Good morning, everyone. My name is Jason Zemansky. I'm one of the mid-cap analysts here at B of A. Thank you for joining us on this, our last day of our 2024 Healthcare Conference in Las Vegas. I'm pleased right now to be introducing Arcus Biosciences, and I have with me here, Terry Rosen, Chief Executive Officer, and Juan Jaen, President. Gentlemen, thank you so much for joining us, for what will, I think, be a very interesting and spirited discussion.
Thanks, Jason.
Well, perfect. Maybe to kick off the discussion, last week, during your earnings call, you pointed to several near-term catalysts that are in place to potentially support your four late-stage clinical programs. For those investors who may be a little bit newer to the story, can you please provide a brief overview of each of these, Dom, Etruma, Quemli, Cas, along with their indications?
Absolutely. So, it's going to be a very catalyst-rich, you know, second half of the year, starting at ASCO. So I'll go chronologically, and I'll start with ASCO, and I'll start with a study that we call EDGE-Gastric. That involves Dom/Zim plus chemo in upper GI cancers. We presented early data from that at the end of last year. We were seeing a very favorable-looking six-month PFS in both a high PD-L1 population 93%, and then the overall population, which was, like, 77%. And we think we're gonna have very meaningful data at ASCO on an update on that, and most importantly, we'll have median PFS.
Importantly, you'll be able to see the safety profile, which is a very good surrogate when you're looking at Dom/Zim plus chemo. And particularly, we think that's important, and maybe we'll get into this a little in light of Merck's announcement of one of their phase III trials in adjuvant melanoma. The second presentation that we'll have at ASCO, that I think is a little under people's radar, that we think will be very meaningful, not only for Arcus but for the field, in the ATP adenosine field, and that's with our A2 receptor antagonist, etrumadenant. I'll remind people, the abstract for that will actually be out a week from today, so you'll be able to see a lot of the data for that program.
It'll be an oral presentation on Sunday, and that's in the setting of third-line colorectal cancer. I'll remind you, that's a randomized study. It's 105 patients, 70 on drug, 35 on the ... What was the standard of care at the start of that study? Regorafenib. That standard of care is evolving. It's currently moving towards LONSURF Bev. To just give you some landmark numbers to keep in mind, the PFS for regorafenib is 2 months and change. It's not a very good drug. OS is about 6 months. There's a new study for the LONSURF Bev called Sunlight. I have this habit of saying Sunshine, but it's a Sunlight study.
The OS in that study is just over 10 months, and the PFS is 6 months and change, and you'll be able to compare to that. We're very excited about the data. We think we compare very favorably to the standard of care there. So I think it's gonna be a big deal for the ATP adenosine field. And what you'll be able to combine with that study is also combine it with the data that we presented in ARC-8, in pancreatic, with our CD73 inhibitor, as well as the data that Roche presented with Itruma, also in pancreatic. And what it really points to is strong evidence that mitigating the effects of adenosine when you're giving immunogenic chemotherapy can have profound effects on the OS.
Then the final catalyst from a presentation standpoint will be an update on our HIF-2 inhibitor that we're planning later this year, that'll include 30 patients that are in an expansion cohort, 100 milligrams in clear cell RCC. Then the two other important catalysts that I'll just point you to, that'll be occurring, involve a trial enrollment, and these are phase III registrational trials. So by the middle of the year, we have every expectation that STAR-221, it's almost 1,000 patients in the upper GI cancer field, that is the same patient population, the same setting, same combination as the EDGE-Gastric data. So that'll be a really good surrogate for what we're gonna see there. That should be fully enrolled by the middle of this year.
And then a little later this year, we expect STAR-121, which is also our anti-TIGIT, anti-PD-1 chemo in PD-L1 all-comer non-small cell lung cancer. That's going right at the underbelly of Keytruda. That should be fully enrolled this year as well. So I'll stop there. That was a long, brief introduction, but wanted to get... We have a lot happening.
