All right. Well, good afternoon, everybody. Welcome. Thank you so much to Arcus Management for joining us. We've got Terry and Jen here with us. I can't wait to go through all the exciting data and all the updates coming soon. But let's start with a minute or two from you. What are you excited about heading into 2026? Where are the strategic focuses, and where should we be paying our attention?
Sure. So I think number one focus should be casdatifan. It's important for a number of reasons. Probably first off is we own it. It gives us an enormous amount of strategic optionality. Second, and really probably the most important is from a probability technical success. It's just so highly de-risked from our own data, but then the validation from Belzutifan, not only biologically, but commercially. Belzutifan's only being sold in late lines now, and it's still at a run rate of $700 million, and that's probably the tip of the iceberg. And then our data look better substantially than Belzutifan on every measure, whether you look at rate of primary progression, response rate, PFS, which is more than double, and that's probably the most important endpoint. We look better.
And then I think the new data with Merck from LITESPARK, well, I shouldn't say the data, the press release describing the data that Lenva plus Bell's looks like it'd be Cabozantinib, I think only enhances the probability that if there were any questions about whether casdatifan plus Cabozantinib will be Cabozantinib, I think those are gone. So we really feel casdatifan is very exciting. We'll have a lot more data in 2026 on that, particularly looking at a number of cohorts and opportunities in the front line, which will define what will be our phase III strategy the second half of next year when we go into a study with casdatifan in the front line strategy. So those are key things on casdatifan.
Second thing, which you know we've been excited about for some time, and I think probably is catching on a little bit more with others. So anti-TIGIT, to some people, it was put to sleep by Merck and Genentech, but I think we've demonstrated clear differentiation between the Fc-silent molecules like Domvanalimab versus the Fc-enabled. And I think you can almost look at those Fc-enabled anti-TIGITs as like ADCs that go and kill cells that are highly enriched in TIGIT, which unfortunately are Tregs in the periphery, and so they get all sorts of immune AEs. So we shared data recently from a study called EDGE-Gastric, which was frontline GI cancers, very simple study that's Domvanalimab plus Zim plus chemo. And what we showed was OS that was on the order of two years plus.
When you look at any of the standards, they're Nivolumab chemo, Keytruda chemo, Tisle chemo, they're at about 13 months or so, so very much differentiated. I think what's also validating there is that AstraZeneca has done similar studies with their bispecific anti-TIGIT, anti-PD-1, and their anti-TIGIT arm is also Fc-silent. They've seen very similar data to us. Between us and AstraZeneca, that's five positive studies. The reason we're so excited about that is because 2026 finally STAR-221, which is the phase III correlate of EDGE-Gastric, will read out. I'll remind you that that was fully enrolled in June of 2024, 1,050 patients. So we'll finally get an answer on that, and we're very excited about those data.
The other important feature on that is that by the end of this year, STAR-121, which is the PD-L1 all-comer non-small cell lung cancer, probably the biggest part of Keytruda's market. So that study will be fully enrolled with 1,000 patients by the end of this year. So if STAR-221 reads out positive, I think you're going to see a dramatic flip in sentiment as to how that STAR-121 study will read out. So it won't be just, "Oh, Arcus gets to start a study in that," but that study will have already been fully enrolled. And then finally, the third phase III study that just fully enrolled in September is our CD73 inhibitor, Quemli on top of gemcitabine and Abraxane versus gemcitabine and Abraxane that was fully enrolled in nine months as of September.
We haven't given any guidance, but given that OS for gem-abraxane is in nine or ten months, you can start to put a timer on when that'll read out. And then we just started to talk about our newer programs in the inflammatory immunology INI space, and we expect to take an HIF-2 inhibitor into the clinic next year. That molecule exists, and that's an exciting early part of the portfolio. Focus is on casdatifan. Domvanalimab will read out in the background, Quemli will read out in the background, and we have other programs coming along and will capitalize with $1+ billion to execute on these programs.
