Arcus Biosciences, Inc. (RCUS) Earnings Call Transcript & Summary

Hello, everyone, and welcome to the updated ARC-20 Casdatifan Data Call. My name is Emily, and I'll be coordinating your call today. [Operator Instructions] I will now hand over to our host, Pia Eaves, Vice President of Investor Relations, to begin. Please go ahead, Pia.

Good morning. Over the weekend, we issued a press release announcing updated data from our Phase Ib ARC-20 clinical trial of Casdatifan or CAS, in clear cell renal cell carcinoma. The full release, along with today's slides, are available on the Investors section of our website. These data were presented at the ASCO GU Conference on Saturday, February 15. Briefly on Slide 2 of our deck, I'd like to remind you that management will be making forward-looking statements, and we encourage you to review our SEC filings. We are joined today by our CEO, Terry Rosen; our CMO, Richard Markus; and our COO, Jennifer Jarrett. For Q&A, we will be joined by our President, Juan Jaen; and our CFO, Bob Goeltz. I'll now turn the call over to Terry.

Thanks very much, Pia. Before we begin, I want to thank Dr. Tony Choueiri for another terrific clinical presentation on Casdatifan this time at ASCO GU. This was the second oral presentation for CAS at a major medical meeting in just the last 4 months. I actually also want to acknowledge the incredible commitment that Tony has to patients and to developing meaningfully differentiated therapies. We really appreciate that. We now have a large body of evidence that clearly supports the potential for CAS to be the best-in-class HIF-2 alpha inhibitor. It was extremely gratifying to hear all of the excitement that investigators shared for Casdatifan based upon the ASCO GU data set and as we approach the start of enrollment for our first Phase III study. Before we get into the data, I'll start on Slide 4 with a very quick reminder on everything that's happening in Arcus. There's a lot. We now have 3 programs in or about to enter Phase III, 2 of which are expected to generate meaningful clinical data over the next 2 months. So not only for Casdatifan, but also for domvanalimab, our Fc-silent anti-TIGIT antibody. We continue to be very well capitalized with approximately $1 billion of cash and investments as of December 2024 and excluding this morning's financing. And we have significant course sharing across our studies as a result of our collaboration partnerships with Gilead AstraZeneca and Taiho. I want to spend a minute on the rights to Casdatifan. These are now ours. We've been very fortunate to receive significant financial support from Gilead for our other programs, but we're thrilled to now have a late-stage oncology asset that is ours to pursue independently. Gilead's financial support has also enabled us to establish a first-rate clinical development organization, and we can leverage that to achieve the full potential of Casdatifan. We have all the key infrastructure in place. Today, we announced a $150 million financing, which includes participation by Gilead. We expect the proceeds to enable us to fund the Casdatifan development plan through data readout for our Phase III PEAK 1 trial. That's our first registrational trial for can. Owning the rights to Casdatifan really represents a transformational change for Arcus, enhancing our optionality for long-term strategic opportunities. This is particularly true given that Casdatifan targets indications that we are strongly positioned to prosecute on our own. Additionally, the AstraZeneca clinical collaboration and corresponding financial and operational support from AstraZeneca enable us to pursue the highly valuable first-line setting in a very capital and resource-efficient manner while retaining our rights to Casdatifan. We have a lot of experience working with AstraZeneca, as you know, on PACIFIC-8, our study for domvanalimab, and we're thrilled to be working with them again on what we both believe is a very exciting opportunity for both molecules. You'll hear more about our plans and the breadth and magnitude of these opportunities later on this call. Finally, the clarity and magnitude of the opportunity, the clarity of the differentiation offered by Casdatifan and our ownership of Casdatifan enable us to think very differently about how we'll manage our resources in our portfolio of molecules, programs and trials. We plan to share more on this as the year goes along. But as we sit here today, we expect that not only will Casdatifan be central to our development plan, but our priorities and resources will be committed to achieving the full breadth of the Casdatifan opportunity. Now let's go to Slide 6, where we summarize data for the 3 cohorts of CAS monotherapy in late-line clear cell RCC, which were presented on Saturday. All 3 cohorts, which included a total of approximately 90 patients outperformed belzutifan benchmarks on every efficacy measure evaluated. Specifically, we observed disease control rates greater than 80%, well above the 60% observed for belzutifan in LITESPARK-005, registrational trial for belzutifan and primary progressive disease in about half the rate of belzutifan. The confirmed ORR is now above 30% for 2 of the 3 cohorts, 50% above the ORRs reported for belzutifan in this patient population. While duration of response is immature, out of 26 confirmed responses across all 3 cohorts, remarkably, only 2 have discontinued due to progression. So we can't even begin to speculate on a median duration of response. And today, for the first time, we're sharing median PFS data. In 9.7 months for the 50-milligram BID cohort, it's nearly twice as long as the 5.6 months reported for belzutifan. The median PFS has not been reached for our 50-milligram once-a-day cohort with a median follow-up of over a year. We'll share Kaplan-Meier curves shortly. Importantly, we observed these efficacy results while maintaining a comparable safety profile to that of belzutifan, particularly with respect to hypoxia and anemia with on-target toxicities associated with HIF-2 alpha inhibition. The ASCO GU presentation focused on data for the 100-milligram tablet cohort, given this is the proposed going-forward dose and formulation for can. As you can see on the right, these data were quite impressive, particularly given the very short median follow-up of only 5 months with an already confirmed ORR of 33% in the vast majority of patients still on therapy. I want to reiterate that. I want to put it all in CAPS. This is confirmed ORR. In addition to the responders, there are another 10 patients still early in their treatment that have already shown reduction in their tumor volumes. So we expect this to get better. Turning to Slide 7. Here, we show some pharmacodynamic data that we first presented in October. These data are profoundly important. As a scientist, one wants to see a strong biological or molecular rationale that correlates with the improved clinical efficacy profile that we're observing for CAS. These data do just that. In this field, inhibition of erythropoietin or EPO production is the gold standard peripheral biomarker for HIF-2 alpha inhibition. On the left are published data, and these are from Merck, showing the time course for EPO suppression for belzutifan. And by week 13, EPO suppression is minimal at best. In contrast, on the right, we show the same analysis for CAS. CAS achieves approximately 60% suppression of EPO, very close to maximum effect over a sustained period of time. We're out at about 9 months. These data reinforce our confidence that CAS has a strongly differentiated efficacy profile relative to that of belzutifan. In our view, this certainly represents the smoking gun behind the improved efficacy. Turning to Slide 8. I want to spend a moment on our overall vision for Casdatifan. RCC is one of the largest cancer markets globally, the sixth largest in the United States by incidents. We believe that our first 2 settings alone, post-IO and IO-naive clear cell RCC are targeting an aggregate peak sales opportunity that's north of $5 billion. That's driven by both a large patient population and long duration of treatment. However, the opportunity for CAS and RCC could be even greater than that. As standard of care today, almost every RCC patient receives both an anti-PD-1 and VEGF receptor TKI during the course of their treatment. Going forward, we believe that the standard of care will also include a HIF-2 alpha inhibitor. Our goal is to ensure that this is Casdatifan. You will see the details shortly, but the efficacy data for CAS appear to be at least as good as those associated with TKIs, but it has a much more benign safety profile. We, therefore, expect that casatofant will move up in lines of treatment, eventually being used across the entire RCC treatment continuum as shown in a high-level development plan on this slide. We have a diversified approach to evaluating Casdatifan as monotherapy and in combination across a wide variety of settings. Our goal is to, over time, maximize access to Casdatifan so that every clear cell RCC patient can benefit from this potential transformative therapy. With that, I'll turn the call over to Richard to review the data.

