All right. Welcome, everyone. Thank you for attending 2024 Jefferies Global Health Conference. My name is Roger Song, Senior Analyst covering SMID-cap biotech at Jefferies, in the U.S. It's my pleasure to introduce next or have a fireside chat with CytomX CEO Sean to have a conversation here. Welcome, Sean. Thanks, Roger. Pleasure to be here. Awesome. So before we dive into, you recently announced very exciting data from your EGFR CD3. We're definitely gonna spend a lot of time discussing that, but before that, can you give us some kind of opening, opening remark, you know, high-level overview, what's going on for CytomX, what's new, and then we can go to the Q&A? Yeah, happy to. So very exciting time for the company. We continue to prosecute a strategy, multimodality strategy- Mm-hmm. relating to our Probody therapeutic platform. This is a masking strategy for therapeutic antibodies that we're applying in multiple formats to T-cell engagers, to antibody-drug conjugates, and to cytokines. And the data that we just recently announced for CX-904, our EGFR CD3 T-cell engager, I think really positions us at the forefront of this field of T-cell engagers. And we'll come to the data in a moment. But also really important to emphasize that the multimodality nature of our platform is allowing us to also show leadership in antibody-drug conjugates and in masking cytokines. So we're currently advancing three programs in the clinic: CX-904, the EGFR CD3 T-cell engager, which is masked; the CX-2051 masked anti-EpCAM ADC, which has just entered phase I; and our CX-801 program, which is a masked version of interferon alpha-2b, that we're also moving into the clinic, in real time. So one thing that these products have in common, these product candidates have in common, is that, the targets all have an, a pre-existing level of validation, whether it's EGFR, EpCAM, or interferon. And, the value proposition from CytomX is to bring masking to each of these targets to broaden, or open, in some cases, the therapeutic window, across multiple tumor types. So really excited about where we are with the platform and with the pipeline and also, as we'll discuss later on, with the many partnerships that we've formed over the years also across multiple modalities. Excellent. All right, so, for the interest of audience who are not necessarily, kind of, fully zooming for your recent data, maybe just, what's the key highlights in terms of the clinical activity you're seeing, safety? I'm talking about the EGFR, CD3 904 program, the phase I-A data. Tell us, so what's the key learning from that? And then we have a, you know, we can, go into the details of the discussion. Yeah. So really excited about the progress we're making with CX-904. So just to take a little step back and talk about the concept of the product. So again, it's an EGFR CD3 masked T-cell engager, and EGFR, of course, we're all very familiar with, is a well-validated oncology target expressed across multiple solid tumors. The vision here is to bring T cell, the power of the T cell, and T-cell killing to EGFR-positive tumors, but to do that in a way that has a manageable therapeutic window. It's been shown by others that, without masking, the EGFR CD3 strategy can be efficacious, preclinically, but is severely toxic. Mm-hmm. We're looking to open a window for this very high potential target combination, and that indeed is exactly what we have done in the clinic. The data that we presented in conjunction with our Q1 earnings call is a first look at phase I data from 35 patients treated across multiple EGFR-positive tumor types. We dose escalated from a pretty low starting dose of seven micrograms, not unusual for a T-cell engager, given the potency. We escalated through non-step dosing and step dosing to a target dose, as of the data cutoff, of 10 mg. We continue to escalate, by the way. We're currently enrolling a cohort at 15 mg- Mm-hmm. Since we're still in the process of defining our RP2D. So in the context of that escalation, we showed a very encouraging safety profile. The first thing, rather remarkably in the step dosing cohorts, zero cytokine release syndrome. This is a first. We've never seen this with a T cell engager before, and it really has allowed us, in a way, to dose through CRS- Mm-hmm ... and achieve levels of clinical activity, and particularly, a very exciting signal in late-stage pancreatic adenocarcinoma. Before I come back to the efficacy, though, just another word on safety. What the safety signals to look out for, of course, with an EGFR agent like this, that's so potent, are rash, so dermatologic toxicities, and gastrointestinal tox. We didn't see any GI