CytomX Therapeutics, Inc. (CTMX) Q1 2024 Earnings Report, Transcript and Summary

Good day, and thank you for standing by. Welcome to the CytomX Therapeutics First Quarter 2024 Financial Results Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Chris Ogden, CytomX' Senior Vice President, Finance and Accounting. Please go ahead.

Thank you. Good afternoon, and thank you for joining us. Before we begin, I would like to remind everyone that during this call, we will be making forward-looking statements. Because forward-looking statements relate to the future, they are subject to inherent uncertainties and risks, that are difficult to predict and many of which are outside of our control. Important risks and uncertainties are set forth in our most recent public filings with the SEC at sec.gov. We undertake no obligation to update any forward-looking statements, whether as a result of new information, future developments or otherwise. Earlier this afternoon, we issued a press release that includes a summary of our first quarter 2024 financial results and highlight recent progress at CytomX. We also issued a press release today announcing positive initial Phase Ia dose escalation data for monotherapy CX-904, which will be the primary focus of today's call. We encourage everyone to read today's press releases and the associated materials, which have been filed with the SEC. Additionally, the press releases and recording of this call and our SEC filings can be found under the Investors and News section of our website. With me on the call today are Dr. Sean McCarthy, CytomX' Chief Executive Officer and Chairman, and Dr. Wayne Chu, CytomX' Chief Medical Officer. Sean will provide an update on the overall pipeline and also outline CytomX' broader strategy for masked T-cell engagers. Wayne will then give an update on the CX-904 Phase I dose escalation study before Sean provides closing comments and we open up the call for Q&A. With that, I'll now turn the call over to Sean.