Thanks, Terry. I'm excited to assume the role of CMO of Arcus and specifically to be overseeing the clinical development of Casdatifan. These data are incredibly exciting, and I'm thrilled to be leading the effort to bring this drug to market as quickly as possible. I'll start with the study design for ARC-20 on Slide 10. The ASCO GU presentation included updated data for the first 2 expansion cohorts of ARC-20, which evaluated 50 milligrams BID and 50 milligrams QD of Casdatifan, respectively, as well as an initial from the 100-milligram QD tablet formulation cohort, which evaluated the same dose and formulation being used in the Phase III PEAK 1 trial. The 50-milligram BID cohort utilized our earlier formulation, a 10-milligram capsule requiring patients to take 10 capsules a day, so the tablet is obviously much more convenient for patients. Slide 11 shows baseline characteristics for the 3 cohorts. All patients have received prior treatment with anti-PD-1 and at least 1 VEGF receptor TKI. As a reminder, approximately 25% to 30% of patients in each cohort received 4 or more prior lines of therapy. So these patients would not have been eligible for LITESPARK-005, the Phase III trial that supported belbutifan's approval in clear cell renal cell carcinoma. Patient demographics were largely balanced across all 3 cohorts. Slide 12 summarizes the efficacy data. There's a lot here, so I'll step through this slowly. First, for ORR, we observed confirmed response rates of 25% for 50-milligram BID cohort, 32% for the 50-milligram QD cohort and 33% for the 100-milligram QD tablet cohort. The 32% ORR for the 50-milligram cohort includes a responder who confirmed after the data cutoff date. The 100-milligram QD numbers are especially impressive given the limited median follow-up of only 5 months. The rate of primary disease progression continues to be very low at only 14% to 15% for the 50-milligram QD and the 100-milligram QD cohorts, much lower than the 33.7% observed with belzutifan. Median PFS has only been reached in 1 cohort, the 50-milligram BID group with 9.7 months. This is a substantial improvement, nearly double the 5.6 months observed for belzutifan in LITESPARK-005. So we now have 3 different cohorts, all of which demonstrate improvement on every key efficacy measure evaluated relative to belzutifan, reinforcing confidence that this is a potential best-in-class drug. On Slide 13, we show the waterfall and spider plots for the 100-milligram QD tablet cohort. These data are early with only 5 months median follow-up, but extremely encouraging and the strong potential to further improve with duration of treatment. The spider plots highlight the speed of tumor response with a median of less than 2 months. Nearly all patients remain on treatment and have experienced some tumor reduction. On Slide 14 are the updated waterfall plots for the 50-milligram BID and 50-milligram QD cohorts. Even at 15 months median follow-up, over 35% of patients remain on treatment in the 50-milligram BID cohort and nearly 2/3 of patients remain on study in the 50-milligram QD cohort. There's one of the patients who shows up here as a PD in the 50-milligram cohort, but you can see that their tumor actually shrunk by more than 30%. Despite scans indicating that the patient progressed, the clinician kept the patient on treatment and they ended up having significant reduction in their tumor growth. So although this patient is classified as PD, the reality is that subsequently, the patient achieved the same level and durability of tumor reduction associated with a confirmed response. And more importantly, the patient is continuing to derive substantial benefit from Casdatifan therapy. The following slide shows updated spider plots and highlights the durability of treatment with Casdatifan. Across all 3 cohorts, only 2 responders have come off therapy to date, which is quite remarkable. Importantly, even stable disease patients are experiencing significant and durable benefit with many of these patients now on treatment beyond 12 months. These patients are obviously contributing meaningfully to PFS. On Slide 16, we show the updated swim lane plots. And again, you'll see the impressive durability of this mechanism as a single agent in late-line patients. On Slide 17, we show the PFS Kaplan-Meier curves for the 50-milligram BID and 50-milligram QD cohorts. On the left, you can see we have reached a median of 9.7 months PFS for the 50-milligram BID cohort. This is nearly double the median PFS seen in LITESPARK-005. The median PFS shown here is stable and unlikely to change. On the right, we show the Kaplan-Meier curve for the 50-milligram QD cohort where the median has still not been reached even with 12 months of median follow-up. Note that the majority of censoring in this graph occurs after 8 months and the 2 patients censored before month 8 are both responders. So we expect the PFS for this cohort to be quite a bit higher than the 50-milligram BID cohort. And if you were to combine these 2 cohorts into 1, the median PFS would be an impressive 13 months. For the 100-milligram QD tablet cohort with a significant number of patients remaining on drug, the PFS is extremely immature, and we'll share these data as soon as we achieve a stable median. Slide 18 shows the safety tables for all 3 cohorts. We showed the rates of serious adverse events as well as on-target anemia and hypoxia relative to what was observed for belzutifan in LITESPARK-005. And you can see that our safety profile continues to be quite similar to that reported for belzutifan. This means we are achieving better efficacy results without a higher incidence of an on-target adverse event. On Slide 19, we compare the data presented today to those from LITESPARK-005. For every cohort, czatofrin performed better on every efficacy measure. This is despite the fact that ARC-20 enrolled a more advanced patient population than LITESPARK-005. Rates of primary progressive disease are close to half that of belzutifan. Confirmed ORR is consistently higher than that of belzutifan with both the 50-milligram and 100-milligram QD cohorts having ORRs greater than 30% and both still have the clear potential to increase. For DCR, over 80% of patients are benefiting from Casdatifan versus just 61% for belzutifan. And lastly, the median PFS of 9.7 months for the 50-milligram BID cohort was meaningfully longer than belzutifan's 5.6 months, with median PFS not reached for the 50-milligram QD cohort. I'd now like to discuss the next steps for the Casdatifan program. For the first 2 settings we are pursuing, we are building on top of standard of care. This is very important for a number of reasons, including the tailwinds that brings to study enrollment. On Slide 22, we show the design of PEAK 1, our initial Phase III study. Here, we are evaluating Casdatifan plus cabo versus cabo, the most common TKI prescribed in the second-line setting in patients that have received prior anti-PD-1. Start-up activities for PEAK 1 are underway with trial initiation on track for next quarter. On Slide 23, we summarize our initial strategy in the IO-naive first-line setting. This year, our partner, AstraZeneca, will initiate and operationalize a new Phase Ib trial, which will be part of their portfolio of EVOL studies. This trial will evaluate Casdatifan plus faristamig or Volu, AZ's anti-PD-1 CTLA-4 bispecific in patients who have not received prior immunotherapy. The combination of nivolumab and anti-PD-1 and ipilimumab and anti-CTLA-4 is the most widely used regimen in the first-line renal cell carcinoma today. We have an opportunity to build on this standard of care and create a highly effective TKI-free regimen for first-line patients. I'd now like to turn the call over to Jaen to discuss the commercial opportunity for Casdatifan.

