Earnings Call Transcript - RCUS Q3 2024

Operator, Operator

Good afternoon, thank you for attending today's Arcus Biosciences Third Quarter 2024 Earnings Call. My name is Tamiya 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. I would now like to pass the conference over to your host, Pia Eaves, Vice President of Investor Relations. You may proceed.

Pia Eaves, VP of Investor Relations

Hello, everyone, and thank you for joining us on today's conference call to discuss Arcus' third quarter 2024 financial results and pipeline updates, including our upcoming presentation. 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 quarterly report on Form 10-Q that has been filed with the SEC. Today, you'll hear from our CEO, Terry Rosen; CMO, Dimitry Nuyten; COO, Jennifer Jarrett; and CFO, Bob Goeltz. We'll also be joined by our President Juan Jaen for questions after the prepared remarks. With that, I'll turn the call over to Terry.

Terry Rosen, CEO

Thank you very much, Pia, and thank you all for joining us today. As we head into 2025, our highest priority is to launch our late-stage development program for our HIF-2 alpha inhibitor, Casdatifan. As you know, just two weeks ago we presented initial data from our ARC-20 study evaluating Casdatifan in late-line clear-cell RCC in an oral plenary session at the ENA meeting. These data clearly validate our conviction that Casdatifan will be a best-in-class HIF-2 alpha inhibitor demonstrating improvement in every key efficacy measure that we analyze versus belzutifan, the only HIF-2 alpha inhibitor on the market today. So let's go to slide five and I'll recap the highlights from our data set. First off, the rate of primary progression in the 100 milligram daily expansion cohort was only 19% and it was similarly low in the 50 milligram daily expansion cohort. In fact, the rate of primary progression for the combined 60 patients in the 50mg and 100mg expansion cohorts was approximately half of what was observed in LITESPARK-005. The primary progression rate and disease control rate (DCR) are the only data points that are fully mature and will not change, so this is a huge difference for the molecule. We reported a 34% ORR and 25% confirmed ORR for the 100 milligram cohort with two to three unconfirmed responses pending confirmation and also multiple stable disease patients still on therapy. As of the data cutoff, every responder across both cohorts remained on treatment with the exception of one patient whose response did not confirm. The belzutifan data provides good precedent for the kinetics of response with HIF-2-alpha inhibition. Approximately 60% of responses occurred within six months of treatment and an additional 20% occurred in each of the ensuing six-month periods, extending out to 18 months. These data illustrate why our ORR could further improve across both cohorts. Keep in mind those follow-up times are 8 months and 11 months respectively for 50 and 100 milligrams. The ARC-20 data also demonstrated that the activity of Casdatifan is extremely durable. As of the data cutoff, a median PFS had not been reached even with that 11 months median follow-up. Recall that belzutifan was approved based upon its PFS of 5.6 months, and our median PFS which we expect to report in early 2025 should exceed that benchmark. Given that PFS is the registrational endpoint, this will be another important source of differentiation. Our Spider Plots show multiple patients either past or approaching the 52-week duration of treatment, and you also see deepening responses with time. I want to emphasize that these data were generated in a heavily pre-treated patient population relative to that of LITESPARK-005. Specifically, approximately 25% of the patients enrolled in ARC-20 were not eligible for LITESPARK-005. For the 50-milligram cohort, despite only 8 months of median follow-up at the data cutoff, we reported a 14% primary progression rate, a 25% ORR, and just over 21% confirmed ORR with one unconfirmed responder pending confirmation and a very impressive DCR of 86%. One of the confirmed responders was a complete response. Beyond the responders, nearly 40% of patients continued on therapy with stable disease, including a few who are extremely close already to the 30% response threshold. While this data set is still evolving and will continue to improve, we now have two different cohorts demonstrating clear efficacy differentiation relative to belzutifan and there’s a lot more data to come. On slide 6, we show the data we expect to share from ARC-20 throughout 2025. We plan to present more mature ORR and median PFS early next year. Later in the year, we plan to present initial data from the 150 milligram and the 100 milligram once-daily tablet