Thanks, Chris, and good afternoon, everyone. It's a pleasure to be here today to share our considerable progress during Q1, including our initial findings from our Phase I study of our EGFR targeted Probody T-cell engager CX-904. CytomX is highly focused on addressing major unmet needs in oncology using our Probody therapeutic platform, a proprietary antibody masking strategy, designed to improve the therapeutic window for multiple antibody modalities through tumor-localized activation. We are leveraging our Probody therapeutic platform to discover and develop new cancer therapies based on masked T-cell engagers, masked ADCs and masked cytokines. Our broad and deep pipeline encompasses more than 15 active programs, including 3 clinical stage molecules and significant retained commercial rates. Strategic partnering is our long-standing components of our corporate strategy, and we're proud to be working closely with Bristol-Myers Squibb, Amgen, Astellas, Regeneron and Moderna on multiple Probody therapeutic programs. We continue to be in a strong financial position with $150 million of cash at the end of Q1, which provides cash runway to the end of 2025, not including any milestone payments under our existing collaborations or any potential new partnership funding. CytomX is very strong organizationally with integrated R&D capabilities, continued investment in our core technology and a deeply experienced team dedicated to our vision of transforming lives with safer, more effective therapies. Moving to Slide 6. The CytomX product design strategy using our Probody therapeutic platform is informed by more than a decade of experience and seeks to balance target selection, masking strategy and effective function to make meaningful impact in key areas of unmet need in oncology. CX-904 brings the EGFR target together with T cell engagement via CD3 with the goal of T cell-mediated killing of EGFR positive tumor types, potentially including those for which conventional antibodies have not shown activity. CX-2051 is our masked conditionally-activated ADC that integrates the high potential of EpCAM as a cancer cell target with the potency of a Topo-1 inhibitor payload, ideally suited, we believe, to high EpCAM expressing tumors like colorectal cancer. CX-801 leverages the potent activity of the cytokine interferon alpha, which in this case is the effector mechanism itself. Our masked interferon is designed to locally activate the intratumoral immune microenvironment with potential to drive responses across multiple cancer types, including melanoma, renal cell carcinoma and head and neck squamous cell carcinoma. Q1 was an extremely productive quarter for CytomX. We are executing to our plans, and we're making progress across the full breadth of our pipeline. Today, we're announcing positive initial Phase Ia dose escalation data for monotherapy CX-904, our EGFR-CD3 T-cell engager in solid tumors, and this is the main topic of our update here today. In addition to our exciting progress with CX-904, during Q1, the first dose cohort cleared in the Phase I clinical study of 2051, our ADC targeting EpCAM, this study is focused largely in colorectal cancer, and we anticipate initial data in the first half of 2025. Also during Q1, Phase I study initiation activities continued for CX-801 and masked interferon alpha, including the execution of an agreement with Merck to supply KEYTRUDA for combination with CX-801, and we announced that agreement last night. Initial data from the 801 program is also anticipated in 2025. We continue to make excellent progress across our collaborations, including earning $10 million of milestones under our T cell engaging bispecific collaboration with Astellas that was for preclinical progress on the first 2 programs in the alliance. We're also delighted to welcome Dr. Zhen Su to our Board during Q1. So a really productive start to 2024 for CytomX on all fronts and our current clinical pipeline is really gaining momentum, and we have a very exciting 12 to 24 months ahead of us. Moving now to our T-cell engager strategy. T cell engaging bispecific antibodies, of course, have enormous potential for the treatment of cancer and first demonstrated meaningful clinical benefit in hematologic malignancies. Looking at the solid tumor landscape for T-cell engagers, however, it's taken time to see meaningful clinical progress. And for this modality to really break through in solid tumors, there are some significant challenges to overcome. Notably, T-cell engagers bring very high potency and this potency can lead to toxicities in normal tissues where the tumor antigen of interest may also be present. Another key limitation for T-cell engagers in solid tumors is cytokine release syndrome, resulting from systemic binding to CD3 on T cells and also neurotoxicity in the form of ICANS. At CytomX, we have a broad-based program focused on masking T-cell engagers to decrease tumor antigen-binding in normal tissues and also decreased CD3 binding in the periphery, thereby improving therapeutic index. In addition to our internal programs, we're working with partners, Amgen, Astellas, Regeneron and BMS in this exciting space. CX-904 is our lead program in the T-cell engager area, and I'd like to spend a few minutes now walking through the history and structure of this molecule. We've had a long-standing interest in EGFR at CytomX, our seminal publication of the first ever successful antibody masking was focused on the EGFR binding antibody cetuximab for which we showed a marked reduction in systemic skin rash for the masked antibody compared to the unmasked version. These findings set the stage for the evolution of the monospecific EGFR Probody into our CX-904 bispecific T-cell engager. We reason that EGFR as a target has so much more potential to be realized and the realization of this potential would require a more potent effector mechanism, leading us to the concept of the masked EGFR-CD3 strategy encompassed CX-904. We did actually publish an early lead molecule from this program in cancer research to demonstrate preclinical proof of concept, and we subsequently refined the structure using the depth of our platform and in collaboration with our partner, Amgen. The next slide shows the molecular architecture of 904. CX-904 has 1 CD3 binding domain and 1 EGFR binding domain. Both domains are masked with unique peptides. Furthermore, the protease cleanable substrates are different in each binding domain, reflecting our preclinical fine-tuning strategy for optimization of therapeutic window. CX-904 also has an Fc region, and so it would be expected to have an antibody like half-life. This overall structure is somewhat similar to Amgen's tarlatamab that has shown impressive results in small cell lung cancer. Shown on the right of this slide is a recap of the therapeutic concept for CX-904 and for our platform generally. The concept is that masking reduces drug binding to target in normal tissues whereas in tumor tissue, the mask are removed by activated tumor proteases. This tumor localization leads to the improvement or creation of a therapeutic window. For the EGFR-CD3 antigen pair, it's been shown previously that the unmasked bispecific is highly toxic in preclinical models. So our masking strategy is, we believe, essential for creating a therapeutic window. In terms of the toxicities, we're looking to mitigate, EGFR antibodies are well known to cause rash and gastrointestinal side effects. And so we've been specifically looking out for our masking strategy to really live it serious EGFR toxicities, particularly Grade 3 and above. With regard to CD3, our masking strategy is, of course, designed to limit CRS and ICANS. Before I hand over to Wayne, let me review the high-level goals and achievements to date for our Phase I study of CX-904. Given the really high potency of T-cell engagers and the widespread expression of EGFR, goal #1 for the study has been to evaluate the safety of 904, and we've made excellent progress, as you will see from Wayne's presentation. We've explored non-step and step dosing. We were very pleased to see very limited CRS with non-step dosing, we believe because of successful CD3 masking. And in step-dosing cohorts, rather remarkably, we've seen no CRS at all. We've also seen no evidence of ICANs at any dose level or schedule. Furthermore, while we have seen some EGFR toxicities, these have been manageable and have not limited us in achieving therapeutically active doses. Again, this shows the success we believe of our EGFR marketing strategy and this success of EGFR masking is consistent with our prior published work that I mentioned earlier. Goal #2 of our Phase I study has, of course, been to look for initial signs of antitumor activity. As we've said in recent months, any evidence of tumor stabilization or tumor shrinkage in this first-in-man study would be very encouraging. I want to emphasize that the patient population we've enrolled, to date, in this Phase I study is heavily pretreated and is a range of tumor types and is unselected for EGFR. All that said, we're delighted to announce today very encouraging early signs of anticancer activity for 904, and including confirmed RECIST responses in pancreatic cancer, a very difficult to treat tumor type that is not typically responsive to EGFR inhibition or for that matter, to immunotherapy. Moreover, our initial assessments of pharmacodynamics are supportive of the mechanism of action of CX-904 as a masked T-cell engager, providing crucial platform proof of concept with read-through, we believe, to the many other programs we're working on at CytomX. Importantly, this Phase I study is ongoing. We're continuing to dose escalate and enroll multiple tumor types. And our next goal is to determine recommended Phase II dose and to define plans for Phase Ib expansions. We see the data that we're sharing today as a very promising initial step in the development of CX-904, and this work positions CytomX at the forefront of the T-cell engager field. Now let me hand over to Wayne to review the data in some detail.