Thank you, Richard. I'll start on Slide 25, which shows the market share for various therapies in first- and second-line RCC. The vast majority of patients in the first line receive either IO plus TKI or IO plus IO, specifically IPI/NIVO, which currently has about 1/3 market share. This share is growing since physicians and patients prefer to avoid TKIs for as long as possible, and this regimen has curative potential. Although IPI/NIVO has been an important advancement in RCC, its weakness is its high rate of primary progression, 25%. We believe that adding CAS can bring down this primary progression rate, enabling more patients to benefit from this regimen while avoiding the toxicities of TKIs. As a result, we believe a cabo combination would not only displace IPI/NIVO, but could also take share from IO/TKI or other combinations. In the second-line plus setting, treatment is typically a TKI. Our PEAK 1 study is adding CAS to cabo, which is the most commonly prescribed therapy in the second line with 30% market share in this setting. Given clinicians significant comfort with cabo, which is why we selected cabo as our TKI combination partner, we believe this will be an extremely attractive option for them. Turning to Slide 26. We highlight here the market opportunity for our first 2 indications. The market potential is driven not only by the number of patients, but also by the very long durations of therapy or DOT, 18 months or more in first line and over a year in second line. The first 2 segments we are pursuing represent a peak sales opportunity of $5 billion or more, and we are actively pursuing additional opportunities in RCC. As Terry previously mentioned, HIF-2 alpha has the potential to become a standard of care therapy for all patients with clear cell RCC with CAF as a HIF-2 alpha inhibitor of choice. On Slide 27, we show the current formulation for CAF. As you can see, with patients taking multiple different medications on a daily basis, pillbird can add up quickly. Belzutifan is currently sold as 3 40 mg tablets per day. However, a single once-daily pill is preferred by patients. Therefore, we plan to offer multiple tablet strengths that will enable patients to take just 1 pill per day while preserving the optionality to dose down without sacrificing any efficacy. This is an important differentiator for Casdatifan that we believe will position us for commercial success as the HIF-2 alpha inhibitor of choice for clear cell RCC patients. I'd now like to turn it back to Terry for closing remarks.

