Arcus Biosciences - Earnings Call - Q1 2025

Executive Summary

• Q1 2025 revenue was $28.0M and GAAP EPS was $(1.14); both missed S&P Global consensus (Revenue $38.6M*, EPS $(1.08)*) as collaboration revenue normalized post-2024 catch-ups and licensing inflows; FY25 GAAP revenue guided to $75–$90M.
• Management reiterated casdatifan (HIF-2α) as the top priority, with Phase 3 PEAK-1 (casdatifan+cabozantinib vs cabozantinib) initiating in Q2 and strong investigator enthusiasm; safety/efficacy signals for the combo expected at ASCO support the trial design.
• Balance sheet remains robust with $1.005B cash, cash equivalents and marketable securities at 3/31/25, enabling funding through initial pivotal readouts (domvanalimab, quemliclustat, casdatifan) including PEAK-1.
• Near-term catalysts: ASCO oral for casdatifan+cabozantinib (initial efficacy/safety), PEAK-1 initiation, AstraZeneca eVOLVE PD-1/CTLA-4 bispecific combo study start; medium-term: EDGE-Gastric OS data in fall 2025 and multiple ARC-20 updates.
• Narrative shift: Arcus will self-execute PEAK-1 and potentially commercialize in the U.S. (Europe partner possible); pipeline reprioritization de-emphasizes etrumadenant Phase 3 while accelerating RCC programs to maximize casdatifan’s “best-in-class” potential.

What Went Well and What Went Wrong

What Went Well

• CEO emphasized casdatifan is “unequivocally” the #1 priority with confidence in best-in-class efficacy/safety and rapid data cadence (ASCO oral for casdatifan+cabozantinib; multiple ARC-20 cohorts).
• Strong cash position ($1.005B) and capital allocation discipline to fund key Phase 3 readouts (domvanalimab, quemliclustat, casdatifan), despite macro volatility.
• Clinician enthusiasm and early combo safety experience underpin PEAK-1 design (cabo in both arms, 2:1 randomization) and support fast enrollment; management expects advantages vs Merck’s LITESPARK-11 design.

What Went Wrong

• Revenue and EPS missed consensus as quarterly collaboration/licensing flows declined vs the unusually elevated prior-year quarter; revenue fell to $28M from $145M YoY.
• Higher R&D expenses ($122M vs $109M YoY) given increased early-stage activity and Phase 2 enrollments, driving net loss $(112)M; management noted 2025 is peak development spend year.
• Etrumadenant (ARC-9) registrational path paused pending prioritization; despite promising mCRC feedback from FDA, Phase 3 not pursued currently.

Transcript

Operator (participant)

Hello everyone and welcome to Arcus Biosciences' First Quarter 2025 Earnings and Financial Results Call. My name's Lydia and I'll be your operator today. After the prepared remarks, there'll be an opportunity to ask questions. If you'd like to participate in the Q&A, you can do so by pressing star followed by one on your telephone keypad. I'll now hand you over to Pia Eaves, Vice President of Investor Relations, to begin. Please go ahead.

Pia Eaves (VP of Investor Relations)

Good afternoon and thank you for joining us on today's conference call to discuss Arcus' first quarter 2025 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 CAHPS runway, our projected 2025 revenue, 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 10Q that is filed with the SEC. Today you'll hear from our CEO, Terry Rosen, CMO, Richard Markus, 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 it over to Terry.

Terry Rosen (CEO)

Thanks very much, Pia, and thanks to all of you for listening in today. While the world around us has been somewhat or maybe definitely tumultuous, at Arcus we've really remained focused on execution, and that execution goes with speed, efficiency, and most importantly, rigor. Before we get into the details, I want to emphasize three points that will be apparent in our discussion today. First off, our late-stage portfolio is rich, but our number one priority is unequivocally casdatifan. So far, the more data that we generate, the better it looks. Our goal is simple: bring casdatifan to market and to patients as quickly as possible and create maximal value for this program. Second, we are well capitalized, and our long-term strategy has positioned us well to advance Dom, kwemli, and cas through their respective initial phase three readouts.

Nonetheless, we're always cognizant of the macro environment, and we're committed to ensuring our resource deployment reflects our ongoing assessment of priorities so that our cash runway extends as long as possible. Third, we expect to have a steady flow of data for casdatifan over the next couple of years that will reinforce the advantages relative to both belzutifan and TKI monotherapy. In that vein, we're thrilled that our abstract describing initial data from the cas plus cabo cohort of ARC-20 was accepted for an oral presentation at ASCO. This is the same combination we're evaluating in our first phase and quarter, and these data should provide further support for the study. This will also be the third oral presentation of casdatifan data at a major medical conference in just seven months, and there are a lot more to come.

Okay, now some important granularity around the casdatifan program. In our phase I-B ARC-20 study, we now have eight cohorts evaluating different dosing regimens, combinations, and settings for cas in clear cell RCC. This is why ARC-20 will generate meaningful data over the next two years that will serve several important purposes. First, continued elucidation of casdatifan's differentiated efficacy profile relative to that of belzutifan and derisking of our first phase III study, PEAK-1. Second, continuing to drive the already extraordinary investigator enthusiasm for PEAK-1 to support its rapid enrollment. Third, demonstrating the opportunity for casdatifan in earlier line settings where casdatifan has the potential to ultimately displace TKIs. Before I turn the call over to Richard, I'd like to touch on a few additional topics, starting with our development plan and our long-term vision for casdatifan.

