Hi. Good morning, everyone. Welcome to day one of our Cantor Healthcare Conference. My name's Olivia Brayer. I'm one of the senior biotech analysts here at Cantor, and really excited for this fireside chat. We have Chris McCarthy, who's President and CEO of CytomX Therapeutics. Thanks for being with us. Or I'm sorry, Sean McCarthy. I'm looking at Chris while I'm saying that. Sean McCarthy, who is President and CEO of CytomX. Thank you, Sean, for being here with us.
You're very welcome, Olivia, and sometimes it does feel like we're joined at the hip, Chris and I, because we do spend a lot of time together.
Yeah. Your faces will just start to blend at some point. Well, Sean, I think a lot of people in the room are familiar with the story, but maybe before we dive in, if you could maybe just give us a brief overview of where the company is today and set the stage for the progress that you guys have made with the Probody platform?
Of course. As many may know, CytomX is, I refer to us as the original masking company. We're the company that really has pioneered a strategy of antibody and biologics masking to improve therapeutic window. We've really led this space now for quite some time, and today we have two lead clinical programs that really demonstrate the power and versatility of the technology. The first that we're highly focused on is Varseta, varsetatug masetecan, Varseta-M, our EpCAM-targeting antibody-drug conjugate that we're developing initially in colorectal cancer, and we're working towards launching potentially a first pivotal study in the first half of next year. I'm sure we'll spend plenty of time talking about that program and the progress that we've been making. The second program is a cytokine that we've used our masking technology also to improve therapeutic window. It's a masked version of interferon alfa-2b.
We call it CX-801, and we are in a phase I study in melanoma, late line post-checkpoint melanoma, and on track to have initial data from that program in the first half of next year. We continue broadly to apply the technology, including in a collaboration with Regeneron that we recently were really excited to expand. We announced a significant expansion of that collaboration resulting in a $37 million upfront payment, which helped strengthen the balance sheet and keep us in a strong financial position to execute on this really exciting pipeline.
What drove the decision to start with colorectal? We will get into it later, but there are obviously a lot of different EpCAM positive solid tumor indications that you could have gone after?
Yeah. One of the defining features of EpCAM as a target is it is so broadly expressed in so many different cancers. It was initially identified in colorectal cancer, believe it or not, in 1979. It was, I guess, relatively easy to identify at that time because there is just so much of it on colorectal cancer cells. We really intentionally designed the drug for CRC initially. We have selected a topoisomerase I inhibitor payload, which is indicated for the treatment of colorectal, as you know, irinotecan is a core component of the standard of care for CRC. We applied the masking technology to localize the antibody in tumor tissue away from normal tissues. That has been a challenge with EpCAM-directed therapies over the years. It has been a very difficult target to drug because of its expression in normal tissues.
It is really the combination of the target, and the payload, and the masking strategy, and it just made total sense to go into CRC first. It was quite a big decision, actually, to decide to do all of our dose escalation only in colorectal given how challenging of a setting that's been over the years. I think it's really paid off.
Okay, great. You had some positive data earlier this year. I think investors are really interested to see the next data cohort that you'll be presenting. Maybe just remind us the data that you have in hand, what gives you the most conviction in the profile of the asset. Then, obviously at some point later this year, you will have, I think it's 40 patients in your dose optimization cohort. As you think forward to that data set, and that being a potential additional de-risking look at your program, what are you most excited to see and to learn later this year?
Yeah. Let me just walk you through how the program has unfolded over the last year and a half or so. We presented the first look at phase I data in May of last year, the first 25 or so patients, and it became clear very quickly that this is a highly active drug in late-line colorectal. We've enrolled patients, and we continue to enroll patients who are fourth line or later. So, we are treating the most difficult to treat patients, but that's also where the unmet need is greatest. So, we think this is an important place to be, at least initially. So, that first data set in May showed clearly this is an active drug. We showed a significant 20%+ response rate across various dose levels, and a really encouraging safety profile. I think at that time, it really caught investors' attention.
I think the key question that came out of that early update was, can that efficacy be replicated as we continue to expand?
We ran three expansion cohorts at three separate doses, 7.2, 8.6, and 10 mg/ kg given on a Q3W schedule. That is the data that we reported in March this year. I think everybody agrees that, yes, the efficacy absolutely held up. In fact, in a way, it strengthened in terms of seeing a clear dose response across those three dose levels. I think really showing that this is an active drug in this late-line population. We also learned a lot more about safety, coming to understand that first of all, things that we do not see, which is great. We see very low rates of hematologic toxicity for a TOP1-ADC. It is kind of a remarkably low rate of hem tox, actually. We see no interstitial lung disease. Crucially, we see none of the classic EpCAM toxicities like acute pancreatitis.
