Arcus Biosciences - Q2 2024

Transcript

Operator (participant)

Good afternoon. Thank you for attending today's Arcus Biosciences second quarter 2024 earnings call. My name is Tamia, and I will be your moderator for today's call. All lines will be muted during the presentation portion of the call, with an opportunity for questions and answers at the end. If you would like to ask a question, please press star one on your telephone keypad. I would now like to pass the conference over to your host, Pia Eaves, Vice President of Investor Relations and Strategy. You may proceed.

Pia Eaves (VP of Investor Relations and Strategy)

Hello, everyone, and thank you for joining us on today's conference call to discuss Arcus's second quarter 2024 financial results and pipeline updates. I'd like to remind you that on this call, management will make forward-looking statements, including statements about our cash runway and our expected clinical development milestones and timelines. All statements other than historical facts reflect the current beliefs and expectations of management and involve risks and uncertainties that may cause our actual results to differ from those expressed. Those risks and uncertainties are described in our most recent annual report on Form 10-K and quarterly report on Form 10-Q that have been filed with the SEC. We strongly encourage you to review our filings. Today, you'll hear from our CEO, Terry Rosen, COO, Jennifer Jarrett, and CFO, Bob Goeltz.

We'll also be joined by our CMO, Dimitry Nuyten, and President Juan Jaen, for questions after the prepared remarks. With that, I'll turn the call over to Terry.

Terry Rosen (CEO)

Thanks very much, Pia, and thank you all for joining us this afternoon. 2024 has already been a very exciting year for us and also very consequential. We completed an enrollment of our first phase 3 trial, STAR-221, a 1,000+ patient study in first-line upper GI adenocarcinomas. We're on the brink of advancing 2 additional molecules into phase 3 studies, both of which are supported by strong data and targeting huge unmet needs and market opportunities. Casdatifan, or CAS, our HIF-2α inhibitor, will be our newest phase 3 entrant. We're going to share a lot of information about this program today and in fact, throughout the rest of the year.

The HIF-2α inhibition mechanism has been clinically validated by the approval of Merck's belzutifan, which has been shown to have robust single-agent activity in clear cell renal cell carcinoma, or clear cell RCC, as we'll call it throughout the call. Belzutifan is already generating over $500 million in the annualized run rate sales just six months after approval in clear cell RCC. This clearly demonstrates the unmet need in this indication, the excitement around the mechanism, and the significant opportunity which we intend to capitalize upon. In addition to belzutifan monotherapy achieving a response rate of roughly 20% and meaningful tumor reduction in a much higher percentage of the late-line patient study population, probably one of the most exciting aspects of the HIF-2α mechanism is its durability.

In the phase 1/2 study for belzutifan, over 20% of patients had not progressed and remained on treatment beyond 2 years, and several of these patients, in fact, are now approaching 4 years on treatment. In the phase 3 registrational LITESPARK-005 trial, at the time of the first data presentation, 4 times as many patients were still on treatment with belzutifan than with the comparator, everolimus. This is pretty remarkable for the third-line plus setting, and it contrasts with the many TKI therapies, where patients may respond quickly, but then they rapidly progress. The tolerability of belzutifan, with on-mechanism anemia and hypoxia being the only meaningful treatment-emergent adverse events, enables patients to remain on treatment for long periods. We've consistently heard from clinicians how well tolerated belzutifan has been for patients, particularly relative to the TKIs.

While belzutifan is a good molecule, with CAS, we have a potentially best-in-class molecule due to its excellent pharmacodynamic and dose-proportional pharmacokinetic profile. It's, it's really a great molecule. CAS's PK/PD profile enables us to deliver five or more times the PD equivalent of the approved dose of belzutifan, which may result in more rapid onset and greater clinical efficacy relative to those of belzutifan. In fact, in our ARC-20 study, we're already seeing this differentiation play out in the data, which we look forward to sharing later this year. To further leverage CAS's improved profile, we're pursuing differentiated combinations relative to those being investigated with belzutifan. You're going to hear more about this today from Jen when we disclose for the first time the design of our first phase 3 study for CAS, PEAK-1.

We have some other exciting studies in the works that we're going to talk more about in the near future. Moving on to our Fc-silent anti-TIGIT antibody, domvanalimab, in STAR-221, our phase 3 trial evaluating Dom plus our anti-PD-1 Zim, plus chemo in first-line upper GI cancers. In June, we completed enrollment of STAR-221, enrolling over 1,000 patients in just 18 months, and we expect STAR-121 to complete enrollment later this year. So we're now turning our focus towards data readouts. While we recognize, you know, the anti-TIGIT program and Dom is a show me story from many of you, our confidence is actually stronger than ever. It's data-driven, and we remain convinced that the Fc-silent configuration has significant advantages over the Fc-active antibodies.