Excellent. Let's get into some details on CAST. So you recently gave updates on all the monotherapy data at an R&D day. I agree with you, Terry, when you say it looks cleanly differentiated versus Bell's in those monotherapy late line settings, especially looks interesting in progressive disease as a driver for PFS, as you've often said. But my question is, as we move into earlier line settings, especially in combination with highly active agents like TKIs, how much does that benefit on progressive disease translate when there just isn't as much progressive disease given the combination?
So, Jim, why don't you talk about it, and you start with the CAST Cabozantinib data that we have?
Yeah. So as Terry was alluding to, we've now shown a benefit on every efficacy measure you can think of with casdatifan versus what's been seen with Belzutifan. So in addition to the rate of primary progressive disease, which as you point out, TKIs are also very, very effective and bring down that rate of primary progressive disease. So in combination, that'll probably be a little bit less of a differentiator, but we showed a much higher rate or much higher overall response rate. We showed a much longer PFS. We haven't gotten close to a duration of response. So we think because the improvement that we're also seeing in those other efficacy measures, combining with cabozantinib or anti-PD-1 or anti-PD-1 and CTLA-4, we are going to add to whatever the response rate or whatever the PFS is that you would expect to see with those other mechanisms.
So we are very, very confident that adding CAST to any of these other standard of care therapies is going to provide meaningful benefit. And on top of that, as you were getting to, CAST has shown meaningful benefit over Bell's. So our combination should show a better benefit than what's been seen with the Bell's combination.
I think so the thing I would add to that is we already, as you know, we shared at ASCO early CAST plus Cabozantinib data. And at least on ORR at the time, we were like with four to five months of follow-up, we were at 40%+ response rate, whereas Belzutifan plus Cabozantinib, similar study after two years of follow-up had a 31% response rate. The other data that we'll have next year, again, to speak to this, we have a cohort running that's almost full that's CAST plus anti-PD-1. We'll have those data actually look interesting already. We'll share those by middle next year, and we'll be looking at other cohorts.
Yeah. And on that combination, I mean, that's something that Merck is never going to want to do because they have that high rate of primary progressive disease and anti-PD-1, unlike TKI. Yeah, it takes a while to kick in, so it doesn't have that low rate of primary progressive disease that TKIs do. So we think we can have a really interesting TKI-free combination, which is anti-PD-1.
And not just for the first line, but.
And CAST and with the combination. Exactly. That Merck probably couldn't do with Bell's.
Now, what about long duration stable disease, which I, Terry, could see you. I know this is your favorite subject. How long has time on therapy been at this point? And we know that some of the HIF-2-driven responses take a while to kick in, but for patients who never get to a response, how long can disease be kept stable?
So I mean, why don't you go ahead.
Yeah, so I mean, I think one of the most interesting charts to me that we showed at the investor event was actually in the commercial section, and what that showed was that 40% of patients on CAST were on treatment beyond 18 months and getting close to 24 months, 40%. That's despite a confirmed ORR in that cohort, which is the lowest confirmed ORR that we saw of any of the cohorts of only 25%, so that tells you there's like 15% of the patients are coming from the stable disease patients that are doing really, really well and are getting long-term benefit. So it's hard to kind of tease out exactly what's happening with stable disease patients, but clearly stable disease patients can look just like a responder from a durability perspective.
I think when you think about what's going on, it's very similar to immunotherapy and maybe even better in that tail part because of the safety profile. So as you know, most anti-cancer agents are poisoning you while they're helping you. And even with immunotherapy, there's a pretty substantial AEs. The thing with HIF2 inhibition, given that really the only thing you see, and you tend to see it early as anemia, you're basically getting the patients getting healthier and better able to fight cancer, their own immune system, everything's kicking in. And so what you see is that these patients that are stable disease, they almost look like they, as you know, response is an arbitrary 30-something%. If you look at the waterfall, the vast majority of the patients are getting some tumor reduction.
