CytomX Therapeutics, Inc. (CTMX) Earnings Call Transcript & Summary

Welcome, everyone, to the 40th Annual JPMorgan Healthcare Conference. My name is Anupam Rama. I'm one of the senior biotech analysts here at JPMorgan. I am joined by Caleb Smith, Malcolm Kuno and Priyanka Grover from the team. Our next presenting company is CytomX. And presenting on behalf of the company, we have CEO, Sean McCarthy. [Operator Instructions] With that, Sean, take it away.

Great. Thanks, Anupam, and good afternoon, everyone. I'd like to thank the JPMorgan team for the invitation to present today. It's really a pleasure to be here. Moving to Slide 2. During my presentation today, I will be making certain forward-looking statements, and I refer you to our regulatory filings. Slide 3. So our goal at CytomX is to destroy cancer differently, leveraging our unique approach to the discovery and development of targeted biologic therapeutics. Slide 4. To achieve this bold and ambitious goal, CytomX has pioneered a multi-modality platform for conditional activation and tissue localization of potent biologic drug candidates. Our Probody platform has enormous potential, and we see a very clear value proposition in opening up unparalleled opportunities for more effective and safer cancer therapeutics. We're using our technology to address some of the biggest challenges in cancer biologics R&D, including discovering and clinically validating new targets for antibody drug conjugates; breaking through with T-cell-engaging bispecifics for solid tumors; and expanding the therapeutic window for immunotherapies, including cytokines and checkpoint inhibitors. Slide 5. Our platform is designed to take advantage of a fundamental hallmark of cancer biology. As cancers develop, grow and metastasize, tumor cells release enzymes called proteases that play a key role in tumor cell migration and invasion. CytomX was the first company by a long way to conceive of and reduce the practice, the idea that we could turn cancer protease biology into an Achilles heel and develop an entirely new class of antibody prodrugs that we call Probodies. The concept is that by masking an antibody in such a way that the activity is conditional on proteolytic removal of the mask, we can decrease antibody binding to normal tissue, increase binding to cancer tissue, and in doing so, make more effective and safer cancer therapies. Slide 6. Over the past decade, we have built a highly differentiated company with an integrated business model for long-term value creation through translation of our leading science into meaningful outcomes for people with cancer. Our tunable multi-modality platform has enabled us to build the broadest pipeline by far in our space with 6 INDs filed and 4 assets currently in Phase II clinical studies across 9 different cancer types. We have 4 very strong partnerships with Bristol Myers Squibb, AbbVie, Amgen and Astellas, with whom we have made terrific progress, including the advancement of 3 programs into the clinic with a fourth coming soon. In addition to broadening the reach of our technology, these partnerships have generated more than $0.5 billion of non-dilutive capital, allowing for aggressive investments in our technology and in our pipeline. We continue to maintain a strong balance sheet through a combination of equity-based and non-dilutive financing, and we reported $336 million of cash at the end of Q3 in 2021. Our R&D investments to date have also allowed us to build a formidable intellectual property portfolio with more than 450 issued and pending patents worldwide. Slide 7. I am honored to work with a very strong team at CytomX with a combined 130-plus years of experience in the biopharma industry, including the discovery, development and registration of multiple oncology therapeutics. Next slide. The CytomX team is a team that does what we say we will do as we execute to our vision of becoming a sustainable commercial-stage oncology leader. To this end, we most recently fulfilled our commitments to achieve 2 major milestones by the end of 2021, namely the release of initial clinical data from our ongoing Phase II expansion studies for our CD71-targeting ADC, CX-2029; and the filing of an IND for our first T-cell-engaging Probody, CX-904, which targets EGFR and CD3. Slide 9. CytomX has established conditional activation as a highly strategic area of biologics R&D. In addition to the major pharma partnerships CytomX has formed in recent years, we have seen several recent public company entrants to the space and also the emergence of M&A activity with the recent acquisitions of Maverick by Takeda and Amunix by Sanofi. Conditional activation for tissue localization of biologics is therefore coming of age, and CytomX remains the leader in terms of the breadth of our achievements to date and our ambitious plans for the future. Our ambition is highlighted in the scope and scale of our uniquely broad and deep clinical pipeline highlighted on Slide 10. With 4 assets in 11 Phase II arms across 9 different cancer types, we are well positioned to deliver data sets over the next 12 to 24 months to point the way to potential registrational studies for our lead programs. Our highly productive research engine also continues to generate new programs for entry into the pipeline. Let me just briefly summarize the pipeline, and I'll then review our lead programs in some detail. So our lead asset is the wholly owned program, CX-2009, otherwise known as praluzatamab ravtansine. This is a conditional ADC targeting the novel cell surface protein, CD166, conjugated to the payload DM4, the maytansine payload. And we are currently in a 3-arm Phase II study in breast cancer with initial