Thanks, Sean, and thanks, everyone, for the opportunity to share our early clinical and translational observations in the ongoing dose escalation study. This slide summarizes the dose escalation scheme, key eligibility criteria and study objectives. Patients with tumors with known EGFR expression were enrolled. However, patients were not selected based on EGFR expression. Dose escalation was initiated using a non-step dosing schedule in which CX-904 was dosed once every 2 weeks, doses starting from 7 micrograms through 6 milligrams were tested. As we will discuss in the subsequent slides, dose escalation of CX-904 continued using a step-dosing schedule with an initial target dose of 5 milligrams. Various step-dosing schedules were tested, after which the target dose was administered every 2 weeks. The data presented today represents safety and efficacy data from a total of 13 dose escalation cohorts through the 10-milligram target dose. And as Sean mentioned, dose escalation continues with the current enrollment testing the 15-milligram target dose. Selected baseline characteristics for enrolled patients are shown in this slide. The majority of patients enrolled in non-step dosing escalation cohorts were those with microsatellite stable or MSS colorectal cancer, which I will term CRC from here on out, which has been demonstrated to be unresponsive to immune therapies such as immune checkpoint inhibitors. With step-dosing escalation cohorts, we have begun to focus on patients with tumors with early evidence of clinical activity as well as other tumor types with known EGFR expression. As a typical for a Phase I first-in-human dose escalation study, patients had advanced late-line disease, enrolled patients received a median of 4 prior cancer therapies, many were refractory to their last prior therapy and a considerable proportion received prior EGFR and/or PD-1 and PD-L1 directed therapy. Early clinical pharmacokinetic data from the non-step dosing schedule was consistent with the CX-904 Probody T-cell engager design. The graph on the left shows that total CX-904 exposure increases linearly with increasing dose, indicating no apparent change in dose-dependent clearance or evidence of target-mediated drug disposition. The graph on the right shows the cycle 1 PK profile of CX-904 at the 3-milligram dose level. The 3 curves show circulating analyte concentrations of intact or masked CD3, intact EGFR and total Probody. Notably, the 3 curves are essentially superimposable, indicating that CX-904 exists in circulation in predominantly intact or masked form. Preliminary estimates of CX-904 half-life are between 2.8 and 5.3 days. This slide summarizes treatment-related adverse events observed with CX-904 in the non-step dosing schedule. It is important to mention that during the CX-904 escalation, no corticosteroids or other prophylactic medication was administered for systemic toxicities such as CRS and ICANS. The safety and tolerability data shown here with non-step dosing, therefore, reflects the ability of the masking to mitigate CRS and ICANS. With that, the virtual absence of CRS and ICANS is quite striking. Through the 3-milligram dose level, no CRS or ICANs of any grade were observed. Even at the 6-milligram dose level where 2 patients had dose-limiting toxicity of Grade 3 tenosynovitis and Grade 3 rash, no patients experienced ICANs of any grade and only Grade 1 CRS characterized by transient fever without any other signs or symptoms associated with CRS was observed. Low-grade musculoskeletal adverse events such as arthralgia and arthritis were observed in addition to the 1 Grade 3 tenosynovitis at the 6-milligram dose level. Musculoskeletal events overall appear to be associated with a dose-dependent increase in circulating IL-6 as shown in the graph. This is in direct contrast with CRS, where the association with circulating IL-6 levels was much less evident. Similarly, except for the Grade 3 rash observed at the 6-milligram dose level, only Grade 1 rash was observed. Overall, the data presented here quite convincingly demonstrate the benefit of masking on effectively eliminating CRS and ICANS, which constitute dose-limiting toxicities with many T-cell engagers. Based on the observations during dose escalation on the non-step dosing schedule, which demonstrated that CRS and ICANs are effectively mitigated by the masking of CX-904, and step-dosing schedule and tocilizumab prophylaxis were used specifically to mitigate emerging musculoskeletal adverse events, maintain a broad therapeutic index, and allow continuation of escalation to higher and potentially more efficacious target doses. These measures enabled escalation to higher CX-904 target doses while continuing to maintain an acceptable safety and tolerability profile. Impressively, no CRS or ICANS of any grade was observed. Moreover, the incidence and severity of musculoskeletal adverse events did not substantially increase with higher CX-904 target doses, no related Grade 3 ratios were reported, and no treatment-related adverse events resulted in CX-904 treatment discontinuation. Overall, the safety profile of CX-904 continues to be favorable and importantly, enable CX-904 administration and management of adverse events in an outpatient setting. In this regard, per protocol, no mandatory hospitalization is required for monitoring at clear dose levels and the safety profile observed to date has not necessitated a change to this practice. In the context of a favorable safety profile, we observed compelling signs of CX-904 anti-tumor activity, highlighted by activity observed to date in patients with advanced pancreatic adenocarcinoma. The responses observed with CX-904 are highly encouraging, given that outcomes in patients with recurrent metastatic pancreatic cancer remain extremely poor with current available therapies. Shown here is the waterfall plot of 6 efficacy-evaluable patients treated across a range of target doses on both non-step and step-dosing schedules. Confirmed partial responses per RECIST 1.1 criteria were observed in 2 of the 6 patients. One was treated with 6 milligrams on a non-step dosing schedule and had an 83% reduction in measurable tumor