seems the masking technology is working. You are not worsening or anything worse than the typical top one. Maybe you talk a little bit about the safety, because that's also very important for cancer therapy as well.
Yes, absolutely. Let's break down the safety profile somewhat. There are really two main components to think about with 2051. First, of course, is the target itself, EpCAM. As I've already mentioned, EpCAM has been of very high interest to many in the oncology space for a long time, but it's been a very difficult target to drug because EpCAM is present on most normal epithelial tissues, as the name suggests, epithelial cell adhesion molecule. Prior attempts to develop systemic therapies against EpCAM have quickly hit tox roadblocks in the clinic that include acute pancreatitis, liver enzyme elevation, and gastrointestinal inflammation. That's across a range of modalities, antibodies and T cell engagers as an example. There have been some interesting clues that actually, if you can get EpCAM therapeutics to the target in a localized way, you can be quite effective in shrinking tumors.
That's been shown in bladder cancer. It's also been shown in the treatment of malignant ascites in the peritoneum of patients with various gynecologic and GI tumors. We've known for a long time that if you can get the drug to the target, you have the potential to shrink tumors. The barrier has been the on-target toxicity, given how broadly expressed EpCAM is in normal tissues. Going into this phase I study, we were very interested to see the extent to which our masking technology could limit or eliminate these on-target toxicities. That seems very much to be what we've observed so far. The other component, of course, of the safety of a drug like this is the payload. The payload is a novel topoisomerase I inhibitor. It's called CAMP59. We licensed it from ImmunoGen, now AbbVie.
This is the first in human experience with CAMP59. It is a topo I inhibitor. We kind of knew what we were on the lookout for in the phase I study in terms of payload toxicity. It is very important to underscore that with our technology, we do not mask the payload. We do anticipate that as we dose escalate and push towards MTD, ultimately payload toxicities would emerge. They are expected. For topo I inhibitors, they are fairly well characterized for irinotecan and others. For example, upper GI toxicity, nausea, vomiting would be expected. Heme toxicity in the form of anemia and neutropenia would be expected. Diarrhea and lower GI toxicity is also a hallmark of many of these topo I agents.
The way the study's played out, first and foremost, we've seen very little, if any, evidence of on-target toxicity, giving us a high degree of confidence that our masking strategy is indeed unlocking EpCAM as a systemic therapeutic target for the first time. With regards to the payload toxicity, as we've escalated, as expected, we have seen some of the anticipated topo I payload tox, actually very low rates of cytopenias in the form of anemia and neutropenia. What we do see is very manageable. Moderate levels of GI toxicity, nausea and vomiting, which is manageable with prophylaxis. Some incidents of diarrhea, including some grade three. Again, we believe, for the most part, attributable to the payload, given that this is the first in man experience.
Taken together with the really impressive clinical activity that we've seen, again, 28% ORR across all dose levels, 43% ORR at the highest dose level of 10 mg per kg, we really think this is a strong start with a very compelling efficacy profile and a very promising safety profile overall.
Yeah, good.
[audio distortion] a lot of us were taken pleasantly by surprise.
Yeah, so let me just repeat the question. The question is, to what extent does the protease profile in CRC differ from other tumors? We believe it's substantially similar based on everything we know about the tumor microenvironment. I think in this case, the masking strategy that we've used is actually quite similar to strategies we've used with previous programs, all of which have shown quite compelling anti-tumor activity across multiple cancer types over the years, whether it's hormone receptor positive breast cancer, triple negative breast cancer, cutaneous squamous carcinoma, multiple tumors where we've seen activity with the platform. I think in this case, where we've really broken through is by directing the technology to a very clear clinical problem, which is metastatic CRC, where the target is very highly and very uniformly expressed, allowing us to really see the full potential of what our technology can do.
Also, the linker is very stable. Maybe because when I look at just side by side, other top one, kind of the ADC, seems you are even less toxic in terms of the on-target, the payload toxicity there. Maybe just that's it.