data expected by the end of this year. Our second asset, also a conditional ADC, is CX-2029. This is targeting CD71, the transferrin receptor. And the payload is MMAE, the auristatin MMAE. We are currently in a 4-arm Phase II expansion study in 4 different tumor types: squamous non-small cell lung, head and neck cancer, esophageal and gastroesophageal junction cancers and DLBCL. This program is partnered in a global co-development relationship with AbbVie, and we anticipate additional data as 2022 progresses. We have a third conditional ADC program in preclinical development, targeting EpCAM, a very high potential target, and we're excited to move this asset forward in due course. Moving to our immunotherapy programs. We have a longstanding collaboration with BMS, the leading edge of which is a CTLA-4-targeting Probody, BMS-986249, which is in a randomized Phase II study in frontline melanoma. I've already mentioned our recently filed IND for our first Probody T-cell-engaging bispecific, targeting EGFR and CD3. And over the last 1 to 2 years, we've also been directing our technology to a very exciting application, which is to improve the therapeutic window of a number of cytokines, including interferon alpha-2b. So the leading platform, the deepest pipeline and the broadest clinical experience with a lot of upcoming data sets over the next 1 to 2 years. So I'll now transition to talking about our lead program, CX-2009, or praluzatamab ravtansine, which, as I mentioned, is a conditional ADC, targeting CD166 conjugated to the maytansine payload, DM4. So I'm now on Slide 12. First of all, let's talk about some characteristics of the CD166 target. CD166 is a multidomain transmembrane protein reported to have several roles in tumor biology, including angiogenesis and cell adhesion and migration. CD 166 is highly expressed on cancer tissues at levels in the same general range as TROP2 and HER2. And as an example here, you can see in the middle of the upper-left panel the high and uniform expression of CD166 in breast cancer. And on the far right, you can see our data from Phase I, showing CD166 is highly expressed in the majority of hormone receptor positive breast cancers and then about half of triple-negative breast cancers. From a functional standpoint, we are the first to have validated that CD166 has the molecular properties to internalize ADCs and kill tumor cells and tumor xenografts. Now the challenge with this tumor antigen is that although it's highly expressed in tumor tissue, it's also highly expressed on many normal tissues, as shown here in the middle of this slide: normal stomach, normal lung and normal liver and many other normal tissues besides. But leveraging our Probody platform, we have successfully targeted CD166 in cancer patients with praluzatamab ravtansine, a conditional ADC designed to effectively target CD166 in tumor tissue but not in normal tissues. Slide 13 shows some of the results from our previously reported Phase I study in which praluzatamab showed clinical activity in several cancer types, including breast cancer and ovarian cancer. Shown here is the clinical activity for breast cancer, the indication that we're currently exploring in detail in Phase II. Meaningful clinical benefit was observed in heavily pretreated patients at doses of 4 milligrams per kilogram and above. Responses were seen in both hormone receptor positive and triple-negative breast cancer. In one hormone receptor positive patient, a complete response was observed in target lesions after more than 40 weeks of treatment. And as we have presented previously, one very advanced patient with triple-negative breast cancer experienced a dramatic response in aggressive skin lesions following progression on sacituzumab govitecan. Clinical benefit rate at 24 weeks was 28%, among the 32 evaluable patients across both breast cancer types. Praluzatamab was generally well tolerated with a toxicity profile consistent with the DM4 payload with ocular toxicities being the most prominent. Based on our Phase I findings, the dose of 7 mg per kg given every 3 weeks was selected as the recommended Phase II dose. Importantly, there were no obvious safety signals in Phase I that were attributable to the target once a binding of the target in normal tissues despite the broad expression of CD166 throughout the body, thereby validating the ability of our platform to open new target space for antibody-drug conjugates. Slide 14 summarizes the design of our ongoing 3-arm breast cancer Phase II study. Arm A is enrolling patients with hormone receptor positive HER2 non-amplified breast cancer for monotherapy treatment. Arm B is enrolling patients with triple-negative breast cancer, also for monotherapy treatment. And arm C is a combination arm, exploring the combination of praluzatamab with our proprietary anti-PD-L1 Probody known as pacmilimab. Our goal is to enroll 40 patients in each arm of this study. For arms B and C, the triple-negative breast cancer arms, we are selecting patients for CD166 expression because, as you saw in one of my earlier slides, about half of TNBC based on our Phase I experience expresses CD166 at high levels. Ocular prophylaxis to manage ocular toxicities was not mandated in Phase I, but it is required in Phase II. And we're using a regimen similar to that used successfully by ImmunoGen in their Phase III studies of mirvetuximab in ovarian cancer. We continue to make good progress with enrollment, and we have 33 sites open. Initial data readouts from arms A and B are anticipated in 2022. Arm C data is anticipated in 2023. In arm C, we are selecting for both PD-L1 and CD166. I'd like to talk for a moment about the positioning of this