Thank you, Jennifer. I'd like to wrap up our discussion of CAS on Slide 29. The value proposition for Casdatifan is simple, but more importantly, it's compelling. Like anti-PD-1s and TKIs, we expect standard of care for clear cell RCC patients will include a HIF-2 alpha inhibitor. The data that we've shared support a clinical profile that is notably differentiated from that of belzutifan with clear potential to be best of-class in this 2-horse race and most importantly, change the standard of care in RCC. CAS is a great example of the success of our in-house drug discovery capabilities. It's a homegrown molecule, one that has been shown to selectively and potently inhibit a notoriously difficult target, HIF-2 alpha, while having optimal drug properties. These features have been carefully engineered by our research team and ultimately, it's the quality of the molecule that drives such robust clinical outcomes. The ASCO GU presentation was just the beginning of a steady stream of data for CAS that we expect to share into next year. Around midyear, we expect to present data from the ARC-20 cohort evaluating CAS plus cabo for presentation at a medical conference that will be midyear. We also expect to present more mature data, including median PFS from the monotherapy cohorts later in the year. And next year, we should have initial data from the new first-line cohorts in ARC-20 as well as more mature data from the cas/cabo cohort. Turning to the last slide. This is a reminder of everything else happening at Arcus. We're rapidly approaching the initiation of our first Phase III study in clear cell RCC. With the opportunity to independently develop and commercialize Casdatifan in the U.S. and Europe, we'll be laser-focused on maximizing the opportunity in clear cell RCC. We want to be clear that CAS now has disproportionate value to Arcus and its shareholders, and we intend to prioritize our resources accordingly. It's transformational for us as we continue to build a long-term sustainable and fully integrated biopharmaceutical company. That said, this is just one of our late-stage programs. We have 2 others dom and quemli that are addressing multibillion-dollar market opportunities in settings with extraordinarily high unmet need. Importantly, with our investment in domanilimab on the decrease as we near our first readout, the transition of focus of our resources to cascatpant is really very organic. It's timely and it's seamless. Recall that our development approach to Dom has been very efficient with Arcus only executing one of the Phase III trials, STAR-221, which was fully enrolled in June of last year and readout is approaching. With approximately $1 billion of cash and investments at the end of 2024, again, that's before today's financing, we're very well positioned to execute an aggressive Casdatifan development plan. We're funded through multiple Phase III readouts, including, most importantly, our first Phase III trial for Casdatifan, it's PEAK-1. We're extremely excited about this weekend's data, the opportunity for Casdatifan as well as multiple other opportunities that we have to make a meaningful difference for patients. So I want to thank everybody again for joining us today, and I'll now open things up to questions. Thank you.

[Operator Instructions] Our first question today comes from Yigal Nochomovitz with Citi.

One big picture question and then one on the data. On the data, could you just provide a little bit more clarity with respect to the PFS results in the 50-milligram BID and 50-milligram QD just with respect to how those play? And then secondly, on the broader picture with the R&D, given the decreased investment in X, can you just articulate a little bit more how you see the relative split on R&D between CAS and the other programs going forward, especially now with Gilead not involved?

Thanks very much, Yigal. So let me start with the question about the 50-milligram once a day and 50-milligram twice a day dose and not only the PFS, but the totality of the data for each. I think it's important to recognize that both of those doses are, in fact, very much up on the dose response curve for Casdatifan. Keep in mind that the 50-milligram mono is basically 2.5 the pharmacodynamic equivalent of the 120-milligram belzutifan dose, basically, which was good enough to change the standard of care in the field. So -- you're looking at a twofold difference between our 100-milligram broken into twice a day and 50 milligram once a day. So you're not really looking at a dynamic range from a dose response. They're both very robust doses. So I would just say, at this point, you should think of those differences probably just as much related to anything as noise. And in fact, if you look at the 100-milligram tablet, I think it's trending that that's going to end up looking like the best cohort. So truth probably is some average of all 3 of them. I'll make a high-level comment on the Casdatifan investment. For us, as I mentioned, it's really got disproportionate value given the fact that from a probability of technical success, it's about as high as you can get. And then on top of it, we own 100% of the rights. So very organically, if the anti-TIGIT programs wind down in spending, we're going to be able to resource Casdatifan such that everything you see in our development plans really can be executed on very efficiently internally by our team, which is all set to go. I don't know if is there anything you would add to that, Jeff?