Our phase III trial, PEAK-1, will evaluate cas plus cabo versus cabo in clear cell RCC patients who have received prior immunotherapy. For our first registrational trial, we chose to combine cas with cabo because cabozantinib is the gold standard and most widely used TKI in the setting. In fact, in our ARC-20 monotherapy cohorts, 78% of patients received prior cabo. That's greater than three times more than any other TKI. Clinicians are extremely comfortable administering and managing the toxicities of cabo, and because of this, there's an extraordinary amount of interest in PEAK-1. Also, because HIF-2α inhibition affords a relatively benign safety profile with the primary AEs being on-target anemia and hypoxia, we do not believe cas will have meaningful overlapping toxicities with cabo.

As such, the key objectives of our upcoming ASCO presentation are to clearly demonstrate that these two molecules can be safely combined and that we can add efficacy to that of cabo monotherapy. We expect the data shared at ASCO will demonstrate exactly this. Longer term, given the strength of casdatifan's efficacy and safety profile, our vision is to develop cas in TKI-free regimens and even to displace TKIs in earlier lines of RCC treatment. TKIs have been very effective in treating RCC. Almost every RCC patient receives a TKI during the course of their treatment, but TKIs come with debilitating side effects that meaningfully impact quality of life. This cannot be overstated. We believe there's a huge opportunity to develop casdatifan in earlier lines, driving a long-sought paradigm shift and enabling patients to avoid TKI therapy for as long as possible.

This, in fact, reflects a core element of Arcus' high-level strategy in oncology, driven by the advances in the understanding of tumor biology in the last decade, being a leader in the development of innovative cancer therapeutics with improved efficacy that preserve quality of life during treatment. Specifically, we're collaborating with AstraZeneca to combine cas with their anti-PD-1, anti-CTLA-4 bispecific antibody volrustomig to create the first TKI-free HIF-2α combination option for first-line RCC. I want to repeat that this will be the first TKI-free HIF-2α combination option looked at in first-line RCC. Anti-PD-1, anti-CTLA-4 is one of the most commonly and widely used first-line regimens, particularly in academic centers, because it is TKI-free and can meaningfully prolong survival.

AstraZeneca will operationalize the study as part of their EvolveD portfolio, so this collaboration enables us to develop cas in the first-line setting in an extremely cost and resource-efficient manner and with a world-class drug developer in oncology. The study is designed to demonstrate the safety of the combination to support late-stage development. This provides another opportunity to generate confidence-enhancing data for casdatifan-based regimens over the next 18-24 months. Beyond EvolveD, we've added three cohorts to ARC-20 to evaluate casdatifan in other early line TKI-free settings. These are casdatifan plus zimberelimab, our anti-PD-1 antibody in first-line all-comer or clear cell RCC, casdatifan monotherapy in first-line favorable risk patients, and casdatifan monotherapy in patients that have received prior IO but have not yet received a TKI.

All three cohorts recently opened for enrollment and have generated significant interest in the investigator community, demonstrating and building on the robust interest in casdatifan and in TKI-free regimens. As a result, these cohorts should enroll quickly and generate efficacy data over the next couple of years, informing future development opportunities. While cas has moved front and center in our portfolio, our two other registrational programs, which are targeting massive patient populations with substantial unmet need, continue to advance towards data. For our Fc-silent anti-TIGIT antibody, domvanalimab, the first phase 3 study readout will be STAR-221, for which we have guided to 2026. This study is evaluating domvanalimab plus chemo versus nivo plus chemo, the standard of care in first-line gastric cancer. Later this year, we'll be sharing overall survival data, OS data, from the corresponding phase II study at gastric.

This is evaluating the same regimen in the same setting as STAR-221. We expect these data to reinforce confidence in STAR-221, which has an overall survival primary endpoint. The competitive landscape in this field has seen a dramatic shift over the last six months, with the Fc-silent anti-TIGIT antibodies, specifically ours and AstraZeneca's anti-TIGIT anti-PD-1 bispecific antibody, now dominating the phase three landscape. These two molecules have generated similar positive data in phase two studies in both lung and GI cancers. AstraZeneca is now enrolling 10 different phase three studies for its Fc-silent anti-TIGIT antibody. In addition, PRISM-1, our phase three trial of quemliclustat, our small molecule CD73 inhibitor, in combination with chemotherapy in first-line pancreatic cancer, is enrolling rapidly.

There's been a tremendous enthusiasm for PRISM-1, and as a result, we anticipate the study will now be fully enrolled by the end of 2025, less than 12 months after initiation. This is our second global phase III study that will complete enrollment well ahead of initial expectations, and our goal is to replicate the success with the enrollment of PEAK-1. This brings me to my final key point. Today, we have a strong balance sheet with $1 billion in cash and investments. This is not an accident. While there has been a dramatic shift in the macroeconomic environment, we are always scrutinizing our capital allocation, prioritizing our molecules and programs, and leveraging strategic collaborations, for example, those with Gilead, Taiho, and AstraZeneca, to maintain a strong balance sheet.

This will be particularly true going forward to ensure that our capital stretches as long as possible and to enable us to continue funding our small molecule research programs. The discovery of casdatifan, an exceptionally high-quality molecule against an extremely intractable target, is a reflection of the secret sauce of Arcus, which is our research organization and small molecule drug discovery capability. Our next INDs are likely to come from our inflammation and immunology programs, which have been quietly but rapidly advancing in our focus on the creation of potential first and best-in-class small molecule drug candidates against validated targets. We're going to share more about these programs later in this year. With that, I'd like to turn the call over to Richard to speak about casdatifan in greater detail.