This is because the Fc anti-TIGIT antibodies substantially deplete peripheral regulatory T cells and correspondingly increase immune-related AEs. While increasing the incidence of AEs and is obviously intrinsically undesirable, perhaps more detrimental is the need to withhold or discontinue drug to manage these AEs, which may negatively impact efficacy. We've now seen two Merck studies where they explicitly called out greater rates of immune AEs, leading to treatment continuation as the primary reason for trial failure. Recall also that Merck is using a co-formulation strategy, necessitating simultaneous discontinuation of both components of their anti-PD-1, anti-TIGIT therapy. Additionally, because TIGIT is expressed on several other types of immune cells, depleting TIGIT-bearing immune cells can be counterproductive for any therapeutic strategy that's designed to stimulate the immune system to eliminate cancer cells.

We have two impactful data sets coming that we're going to talk about a bit later, both of which we believe will not only restore but enhance confidence in the potential of the TIGIT pathway, so TIGIT pathway in general, but in particular, in Dom, which is an Fc-silent anti-TIGIT antibody. I want to briefly comment on our CD73 and adenosine receptor programs, quemly and etruma, respectively. For etruma, at ASCO, we presented data from our randomized ARC-9 study, which showed unprecedented median overall survival of over 20 months for an etruma-based combination of third-line colorectal cancer. These results surpassed any survival results reported for clinical trials in third-line colorectal cancer.

In the second half of the year, we also plan to present biomarker data from this study that describe the ability of etrumadenant to block the effects of adenosine in tumors, as well as the relationship between CD73 expression and patient survival. So we're going to link mechanism to clinical outcomes. Both we and our clinical advisors are eager to advance etrumadenant in colorectal cancer. We're going to update you once we finalize next steps for this program. For quemliclustat, we expect to start our phase 3 study in pancreatic cancer, which we are now calling PRISM-1, PRISM-1, by early next year. We're extremely excited that Taiho decided last month to exercise its option to the quemliclustat program. Taiho will make a payment for the option exercise, and they're also obliged to pay us development milestones, which are expected to be triggered next year.

In return, Taiho received development and commercialization rights to quemliclustat in Japan, as well as other countries in Asia, but excluding mainland China. They'll now operationalize and be responsible for the costs of PRISM-1 in Japan. Their exercise of this option further illustrates the potential for quemliclustat in pancreatic cancer, and we expect Taiho to play a valuable role in the successful execution of the PRISM-1 study. Finally, we're well enabled to continue to advance our large portfolio with $1 billion in cash and investments on hand, plus the $100 million continuation payment due from Gilead, as well as the multiple partnerships that provide significant funding for our programs. So let me summarize where we are today.

We are extremely well-positioned due to the investment that we've made in Dom, including our three phase 3 studies, one of which was completed in enrollment, and the second that is expected to complete enrollment this year. As such, we anticipate 2024 will represent the peak of our R&D investment in Dom. With enrollment of STAR-221 behind us, we're now preparing for data and potential registration. The timing of this is perfect. We're now able to shift resources and investment to our next strategic priority, casdatifan. Casdatifan represents a very rare opportunity. We have a validated target in HIF-2α. Belzutifan has been embraced by physicians and patients as an important new standard of care, despite what are very clear limitations. Casdatifan has an approved profile, and this program is now central to our development focus.

Our emphasis is on creating a comprehensive development program that fully leverages everything that we have been able to learn from belzutifan and our growing CAS dataset. We expect to share a continuous flow of data and plans over the next year. Our initial phase 3 trial, PEAK-1, is the start of this transition and commitment. I'd like to now turn things over to Jen to speak a bit about CAS in greater detail.

Jennifer Jarrett (COO)

Thanks, Terry. Slide 26 shows the design of ARC-20, our phase 1 study for CAS in late-line clear cell RCC. It includes three monotherapy expansion cohorts, each initially enrolling approximately 30 patients that are evaluating 50 mg, 100 mg, and 150 mg of CAS, as well as a combination cohort that is evaluating CAS plus cabozantinib. Patients in the monotherapy cohorts had to have progressed on both an anti-PD-1 and TKI therapy in a metastatic setting to be eligible. We have submitted data from the 100 mg cohort for presentation at a fall medical conference. The presentation will include safety and efficacy data, including ORRs, as well as waterfall charts and swimmer lanes, so that you will be able to assess the depth and duration of responses.