asset in the 2 indications that we're pursuing in breast cancer from a commercial and competitive standpoint, so starting first with the hormone receptor positive opportunity on Slide 15. As a first-in-class drug candidate against a novel target, we see praluzatamab as having broad potential in the current hormone receptor positive/HER2-negative treatment paradigm. Hormone receptor positive disease comprises about 70% of all breast cancer, and we see significant commercial opportunity in the late-line metastatic setting. We're anticipating that our enrolled patient population in Phase II will be largely in the post chemo setting, where the unmet need continues to be high. In terms of anticipated outcomes from this arm, we'll be particularly focused on the clinical benefit rate at 24 weeks as a surrogate of progression-free survival, which our KOLs emphasize as the most meaningful measure of success with this difficult-to-treat patient population. Moving now to Slide 16 and where we see praluzatamab being initially positioned in triple-negative breast cancer. To characterize the unmet need here, in the ASCENT trial, the basis for sacituzumab's approval in triple-negative breast cancer, the overall response rate in the control chemo arm was 5% with a progression-free survival of about 2 months. With sacituzumab approved in the second-line setting, the third line becomes a significant unmet need. And I want to reemphasize here that one of the partial responses that we observed in our Phase I study was in a patient who had progressed on sacituzumab. Our combination study evaluating praluzatamab with our PD-L1 Probody, pacmilimab, also has potential to move this asset earlier in the treatment paradigm, in addition to other combinations that we plan to explore as this program advances. Moving now to our second clinical stage ADC program, CX-2029, which is a first-in-class, MMAE-conjugated, conditional ADC targeting CD71, the transferrin receptor. As described here on Slide 18, CD71 has been recognized for decades as an attractive target for the delivery of therapeutics into cancer tissue because of the efficiency with which it can transport antibodies and drug candidates into cancer cells. CD71 is highly expressed in many solid and hematologic tumors and has ideal properties as an ADC target, except for its expression on many normal tissues, including the hematologic compartment. This makes the development of a conventional ADC to CD71 impossible. And in fact, we have demonstrated that a conventional ADC to CD71 is lethally toxic in animal models. Moving to Slide 19. We have demonstrated in a dose-escalation study published earlier this year in Clinical Cancer Research that using our technology, CD71 can indeed be a viable tumor target. We are the first to have reached therapeutically active levels of a CD71-targeted ADC in patients, leveraging our Probody approach. Shown here is the clinical activity observed at doses of 2 milligrams per kilogram and above in late-stage refractory squamous non-small cell lung and head and neck cancers. This antitumor activity in 2 very difficult late-line settings is now being further explored in our ongoing Phase II expansion study at the recommended Phase II dose of 3 mg per kg. In Phase I, CX-2029 was generally well tolerated with the most frequent grade 3 and above adverse event being anemia. Anemia was managed with red blood cell transfusions, dose reductions and dose delays. Our ongoing Phase II expansion study design is summarized here on Slide 20. Our goal is to enroll 25 efficacy-evaluable patients per cohort in 4 tumor types: squamous non-small cell lung cancer and head and neck squamous cell carcinoma, where we observed clinical activity in Phase I; esophageal and gastroesophageal junction cancers and DLBCL, these being indications with strong preclinical activity selected by CytomX and our partner, AbbVie. For the lung, head and neck and esophageal cohorts, patients are required to have experienced prior platinum-based chemotherapy and a checkpoint inhibitor. Moving now to Slide 21. We were very pleased to report at the end of 2021, as planned, interim Phase II data from the first 2 CX-2029 expansion cohorts, starting with squamous non-small cell lung cancer. With 16 efficacy-evaluable patients enrolled as of the October 2021 data cutoff, we reported an ORR of 18.8% and a disease control rate of 87.5%. All 16 patients were heavily pretreated and checkpoint inhibitor experienced. This was an unselected patient population for target expression. Given the interim nature of this update, duration of response was not fully characterized. Although of the 3 partial responses seen to date, 1 response had a duration of 5.6 months and the other 2 patients remained on treatment at the time of the data cutoff. To put these preliminary monotherapy results into the context of the current treatment landscape for squamous lung cancer, several randomized studies conducted in the second- or third-line setting have reported ORRs to docetaxel of between 8% and 11% and notably in patients who were checkpoint inhibitor-naive. As an additional reference point for nivolumab approved by the FDA in 2015 for the treatment of squamous lung cancer, reported overall response rates were 20% and 12.8% in the second- and third-line settings, respectively. Given the prior treatment regimens and the unselected nature of the study population, we're encouraged by the activity in patients with squamous lung cancer, and we remain focused on completing enrollment of 25 efficacy-evaluable patients as this year progresses. Moving on briefly to head and neck cancer. This expansion cohort was fully enrolled by the reported data cutoff