Richard Markus (CMO)

Thanks, Terry.

I'll first recap the highlights of our recent ASCO GU presentation for casdatifan monotherapy in late-line clear cell renal cell carcinoma. After that, I'll speak about our upcoming data presentations and near-term development plans for casdatifan. I'll start with a reminder of the study design of ARC-20 on slide nine. ARC-20 now includes eight cohorts evaluating casdatifan monotherapy or casdatifan combinations in clear cell RCC. As a reminder, our ASCO GU presentation included data from three of the monotherapy cohorts in late-line clear cell RCC. I also want to highlight here the cohort evaluating 100 milligrams of cas plus 60 milligrams of cabozantinib, and this is the same combination and dosing regimen we will evaluate in PEAK-1 and the cohort that is subject of the data presentation at this year's ASCO.

Patients in this cohort are all previously treated and have received one or two prior lines of therapy, with their most recent prior line being an anti-PD-1, and patients did not need to have received prior TKI therapy, so this is a very similar population to that of PEAK-1. On slide 14, we compare the efficacy assessments for the monotherapy cohorts relative to data from LYTE-SPARK-5, the phase III study of belzutifan. Importantly, we enrolled a more advanced patient population than that of LYTE-SPARK-5. In fact, approximately one-third of our patients would not have been eligible for LYTE-SPARK-5. We recognize the limitations of cross-trial comparisons. Cas performed better on every efficacy measure in every cohort, despite this more advanced patient population. Rates of primary progressive disease were close to half that of belzutifan.

Confirmed ORR was consistently higher than that of belzutifan, and two cohorts achieved confirmed ORRs greater than 30%. The ORRs for belzutifan monotherapy studies have ranged from 18-21.9%. The casdatifan ORR is trending about 50% higher. For disease control rate, or DCR, over 80% of patients should benefit from casdatifan versus just 61% for belzutifan. Lastly, the median PFS of 9.7 months for the 50 milligram BID cohort was meaningfully longer than the 5.6 months for belzutifan, and the median PFS had not even been reached for the 50 milligram QD and 100 milligram QD cohorts. However, when we pooled data from the 50 milligram BID and 50 milligram QD cohorts, the median PFS was 13 months, significantly longer than that of belzutifan.

Slide 11 shows the waterfall and spider plots for the 100 milligram QD dose, and these data give us confidence in the selection of 100 milligram QD as a dose for our phase three studies of casdatifan. On slide 12, we show the spider plots for the 50 milligram BID and 50 milligram QD cohorts, which highlight the durability of casdatifan's efficacy. Across all three cohorts, remarkably, only two of the 26 confirmed responders have progressed, and many of the stable disease patients clearly derive benefit and will therefore contribute meaningfully to the median PFS. We have a number of upcoming data presentations for ARC-20, and these are summarized here on slide five. First up will be initial data from our casdatifan plus cabozantinib cohort at ASCO. A key objective of this data set will be to demonstrate that these molecules can be safely combined.

In addition, given that we had approximately 25 patients enrolled by the end of the year, we plan to present overall response rate data for those patients who are eligible for two or more scans at the data cutoff. To be clear, the ORR denominator will include all patients who were enrolled at least 12 weeks prior to the data cutoff, regardless of the number of scans actually recorded. Last, I want to point out that the data included in the ASCO abstract are from a prior data cut, and the ASCO oral presentation will feature data from a more recent data cut. Later in the year, we expect to present more mature data from all four monotherapy cohorts of ARC-20 in late-line clear cell RCC.

In 2026, we plan to share more mature data from the casdatifan plus cabozantinib combination cohort, as well as initial data from the newly added cohorts evaluating the TKI-free regimens in early line settings. Now, onto the development plan, slide 16, which shows the design of PEAK-1, where we are evaluating casdatifan plus cabozantinib versus cabozantinib in IO-experienced patients who had one prior line of immunotherapy. Target enrollment is 700 patients, and we expect that the study will enroll quickly for several reasons. First, as Terry mentioned earlier, we are using cabozantinib, the most widely used and preferred TKI, in both arms of the study. Second, patients will be randomized two to one between the experimental arm and the control arm. Third, there is already very substantial awareness of casdatifan in the clinician community, and we expect to include multiple ARC-20 sites in the PEAK-1 study.

Merck is running a somewhat similar study called LYTE-SPARK11, which is evaluating belzutifan plus the TKI and is now expected to read out in 2027. However, there are some important differences I'd like to highlight. First, while PEAK-1 has cabozantinib in both study arms, LYTE-SPARK11 has lenvatinib in the experimental arm but cabozantinib in the control arm, and using different TKIs in the same experiment could add risk to the trial outcome for LYTE-SPARK11. In addition, we are using a single primary endpoint of PFS in PEAK-1 rather than a dual endpoint of OS and PFS, which is being used in LYTE-SPARK11. Given how quickly we expect PEAK-1 to enroll and the anticipated timing of the PFS primary endpoint, we have significantly narrowed the gap between our readout and that of LYTE-SPARK11. Meanwhile, in the IO naive setting, our strategy is very different.