Patients in this cohort had a median of 3 prior lines of therapy, and 25% of patients had 4 or more prior lines. In comparison, the phase 3 trial for belzutifan, LITESPARK-005, enrolled only patients who received 1-3 prior lines of therapy. And as a reminder, the ORR for LITESPARK-005 was 21.9%, and the primary progressive disease, or primary PD rate, was 33%. We expect our data presentation to support casdatifan's potential best-in-class profile, specifically better efficacy with comparable safety relative to that of belzutifan, even when evaluated in a more advanced patient population than LITESPARK-005. Because of the significant interest in ARC-20, we actually just reopened the 100 mg cohort and are close to enrolling another 30 patients.

This would bring us to 120 patients that have been enrolled in total in approximately a year across the three monotherapy cohorts, which is incredible for a phase 1 study and a single tumor type. Moving on to the 50 mg cohort, which completed enrollment in April, these data are maturing very nicely. So we also now expect to share some information from this cohort in the fall. All patients are eligible to have had at least one scan, so we already know the primary PD rate or the percent of patients that progressed at or before their first scan. Like we observed in the 100 mg cohort, the primary PD rate is substantially less than the 33% observed in LITESPARK-005. This is another data point demonstrating that CAS seems to bring tumor growth under control more quickly than belzutifan.

Also, like the 100 mg cohort, we're seeing a very significant percentage of patients with tumor reduction. The ORR for this cohort, including one response that is pending confirmation, is already higher than what was reported in LITESPARK-005, even with very limited follow-up. Finally, we recently completed enrollment of the 150 mg expansion cohort. So between now and the end of 2025, we expect to present a steady stream of data from ARC-20, including at least 120 patients worth of data for CAS monotherapy, as well as potentially initial data from our CAS plus Cabo combination cohort. These data will be used to support rapid initiation and enrollment of our first phase 3 study, which brings me to our development plan for CAS.

Following feedback from the FDA later this year, we plan to begin our first phase 3 trial, PEAK-1, in the first half of next year. The proposed design of PEAK-1, which is shown on slide 29 of our corporate deck, is simple. We will evaluate casdatifan plus cabozantinib versus cabozantinib in clear cell RCC. Cabozantinib is the leading TKI prescribed for clear cell RCC, and cabozantinib monotherapy is the standard of care in the post-IO setting. PEAK-1 will enroll patients who have received prior anti-PD-1 therapy. This includes patients who received pembro in the adjuvant or post-nephrectomy setting, as well as patients who received anti-PD-1 in the first-line metastatic setting. So PEAK-1 will target a huge patient population and the patient population that we believe will significantly benefit from HIF-2α inhibition.

We plan to use a once-daily dose of 100 mg of casdatifan in this study. All of our PK/PD exposure, response, and safety data from our dose escalation and expansion cohorts support 100 mg as a go-forward dose for more combination studies, and the primary endpoint of this study will be PFS. We expect the PEAK-1 design to be extremely attractive for both clinicians and patients for a number of reasons. First, simplicity. We are using Cabo in both the experimental arm and the control arm. In contrast, in Merck's LITESPARK-022, their similar studies, they are evaluating belzutifan with lenvatinib as the TKI in experimental arm versus Cabo in the control arm. Second, our choice of combination partner is Cabo, the most widely used TKI.

We have received consistent feedback from physicians that Cabo is preferred over other TKIs because of its proven efficacy, their comfort with managing Cabo-related AEs, and the simplicity of dosing. Specifically, there are only two approved doses for Cabo, compared to five different doses for lenvatinib. So Cabo is used as relatively easy to titrate. And importantly, Cabo has also been shown to have a more benign safety profile than that of lenvatinib. PEAK-1 is just the beginning of our investment in a late-stage development program for casdatifan, and there's much more to come. We are in advanced stages of planning for a study with a collaboration partner that will evaluate casdatifan in a potential first-in-class combination and would expand our development plan into the first-line setting.

We are also in the process of evaluating multiple other opportunities for CAS within the RCC space and potentially beyond, and we'll share more on these over the coming months. The market opportunity for CAS is substantial. The class of TKIs primarily used for RCC now generate well over $5 billion in sales, as shown on slide 31 of our corporate deck. With an annual incidence of 12,000 patients per year in the U.S. alone, it is a large population, and patients frequently remain on therapy, cycling through different treatments for many years. We believe our CAS combinations have the potential to be best in class, allowing us to capture a significant share of this large and growing market. I'll now turn the call back to Terry to discuss DOM, our Fc-silent anti-TIGIT antibody.