The payload toxicity itself. Yes, I think that's a key observation. The linker on 2051 that links the CAMP59 payload to the antibody is also a novel linker. It's a tri-alanine peptide linker that has been designed by our colleagues at ImmunoGen to be cleavable in the extracellular microenvironment in the tumor to promote bystander effect. It is a novel payload that was selected to have a kind of a moderate level of cleavage compared to perhaps some other ADC linkers, which can tend to run into higher levels of systemic payload toxicity, particularly in the bone marrow. We're still characterizing the full profile of this tri-alanine CAMP59 linker payload module, but we are very gratified by these initial findings. We think that the work, the foundational work that ImmunoGen did to build this particular approach to inhibiting topo I is really looking very, very encouraging indeed.
Awesome. All right, great. I think the data is appreciated by the investors' community for sure. And then we always ask for more, right? You are moving forward with the dose level three to five, and then also you continue dose escalation. Maybe just tell us the rationale you're expanding three, five, and then the six and seven, what should we expect from the next data update, I believe the 1 Q next year?
Yeah, so far in dose escalation, we've actually proceeded through seven dose levels. The data that we just presented was through dose levels one through five. Again, to recap, doses of 2.4 mg up to 10 milligrams per kilogram. Based on the really compelling profile of the drug at the 7.2 mg, 8.6 mg, and 10 mg per kg dose levels, we've already started to expand at each of those doses. Our goal is to increase each of those dose cohorts to 20 patients by the end of this year to gain additional experience of efficacy, safety, PK, exposure, and such like. We anticipate having that full expansion data set and releasing that in Q1 of 2026.
Fast forwarding to that timeline, Q1 of 2026, I would expect our data set to be in the 70 patient range, including, of course, the first two patients that we treated in single patient cohorts at 2.4 mg and 4.8 mg per kg, a handful of patients at dose level six and seven. We do not have any plans at the moment to expand those dose levels. We do think at dose level six and seven, we are pushing up against our maximum administered dose. Again, we will learn more in the coming months. The majority of the data that will be the next update in Q1 of 2026 will come from the dose levels that we are expanding on those 60 patients. We fully anticipate that our recommended phase II dose or doses will come from within those three dose ranges.
The selection of doses, of course, for the go forward study, which we'll talk about in a minute, I'm sure, will depend, of course, on how the data shows itself over the rest of this year.
Excellent. Okay, great. I think we obviously have a couple of months to see the next data update. Before that, you may have some interaction with the FDA to think about what's the next step, right? I think the lay line, third plus line, metastatic CRC, no standard of care, potentially have some opportunity for accelerated approval, but your ambition can go even earlier line. Just tell us the overall strategy for the CRC for 2051.
Yes. The first thing to say there is that the profile of 2051 is just so interesting because we see the drug as having truly disruptive potential in the treatment of metastatic CRC. What we mean by that is that our clinical evidence to date shows activity independent of the typical clinical features that are used to manage and triage patients through their treatment course. For example, we have activity in KRAS wild type patients. We have activity in KRAS mutant patients. We have activity in patients with liver mets. We have activity in patients without liver mets. We have activity in patients with left side or right sided tumors. As you all know, these features are used and have been characterized historically to direct patients down certain treatment pathways.
EpCAM is expressed so highly and so consistently in CRC that once we, and hopefully in the not too distant future, secure our first approval in late line metastatic, this drug should be able to come earlier and earlier in the treatment paradigm. Our vision for 2051 has always been to replace systemic chemotherapy in earlier lines of treatment. Our development strategy right now, we are obviously laser focused on enrollment of these expansion cohorts to get this more robust phase I data set in Q1 of 2026. In parallel with that, we are actively developing our phase II slash phase II-III strategy. Have not pinned that down yet, but there's a number of ways we can go.
Given the, we believe, given the extraordinary unmet need in the fourth line in CRC, given the extraordinary activity that we're seeing of the drug, and given the very poor nature of the existing therapies in standard of care, this is a line of therapy where we do think we could go very, very quickly, and it could potentially lend itself to an accelerated approval path. We have not yet spoken with FDA. We don't know that that's the case, but there are a number of conversations we'll be having to lock in that next step in development. Our goal is to initiate the next study, potentially registrational in the first half of 2026. Looking earlier, we're really excited to bring 2051 into the third line, potentially into the second line. In the third line, standard of care, as you know, has become bevacizumab and LONSURF.