The one safety signal that we are focused on and learning more about is a GI signal, where we do see a certain level of grade 3 diarrhea, which we are learning more about now as we continue the current stage of the phase I, which is dose optimization. Over the last six months or so, we have been enrolling patients into two dose optimization cohorts, focused on the two highest doses from the expansion phase, 8.6 and 10 mg/kg Q3W. Also implementing upfront prophylaxis with loperamide and budesonide to try to get ahead of that grade 3 diarrhea and also using adjusted ideal body weight dosing. The goal of the AIBW being to really normalize dosing across a patient population that has quite a wide range of body weight.
We noticed in our expansion phase that patients that were achieving higher exposures than perhaps desired due to having high body weight did seem to be having a slightly tougher time on the drug. That is why we have implemented AIBW. The next update for the program, which we are gearing up to give by the end of this year, will be a data update across now what is a 113-patient phase I study, including response rate, PFS, and OS from the escalation and expansion phases. That will be the first look at overall survival that we have given to investors. Then we will have ORR and PFS from the optimization cohorts.
All of that data, of course, will be taken together to go talk to FDA as we move through this year to discuss with them the strategy for this first pivotal study, including what is the patient population, what is the comparator arm, and critically, what is the dose that we are going to move into that first pivotal. That is where we are headed for the next update.
Yeah, and we'll get to that pivotal in a minute because I do think it's important to talk through. Maybe just as you think about some of the learnings that you've had from adding some of these prophylaxis agents from using the adjusted body weight dosing, the AIBW, what have been some of the key learnings as to how to mitigate some of that GI or diarrhea onset that you maybe have been seeing in these patients?
Yeah, we continue to learn, as is not unusual for a drug that's just been in the clinic for a couple of years. We continue to learn a lot about the safety profile, and specifically the GI toxicity, and even more specifically, the diarrhea in terms of time to onset, duration, and the role that these prophylaxis strategies can play. We first began to see the impact that specifically budesonide could have on diarrhea in the expansion phase. We have reported previously that of 14 patients that we could see in our database who had been treated with budesonide as a way of ameliorating their diarrhea, 12 of those patients had at least a one-grade improvement in their diarrhea symptoms, giving us a clue that the GI toxicity appears to have an inflammatory component. That's not unexpected.
Irinotecan, Topo I inhibitor, is also known to induce quite high rates of diarrhea, and that can be inflammatory. We decided to really jump on that observation and bring budesonide earlier in the treatment paradigm to pre-treat patients. It's a relatively straightforward prophylaxis for patients to take. They're highly compliant with it. It's an oral drug. It's taken once daily. They take it for seven days for the first week of each three-week cycle, and it appears to be effective. That was exemplified by data we showed in March this year from the first 20 patients enrolled in the optimization cohorts where we were able to show a reduction of grade 3 diarrhea to 10%.
Now, that's still early days. That could evolve a bit because it was just a couple of months of follow-up, but a very encouraging start, suggesting that the prophylactic strategies, perhaps together with AIBW, is really helping us manage the grade 3 diarrhea. The other thing that we'll be learning over time is what we'd like to also manage is, it's not just about the headline number of what's the percentage of patients that get high-grade diarrhea with this drug. It's also how long are they in that place. We also want to reduce the number of days, and I feel pretty confident that we can do that, again, using these interventions.
Yeah. You bring up a really important point, right? About onset of diarrhea, the length of time that these events are happening, how long patients can stay on drug versus having to cycle off therapy. When you put that all together, what is more important? Is it about reducing, or maybe I'll ask, how do you reduce the amount of time that these events are happening? What are you seeing with your dataset that's giving you confidence that on a go-forward basis, that this won't necessarily be an issue commercially?
Well, we have a lot more to say about that as the year goes on. We're going to be analyzing that data over the next few months, and I think, again, our goals are clear. In terms of commercial impact, we've done a lot of work, and I know investors and analysts, including yourself, have done a lot of work talking to GI oncologists about what is an acceptable rate of grade 3 diarrhea in this patient population. And our goal is to keep it in the 10%-20% range. We think that's going to be perfectly fine in terms of the benefit that this drug brings to these patients. At the end of the day, it's all about risk-benefit.
Given what we saw in the early experience of dose optimization, we're pretty confident that we can control and manage this, and that ultimately the commercial success and uptake of this drug will be driven by the quite remarkable activity that it's shown in these patients who, quite frankly, have zero options. And in the late line, very few options. Just to put that in context, the response rates that we've shown so far, 20%-30% ORR, compares to 1%-2% for standard of care in the fourth line. There's a lot of room to maneuver there and a lot of benefit that we can bring to patients.