with 25 patients being efficacy-evaluable. We observed 1 confirmed partial response at the time of the data cutoff for an objective response rate of 4%. The disease control rate was 56%. This again was a heavily pretreated patient population with a median of 3 prior therapies, and enrollment into the head and neck cohort is closed with additional follow-up ongoing. The tolerability profile of CX-2029 in the expansion phase has continued to be consistent with that reported from the Phase I -- from our Phase I experience with no new safety signals identified. As with our Phase I experience, the most common grade 3 and above treatment-related adverse event in the 52 patients that received at least one dose of CX-2029 at 3 mg per kg was anemia, which continue to be managed with red blood cell transfusions, dose delays and dose reductions. Importantly, none of the responding patients discontinue treatment for anemia. Moving to Slide 22. In summary, we are encouraged by the clinical activity observed with CX-2029 in patients with refractory squamous lung cancer. Given the lack of therapeutic options in the post checkpoint inhibitor setting for this cancer type, we believe these initial Phase II results bring into focus a potentially significant initial commercial opportunity for CX-2029 as a monotherapy, together with the potential combination strategies, including checkpoint inhibitors, to bring this agent into earlier lines of therapy. We look forward to completing the CX-2029 expansion phase in 2022, and we continue to work closely with our partner, AbbVie, to map out next steps. As I mentioned a little earlier, in addition to progressing our most mature clinical assets, CytomX continues to advance new programs into development as we explore the full range and potential of our multi-modality platform. Our most recent addition to the clinical pipeline is CX-904, our first Probody T-cell-engaging bispecific, targeting EGFR and CD3. So moving to Slide 24. We're really excited about the potential for our platform to address the biggest challenge in the bispecific field today, which is to bring these highly potent therapies into the solid tumor realm. T-cell-engaging bispecifics have tremendous potential for the treatment of solid tumors by directing T cells against tumor antigens into the tumor. But the biggest challenge is that the extraordinarily high potency of these agents means that therapeutic window can be very, very narrow when target is present on normal tissues. So the CytomX Probody platform is ideally suited to taking this challenge head-on by decreasing engagement of T-cell engagers in normal tissues. We have several active programs in the space, ourselves and with our partners, Amgen and Astellas, and CX-904 is the first to enter the clinic. Slide 25 just provides a little bit more background on EGFR, which is, of course, a very well-understood and widely targeted tumor antigen and one of the most frequently altered oncogenes in solid tumors. Multiple anti-EGFR monoclonal antibodies are approved, but our conditionally activated EGFR-CD3 has the potential to unlock broad opportunities for targeting EGFR in many EGFR-expressing cancers and potentially cancers that express EGFR at both high and low levels. Slide 26 just summarizes some of our previously reported lead optimization work that led to the selection of CX-904 as our clinical candidate. Our masked EGFR-CD3 T-cell engagers show several key pharmacologic properties that we believe will be important for successful translation into the clinic, including substantially improved tolerability relative to unmasked T-cell bispecifics, extended half-life and highly potent tumor regressions. The CX-904 IND was filed, as planned, late last year, and we plan to initiate a first-in-human Phase I dose-escalation study in the first half of this year. Before closing, I would like to spend a few moments on Slide 28, just revisiting our clinical pipeline and making a few comments on our ongoing collaboration with BMS and specifically the development of the ipilimumab Probody, BMS-986249 which targets CTLA-4. The recent publication of 6.5-year follow-up data from CheckMate 067 reported median survival on the ipi/nivo arm being double that of nivo monotherapy. And treatment-free survival was the longest reported in any solid tumor immuno-oncology study, underscoring the importance of CTLA-4 and the potential for safer, more effective CTLA-4 therapeutics to broaden the impact of this foundational combination. Building on a successful Phase I study of our ipilimumab Probody reported at ASCO 2020, BMS is currently running a randomized Phase II study, evaluating 249 in frontline metastatic melanoma. This important study is directly comparing ipi/nivo to Probody ipi/nivo. Enrollment continues, and we look forward to data in due course. In closing, on Slide 29, CytomX continued to extend our leadership position and make broad progress throughout 2021, and we look forward to a highly productive 2022. The key milestones that we're executing towards are initial data for praluzatamab ravtansine in our ongoing 3-arm Phase II breast cancer study and specifically from arms A and B; additional data from the expansion phase for CX-2029, including completion of this stage of the drug's development and new data updates and particularly completion of the squamous non-small cell lung cohort; clinical initiation for dose escalation for CX-904, our T-cell-engaging bispecific to EGFR and CD3; and continued early-stage pipeline progress, including with our broad-based cytokine program that we introduced at SITC in 2021. So thank you very much for your time today, and I believe we will open up for a few questions.

