RCUS - NYSE

Hello, everyone. And welcome to Arcus Biosciences First Quarter 2025 Earnings and Financial Results Call. My name is Lydia, and I'll be your operator today. After the prepared remarks, there'll be an opportunity to ask questions [Operator Instructions]. I'll now hand you over to Pia Eaves, Vice President of Investor Relations to begin. Please go ahead.

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 cash 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 10-Q that has been 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 the call over to Terry.

Thank you very much, Pia. And thanks to all 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. And so before we get into the details, I want to emphasize three points that will be apparent in our discussion today. So 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. So our goal is simple, to bring cas 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, quemli and cas through their respective initial Phase 3 readouts. Nonetheless, we are always cognizant of the macro environment and we are 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 casdatifan and TKI monotherapy. And in that vein, we are 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 are evaluating in our first [patient] [Technical Difficulty] 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. Now some important granularity around the casdatifan program. In our Phase 1b ARC-20 study, we now have eight cohorts evaluating different dosing regimens, combinations and settings for cas and 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 elastizudafan and derisking of our first Phase 3 study PEAK-1. Second, continuing to drive the already extraordinary investigator enthusiasm for PEAK-1 to support its rapid enrollment. And 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 would like to touch on a few additional topics starting with our development plan and our long term vision for casdatifan. Our Phase 3 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 cabo 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 3 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-2 alpha inhibition affords 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 cas' 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 can not be overstated. So we believe, there is a huge opportunity to develop cas in earlier lines driving a long sought paradigm shift 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 Astra

Thanks, Terry. I'll first recap the highlights of our recent ASCO GU presentation for cas 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 cas. I'll start with a reminder of the study design of ARC-20 on Slide 9. ARC-20 now includes eight cohorts evaluating cas monotherapy or cas 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 Lightspark V, the Phase 3 study of belzutifan. Importantly, we enrolled a more advanced patient population than that of Lightspark V. In fact, approximately one third of our patients would not have been eligible for Lightspark V. Though 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% to 21.9%. So 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 cohorts. However, when we pooled data from the 50 milligram BID and 50 milligram QD cohorts, the median PFS was 13 months, so 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 milligrams QD as a dose for our Phase 3 studies of cas. 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 5. First up will be initial data from our cas plus cabo 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. So 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. I also 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 cas plus cabo combination cohort as well as an initial data from the newly added cohorts evaluating the TKI-3 regimens in early line settings. Now on to the development plan, Slide 16, which shows the design of PEAK-1 where we are evaluating cas plus cabo versus cabo in IO experienced patients who had one prior line of immunotherapy. Target enrollment is 700 patients and we expect the study will enroll quickly for several reasons. First, as Terry mentioned earlier, we are using cabo, the most widely used and preferred TKI, in both arms of the study. Second, patients will be randomized 2:1 between the experimental arm and the control arm. And third, there's already very substantial awareness of cas 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 Lightspark XI, which is evaluating belzutifan plus a 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 cabo in both study arms, Lightspark XI has lenvatinib in the experimental arm but cabo in the control arm. And using different TKIs in the same experiment could add risk to the trial outcome for Lightspark XI. 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 Lightspark XI. And 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 Lightspark XI. 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 Astra

Thank you, Richard. RCC is a unique oncology market and 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 cas. First, we show the IO naive patient population, which we are addressing with cas plus volru. 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 onto subsequent therapies, the addressable patient population for the IO experience 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 from 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 settings. This explains why our first Phase 3 study will focus on a cas 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 treatment, particularly given cas' 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.

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 dom, quemli and cas, 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 dom 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 recognized GAAP revenue for 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 GAAP revenue of $75 million to $90 million for the full year 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.

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 Instructions] Our first question comes from Peter Lawson with Barclays.

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

I'll answer that all together. So 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 etruma, that's a perfect example. So we did have a meeting and quite good meeting actually with the FDA on that there's 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 and dom, zim, as Bob articulated, is on its natural trajectory. We are 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 will be heading towards data shortly. Keep in mind, the standard-of-care there has an OS on the order of 10 months. So we are going to get to a readout pretty quick on that. And then on the other side of things, our early stage portfolio, we have been evolving that too. We still have a number of oncology targets but we have been quietly, as I described, pushing along some really great inflammation and immunology targets. And so later this year, I think we will disclose those and you will find those exciting as well. So the way you can kind of look at it is, strong investment, biggest investment in 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.

