Earnings Call Transcript - CTMX Q1 2024

Operator, Operator

Good day, and thank you for standing by. Welcome to the CytomX Therapeutics First Quarter 2024 Financial Results Conference Call. Please be advised that today's conference is being recorded.

Chris Ogden, Senior Vice President, Finance and Accounting

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. 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 highlights 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. 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.

Sean McCarthy, CEO and Chairman

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 a long-standing component 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 a 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 our plans and 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 CX-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 CX-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. 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 decrease 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 on 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 reasoned that EGFR as a target has so much more potential to be realized, and realizing this potential would require a more potent effector mechanism, leading us to the concept of the masked EGFR-CD3 strategy encompassed in 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 CX-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 masks 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 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. So we've been specifically looking for our masking strategy to really limit 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 CX-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. In the step-dosing cohorts, 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 includes 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 CX-904, 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. Our next goal is to determine the recommended Phase II dose and to define plans for Phase Ib expansions. We see the data 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.

Wayne Chu, Chief Medical Officer

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, with doses starting from 7 micrograms through 6 milligrams being 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. The data presented today represents safety and efficacy data from a total of 13 dose escalation cohorts through the 10-milligram target dose. 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 is typical for a Phase I first-in-human dose escalation study, patients had advanced late-line disease, with enrolled patients receiving 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. 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, step-dosing schedules 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 rashes 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, it enables 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 every 2 weeks thereafter. The patient did not experience cytokine release syndrome or ICANS. The patient experienced Grade 3 related arthralgia, but this resolved to Grade 1 after a 1 cycle delay in the administration of corticosteroids. As shown in the CT scan images, the patient achieved a partial response with a deeper reduction in tumor burden observed in the confirmatory CT scan. 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. 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 cancer 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.

Sean McCarthy, CEO and Chairman

Taking a step back from the early but compelling activity of CX-904 in patients with pancreatic adenocarcinoma, shown here is the waterfall plot where efficacy-evaluable patients treated with CX-904 at 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 a 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 from 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 contains 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 combination 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. 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 in many tumor types. 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 CX-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 need in oncology today, and it's notoriously difficult to treat. Second-line response rates were in the single digits, and mPFS and overall survival are 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 two 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 two 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 with the many T-cell engagement programs we're advancing through preclinical discovery and development. We look forward to providing an additional CX-904 update later this year. Of course, today's update has been very 904-focused. 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. 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, Operator

Your first question comes from the line of Peter Lawson from Barclays.

Peter Lawson, Analyst

It's really exciting. Do you believe the masking benefit you've noted can also apply to other T-cell engagers? Additionally, based on the responses you've observed so far, do you think there’s something unique about pancreatic cancer, or is it possible to achieve deeper responses in other tissues as well?

Sean McCarthy, CEO and Chairman

Yes, Peter, great questions. Thanks. Regarding the extension and the implications for other programs, we're very optimistic about that potential. We need to start somewhere, and CX-904 is a strong beginning for us. We've gained significant insights from this study. As we've mentioned, both internally and with our partners, we are heavily invested in T-cell engagers. The majority of our partnered work focuses on this area, and we expect to achieve substantial progress in the coming years. As for pancreatic cancer, it's a fascinating topic that we've been thinking about a lot. Pancreatic tumors are typically considered immunologically cold or like an immunologic desert. However, emerging evidence, such as the Roche BioNTech vaccine data recently presented at AACR, suggests the presence of neoantigens in pancreatic cancer along with some immunologic microenvironment. This combined with the presence of EGFR might indicate a unique interaction in this particular tumor type. Nonetheless, this does not imply that other tumors wouldn't respond to CX-904. We're still in the early stages of this study. As Wayne pointed out, the colorectal data we shared today involves all MSS patients, which is another cold tumor type. Progress with T-cell engagers in colorectal cancers has been limited, so we will be exploring combination strategies there. For other tumor types, we're still in very early days. For instance, in lung cancer, we have only two patients in the dose escalation study so far. One of those was treated with a low dose, which may not be significant. We are just beginning the experimentation process. Therefore, we will continue enrolling patients across various tumor types in Phase Ia to explore the pancreatic signal and further define the drug's activity across multiple tumor types over time.