Terry Rosen (CEO)

Thanks very much, Jen. In ASCO, in early June, we had two oral presentations, something we think is pretty incredible for a company of our size and stage. That included new data for EDGE-Gastric, our phase 2 trial evaluating domvanalimab plus chemo in upper GI cancers. As you can see on slide 16 of our corporate deck, in a 40-patient cohort, the domvanalimab combination demonstrated a pretty impressive median PFS of 12.9 months for the overall population and 13.8 months for the PD-L1 high population. These far exceed the benchmark PFS data for anti-PD-1 plus chemo that's in the 7-8 month range. And in fact, the median PFS data for EDGE-Gastric actually approached the benchmark median OS of 13-14 months for anti-PD-L1 plus chemo, as we've highlighted on slide 17.

Based on this outcome, our OS result should substantially exceed those from all of the benchmark studies. These results meaningfully de-risk our STAR-221 phase 3 study, which is evaluating the same combination in the same setting as EDGE-Gastric. We expect to have overall survival data for EDGE-Gastric in 2025. Given this is the primary endpoint for STAR-221, these data should further enhance the likelihood of a successful outcome for our phase 3 study. We continue to believe not only that anti-TIGIT will be an important advance in anticancer therapy, but that Dom will have important advantages over its Fc-enabled counterparts. There continues to be a steady flow of data supporting this. While the failure of SKYSCRAPER-06, Roche's phase 2/3 study, which evaluated tiragolumab plus atezolizumab plus chemo versus pembrolizumab plus chemo, is disappointing for patients.

We've articulated to you the many important differences between our studies and SKYSCRAPER-06, and we really think that most of you have agreed with us on these points. We've generated a tremendous amount of data that supports Dom's potential to add meaningful clinical benefit in both non-small cell lung cancer and upper GI cancers. We expect to present two new data sets that will further support Dom's significant potential in lung and upper GI cancers. First off, by year-end, we and Gilead plan to report data from ARC-10, Part 1, a randomized phase 3 study in PD-L1 high non-small cell lung cancer. Let me just give you a reminder. We stopped enrollment for strategic reasons early this year to focus on the much larger opportunity with STAR-121. The initial design of ARC-10 evaluated Do plus Zim versus Zim versus chemotherapy.

Approximately 40 patients were enrolled in each of the DOM plus Zim and Zim monotherapy arms, and approximately 20 patients were enrolled in the chemotherapy arm. As we promised at the time, we shifted our focus to STAR-121. We will present both PFS and OS, including hazard ratios, and we believe that these data will reaffirm what we observed in ARC-7. That DOM plus Zim demonstrates clinically meaningful improvements over anti-PD-1 monotherapy in this setting, with limited additional toxicities. Second, we and Gilead expect to present OS data from Edge Gastric in 2025. As I mentioned, given that our median PFS is already in line with the OS results observed for anti-PD-1 plus chemotherapy alone, we expect to report very compelling overall survival data. I can say today, well over 50% of patients remain on study 18 months after enrollment completed in this cohort.

We continuously evaluate the entirety of our data to confirm our confidence in our study designs, and we remain as confident as ever about our three phase 3 studies, and we have the potential best-in-class anti-TIGIT, anti-PD-1 combination. This brings me to the potential timing of our phase 3 readouts. We've consistently said that our first readout will most likely be STAR-221. So let me spend a minute on the study design, which we show on slide 18. Importantly, this trial has dual primary endpoints of OS in the PD-L1 high population and in the ITT population. So simply put, the study will be positive if the DOM Zim arm shows a statistical improvement in the PD-L1 high patients or in the ITT population.

The study is well powered with over 1,000 patients, and we've closely monitored recruitment to ensure the ratio of PD-L1 high to PD-L1 low patients is consistent with the assumptions used for our statistical analysis plan. Given that OS has been in the 13-month range for anti-PD-1 plus chemo studies, and we completed enrollment in June, I think all of you can do the math on when we might get to a readout. The addressable market here is enormous, with 24,000 patients in the U.S. alone, approximately 50% of whom are PD-L1 greater than 5, and 80% of whom are PD-L1 greater than 1. This translates into a market opportunity of well over $3 billion in the U.S. alone. Before I close, I'm going to turn the call over to Bob to review our financial results for this quarter.

Bob Goeltz (CFO)

Thanks, Terry. Arcus continues to be in a strong financial position. Our cash as of June 30th, 2024, was $1 billion, as compared to $1.1 billion as of March 31st, 2024. Turning to our P&L, we recognize GAAP revenue for the second quarter of $39 million, which compares to $145 million for the first quarter of this year. Our revenue is primarily driven by our collaborations with Gilead and Taiho, and in the first quarter, included a cumulative catch-up of $107 million resulting from the Gilead amendment we executed in January. We continue to expect to recognize GAAP revenue of approximately $30 million per quarter for the remainder of 2024.