And then 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?

I am wondering if someone planted that question. It's one we think is important. So the -- I think you should recognize, everyone should recognize the abstract is more of a placeholder abstract. And so the data cut that we'll be sharing at ASCO will be much more recent. And 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. So 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 will see waterfall plot -- obviously, the data are far too mature to talk about maturity. And I think the data, I think you will 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.

Our next question comes from Daina Graybosch with Leerink Partners.

I have two really different questions. First on TIGIT. As you pointed out, the TIGIT Phase 3s are dominated by the Fc-silent, yours and Astra bispecific. And let's say we assume, 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 2? And is there a gate of success that you might actually ramp investment back up? And then I have one on cas after that.

I think -- so first of all, I think we feel very good about the best that we've made, because they're targeting some of the largest IO markets out there. So our study in lung STAR-121 is targeting all comer non-small cell lung cancer patients, obviously, the biggest market there is for anti PD-1. And then our other Phase 3 study, STAR-221, is targeting all-comer gastric cancer patients, which is another really, really good market. So 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. So I'd say there's other things that are keyed up and ready to go if our first Phase 3 readouts are positive. But we agree with what you're saying. And then the other study to point out, Terry's just reminding me is the Phase 3 lung cancer study that we're doing with Astra

And then on cas and the potential for cas to mono to replace TKI in second line, you have that ARC-20 cohort. Is there any particular bar for efficacy you're looking for that would give you conviction to go head-to-head versus a TKI?

So 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. So if you see reduction, meaningful reductions in tumor, given the safety profile, we think that could encourage people to want to invest in this. And keep in mind, those patients could be a couple of years. So the idea there is to get a sense what -- 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 are -- one of those areas where we don't necessarily have something numerically in mind, but we are looking to see if there is a signal and we think there is a really good opportunity there.

I think I would like to [Technical Difficulty] our studies that are out there for TKI and mono range anywhere from sort of high teens, 20%. It's a very high end of the range 40%. So 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 cas, cabo cohort. She just put her first patient on the cohort that you're asking about, the cas mono second line patients and she was very excited about how that patient was doing. And so we look forward to hearing more anecdotes like that.

I think the thing is, 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. And 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's probably why you haven't seen bells be able to go there and that's really important as you go to the earlier lines. But 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.

The next question comes from Yigal Nochomovitz with Citigroup.

Can you just talk about the timing for PEAK-1 PFS primary? And then you said Lightspark is going to be dual. So which -- do we know which of these is coming first? And if Lightspark hits on OS and PFS then what's the plan to answer the OS question for PEAK-1? And then under what timeframe would that happen relative to the mark?

So there's a lot of questions in there. So first of all, it's too early for us to give [Multiple Speakers]. So PEAK-1 I think it's too early given we're just about to start the study to give guidance on what we might see PFS data. We talked to some of your [indiscernible] back of the envelope math to say sign and how likely we think it would take to complete enrollment based on other RCC studies and then what the PFS is expected to be in the control arm and how to get or when you might expect to see a readout. So it's not in the too far distance because we do think this is a study that's going to roll quickly and because it is a PFS readout. On your question on OS or what we're doing, OS is a key secondary endpoint. So to your point, yes, we do think it's 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 XI, they had it as a dual primary endpoint of OS and PFS. So if they hit on one of those then the study would be successful. You do have to split alpha in that case, because there's two different endpoints versus what we're doing, which is the sole primary. So that can work against you. But 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.

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. So whenever you do your back of the envelope calculations while we haven't given guidance that even that potential delta is dramatically close from when we first started contemplating this. And we actually do feel we're going to have -- Jen didn't comment on this, but we've got real tailwinds as we launch this study. The 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 kind 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. But the other practical matter is that we have got 30 or 40 sites that are going to transition potentially into PEAK-1. So I think we are really going to be hitting the ground running in an unusual way versus going from a standing start.