Yes. No, the other thing I would just say is for TIGIT spend because we're kind of past peak enrollment, the development spend, as Terry was alluding to, is on the decline. And next year, in particular, there's a pretty significant drop of about half and then it drops another 50% the following year. So to Terry's point, TIGIT spend is starting to decline as we're past peak enrollment. And obviously, cash spend will start to increase as we ramp up these other studies.

Our next question comes from Umer Raffat with Evercore.

So obviously, Gilead doubled their equity ownership in Arcus last year. And on HIF-2 in particular, they could have either opted in and/or they could have been a part of the syndicate. I guess a couple of questions, if I may. First, their ownership is at 33% already. Is that why it wasn't possible for them to have additional participation in the syndicate? Secondly, from an opt-in perspective, what was the key feedback you guys heard from Gilead? Did they have certain expectations on dose response, for example, or the cross-trial comparisons on PFS? I'm just curious. And then finally, I know the cabo combo, it was -- at least for clinical trials, it was only added as of June last year. So can you speak to what level of data has been generated internally so far? And did Gilead have any visibility into that cabo combo?

Thank you, Umer. So the first -- on the first point, Gilead actually did participate in the equity offering. So I want to be very clear on that. On your second point, honestly, we think like if people want to understand Gilead's thoughts, it's best to ask Gilead. We don't want to talk about other strategy, put words into their mouth. I would just come back to the point that from our standpoint, we're thrilled. I mean, we couldn't have been happier about this for all the reasons we talked about, given the value of this asset, given the opportunity, given the ability to sort of control our own destiny with the development. And then most importantly, the strategic optionality that, that provides us. To your final question on CAS cabo, in fact, we have shared that as of the end of last year, we had enrolled 25 patients. We're probably up to closer to 40 now. We intend to share data from that midyear. And in fact, we have already submitted an abstract, so we know how it's looking. And what we've said publicly is there's no surprises. So both from a safety standpoint, the data look as expected. You see just what you would expect from combining the 2 mechanisms. And I think efficacy is emerging similarly. And certainly, Gilead saw all the data that we have. But basically, the way I would describe it is they saw what is early data that looked just as I'm describing right now. No surprises.

One other point that I get you obviously have the clinical collaboration with AstraZeneca, which we're both very excited about. And they've obviously seen all of our data as well.

If I may, could you just clarify -- sorry, 2 things. One, what's the updated ownership of Gilead and Arcus? I know it's 33 previously. What is it now? And secondly, Terry, when you said efficacy is emerging similarly for the combo, what do you mean by that?

So I'll answer that. I'll let Jaen or Bob deal with the ownership question. I don't think I meant to say something similarly. I would just say that the efficacy is looking as one might expect for 2 agents that both have good activity combined. And you'll see them in -- and we'll see them as they continue to evolve, but nothing looks different than you might have expected from a safety or efficacy standpoint at this point in time.

In terms of their ownership, Umer, I would just say that this round of financing didn't meaningfully change Gilead's ownership percentage and definitely, the participation was meaningful.

The next question comes from Daina Graybosch with Leerink Partners.

Congratulations on the data. I'd like to talk more about your biomarker HPO. And that really stands out to all of us as being distinctly different between CAS and belzutifan. And I wonder if you could walk through the hypotheses for why that may be relevant and give us all more confidence that ultimately CAS will continue to stand above belzutifan in efficacy and arguments for why it's irrelevant. And in that, anything you're doing translationally that we may see midyear to further understand this?