That combination shows relatively modest ORR in the single digits, about five, five and a half months of PFS, the combination of Bev-LONSURF. As we learn more about the monotherapy profile of 2051, we'll be able to evaluate the potential for 2051 to compete directly in the third line with the Bev-LONSURF combination, or whether or not we would need to combine with Bev to do a head to head Bev-2051 versus Bev-LONSURF. That will, as I said, depend upon how the data continues to shape up over the rest of this year with the monotherapy. Looking to second line, second line in the United States at least is dominated by the use of FOLFIRI. Irinotecan being a key component of second line treatment. Our ambition is to replace irinotecan in that setting.
We will be initiating in the not too distant future the appropriate combination studies to begin to lay the groundwork for moving 2051 into the second line. Looking even further ahead, as we've been seeing, including at ASCO just last week, ADCs continue to progressively move earlier and earlier in the treatment paradigm. I would cite TRODELVY as an example showing impressive activity in the front line in combination with KEYTRUDA in the ASCENT-04 study in triple negative breast cancer, now presenting a new standard of care for first line treatment of TMBC. Our longer term vision for 2051 would be to bring this drug into the front line of treatment of CRC. If you add that all up, you can see why we see 2051 as being really potentially disruptive in the treatment of metastatic colorectal cancer.
Yeah. I believe the guidance is also you will give us some regulatory updates when you report the data next year and then start the phase II potentially pivotal first half next year.
That's right. In conjunction with our next data update in Q1 2026, we very much would hope and plan to be announcing our go forward strategy at that time. That should all be announced concurrent in the early part of next year.
Is that possible? You can do the third plus line versus the fourth plus line as the initial indication because you seem to separate these two populations.
It's a really good question. Quite honestly, the market opportunity in the fourth line is so compelling and the unmet need is so great and our drug is performing so well. We think that the probability of technical success in the fourth line is high and therefore the right study to do next. I think third line would follow, as I mentioned, depending upon how the profile of 2051 develops in terms of PFS in particular. The other thing about the fourth line to say is that there are about 15,000 treatable patients in the U.S. every year in fourth line CRC. A very interesting commercial benchmark is presented by fruquintinib, the TKI that is one of the components or one of the options for treatment of fourth line patients.
Fruquintinib, in its first year of sales, first year on the market, generated $350 million-$400 million of sales in CRC. This is not a small opportunity. That was with relatively modest penetration of the market. We see the fourth line as a multi, in and of itself, as a multi billion dollar opportunity. We currently own, we control this drug. We have full rights to 2051, full commercial rights. We see the fourth line as a terrific place to start, even more so for a company of our size and shape and an opportunity that can help us drive CytomX to huge value creation as we drive towards potential commercialization ourselves.
Okay. Maybe just since we're on this market opportunity. Fourth line, 15,000, and then how about the third line, second line, and then for the CRC opportunity that you move earlier line?
You're looking at about 150,000 patients across multiple lines of treatment in the U.S. in metastatic CRC. Of course, that does evolve as you go from first line through to late line. Across the treatment paradigm, this is a very, very large market.
Right now, as you fully own this asset and then it's in early development, what's the corporate strategy to move this into the later line? Seems it's very doable in the later line kind of therapy, particularly if you can do this accelerated approval. Overall strategy, you want to do this by yourself or through the partner?
As I'm sure we'll discuss in a moment, EpCAM is not just a, sorry, 2051 is not just a CRC drug. One of the really additional compelling features of EpCAM is that it's expressed on just about every other solid tumor, and in many of them, at very high levels. We see 2051 as really having pipeline in a product potential, and we're keen to begin work in certain non-CRC indications. That could take a little bit of time because we're having many capital allocation conversations at the moment, having just raised a successful round a few weeks ago. We're very excited to move over time 2051 into other tumor types where there remains significant unmet need.
