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

Good day, ladies and gentlemen. And welcome to the CytomX Therapeutics review of ASCO20 Virtual Scientific Program presentations. [Operator Instructions] As a reminder, this call will be recorded. I would now like to introduce your host for today's conference, Christopher Keenan, Vice President of Investor Relations. Chris, you may begin.

Thank you, Andrew. Good afternoon. And thank you all for joining. This morning, we issued a press release highlighting the 7 presentations made by CytomX and our partners as part of the Annual Society of Clinical Oncology's ASCO20 Virtual Scientific Program. The press release can be found under the Investors and News section of our website at cytomx.com, as will also be a recording of this call. During today's 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 public filings -- most recent public filings with the SEC sec.gov. We undertake no obligation to update any forward-looking statements, whether as a result of new information, future developments or otherwise. Turning to our agenda on Slide 3. I'm pleased to be joined today by CytomX President, Chief Executive Officer and Chairman, Dr. Sean McCarthy; Dr. Amy Peterson, CytomX' Chief Development Officer; and Dr. Alison Hannah, CytomX' Chief Medical Officer. Sean will open the meeting with a brief company overview. Alison will then provide commentary on the presentations from our potentially first-in-class programs, the Probody drug conjugates, CX-2029 and CX-2009. Amy will then discuss today's data from our potentially best-in-class programs, the Probody therapeutics, CX-072 and BMS-986249. Sean will wrap up with some concluding remarks before opening up the call to questions. I would like to turn the call now over to Sean.

Great. Thanks a lot, Chris, and good afternoon, everyone. Thanks for joining. It's a pleasure to have the opportunity to review our ASCO 2020 presentations with you all. What we'd like to do over the next hour or so is to put our presentations today into broader context, discuss their significance and also review next steps for the pipeline. We're currently very focused on using our unique Probody technology to address first-in-class undruggable targets to develop novel anticancer agents, with single-agent therapeutic activity. We also continue to advance potentially best-in-class cancer immunotherapies. Moving to Slide 4. Let me start with a brief recap of our pipeline with a focus on our later-stage programs. We currently have 4 assets in or moving towards Phase II studies. These are the potentially first-in-class drug candidates, CX-2009 and CX-2029 that target CD166 and CD71, respectively, both previously considered as undruggable targets. Also, CX-072 and BMS-986249, respectively, Probodies directed against the checkpoint targets, PD-L1 and CTLA-4. Moving to Slide 5. Our lead programs have been the subject of 7 presentations at ASCO today. Dr. Melissa Johnson of the Sarah Cannon Research Institute at Tennessee Oncology presented our Phase I data for CX-2029. This presentation was also discussed by Dr. Geoffrey Shapiro of the Dana-Farber Cancer Institute. Dr. Valentina Boni of START Madrid reviewed a poster describing our latest experience with CX-2009, with a particular focus on our findings in breast cancer. Dr. Mark Stroh of CytomX also presented a poster with preliminary clinical PK findings that support the selection of our Phase II dose for this asset. Turning to our cancer immunotherapy programs. On behalf of Bristol-Myers Squibb, Dr. Martin Gutierrez of the Hackensack University Medical Center, presented a poster describing the Phase I safety data for the anti-CTLA-4 Probody, BMS-986249. And Dr. Fiona Thistlethwaite take of The Christie NHS Foundation Trust, University of Manchester, U.K., delivered an oral presentation updating our clinical experience with the anti-PD-L1 Probody CX-072. This presentation was discussed by Dr. Sandip Patel of UC San Diego Medical Center; and CytomX scientist, Dr. Mark Stroh and Dr. Susan Lyman also presented updated translational and clinical pharmacology data for CX-072 in 2 additional poster presentations. Turning to Slide 6. Taken together, the updates presented today show broad progress across our pipeline and comprise a growing body of evidence that the Probody platform can unlock potential in undruggable targets and enhance the clinical profiles of immune checkpoint inhibition. The Phase I data presented today on CX-2029, underpin the recent $40 million milestone we received from AbbVie to advance this asset into Phase II expansion studies. This target is probably the most stringent test yet of our technology, since we know this is an unmasked antibody drug conjugate to CD71 shows lethal toxicities. And we and AbbVie are encouraged by our findings so far with this program. Regarding our partnership with AbbVie, just a reminder that we are in a global co-development arrangement which includes 35% of U.S. commercial rights retained by CytomX should this program ultimately reach the market. Our update today on CX-2009 underscores the activity we have seen for this potentially first-in-class asset in breast cancer and our Phase II strategy for this program. This program remains wholly owned by CytomX. Regarding our checkpoint inhibitor programs, as you will hear, the BMS safety data presented today for the ipi Probody supports their recent advancement of the program into Phase II and our comprehensive update on CX-072 reinforces the fact that the Probody platform can result in durable clinical benefit across multiple cancer types with a favorable tolerability profile that has the potential to enable combination therapies. Let me now hand over to Alison Hannah, our Chief Medical Officer, who will review CX-2029 and CX-2009; and then to our Chief Development Officer, Amy Peterson, who will review the BMS program and CX-072. I'll then return for some concluding remarks, and we'll then move to Q&A.