So having the ASCO presentation of the cabo cohort is obviously perfect timing. I think investigators are particularly interested in seeing -- efficacy is obviously important. I think everyone believes we're going to add efficacy but they really want to see o safety and just make sure there's no additional toxicities or overlapping toxicities or drug discontinuations, et cetera, to worry about. And so that will be a very important part of the data presentation.

And then post 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?

So the first thing I want to mention, because I think it's an important point because of a lot of the questions that were out there right at that time. These new data are new. So this will give you yet another look. The cas, cabo 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 got a steering committee that couldn't be better, they are excited. We feel we are 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. So our plans are to execute PEAK-1 on our own. With that said, could there be some other collaborations? As we mentioned, we would like to use collaborations in an efficient manner. As an example, the Astra

The next question comes from Umer Raffat with Evercore.

I have a few here if I may. Perhaps first, the choice of dose being 100 milligrams for your first Phase 3, which admittedly is a cabo combo. Is there anything to read into the choice of that one 100 milligram dose relative to any early data you're seeing on the 150 and 200 milligrams? And I have a couple of follow ups.

I mean you can have as many questions as you like, Umer. So nothing based upon any new data that we have 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 look 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 one 150, I think we'll share that at the end of the year. But 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. But obviously, we will have some sort of landmark PFS. And it may be that there is a bit of more AE creeping in on the 150. I couldn't even say that with certainty now. So 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. So there's not a whole lot of rationale to even be thinking about the 150.

And what about 200?

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

I think the other thing that we're actually thrilled about, it's not a surprise but -- and will draw your attention when you look at the cas, cabo data is an important aspect of that is being able to keep patients on therapy. And the data look we think pretty compelling even though they are early and obviously with time you might see otherwise. But I think you'll come away feeling like efficacy on those patients that have had two scans, looking good, waterfall looks good and the AEs look like cabo by itself plus cas by itself and very well tolerated combination.

And 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 greater hypertension whatever it is, it 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-2 inhibitor. So you're still getting an active drug and that's one of the things that I think positions the combination to perform very well relative to cabo monotherapy, because throughout, in most cases, patients are going to be getting at least one of those two drugs. So if you do get TKI related toxicity, they will stay on cas.

So 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? And I asked because you could have double IO experienced or you could have IO plus VEGF TKI experienced. And my understanding is ORR is a little lower when it's IO plus VEGF TKI versus dual IO. So what exactly is that? And is there any data to read into from your cas mono arm, which is also second line plus and may presumably have some of these post IO patients as well?

So you're right. It's going to be a mix and we'll disclose that mix. And it's in line actually with the Lightspark III study, like a cas plus cabo. 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. So there's not seem to be a difference if patients have gotten prior TKI versus just prior IO. Does that make sense?

And, Jen, do you acknowledge about third [Multiple Speakers] and would you acknowledge, from cabo point trial about low 30s and ORR is the comp for cabo monotherapy following IO therapy?

I think the cabo alone has a range of four hours depending on what study you look at and what data source you have. So kind of in the 20 to 40. So if you pick 30, that's one of the choices I'd say but it's quite a range across the different data sets there for cabo alone.

And the one other relevant data set -- Umer, the one other relevant data set is there was a bell's cabo arm, and that again on the ORR front came in just over 30% and it's 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.

And again, just so I'm clear, we talked about 20 to 40 being the range, maybe 30-ish being the midpoint, which is also consistent with the cabo point trial. But 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?

Absolutely have both [Multiple Speakers]. We're just saying both is important and we're 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. So the more we think we can safely combine these two drugs that should further enhance efficacy. The goal is absolutely to show an improvement on both those metrics [Technical Difficulty] on efficacy and safety that you are getting additive toxicity or even worse toxicity than what you'd expect with either agent alone.

Next we have Asthika Goonewardene with Truist.