tox of any kind in the phase I study, and the rash that we saw at the higher doses was manageable and at low grade. Over the entire study, 35 patients treated, we only saw one Grade 3 rash at the dose of six milligrams in the non-step dosing cohorts. So safety looks really good. We did see, as has been seen with other T-cell engagers, a certain incidence of musculoskeletal events like arthritis and arthralgia. However, this is manageable by prophylactic tocilizumab, which we implemented in the step dosing cohorts. So now to the efficacy, you know, when you do a phase I study with an agent like this, and a basket study across multiple tumor types, of course, you're looking for signals. You're signal seeking, and we got a very exciting signal in pancreatic cancer. So of six efficacy evaluable patients, two confirmed PRs, one of those an 83% reduction in tumor burden, another patient with more than a 50% reduction in tumor burden, and these are heavily pre-treated patients. Third, fourth, fifth line, pancreatics are very difficult to treat, so deep, durable responses in these patients. And in fact, of the six patients treated, everybody benefited from the drug. There was a 100% disease control rate, stable disease, or a PR seen in all of these patients. In a way, a little bit of an unexpected finding, although, and maybe we'll talk about this in a moment, EGFR is known to be expressed on 90% of pancreatic adenocarcinoma, and we're really excited to follow this signal up, as the months move forward. Excellent. Yes, we're gonna talk about some of the nuance here, but before we talk, that is, we have to appreciate this is early stages, like you said, you know, initial dose escalation. We're talking about small N when we interpret the data. And then, you know, it's kind of just the nature of the early stage development. And then, so the nuance is, you know, we focus on the pancreatic versus other tumor, right? So you have also dosed in the particular for the CRC. You have quite a lot kind of patient there and talk a lot in the ten-ish patients. So, what's your hypothesis? You know, you have a very good activity, disease control, and the response for pancreatic versus, you know, no response for CRC, but you do also have some kind of a two, kind of disease control for CRC. How should we think about how to interpret that data? Yeah, I think the first thing to reemphasize is this, of course, is a phase I signal-seeking study with really the first objective of any T-cell engager study in solid tumors is to really characterize the safety profile of the drug. And so we did see, particularly in the non-step dosing cohorts, we did enroll a reasonable number of CRC patients, most of them at lower doses, and of course, all of them MSS CRC. And in contrast to pancreatic, where the signal really jumped out at us, which is really the kind of thing you love to see in a phase I study, we didn't see any confirmed activity in CRC to date. In a way, not that surprising. You know, we know it's a very resistant microenvironment for immunotherapies. We're not currently enrolling any additional CRC patients in phase I. Not to say that we won't in the future. I think, you know, in a way, you know, until we have our RP2D, you know, I think the jury is still out on whether CRC could be an indication for 904, but we'll reserve that work for the future. We did see a very intriguing pharmacodynamic phenomenon, though, in one of our MSS CRC patients, where in pre- and post-treatment biopsies, we saw a dramatic infiltration of T cells post-treatment with 904. That patient didn't respond to the drug, but it does suggest we can get T cells into MSS CRC, and perhaps another signal or a combination strategy could be effective. Looking more broadly across the entire patient population, it's really way too early to draw any conclusions about any other tumor type. Mm-hmm. We only enrolled two head and neck patients, two lung patients, and we're very focused now moving forward on enrolling, of course, additional pancreatic patients, additional head and neck, and additional non-small cell lung patients to look at what the signal could be in those additional tumor types, which are a bit more immune sensitive. Of course, we know express EGFR in addition to firming up the signal in pancreatic. Yep, got it. And so I think it makes sense that that is a little bit kind of wider range for CRC, and also it's well known kind of our immune desert for the CRC. The pushback maybe from the investor is EGFR is kind of out there, small molecule and the monoclonal antibody there, so the activity is seen in CRC. So how you contrast compare your CD3 engager versus the approved