With us, joining us on the panel is Sean McCarthy, CEO of CytomX. Sean, thank you for joining us. Thanks much for the invitation. Thanks for having us. Pleasure to be here. Great. So let's just jump into it. I would love to just get an introduction to the company for those who may not be familiar with the company. The antibody conditional activation landscape has been heating up recently, and there's a lot of momentum in the space, particularly with respect to the T cell engagers. So if you could just talk about the CytomX story and your current efforts there and elsewhere. Yeah, great. Thanks again much for the invitation to participate today. I'm really happy to be able to share our really exciting progress in Probody T cell engagers in solid tumors. And as you know, CytomX is a leading innovator in the field of antibody masking with the goal of improving therapeutic window and outcomes in oncology. And so using our proprietary Probody platform, the Probody therapeutic platform, we're developing next-generation T cell engagers, antibody-drug conjugates, and cytokines, and continuing to really pursue a multi-modality strategy at the company. And of course, we're here today to talk mostly about T cell engagers, but we're doing a lot more as well. And our platform, the Probody therapeutic platform, is really the first platform to show how to enable tumor-specific therapeutic activation, sparing healthy tissues. We've achieved many, many firsts with this platform over the years, showing how antibody masking can work in patients in different formats, different modalities, different tumor types. Our three lead programs today are CX-904, which is our masked EGFR CD3 that we'll spend most of this discussion focused on, CX-2051, which is our EpCAM targeting TOPO- 1 ADC, which we're in phase I dose escalation with, so super exciting next-gen ADC. Then our third program going into the clinic in real time is CX-801. That's our masked version of interferon alfa-2b, so designed to be a potent immunotherapeutic, particularly in combination with checkpoint inhibition. So the pipeline is looking great and lots of momentum in the pipeline and additional progress anticipated over the next months and years. And we've also got very strong partnerships. Of course, CytomX is known for having been very productive in partnering, and we have currently very strong alliances with Bristol Myers, Amgen, Astellas, Regeneron, and Moderna. And now coming back to T cell engagers and today's discussion, we really do see this as a potential sweet spot for our technology at a time when we're really starting to see breakthroughs in solid tumors. So an exciting time for us and for others in the field. And again, delighted to be here today for the discussion. Thanks, Sean. That's a great overview. Like you said, we're going to spend most of the time on CX-904. Just moving towards that asset, could you speak to the rationale for the need for a masked T cell engaging bispecific? And can you talk about the context of EGFR and CD3 targets and the unmasked bispecific space there? And how toxic could this approach be without a mask? Yeah, we think without a mask, it would be very toxic, and that's why it hasn't been developed before. So EGFR is a great target. It's very highly validated, multiple approved therapies, and it's broadly expressed across multiple tumor types, of course. And there are different ways to target it. Excuse me. EGFR has been targeted with small molecules with antibodies that block EGF binding to the target. But in our case, we're using EGFR as an address to redirect T cells with a Probody T cell engager. And this is really a big idea. And without our technology, excuse me, without our technology, EGFR CD3, this combination is an undruggable combination of targets. Now, our prior work, going back a few years, that really laid the foundation for 904 was to show that by masking cetuximab, we could open the door for a T cell engager. We showed in Cynomolgus monkeys that masking cetuximab dramatically reduced the incidence of skin toxicity but retained anti-cancer activity. So that was our first proof of concept. We published that work in Science Translational Medicine, showing that there is a way to control these skin toxicities for EGFR. And that encouraged us to start to really push the envelope with an EGFR CD3. So what would it look like without masking? Well, it's a little hard to tell because there's no clinical experience yet with an unmasked EGFR CD3 for good reason. The Micromet team some years ago published that the unmasked EGFR CD3 BiTE is severely toxic in cynomolgus monkeys. And to the best of our knowledge, that was not advanced into the clinic. But what we would anticipate if an unmasked CD3 EGFR was advanced into patients is, of course, we'd expect very high levels of grade three and above skin rash. And on top of that, high levels of CRS and probably, based on our preclinical modeling, pretty complex interplay between those two mechanisms, which I think would be very devastating for patients. And so that's the reason that we've never, no one has advanced an unmasked EGFR CD3 into the clinic. But of course, this combination has so much potential if we can, by using our masking strategy, use EGFR as an address to redirect T-cell-mediated killing across multiple EGFR-positive tumor types. And that's exactly what we're doing. 