In this setting, Merck is evaluating belzutifan in combination with pembro and lenvatinib. In contrast, we are collaborating with AstraZeneca to evaluate casdatifan plus volrustomig, AstraZeneca's anti-PD-1/CTLA-4 bispecific. As Terry mentioned, this is a highly attractive TKI-free combination that may enable patients to remain on therapy for several years while avoiding TKI-related toxicities. We have not yet disclosed the design of the study, but we expect to share more information very soon, and we think you'll be excited about our strategy in this setting. I'd now like to turn the call over to Jen to speak about the market opportunity for casdatifan.

Jennifer Jarrett (COO)

Thank you, Richard. RCC is a unique oncology market in that metastatic patients can remain on therapy for many years.

In fact, five-year survival is becoming the norm in this disease, and patients will cycle through multiple treatments, often staying on treatment for well over a year, even in the second-line setting. As a result, we believe the revenue opportunity for a good RCC drug is very substantial. On slide 17, we highlight the total market opportunity for the first two settings we are pursuing for casdatifan. First, we show the IO naive patient population, which we are addressing with casdatifan plus cabozantinib. The addressable population here is about 13,000 patients in the US and 20,000 in other major markets. Given that most of these patients progress and go on to subsequent therapies, the addressable patient population for the IO experienced setting is very similar.

With a two-plus year duration of therapy in IO naive patients and a 12-month-plus duration of therapy in IO experienced patients, we believe the total market opportunity for these two settings combined is $5 billion. With a better molecule than belzutifan and differentiated combinations and development plan, we should capture a significant share of this market. On slide 18, we show US market share by regimen. TKI-based regimens dominate the clear cell RCC market with approximately 65% share in first line and 75% in the second-line setting. This explains why our first phase three study will focus on a casdatifan TKI combination, and you can see here why we chose cabo as our combination partner. We believe there is a strong clinician preference for cabo.

However, as Terry described earlier, our vision is that over time, casdatifan will move up in lines of therapy and take share from TKI-based regimens, either as monotherapy or in combination with IO treatments, particularly given casdatifan's low rate of primary progressive disease relative to the one competitor, belzutifan. We believe belzutifan's high rate of primary progressive disease is a key reason why it's used today primarily in the third-line setting. I will now turn the call over to Bob to review our financials.

Bob Goeltz (CFO)

Thanks, Jen. Our cash as of the end of the first quarter was $1 billion as compared to $992 million as of the end of 2024. Our cash position was bolstered by a $150 million equity financing, which we completed in February 2025.

We expect our cash and existing facilities will enable us to fund operations through our initial pivotal readouts for DAM, kwemli, and cast, which include the PEAK-1 readout. Given the faster-than-anticipated enrollment of our PRISM-1 trial in pancreatic cancer and the completion of enrollment of STAR-221 last year, we expect 2025 to be a peak year for development expenses. We expect both our DAM-related and aggregate development expenses to decline meaningfully in 2026 and 2027, inclusive of our investment in casdatifan. As Terry mentioned, we have also carefully scrutinized our capital allocation and have made pipeline prioritization decisions to ensure we maintain our strong financial position. Turning to our P&L, we recognize GAAP revenue for the first quarter of $28 million, which compares to $36 million for the fourth quarter of last year. Our revenue is primarily driven by our collaboration with Gilead.

We expect to recognize gap revenue of $75 million-$90 million for the full year of 2025. Our R&D expenses for the first quarter are stated net of reimbursements from Gilead and were $122 million as compared to $111 million in the fourth quarter of last year. G&A expenses were flat at $28 million for the first quarter compared to the fourth quarter of last year. Total non-cash stock-based compensation was $16 million for the first quarter compared to $17 million for the fourth quarter of last year. For more details regarding our financial results, please refer to our earnings press release from earlier today and our 10-Q. I will now turn it back to Terry.

Terry Rosen (CEO)

Thanks, everyone, for joining us. We appreciate your interest and your continued support of Arcus, and we'll now open the call for questions.

Operator (participant)

Thank you.

Please press star followed by the number one if you'd like to ask a question, and ensure your device is unmuted locally when it's your turn to speak. Our first question comes from Peter Lawson with Barclays, please. Your line's open. Please go ahead.

Peter Lawson (Managing Director)

Great. Thank you so much. I guess the first question was just off the back of your comments around pipeline reprioritization. I wonder if you could talk through that a little bit more and then whether you're exploring the adenosine inhibitor further if that's the program ended?

Terry Rosen (CEO)

Thanks, Peter, and I'll answer that all together. As I mentioned, we're always doing this, and in the context of your question about the adenosine modulator, and I think you're probably speaking to the A2 receptor antagonist etrumadenant, that's a perfect example. We did have a meeting, and quite good meeting, actually, with the FDA on that.

There's a path forward, but our plans right now are not to move forward at this time, at least. The way I think you should look at our portfolio and how we prioritize things is we have those three late-stage programs. Our number one priority, of course, is casdatifan. Domvanalimab, as Bob articulated, is on its natural trajectory. We're excited about data coming, but spend is winding down. PRISM-1, our other adenosine-related molecule, so the CD73 inhibitor, will be fully enrolled this year, so that'll be heading towards data shortly. Keep in mind the standard of care there has an OS on the order of 10 months, so we're going to get to a readout pretty quick on that. On the other side of things, our early-stage portfolio, we've been evolving that too.

We still have a number of oncology targets, but we've been quietly, as I described, pushing along some really great inflammation and immunology targets. Later this year, I think we'll disclose those, and you'll find those exciting as well. The way you can kind of look at it is strong investment, biggest investment in the later-stage programs, nothing overly heavy on the middle, and then keeping the sustainable pipeline with what's a relatively minimal investment, but with really that secret source of Arcus to generate the next IND candidates beyond those we talk about now.