burden and the second patient was treated on a step-dosing schedule with a target dose of 5 milligrams and had a 51% reduction in tumor burden. Furthermore, of note, all 6 patients had disease control. Of the 6 patients, 2 remain on study treatment, and we will now discuss these patients in greater detail. The first case describes a confirmed partial response in a 49-year-old patient with metastatic pancreatic adenocarcinoma. Prior therapies included surgery, radiation therapy and 3 lines of prior chemotherapy. The patient received CX-904 on a step-dosing schedule with 1.5 milligrams administered on day 1 and the target dose of 5 milligrams administered 1 week later and then 2 weeks thereafter -- every 2 weeks thereafter. The patient did not experience cytokine release syndrome or ICANS. The patient experienced Grade 3 related or arthralgia, but this resolved a Grade 1 after 1 cycle delay in administration of corticosteroids. As shown in the CT scan images, the patient achieved a partial response with deeper reduction in tumor burden observed as the confirmatory CT scan. And as I mentioned, this patient remains on CX-904 treatment having received over 3 months of treatment to date. This next case illustrates durable stable disease with CX-904 in a 59-year-old patient with metastatic pancreatic adenocarcinoma who had received 3 prior lines of systemic chemotherapy. The patient received CX-904 on a step-dosing schedule with 1.5 milligrams administered on day 1, 5 milligrams on day 8, and 10 milligrams on day 15 and every 2 weeks thereafter. The patient tolerated CX-904 treatment well with no CRS, ICANS or musculoskeletal events and only Grade 1 papulopustular rash, which resolved with topical treatment. The patient was able to maintain stable disease with no evidence of measurable tumor growth and additional information supporting continued clinical benefit included a greater than 50% reduction in serum CA19 levels and overall improvement of performance status from baseline. This patient remains on CX-904 treatment having received over 3.5 months of treatment to date. Preliminary translational data indicates T cell pharmacodynamic activity that is consistent with the mechanism of action of CX-904 in pancreatic adenocarcinoma. The figure on the left is an immunofluorescence image from a biopsy obtained prior to CX-904 treatment in a patient with pancreatic cancer who achieved a deep partial response. The colors indicate T cell markers in red, dark blue and magenta and cancer cells in light blue. And as you can see, the pretreatment biopsy showed a high level of CD8 positive T cells within the tumor microenvironment, indicating their contribution to T-cell engager antitumor activity. The figure on the right shows the reduction of peripheral CD8-positive T cells as it relates to RECIST 1.1 response. Both pancreatic patients with confirmed partial response had among the greatest reduction of peripheral CD8-positive T cells following CX-904 treatment consistent with the trafficking of T cells from the periphery to tumor sites as a mechanism of action of T-cell engagers. Taking a step back from the early but compelling activity of CX-904 patients with pancreatic adenocarcinoma shown here is the waterfall plot where efficacy evaluable patients treated with CX-904 target doses greater than or equal to 0.75 milligrams. While no objective responses were observed in patients with other tumor types, reductions in measurable disease burden were observed in the total of 8 patients, including the 2 pancreatic cancer patients with partial responses. Reductions in measurable disease burden were also observed in patients with CRC, esophageal carcinoma and non-small cell lung cancer. We believe that the early signals of CX-904 activity in pancreatic cancer are compelling and that currently tested target doses are efficacious. As a result, study enrollment moving forward in addition to continuing to enroll patients with pancreatic cancer will focus on patients with other EGFR positive tumor types including lung cancer, upper GI cancers and head and neck cancers. This slide summarizes the time on study treatment for patients treated with CX-904, again, highlighting the patients with pancreatic adenocarcinoma that continue to derive clinical benefit with ongoing CX-904 treatment. Importantly, while CX-904 has had minimal clinical activity to date in patients with CRC, CX-904 retains its pharmacodynamic activity as illustrated in this slide, which are immunofluorescent images of biopsies taken from a patient with MSS CRC at baseline and while on CX-904 treatment. As you can clearly see at baseline, the tumor is notable for the almost complete absence of CD8-positive T cells within the tumor. In contrast, the on-treatment biopsy showed a substantial increase in the number of CD8-positive T cells within the tumor. This observation is a clear demonstration of the CX-904 mechanism of action and demonstrates potential combinations strategies for the treatment of CRC. In summary, we are very encouraged by this early clinical data of CX-904 in the ongoing Phase I dose escalation. CX-904 has a favorable safety profile, which given the broad expression of EGFR in normal tissues in addition to cancers is indicative of the ability of masking to maintain a meaningful therapeutic index. Second, CX-904 has promising early efficacy and pharmacodynamic activity highlighted by the confirmed partial responses in patients with metastatic pancreatic adenocarcinoma and early demonstration of CX-904 mechanism of action, including in colorectal cancer. The clinical and translational observations have been extremely valuable in demonstrating not only the early clinical activity of CX-904, but also provide clear direction to plans to ultimately determine the recommended Phase II dose. And this includes continued enrollment in pancreatic cancer and enrollment in other EGFR positive tumor types that are also more responsive to immune therapies based on prior clinical experience. Together, these data will inform future development of CX-904, which include considerations of combination strategies. And with that, I will now turn it back to Sean for concluding remarks.