Do you think at this point you have found the right dose strategy and prophylaxis strategy to go along with it?
That's exactly what we're working on. Our communication later in the year, our goal is for that communication to be on the other side of FDA dialogue, because of course, one of the crucial things we need to do is go talk to FDA in the context of Project Optimus and lay out everything that we've learned from this 113-patient study in terms of the relationship between exposure and safety, and exposure and activity. All of that data will go into our recommendation to FDA as to what our go-forward dose will be.
Yeah. You brought up the efficacy profile. Obviously, you've had a very impressive efficacy profile so far. The OS data point, maybe just talk about the importance of OS, especially as you have those conversations with regulatory agencies, as you think about ORR, PFS, OS, what will ultimately be your registrational endpoint. Then maybe as a follow-up to that, what level of disclosure can we start to expect later this year as you do start to come out with some of those initial OS data points?
Yeah. We are working on the assumption, as you suggest, that the first registrational study in late-line CRC will be a randomized study with an OS primary endpoint. In the late-line setting in colorectal, because there are so few drugs that have shown this kind of activity, the only other drugs that have shown anything close to what we've shown are the other ADCs being developed in parallel with ours by AbbVie and Merck Serono, that I'm sure we'll come to in a moment. But because there is no precedent, it's just our assumption that OS will be the endpoint.
In actual fact, whatever we select as our control arm is likely to move so quickly, because unfortunately, these patients progress so quickly on standard of care, that a study with an OS endpoint would, we think, read out pretty quickly and would get us to a full approval. So it really does seem like the right thing to do on multiple fronts. In terms of what we've seen so far, pointing the way towards that OS endpoint, we can talk in terms of progression-free survival so far, right?
Sure.
I've already laid out the ORR numbers that we've seen for the drug to date, but the PFS has also been really impressive. We've reported at the 8.6 and 10 mg/ kg doses PFS of six to seven months. That actually compares very well to overall survival in the late-line setting in this patient population. That I think portends well for what OS could look like, and as I said, we'll have a first disclosure of overall survival from the first 73 patients treated in this update later in the year. OS for the optimization cohorts will come later, so we're not expecting to have that by the end of the year. The decision on dose selection for the first pivotal will be an integration and a modeling across all of the patients.
We'll have to extrapolate somewhat to where we think the OS could land in the pivotal, but the modeling should get us there, and I think we're going to have more than adequate data to go and have, I think, a very robust conversation with FDA.
For that dose optimization cohort, will you break out ORR and PFS for those 40 patients?
Yeah, I think that's most likely that we will do that.
Any reason to think it wouldn't look very similar or in line to what you've already reported?
We're treating a very similar patient population with the same drug. The only thing that we're changing is upfront prophylaxis and AIBW dosing. AIBW itself shouldn't dramatically change the doses that patients receive. It does result, on a population basis, on a somewhat lower dose because, of course, we are adjusting so that outlier patients are not receiving too much drug. We are enrolling the same patient population.
Okay. Fair enough. As for the registrational path, obviously you'll have more data later this year. You'll have a conversation with FDA potentially later this year, potentially next year. I don't know if you guys have commented on timing there. What are you thinking in terms of going after third-line versus fourth-line patients in your registrational, just given that that could ultimately change the way you're thinking about a potential comparator arm?
Well, we think we've got great options here, and it's really a question of the order in which we build value in the program and bring the program and bring this drug to the market. We're highly motivated to get this drug approved and launched. Patients need it. The options in the late line are so poor, and it's just been so exciting to see the speed and rapidity with which our investigators have brought patients onto the study. In terms of FDA dialogue, obviously we're already having dialogue. We just announced a couple weeks ago that we just got Fast Track designation for relapsed refractory metastatic CRC. Our decision-making algorithm for third line versus fourth line is really around how the data shapes up, particularly in terms of overall survival from the first 73 patients. In the late line, OS is about six to seven months.
PFS is about three months, and I've already mentioned response rates are in the low single digits, if any response rate. The market for fourth line we think is substantial. In fact, we see 10,000, 15,000, perhaps 20,000 patients treatable in the United States. We think if this drug was launched today, it would have a very high percentage of the market based on how differentiated it is from current standard of care, and it probably is the fastest to market opportunity, so with monotherapy. There's a lot of good reasons to go in the fourth line.