904 is designed to unlock the potential of bringing EGFR and CD3 together as a really unique and integrated anti-cancer pharmacology. Absolutely. We agree there for sure. To frame our discussion, could you just talk about the recent CX-904 data set that we saw and the different tumor types, just kind of if you could walk through that data, including your experience with the step dosing and non-step dosing paradigms? Yeah, so we're super excited about this data, this first data with CX-904 in humans. We reported on our Q1 earnings call on 35 heavily pretreated patients enrolled across multiple tumor types, tumors generally known to express EGFR, not selected for EGFR expression. This is an early phase I study. At the time of the data cutoff, we'd escalated from a starting dose, a very low starting dose of 7 micrograms, all the way up to a target dose of 10 milligrams as of the data cutoff. In our initial non-step dosing cohorts, we reached a target dose of 6 milligrams, at which we did see a couple of DLTs. That then enabled moving to step dosing, and we continued escalation to actually the current target dose, which is 15 milligrams. Dose escalation continues as we continue to push towards RP2D. So very successful escalation. It took some time because, of course, we began at such a low dose, but we made a ton of progress getting to the current dose of 15 milligrams. In terms of safety, masking worked very effectively. Importantly, we saw no CRS in non-step dosing at doses of up to 3 milligrams or with step dosing up to 10 milligrams, which was the highest dose as of the data cutoff. Very effective CD3 masking, really clamping down CRS, which is exactly what we wanted to see in this early phase I study. The AEs that we saw were, we did see some rash. We saw some musculoskeletal events, including arthralgia and arthritis, but these were manageable. We only saw one grade three rash across the entire 35-patient safety cohort. So also strong evidence that EGFR masking is enabling us to manage and mitigate EGFR toxicity, even in the context of this highly potent mechanism of a CD3 T cell engager. We also, since we were able to escalate to these doses safely, we were really thrilled to see highly encouraging signs of anti-cancer activity, including in pancreatic ductal adenocarcinoma, where in six efficacy evaluable patients with pancreatic, we saw two confirmed partial responses and four stable disease for an overall response rate of 33% and a disease control rate of 100%. We also saw stable disease in 3 colorectal patients, in 1 non-small cell lung cancer patient and 1 esophageal patient. Escalation continues. Now we're highly focused on enrolling more patients in pancreatic and also in head and neck and in non-small cell lung. Great. And can you contextualize the activity and those responses seen in pancreatic cancer? What does it mean for these patients? What would these patients be facing otherwise? And what's considered the threshold for meaningful activity in pancreatic cancer? Yeah, well, historically, pancreatic cancer doesn't respond either to anti-EGFR antibodies or to immunotherapy alone. So what we saw, we saw rapid and deep responses with 904, bringing EGFR and CD3 together in the way that we've been able to do. And really interestingly, in one patient who had an 83% tumor reduction by RECIST, that included one target lesion, which was a 29-millimeter pelvic lesion that actually became undetectable. So that lesion was essentially eliminated by treatment with 904. This is incredibly encouraging in this very, very difficult to treat tumor type. Now, as we all know, pancreatic cancer is one of the most difficult to treat cancers today. It's one of the areas of greatest unmet medical need in oncology, and it's really notoriously difficult to treat. Second-line responses to standard of care are in the single digits. PFS is around three months. So it's a very tough cancer, but it's a significant prevalence, and we see it as a very significant commercial opportunity for a drug like 904, not to mention other potential tumor types where 904 could work in the future. So in a way, our results with 904 today are the absolute embodiment of what this drug was designed to do, to treat difficult to treat EGFR positive tumors. We know that pancreatic expresses EGFR, and we plan to aggressively pursue this signal for the benefit of people afflicted with this devastating tumor type. That's great. Thank you for that. And thinking about some read-through we may have seen from ASCO, could you talk about what we've been seeing in the PDAC bispecific space and how that might validate what we're seeing here at CytomX with your data? Yeah, it's really amazing how science converges sometimes. And going into ASCO, we were, to our knowledge, the first to show activity for a T cell engager in pancreatic cancer. And I think we got quite a lot of questions about that because it was the first time anyone had seen it, and I think everyone was trying to make sense of the data. What does it mean? So it was great to show up in Chicago and see the Claudin 18 data, 18.2 data from Innovent, very similar, a 30-ish% response rate in pancreatic ductal adenocarcinoma for a Claudin 18 CD3 T cell engager. So we look at this data as showing additional evidence that pancreatic can respond to this mechanism, to CD3 T cell engagers. We all have more work to do to really understand mechanistically at the immune biology level what's going on in these. Maybe we can come to that a bit later on. In terms of the overall profile of the Claudin 18.2 data, we think it's really interesting. We'd like to see more data over time on the safety and efficacy profile as to whether our technology could be useful on that target. But I'd say at first look, it does seem like there are some opportunities for improvement as well. Interesting. Do you think that their asset could benefit from a masking strategy as well? Are there things in the data that you're seeing that say, hey, if they had a mask, this could be a better strategy? And obviously points