This is [Karina] for Asthika. I had a question on casdatifan. So beyond the Astra

So nothing registrational that we've disclosed so far. So as Terry talked about on the call, we did just open a cohort in ARC-20 where we're combining cas with our anti-PD-1 zimberelimab in first line patients. So that's something we could ultimately initiate a registrational study for some sort of more NCCN guideline enabling study, but that's the combination we're super excited about and investigators are super excited about. We think that cohort is going to enroll incredibly quickly, because, again, yes, I think there's a lot of interest in just avoiding TKIs in the frontline setting where patients are still feeling really good and are relatively healthy. So we'll see how that goes with some of these other cohorts that we started and this could be future registrational studies for sure.

I think the way you should think about our approach is that, basically, we are 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 are not just going to start peppering the world with Phase 3 studies. So we are going to do early work to ensure that any Phase 3 study we do really makes sense.

The next question comes from Li Watsek with Cantor Fitzgerald.

This is Dan on for Lee. I was wondering if you could kind of set expectations for your combination with the volru and what you're looking for in the IO naive setting and for a potential pivotal frontline trial, what would you be comparing your doublets to?

So a lot of good questions and it's a lot of information that we just haven't disclosed yet for competitive reasons. And as Richard alluded to on the call, probably around midyear, which I think we're getting close to, we should be able to talk a lot more about that study. And so right now, really all we can disclose is that the plan is to go by cas with volru in the first line setting. The big issue with EpiNivo and [indiscernible] [PEAK] CTLA-4s is that you do have a very high rate of primary progressive disease. So about 25% to 30% of patients don't respond to EpiNivo and just flow right through therapy. And so that's why today actually EpiNivo is typically used in patients that don't have really aggressive disease, so more slower growth tumors. And so one of the reasons why I think Astra was very excited about combining volru and cas 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 cas. And so 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. And then, we will be looking at some of these early signs of efficacy, particularly the rate of PD and then eventually, we'll be looking at ORRs, et cetera. But 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 EpiNivo. [Multiple Speakers] there's a huge amount of interest in that combination, I just want to point out. We talked about it on the call, we actually did some market research. And 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 on the front lines.

Our next question is from Salveen Richter with Goldman Sachs.

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? And then on the broader portfolio, any thoughts on the newly announced [indiscernible] Director from just kind of a portfolio risk perspective?

So on the first question, our intent is to commercialize. We want to fully leverage the opportunity. We think this is really huge for Arcus. I think we probably consider a partner in Europe but we feel really good about taking this forward and 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. So I would just -- in macro, I would even elevate that our whole sense about everything happening at the FDA when it comes to what we are doing, what we are executing, things have just been business as usual as far as we can tell. So what's happening in the news I have no comment. But from a practical standpoint, we are pretty comfortable with everything we are doing right now that it's proceeding just as it would have six months or one year ago.

Our next question is from Eva Fortea with Wells Fargo.

A couple from us. First, on the full 2025 update forecast. Can you just provide a bit more color on like expectations here in terms of like the different cohorts, number of patients and duration of the follow-up? And 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?

I could address the first part of the question at least with regards to the follow-up in the fall and it's really looking again at the monotherapy data we had at ASCO GU. We'll have more mature data coming, so 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. But we will be able to provide updates to that data since we'll have matured a fair bit since the cut at the beginning of this year.

And on the immunology inflammation 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 will find a form to describe the breadth of what we are doing and where we sit. And I think it's an exciting portfolio. It takes advantage of what we do well and I think that will be highlighted, the small molecules for challenging targets, where the targets are highly validated, but there is not a great molecule. So we have been building on that. I will remind you, because we are like a real company in terms of with people and we have biology group, we have a good med chem group and all of the associated functions that there is, but our biology is actually more immunology because the roots are in immuno oncology. And so even though where oncology has been our clinical endpoint, we have a strong immunology group and in fact have invested in that and now we are getting to the point where we can start to talk about those programs with -- we like to talk about things when we have got tangible matter not glint in the eye, and I think that will be very tangible. And all done without machine learning but we have machines.

We'll take one more question before ending. And our final question comes from Emily Bodnar with HC Wainwright.

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

So there's really no timing update yet on 121 study. Two things, it's still enrolling and then it has OS plus standard care is over 20 months. So it's premature. It's obviously enrolled well and we'll 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. And so I think as we get towards the end of the year, we don't even know for sure that we will be there. But if we are not we still will be sharing data and it would then undoubtedly include some sort of landmark PFS.