Thank you, Daina. So just to clarify for everyone else on the phone, what Daina referring to our time course data for tracking that gold standard biomarker for HIF-2 alpha inhibition in a human, the suppression of erythropoietin production in a healthy kidney, and that's HIF-2 mediated. And what you see is if you look on day 1, both ccatifan and belzutifan essentially inhibit that to a maximal effect. The reason that you don't see differences in rates of anemia has to do with the sort of a break if you will, in how humans respond to that inhibition. And so the maximum suppression of erythropoietin is somewhere likely between 65% and 80% in -- depending on the individual patient. But what's very interesting are the data that Merck published in a clinical pharmacology paper in October of last year that show that, in fact, roughly about 3 months into treatment, they lose effect on that biomarker. We've shown with our molecule that out roughly at 9 months, 36 weeks or so, we still maintain a near maximal effect. Now I think it's important that everyone understand, and we made this point year ago before these data even exists that we don't look at erythropoietin production or suppression as a one-to-one correlate with activity. But HIF-2 as a transcription factor, since it regulates hundreds of genes, you can sort of think of it as a surrogate for things that might be going on with other genes. So our notion is that what this tells you is there may be genes involved and in fact, probably are that all have different dose response curves and some of them even day 1 might look like what you see in the later point with belzutifan and some may evolve with time upon treatment like belzutifan. So what's clearly going on is there's some sort of feedback in the kidney that's pushing back on that inhibition and overcoming it. So we think that what that tells you, it's a smoking gun for the difference between the 2 molecules. And the reason -- so I'm going to give you 2 things that are going on. The first thing is that there is evidence in the literature that when you inhibit HIF-2 alpha in the kidney, it can become phosphorylated and actually have increased activity. So it's not unreasonable, the same sort of thing might happen in other important genes. So since belzutifan is basically at their clinical dose is about 0.9 to 1x that dose that gets you that maximal inhibition, but Casdatifan is 500% or 5x the pharmacodynamic equivalent of that maximal inhibition. If you shift that activity, if that HIF-2 alpha becomes more active, we have a lot more headroom as that dose response curve changes. Now I'll make one other point that it's really -- we've shared this occasionally, but we haven't -- it hasn't been a major point, but I'll just mention something that we feel sort of strengthens the argument. We actually looked at our -- in our dose escalation study. And if you go to the 20-milligram dose of the Casdatifan, keep in mind, it's only 3 patients. But what's very interesting is 2 things. as we talked about from day 1 when we did our dose escalation study, the 20-milligram dose of Casdatifan is essentially the pharmacodynamic equivalent of the 120-milligram dose of belzutifan. So 20 milligrams Casdatifan, 120 milligrams of belzutifan. And interestingly enough, if you look at those 3 patients, on average, they're also losing that effect out at about 3 months. So we think that pharmacodynamic argument applies quite well to the situation and it is very much a surrogate for what might be going on with other genes as well. Well, you ask -- sir also comment on what else we might talk about. So the first thing on biomarker work around this mechanism, one thing, at least in clear cell RCC that I'd point out is a lot of this from our standpoint is thinking about understanding what's going on and also thinking about how it might play into other settings outside of clear cell RCC. But one important thing to note, oftentimes, when you're looking for a biomarker, it's because you're trying to find the sliver of population that's responsive. Keep in mind, we're seeing roughly an 85% disease control rate. So in clear cell RCC, where we know that probably greater than 90% of the patients have some component of HIF-2 driving their cancer, there's not a screening need for a biomarker. Nonetheless, the work that we've been doing and at some point this year, we may share some of that is basically in our translational efforts, we've been looking for blood -- things that we can measure in blood that are more reflective of the antitumor activity than just erythropoietin readouts. And we've actually seen some interesting things there, and it's -- those are data that we will likely share at appropriate time when we have enough confidence in those data sets. But again, what we're measuring are proteins that are reflective of what might change that we would expect might be actually things that are coming from the tumor.

Our next question comes from Peter Lawson with Barclays.

So Peter, we aren't hearing anything. It sounds like you're scuba diving. Do you want to try repeating that, Peter? Sorry.

Yes. Can you hear me now?

Awesome.

Perfect. If you can give us any details around why Gilead didn't opt in? It seems that there's a lot to like around the data set. And then I've got a follow-up question around PFS data in mid-'25, if we see that.

Yes. I mean we can't imagine there's anything in the data that resulted in their decision to not opt in. I mean you'd have to ask them for specifics, but I think it was just a strategic and prioritization decision for them. And I think it's all good for us. Like we couldn't be more excited to have all the rights to ourselves. We have the Phase III study TDP ready to go. We now know we can go full steam ahead on that. So we can move even more quickly, we think, without them having opted in. So we think it's very good for us. Like I said, I can't imagine there's anything in the data that led up to their decision. Everyone saw the data over the weekend. I think everyone thought the data looked fantastic. The response from the investigator community could not have been better. We've had inbound e-mail throughout the weekend from investigators that want to make sure they're able to participate in the PEAK 1 study. So I wouldn't read anything into their decision other than they're just making priority decisions.

Great. And then just a follow-up question. As we think about the combination data mid-2025, would we see PFS data as well?

It's going to be way too early. But you'll see early ORR data, and we think those will look good.

Got you. Would we see anything around duration, so like swim lanes and spider plots.

It will probably be pretty early. I mean most patients will have like 2 or 3 scans on. So it will be more like ORR. And I think the idea is that the ORR for the combination would be better than what we would expect to see for monotherapy for either of those 2 agents alone, so cabo versus CAS. But it will definitely be way too early for PFS and the OR. So the focus would be on safety and then ORR.

Peter, keep in mind, the purpose of that cohort was to generate safety data that supports what we're doing in Phase III. So because we are what we are, we're sharing those data early, they're going to look good, but they're not mature data. So you're not going to have any types of readouts and durability. But you'll get a good feel for the ORR in the context of safety. And those are going to be -- if you sit and think about what you might expect, we've obviously submitted abstracts, and we know how those data are trending and they're going to look like you would expect.

The next question comes from Asthika Goonewardene with Truist Securities.

On the update over the weekend and today as well. It's good to see all that. I want to go back to Umer's question on CAS and cabo here, and I'll add a little extra to it. We saw the LITESPARK-003 data for Cohort 2 as well, and that's where cabo plus belzutifan got you around 30% ORR and about 40 months of PFS. Your 100 mg QD is already at a similar ORR. So maybe I want to push you back on just one thing. Where do you think the CAS and cabo combo will have the most pronounced efficacy effect? And then 2 quick ones on the data, if I can squeeze in here. The patients who had progressive disease but still had a substantial target tumor reduction. Was there any evidence of pseudoprogression or do you see any T cell infiltration on treatment with CAS? And Jen, what's the duration of therapy that you're seeing for CAS? I know you mentioned you had some assumptions going into your forecast there, but what are you kind of seeing right now in that second-line setting, the duration of therapy with CAS?