And then I think if you, and that's why that rate of primary progression is so important, because it seems like if you can get past that first scan as a patient on HIF2 therapy, you're going to do quite well. And it may just be that that 15% or so are the patients. If you look at the biology, about 80%-90% of clear cell RCC patients have some component of HIF2 as a driver. And I think it may just be that those other are the few patients that are just borderline activity.
But you mentioned tolerability. How is resolution of those anemia signals? That's the only tolerability issue, but it is an on-target tolerability issue. So do you see resolution of those in patients who have been on therapy for a long time?
So far, when we looked at 120 patients' worth of data, zero patients have had to discontinue due to anemia. So that's probably the easiest. I can give everyone something on that.
Yeah. And also, I mean, just when you talk to RCC clinicians, they're so used to managing anemia. Most of these patients have anemia to begin with. So there's no concern whatsoever as far as managing anemia. They're already looking for it. And they're getting, I think, more and more proactive in terms of how they manage the anemia. So using ESAs versus waiting for hemoglobin to drop to a certain level and having to transfuse the patient.
Moving to some of the combo cohorts that we're excited to see next year, Terry, you mentioned obviously the Cabozantinib combo cohort. You mentioned PD-1 combos. I'm especially interested in Cabozantinib combo given the read across to PEAK-1. So maybe we should talk about what the expectations should be there, especially in terms of duration, duration of the therapy, duration of response data that you may have next year.
Yeah. So next year, we'll be presenting more mature data from that CAST plus Cabozantinib cohort. So as a reminder, we last presented that data set at ASCO, so just about four or five months ago. It was 24 patients. It was all patients that had had at least two scans, and there was about five months median follow-up. There will be 44 patients in total that were enrolled in that cohort. So when we present the data next year, it'll be on that full 44-patient data set, and then obviously with much longer follow-up relative to what we've discussed.
Terry, I think you said they're not fully enrolled quite yet.
No, that's clear.
That's what I heard. That way we're just talking about the new cohorts. Yeah. So we're hoping by the time we present data, we'll be able to show some sense of where PFS could fall out. And that's to your point on understanding durability and PFS. That will be the focus of that data presentation.
You know one nice thing that it's subtle, but I think it's going to be an important data point is when Merck shares their Lenva, Bell's versus Cabozantinib data, that'll give a good contemporary look at how Cabozantinib performs in 2026.
Maybe can you talk a little bit more about that? I mean, obviously Cabozantinib is widely used. Clinicians are very familiar with it. You think there's a ton of data out there, but how has that evolved over time?
Why don't you describe it?
Yeah. So Cabozantinib is the most widely used TKI in both the front line and the second line. So clinicians are very, very comfortable using Cabozantinib. The reasons that clinicians like Cabozantinib and the second most widely used TKI is Lenva, which is what Merck is combining their HIF-2 alpha inhibitor with. But there's two things that they tend to point to. One is just tolerability. So most clinicians think that Cabozantinib is a better tolerated TKI relative to Lenva. There's less fatigue, less hypertension, less diarrhea. Pretty much every TKI toxicity that you can think of, there's a lower incidence with Cabozantinib versus Lenva. The other thing that they point out is that Cabozantinib is a lot easier to dose. So there's only three dosages that are available. Clinicians typically start with a 60 mg dose of Cabozantinib. If you see AEs, you would lower the dose to 40.
If you continue to see AEs, it's to 20. In contrast, Lenva is available in, I forget, like six to eight different dosages. And so one of the pieces of feedback that we get from clinicians is that they don't even know what the right starting dose of Lenva to use is. In every RCC study, they've used a slightly different dose. So we think by using a better tolerated TKI, a TKI that clinicians have more experience with, and a TKI that's easier to dose, especially since we're going on top of something else, makes that the best TKI for us to be combining with. And what people also forget about Lenva, in practice, Lenva is actually used with everolimus. So that's what it's approved in RCC as, Lenva plus everolimus.