To go into the third line first, we have to bear in mind that we'd be competing against a combination a gainst the combination of bevacizumab and LONSURF, where OS is 9 - 11 months, depending upon whether or not patients have seen bev previously. Bev-experienced patients have an OS of about nine months. We will look at our OS numbers, and we'll decide how large would a study need to be in the third line setting to be competitive, to be powered, to be successful, and that will be one of the determining factors. But we do really like the fourth line opportunity. We think it's the fastest to market.
It's a very substantial unmet medical need. We feel confident the drug would be broadly utilized. One of the reasons we feel confident the drug would be broadly utilized, in addition to its robust activity, is we don't need to select patients in any way. We don't need to select patients for target or for any other clinical characteristic, whether it's KRAS mutations, BRAF mutations, left-side or right-sided tumors, whether or not they've got liver metastases. So, it's a very easy decision for a treating oncologist to make to put them onto our drug, we believe, in that late line setting. So a lot of reasons to go down the fourth line road. We'll be making that decision, and we'll let you know when we have.
It sounds like the decision will essentially come down to what you're seeing on the OS front.
That will be an important determinant.
Oh.
Yeah, that's right. From there, let's say, for example, that we decide to go into the fourth line. As I said, we just need to take these opportunities one by one. We then have a decision as to do we then run a third line study in combination with bevacizumab, and we're already looking at combining the drug with bevacizumab. We're also looking at beginning to combine the drug in Q4 this year with chemotherapy, specifically with 5-FU. We'll need to make a decision then about do we go to third line or actually do we skip third line and potentially go even earlier depending upon how our early combination data looks. So a lot of different ways we can develop the drug and build value over time, but I'd say our number one goal is to get this drug to patients as fast as we can.
Yeah, and you mentioned that the fourth line opportunity would be the fastest get to market strategy. Is that because of the duration of the study would be shorter because it's shorter time to get to events just given what we've-
Yeah.
Seen historically, or could there be a difference in terms of the trial design in terms of number of patients just given statistical powering that you would need if you did a third line versus a fourth line study?
I think it could be both. I think we do not know yet, but you could imagine both. I mean, certainly the time to enrollment I think would be faster. Yeah, the study size could be a little smaller. I think we just have to see where the data comes out and how to power the studies.
Okay. You mentioned there are other ADCs and other agents and other combos in development for CRC. As you think about the competitive landscape today, maybe I will ask a two-part question. One, where do you see your biggest level of differentiation? Two, as you think about the field evolving over the next, let us call it five years, is there an opportunity for sequencing of some of these different drugs or at least different mechanisms?
Yeah, great questions. The two competitors that we are most focused on at the moment are the two other ADCs, the c-Met ADC, ABBV-400, and the CEACAM5 targeting ADC being developed by Merck Serono, both of which have shown pretty interesting activity and also both of which are in phase III studies in combination in the third line. They have both elected to go third line with the bev combination up against bev LONSURF. Potentially a slightly different strategy to what we take if we decide to go fourth line first. If we fast-forward a few years, let us just say, okay, all three drugs are approved, which is terrific for patients. It is amazing that antibody-drug conjugates are coming to colorectal. It has taken a while for ADCs to break through in CRC and yeah, we have got a really good one, we believe.
But let us talk about the potential differentiation. First of all, we have a first-in-class EpCAM ADC. We have, I think, intrinsic activity that is highly compelling in terms of ORR and PFS, and we also have a differentiated safety profile. I do think the hematotoxicity could be quite differentiating in the combination setting.
Both AbbVie and Merck Serono have fairly high rates of high-grade anemia and neutropenia. AbbVie also sees a not insignificant rate of ILD. This is a massive market, whether it is third line, fourth line. If you put third and fourth together, even just fourth, this is a very, very substantial, unexplored, unmet medical need on a global basis, so there is room for multiple drugs. We think these will provide great opportunities for treating physicians, and we believe that the value proposition for Varseta-M will be highly compelling.
If there are, in the future, other ADCs that are approved in the third-line market, could that change the way that docs think about prescribing an ADC in the fourth line?
Yeah, that is a sequencing question. Thanks for reminding me of the question.
I asked it in a different way.
It was very well done. At this point in time, we see the sequencing question as a bit theoretical.
There's a lot of discussion and debate around, let's call it TOP1-ADC after TOP1-ADC. There is evidence, of course, in breast cancer that a patient who has been treated with a TOP1-ADC may not do as well if subsequently rechallenged with another TOP1-ADC. I think it's way too early to really conclude that that is the truth, even in breast cancer, in our opinion. In colorectal cancer, we really have no idea yet. What we do know is that all the patients that we've enrolled into our study have seen irinotecan previously. So, they've already been TOP1-treated, and they respond to our drug. They can also respond to the other TOP1-ADCs.