Given the scope of the opportunity in CRC and also in those other tumor types, it's not lost on us that CX-2051 is a drug candidate that could benefit from a partner. We've always said at CytomX, we've done a lot of BD over the years. We're all about doing the right deal at the right time. We do anticipate high strategic interest in this program, not just from companies that are already decidedly in the GI space, but certainly from those who are looking hard at getting into it as one of the key areas of unmet need in oncology today. We're in no hurry. We're well funded. We want to generate more data. We do anticipate having partnering conversations in the future.
Yeah, that makes sense. You mentioned the Adium move earlier line, likely going to be the combination. When will you start to do some combo work in?
I think we'll be in combinations by 2026 or sometime in 2026. Like I said, we're right now super focused on getting this expansion data. We do want to move the combinations. The one just most likely that we would start with would be with bevacizumab. We're highly incentivized to get that combination moving as quickly as we can.
Yeah. And how about beyond the CRC? That's probably, you know, you have some bandwidth, you will start to think about beyond the CRC?
Yeah, not quite ready to put a timeline on that. Let's just say we have high enthusiasm, but we've got a lot of things on our plate right now.
Yeah, absolutely agree. Okay, maybe a couple more minutes because it is a platform, right? It takes a long way to get here and then you get this, seems a couple of things all together in the right place and then you get this very promising data. You have some couple other early pipeline and your Probody platform. Give us some highlights, updates from your early pipeline and the platform. Then we'll talk about the partnership as well.
Yeah, so the second drug we currently have in the clinic that we began phase I for last year is also, we believe, very compelling. It is in a way another old friend in the way that EpCAM is, and it is interferon alpha. Interferon alpha was, as many of you I'm sure know, actually the first immunotherapy to be approved way back in 1986. It has established anti-tumor activity. Interferon is a very, very powerful modulator of the immune system. It drives multiple immune pathways in the tumor microenvironment, including broad and diversified antigen presentation. It has fallen out of use over the last couple of decades because its single agent activity is relatively modest in tumors like melanoma or renal. It is also quite poorly tolerated by patients in terms of its peripheral side effects.
It is, just from an immunobiological standpoint, it is an ideal mechanism to combine with checkpoint inhibition. Since we've in the field, we've kind of hit the kind of the limits of checkpoint inhibitor utility in tumors, particularly cold tumors, we're very, very interested to see what 801, as we call our masked interferon, can do in combination with PD-1 inhibition. We have access to KEYTRUDA from Merck. We actually announced just a couple of weeks ago the treatment of our first patient with the combination of CX-801 with KEYTRUDA. We are on track to have an initial data update for our initial biomarker evaluation of monotherapy by the end of this year, building a foundation for an evaluation of the KEYTRUDA combination in 2026.
I should also say that the study of 801 is following similar principles to the study of 2051 and that we're very, very focused in a single tumor type. Every patient that we're enrolling for 801 is a melanoma patient. It's obviously a highly immunogenic tumor. It's where we know interferon works. And there's very, very good evidence from a study completed by Merck not too long ago that PD-1 inhibition and interferon can synergize very effectively in early line melanoma treatment. The problem was that there's significant toxicity just not tolerated without our masking strategy. So very excited about 801. It's coming to you soon. And we think another great example of the versatility of our technology platform.
All right, great.
[audio distortion]
It's double masked. It's masked in a very unique way. The question was, what's the masking of the cytokine? The cytokine itself is masked with a peptide mask. And then we also have an FC mask, which is protease cleavable as well, which actually helps with half-life modulation.
Got it. Just last minute for the cash runway. And then you recently did the financing and then seems you are well capitalized at this point. What's the runway guidance right now?
Yeah, so really, really thrilled to have completed a financing concurrent with our data release in this rather challenging market. That puts us in a very strong cash position with cash into Q2 of 2027. We are well funded to execute through the expansion phase of 2051 to share that data in the early part of next year and to initiate our phase II study.
Excellent. Thank you, Sean, for being with us this afternoon. Thank you, everyone, for listening.
Thank you, Roger. Thanks so much.