Peter Lawson (Managing Director)

Gotcha. On the oral presentation, ASCO, what should we expect to see in the abstract versus the oral presentation, and will you kind of press release beyond the abstract?

Terry Rosen (CEO)

I'm wondering if someone planted that question. It's one we think is important.

I think you should recognize, everyone should recognize, the abstract is more of a placeholder abstract, and the data cut that we'll be sharing at ASCO will be much more recent. What it will include is, you can think about it as two populations. First, the safety population will be about 40 patients, and then we'll also want to give you a read on efficacy. Even though probably the median time of follow-up is barely over four months, what we've done is we've assembled all the patients who've had at least two scans, so that gives them the opportunity to potentially have had a confirmed response, and we'll be sharing efficacy data for that 25 or so patients. You'll see a waterfall plot.

Obviously, the data are far too immature to talk about maturity, and I think the data, I think you'll find them compelling, but you should recognize, given that they are early, they will likely continue to improve beyond what we share at this conference.

Peter Lawson (Managing Director)

Great. Thank you so much.

Terry Rosen (CEO)

Thank you, Peter.

Operator (participant)

Our next question comes from Daina Graybosch with Leerink Partners. Your line's open.

Daina Graybosch (Senior Research Analyst)

Hi. Thank you. I have two really different questions. First, on TIGIT. As you pointed out, the TIGIT phase threes are dominated by the Fc-silent, yours and Astra bi-specific. Let's say we assume, as I think you believe, that Fc-silent is really the key to maximizing TIGIT benefit. Are you under-investing and ceding leadership to Astra? Can you just remind us what you're learning in phase II, and is there a gate of success that you might actually ramp investment back up?

I have one on casdatifan after that.

Jennifer Jarrett (COO)

Yeah. First of all, I think we feel very, very good about the bets that we've made because they're targeting some of the largest IO markets out there. Our study in lung, STAR-121, is targeting all common non-small cell lung cancer patients, obviously the biggest market there is for anti-PD-1. Our other phase three study, STAR-221, is targeting all common gastric cancer patients, which is another really, really good market. We feel like those are two great bets to make. We do have active discussions going on all the time about other things that we would want to do if those studies read out positively. I'd say there are other things that are teed up and ready to go if our first phase three readouts are positive. We agree with what you're saying.

The other study to point out, Terry's just reminding me, is the stage three lung cancer study that we are doing with AstraZeneca, which AstraZeneca is operationalizing, PAC8. They have obviously seen a lot of our data because we have that partnership on PAC8, and we do think that is something else that has given them even more conviction in their own PD-1 TIGIT program.

Daina Graybosch (Senior Research Analyst)

Awesome. On cast and the potential for cast mono to replace TKI in second line, you have that ARC-20 cohort. Is there any particular bar for efficacy you are looking for that would give you conviction to go head-to-head versus a TKI?

Terry Rosen (CEO)

I think at this point, we would look at those as a little bit more exploratory. They are different.

In the monotherapy, keep in mind in those favorable risk patients, basically the standard these days would be more just watch and wait. If you see reduction, meaningful reductions in tumor, given the safety profile, we think that could encourage people to want to invest in this. Keep in mind, those patients could be a couple of years. The idea there is to get a sense of how it looks in those favorable risk patients. I know that's not a patient population that's getting TKI, but that's sort of where we're one of those areas where we don't necessarily have something numerically in mind, but we're looking to see if there's a signal, and we think there's a really good opportunity there.

Jennifer Jarrett (COO)

Yeah. I think like some of our studies that are out there for TKI mono range anywhere from sort of high teens, 20%.

It's a very high end of the range, 40%. If we could be in line with that with a better safety profile, we think that would be really exciting for clinicians. We were actually just talking to a clinician yesterday that's one of the high enrollers in our casdatifan combo cohort. She just put her first patient on the cohort that you were asking about, the casdatifan mono in second-line patients, and she was very excited about how that patient was doing. We look forward to hearing more anecdotes like that.

Terry Rosen (CEO)

I think the thing is, even if you look at our late-line study, it's already pointing to something that would tell you you've got a good chance to be better than TKI.

The enthusiasm there really does ramp up because of two things: the fact that it is TKI-free in the safety profile, but also because of the low rate of primary progression. That is probably why you have not seen belzutifan be able to go there. That is really important as you go to the earlier lines. We feel like we are already seeing numbers, even in the later line, that would encourage us for the opportunity going earlier as a mono.

Daina Graybosch (Senior Research Analyst)

Great. Thank you.

Terry Rosen (CEO)

Thanks, Dana.

Operator (participant)

The next question comes from Yigar Nochomovitz with Citigroup. Your line is open. Please go ahead.

Yigal Nochomovitz (Biotech Analyst)

Yeah. Hi. Thanks. Can you just talk about the timing for PEAK-1 PFS primary? And then you said Lightspark is going to be dual. Do we know which of these is coming first?

If Lightspark hits on OS and PFS, then what's the plan to answer the OS question for PEAK-1? And under what timeframe would that happen relative to Merck? Thanks.

Jennifer Jarrett (COO)

Yeah. There's a lot of questions in there. First of all, it's too early for us to give—sorry. Yeah. No. No worries. All the right questions. All the right good questions. On PEAK-1, yeah, I think it's too early given we're just about to start the study to give guidance on when we might see PFS data. We've talked to some of you. You could probably do some back-of-the-envelope math just based on how likely you think it would take to complete enrollment based on other RCC studies. And then what the PFS is that you would expect to see in the control arm.