Yes. I think for ORR, I mean, you raised a good point that we're already seeing a pretty high ORR for CAS monotherapy north of 30% confirmed ORR. So all I would say is I repeat what I said earlier that our goal for the combination is to show an ORR that's higher than what we see with CAS mono and what we'd expect to see with cabo mono. So you can go back and look at the cabo mono data sets to give you a sense for where we want to be. As far as -- did I answer that first question?

But I'm also wondering, do you think you'll also see a substantial PFS benefit and duration of therapy...

Yes, our goal would definitely be to see a PFS benefit. Obviously, we're seeing whether it's 9.5 months, 13 months, if you look at the combination, again, the goal would be to show a greater PFS benefit than what we're seeing with CAS mono and what we'd expect to see with cabo mono. And as a reminder, the right comparison for cabo mono was from CONTACT-03, where they talking about a 10.5-month PFS for cabo mono. And really, the goal of this study, and I think this is what we've been able to show so far and we'll be able to show when we present the data is to really be able to maintain the full doses of both drugs as much as possible. And as you know, the hips of death in these studies can be when you see some toxicity and that results in patients coming off treatment or dose reductions. There was an example of that over the weekend with COSMIC-303 that I'm sure a lot of you saw. So that's something that we're really keeping a close eye on with the CAS cabo cohort. And so far, I think we've been very happy with our ability to keep patients on full doses of both drugs and to minimize dose interruptions and discontinuations. For the next -- and obviously, we'll share all of that data when we present the data in the middle of the year. As far as the pseudoprogression question, it was a little bit tough one to answer. I think I wouldn't say that's something we're really looking for. We did highlight one interesting anecdote that maybe speaks to the possibility of pseudo progression, but there was one patient in the 50 mg cohort, if you look at the waterfall, it's a black bar in the middle of a bunch of blue bars. And that patient was originally marked as a progressor or a PD on the first scan by the clinician. They thought that maybe was an artifact of the scan, decided to keep the patient on treatment. 2 scans later, that patient actually ended up becoming a responder. Next scan confirmed responder. They now have 40% tumor reduction still on treatment doing amazing. But because they were originally marked as a PD, we counted them as a PD. But that may speak a little bit to your question about like pseudo progression. And you do hear anecdotes of sometimes with these kidney tumors that it can be a little bit difficult to read some of the scans. -- that you may have scarring and other things that look like the tumor. But we're keeping a close eye on that, and we'll see over time if we do see more signs of pseudoprogression. And then your last question on duration of therapy. As Terry pointed out, of the 26 responders across 3 cohorts, only 2 of those responders have progressed, which is just amazing. So we don't have a median duration of therapy yet. We'll follow that closely. But our expectation is that it's going to be on the high side. And obviously, that will drive the commercial opportunity for the drug.

I think one very important thing about this mechanism, and it's obvious if you look at the spider plots, particularly focused on the more -- the 2 that are more mature, the 50-milligram once a day and the 50-milligram twice a day. What you actually see is that the stable disease patients are very meaningfully contributing to PFS and in fact, getting great benefit. I think what's important, when you have a mechanism like this where, in particular, it's very important in the cancer and it's very safe. So you're not having to take patients off of therapy, do dose reductions. Those stable disease patients look very much like an IO therapy where that tail just goes on and on. So if you look, the yellow lines in those spider plots look just like the blue lines and you have that arbitrary 30%, which is important, but it's not the ultimate driver. So you're seeing substantial benefit on any patient that can make it through that first scan. And that's why we feel, and I think investigators feel why the rate of primary progression is such an important component here. Before we even started our studies, when we first talked -- when we had our first ad board, investigators pointed out that they love the mechanism, they like belzutifan, but the Achilles heel was at 34% rate of primary progression, which was actually even worse than everolimus in the registrational study. So patients that can make it past that first scan, as you can see from the spider plot, now you have 3 cohorts do quite well. And I think it will be obvious if you look at the 100-milligram tablet formulation, even though it's early, you can play out the movie because you have enough data from the 50-milligram and 100-milligram with the capsule to see how those lines, which are already on the same trajectory, how those patients are going to look over the long term. So probably the most exciting thing about this therapy is the fact that you get great durability.

Our next question comes from Li Wang Watsek with Cantor Fitzgerald.

Congrats on the data. Just a couple of questions from me. First, on the time line for the PEAK-1 study, can you just remind us what you expect the top line to read out given it's a PFS endpoint and 2:1 randomization relative to bezutfen's second-line study? And then second, wondering what's the rationale to go after the favorable risk patients with monotherapy? And what do you think the risk benefit needs to be for this population?

So the 2 questions then when do we expect this to read out and the second about the monotherapy. I'll take the first question and then Jen, take the second. So obviously, we get whacked in the nose for giving guidance for when a Phase III trial is going to read out before we've even started the Phase III trial. But we're certainly willing to share how we might anticipate this type of trial going. So we think it has extraordinarily positive tailwinds in terms of enrollment. So we have great steering committee. Tony is leading things. A lot of the early sites will be participating in PEAK 1. So -- and the other important thing is in clear cell RCC, there's not a whole lot going on. So there's a very strong enthusiasm for HIF-2 inhibition. And basically, a lot of investigators have seen casatfan and think it is -- does have a superior profile. So we expect the study to enroll very well. It's the type of study that you could imagine enrolling in 1.5 years or less. And so then you can take your own calculations in so far as what the expected PFS. Keep in mind that PFS is the approvable readout in this setting. So again, that makes things faster. And you can do your own math as to when we might have a readout. Jen, I don't know if there's anything more you want to say on that and then the second question.