Great. Thanks, Wayne. So staying with CX-904 for a moment, we're excited by our progress to date, developing this very novel drug candidate. EGFR is such a high potential target with expression of many tumor types. And we're just at the beginning of learning what CX-904 can do for patients. We clearly have a drug candidate with confirmed monotherapy activity and we're redoubling our efforts to generate data in additional tumor types as we more broadly explore in 904. Our data also unlocks potential strategies for future combinations, as Wayne mentioned. Focusing for a moment on pancreatic cancer. This is one of the greatest areas of unmet needed oncology today, and it's notoriously difficult to treat. Second-line response rates were in the single digits, mPFS and overall survival is just a matter of months. To reiterate the importance of our data shared today, pancreatic cancer does not respond to either anti-EGFR antibodies or to immunotherapy alone. What we have shown today is that when we combine these 2 powerful strategies in bispecific form, enabled by our Probody masking technology, we can elicit meaningful responses in late-stage pancreatic cancer patients. CX-904 brings these 2 mechanisms together into an integrated and unique pharmacology that could impact this very difficult-to-treat disease, showing how masked Probody T-cell engagers can be a new frontier in the war on cancer. These results are the embodiment of exactly what CX-904 was designed to do, and we plan to aggressively pursue the signal for the benefit of people afflicted with this devastating tumor type. Now zooming back out to our full pipeline and looking also into 2025, we anticipate a great deal of additional progress at CytomX. We see the data we're showing today on 904 as a promising initial step in developing this asset and also our T-cell engager portfolio overall. T-cell engagers are starting to break through in solid cancers, and it's exciting to be playing our part here at CytomX in this highly promising field, not only with 904 but also the many T cell engagement programs we're advancing through preclinical discovery and development. And we look forward to providing an additional CX-904 update later this year. Of course, today's update has been very 904 focus. But before I wrap up, I'd like to remind everyone to also keep our other programs in mind. We're making a lot of progress on multiple fronts. CX-2051 and CX-801 are wholly owned assets. And we anticipate Phase Ia data for both in 2025. We're already in our second Phase I cohort with 2051, our masked anti-EpCAM ADC and clinical initiation for CX-801, our masked interferon is imminent. I'd like to close by thanking everyone involved in this work for their commitment to our vision. The CytomX team is intensely focused on delivering an innovative pipeline for the benefit of people living with cancer and it's truly a privilege to work with such a talented team. I also want to sincerely thank the patients who join our studies, their families and our investigators. And with that, operator, let's go ahead and open up the call for questions.