Thank you, Sean. Can we advance to Slide 8, please? I will be reviewing 2 presentations that have been published earlier today on the virtual ASCO website. These presentations describe 2 first-in-human clinical trials of CytomX' Probody drug conjugates: the first, CX-2029, targeting the transferrin receptor or CD71; and CX-2009, targeting ALCAM, also known as CD166, both of these receptors were considered to be previously undruggable targets given their high expression on normal cells. Next slide. The first presentation was made by Dr. Melissa Johnson with Sarah Cannon Research Institute and Geoffrey Shapiro of Dana-Farber provided his review of these study results. Next slide, the transferrin receptor is an attractive anticancer target for a Probody therapeutic given its high degree of expression on a variety of malignancies. This receptor is one of many proteins upregulated in cancer cells and promotes iron import and can expand available intracellular iron that can participate in DNA synthesis, DNA repair and energy generation. CD71 expression in normal cells prohibits development of a traditional antibody drug conjugate due to lethal on target toxicity. CytomX has designed a prodrug antibody that remains inactive in the periphery with activation in the tumor microenvironment by tumor-associated proteases. Next slide. CX-2029 consists of an immunoglobulin, directed against CD71, a mask that substantially reduces binding to normal tissue. And finally, a substrate to be cleaved by tumor-associated proteases. This antibody is conjugated to a potent microtubule toxin called monomethyl auristatin E, with a drug antibody ratio of approximately 2. Probody technology masks the antibody to prevent activation in the periphery. I would note that it does not mask the payload. We expect to see hematological toxicity for this payload toxin. Next slide. CD71 is expressed in normal tissues with the highest expression levels in bone marrow and immune cells. Using immunohistochemistry, CytomX investigated expression levels in a variety of malignancies. High levels are observed in many tumor types, including tumors of squamous histology, such as cervical, esophageal, head and neck and lung. Next slide. Dr. Johnson and colleagues conducted a Phase I dose escalating trial in 45 patients over 8 dose levels. The starting dose was conservatively chosen. Dose escalation followed standard 3x3 rules. Eligibility criteria were typical for a first-in-human trial. Patients were not prospectively selected for CD71 positivity, however, archival tissue was requested in order to investigate expression patterns and possible correlations with response. Of note, nonclinical data, both PK and nonhuman primate toxicology predicted a likely range in which biological activity might be observed between 2 and 4 mgs per kg. The Maxim administered dose of 5 mgs per kg was not expanded as 2 out of the first 4 patients experienced cycle 1 dose-limiting toxicity. The lower dose of 4, although initially considered tolerable in the first 3 patients, was subsequently also determined to be too high a dose with 2 out of 6 patients experiencing DLT. Dose levels of 2 and 3 were subsequently expanded to better describe the safety profile of CX-2029. Next slide. Demographics were not unexpected for a Phase I trial. Most patients had slightly impaired performance status. Patients had received a median of 3 prior anticancer regimens with a maximum of 16. Approximately 1/3 of each had high or low or unknown CD71 expression by immunohistochemistry using an antibody proprietary to CytomX. The median exposure was 9 weeks. Next slide. Common toxicities are listed on this slide. Infusion related reactions, although frequently observed, were managed with supportive care and typically occurred only with the first infusion. MMAE payload associated toxicities were seen, including dose-dependent anemia and neutropenia. On the next slide, you'll see severe toxicities, and these were also most commonly, anemia and neutropenia. Patients were typically managed with red blood cell transfusion and/or supportive care, with a median of 2 transfusions administered per patient. The etiology of the anemia is under active investigation. It is likely to be multifactorial in nature, including both MMAE associated toxicity as well as on target toxicity, given the CD71 expression in red blood cell precursors in bone marrow. Next slide, we show the plasma concentration time profile of the intact or the masked CX-2029. As designed, the MMAE payload remains largely conjugated in the peripheral compartment to the antibody, with approximately 4% of MMAE circulating freely. Next slide. We show 2 spider plots. On the left, we depict patients low doses, and on the right doses between 2 and 5 mgs per kg. At the lower doses, tumors in most patients progressed at the first or second scan. 1 patient with ocular melanoma treated at 0.5 mgs per kg had stable disease for 36 weeks. At the higher doses, patients with partial responses are shown with golden triangles. We get both partial responses and some long-term stable disease. On the next slide, the waterfall plot, you see 3 patients shown to have had confirmed partial responses, 2 with squamous non-small cell lung cancer and 1 with squamous head and neck cancer. Of note, activity was predominantly seen in patients whose tumors were of squamous histology. Many of the tumor types represented on the left side of the waterfall plot would be considered less likely to respond to a microtubular inhibitor, such as colorectal cancer or hepatocellular carcinoma. Next slide. I will be showing you 2 case studies today. The first had been previously presented by Dr. Johnson. This is a 75-year old gentleman with squamous non-small cell lung cancer who had been diagnosed about 3 years prior to study entry. The patient had received standard of care for his malignancy, carboplatin, paclitaxel, combined with radiation, followed by durvalumab in the adjuvant setting, gemcitabine the docetaxel, ramucirumab for metastatic disease. The patient experienced a partial response initially seen at week 8 and confirmed at week 16. On the CT scans, you can see resolution of both target and nontarget or nonmeasurable disease in the lung metastasis of this patient. Here is a second case study. This is a 66-year old gentleman with head and neck carcinoma, specifically nasopharyngeal, diagnosed about 2 years prior to study entry. His prior therapy would also be considered typical for his malignancy consisting of docetaxel, 5FU and cisplatin with radiation, followed by high dose cisplatin. The patient subsequently received pembrolizumab combined with an investigational agent. The patient had a single target lesion in the liver at baseline. This visceral lesion was found to have decreased in size by 43% of the week 8 scan and again further diminished at the week 16 scan by 78% compared to baseline. In summary, this 45 patient first-in-human trial of the CytomX' Probody therapeutic validates the transferrin receptor as a viable therapeutic target in patients with advanced malignancies. We were able to define a tolerable dose for this agent with signs of clinical activity. There are hematologic dose-dependent toxicities with anemia being the most commonly severe toxicity. CytomX will continue to investigate the etiology of this toxicity. CX-2029 at a dose of 3 mgs per kg will be further evaluated in dose expansion cohorts, including patients with head and neck squamous carcinoma, squamous non-small cell lung cancer, diffuse large B-cell lymphoma and esophageal carcinoma. Next slide, please? My second presentation today will focus on a poster whose lead author is Valentina Boni of START Madrid. Slide 24. CD166, or ALCAM, is a transmembrane protein that functions as a junctional adhesion molecule, facilitating cell migration, differentiation and hematopoiesis. It is both broadly and highly expressed as a tumor antigen while also observed in many normal tissue, again, making the Probody approach essential in order to safely target this receptor. CX-2009 is a proprietary anti CD166 antibody coupled to DM4 [indiscernible] payload. DM4 is a well-characterized microtubule inhibitor active against a variety of cancers, whose toxicity profile is well-known and includes ocular, neuropathic and hepatic toxicity. Slide 25 shows the CD166 expression pattern by immunohistochemistry in a variety of malignancies. You will see that expression in breast cancer has been highlighted in this figure. On the right side of the slide, we show immunohistochemistry data generated from this Phase I trial using a CytomX antibody in 2 subtypes of breast cancer. CD166 expression is high, greater than 80% for the hormone receptor positive HER2-negative breast cancer patients and approximately 50% for patients with triple-negative breast cancer. Next slide. Dr. Boni presented results from a Phase I dose escalating trial starting at a dose of 0.25 mgs per kg, escalating over 11 dose levels to 10 mgs per kg in patients with advanced solid tumor malignancies. 86 patients were treated when CX-2009 was administered every 3 weeks. An additional 10 patients received CX-2009 every 2 weeks. Their demographics are shown here. The most common malignancy was breast cancer. The demographics of this specific group, which is now limited to hormone receptor positive and triple-negative breast cancer are separately presented. As you can see, the expression of CD166 was high, 6 out of 11 patients with triple-negative breast cancer, 23 out of 25 patients with hormone receptor positive breast cancer. The median number of prior regimens was 7. Most TNBC patients have received prior platinum. Most hormone receptor positive patients had received prior CDK4/6 inhibitor. Median number of doses was 2. In the next slide, we show you a summary of adverse events. No dose-limiting toxicity was observed up to a dose of 7 mgs per kg. Doses of 8 mgs per kg and higher were not considered tolerable doses for future study, primarily due to ocular toxicity. Ocular prophylaxis was not incorporated into the trial until the 8 mgs per kg dose level. At first, prophylaxis was optional, and subsequently, the use of ocular prophylaxis became mandatory. Going forward, all patients will receive mandatory ocular prophylaxis, consisting of ophthalmic steroid and vasoconstrictor eye drops, as well as cold compresses during the infusion. Given this toxicity profile here, including no treatment-related discontinuations due to treatment-related adverse events at the 7 mgs per kg dose. We selected this dose as the recommended Phase II dose for future study. Slide 28 shows 4 waterfall plots. In patients receiving doses of 4 mgs or higher, including patients with breast cancer, we see both the hormone receptor positive and TNBC represented in different colors on the left. We show head and neck squamous cell, non-small cell lung cancer and ovarian cancer. Target lesion reductions were observed in all these tumor types. Slide 29 focuses on the breast cancer population treated at 4 mgs per kg or higher. We see unconfirmed partial responses in 8 evaluable TNBC patients and 2 confirmed partial responses in the 18 evaluable hormone receptor positive patients. The overall CBR 24 was 35%. Slide 30 shows the spider plot of the breast cancer patients, again, treated at 4 mgs per kg or higher. Partial responses are depicted using a blue square. Most partial reposes occurred early, but 1 response was observed at 40 weeks. There are also some interesting stable disease patients with tumor control out to 8 to 12 months. In summary, similar to CX-2029, this is a second example of a CytomX first-in-human trial, whose results validate a novel target, CD166, as a viable therapeutic target for patients with advanced malignancies. Probody agent targeting CD166, a previously undruggable ADC target, can be safely administered with toxicities likely secondary to DM4. The dose of 7 mgs per kg administered every 3 weeks will go forward as the recommended Phase II dose. We observed confirmed partial responses and clinically meaningful disease control in patients with 2 types of breast cancer. CX-2009 is currently explored as monotherapy in patients with hormone receptor positive HER2-negative breast cancer. In addition, this agent will also be evaluated as monotherapy and in combination with a checkpoint inhibitor, CX-072, a CytomX anti-PD-L1 Probody in patients with triple-negative breast cancer. I will now pass today's presentation over to Dr. Amy Peterson.