Our R&D expenses for the second quarter are stated net of reimbursements from Gilead and were $115 million, as compared to $109 million in the first quarter of this year. In the second quarter, non-cash stock compensation represented $10 million of our R&D expenses. The increase in the second quarter expenses was related to higher clinical trial costs, offset partially by lower clinical manufacturing costs associated with our late-stage programs. We continue to expect modest increases in R&D expenses through 2024, and for spend to level off heading into 2025 as our late-stage investments shift from Dom towards CAS and Quemly over time. As Terry noted, we expect our R&D investment in Dom to peak this year. G&A expenses were $30 million for the second quarter, compared to $32 million in the first quarter of this year.

Non-cash stock compensation represented $10 million of our G&A expenses for the second quarter, and we expect G&A expenses to remain stable for 2024. Finally, we now expect our cash and investments balance at the end of 2024 to be between $885 million and $925 million, as compared to our prior guidance of $870 million-$920 million. We continue to expect these resources to fund operations into 2027. As a reminder, this guidance includes a $100 million partnership continuation payment from Gilead and the quemli opt-in payment from Taiho of $15 million. Both payments are due in the third quarter. Our guidance excludes, however, additional potential opt-in payments and milestones from our partners.

For more details regarding our financial results, please refer to our earnings press release from earlier today in our 10-Q. I'll now turn it back to Terry for concluding remarks.

Terry Rosen (CEO)

Thank you very much, Bob. So please let me end by reviewing our near-term data events. You know, they're both meaningful and very substantial. First, in the fall, we expect to present ORR and other data from the 100-milligram dose expansion cohort of CAS. Those data will be followed closely by results from the 50-milligram and 150-milligram dose expansion cohorts, and then data from our Cas+Cabo combination cohort in 2025. We also expect to initiate our first phase 3 trial for CAS in the first half of 2025. With respect to Dom, we expect to present a few important data sets ahead of our first phase 3 readouts.

These include PFS and, very importantly, OS data from our original ARC-10 trial, which evaluated Dom plus Zim versus Zim versus chemo in PD-L1 high lung cancer by year-end, followed by OS data from our EDGE-Gastric phase II study in 2025. Meanwhile, we are continuing to advance our other programs, including the initiation of a phase III trial for quemliclustat in pancreatic cancer and the evaluation of next steps for etrumadenant in colorectal cancer. All of these studies are enabled by the strength of our balance sheet and the great relationships with our partners. Lastly, we continue to have a robust discovery engine at Arcus that enables a sustainable pipeline of future programs. The next program we expect to advance into mid-stage studies is AB-801, our highly selective AXL inhibitor. I want to conclude by thanking all of you.

Thank you very much for your continued support of Arcus and our mission to bring innovative therapies to patients in need. So we'll now open up the Q&A call for questions. Thank you.

Operator (participant)

We will now begin the question-and-answer session. If you would like to ask a question, please press star followed by one on your telephone keypad. If for any reason at all you would like to remove that question, please press star followed by two. Again, to ask a question, please press star one. As a reminder, if you're using a speakerphone, please remember to pick up your handset before asking your question. The first comes from Yigal Nochomovitz with Citi. You may proceed.

Yigal Nochomovitz (Director and Biotech Equity Research)

Hi. Great, Terry and Jen and team, thank you. A lot of updates there. So on the expansion cohort that you're embarking on with CAS and Cabo, can you just explain, is that something that you need to check the box on before initiating the PEAK-1 phase 3 trial? Is there some expected overlapping talks that you may or may not see with CAS and Cabo? And is the goal there mainly just to clear on safety before moving into the phase 3 with that combo? Thanks.

Terry Rosen (CEO)

Thanks, Yigal. Dimitry, why don't you give a clear and concise answer to that question, please?

Dimitry Nuyten (CMO)

Thank you, Terry. Question. Yes, it's. I wouldn't call it a checkbox, but it's important to establish safety information for a specific combination before you start a larger trial. So that's what the cohort is designed for. I do have to say, to your point of overlapping toxicities, based on the individual safety profiles, CAS has now been studied in quite a few patients as monotherapy. Cabo, of course, is very well established. We don't expect any relevant overlapping toxicity, with the exception of fatigue, something that's impactful for patients but typically can be managed with dose interruptions. Also, I'd like to note for CAS, in our experience so far, it is really rare for people to have even to be dose reduced, let alone discontinue treatment for toxicity.

It's a very well-tolerated agent, where short interruptions is pretty much what we need to do, in the case of drug-related toxicities. And then lastly, we can refer to the experience with belzutifan and cabozantinib that was published in The Lancet, a series of about 55 patients, showing indeed that the combination does not show any unexpected toxicities.