expansion cohorts, as well as initial safety data from our Casdatifan plus Cabo combination cohort. The safety data from this cohort, already shared with the FDA as part of our pre-phase 3 meeting, are consistent with the profiles of the individual drugs and the dose intensity of 100mg of Casdatifan and 60mg of Cabo has been maintained. Given the importance of the ARC-20 data, we’re considering additional opportunities to provide updates from this study in the near term. We remain full steam ahead towards the initiation of our first Phase 3 study PEAK-1. The investigator enthusiasm for the study is incredibly high, which we believe will support rapid enrollment. Now let me switch gears to Domvanalimab, our Fc-silent anti-TIGIT antibody. Just yesterday, the SITC abstract was released with data from part one of our ARC-10 study which evaluated Domvanalimab versus Zim versus chemotherapy in first-line PD-L1 high non-small cell lung cancer. We terminated the study for strategic reasons to focus on STAR-121, our chemo combination study. But the early termination gave us both an opportunity to generate and now present a dataset from a study that was conducted under phase 3 conditions. On slide 27, we summarized the abstract. We showed that Dom plus Zim exceeded Zim monotherapy on ORR, PFS, and OS. For both PFS and OS, we achieved a hazard ratio below 0.65, which is considered clinically meaningful in the setting, with median PFS of 11.5 months and median OS not reached for Dom Zim — these results are meaningfully above contemporary benchmark studies for anti-PD-1 monotherapy. Dimitry will discuss these data in detail, but I want to make two important points. First off, these data reaffirm the growing recognition that Fc-silent anti-TIGIT antibodies have a differentiated safety profile relative to Fc-enabled antibodies. There are only two Fc-silent anti-TIGIT antibodies in late-stage clinical development today: Dom and AstraZeneca's anti-PD-1 anti-TIGIT bispecific antibody. In the last few months, AstraZeneca presented two datasets for their antibody in first-line non-small cell lung cancer and first-line gastric cancer. Interestingly, both datasets look very similar to our own, with comparable efficacy as well as AE rates in line with anti-PD-1 therapy alone. This is an important component of the profile. In contrast, for the Fc-enabled anti-TIGIT antibodies, we continue to see reports of higher rates of immune-related adverse events and treatment-related discontinuations. Combining these Fc-enabled antibodies with chemotherapy seems to exacerbate these issues. The second point is that with this ARC-10 dataset, which will be presented in more detail at SITC, the ARC-7 results in PD-L-1 high non-small cell lung cancer that we shared last year, and the EDGE gastric data that we presented earlier this year at ASCO, we now have three compelling datasets supporting the potential of Dom Zim in both lung and gastric cancers. For our EDGE gastric study, we showed a median PFS of 13 months for Dom Zim in first-line gastric cancer which meaningfully surpassed the PFS of 7 to 8 months seen in benchmark studies. We continue to execute on our three Phase 3 trials for Dom Zim. In first-line gastric cancer with our STAR-221 study, we have the potential to be first to market with an anti-TIGIT antibody in this setting. With this study fully enrolled, we're actively preparing for readout and potential submission to health authorities. We believe this setting alone is a $3 billion opportunity. In lung cancer with our STAR-121 and Pacific-8 studies, the collaboration with AstraZeneca presents a potentially differentiated anti-TIGIT combination in the two settings we're pursuing: first-line and stage three non-small cell lung cancer. We continue to evaluate our statistical analysis plans for all our Dom Zim studies to optimize them for probability of success while addressing the largest patient population. We also continue to advance the other programs in our pipeline. We've initiated PRISM-1, our Phase 3 study evaluating Quemli plus chemotherapy in first-line metastatic pancreatic cancer, and with Taiho's opt-in for this program, they're executing the study in Japan. Early next year, we expect to advance AB801, a highly selective AXL inhibitor, into expansion cohorts in non-small cell lung cancer. Our relationships with Gilead, AstraZeneca, and Taiho are strong, enabling us to aggressively advance all of our programs resource-efficiently. With $1.1 billion in cash and investments and runway into mid-2027, we're comfortably funded through multiple clinical readouts. Before we go to the ARC-10 results, I'd like to turn it over to Jen to discuss our development plans and the market opportunity for Cas.