You could kind of get to when you might expect to see a readout. It is not in the too far distance because we do think this is a study that is going to roll quickly and because it is a PFS readout. On your question on OS and what we are doing, OS is a key secondary endpoint. To your point, we do think it is important to collect that information, and it is a key secondary endpoint in our study so that data will be collected. As far as Lightspark 011, they had it as a dual primary endpoint of OS and PFS. If they hit on one of those and the study would be successful, you do have to split alpha in that case because there are two different endpoints versus what we are doing, which is a sole primary. That can work against you.

If they are waiting for that OS endpoint, that is what's giving us the opportunity to really catch up to them and narrow that gap between when our readout might occur versus theirs.

Terry Rosen (CEO)

Just to put something out there that is out there, Merck recently pushed out that study on clinicaltrials.gov for a second time out to 2027. Whenever you do your back-of-the-envelope calculations, while we haven't given guidance, even that potential delta is dramatically closed from when we first started contemplating this. We actually do feel we're going to have gender in common on this, but we've got real tailwinds as we launched this study. Investigator enthusiasm not only is very strong, but from a practical standpoint, because we've invested pretty heavily in these monotherapy cohorts, not only have we engendered a lot of enthusiasm, all kinds of anecdotal studies.

Every one of these investigators has their own interesting story of what they've seen, so they want to jump on this. The other practical matter is that we've got 30 or 40 sites that are going to transition potentially into PEAK-1. I think we're really going to be hitting the ground running in an unusual way versus going from a standing start.

Jennifer Jarrett (COO)

Yeah. Having the ASCO presentation of the Cabo cohort is obviously perfect timing. I think the investigators are particularly interested in seeing efficacy, which is obviously important, but I think everyone believes we're going to add efficacy. They really want to see safety and just make sure there's no additional toxicities or overlapping toxicities or drug discontinuations, etc., to worry about. That will be a very important part of the data presentation.

Yigal Nochomovitz (Biotech Analyst)

Okay. Okay. Gotcha.

After the Gilead decision on CAS, is the plan now to just fund this to completion yourselves, or would you entertain help from another partner potentially?

Terry Rosen (CEO)

Yeah. The first thing I want to mention, because I think it is an important point because of a lot of the questions that were out there right at that time, these new data are new. This will give you yet another look. The cas combo data are, we think, quite exciting, and obviously, they were not mature data when Gilead made their decision. Getting to the specific question, we feel really confident in our abilities for some of the reasons we were just talking about. We have been working with the molecule. We have been working with the sites. We have a steering committee that could not be better. They are excited.

We feel we're in a great position to execute this, not only from a capital position, as we talked about. We have the resources, but from the people standpoint, our team has been working with this all along. Our plans are to execute PEAK-1 on our own. With that said, could there be some other collaborations? As we mentioned, we'd like to use collaborations in an efficient manner. As an example, the AstraZeneca collaboration, we might do other things like that. Of course, on an opportunistic basis, there could be other things we would do. The base case you should be thinking about is that we feel very good about our ability to execute this trial in a very efficient and strong manner.

Yigal Nochomovitz (Biotech Analyst)

All right. Thank you, Terry. Thanks, Jen. Appreciate y'all.

Operator (participant)

The next question comes from Umer Riffat with Evercore. Please go ahead.

Umer Raffat (Senior Managing Director)

Thanks for taking my question. I have a few here, if I may. Perhaps first, the choice of dose being 100 milligrams for your first phase three, which admittedly is a cabo combo. Is there anything to read into the choice of that 100 milligram dose relative to any early data you're seeing on the 150 and 200 milligrams? I have a couple of follow-ups.

Terry Rosen (CEO)

Okay. You can have as many questions as you like, Umer. Nothing based upon any new data that we've seen. We had a really good discussion with the FDA in the context of Project Optimus. The 100 milligram dose, we talked about that. We talked about potentially 150. We talked about potentially 50. Safety profile of the 100 looked great. We feel, based upon all the data we've seen, that the 100 is essentially on the asymptote for efficacy.

What we're seeing with 150, I think we'll share that at the end of the year. I would just foreshadow that you're going to see something that looks pretty similar, and we'll see just how things play out. One thing that's important to note for our 50 and 100 milligram doses, we still do not have median PFS. Maybe as we get towards the end of the year and we're sharing data, we'll be there. Obviously, we'll have some sort of landmark PFS. It may be that there's a bit of more AE creeping in on the 150. I couldn't even say that with certainty now. I think the way to look at the 100 milligram dose is everything we've seen suggests that you're essentially maxing out efficacy there, and it's a very safe profile.

There's not a whole lot of rationale to even be thinking about the 150.

Umer Raffat (Senior Managing Director)

What about 200?

Jennifer Jarrett (COO)

Yeah. Same. I mean, we only looked at 200 in the dose escalation. Didn't see any DLTs, which was good. We haven't looked at it beyond the dose escalation. I think, as Terry was saying, based on everything we've seen so far, we now have 30 patients worth of 50 mg, 100 mg, 150 mg data. I think that all gives us a lot of confidence that 100 mg is the right dose.

Terry Rosen (CEO)

The other thing that we're actually thrilled about, it's not a surprise, but will draw your attention when you look at the cas combo data, is an important aspect of that is being able to keep patients on therapy. The data looked, we think, pretty compelling, even though they're early.