Yigal Nochomovitz (Director and Biotech Equity Research)

Okay, great. Thanks.

Dimitry Nuyten (CMO)

Thank you.

Yigal Nochomovitz (Director and Biotech Equity Research)

I just wanted to confirm on what you said, Jen, what you mentioned in terms of the data for the 50 milligrams, the primary progressive disease was less than the rate seen in LITESPARK-005, and we're going to get the 50- and 100-milligram data separately from the 100-milligram data later this year. Is that correct?

Jennifer Jarrett (COO)

Yeah, so, so first of all, you heard correctly on primary progressive disease. So for, LITESPARK-005, the primary progressive disease was 33%, and I said that for the 50 mg cohort, some of what we saw for the 100 mg cohort were significantly or substantially lower primary progressive disease rate. As far as data presentation, we would present the, the cohort separately, but the point I was trying to make is that when we present the 100 mg cohort of data in the fall, we will likely say, at least say something about the 50 mg cohort, and probably show some data from that as well. But, but it wouldn't likely be pooled. They'd be showed separately.

Yigal Nochomovitz (Director and Biotech Equity Research)

Okay. And then for the first-line trial, which you-- Yes, thank you. And then for the first-line metastatic study, what, what sort of combo partners would you be considering there? TKI and PD-1 or, or anything else?

Terry Rosen (CEO)

Yeah, we're gonna be disclosing that very shortly. We would have loved to be able to disclose it today, but it's, it's probably a couple of weeks off, and I, I think it'll fit within something that would meet your expectations. But the, the key thing about it, and the reason we wanted to get it in today, is because we wanted to show sort of comprehensively both what data we're gonna have and what we're gonna be starting in the next year. And we want to make it really clear that we're gonna be going into the frontline setting, and we're gonna be doing it with a combination that Merck is not doing, and we're, you know, we feel we're gonna be ahead of Merck.

Jennifer Jarrett (COO)

Yeah, and then one last thing to mention, we called out that we would be doing this with a collaboration partner just to make it clear that we would be doing this in a very capital and resource-efficient manner.

Yigal Nochomovitz (Director and Biotech Equity Research)

Okay, gotcha. Thank you.

Terry Rosen (CEO)

Thanks, Hugo.

Operator (participant)

Thank you. The following comes from Terence Flynn with Morgan Stanley. You may proceed.

Speaker 11

Hello, this is Alex, and calling in for Terence, and thank you guys for taking our question. Probably, can you give us any insights on potential presentation venue for this, CAS HIF-2 alpha inhibitor for ARC-20 data, that you presented in the fall? And can you remind us on the number of patient and duration of the follow-up we should expect with this update?

Jennifer Jarrett (COO)

Yeah, sure. So, we're not gonna, unfortunately, disclose the medical meeting that we've submitted the data for presentation at. It's in the fall. You may be able to guess it, since we're running out of conferences, that it could be presented at. It won't be at ESMO, just to be clear on that. And then, for the second part of your question, and I've actually forgot—wait, the second part of your question was?

Operator (participant)

The patient, number of patients.

Jennifer Jarrett (COO)

The patient, sorry, the number of patients. It'll be about 30. It'll be just a little bit above 30, and we'll have about 10 months of median follow-up at that point in time.

Speaker 11

Thanks. Okay, thanks. Maybe just on-

Jennifer Jarrett (COO)

Yeah, sure.

Speaker 11

The PEAK-1 trial. Right. Right. Thank you. On your new trial design, like, is, can we do any read-through from your expansion cohort that you're currently enrolling? Is like, is it gonna be the same patient population? Anything you can comment on that?

Jennifer Jarrett (COO)

Yeah, so what we said, so PEAK-1 will enroll a somewhat healthier, less advanced patient population than what we're looking at in ARC-20. So obviously, the fact that the drug is looking very good in ARC-20, obviously, we think bodes positively for PEAK-1. But the patient population that we would be looking at is a bit of a mix of first- and second-line. So it would include patients that receive PD-1 therapy in the adjuvant setting. So as a reminder, pembro is approved in the adjuvant setting. So that is used in patients post-nephrectomy that are at high risk of recurrence, will go on pembro. And then we'll also include patients that receive PD-1 in the first-line metastatic setting, so they would then be part of our study as a second-line metastatic patient.

But as we've spent a lot of time analyzing all the data that's out there for the different LITESPARK studies, we feel like this is a patient population that will benefit particularly well from HIF-2 alpha inhibition. So we spent a lot of time working with our advisors to identify what we think is the best patient population for this drug, and this is what we've decided upon.

Speaker 11

Great. Thank you very much.

Operator (participant)

Thank you. The next question comes from Jonathan Miller with Evercore. You may proceed.