[Operator Instructions] Your first question, it comes from the line of Peter Lawson from Barclays.

Really exciting. The masking benefit you've seen, do you think that can also extend to other T-cell engagers. And then the responses you've seen so far -- do you think there's something special about pancreatic cancer? Or do you think you can get deeper responses in other tissues as well?

Yes, Peter, great questions. Thanks. Regarding the extension and the read-through to other programs, we're obviously very optimistic that, that will be the case. You've got to start somewhere, and 904, I think it's a very strong start for us. We've learned a lot with this one in the clinic. And as we've mentioned, both internally and with our partners, we're doing a lot of work in T-cell engagers. We've got multiple programs. In fact, the majority of our partnered work is in T-cell engagers. So we would expect to make substantial additional progress here over the next few years. In terms of pancreatic, I think it's a great question. It's been interesting to see -- we've done a lot of thinking about this, obviously. And pancreatic is typically thought of as an immunology cold tumor or an immunologic desert, if you like. But actually, evidence is beginning to -- I'm not suggesting that, that might not be the case. If you look at the Roche BioNTech vaccine data, most recently updated at AACR. It's really interesting. It suggests that there are neoantigens in pancreatic cancer that there is some immunologic microenvironment. And it looks like with this combination of each -- well, there's also EGFR, of course, there. But no one has been able to break through with an anti-EGFR directed therapy. So we think that could be something very unique about EGFR and CD3 in this particular tumor type. But it absolutely does not indicate that others would not respond to 904. We're still very early in this study. As Wayne mentioned, the colorectal data is interesting. They're all MSS patients that we're showing today. That's another cold tumor. Not a lot of progress has been made with T-cell engagers yet in CRCs, so we would be looking to combination strategies there. As far as the other tumor types are concerned, it's just very, very early days. For example, just like I'd lung, where we have 2 patients in the dose escalation study to date. One of those was treated at a very low dose, so probably not relevant. We've already only -- we just haven't done the experiment yet. So we're going to keep enrolling across multiple tumor types in Phase Ia as we continue to pursue both the pancreatic signal and define the activity of the drug across hopefully multiple tumor types over time.

Great. And then the depth of the responses. Is that correlated with EGFR expression or is it tumor microenvironment?

One thing we have not shown as -- that's shown in this presentation, but we continue to evaluate is the level of EGFR expression as assessed by immunohistochemistry assay. And we've been doing this on a retrospective basis for all the patients that have enrolled. To date, based on our early data with eGFR by this IHC assay, we have not seen a clear association between EGFR expression and the depth of the response. And just as an example, the 2 patients in pancreatic cancer who had the confirmed partial response. One patient had a moderately high level of EGFR expression by IHC, but the other patient had a very low level of EGFR expression, and it's actually the patient who had the 83% reduction in measurable tumor burden that has the low level of EGFR expression.

I think more -- yes, more work to be done there. But Peter, a lot of it depends also on the assay itself. So we'll continue to look at that relationship.

Your next question comes from the line of Roger Song from Jefferies.

A few questions from us. The first one is related to the dose relationship since the efficacy or antitumor activity is not clearly correlate with the dose level. My question is, how do you think about as you dose higher -- even beyond 10 mg, now you're at 15. How do you think about the balance between the efficacy and CRS, ICANS, more CD3 or EGFR-related tolerability profile, how confident you are you can keep dosing higher?

Yes. Thanks, Roger. Let me kick that one off. I'd say that there is a dose response in that the responses that we're seeing, the confirmed RECIST responses, we've seen at 5 and 6 milligrams. Remember that we began this dose escalation at 7 micrograms. So the range of doses where we're seeing activity is actually really consistent with our predictions from modeling of where the biologically effective range would be. So we think we're in the zone. We do believe, however, because of the safety profile, we can dose higher. Whether that will help or not, I don't think we know. I think all of us, in the T-cell engager field, are kind of trying to figure this out. And if you look at Amgen's tarlatimab, I mean, they went all the way to 100 and concluded in the end that 10 milligrams was the dose to move forward because the 100 didn't give significant additional efficacy. So I think we've got to learn more, but we're very encouraged that we have this clean safety profile with EGFR, I think it exceeded our expectations and it will allow us to dose escalate further, and we'll do that and we'll see where it takes us.

Got it. My follow-up question is related to your partner, Amgen. So this data, have you shared with the partner? And if so, any initial feedback and also understanding you will give an update by the end of the year, what you are looking for in order for both of you 2 parties to make the Phase Ib study design and the decision?