EGFR kind of antibody, so why you don't see the activity, but the monoclonal antibody see the activity? Yeah, I think we have to, I think we have to peel the onion another couple of layers on- Yeah. - On EGFR and cetuximab here. So, yes, cetuximab is active, and our T-cell engager, 904, is the EGFR binding domain based on cetuximab. Mm-hmm. So yes, cetuximab is approved in KRAS wild type CRC. Mm-hmm. We have to remember that cetuximab, first of all, its response rate is relatively low. Yeah. Quite low, actually. Secondly, cetuximab's mechanism of action is to block receptor function, so to block EGF and related EGF- Mm. - ligands binding to EGFR. Mm-hmm. That's not the mechanism of action of a T-cell engager. The doses are way lower- Mm-hmm. because these agents are highly potent. We're simply using EGFR as an address- Mm. - to redirect T-cell killing to tumor cells. So, given that, mechanism of action of cetuximab and also the fact that it, it's not indicated, doesn't work in KRAS mutant CRC- Mm-hmm. That would also suggest that cetuximab does not work through direct cell killing. So there is no direct mechanistic analogy between the T cell engager and cetuximab itself. Mm-hmm. I think it's also worth noting that when we look at a couple of other companies who are in this same space, developing T-cell engagers against EGFR. One of them, Takeda, appears to be now focusing their study in lung cancer, having previously explored CRC. So in a way, to us, there are multiple reasons why the, at least so far, the lack of single agent activity in CRC is not that much of a surprise. We're much more focused on what - where we are seeing activity- Yeah. which is in pancreatic. I want to emphasize that I do think we've broken through here in a very important way. We're the first company to show activity of a T-cell engager in pancreatic cancer, and this continues to be one of the most robust signals we've seen with any T-cell engager in any solid tumor. Mm-hmm. Mm-hmm. Yeah, got it. That makes sense, and it's not—it's a direct blocking versus the killing. So T-cell engager is really kind of driving the immune cell to talking, targeting this tumor. For pancreatic, as far as we know, it's not really responding to immunotherapy as well. Maybe because you have a masking technology. We haven't really talked about that Probody. So is that something related to your protease profile? Maybe pancreatic have some, you know, unique microenvironments, or that's really driven by the, you know, a little bit more kind of a T-cell infiltration already in that tumor microenvironment. And then we can see this from the non-small cell and the head and neck, which you haven't enrolled too many patients. Yeah. So I think let's talk about at the pure platform standpoint. Yeah. Yeah. Yeah. Yeah. Let's talk about the mechanistic aspect of unmasking of the Probody, as we call it. Yeah. So the Probody therapeutic is the masked agent. Yeah, we've shown across multiple programs, and again, these are just examples of the many firsts that CytomX has led over the years. You know, we've shown across multiple programs that if you look at intratumoral activation, unmasking of the Probody, that we see consistent unmasking across multiple tumor types that is independent of cancer type and independent of dose, and this is work that we've done- Mm. -on tumor biopsies, and also work that our partner, Bristol Myers Squibb, has done and presented in poster form. So we feel pretty good that the Probody platform delivers activity through unmasking- Mm-hmm. -consistently across tumors. And there's no, there's no direct evidence at this stage that there's anything particularly different about pancreatic cancer from our perspective. Of course, it's something that we continue to look at. Yeah. We are real experts in protease biology, as you know, Roger, you've followed us for a number of years. Yep. So we'll continue to look at that, but I don't think you need to invoke that hypothesis to explain our data. Okay. Another reason we don't need that hypothesis, I think, to explain our data is that pancreatic cancer may be more immunocompetent than we think. Mm. Or that is the widely held belief, and here's why. So there's evidence from a cell therapy. It's a New England Journal paper a couple of years ago, showing that a mutant KRAS-directed TCR-engineered T-cell therapy had a pretty dramatic response in a patient with pancreatic cancer. So that would suggest that from a neoantigen standpoint, that you can elicit responses in pancreatic. Mm. Also consistent with that finding is, of course, the BioNTech/Roche neoantigen mRNA vaccine, which most recently updated at AACR, is