Obviously, with time, you might see otherwise. I think you'll come away feeling like, "Efficacy on those patients that have had two scans looking good. Waterfall looks good." The AEs look like combo by itself plus casdatifan by itself in a very well-tolerated combination.

Jennifer Jarrett (COO)

Yeah. I think one of the really exciting opportunities about the combination too is that if you're just getting TKI mono and you get hand-foot-mouth syndrome or grazer hypertension, whatever it is, you would typically have to come off your TKI for a bit. In this case, even though you're coming off the TKI, you're still getting a HIF-2α inhibitor. You're still getting an active drug.

That's one of the things that I think positions the combination to perform very well relative to combo monotherapy because throughout, in most cases, patients are going to be getting at least one of those two drugs. If you do get TKI-related toxicities, they will stay on cast.

Umer Raffat (Senior Managing Director)

Got it. I guess that brings me to my sort of main question here, which is, what exactly is the makeup of this post-IO cohort in ARC-20 that we're going to see at ASCO or the cohort in general? I ask because you could have double IO experienced, or you could have IO plus VEGF TKI experienced. My understanding is ORR is a little lower when it's IO plus VEGF TKI versus dual IO. What exactly is that?

Is there any data to read into from your casdatifan mono arm, which is also second line plus and may presumably have some of these post-IO patients as well?

Jennifer Jarrett (COO)

Yeah. You're right. It's going to be a mix, and we'll disclose that mix. It's in line actually with the Lightspark 003 study that looked at casdatifan plus combo. One thing that I would mention, when you look at patients that got IO IO versus patients that got IO plus VEGF, so far, the ORRs actually look very similar. There does not seem to be a difference if patients have gotten prior TKI versus just prior IO. Does that make sense?

Umer Raffat (Senior Managing Director)

Okay. Jen, do you acknowledge about 30? Right. Would you acknowledge from Cabo Point Trial about low 30s in ORR is the comp for Cabo monotherapy following IO therapy?

Terry Rosen (CEO)

Go ahead.

Go ahead, Richard.

Richard Markus (CMO)

Yeah. I think the combo alone has a range of ORRs depending on what study you look at and what data source you have. Kind of in the 20-40. If you pick 30, that's one of the choices, I'd say. It is quite a range across the different data sets there for cabo alone. Yeah.

Terry Rosen (CEO)

One other relevant data set, Umer, the one other relevant data set is there was a belzutifan cabo arm. That, again, on the ORR front, came in just over 30%. Its PFS in that study, obviously, we won't have PFS to compare to yet, but the PFS there was on the order of 13 months.

Umer Raffat (Senior Managing Director)

Again, just so I'm clear, we talked about 20-40 being the range, maybe 30-ish being the midpoint, which is also consistent with the Cabo Point Trial.

The critical thing is you guys are emphasizing safety, not an efficacy advantage. Is that reasonable? Or do you want to have higher ORR as well?

Jennifer Jarrett (COO)

I think goal is absolutely to have both. We are just saying both is important. We are just trying to make the point that safety is going to feed into efficacy because you want to keep patients on drug. You want to avoid dose reductions. The more we think we can safely combine these two drugs, that should further enhance efficacy. Yeah, the goal is absolutely to show an improvement on both those metrics. Not, sorry, on efficacy and safety that you are not getting additive toxicity or even worse toxicity than what you would expect with either agent alone.

Umer Raffat (Senior Managing Director)

Thank you so much.

Terry Rosen (CEO)

Yeah. Thanks, Umer.

Operator (participant)

Next, we have Asthika Goonewardene with Truist. Your line is open.

Karina Rabayeva (VP of Biotech Equity Research)

Hi. This is Karina for Asthika.

Thanks for taking my question. I had a question on casdatifan. Beyond the AstraZeneca study with the bowel or stomach, are there any plans to initiate registrational studies, potentially in combinations with PD-1s or zimberelimab in the front line?

Jennifer Jarrett (COO)

Yeah. Nothing registrational that we've disclosed so far. As Terry talked about on the call, we did just open a cohort in ARC-20 where we're combining casdatifan with our anti-PD-1s and zimberelimab in first-line patients. That's something we could ultimately initiate a registrational study for, some sort of more NCCN guideline-enabling study. That's a combination we're super excited about. Investigators are super excited about it. We think that cohort's going to enroll incredibly quickly because, again, I think there's a lot of interest in just avoiding TKIs in the front-line setting when patients are still feeling really good and are relatively healthy. Yeah.

We'll see how that goes. Some of these other cohorts that we started in, those could be future registrational studies for sure.

Terry Rosen (CEO)

I think the way you should think about our approach is that basically, we're not just going to be throwing a bunch of spaghetti up on the wall where we jump. We think we have a great molecule, but we're not just going to start peppering the world with phase three studies. We're going to do early work to ensure that any phase three study we do really makes sense.

Karina Rabayeva (VP of Biotech Equity Research)

Okay. That's helpful. Thank you.

Terry Rosen (CEO)

Thank you.

Operator (participant)

The next question comes from Li Watsek with Cantor Fitzgerald. Please go ahead.

Hey, this is Dan on for Li.

I was wondering if you could kind of set expectations for your combination with Volrustomig and what you're looking for in the IO naive setting and for a potential pivotal front-line trial. What would you be comparing your doublet to?