Jennifer Jarrett, COO

Thanks, Terry. Starting with PEAK-1, our first phase 3 trial for Cas and clear cell RCC. We expect to begin this study in the first half of next year. The design is shown on slide 23 of our deck. The study will enroll approximately 700 patients and will compare CAF plus cabozantinib to cabo monotherapy in IGO experienced clear cell RCC. Cabo is the standard of care in this setting, so clinicians are extremely comfortable administering Cabo and adjusting its dosing to optimize both Cabo's efficacy and safety. We believe that the vast majority of the second-line patient population, approximately 80%, will be eligible for PEAK-1 given this study only excludes patients who received prior treatment with Cabo in the first-line setting. You can see on slide 24 that this study targets an approximately 11,000 patient population in the U.S., assuming a treatment time in excess of 15 months. This is a $2 billion market opportunity in the G7 countries alone. We are excited to move into the IO naïve setting with our collaboration with AstraZeneca to combine Cas with their anti-PD-1 CTLA-4 bispecific barista mix. The anti-CTLA4-PD-1 combination TiNivo currently has about 1/3 market share in the first-line setting, and that share is growing given the preferable safety and tolerability profile of IO-based regimens relative to those of TKIs. By combining Cas with the bispecific, we have the potential to develop a first and best-in-class TKIS bearing regimen. This represents a patient population of approximately 12,000 in the U.S. alone, and assuming a potential median treatment duration of 20 months, the total addressable market would exceed $3 billion across the G7 countries. Additionally, we are working to further expand the development program of CAF into other RCC subpopulations, and you'll see us add additional cohorts to ARC-20 in the coming months. We remain confident in Cas’s ability to play a very meaningful role in the RCC market today. Today, patients cycle through different treatment options for years, receiving multiple different TKIs with seven TKIs on the market. But today in the HIF-2 alpha field, it is just Cas and belzutifan.

Dimitry Nuyten, CMO

Thanks, Jen. Our abstract for ARC-10 was released yesterday morning, and data will be presented in a late-breaker poster session this Friday at SITC. ARC-10 was originally a global Phase 3 study evaluating Dom and Zim versus Sim versus chemotherapy in patients with PD-L1 high non-small cell lung cancer. This is important since the trial conducted with the same rigor as expected from a registrational Phase 3. Though ARC-10 was discontinued for strategic reasons, we continue to follow patients and with over two years of median follow-up, we are presenting our first overall survival data for Dom and Zim in any setting. Starting with the design on slide 30, the trial was randomized 2 to 2 to 1, with 38 patients in the Dom and Zim arm, 40 in the Sim monotherapy arm, and 17 in the chemotherapy arm. Baseline characteristics were generally well balanced across the arms, with some prognostic imbalances favoring the chemotherapy arm. The data cutoff for this analysis was May 17, 2024, and the median follow-up was 24.5 months. On slide 31, we show the Kaplan-Meier curve for overall survival. These results are quite impressive. In fact, even with two years of median follow-up, a median OS has not been reached for Dom and Zim. The hazard ratio for overall survival was 0.64, which is very clinically meaningful. Additionally, the Sim control arm performed right in line with the benchmark studies of pembrolizumab in this setting with a median overall survival of 24.4 months. When compared to chemotherapy, Sim demonstrated a hazard ratio of 0.63 for overall survival, again right in line with benchmark studies. The poster presentation will also highlight additional data including progression-free survival and overall response rates, which also showed a clear benefit for Dom and Sim over Sim and put Sim performance in line with the benchmark studies for pembrolizumab. The safety profile was also consistent with prior observations for Dom and Zim. Immune-mediated adverse events were similar for Dom and Zim relative to those for Sim alone at 23.7% and 20%, respectively. These results are substantially different from data reported from studies with the Fc-enabled anti-TIGIT antibodies where immune-mediated adverse events and treatment interruptions have been meaningfully higher than the anti-PD1 or PD-L1 alone arm. The compelling data from ARC-10 for efficacy and safety increases our confidence that combining Dom Zim with chemotherapy in STAR-121 will further improve outcomes and provide lung cancer patients with the best chances of success in their first-line treatment. Now I'd like to turn the call over to Bob to cover our financials.