Thank you, Alison. I will be taking you briefly through some of the highlights from the presentation pertaining to IO Probody therapeutics, starting with BMS' presentation on BMS-986249, a Probody to ipilimumab, which I will refer to as 249. Next slide. As a reminder that there are 2 Probody therapeutics in development by BMS that masked CTLA-4. 249 is basically masked ipilimumab. Data from the Phase I dose escalation study was presented today by Dr. Martin Gutierrez at Poster 19. 249 is currently being assessed in a large randomized Phase II study testing 3 different doses in combination with nivo versus nivo with or without ipilimumab. The other Probody, data for which will be presented at AACR is BMS-986288. This is a masked version of non-fucosylated ipilimumab, which I will not be discussing further today. On Slide 34, I will try to briefly summarize the key points from a rather data-rich presentation of the Phase I dose escalation study. This study was designed primarily to assess the tolerability and pharmacokinetics of 249 as a monotherapy or in combination with 480 milligrams of nivolumab given every 4 weeks. Monotherapy evaluated 5 fixed-dose levels approximating 3, 10, 20 and even 30 mgs per kg of ipi. Of particular interest is that doses equivalent to intolerable or never even attempted, doses of ipilimumab were tolerated using our Probody approach. Across all dose levels, only 10% of patients discontinued for a treatment-related adverse event and only 23% experienced a Grade 3 or 4 treatment-related adverse event. Immune-related adverse event, especially high-grade were also infrequent. There were none reported at 240 milligrams nor were there any Grade 3 treatment-related adverse events at this dose. At 1,600 milligrams or approximately 20 mgs per kg of ipi, given on a 8-week schedule, again, there were no immune-mediated adverse events of any grade. And only 1 Grade 4 event of hyponatremia, also a DLT, was reported. Only 1 additional DLT across all dose cohorts, a Grade 3 diarrhea was observed. In the combination cohort, 4 different dose levels of 249 were evaluated, approximating 3, 10 or 15 mgs per kg of ipi. The starting dose in the Phase Ib administered full doses of nivo with a 249 dose approximating 3 mgs per kg of ipi. I will remind you that 50% of patients receiving ipi 3 plus nivo 3 experienced a DLT exceeding the maximum tolerated dose in the original Phase Ib reported in 2013 by [indiscernible] and colleagues. Using a Probody approach, doses up to 1,200 milligrams or 15 mgs per kg of ipi could be combined with full doses of nivo. Only 9% of patients who discontinued treatment did so for a treatment-related toxicity. And of the 31 patients receiving full dose nivo plus the dose equivalent of 10 or 15 mgs per kg of ipi, only 2 experienced Grade 3, 4 immune-mediated events, and both were hepatitis. The majority of immune-mediated events were low grade. No new safety signals were reported. Slide 35 highlights some key conclusions. Specifically, the PK profile of 249 at 240 mgs and 800 mgs was similar to that of ipi 3 and 10. The safety profile of 249 enabled testing of higher doses than previously tested with ipi, both as monotherapy and in combination with nivo. The incidence of high-grade events support that the Probody platform works as designed, allowing higher levels of CTLA-4 exposure in the tumor while sparing systemic and immune-mediated toxicities and provides further confidence for additional clinical evaluation as is underway in the randomized Phase II study in advanced melanoma. I would now like to focus on data presented on CX-072, our Probody to PD-L1. Slide 37, please. As Sean has already described, 3 presentations were released today on this molecule, including an oral presentation by Fiona Thistlethwaite of The Christie in the U.K., describing updated clinical data from the Phase I/II study, plus 2 additional poster presentations, one describing translational data, the other describing the population PK. Next, Slide 38. The design of the study has been previously presented and is shown on the right on the next -- on this slide. A total of 178 patients were enrolled in either monotherapy cohorts or in combination dose cohort with ipilimumab. Before going into the clinical update, I will first show a few highlights from Susan's translational poster. Slide 39, please? One of the questions we commonly get is whether the Probody mask comes off in the tumor. The answer is yes, and it's quite clearly demonstrated on the left-hand graph. Open symbols are intact, CX-072, blue represents active CX-072. At 10 milligrams per kilogram, the Phase II dose, all tumor samples tested had measurable levels of active CX-072. And on a log scale, detectable levels of active CX-072 increased with dose. Not all tumors tested had measurable amounts of activated Probody, this could be due to the technical limitations of the assay, but please also keep in mind that these data represent a snapshot in time in a single metastatic site. Nonetheless, the data clearly demonstrate that unmasking of CX-072 occurs in patient tumors, an important proof-of-concept for the Probody platform to estimate whether there's sufficient activation to achieve intended blockade of the PD-L1 pathway we calculate the target occupancy of PD-L1, and you can see on the right that at 3 mgs per kg or higher target occupancy was nearly 100%. Slide 40. We next assessed weather activation and saturation would result in the expected biologic effect of inducing an antitumor T-cell response, 11 of 18 paired tumor biopsies showed an increase in CD8 positive killer T-cells following initiation of treatment with CX-072. This slide shows the increased staining of the CD8 positive T-cells, the brown cell in 3 patients following initiation of treatment. There were other interesting analytics measures, I would encourage you to review Susan's presentation in detail. Next slide, please? I will now focus on Fiona's presentation of the updated results from our Phase I/II study. Specifically, the presentation will focus on the 114 patients with 1 of 7 tumor types listed on the left who were enrolled in the Phase II monotherapy expansion arm and the 27 patients enrolled in the Phase I dose escalation arm examining ipilimumab every 3 weeks for 4 doses plus continuous CX-072 at the indicated doses. The presentation is built on previously reported findings presented by Dr. Ang Meng in 2019 and provides both an update on the activity observed in these arms as well as a deeper dive into the tolerability profile observed in patients who received at least 6 months of treatment with CX-072, referred to as long-term treatment. Slide 42, on demographics, shows the breakdown between short and long-term treated patients. 80 of the 114 treated with monotherapy received a short-term treatment, whereas 34 patients were able to tolerate treatment exceeding 6 months in duration. The third and fourth column show that 21 short-term and 6 long-term patients treated with the combination. Median prior treatments range from 2 to 4, more heavily pretreated being in the combination arm. Tumor PD-L1 expression was low or not detectable in a significant portion of the patients. The combination arm enrolled a highly heterogeneous group of tumor types. Remarkably, long durations of exposure to CX-072 were observed in the long-term patients. 11.3 months for the 34 long-term monotherapy patients and 21.3 months in the 6 long-term combination patients. Slide 43 highlights the antitumor activity that can be observed or that was observed in the 114 patients treated with monotherapy who had IO sensitive tumors like anal or cutaneous squamous cell carcinoma, on the far left, triple-negative breast cancer and tumors with high mutational burden, representing a variety of tumor types as indicated across the top row. Where signs of activity were seen in less IO sensitive tumors depicted in the 3 right-hand plots. The spider plot below each waterfall highlight that responses were generally durable, stars indicate patients that are still on treatment. Slide 44 shows the deepest responses on the left and the duration of response on the right in the 21 response evaluable patients treated with the combination. The combination was active in a variety of tumor types, including those that are historically less sensitive to checkpoint inhibitors. Responses were durable, and continue to deepen, following the completion of ipilimumab at week 12 suggesting further benefit from ongoing treatment with CX-072. 1 patient with anal squamous cell carcinoma achieved a CR at 9 months and remained in complete remission at 2.5 years. Drilling down now in Slide 45, into the 2 groups, and focusing on the tolerability profile between long-term and short-term treatment group, we can see that Grade 3 or 4 treatment-related adverse events on monotherapy were relatively rare, 10% and 6% in short and long-term treatment groups, respectively. Colitis, commonly observed with ipi, was only reported in short-term combination groups. And all of the high-grade events reported in the 6 patients in the last column on this slide actually occurred within the first 6 months of their treatment. These were not late onset events. The rates of CX-072 discontinuation due to adverse events are not shown here, but were part of the presentation, and were low. Slide 46 focuses on immune-related adverse events which are the most common adverse events resulting in permanent treatment discontinuation for IO-based therapy. There were no reports of any high-grade irAEs in patients who tolerated at least 6 months of treatment. Nearly 30% of patients in the short-term combination group had a high grade irAE. And this is a rate that is consistent with ipilimumab monotherapy. The pneumonitis and 1 event of colitis occurred in patients receiving 0.3 mgs per kg of CX-072 suggesting that these may have been primarily driven by ipilimumab. All grade immune-related adverse events reported with monotherapy were infrequent and appear lower than historical data. Next slide, please? In summary, the translational data presented to date allow us to safely conclude that tumors have protease activity. This activity is sufficient to activate the Probody at measurable levels, resulting in target engagement and downstream biologic effects. These measured outputs directly support what we observe now in terms of activity and tolerability. That is deep and durable responses in patients with a variety of tumors who were treated with monotherapy and a favorable tolerability profile, both as monotherapy and in combination with ipilimumab, which could improve a patient's chance for long-term treatment, maximizing their potential to respond to such agents. All together, the data presented in these 7 abstracts established that the Probody platform applied to IO therapy or as a Probody drug conjugate to previously undruggable targets performs as designed. Furthermore, the clinical activity and tolerability profile is presented for each of the 4 clinical-stage molecules supports the continued exploration in Phase II, specifically in head and neck and squamous cell non-small cell lung cancer, esophageal cancer and diffuse large B-cell lymphoma for CX-2029, in hormone receptor positive HER2-negative and triple-negative breast cancer for CX-2009 as monotherapy or in combination with CX-072. And finally, in metastatic melanoma or BMS-986249. Before handing back over to Sean and on behalf of CytomX, I would like to thank the patients, their caregivers and our investigators and site staff who have demonstrated their shared commitment in our vision to improve the lives of patients living with cancer by participating in these studies. Sean?