showing durable responses in metastatic pancreatic cancer. Mm. And lastly, actually most recently, I think, I think intriguingly at ASCO, we saw a presentation on a claudin 18.2- Yeah. CD3 T-cell engager Mm. -which also, again, intriguingly, has shown a 30% response rate in metastatic pancreatic cancer. So I think it's not, you know, that much of a surprise actually. I think that we're onto something, and we're really excited to follow up on this signal, which of course would be incredible for patients if we can continue to move this drug forward. Excellent. That's a very, very helpful discussion. I think a lot of the topics, investor has some question. Not saying they just... You know, probably just that we just don't know much about this. I think this is a this kind of understanding and hypothesis is really helpful. Okay, let's talk a little bit about the partnership, because understanding this program is with Amgen. So far, because it has a couple weeks from the data, have you talked with the Amgen before and after this data release? And what's the feedback so far? How should we think about, you know, the next step? Because you, understanding is you were moving to the expansion, but you need to make that decision with Amgen later this year. Yeah. So first of all, let me say that we're just absolutely thrilled to be working with Amgen on this program. You look at the leadership that they're showing in bringing T-cell engagers to solid tumors, and, you know, want to congratulate the company for the incredible success with Imdelltra. So, of course, I'm not at liberty to speak for Amgen, but, we are working very closely with them. And what we're highly focused on as we now move towards the second half of 2024, is to really continue to aggressively enroll in pancreatic, head and neck, and lung cancer- Mm. to further explore the activity of this drug candidate so that we can have what I anticipate to be highly productive dialogue with Amgen later this year towards defining our phase I-B strategy. So, we're on track and looking forward to those discussions and to providing an update later in the year, I hope, as to where we're going with this program. Excellent. Is that fair to say you at least have a preliminary or initial discussion with the Amgen regarding those data, and then it's supporting you moving to more data, enrollment in the pancreatic, non-small cell, and head, neck? Towards the end of the year, you have some additional update? Yeah, that's exactly right, and so we're obviously in close dialogue with our partner. Okay, got it. And then how much, how much more data are we gonna see at the end of the year, next data update? Because how many patients, particularly you have a three different tumor type, you have limited time, how much more meaningful or materially change the profile for now in the next data update? Yeah, well, first of all, just to reiterate that, our data update on Q1 earnings represented a summary of two years of work- Mm-hmm. At the company, you know, these programs do take some time to develop and to mature. Our update at the end of this year is likely to be a program status update. Mm. -on where we're headed next as we make that transition from phase I-A to phase I-B, in collaboration with our partner, Amgen. So, no real guidance at this point on additional numbers of patients or what that data update might look like, and the data update could potentially come later, depending upon the dialogue with Amgen. Ah, okay. So it's a program update. Take a look at what will be the next step for the program? That's right. Perhaps more of a strategic update. Yeah. Got it. Okay, good. Because I, because sometimes we wanna see data, but also we don't wanna see just incremental data. Say, okay, what gonna change our view for, either pancreatic or non-small cell lung- Yeah. or the head, neck? We wanna see more meaningful data. I'd say we're very much on the same page there. Okay, awesome. Anything else before we talk about a little bit about your earlier pipeline and then your other kind of partnership, except the 904? No, I think it'd be great to spend a few minutes on- Yeah ... other programs in the pipeline, because we have a lot going on at CytomX. Yeah. Okay, let's talk about it. So, EpCAM and the interferon alpha-2b. So, in moving to the clinic, what have you seen in terms of preclinical profile makes you feel this is a very meaningful therapeutics? Because those are known target, but you have masking technology, seems you are broaden the therapy window. How did you do that? Yeah. Yeah. So very briefly, first of all, on the EpCAM ADC, super excited about this program. It really, it really