Peter Lawson, Analyst

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

Wayne Chu, Chief Medical Officer

One thing we have not shown, but we continue to evaluate, is the level of EGFR expression as assessed by immunohistochemistry assay. We've been conducting this on a retrospective basis for all the enrolled patients. To date, based on our early data with EGFR measured by this IHC assay, we have not observed a clear association between EGFR expression and the depth of the response. For example, in the two pancreatic cancer patients with a confirmed partial response, one had a moderately high level of EGFR expression by IHC, while the other had a very low level of EGFR expression. Interestingly, it was the patient with the low level of EGFR expression who experienced an 83% reduction in measurable tumor burden.

Sean McCarthy, CEO and Chairman

I think there's still more work to be done there. However, a lot of it also depends on the assay itself. So we'll continue to examine that relationship.

Operator, Operator

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

Roger Song, Analyst

I have a few questions. The first one is about the relationship between dose levels since the effectiveness or antitumor activity doesn't clearly link to the dose. How do you view the trade-off as you increase the dose, going beyond 10 mg to now 15 mg? How do you balance efficacy with CRS, ICANS, and the tolerability profile related to CD3 or EGFR? How confident are you in your ability to continue increasing the dose?

Sean McCarthy, CEO and Chairman

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, were 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. If you look at Amgen's tarlatamab, 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. It will allow us to dose escalate further, and we'll do that and we'll see where it takes us.

Roger Song, Analyst

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

Sean McCarthy, CEO and Chairman

Yes, those are great questions. Let's take a step back and recap our agreement with Amgen. We are currently running the Phase Ia study and sharing data with them as it becomes available. We are also responsible for initiating the Phase Ib once we are ready. The decision to transition from Phase II to Phase Ib will be made jointly with Amgen. Our objective for Phase Ib is to focus on specific EGFR positive tumor types, particularly pancreatic tumors, given the promising signals we have observed. However, since we haven't enrolled many patients in lung or head and neck cancers yet, we want to include a few more patients to gain additional experience in those areas before discussing the Phase Ib strategy with Amgen later this year. The upcoming update may include new data from approximately 10 additional patients that we expect to have by the end of the year, as well as an operational update regarding agreed next steps with Amgen. We need to engage in discussions with them about this. As for their views on the data, I believe it’s best to pose that question to them directly at this time. We are certainly excited about our progress.

Operator, Operator

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

Joseph Catanzaro, Analyst

I guess maybe first one on the EGFR-mediated toxicity that you're seeing. My question is: what do you think is happening? Is that some small amount getting unmasked in the periphery or maybe a small amount getting unmasked in the tumor and then reentering circulation? Is that toxicity 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? I may have one follow-up.

Sean McCarthy, CEO and Chairman

Yes. Joe, thank you for your question. First, I want to express our satisfaction with the very low occurrence of Grade 3 rash in this study. We had only one patient out of 35 experiencing a Grade 3 treatment-related rash, which we consider a significant accomplishment because it opens the door to using this approach to reduce tumors that previously could not be treated with the EGFR. We are encouraged by these results, although it is still early and there is more work ahead. With any drug, there will be some adverse events; it is challenging to determine their origins—whether they are local or systemic is unclear, and we may never fully understand them. However, this uncertainty may not be critical since the focus is on the risk-benefit profile, and we believe we are providing something very important, particularly for patients with advanced pancreatic cancer. Regarding the type of rash observed, the cetuximab rash typically presents as an acneiform rash, which we note in Grade 1 and Grade 2. Additionally, as Wayne pointed out, there are maculopapular rashes that may involve more T cells. We will need to learn more about this, but we aren't concerned because most effects are Grade 1 and 2 across the study. The overall incidence of rash among the 35 patients was 40%, with nearly all cases being Grade 1 or 2 and manageable. Hence, we feel quite positive about the adverse event profile here, not to mention the CRS profile, which honestly exceeded our expectations.