back to CytomX. Yeah, I think it's possible. As I said, I think we need to see a bit more data on the overall therapeutic window. The activity of that drug is very encouraging, again, in a difficult to treat cancer type like pancreatic. It suggests that the immune microenvironment is there to mount anti-tumor responses. I think we'll take a closer look at that data as it continues to emerge. We'll look at it closely from the standpoint of the benefit that our technology masking could potentially bring. Gotcha. Makes sense. And then on the mechanism and the responses you're seeing in pancreatic cancer, do you think that for CX-904, mechanistically, pancreatic might be the best fit, or do you have a different take? And then what other tumor types are you exploring where maybe you could draw some conclusions there? I think what we can conclude so far is that pancreatic is a good fit, such a great fit for our technology, but there's no reason to think it's the only tumor that will respond to 904. It's the first signal we have. It's the one that we're going to pursue aggressively, but we're continuing to enroll at the tumor types to give the drug its opportunity to show us what else it can do. In terms of pancreatic itself, the very nature of this tumor is pancreatic ductal epithelial adenocarcinoma. So it's an epithelial tumor. It's known to express EGFR more than 90% of pancreatic ductal epithelial cancer expresses EGFR. So that's consistent with our activity. But historically, it's been thought of as a non-immune responsive tumor, a tough one to treat, a highly fibrotic tumor. But there is increasing evidence that pancreatic cancer can be responsive to immune therapies and that it can be immune competent, not only the Claudin 18 data that we just reviewed from ASCO, the CD3 T cell engager, but also the BioNTech Roche personalized neoantigen vaccine, which is being developed in pancreatic, is also showing meaningful clinical benefit. So there's more to be learned there. And even already, we've seen in our own work, and we shared some of this on our earnings update, we are seeing that in responders in pancreatic, that we are seeing a pre-existing immune microenvironment that is supportive of the tumor responding to the drug. I think in the field in general of T cell engagers and particularly CD3, there's a lot more to learn about exactly how these drugs are working mechanistically in terms of the cell populations that they're activating within the tumor microenvironment to drive these robust tumor responses. We're obviously right in the middle of that with our work here at CytomX. You're still dose escalating in this trial and wondering about the design of 904, what we can tell so far as it relates to the emerging therapeutic window for the drug. Are there points of evidence that you can kind of point to that say, this is a good therapeutic window you're starting to see? Yeah, but obviously, we thought really hard about the design and optimization of 904 before moving it into the clinic in terms of masking affinity, protease cleavability, and the overall PK of the drug as designed. And the doses that we've reached where we're seeing activity in the clinic are right in the predicted therapeutic range based on our preclinical and computational modeling. And we continue to escalate to further refine RP2D, but we're really encouraged by the performance of 904 in the context of exactly how we designed it. And we know from our previous clinical work with earlier Probody therapeutic programs at CytomX that we typically see a much higher percentage of cleaved activated drug in the tumor compared to the plasma. And it's this ratio of low activation in the periphery and high activation in the tumor that we've presented previously that leads to the therapeutic window. So intra-tumoral activation, systemic stability, activation in the tumor, retention in the tumor, and eliciting of anti-tumor effect. That's how Probody therapeutics are designed, and that's how we believe 904 is working. Consistent with all of our prior work, the measurements that we've made so far for 904, we see very little active drug in the plasma. Based on everything that we know about the platform to date, we believe we have a favorable ratio of tumor activation relative to systemic activation. That's what's driving the really attractive profile of 904 so far in terms of its great safety profile and its clear evidence of single-agent anti-tumor activity. Just to recap, because it's really, we think, important for everyone to understand what we've achieved so far with this drug. 904 has very low cytokine release syndrome. In 35 patients treated so far, only one patient with a grade three rash. This is really, really good. It's allowing us to get to therapeutically active levels of the drug, which is a big success and is entirely consistent with our vision for the program. Then lastly, on the question, it's a great question, Mitch, which is why I'm going a bit long here. There's been quite a bit of discussion around the importance of the half-life of masked T cell engagers and whether it should be short, whether it should be long, whether it should be something in between. At CytomX, our view is that the moderate half-life of a few days that we have for CX-904 really strikes the right overall balance by enabling convenient dosing schedules and maintaining efficacy pressure on the tumor. We've got more to learn, of course, but we're really encouraged that the design of 904 is working exactly as we had hoped in the clinic. Great. Could you explore combination therapies with 904, and what combinations might make the most sense? Yeah, so obviously, we're thrilled to have seen single-agent activity