does build on a wealth of experience that we have at CytomX in the ADC space, and first of all, the target EpCAM, very high potential, very highly expressed tumor antigen that has been validated previously with locally administered therapeutics. Yeah. It can effectively shrink tumors, when targeted, but no one has yet been able to treat patients with a systemically active anti-EpCAM therapy successfully. So our thesis here is that by masking the ADC and also, conjugating it to a topoisomerase I inhibitor payload, that we've created a product candidate that is particularly well-suited to the treatment of CRC. EpCAM is really highly expressed in CRC, and our, our drug is very potent in preclinical models. We've opened a broad therapeutic window according to our, preclinical studies, and we're, very optimistic about what this drug could do for patients with CRC and many other EpCAM-positive tumors. The drug does have, we believe, a pan-tumor potential. We think of it as an HER2-like, and we're in the clinic. So we've, initiated dose escalation. We treated our first patient a few months ago. We've cleared our first dose cohort, and we're on our way towards having, data, and we anticipate an initial data update in the first half of 2025. Mm-hmm. Moving to interferon alpha, you know, we think this cytokine has been a little bit overlooked. There's a lot of activity, of course, on IL-2, but interferon, as you well know, was the first immunotherapy to actually ever be approved. It does have potent activity in terms of remodeling and activating the intratumoral tumor microenvironment, the inflammatory microenvironment in the tumor. It has a dual mechanism of action of directly killing tumor cells while also driving antigen presentation, and it synergizes preclinically with checkpoint inhibition. The challenge with interferon historically has been that it's just very poorly tolerated in patients due to its broad-based systemic activity. So the way that we've addressed that is we've made a dually masked version- Mm. of interferon alpha, and it's that masking really shuts down its systemic activity. We've shown preclinically, as we have for multiple programs, that unmasking happens in the tumor. The unmasking leads to activation of inflammatory cells in the tumor microenvironment, driving antitumor responses and synergizing with PD-1 inhibition preclinically. So, the stage is set for bringing this program to patients, and our overriding objective in our phase I study is to quickly escalate through monotherapy dose cohorts and get into combination with PD-1. We announced a relationship with Merck a few weeks ago, actually just before earnings, to access pembro Keytruda to combine with 801 in phase I dose escalation. We're working towards having a data update towards the end of 2025. Mm. So really excited about the progress at the company across all of these programs, multiple modalities, and then, of course, a large body of work that we're doing with our partners- Mm-hmm ... BMS, Amgen, Astellas, Regeneron, and Moderna. Yeah. Yeah, you know, as we said in the beginning, it is a true platform company, and then you already signed the partner with almost all the kind of major pharma out there, and you are keep accumulating this partnership relationship. So just to clarify for the EpCAM and the interferon, is your fully owned internal program, and then you have some other pipeline, some other partnership with the pharmas? That's right. We currently have more than 15 active programs at the company, 904 being the most advanced at the moment in a global co-development relationship with Amgen, where I should emphasize that we retain significant U.S. commercial rights to 904 in the form of a U.S. profit split. Mm-hmm. 2051, the EpCAM program, and 801, the interferon program, both wholly owned, and then multiple other early-stage programs that we're working on at CytomX, together with many T-cell engager programs, in particular with our partners. So I do think, in particular in T-cell engagers, we really are positioning, positioned as, a leader in this field and really at the forefront of this really exciting area as we push the boundaries, in the treatment of solid tumors with this modality. Excellent. Thank you. Lastly, cash runway, and then we can wrap up. Yeah, we just reported about just about $150 million on the balance sheet as of the end of Q1, so company continues to be well-funded. That's a runway through 2025, and that wouldn't include--that does not include any additional milestones from existing alliances or any additional BD. Excellent. Thank you, Sean. Thank you, Roger. Thanks for having us. Sure. Thank you, everyone.