Yes. [Operator Instructions] We actually have a couple of questions on the portal, which really relate to the trial design. There's actually 2 of them. So are all the breast cancer trials pre-radiation? Can you walk us through the process for the patient diagnosis and then surgery and for some chemo then? And then do the trials preclude those who take aromatase inhibitors?

Yes, good question. So as I mentioned in my comments, the study is enrolling patients who are at the chemo stage of their treatments. They would have gone through hormonal therapy. They would have gone through potentially additional second-line therapies and progressed on to chemotherapy. So we're expecting that the patient population will be chemo-experienced, probably 1 to 2 chemo regimens. And to the best of my knowledge, aromatase inhibitors are not excluded. It's possible that patients will be experienced on aromatase inhibitors.

Maybe for 2009 here, the guidance is broadly for 2022 for an update. You've talked about opening additional sites globally and pushing enrollment. How are you thinking about enrollment curve now? You've got a new variant that you're dealing with, all of us are dealing with. How do we think about that and maybe when we might get some more granularity on time lines?

Yes. So right now, the guidance is 2022. As I mentioned, the team has made terrific progress in the second half of last year with 33 sites open, which is really terrific. We reported on our Q3 earnings call last year that the enrollment had really picked up during Q3. That continued during Q4, so we're making solid progress. We're maintaining -- we're giving ourselves some breathing room here on the time line because who knows what's coming next with COVID and the pandemic, but we are continuing to make good progress.