Joseph Catanzaro, Analyst

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 were you able to sort of profile it and see what's going on? Just anything you could say there, I guess, would be interesting.

Wayne Chu, Chief Medical Officer

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 characterized by an over 80% reduction in measurable tumor burden. The patient did progress based on growth of the target lesion and the appearance of, I think, one new target lesion. So that was the nature of the progression for that particular patient. But throughout the treatment course, the patient did quite well clinically. It was just based on the radiographic progression.

Joseph Catanzaro, Analyst

Okay. And then maybe if I could just squeeze in one 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?

Sean McCarthy, CEO and Chairman

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 that is 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.

Operator, Operator

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

Etzer Darout, Analyst

I would like to hear your current thoughts on the step versus non-step dosing, particularly regarding pancreatic patients who have shown a response. How do you envision moving forward with one option or the other as you expand the patient group? Additionally, have you discussed the EGFR expressions among the patients you have seen so far? Will you be looking at EGFR expressions moving forward, or is there a chance to analyze EGFR expression in the individuals already enrolled in the study? I'm not sure if I understood that correctly.

Sean McCarthy, CEO and Chairman

Yes, thank you, Etzer. Regarding our approach moving forward, we have not yet reached a decision on whether to implement step or non-step strategies. However, based on our current experience, it seems more probable that our Phase Ib doses will utilize step strategies, enabling us to achieve significantly higher target doses. We believe there is some dose response involved, and there is more to learn in this area. When considering project Optimus, we will likely incorporate more than one dose and schedule in Phase Ib to gather additional experience with the drug candidate, not just in pancreatic tumors but in other types as well. Concerning EGFR, it's somewhat surprising that the available assays, particularly the IHC assays for EGFR, are not flawless. We are uncertain how much we can rely on them going forward, especially since our initial data suggests this may not be a straightforward ADC scenario where high target levels are essential for activity. Drugs like T-cell engagers are expected to be effective even at low target levels due to their mechanism of tumor destruction, where one T cell can eliminate multiple tumor cells. Therefore, we have more exploration to do, and based on our observations so far, we may not need to prioritize EGFR selection in the future.

Operator, Operator

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

Anupam Rama, Analyst

Can you comment on whether there were any baseline characteristics, such as the number of prior treatments, in the PDAC case study where there were 3 lines of therapy, that might predict a response? Based on the first question, EGFR expression didn't correlate. Also, can you provide information on the duration of the other 3 stable disease patients?

Sean McCarthy, CEO and Chairman

I will address the first question regarding whether there were any patient characteristics that might predict response. To that, I would say no, not really. These patients are generally in the later stages of life. We did show a slide indicating a pretreatment biopsy of a patient with notably high levels of CD8-positive cytotoxic T cells, which is interesting and may have contributed to the response. However, we lack systematic data on this across the entire study, as it is challenging to obtain for every patient. But it is a point of interest. As for the stable disease, Wayne can quickly address that question.

Wayne Chu, Chief Medical Officer

Yes. As we indicated in the swim lane plot during the presentation, several patients were able to maintain stable disease following at least one tumor response, along with a few patients who experienced durable stable disease through tumor responses. However, for other patients, after achieving stable disease, they later progressed to progressive disease.

Sean McCarthy, CEO and Chairman

I believe it's important to reiterate that pancreatic cancer is a very rapidly progressing disease. Most of these patients have had three or four prior treatments. Therefore, we find this data to be really exciting.

Operator, Operator

Your next question comes from the line of Mitchell Kapoor from H.C. Wainwright.

Mitchell Kapoor, Analyst

Congrats on the positive data. I wanted to ask about the total 8 patients with tumor reductions. I guess, if you could just broadly comment on what a spider 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?

Sean McCarthy, CEO and Chairman

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.

Wayne Chu, Chief Medical Officer

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

Operator, Operator

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.

Sean McCarthy, CEO and Chairman

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. As we continue to build our company for the long term to make the biggest difference we can for patients. Thank you very much. Have a good evening.

Operator, Operator

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