Great. Thanks very much, Amy. So let's move quickly to Slide 51, company summary. Before opening up for questions, I just want to quickly reiterate that we're building what we consider to be a very unique company around our Probody platform. As demonstrated today, we've continued to do groundbreaking science and advance a broad pipeline of novel assets into clinical development. We've demonstrated that our platform can deliver meaningful anticancer activity across a wide range of targets and cancer types. Our initial clinical findings in targeting CD71, while early, provide an important new window into what our technology may be capable of in terms of opening up undruggable target space. We're now at an important stage in our company's evolution as we move several novel assets into Phase II, but also prepare for our next wave of INDs from the platform, leveraging our ongoing learning about the technology and including new ideas, like Probody T-cell bispecifics and other previously undruggable targets. We have strong partnerships with BMS, AbbVie, Amgen and Astellas. And we remain in a strong cash position to advance our platform and our pipeline. Moving to Slide 52. We have enjoyed a very productive 2020, notwithstanding the challenges of COVID-19, of course, and we're now looking ahead to multiple future milestones as we advance our pipeline. Given the pandemic, we're not in a position to guide on specific future timelines at this stage. But we look forward to providing updates in due course. I also just want to close by thanking our employees who have done an incredible job this year of moving our programs forward, again, in the context of an unprecedented pandemic. So thanks to all of you guys. With that, the team and I will be happy to take your questions. And I'm sure that your questions will be mostly for Amy and Alison. So I'll turn it back to Chris.