Bob Goeltz, CFO

Thanks, Dimitry. Our cash as of the end of the third quarter was $1.1 billion, up from $1 billion as of the end of the second quarter. Our cash position was bolstered by a $100 million collaboration continuation payment from Gilead. Turning to our P&L, we recognized GAAP revenue for the third quarter of $48 million, compared to $39 million for the second quarter of this year. Our revenue is primarily driven by collaborations with Gilead and Taiho, including $15 million from the Taiho opt-in for Quemli in July. We expect to recognize GAAP revenue of approximately $30 million for the fourth quarter of 2024. Our R&D expenses for the third quarter, stated net of reimbursements from Gilead, were $123 million compared to $115 million in the second quarter of this year. We continue to expect modest increases in R&D expenses for the fourth quarter. G&A expenses were $30 million for the third quarter, flat compared to the second quarter of this year. We expect G&A expenses to remain stable for the fourth quarter. We expect our cash and investments balance at the end of 2024 to be between $950 million and $985 million compared to our prior guidance of $885 million to $925 million. We expect these resources to fund operations into mid-2027. Our guidance excludes additional potential opt-in payments and milestones from our partners. For more details on 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 all again for joining us this afternoon. As I mentioned earlier on the call, we have a lot coming, starting with our Citi presentation for Dom Zim on Friday, followed by additional presentations from ARC-20 and the initiation of our first phase 3 study for Cas over the coming months. As we head into 2025, we'll be approaching our first phase 3 data set for STAR-221 in first-line gastric cancer. We appreciate your interest and support of Arcus, and I'll now open the call for questions.

Operator, Operator

Thank you. The first question comes from Yigal Nochomovitz with Citi. You may proceed.

Yigal Nochomovitz, Analyst

Hi Terry and team. Thanks for taking the question. I'm getting a lot of interest in Casdatifan and people are asking about the potential for Gilead's opt-in. Can you provide any more color there regarding whether there are any specified windows? Obviously, you mentioned that you need a qualifying data package. Does that mean it could be the monotherapy or is Gilead interested in seeing some of the combo data with Volru or the initial combo data with Cas plus Cabo coming up soon? That's my first question, thanks.

Jennifer Jarrett, COO

Yes, so we have aligned with Gilead on what data is needed for the qualifying data package. We're very close to meeting that data requirement. So we will be delivering a package to them relatively soon. And as we've been saying, we expect a decision to be made either late this year or early next year.

Yigal Nochomovitz, Analyst

Okay, thank you. I am curious if any preclinical work was done with Volru and Cas to do a quick validation of the combo safety in NHPS before going into collaboration with AZ?

Terry Rosen, CEO

No, there was no preclinical work done. It was a very typical situation where you have two molecules with well-defined profiles that we simply took into those studies initially in humans.

Yigal Nochomovitz, Analyst

Okay. Last question: I’m curious about Etrumadenant. Obviously, you had the data at ASCO for the ARC-9. What are you thinking there in terms of later development? Is the second-line cohort (Cohort-A) what you're waiting for before you decide on a registrational study, given the strong OS that you saw in the third line?

Terry Rosen, CEO

No, to be honest, it’s just a matter of us moving. We're extremely excited about the data set and we're just working through with Gilead. We're starting a number of later stage trials and have the full portfolio going. So we're working through what our next steps will be and we'll share them once they're defined together with Gilead.

Yigal Nochomovitz, Analyst

Okay, thank you, Terry.

Terry Rosen, CEO

Thanks, Yigal. Appreciate it.

Operator, Operator

Thank you. The next question comes from Lee Watsik with Cantor Fitzgerald. You may proceed.

Unidentified Analyst, Analyst

Hey guys, thank you very much for taking my questions. I guess, Juan, in the IO naïve renal cell cancer setting, I understand AZ is running the study, but what can you say about what the next step might be and the timing of a potential pivotal trial?