Absolutely, and a very interesting time for the company, a very exciting time for the company. I was hoping that before we focus on ASCO, maybe we could take a step back and chat about TIGIT. You know, I think it's safe to say that despite a lot of initial interest and promise, we haven't seen thus far much from the mechanism. I know you mentioned Merck's setback in melanoma. So arguably, some investor skepticism. What continues to give you confidence in the mechanism? And then maybe you could speak a little bit to your Fc-silent receptor as Domvanalimab . Is this what needs to kind of get us over the efficacy hump?
Yeah, so on the first piece, I'd say our own data, primarily ARC-7. We actually think the Sky One data, whether or not Genentech Roche hits statistical significance, clearly shows the mechanism works. We've seen some favorable GI early data out of Roche Genentech as well. We think that the data that we'll share at ASCO and from EDGE-Gastric will further enhance the confidence. So we think the totality of data really point to anti-TIGIT being important. And we feel... What's interesting, if you look at the field, and you look at the combinations of anti-PD-1 or anti-PD-L1 and anti-TIGIT, there's really only two molecules that we think are substantially different. And that's Atezo, not only anti-PD-L1, but also he has the issue of ADA, so we feel that's a weak point.
Then we feel that all of the Fc-enabled anti-TIGITs are pretty similar. So this gets to your question about the Fc-silent. What we've seen consistently is that Fc-silent anti-TIGIT on top of the other therapy basically doesn't bring any additional toxicity or AEs. And I think that'll be very clear from the EDGE-Gastric presentation. Nice timing, Merck just talked about a phase III study that they were doing in melanoma that very much gave an explanation that's something we've been foreshadowing for some time. Now, let's recognize that the setting they were in, this is phase III in adjuvant melanoma, so the safety bar is really high in that. But what they did report is that they stopped the study for futility, but they pointed out that what they were seeing were high levels of immune AEs.
Keep in mind, they're developing a co-formulation, so they've got their anti-TIGIT and their anti-PD-1 in one bag. So if they take a patient off for an AE, they run a risk of an efficacy issue as well. And they have an Fc-enabled anti-TIGIT. We've also noted that Merck, when they did their early studies, explored 200 milligram and 700 milligram doses of their anti-TIGIT, and they went with the 200 milligram. So we think this illustrates what will be a continuing issue for the Fc-enabled anti-TIGITs, which the one thing that's been shown clinically, demonstrably across them, is that they deplete peripheral Tregs, and that's what leads to those immune AEs. So we feel really well-positioned-
Mm-hmm.
with the Fc-silent anti-TIGIT, and like I said, I think our EDGE-Gastric data will reinforce that concept.
Great. And you know, you mentioned Roche's,
Mm-hmm
... Skyscraper-01 data. I think it's still top of mind for many investors. If the data are positive, does this complicate the potential commercialization of Dom in at least lung, especially with Atezo being somewhat already used in this indication?
So actually, for us, because strategically we moved away from the high PD-L1, we feel we're right in the race with Merck in the PD-L1 all-comers. We're gonna be fully enrolled this year. So if anything, we think a positive result for the field will be good. We'll be thrilled with that being statistically significant, and we feel we're gonna be, you know, likely second, in the PD-L1 all-comer and feel like we're gonna have a best company. So a positive for them, we think is good for the field and good for us.
Perfect. Well, let's pivot to ASCO. I mean, you mentioned the Cohort A one presentation. You know, last November, I think, it was fair to say the discussant was very impressed by your ORR, but did flag the outcomes in the PD-L1 low expressers. Will we see data stratified by PD-1 expression, and any concerns here?
I'll actually... Why don't you-
Yeah, sure.
Take a shot.
So the answer to your question is yes, we're gonna break it down by PD-L1 expression. You're gonna see objective response rate as well as median PFS and landmark 12-month PFS as well for both groups.
Great.
And we're really looking forward to sharing those numbers with the rest of the community.
Excellent. And then in terms of mPFS, what do you think is sort of the benchmark here to really get the community jazzed about what we're seeing?