Operator, you can open the call to questions.

[Operator Instructions] And our first question comes from the line of Peter Lawson with Barclays.

This is Waleed on for Peter. Congrats on the data. I just had a couple of questions on 2029. Wondering if you saw any correlations with CD71 expression and activity, and of the responding patients, what were their CD71 expression levels? And then another question on safety. How should we be thinking about the observed neuropathy that you saw associated with the payload? And is that a concern going forward?

Let me hand that one over to Alison.

Thank you, Sean. We -- as you saw on the demography table, we got about 1/3 patient with high expression, 1/3 with low and 1/3, unfortunately, for a variety of reasons, typically not enough tumor cells to do the assay, the CD71 expression was unknown. If you look at the patients who have target lesion reduction, it was actually quite heterogeneous. Some were high. Typically, the head and necks were high. Lung cancer varies between low and at high expression. So right now, we're still working on this. This is a key component for the expansion cohort. We're actually moving towards a different system where we will mandate that we have analyzable tumor tissue so that we can really look at any potential correlations between CD71 parameters, whether it's immunohistochemistry or something else. And response on those forward dose expansion cohorts. So in terms of peripheral neuropathy, I will tell you, no, that's a -- it's not really a clinical issue at this time. We had negligible neuropathy for 2029. We may see it as we go forward. We may see it if we get into a population less heavily pretreated, where we can get longer duration of therapy, but no, it has not been a problem, to date.

And our next question comes from the line of Etzer Darout with Guggenheim Securities.

This is Paul on for Etzer. Just a couple from us. I have another one about the safety for CX-2029. I was wondering if you could help us interpret how the rates of Grade 3 and 4 anemia and neutropenia across those groups for 2029 compared to what's observed with the other MMAE conjugated antibodies? And is this something that you believe can be mitigated?

Again, let me pass that one over to Alison.

Thank you. That's a good question. We are aware that the drug is showing MMAE payload related toxicity. And in addition, there could be some additional component given CD71 expression in red blood cell precursors. I think your question was more specifically on neutropenia. We are not finding neutropenia to be a major concern. It has not been associated with fevers and infection. It is responsive to growth support, growth active support. We haven't had any adverse event discontinuations due to it. I would caution that direct comparisons between a Phase I trial that goes to the higher than recommended doses. And we're looking at a treatment-related adverse event. When you compare to drugs that are used in a Phase II population at the 1 recommended dose and in hematopoietic tumor types, for example, the lymphomas that are used for polatuzumab and brentuximab, treatment-related toxicity for hematological toxicity, very frequently, you're going to call a neutropenia and anemia, just part and parcel of the disease. So I think we really have -- the idea of getting the polatuzumab and brentuximab data on that slide was to show the spectrum of hematological toxicities, MMAE payload will bring you anemia, neutropenia and thrombocytopenia. Our primary is anemia. We do see some dose-dependent neutropenia. It has not been problematic in terms of clinical sequel.

Great. That's really helpful. Just one more then on CX-2009. So there was some preliminary data at AACR that's just that the association between CD166 expression levels in clinical activity. Can we expect any updates on biomarker analysis for this study? And how might it factor into your advancement of this program moving forward?

We'll keep going with the theme and give that one to Alison.

Thank you very much. So we are able to study CD166. We do have a proprietary antibody in which we can do immunohistochemistry analysis. You will note that we have 2 primary populations for the initial Phase II program, and that's hormone receptor positive breast in which the expression, if you remember the data, was 23 out of 25. You don't need a patient selection strategy based on a companion diagnostics when the expression is that high. Triple negative, however, brings some questions. It was about a 50% -- 6 out of 11, so a very small sample size. But nonetheless, the CD166, we are working to better understand what is going on with expression versus response and the triple-negative responders. We had 3 unconfirmed PRs. We did not get tissue on everybody. That's one of the things that happened in Phase I, but it did appear that the TNBC responders did have CD166 expression, 2 out of the 3 PRs had it. The third was unable to be analyzed. So we're working on how we might incorporate it in future studies. But I'd have to leave it at that to be very frank.

And our next question comes from the line of Mohit Bansal with Citi.