Yes, great questions. So with Amgen, let's take a little step back and talk about we just recap the agreement that we have with Amgen. So we're obviously running the Phase Ia study. And we do share data with them as it emerges. We are also responsible for running the Phase Ib once we get that up and running. And the transition from Phase II to Phase Ib is a decision that we'll take jointly with Amgen. And of course, the goal would be to in Phase Ib to enroll specific EGFR positive tumor type, for which one now, quite obviously, would be pancreatic. We would assume based on this exciting signal that we've seen. So we -- because we -- the way that enrollment has unfolded, we still have just not enrolled many patients in lung or head and neck, for example, -- we do want to bring in a few more patients to get some additional experience in those tumor types. Before we have the conversation with Amgen later in the year about what the Phase Ib strategy would be. So the update later this year could be a couple of things. It could be additional data from -- we would ballpark -- we should have by end of year, another 10 or so patients of data. It could also be an operational update that we've agreed with Amgen on the next steps. We just have to have that dialogue with them. But in terms of their perspective on the data, I think that's a question best asked from them at this point in time. But obviously, we're really excited by our progress.

Your next question, it comes from the line of Joe Catanzaro from Piper Sandler.

I guess maybe first one on the EGFR-mediated tox that you're seeing, I guess my question is like what do you think is happening? Is that some small amount getting unmasked in periphery or maybe a small amount getting unmasked in the tumor and then reentering circulation? And is that tox that you're seeing typical of sort of historical EGFR experience, say, cetuximab? Or is there anything indicative that it's T cell targeting of EGFR on normal tissue, and I may have 1 follow-up.

Yes. Joe, thanks for the question. Well, first of all, let me say that we're really, really pleased with the very low incidence of Grade 3 rash in this study. We only have 1 patient over the 35 patients with a Grade 3 treatment-related rash. That's a significant achievement, we think, because it unlocks the opportunity to use this mechanism to shrink tumors that otherwise couldn't be shrunk with the EGFR. So we're very pleased about that. Obviously, early days, more work to do, but we're encouraged. With any drug, you're going to see some -- you're going to see AEs, it's very hard to say what are they -- where they're coming from? Is it local? Is it systemic? We don't know and we may never know and in a way might not matter that much because it's all about the risk benefit profile, and we're obviously delivering something we think very important here -- at least initially for patients with very late-stage pancreatic cancer. I would say -- on the type of rash that we see cetuximab rash is typically the acneiform rash, we see some of that Grade 1, Grade 2. They're also, as Wayne mentioned, maculopapular rashes, which are maybe more T cell -- involved T cells. So I think we're going to have to learn more about it, but we're not worried about it because it's mostly Grade 1, 2 effect across the entire study, the incidence of rash across the entire 35 patients was 40% and just about all Grade 1, 2 and manageable. So we're really encouraged by the AE profile here. Not to mention the CRS profile, which really quite frankly surprised us to the upside.

Yes. That's helpful. I guess my follow-up for the pancreatic cancer patient that had that deep response and then subsequent progression. Wondering if you could maybe elaborate a little bit more on that progression event. Was it a new lesion, growth of a target lesion. If it was a new lesion, maybe we were able to sort of profile it and see what's going on. Just anything you could say there, I guess, would be interesting.

Yes, I could provide some details on that. This is a patient that was treated with the 6-milligram non-step dosing had a confirmed partial response that strikingly with an over 80% reduction in measurable tumor burden. The patient did progress based on growth of the target lesion from the [indiscernible] as well as the appearance of, I think, of 1 new target lesion -- on -- sorry, on new lesion. So that was the nature of the progression on that particular patient. But all through that treatment course, the patient did quite well clinically. It was just based on the radiographic progression that...

Okay. And then maybe if I could just squeeze in 1 more, quick one, maybe going back to an earlier question. Just if you could maybe speculate more on what you think is maybe going on in MSS CRC. It seems mechanistically like you're seeing T cell infiltration, but that's not translating to tumor reduction. So I'm wondering if you have any other sort of hypotheses of what may be going on in those patients?

I think mechanistically, it's really interesting when we think about how T-cell engagers work overall, right? CD3 combined with the tumor antigen, we think that these typically as being MHC nonrestricted mechanisms. That may very well be what's going on. But there could be more necessary to really mount an antitumor response. I think we're again, in the field, I think there's more to be learned about specifically how CD3 T-cell engagers kill cancer cells. Clearly, we're doing it in pancreatic cancer. We're getting the T cells there in CRC, but it draws one's attention to think about what combination strategies could get you to actual objective tumor responses. So I think more work to do there in some of the basic science and then also clinical work that we can do in terms of clinical combinations. It's quite intriguing.

Your next question, it comes from the line of Etzer Darout from BMO Capital Markets.