I think we'll have to cross that bridge when we come to it, but there's nothing at this point that overtly points to Varseta-M not being active in a fourth-line setting in the context of other ADCs being approved in the third line. But remember, this is just the beginning of our development program. If we get this drug, or hopefully when we get this drug approved in the fourth line, it is just the beginning, and we will bring this drug. We will march it into earlier lines of therapy where I'm confident it will be competitive.
Yeah, to that point, you brought up earlier how you are combining with bevacizumab, and I know you're obviously combining with chemotherapy as well to hopefully move further upstream. So how do you think about the opportunity set that you do have as a combination agent? When will we start to see some of those data, just to give us a little bit more confidence in the competitive profile of combining with other agents?
Yeah. So we're actively combining the drug with bev, again, in the late-line setting to get some initial experience of that combination. Bevacizumab, as you know, is foundational in the treatment of earlier stage colorectal cancer, so this is an important study for us to do. We're guiding towards initial data from the combination in the first half of next year.
What level of data will we ultimately get? Have you disclosed how many patients that you'll be enrolling? How many patients you'll have data in the first half of next year?
We haven't disclosed number of patients yet, but we expect it should be a meaningful number of patients that's giving us some early clues as to what we're seeing from the dose finding.
In combination with Varseta-M. Remember that we began the bev combination work. We're doing this bev combination work before we've locked in on a monotherapy registrational dose, so it's still experimental.
Sure.
But it was important, we thought, to get ahead of that and begin that work. In a similar way, we'll be starting the combination with 5-FU later this year to enable a potential second-line strategy, where in the second line, our ultimate vision is for Varseta-M to replace irinotecan in the context of the FOLFIRI regimen.
Then, of course, ultimately, we're excited about the potential for Varseta-M to actually replace systemic chemotherapy in CRC as a whole. But we've got quite a bit more work to do before we get there.
Yeah. Then maybe just sticking with colorectal, and then I do want to ask you about some of the other indications that you're working on. If you think about the next 24 months, so you'll have data later this year. Eventually, you'll have a registrational pivotal trial design that you'll come out with. You'll start enrollment there. How do you think about next steps with a combo agent? I know we haven't seen data yet, so I recognize it's a premature question, but could you potentially slot in a second pivotal study with a combo agent? Would you run a larger phase I? What does the kind of path forward look like for developing your agent with bevacizumab?
Well, I think that's all TBD. I think it is a little bit one step at a. Well, it's kind of three steps at a time in terms of what we're doing right now. Get the monotherapy into a registrational study, get experience with the bev combination, get experience with the chemo combination, and then also watch the competition. So, the other ADCs, yes, they're in phase III. They're looking promising, but anything could happen. So, we need to monitor the competition very closely, and that will inform our strategy. It's really too early to comment on exactly what we do next. In terms of the other tumor types, I should say that we are setting our sights on becoming a commercial stage company, launching Varseta-M, particularly in the United States., in the late line, wherever we decide to go.
And with that in mind, with that company build in mind, we very purposefully have selected three other GI tumors as the first place to go to get additional experience of what Varseta-M can do, gastric GEJ, pancreatic, and biliary tract tumors. So, they're CRC-adjacent GI. I hope you can see, we can see our way towards building CytomX initially as a company focused with a GI oncology franchise, and that's just a really exciting prospect for us.
And then maybe just in the last minute here, you do also have a masked interferon program?
We do.
CX-801, I believe. So where does that program stand today, and how big of a strategic priority is that, just given the success that you are having with your EpCAM program?
Yeah. Clearly, the EpCAM program, I think, shows definitively that the masking strategy can add substantial value to challenging targets. Interferon's a similar story in a way. It's a powerful cytokine. It's active across multiple tumor types, including melanoma. But it's a very difficult drug to use because of its systemic toxicity. So, we're employing our masking strategy to open a therapeutic window or broaden the therapeutic window for interferon alfa-2b, particularly in combination with KEYTRUDA, which we think has enormous potential in treating late-line checkpoint refractory or post-checkpoint inhibitor metastatic melanoma. We're actively enrolling both monotherapy and combination arms, and we're on track for an initial data update on the safety and efficacy front in the first half of next year. So, it's a program that really underscores the versatility of the Probody platform, and we're excited to see data next year.
Yeah. Busy 2027 coming up for you all.
No question about that. Yep.
Great. Well, thank you very much, Sean. Really appreciate the discussion.
Thanks, Olivia. It's been a pleasure.