Congrats on the progress. So just wanted to probe further on the safety side, and specifically anemia. So from the presentation this morning, it kind of seemed like there was a little bit of CD71 related anemia as well. So can you just help us pass-through what to -- how much do you think it is because of the payload versus the target here? Because with other similar payloads, I mean, you don't see that much anemia. So that's the first question. And then the second part is how -- so I think, most of the patients actually were transfused because of anemia. In the clinical setting how practical is it for the patients to manage them using transfusions? Those are the questions.

Great. Thanks, Mohit. Good to hear from you, and thanks for the questions. Let me make a quick comment on your first question, then I'll hand over to Amy and I'm sure Alison will have a couple of comments as well. These are obviously important questions that you're asking. First of all, I want to remind everybody that the whole construct here is to take a target that we know in antibody drug conjugate format has a 0 therapeutic window. We've demonstrated this. We've shown this data before, most recently in our World ADC presentation that an ADC conjugated MMAE, given to a cynomolgus monkey is lethal, quite rapidly lethal, unfortunately. And so -- but the potential of this target to deliver payload has been recognized for a long time, if we could open up a therapeutic window. So where are we today? Fast forward to what we've demonstrated and presented today, we have been able to achieve therapeutic doses of the Probody drug conjugate by masking, which is very exciting. And not super surprisingly, we're seeing anemia as the principal toxicity to manage and think about and learn more about. Now given that the target CD71, as Alison mentioned in her presentation, is known to be present at high levels on red blood cell precursors. This is one of the things that precludes the development of the antibody drug conjugate. It's, among other things, particularly toxic to the bone marrow. We've achieved a therapeutic dose with the Probody, but we have anemia to manage. So where is the anemia coming from? Certainly, it's very likely to be coming from the payload itself. But it's -- we can't rule out at this stage given how much target there is that there could be some low level engagement of the Probody with the target in the bone marrow. We have to look at that in more detail. That might not be super surprising, given the fact that at the end of the day, a Probody is, in masked form, is a a low affinity antibody. It's all about the delta between what we get in the tumor and the responses we see in the tumor and how we can maintain masking in the periphery. I want to refer you to one other slide before I hand over to Amy, and I will do so in a moment. But this is a key question. I want to refer you to one of the slide in the deck that Alison presented, which shows the clinical PK of the Probody in the blood of the treated patients. And consistent with every other Probody clinical program that we presented on, the masking remains intact on the Probody in the blood, which is important. This is, we think, a large determinant of the therapeutic window that we have demonstrated but we do need to understand a bit more about this. And at this point, we can't rule out that there is at least some component of an on-target contribution to the overall anemia. Regarding transfusions and management of the talks, let me hand over to Amy to make comments, and I'm sure Alison will have a comment as well.

Yes, sure. I'll do what I can. Probably Alison can give a little bit more flavor to this. She's much closer to the data. Managing patients with a transfusion is certainly possible. Other methodologies that we would be investigating would be including incorporation of growth factor support to minimize the requirement of red blood cell transfusion. I think many of the blends of anemia, from my understanding is, patients were not symptomatic with the anemia. They were not hypoxic. They were not fatigued. It was rather a number. And some patients did not -- many patients did not require repeat transfusions with each dose. With that, I'll let Alison add any additional flavor that you know.

Thank you. Thank you, Amy. So a couple of just thoughts spring to mind. I think it's very important when we show it's a Grade 3 or higher toxicity table, there was no Grade 4 anemia. We're using CTCAE version 4.03. And Grade 4 is life-threatening consequences, urgent intervention indicate. We didn't have any of those. So I'm emphasizing what Amy Peterson had said, which -- it was Grade 3 anemia, it was a laboratory abnormality. We are aggressively interrogating for whether patients were clinically symptomatic, for example, fatigue, lethargy, asthenia, weakness, dyspneic, short of breath. So we're aggressively trying for clinical sequela. And it's essentially it's a Grade 3 laboratory abnormality at this time. Finally, we're also really trying to understand -- originally, we had not used erythropoietin stimulating agents like, for example, darbepoetin. And we're starting that. We're going to be saying that might be a useful modality. We don't have data at this point. We have anecdotes in a very small number of individuals, but there may be some benefit, and we will be able to present on that in the future. But thank you for your question.

And our next question comes from the line of Mara Goldstein with Mizuho.

Just to pick up on the anemia for a minute. I think that it was said that most of the patients who did require transfusions didn't require multiple transfusions. But as per the table, the median number of transfusions is broadly 2. So I'm wondering: a, what the max that you saw was and the time interval between the transfusions for patients who required a first transfusion? And I guess the other question would be as it relates to this, again, understanding that this is not the therapeutic dose that you would use. But in the 5-milligram per kilogram, you saw a median of 15 days to time to transfusion versus 30 plus for the lower doses. And was that 15 days driven by laboratory abnormality or symptomatically?

Hi, Mara, thanks for the questions. Again, good to hear from you. I think we should -- I think we -- I don't think we want to drill down too deeply here. After all, this is a Phase I study. And as Alison pointed out, of course, we've -- as one typically or very often does in a Phase I study, we tested supra-therapeutic doses to really get an initial sense of this very unique drug candidate. So with that caveat, let me hand over to Alison to make just a few general comments. And of course, we're going to be learning a lot more about this as we move into the expansion phases at the recommended Phase II dose. But Alison, any additional comments?

So certainly. Thank you. So we do see transfusions. It is dose dependent. But as you can see, even at the high dose, it was 4 out of 4 with red blood cell transfusions. If you go to the lower doses, it's 1 out of 3. This is a Phase I trial. And I would say that we're trying to get a grip, better understanding of etiology. I think somebody in the past that says, well, what is payload versus what is target? We haven't done that yet. So we really can't make an awful lot of claims on that. We do know it's multifactorial. We've been asked a lot of questions. And I think when we present on anemia in the future, we should be able to provide a lot more require -- a lot more parameters, a lot more data. But at this point, I think we're limited by the presentation we have.

Okay. If I could just ask a follow up to that and then one other. And just if you know it, just the time to transfusion, I know that you said that, that was asymptomatic and per laboratory, but was that protocol specified? Or was that investigator preference?

No, we didn't mandate transfusions. You'll see that our Grade 3 anemia rate was 7 out of 12, that our transfusion rate was 10 out of 12. So if that was very much -- if a principal investigator thought it was in the best interest of his or her patient, that was obviously permitted per protocol.

Okay. And if I could just ask a question...