Just wondering if you could maybe talk through your current thoughts on sort of the step versus the non-step dosing, particularly in the pancreatic patients that sort of had the response and how you're kind of thinking about potentially moving 1 or the other option for it as you sort of expand the patients? And then I don't know if you said this specifically but about sort of the EGFR expressions across sort of the patients that you've seen so far? Is it that you're going to -- moving forward, you will look at EGFR expressions? Or is there an opportunity to kind of look at EGFR expression across the folks that you've already sort of enrolled in the study. I don't know if I caught that correctly.

Yes. Thanks, Etzer. In terms of moving forward with step or non-step, we obviously haven't made a decision on that yet. But I would say based on our experience to date, more likely that our Phase Ib doses will be step strategies, because it's allowing us to get to significantly higher target doses. And we do think there's a dose response here of sorts. So more to be learned there will also likely take -- when you think about project Optimus considerations, we'll likely want to take more than 1 dose and schedule into Phase Ib to gain further experience of the drug candidate, not only in pancreatic, but also in other tumors as well. In terms of EGFR it's surprising actually -- how should I put this -- the available assay for EGFR or assays for EGFR by IHC, it's just that it's not perfect. And so we're not sure how much 1 would want to rely on it moving forward, particularly because it doesn't seem from our early data that this is a straightforward ADC type thing where you -- high target is required for activity. These drugs like T-cell engagers just would be predicted to be active at low target levels because of the mechanism of -- the amplified mechanism of tumor killing where 1 T cell can kill multiple tumor cells. So I think we've got more to do in there, and that's why we're -- we may not be needing or leveraging EGFR selection on a go-forward basis based on what we've seen so far.

Your next question, it comes from the line of Anupam Rama from JPMorgan.

Can you comment -- was there anything in the baseline characteristics, a number of prior treatments I think the PDAC case study that you said was 3 lines of therapy or otherwise, that might be predictive of a response. I think based on the first question, EGFR expression didn't correlate. And then can you comment, and I'm sorry if I missed this, the other 3 stable disease patients, what was their duration?

I'll take the first question in terms of which I think was anything in the patient characteristics that could have been predictive of response and I'd say, no, not really. Again, these are all pretty late-life patients. And aside from EGFR, we did show -- that said, Wayne showed a slide of a pretreatment biopsy of a patient with pretty high levels of pretreatment, CD8-positive cytotoxic T cells which is intriguing, and certainly could have contributed to the response. And so -- that's something that we have observed. We don't have that data systematically, across the whole study. That's difficult data to get for every patient, but it is intriguing. In terms of the stable disease, Wayne can address that question real quick.

Yes. So as we showed in the swim lane plot during the presentation, there were a number of patients who were able to maintain a stable disease through at least 1 tumor response and smattering -- that included a smattering of patients that had durable stable disease through tumor -- to tumor responses. But otherwise, patients were able to achieve a stable disease and then it was followed by progressive disease.

I do think it's important to reemphasize that these -- again, the pancreatic are very -- as everyone knows, it's a very rapidly progressing disease. These are patients who, for the most part, had 3 or 4 priors. And so this -- so yes, we think this is a really exciting data.

[Operator Instructions] Your next question, it comes from the line of Mitchell Kapoor from H.C. Wainwright.

Congrats on the positive data. I wanted to ask about the total 8 patients with tumor reductions the other -- well, I guess, if you could just broadly comment on what a slider plot for these patients might look like. Are you seeing a trend in depth of response over time? Or how are we seeing those tumor reductions evolve?

Yes. I mean it's early days. I think those 8 patients, obviously, 2 of them are the pancreatic patients, and you can see them in the waterfall plot. I think there's encouragement there in terms of the fact that escalation continues, we'll keep pushing the dose here. So at this point, I think it's fair to say the [ spider plot ] will be relatively immature.

Okay. And could you just comment on the other confirmed partial response patient? And how much duration of follow-up that patient ahead?

That patient, again, was treated at the 6-milligram non-step dosing schedule, had confirmed partial response, and that patient remained on study about -- on study treatment approximately 18 weeks before having progressive disease.

Thank you. And I'm showing no further questions. I would now like to turn the conference back to Dr. Sean McCarthy, CytomX' Chairman and CEO, for closing remarks.

Great. Thank you very much, and thanks, everyone, for listening in today. CytomX has made terrific progress so far in 2024, and we look forward to providing additional updates as the year proceeds. And as we continue to build our company for the long term to make the biggest difference we can for patients. And so thank you very much. Have a good evening.

This concludes today's conference call. Thank you for participating, and you may now disconnect.