Juan Jaen, President

We've agreed with AstraZeneca to not comment further than those initial plans, and we'll say more once the study shows up on clinicaltrials.gov.

Unidentified Analyst, Analyst

Okay, understood. I know you mentioned on the call that you're looking to optimize the step plan for the phase 3 non-small cell lung for Dom. Can you expand a little bit on that? What does that entail?

Terry Rosen, CEO

My comment was more general than that. We make that point for all of our studies that we're continuously looking at the stat plans for all of our programs. Obviously in the anti-TIGIT field, there have been changes made by others. There have been comments or statements from the ODAC with the FDA. At this point, we're not making any changes, but we wanted to acknowledge that we’re always considering that possibility.

Unidentified Analyst, Analyst

Okay, got it. Lastly, can you talk about the clinical benefits you're seeing for stable disease patients from the Cas study? It seems like you have a decent number of them still on study. How clinically relevant is disease control for these patients?

Dimitry Nuyten, CMO

Yes, so this is Dimitry. The relevance of stable disease for patients is significant. The RESIST criteria were determined based on large datasets primarily for chemotherapy. There has been an effort to standardize assessments of treatment, and based on reproducibility and interobserver variability, a threshold of 30% was established. It's widely accepted that whether you're at 25% or 35%, depending on the tumor volume, that distinction is less important. What really matters is having a tumor that doesn't grow and has decreased in volume. From a regulatory perspective, response rate is never a registrational endpoint beyond accelerated approval. In kidney cancer, progression-free survival is the relevant endpoint, and anyone who does not progress contributes to that. The longer you are free of progression contributes equally for each patient to the Kaplan-Meier estimate for PFS. So both from a clinical perspective for patients and from a registrational perspective, they are very important.

Unidentified Analyst, Analyst

Thank you.

Pia Eaves, VP of Investor Relations

We'd like to be able to get to everybody, so if you have more than a couple of questions, can you please hop off and join the queue at a later point? That would be great. Thank you.

Operator, Operator

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

Jonathan Miller, Analyst

Hi guys. Thanks for taking my question and reminding us to limit our questions just before I got my chance in the queue, I appreciate that. Can I start with some questions about HIF-2? I noticed in your prepared remarks you talk about two unconfirmed PRs that could still confirm. I'd really like to get some detailed color on that. We hear reports there have been papers written that suggest that maybe one of those had a subsequent scan indicating stable disease. So can you comment on the two unconfirmed partial responses you’re discussing, how many of those have not had a follow-up scan yet, or might be expected to confirm based on one additional follow-up scan? And maybe building off that, given that a lot of the differentiation you're discussing compared to belzutifan is in the PD rate at the first scan, how well do you anticipate that to translate to a better profile versus belzutifan in a combo setting, especially combos with drugs like TKIs which show benefits rapidly at those first couple scans?

Jennifer Jarrett, COO

The first question, there are a lot of queries there, but jumping to the back part of your question regarding who has not had a follow-up scan yet, the responders. There was one patient in the 100mg cohort that had not had a follow-up scan yet, and one patient in the 50mg cohort. Their last scans show them as responders for the first time, and they are waiting for their confirmatory scans now. As we stated for the 100mg, there is one patient that did not confirm. So far, only one patient. Out of all the responders, every responder is still on treatment, with the exception of one patient that did not have a confirmed response in the cohort.

Jonathan Miller, Analyst

Yes, I was counting the UPRs to get a sense of where the ORR could realistically get to in the end, specifically in the 100mg cohort.

Jennifer Jarrett, COO

Yes, 33.3% was the ORR. We said one patient will not confirm, which means the maximum confirmed ORR we can get to based on the current responders. This excludes stable disease patients that have also seen significant tumor reduction. Based on the current responders, the maximum confirmed response rate we can get to is 31%. If just one of those pending responders confirms, that would take the ORR to 28.3%.

Jonathan Miller, Analyst

Great, thank you.