And then for 2009 here, you've talked about part A, part -- or arm A, arm B results this year, the monotherapy arms. Maybe you could talk about when you flip the card, the size and the scope of the data that you might be getting, the key endpoints, what's the benchmark for success here?

Yes. So just to recap, let's take triple-negative first. With the approval of sacituzumab in the U.S. and the anticipated approval ex U.S., we point to the data from the ASCENT study, which was the trial that led to the approval of saci in the second-line setting in breast cancer as providing some important benchmarks. So first of all, of course, the response rate of sacituzumab in that study was about -- was in the mid-30% range. The control arm, the chemo control arm showed a response rate of about 5%. So in patients that are -- assuming that will be, for the most part, in the post-sacituzumab setting, patients who have progressed on sacituzumab, the chemo -- it would be expected that their chemo response will be 5%, potentially even lower. So the bar is low. We obviously want to see a significant response rate to move the drug forward, but the benchmark there and the unmet need is really high. It's a very rapidly progressing disease. And as I've mentioned a couple of times in the presentation, we were very encouraged to see in Phase I a patient with highly aggressive disease post sacituzumab who mounted a deep response to praluzatamab in the Phase I setting. Duration of response, again in the post-sacituzumab setting with chemo, would be expected to be just a couple of months, and so several months of clinical benefit would be an achievement, we believe. In the hormone receptor positive setting, we -- as we talked to our advisers and Sara Tolaney spoke to this at our analyst event last year, we see clinical benefit rate, specifically CBR24, as being probably the most important benchmark in metastatic, late-stage, post chemo hormone receptor positive disease. And looking for a CBR24 of 30% in that range would be, we think, very successful in hormone receptor positive.

Can you talk about the ocular tox that's been observed and what you're doing -- what the prophylaxis regimen is in Phase II?

Yes. So we're using a regimen that's very similar to what ImmunoGen has used in their successfully, I should say, in their Phase III studies. So it's steroidal eye drops, vasoconstricting eye drops. It's cold compresses on the eyes actually during the infusion of the drug. And it's actually interesting to note that, in fact, in the most recently reported data from ImmunoGen in the SORAYA study in ovarian cancer, they demonstrated they have a really pretty good handle on management of ocular toxicity using this kind of regimen where they saw the most common treatment-related adverse event was blurred vision: 41%, all grade; 6%, grade 3 and above. So these prophylactic measures have been shown to work, and that's what we're implementing -- we're mandating in the Phase II study.

Maybe a question here on 2029. Just on back of the December update, I think there continues to be concerns on anemia signal observed. What can be done to kind of better control this AE? Maybe -- or maybe you can put the AE in the context of the patient population enrolled.

Yes. So I think, as we've commented previously, the anemia is predictable, we believe manageable and reversible. The experience in the Phase II expansion has been very similar and very consistent with our experience in the Phase I setting in terms of its onset, in terms of the frequency with which we see grade 3 and above anemia. It's manageable with dose reductions, dose delays and red blood cell transfusions. As I mentioned, no patients who responded discontinued for anemia, and our overall discontinuation rate in the study was low at 5.8% so far. So we will continue to learn more about how to manage and mitigate anemia. We have more work to do to understand the potential for erythrocyte-stimulating growth factors. We have more than 20 patients who have experienced. Now we need to analyze that data in a lot more detail to determine any potential benefit, and we continue to look for -- we continue to learn and look for other ways to manage anemia moving forward. But I should stress that our clinical experience, thus far, is that anemia has not been a barrier to the progression of this drug candidate and to seeing encouraging clinical activity in several tumor types.

Maybe a final question for me, which is what are the gating factors to the CX-904 Phase I study initiation?

Yes. So absolutely thrilled at the IND. We obviously did a great job getting that done at the end of last year. So we're in the review period with the agency, and we're hopeful that this study will be up and running first half of the year. So gating factors really are IND clearance and site initiations and all the usual stuff to get those first patients on.

Great. Okay, Sean, well, I want to thank you so much for a super productive session. And I hope you have a great rest of the conference. I hope that listeners have a great rest of the conference.

Yes. Great. Thanks a lot, Anupam. Take care. Thank you very much.

Yes. Thanks.