Yeah, so what's nice is there are three registrational datasets out there, and the numbers are tight. So CheckMate 649 is clearly the most important because Nivo chemo is really the standard of care. And you also had, in the past few years, approvals for Tisley chemo and Keytruda chemo. The numbers come in really tight, somewhere between just under 7 months median PFS to just about 8 months PFS. So you could do the math. It's just a couple of weeks away, but something meaningfully different from those should be exciting to the field.
Got it. And then, as you mentioned, STAR-221, enrolling very quickly, setting it up to potentially be your first indication, your first commercial, first point of commercialization, but how important is it to your overall strategy here, you know, to get established in gastric and potentially move out into other indications?
You know, we do see that as very important because it gives us an opportunity to start to build a halo for the Fc-silent anti-TIGIT. I think it's gonna that this will be a place where it can stand out because it is in combination with chemotherapy. So we just like the way that very organically things have played out and the timing there, and that, you know, getting that out there. By the way, no one else has even started a registrational trial in that setting. So, you know, for us, we hedged our bets going into this setting, and we think that's gonna play out for us very favorably strategically.
Got it. One more maybe on gastric. Again, I think the field is. It's safe to say things are evolving. We have the anti-claudin class coming in. You know, on one hand, there are maybe more toxicities, but on the other hand, you know, combining a PD-1 with a claudin is you're mixing two different modalities, which isn't necessarily the same with a TIGIT PD-1. Can you walk us through the scenarios here? I mean, is claudin overall a competitive threat?
Well, sure. Yeah. So just a point of clarification, we're going after gastroesophageal adenocarcinoma. So the majority of gastric and a good chunk of esophageal fall within the scope of what we're studying. We're not particularly worried. Primarily, I think, claudin 18.2 seems most prevalent in the PD-L1 low population, as just pointed out. Those agents tend to be fairly toxic. We think that an Fc-silent TIGIT antibody will definitely be very competitive in that PD-L1 low population with an infinitely safer profile. The natural barrier to claudin 18.2 testing in the general community. I think it's gonna be an additional barrier.
We think we're gonna be very competitive on efficacy, superior and safety, and much easier to select patients for.
Fair. Great. And then I know you briefly touched upon STAR-121, you're pivotal in lung. You know, if you look at the lung market overall, there are a number of modalities moving forward, not only next gen IOs like TIGIT and LAG, but ADCs as well. And then you've got some established regimens with, you know, 5-year+ survival rates and, you know, CTLA-4, PD-1. So I'm curious, you know, how does TIGIT fall into the overall mix here, especially as kind of the market remains, you know, fairly in flux?
So we think it's probably right down the middle of the fairway, because the way we look at it, the real leader there is, you know, anti-PD-1 chemo, and this is going to enhance that effect. You're running against that standard of care. We're running against Keytruda chemo, so we're feeling really good about where this positions us, not only in the context of the anti-TIGIT field, but in that, you know, front line non-small cell lung market.
Got it. And then, you know, looking, I think, more towards the commercial side of things, you're obviously partnered with Gilead, has a very strong commercial footprint, but at the same time is maybe a little newer to lung than some of the other entities here. You know, can you talk to us about, you know, what the partnership means in terms of your strategy here? And then, you know, what is it like having been working with Gilead? How's that partnership?
You know, I'm sensitive to time on this. Partnership's been awesome. We actually feel that, you know, what's unusual about it, I would actually say, and you know, I've been working almost 40 years and collaborated with almost everybody. It's probably the best collaboration I've ever been involved in, and it's also the broadest. Like, I've, there's literally hundreds of people working on the programs at Gilead, so it's not one of these things where you meet every quarter, but it's day-to-day, and that's through the level of Dan to everybody working in the teams. We talk daily.
To your point about the commercialization, we're feeling really good about that because we recognize a lot of early-stage companies, really, when they are successful, technically, development-wise, they stumble there, and we feel the ability to titrate in with them. And their head of commercial, actually, background is BMS immuno-oncology, so we feel we're with the, you know, right partner. They know how to commercialize combinations well, so we're pretty thrilled with how the collaboration's going and, you know, the future as well.