And so when some people look at the data set side by side, Lenva, everolimus versus Cabozantinib, Lenva, everolimus sometimes look better from an efficacy perspective, but that is with everolimus, which has toxicity. Bell's is only combining with Lenva. They're not combining with Lenva and everolimus. So I think some people forget that actually what they're combining with is not what's used today in the real world.
Makes sense. On the IO combos, obviously there's a couple of different things running here now. Maybe we could start with the bispecific. Or I suppose I'll ask you this. If you've got combos running with the bispecific, we're excited about seeing how that reads out, and that's effectively shutting down the PD-1 axis. Why do additional combos with PD-1?
So the PD-1, we started it. We don't know for sure how the Volrustomig will read out. You know we paused enrollment there. We're also going to.
We're going to touch on that in a second.
Yeah. Okay. So what I'll tell you is we're also going to be, we will have a cohort that looks at Ipili PD-1 plus KES alone. So we'll be able to compare that to Volrustomig.
In a 214-like setting or in an adjuvant setting?
Oh, in a front line setting. And we'll also probably end up through collaboration looking at the VEGF anti-PD-1 combination as well, which makes sense. It doesn't make sense everywhere, but makes sense in clear cell RCC, may make sense also in HCC. And I think it's highly probable that we'll end up doing a study there. So we'll have the, we basically want to make sure, and what's interesting is the anti-PD-1 combination is looking today very interesting. We'll have more mature data by the middle of the year. But you can imagine that the thing that drove us to think about that is casdatifan is looking as good or better than TKI alone, only has the better AE profile. And so the idea of combining that with anti-PD-1, we thought was worth looking at.
We felt that the sort of best from an efficacy standpoint is, as you mentioned, anti-CTLA-4 and anti-PD-1, but it's also the most risky because that comes with the most AEs. We wanted to have the anti-PD-1 as well.
I'll also ask about the other combo that Merck is running, the triplet with TKI and PD-1, but you're not running that quite yet.
Right. And so we probably will generate a data set. So we obviously will have KEYNOTE Cabozantinib, and we'll have KEYNOTE anti-PD-1. We'll probably generate a safety data set, but we're very strong believers, and we feel like we're skating right to where the investigators want to go to pushing the TKI later. So the idea, and you probably, from everything we know, you were talking about that durability, you can probably get, we'll see how it plays out, two to five years of benefit on those early stage patients and not have to subject them to the TKIs.
You start talking to the physicians, they'll tell you, like when I've talked to guys, I talked to someone I didn't even know they were participating in our study, and they said, like when you give someone casdatifan or HIF-2 inhibitor, anybody who's experienced TKI feels like they're on a vacation. So the physicians feel like drive the TKI, reserve it for later, give that quality of life. It's not like you have to hit that TKI early. So we like those TKI sparing regimens as a default.
All right. Well, so now let's talk about the Volrustomig combo, and I'll ask you about the clinical hold. How much visibility do you have on data so far there, and how much do you have on the hold?
So we don't, the only visibility we have, what it is, is that these were early. So the study started to enroll much quicker than a typical phase I, and these AEs essentially look like CTLA-4 AEs. So what the decision was is let's let those group of patients continue on therapy, see how they play out, see how much difference there is versus what you might expect for CTLA-4 plus anti-PD-1 alone, and then potentially consider would you need to do some sort of protocol amendment where you might dose a little differently, whether that be a loading dose, a lower dose, et cetera. But we'd always planned to also have, and that's why I mentioned the IPPI anti-PD-1, where you get another degree of freedom in terms of how you do your dosing.
Makes sense. Well, we're out of time. We didn't talk about TIGIT. We didn't talk about the HIF-2. But obviously we're excited to see phase III data sets, whenever they come up, including TIGIT. I can't wait to see that data next year. But thank you so much, Terry.
Thank you, and thanks everyone for listening. We appreciate it.