Dimitry Nuyten, CMO

Yes, I can take the second part of your question about stable disease in the combination. A few things. In the combination, we are going against Cabo, building on top of that. Everyone in the control arm would receive Cabo, and we are doing the combination. The combination can help patients in different ways. With Cas, we see early responders. We have many patients responding at the first scan at six weeks, and we've disclosed two patients that received responses respectively at 12 and 14 months. That builds on top of the TKI response rate. The primary progression response rate for Cabo is about 20% or a little less. We hope to catch more patients from that 20% with a different mechanism for the combination. We can't speculate on what that would be, but we expect it to also improve on top of a TKI.

Jonathan Miller, Analyst

But I’m asking specifically about the comparison to the other F2 here to belzutifan. If differentiation from them is in the PD rate, or at least a lot of it is from the PD rate, how well do you expect to observe that differentiation in a combo setting where you have the TKI addressing the early effects?

Terry Rosen, CEO

I'll comment there. You are speculating, but as you know, greater than 90% of those patients have some sort of HIF-2 driven component. There is still room to reduce the rate of primary progression. This leads more patients into potential further options with every other efficacy measure, including ORR, PFS. There’s no reason to think you wouldn’t see advantages in OS either, even though that’s not the approvable endpoint at this stage. There's nothing intrinsic about clear cell RCC that would indicate prolonged OS couldn't be observed.

Jonathan Miller, Analyst

Thank you.

Operator, Operator

Thank you. The next question comes from Peter Lawson with Barclays. You may proceed.

Peter Lawson, Analyst

Great, thank you. Just a couple of follow-ups on the opt-in. What drives that decision for Gilead between this year and next year? Is it something from your side, their side, or is there a different data cut? If Gilead doesn't opt in, what are the next steps?

Terry Rosen, CEO

First, there’s nothing specifically driving it other than how long they take to make a decision. Because of when we are delivering it, it's relatively near the end of the year. They have a certain amount of time that could creep into next year. That’s the only ambiguity in our timeframe. They could opt-in yesterday if they wanted. This defines the latest point of when they can opt-in. Second, there’s not anything immediate we would do if they don’t opt in; we feel comfortable continuing on our own. We love the program and think it's a great opportunity. Alternatively, we have had interest from others recognizing that there is an opt-in decision, and other companies have expressed that they think Gilead would opt in, but we could consider a partnership with another company as well.

Bob Goeltz, CFO

Just on the economics, Peter. So it's a $150 million opt-in fee should they decide to opt-in. We would then share costs 50/50 on the program going forward. If Gilead were to opt in, we'd work through any additional studies we think might be added to our clinical development plan together.

Peter Lawson, Analyst

Great, thank you so much.

Operator, Operator

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

Asthika Goonewardene, Analyst

Hey guys, thanks for taking my question. I'm going to repeat what Jon did and ask a multi-part single question. On full adjuvant, when you think ahead to the right comp for some sort of pivotal study down the line, what do you think the right comparator is? I ask because Nebo EP is the most logical comparator, but obviously, that's a very high bar. And related, the durable CR rate with Nebo EP is something that's quite attractive about that combination in RCC. But how important is it for you to replicate that or beat that specific endpoint along with the regular primary endpoints you would consider?

Dimitry Nuyten, CMO

Yes, this is Dimitry. The relevant benchmark would be Checkmate-214, although that is now somewhat outdated. With mature follow-up, the data has held up very well. We are building on the bispecific data for 42, which was presented last year at ASCO in kidney cancer. I think most people would agree it looks at least as good as or perhaps a bit better than IPI-NIVO. Some of the toxicity is a bit better. We don’t expect to beat IPI-NIVO with Cas alone. We know we have a solid CTLA-4 PD-1 backbone and can build on that. Investigators typically don’t use IPI-NIVO where they need a fast response for a patient, and we might be able to change that, with a potential lower primary PD rate when we build on it. Every other benchmark we expect to deepen or lengthen: longer duration of response and hopefully longer progression-free survival and overall survival as well.