Jonathan Miller (Analyst)

Hi, guys. Thanks for taking my question. Thanks for all the detail this afternoon. Jen, I just feel like I missed it, and I wanted to get clarification. You suggested that the ORR was better than Merck in the 50-milligram CAS cohort, and I just wanted to get some confirmation that that was what you said, and also, is the ORR better in the 100 mg arm as well? I know you've sort of stopped short of saying that in the past. And then I guess, given what you've seen so far with primary progression rates and ORR data that you've got in hand, do you see a dose response in those higher dose cohorts, 50, 100, 150, at this point?

Jennifer Jarrett (COO)

Yeah. So, good question, John. So yeah, so for 50 mg, I did say that we're seeing a higher ORR today than the 21.9% that was seen with LITESPARK-005. I did also clarify that that's with one response pending confirmation. We would be above the 21.9%, and so pointed out that 50 mgs, given that started enrollment after the 100 mg, that's a much less mature cohort from a follow-up perspective relative to the 100 mgs, and then the 100 mgs, yes, you know, we're now north of where LITESPARK-005 is, and I'll let Terry speak about it.

Terry Rosen (CEO)

I'll take to the dose response question. So the first thing to sort of caveat is that the patient populations also are slightly different. So the 100-milligram cohort is slightly more advanced patient population. And as we've noted, it's a more advanced population when compared to LITESPARK-005. But with that said, I would say at this point, particularly given that the 50-milligram cohort is somewhat or substantially less mature, it would be hard to distinguish. So I actually think, given that they're each in the 30-ish range, as you might anticipate, John, more likely than not, any distinguishing that we'll be able to do between them will probably potentially be reflected in durability.

So I don't think you're gonna the 50 is looking good enough that you won't be able to probably tell a difference between the 50 and 100. The last point I want to remind you on that, though, is that to contextualize that you're actually even the 50-milligram cohort is at 2.5 the PDE equivalent of belzutifan, and as you know, belzutifan you know was enough to really shift this a change in the standard of care. So the nice thing about that, as all these data start to unfold as well, they're 30 milligram... I'm sorry, 30-patient cohorts.

While we're not gonna combine the data from just an understanding of the program and the potential of the molecule, you're gonna start to be able to look at these and, you know, treat these cohorts, not like one was at homeopathic, one was at medium, and one was sitting at hard. You're gonna have doses that let you sort of look at these patients in total and make an assessment of how you feel our molecule looks compared to anything you've seen with belzutifan.

Jonathan Miller (Analyst)

All right. Great, makes sense. Then maybe one more question on CAS strategy. Obviously, you talked about a cabo combo going to phase 3, this other mystery combo in first-line setting. Should we expect to see how broad should we expect to see the late-stage development program for CAS get in terms of different number of different combos, number of different settings, maybe beyond RCC as well?

Jennifer Jarrett (COO)

Yeah. So, you know, as I say, over, you know, sort of the next six to nine months, the two Phase III studies that we called out today will probably be it for us for now. As far as Phase III studies, that's a lot. Market opportunity is massive, so, so we will be focused on getting the studies off the ground. Where you should expect to see some of the additional work is in ARC-20, where, you know, we're looking at some other interesting patient populations that we wanna explore within that study that could then lead to later-stage studies in the future. But we have some really interesting populations in mind where we think HIF-2α inhibition, even as monotherapy, could have a really interesting effect. And so, we'll talk more about those over the coming months.

And then I'd say, you know, your question on other tumor types, you know, we do think there are some interesting opportunities there as well, but I think, you know, over the near term, you should expect to see more out of us from RCC, which is kind of keeping our hands full. Although, you know, interestingly, we're getting a lot of IST requests for studies in HCC, so there's definitely a lot of interest out there in the clinical community in evaluating casdatifan in HCC in particular.

Jonathan Miller (Analyst)

All right, that makes sense. Thanks so much.

Terry Rosen (CEO)

Thank you.

Operator (participant)

Thank you. As a quick reminder, if you would like to ask a question, please press star one on your telephone keypad. The next question comes from Salveen Richter with Goldman Sachs. You may proceed.

Speaker 10

Hi, this is Lydia on for Salveen. Thanks so much for taking our question. We just have one on etrumadenant in colorectal cancer. Just given the phase I/II data that you shared at ASCO, what do you see as the likely registrational path here, and when do you expect to share next steps for this program? Thank you so much.

Terry Rosen (CEO)

Thanks. So obviously, you can tell from what we've been talking about today, we've been doing a lot of planning and execution, and that's certainly a program that we're very excited about, Gilead is very excited about. We're working through. I'll just toss out there, since you asked a question, we like to give answers. We have had a lot of push from our ad board that it might be smart to move this towards the frontline setting, move a little earlier than where we were. But we haven't sorted through all that, and we're literally in the midst of those discussions to decide exactly where we might go, but you shouldn't be surprised if we end up going in that direction.