I just want to clarify one thing in addition to this, which is one of your questions in the first question, or subquestion to it was, the day 15 or coming out at day 15, how did you identify that Was a symptomatic? So in these dose escalation Phase I studies, we get weekly labs. And so you get a lab at day 1, day 7, day 15, day 21, for example. So it still can be asymptomatic but observed at an earlier time point, if you -- if I'm answering that part of your question.

Yes. I appreciate it. And I just wanted to ask a question on CX-2009. As you see the profile emerging, again, early, but I'm just curious as to how you see the drug fitting into the treatment landscape for hormone positive HER2-negative disease, just given the broad number of treatments that are out there in the metastatic setting and where you would look to profile this compound?

Certainly...

I know Alison will be ready to get all over that one.

Yes, I was going to say the same.

Okay. Thank you very much, everyone. So I think we're all very pleased that we've got 3 CDK 4/6 inhibitors, 2 of which have a statistically significant survival benefit, and that's beneficial to patients. We know everolimus on a backbone of [indiscernible], that also is a useful treatment option. We know for a subset of patients, a PI 3-kinase inhibitor, again, on a backbone of hormonal therapy, useful treatment option. I would say that these are non curative. Patients do progress. Once they get visceral symptoms, dyspnea, pain, liver issues, they go on to cytotoxic chemotherapies. And at that point, it's a sequential single agent chemotherapy, and that has been true since -- for a very, very long time, more than 20 or 30 years. So when we're designing our next study, we understand what a Phase II population would need to be in order to generate the necessary -- if we can, we'll get our proof-of-concept of that. We need to see an objective response rate in that population. And also for hormone receptor positive, CBR 24 is a very important parameter. Not all patients respond, but as you can even see in our data, patients can go for a year. And for those patients, that's a clinical benefit. So we're designing the trial at this point. We do have to take into account those agents that have shown a survival benefit that we have to move to mandatory use of a CDK4/6 inhibitor, if we wanted to have it as a registrational population or regulatory population. So we're working it into the landscape. And all I can say is, I personally am grateful we have more treatment options for our patients at this juncture.

And our next question comes from the line of Biren Amin with Jefferies.

Sean, I think earlier you mentioned that you opened up a therapeutic window for 2029. And so I just wanted to ask around this because it seems like when we look at the data, it seems like 2029 has a limited therapeutic index, given you saw clinical activity at the 2-milligram per kilogram dose. And yet, I think are moving ahead with a 3 mg per kilogram dose, given the AEs that you saw at the 4 and the 5-milligram per kilogram dose. So can you just maybe talk about that? Because it seems like 2, you're not getting efficacy and the 4 and the 5, you're hitting tox. And even, I guess, at the 4 milligram per kilogram dose, you had 4 patients that had progressive disease. So it wasn't quite clear whether you saw a dose response there. So maybe if you could address some of those points.

Yes. Biren, thanks for the question. I'll kick it off again, and then we'll hand over to my colleagues. So there's a couple ways to look at this, well, maybe at least 2. First of all, relative to the, as I commented, the antibody drug conjugate to this target. We know that, that would not be developable at all. So we'd never be able to get to the point in patients of showing objective confirmed responses in late-stage cancer. So that in and of itself is a -- we think, a box check, an important box check and an illustration of what masking can do against what I mentioned in my remarks, is probably the most stringent test yet of our technology. Regarding the relationship between efficacy, anticancer activity here and overall tolerability, we're obviously still learning about that. We're encouraged by the data we have so far. We see clear evidence of clinical activity at 3 milligrams per kilogram. We are optimistic that this will be a dose at which we can manage the adverse events as we move forward. And I would also emphasize, of course, as Alison has said, this is a Phase I study with a fairly heavily treated -- pretreated patients. And as we move into more focused patient populations in the expansion phase, we're going to learn a lot more. But let me hand over to Alison.

Thank you, Sean. So I would caution -- the 4 mgs per kg dose, if you look at the waterfall, those are colorectal 2 patients, a thyroid, 1 patient a mesothelioma and other patients. So all 4 of those would be essentially not a sensitive tumor type for a microtubular inhibitor. They just -- they don't respond to taxanes and things along those lines. They don't respond to eribulin. We also did have a target lesion reduction at 2 mgs per kg in a head and neck squamous. So again, following on on the consistency of that squamous histology observation. And finally, one last comment, which is antibody drug conjugates, you should be dosing. I mean, this is a good rule of thumb. You should be dosing to a high but tolerable dose. And we're following that general paradigm. 3 appears to be a tolerable dose and that's how we're going to move forward. We have standard toxicity and dose modification tables in the protocol so that if you see this toxicity, you bring the dose down from 3 down to 2. So we think we have an acceptable way forward here.

And maybe if I could have a follow-up, Sean. This is a question related to CX-072. I think on Slide 39, you were trying to show activated CX-072 antibody relative to intact. Where you're seeing very close correlation at the 10-milligram per kilogram and 30-milligram per kilogram doses. But I think when you look at the scales, there's pretty wide range on the scales above, I think, 10 nanomolar, as I don't have this slide in front of me. And also, I think when we go back and look at the data that you presented about 1.5 years ago at SITC 2018, with 6 patients that were dosed higher than 10 mgs per kg. It seems that the median and mean was around 26% to 29% activated antibody versus intact antibody. So can you just maybe talk about whether you're seeing similar averages with the more additional patient data that you presented today? And also, have you been able to correlate the responses with 072 to activate an antibody on the biopsy data that you're presenting?

Yes. Thanks, again, Biren, for the questions. And for pointing out that data from SITC previously. We've been focusing on this particular translational question as you would expect for some time. I think it's important to bear in mind that as Amy mentioned in her presentation, that these studies obtaining these types of biopsy materials are never that straightforward, and this is a snapshot in time, right? So the -- what are we learning from this latest analysis? We're learning that we can measure in extracted tumor biopsies, significant levels of activated Probody that are sufficient to engage the receptor. And you have to take it in my view, you have to put everything together in terms of the clinical pharmacology, the clinical activity and the safety of this drug candidate to come up with a holistic picture of how it's functioning in patients. So this is just 1 piece of a complicated puzzle. And the Phase II dose of 10 mgs per kg. Here, you can see significant activation in the tumor. We really don't know how that evolves over time. We don't know the kinetics of activation. We don't know at this stage, what is the maximum activation we can drive towards. And we don't yet have correlations, Biren, to your question of activation in the tumor in the clinic versus response. This is -- we look at it a little bit differently, which is the integration of all of the data. So clearly, we -- you can see the maturing waterfall plots for CX-072, which I hope will be convincing in showing that this is an active drug candidate in multiple tumor types. That's -- I think we can say that now with a high degree of certainty. The safety profile that Amy reviewed in terms of a quite impressive low rate of immune-related adverse events, consistent with the clinical pharmacology and pharmacokinetic measurements that we've made showing that masking is maintained in the periphery of patients -- of cancer patients. So I think you have to look at this whole thing holistically. It's hard to get the perfect answer from a biopsy experiment, and we think it's actually all pretty encouraging.