Jennifer Jarrett, COO

To emphasize the point around primary PD, AstraZeneca’s interest emerged from the fact that there are 25% of patients who simply do not benefit from IPI-NIVO. By adding a drug that seems to have a relatively low primary PD, we can greatly enhance the front end of the PFS curve.

Dimitry Nuyten, CMO

Lastly, the safety profile for HIF-2 targeting, specifically Casdatifan, would be significantly more favorable than adding a TKI to that regimen. We refer to this as a TKI-sparing approach, as first-line patients can be on treatment for a long time, making it cumbersome and burdensome if they need to stay on a TKI for a long duration.

Asthika Goonewardene, Analyst

Great, thanks so much, guys.

Operator, Operator

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

Daina Graybosch, Analyst

Hi, I want to follow up on what Asthika just asked about the trial conduct for both PEAK-1, the combo with Cabo and the combo with the CTLA-4 bispecific. We've seen in RCC that keeping patients on study seems crucial; managing toxicities and discontinuing can drive primary efficacy endpoints. Can you discuss your strategy in both trials to manage treatment exposure, particularly as you start with the 60mg dose of Cabo since that's not always done in their combination studies? What are you doing with Astra to manage TOX with a pretty toxic anti-CTLA-4 as well?

Dimitry Nuyten, CMO

I'll start on the Cabo combination. Two points: Starting with 60mg in trials where the TKI, Cabo, wasn't started at full dose was based on toxicities identified with a combination. It's important for patients to be able to start at full dose, which is the safety data we are generating right now. The data we've shown is convincing; virtually no one is discontinuing the drug due to toxicity. We have interruptions, but people can manage the toxicities and stay on. The specific profiles of toxicity for both Cabo and Cas are straightforward, with no significant overlapping toxicity, making it easier to guide potential dose reductions. In this trial, we call it an active comparator placebo-controlled trial, meaning that the control arm will receive Cabo and a placebo to remove any bias from the investigator and patients regarding the AE profile. Regarding AstraZeneca, we can’t comment as much on that trial. It’s currently in startup, led by AstraZeneca. Our colleagues there have generated safety data, some of which is in the public domain, and there's a lot more not in public. They have experience providing specific guidance on toxicities they are seeing, with as you know, Epinephrine has been on the market for some time, and kidney cancer investigators are experienced with the management of the toxicity profile of IPI-NIVO. Lack of overlap in toxicities helps provide guidance for each agent.

Operator, Operator

Thank you. The following comes from Salveen Richter with Goldman Sachs. You may proceed.

Unidentified Analyst, Analyst

Hey, this is Mark on for Salveen. Thank you for taking our questions. We have a question on TIGIT and lung from the ARC-10 data at SITC. It looks clear that TIGIT adds a survival benefit, but why do you think the benefit on ORR is less clear? Also, how do you expect this data to translate to the STAR-121 study, where it seems like OS benefit from the Dom Zim doublet is likely already above KEYTRUDA chemo combo? When should we expect to see initial data from STAR-121? Is it possible that we could see it in the second half of 2025? Thanks.

Terry Rosen, CEO

Let me start. The first question regarding ORR: We think the ORR improvement is reasonable. This is immunotherapy; the key benefit is in enhancing OS and its durability, and that’s the tail end. That’s why it’s a profound signal we see in OS. The primary use of ORR is as a surrogate for PFS and OS, and we’re at two years with OS data. There’s nothing unusual about the advantage on ORR. Regarding STAR-121, while we halted ARC-10 for strategic reasons based on market evolution, it's clear that physicians are moving towards using KEYTRUDA with chemo, even in high PDL-1 situations. The Fc-enabled anti-TIGIT have a lack of efficacy due to higher adverse events in the context of chemo. We feel well-positioned to have a stronger advantage over competitors. Scientifically, the anti-TIGIT enhances anti-PD-1 effects, a phenomenon shown in other studies, particularly in GI cancers with the data from EDGE-Gastric. The initial OS of the standard-of-care is about 13 months, above 20 months for non-spoil cases. We'll provide guidance on readout sometime next year.

Unidentified Analyst, Analyst

Sounds good. Thank you.