Yes. So on the first-line question, yes, so first of all, stepping back, we added 3 new cohorts to ARC-20. The idea being starting to look for opportunities where we could displace TKI given that we strongly believe that CAS has a similar, if not maybe even better efficacy profile and obviously much better tolerability profile. The first of those cohorts is looking at first-line patients and evaluating CAS plus PD-1. The second, which was the one that you asked about was a CAF monotherapy in first-line favorable risk patients. And then the third cohort is looking at first- and second-line patients that have received anti-PD-1 but have not received TKI. So the idea behind all of these is to move up in lines of therapy. As far as the first-line favorable risk study, this is one -- all of these actually were suggestions from clinicians or advisers that we work closely with. There's a huge amount of interest. We have literally like studies reaching out to us to now get involved in ARC-20 specifically to be involved in these cohorts. But this one, if you look back at LISBERK-013, which was basically dose optimization study that worked in, but they did some interesting subgroup analysis, and they showed a clearly higher ORR and PFS in patients that were favorable risk. Given these patients can have a little bit more indolent disease, we think the HIF-2 alpha inhibition mechanism may be particularly well suited for these patients, particularly as monotherapy. So that's really the idea there. A lot of these patients, they're super healthy. They have no symptoms. So the last thing they want to do is go on a TKI. So that was really another reason why there's been a lot of interest in exploring HIF-2 alpha inhibition, a much better tolerated mechanism in these patients. And these are all starting as we speak.

The next question comes from Salveen Richter with Goldman Sachs.

This is Matt on for Salveen. Congrats on the data. Could you share anything on the registrational path or potential registrational path for the IO-naive combo with bezutfen? And also the CAF monitoring approach, how are you thinking about? Like could you add a CAS mono arm to the Phase III PEAK-1.

So for VolRU, all we're going to disclose today is that we're gearing up to start the Phase Ib study. So as we said, as part of the EVOLVE platform of studies, AstraZeneca is operationalizing the study. We obviously, as Terry pointed out earlier, have a relationship with them. So it's been very easy to work with them on another study. They are super excited about the combination. They really would love to get VolLRU, I think, eventually approved in RCC. So I think they do view this as an interesting path. It's, I think, too early to comment publicly on what the registrational path would look like. But we'll obviously start this Phase Ib soon and look forward to seeing the data from that combination. And the other part about working with AZ on this is it's obviously very resource and cost efficient for us. Obviously, there's cost sharing involved, and we don't need to hire the people, build the additional infrastructure to do that study ourselves. So we think that's a win-win. As far as mono, we could not -- I think it would be too difficult to include that in a peak one. So either we would expand that out as part of ARC-20, it would become more of a guideline incorporation type of study or we would start another study that's bigger, that would be registrational or we could even do like an IST, a large IST or cooperative group study that could potentially support the registration of that regimen. Interestingly, as I think we've talked about a bit is we're also starting an IST in the neoadjuvant setting. So that's something else that we're looking at. That's going to be an IST with study at Dana-Farber. It's going to be the largest IST. So kind of same idea. If that data looks interesting, it could be helpful as far as getting incorporated into treatment guidelines.

Our final question today comes from Emily Bodnar with H.C. Wainwright.

I wanted to go back to the 50 mg QD versus the BID and 100 mg QD. It looks like you're seeing fairly similar efficacy across all 3 of those cohorts. So I want to kind of understand how confident you are that the 100 mg makes the most sense as the go forward versus the 50 mg QD.

Sure. So we're like as confident as it can be and in fact, have discussed at least the data that look similar to this with the FDA when we agreed upon our Project Optimus plan, which is playing out the same. I think that the key driver in that is that if you look at the safety data, it's very clear that the 100-milligram dose looks similar from a safety standpoint to the 50-milligram dose. And as you know, Project Optimus is certainly more focused on safety, although efficacy certainly enters into the equation. And then what you can see is if you look -- and keep in mind, it's twofold dose difference. But what you do see in both of those -- both the 50-milligram BID and the 100-milligram tablet formulation, you see a faster time to onset, which again is suggestive of more potential efficacy. And then if you look at the 100-milligram tablet, I think there's no question, you can do your own betting as to where the ORR is going to end up. All those patients that are going to contribute to PFS, it's certainly trending to look better. The other thing to keep in mind is that, that does give us the option, and this will always happen. When there will be dose reductions, we'll be able to go from 100 to 50. And obviously, that 50 is a very robust dose as well. So in totality, it's probably the safety piece that makes it 100% straightforward call. But we do think that the efficacy coming from the 100-milligram is and will continue to be better as time goes along versus the 50-milligram dose.

Thank you. We have no further questions. And so this concludes today's call. Thank you, everyone, for joining us today. You may now disconnect your lines.