already in this early stage of development of the drug that provides a very solid basis for the further development of 904. But yeah, of course, combinations are likely to be an important area. And that's what we're seeing with other EGFR bispecific strategies like LGR5 or TGF- beta. So something that we're certainly going to explore. And as we learn more about the immune tumor microenvironment and how CD3 T cell engagers modulate and modify the tumor microenvironment in terms of immune cell populations, that data will help inform specific combination strategies for synergistic mechanisms, which could be checkpoint inhibition, could be co-stimulation strategies, could be cytokines that target particular immune cell populations. And so this will all, I think we're all learning in real time as we push on this new frontier of T cell engagers for solid tumors. And it's just a really exciting time to be at the forefront of this field here at CytomX. Great. Well, we're definitely looking forward to the next update for the program. With respect to that, could you talk about the goals you have with Amgen by year-end, and what's the potential for the timeline for the next data update? Yeah, delighted to continue to work with Amgen and our global co-development alliance. So just to recap the way this collaboration works, CytomX is in the driver's seat for running phase I-A that we're doing right now, and then also for phase I-B that we aim to start in 2025. Our goal is to initiate phase I-B expansions in specific tumor types, one of which will clearly be pancreatic in 2025, and with Amgen to align on that phase I-B strategy. We'll be asking Amgen to make a decision by the end of this year on their opt-in to the program for its long-term development. The way this would work in the longer run is that once we complete phase I-B, the asset goes back to Amgen for running phase II and global registrational studies and CytomX co-funds that work, and we retain significant U.S. commercial rights in the form of a very attractive profit share. So this drug candidate has huge potential to build value in our company in the long run in the context of the alliance with Amgen. We need to get, in the context of second half and that conversation with Amgen, we need to get to our RP2D, a recommended phase II dose. We're on track to be there in second half. And as I said, we anticipate that we'll have that decision from Amgen by the end of the year and then move into phase I-B and beyond in 2025 and thereafter. In terms of additional data updates, obviously, the data that drives that conversation with Amgen will likely present that next year. Great. Okay. And how could the Probody masking strategy be applied to other T cell engagers? Well, we think very broadly. We're very, very active in this area at the moment. We have active, successful partnerships with Amgen, Regeneron, and Astellas, each of which is focused in the area of bispecific immunotherapies. We're really becoming experts in this field through working with them and our own work on 904. Then we're also working on several additional, as of yet, undisclosed programs in the lab, also using our masking strategy to, again, open therapeutic windows. We're really feeling like we're on the cusp of big advances in the coming years in T cell engagers. Our masking strategy, we think, is at the absolute forefront. Great. To wrap up our discussion, could you just talk about the next 12 months and the road ahead for CytomX, what we can expect during that timeframe? Well, very happy to have reported at Q1. In addition to our update on 904, the company is well funded. We ended Q1 with $150 million on the balance sheet. That's funding through 2025. So happy to be in that cash position. And that does not include any additional milestones that we may earn from our partnerships or, of course, any new business development. So CytomX continues to be in a robust financial position, allowing us to achieve key milestones coming up on the horizon. So, of course, in the relatively near term, as I said, we're very focused on broadening out the data set for CX-904 in pancreatic, head and neck, and lung cancer, discussing that data second half of this year with Amgen, getting to a decision with them about what phase I-B looks like, and moving into those phase I-B expansion cohorts with a data update being in 2025. CX-2051, let's just talk for a moment about our ADC targeting EpCAM. So EpCAM is a very high potential ADC target. We believe it's highly expressed on most solid tumors. It's particularly highly expressed on colorectal cancer. We've designed CX-2051 as a TOPO-1 inhibitor payload ADC. That is ideally matched, we believe, to where the target's expressed, which is most highly in CRC. We've begun phase I. We treated our first patient in April of this year. Dose escalation is ongoing. We are working towards an initial data update in the first half of next year. Then we're also initiating phase I for CX-801, our masked interferon alpha. Very excited about getting this into combination with KEYTRUDA. We signed a collaboration agreement, a drug supply agreement with Merck recently to access KEYTRUDA. We'll be moving rapidly in phase I to the combination of our masked interferon 801 with KEYTRUDA in melanoma, renal, and head and neck cancers. I would anticipate an initial update on 801 by the end of 2025. Then we just continue to execute across this multimodality pipeline across our partnerships and make progress across more than 15 active programs at CytomX today. Great. Thank you so much, Sean. And thank you to the CytomX team for joining us today on our panel. And thank you to all the investors that dialed in for this call. We really appreciate it.