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

Maybe one first on CX-2009. In the 8 evaluable TNBC patients, there were 3 unconfirmed PRs. But if I remember correctly, at least 2 of those unconfirmed responses may have been due to patients coming off-treatment early because of ocular tox. So if we consider that the response rate, could it be very encouraging early signal there. So any consideration given it seems that ocular tox is now under control to advance 2009 as a monotherapy in TNBC?

Let me hand that one directly over to Alison.

So thank you. It's a good question. Yes, we did have -- in those patients, they were treated at 8 and 9 mgs per kg. And ocular prophylaxis was really not understood regarding how much it was required to mitigate that particular toxicity. As noted in my presentation, it started as optional. It eventually became mandatory. It needs to be mandatory. Patients do need to self-care. They need to use the ophthalmic -- the steroids, the vasoconstrictors, the artificial tears. And we think with that protocol, with that actual way to self-care, we can get this particular ocular toxicity well under control. We don't have an enormous experience. We're just beginning, but we are in the point of doing hormone receptor positive at the 7 mgs per kg dose every 3 weeks. We will be beginning the triple-negative later this year. And all of this will have the mandatory ocular prophylaxis. We were very fortunate. We have a consultant, Stella Kim, who also worked on other DM4 antibody drug conjugates. So she's well versed in how to care for these patients. So we think we have a very good protocol for both prophylaxis as well as management. But thank you for the question.

And Joe, again, thanks for the question. I would just add that -- so we agree with you. We do think that is encouraging activity in TNBC. We do believe the optimal way forward is with -- for us, is going to be with the combination with 072, whereas you've seen in the presentation Amy gave, that we have single-agent activity in TNBC with 072 as well. So the combination makes a lot of sense based on what we've observed in the clinic already. We don't have any plans at this point to advance the monotherapy in TNBC, but we'll continue to look at that.

Hi. This is Amy. Sorry. I don't mean to correct, Sean, on an earnings call or on an investor call, but we have stated that we would be looking at monotherapy, CX-2009. Is that what you're talking about, monotherapy CX-2009 with and without 072? Or was the question 072 monotherapy? I thought the question was 2009 monotherapy.

Yes, the question was 2009 monotherapy in TNBC.

Right. Yes. Yes. There is -- we have indicated that we will be investigating 2009, both as monotherapy and in combination with 072 in TNBC.

Okay. Got it. That's helpful. And I could just ask one quick follow-up on 2029. So you've spoken to working to determine whether the myelosuppression you're seeing is target mediated or payload mediating -- mediated. I'm just wondering if you could figure out what is contributing what? Does that, in any way, influence the mitigation strategy that you could potentially put in place?

I think it's too early to tell there, Joe. I think we need to learn more as we continue investigating the drug candidate. And thanks, Amy, for the clarification.

Yes. Yes, I thought maybe you were confusing it with 072 monotherapy, which we are not doing as monotherapy in triple-negative breast cancer. So I just wanted to make sure that we were all straight.

Our next question comes from the line of Robert Driscoll with Wedbush Securities.

This is Ashik Mubarack on for Rob. I had a couple more on 2029. I guess, I heard that you mentioned that the rates of free floating payload for MMAE was around 4% to 5%. Can you kind of put that into context in terms of what you're seeing with the tox, maybe what's been seen before with other conjugates using MMAE? And then my second question was on your expansion goals for 2029. I think you mentioned 4 different expansion cohorts, including esophageal and DLBCL. Unless I'm mistaken, I didn't see either of those enrolled in the Phase I. So I was just wondering if you could remind us about what gives you confidence in those 2 expansions?

Let me briefly comment on the second question first and then ask Alison to comment on the question on free payload. If you've had the chance to look at our preclinical data in the World ADC presentation, we have shown preclinical activity in DLBCL and in esophageal. The only other thing I can say is that those selections of those additional expansions, which are not represented in the data set that we presented today have been -- those selections have been made in close collaboration with our partner, AbbVie, and that's really all we can say at this point. Let me ask Alison to comment on some of the clinical pharmacology of the free payload. And again, we're still in the early days of understanding this with regard to our drug candidate, but perhaps Alison can comment relating to -- make a comment relating to other ADCs.

So there are multiple other ADCs that use MMAE. I think the most commonly known or 2 approved drugs, the polatuzumab and the brentuximab are both used in lymphoma patients. There's a recent one also the enfortumab vedotin, which is used in bladder cancer. We're actually trying to do some of those cross-trial comparisons, again, that's not the easiest way to go forward at this point. We will probably get our best comparator data in the solid tumor, the enfortumab dataset. I don't have the data that I'm able to discuss intelligently today. But we can actually look into that. And if necessary, have a follow-up question. Thank you.

And I'm showing we have a follow-up from Mara Goldstein with Mizuho.

Just I meant to ask this before, but on the expansion cohorts for CX-2029 and the preference to look at squamous histologies. I'm just curious as to where DLBCL fits into that?

Yes. Again, Mara, there's nothing really much more we can say at this point other than the expansion indications have been selected in close collaboration with our partner, AbbVie, but thanks for the question.

I will now turn the conference back over to President and CEO, Sean McCarthy, for any closing remarks.

Great. Thanks very much. And once again, thanks, everyone, for spending some time today, the last 1 hour 15 minutes. We appreciate it on this very hectic day. We've been very pleased to be able to present such a large amount of data today at ASCO. And I want to wish you all a safe and enjoyable ASCO weekend, and we all look forward to following up soon. So take care, everybody.

Ladies and gentlemen, thank you for participating in today's conference. This does conclude the program. And you may all disconnect.