Operator, Operator

Thank you. The following comes from Jason Szymanski with Bank of America. You may proceed.

Jason Szymanski, Analyst

Good evening. Thank you for taking our questions and congratulations on both the quarter and the recent presentations. A couple of follow-ups on the PEAK-1 study. In terms of the primary endpoint, you have PFS. Merck is advancing a number of similar studies with belzutifan, with Lenvatinib in different settings, including a second line where the primary endpoint is PFS and OS. Curious about your decision behind making the primary endpoint PFS and fundamentally what you think you need to do to distinguish yourself from Merck's combinations, given their potential first mover advantage. Particularly, if you look at the first line setting, there are a range of different studies, which might not show the same kind of efficacy but somehow that inertia keeps them in use. For example, Keynote 426 looks like it’s still being used in about 17% despite not being as good as CheckMate 214 or CheckMate 9ER. Thanks.

Dimitry Nuyten, CMO

When it comes to treatment preferences, several factors come into play. I mentioned earlier that IPI-NIVO is recognized for durable responses and long-term survival benefits. However, the downside is recognized as primary progression, meaning patients with bulky disease, those needing a prompt response, are rarely put on IPI-NIVO. We believe Merck isn't conducting this trial; they don’t have a TKI-free first-line trial. From a physician and patient perspective, avoiding TKI toxicity is a major differentiator. Physicians report that Cabo is much easier than Lenvatinib to manage due to its complex dosing levels and overall toxic profile. Another differentiator is Merck's earlier trial, which limits their experience in post-adjuvant cases. This could lead to a broader label for us. Regarding Merck’s dual primary endpoints, I can’t comment on their logic. Speculating, doing it as a dual primary endpoint makes a trial larger when they might just have aimed for a powered OS secondary endpoint.

Jason Szymanski, Analyst

Got it. So if I’m hearing correctly, you believe that between PEAK-1 and LITESPARK 011, you will have a tolerability edge. Do you think you can also have an efficacy edge as well?

Dimitry Nuyten, CMO

Absolutely. If we can keep a patient on a TKI longer due to better tolerance, you'll see more benefits. We’ll be generating Cas data that looks increasingly differentiated from belzutifan on efficacy, particularly when it goes into the primary PD rate, along with other metrics. We’re confident both the combination partner and our HIF-2 alpha inhibitor will be part of this better efficacy and safety story.

Operator, Operator

Thank you. The following comes from Eva Fortea with Wells Fargo Securities. You may proceed.

Eva Fortea, Analyst

Hi. Thanks for taking the question and congrats on the progress. A quick one: for the Dom pin combo in the Phase 2 EDGE Gastric, you guided to OS data in 2025. If I recall correctly, you've only shown data for one arm, but the study included more arms. I wonder if you're going to share data from the other arms together in the same update, or if this might come at a later time next year?

Dimitry Nuyten, CMO

The guidance is correct; we’re committed to the OS data for EDGE Gastric, maturing for 2025. We've previously indicated that the enrollment in ARM A1 is complete while A2 is still pending. Those data are maturing and I’d say it's unlikely we’ll present everything at once because they won't mature simultaneously, but we will present mature data as it comes available.

Operator, Operator

Thank you. Our final question comes from Yigal Nochomovitz with Citi. You may proceed.

Yigal Nochomovitz, Analyst

Yes, hi. Thanks for the follow-up. Terry, you mentioned in the prepared remarks that you may be in a position to provide updates in the more near term. Does that mean that we might get some of this data in this year, or just clarify what you meant there? Thank you.

Terry Rosen, CEO

We didn't want to get too specific, but when you look at all those studies ongoing, we have multiple cohorts within the study. We’re considering ways to update the important ARC-20 data as they become meaningful and available. Right now, we don't have any specific plans, but we want to ensure transparency as data matures.

Yigal Nochomovitz, Analyst

Alright, thank you, got it.

Operator, Operator

Thank you. There are currently no other questions in queue. This concludes today's conference call. Thank you for your participation. You may now disconnect your line. Thank you.

Pia Eaves, VP of Investor Relations

Goodbye.