Jennifer Jarrett (COO)

Those are a lot of good questions. It's a lot of information that we just haven't disclosed yet for competitive reasons. As Richard alluded to on the call, probably around mid-year, which we're getting close to, we should be able to talk a lot more about that study. Right now, really, all we can disclose is that the plan is to combine casdatifan with Volrustomig in the first-line setting. The big issue with IpiNevo and PD-1 and CTLA-4s is that you do have a very high rate of primary progressive disease.

About 25-30% of patients don't respond to IpiNevo and just blow right through therapy. That is why today, actually, IpiNevo is typically used in patients that don't have really aggressive disease, so more slower-growth tumors. One of the reasons why I think Astra was very excited about combining Volro and cast is that opportunity to bring down the rate of primary progressive disease, given we're seeing a very low rate of primary progressive disease so far with cast. What we will be looking for initially is obviously that you can safely combine these two mechanisms, which today we have no reason to believe you couldn't. Then we will be looking at some of these early signs of efficacy, particularly the rate of PD. Eventually, we'll be looking at ORRs, etc.

We do think that PD rate could be particularly interesting to look at because you do have that high rate of primary progressive disease with IpiNevo. There is a huge amount of interest in that combination, I just want to point out. We talked about it on the call. We just actually did some market research. I think we were actually even surprised about how much interest there is in the investigator community to combine these two mechanisms and to try to avoid TKIs in the front line.

Okay. Great. Thank you.

Operator (participant)

Our next question is from Salveen Richter with Goldman Sachs. Your line's open.

Great. Thanks. This is Matt on for Salveen. Maybe first just on cas to follow up on a prior question.

Is it fair to say you guys would consider a commercialization partnership post PEAK-1 or when you're close to reading out PEAK-1, or is that no longer of interest to you? On the broader portfolio, any thoughts on the newly announced SEBR director from just kind of a portfolio risk perspective? Thank you.

Terry Rosen (CEO)

Yeah. On the first question, our intent is to commercialize. We want to fully leverage the opportunity. We think this is really huge for our case. I think we'd probably consider a partner in Europe, but we feel really good about taking this forward, commercializing it. The whole piece for us seems very manageable. I don't have any comments on the latter. I don't think anyone here does.

I would just, in macro, even elevate that our whole sense about everything happening at the FDA when it comes to what we're doing, what we're executing, things have just been business as usual as far as we can tell. What's happening in the news, I have no comment. From a practical standpoint, we're pretty comfortable with everything we're doing right now that it's proceeding just as it would have six months or one year ago.

Thank you.

Sure. Thanks.

Operator (participant)

Our next question is from Eva Fortea with Wells Fargo. Please go ahead.

Eva Fortea (Biotech Equity Research Analyst)

Hi. Thanks for taking our questions. A couple from us. First, on the fall 2025 update for cast, can you just provide a bit more color on expectations here in terms of the different cohorts, number of patients, and duration of the follow-up?

The second question, as you mentioned, an emerging INI franchise. When should we expect to learn more about this? Would this be more towards the end of the year in an R&D day type of event? Thanks.

Terry Rosen (CEO)

Yeah. Just the first part of the question, at least with regards to the follow-up in the fall. It's really looking at, again, at the monotherapy data we had at ASCO GU. We'll have more mature data coming. We'll have another data cut there. We haven't stated or selected if this will be at a medical conference or other ways of sharing that data. We will be able to provide updates to that data since it'll have matured a fair bit since the cut at the beginning of this year.

On the immunology information front, I think the way to think about that is conceptually, whether it's an R&D day or part of one of our other releases, we'll find a form to describe the breadth of what we're doing and where we sit. I think it's an exciting portfolio. It takes advantage of what we do well. I think that'll be highlighted, the small molecules for challenging targets where the targets are highly validated, but there's not a great molecule. We've been building on that. I'll remind you, because we're like a real company in terms of with people. We have a biology group. We have a med chem group and all of the associated functions that there is. Our biology is actually more immunology because the roots are in immuno-oncology.

Even though oncology has been our clinical endpoint, we have a strong immunology group and, in fact, have invested in that. Now we're getting to the point where we can start to talk about those programs. We like to talk about things when we've got tangible matter, not glint in the eye. I think that these will be very tangible. All done without machine learning. We have machines.

Operator (participant)

We'll take one more question before ending. Our final question comes from Emily Bodnar with H.C. Wainwright. Please go ahead.

Emily Bodnar (Biotech Equity Research Analyst)

Hi. Thanks for taking the questions. My first one for cas, the monotherapy doses. Can you comment on how the 100 mg QD cohort is progressing relative to the 50 mg BID cohort and if you're starting to see similar results in terms of median PFS?

If you could just comment on timing for the STAR-121 trial for DAM in lung cancer and if there's any timing updates for the top-line results? Thanks.

Terry Rosen (CEO)

Yeah. There's really no timing update yet on 121 study. Two things. It's still enrolling. It has OS for the standard care is over 20 months. It's premature. It's obviously enrolled well and will continue to enroll, but we haven't said anything on timing there. Nothing to say yet really on the maturing data other than to point out that we haven't reached a median PFS. I think as we get towards the end of the year, we don't even know for sure that we'll be there. If we're not, we still will be sharing data. It would then undoubtedly include some sort of landmark PFS.

Emily Bodnar (Biotech Equity Research Analyst)

Okay. Got it. Thank you.

Terry Rosen (CEO)

Thank you.

Operator (participant)

Thank you. This concludes our Q&A session today as well as the call. Thank you, everyone, for joining. You can now disconnect your line.

Terry Rosen (CEO)

Thank you.

Operator (participant)

Good.