Speaker 10

Thanks so much.

Terry Rosen (CEO)

Thank you.

Operator (participant)

Thank you. The next question comes from Daina Graybosch with Leerink Partners. You may proceed.

Daina Graybosch (Senior Managing Director)

Hi, I have a question on TIGIT on ARC-10. I wonder if you can help set expectations, given this is from, you know, early in the ARC-10 design, about the type of patients you enrolled in terms of prognosis and region, so that we can think about comparing the data to the other-

Jennifer Jarrett (COO)

... trials in the setting, including ARC-7?

Terry Rosen (CEO)

Great. So I'll set a little bit of expectations on the data, and then I'm gonna let Dimitry get to the specifics of your question on patient demographics. But I'll just say that, you know, we believe that these data will be, you know, positive for the field, positive for domzim, and positive for zim in terms of it being a really nice data set. And in fact, if you think about all of the randomized data sets out there, you know, I would put this against any of them in terms of the information that it'll convey with, you know, a good anti-PD-1 and the Fc-silent anti-TIGIT.

So you should, you know, we definitely want to lean into this being an important and good data set, and I'll let Dimitry say a little bit about the patient population.

Dimitry Nuyten (CMO)

Yeah. So the patient population, just to break it down and also for others, it was a three-arm trial, ARC-10, part one. It was a 2:2:1 randomization, so it's about 40 patients, 40 on dom and zim, another 40 on zim alone, and then about 20 on chemotherapy. That does mean that the study was run ex-US and did not include some of the core European countries, because of the availability of checkpoint inhibitors as standard of care and monotherapy there. However, it is still, let's say, by inclusion criteria, very comparable to other trials run in this space, and it has the chemotherapy control arm that of course can be compared to other chemotherapy trials that were run slightly earlier.

I think that's gonna be very helpful to benchmark the population, but in principle, it's a very straightforward first-line population.

Jennifer Jarrett (COO)

And one other thing to point out with that data set that's, I think, interesting, is there's really two different readouts within the data set. One is dom plus zim versus zim, and the other is zim versus chemo, which is how the study was set up. So, you'll also see that comparison of zim versus chemo in that readout.

Operator (participant)

Thank you. The next question comes from Asthika Goonewardene with Truist Securities. You may proceed.

Asthika Goonewardene (Managing Director)

Hey, guys. Thanks for taking my questions. Apologies if I asked something that already has been asked. I just recently jumped on the call here. But just very quickly, can you tell us when cohort A of the tumor ncRCC study is going to be reading out? You just made a comment about how the clues are pointing that that's a suitable tumor type to go into. So just wondering about that. And then when we think about the HIF combination, obviously, with Cabo, you know, that makes a lot of sense. And given the function on Treg, you know, you can use both PD-1 and CTLA-4 as good combination partners. I just want to get your thoughts on that. Thank you.

Jennifer Jarrett (COO)

Um...

Terry Rosen (CEO)

Okay, so I'll take - let me take the question on the second cohort. It'll be likely sometime next year. It's simply, again, the OS in that setting is, you know, substantially longer and data simply aren't sure at this point. So were you... Remind me the second question.

Jennifer Jarrett (COO)

The second question was on Treg.

Asthika Goonewardene (Managing Director)

Thank you.

Jennifer Jarrett (COO)

Yeah, could you remind us the second question?

Asthika Goonewardene (Managing Director)

Yeah, when we think about HIF and in combination with PD-1, obviously, it makes sense, to-

Terry Rosen (CEO)

Oh.

Asthika Goonewardene (Managing Director)

think about a combination.

Terry Rosen (CEO)

No, no, I got you.

Asthika Goonewardene (Managing Director)

-PD-1. But yeah, how do you like?

Terry Rosen (CEO)

Yeah, so actually, we're gonna be disclosing very shortly a second registrational trial that takes us into the frontline setting. But your point about, you know, anti-PD-1, anti-CTLA-4, combination thereof, obviously, those are all reasonable combinations to be thinking about that would make a whole lot of sense to go with HIF-2 inhibition.

Asthika Goonewardene (Managing Director)

Thanks, guys.

Terry Rosen (CEO)

Thank you.

Operator (participant)

Thank you. There are currently no other questions queued at this time. I will pass it back over to the management team for closing remarks.

Jennifer Jarrett (COO)

Thank you all for joining us. We look forward to speaking with you.

Terry Rosen (CEO)

Thanks, everybody.