Cool. Let's switch gears to the adenosine pathway. You mentioned again, ASCO. We'll see Cohort B for ARC-9. You know, obviously, the comparator here is necessarily imperfect. You know, on one hand, regorafenib is the benchmark. Not a lot of clinical benefit, though. So you know, you're adding etrumadenant to a background of chemotherapy. How should investors interpret the results in terms of, you know, teasing out the added benefit? I mean, what do you think is the appropriate benchmark here?
Yeah, you know, it's interesting, we just had an ad board, and without sharing the details, one of the things that I was thrilled the most about that meeting was their comments about how well we analyzed the data. So I think here's the way I would suggest to investors that they come in, and again, I'll remind you, the abstract will be out the 23rd, so they have plenty time to look and if you want to prepare. I would say the nice thing about regorafenib is it's well understood how it should perform. So it tells you we got the right patient population. You'll see how we performed in liver met patients. You'll see how we performed in peritoneal patients, so pretty decent-sized study. But what's nice about having the regorafenib in there is that standard of care is evolving to LONSURF Bev.
You'll be able to compare to that, and then to the extent, you know, there is use of FOLFOX Bev out there, but there aren't big comprehensive studies. So what I would just suggest is, once you see our data, you can pick and choose your favorite standard of care that you want to go compare it to in the literature, and I think we'll compare quite favorably. So we're excited. You know, look forward to talking to everyone about those data in a couple weeks.
Got it. You know, the interesting thing is you're re-challenging with FOLFOX, the chemotherapy regimen. So, you know, the implication would be that if the regimen works, you know, third line, then it probably works better earlier line. So I don't know. I mean, can you comment on that? I mean-
Yeah.
not to give you too much-
I'll let Juan-
Softball here.
I'll let Juan talk about, but we, we like the idea of going earlier.
Absolutely. So, you know, you got to... On the one hand, you got to build on the data that's in front of you, but then the question is, would-could you push it into an earlier line? And that's something that our, the participants in this ad board that Terry mentioned, were strongly encouraging us to consider. Clearly, FOLFOX is standard of care in front or second line, depending on the geography, and mechanistically, there's no reason why whatever it is that we are seeing in third line should not be equally applicable to front.
You know, I'll remind you, what we're seeing is exactly... When we got into the ATP adenosine pathway, where we felt there had only been poor molecules. Well, it takes time, but mechanistically, the primary hypothesis we were looking at is that in the presence of immunogenic chemotherapy, if in fact you could generate a T-cell response, you're just producing so much adenosine as those cells die, that you're inhibiting that, and that seems to be what's playing out, whether you look at the ARC-8, ARC-9, this current study, or the Genentech PDAC Morpheus study.
Well, again, great segue here. Still on adenosine. Let's talk Quemli in first-line PDAC. You know, ARC-8, I think fairly impressive, overall survival data, 15.7 months. But, you know, at the same time, I think it's important to take, you know, a very long look at the data. This is an indication where we've seen, you know, pretty compelling early phase data that just doesn't materialize. So, you know, what gives you confidence that as you move, you know, into later development, those numbers are going to stick?
Yeah. So I think the, like, a lot of the misconception about the data that's driven people to do studies that have failed, that it was strong, compelling. I think they tend to be small studies, more based on ORR, more based on PFS. We had mature OS. That data was further enhanced by the Genentech data, which again, was controlled, and it was with etrumadenant, so a similar experiment, but a different experiment. They saw over sixteen months OS, a hazard ratio versus gemcitabine on the order of 0.66 and change. So we feel it's about as strong a data set, and that the data that drove others may have had less rigor, despite a nice-looking number at some point.
Got it. Maybe one more on adenosine. I know this came up during the first quarter call. But if you, you know, one of the interesting things was, is that if you looked across the landscape of tumor types that had high adenosine expression, you know, you've had some setbacks there with prostate cancer, presumably NSCLC. You know, you mentioned that immunogenic chemotherapy may be the trigger here. What does that mean in terms of looking at additional indications? You know, I know an early slide of your corporate deck, you know, you had listed things like TNBC. Is that high on your list?
I'll, I'll let Juan talk about holistically how we think about that now.
Yeah. So we're really, really focused on immunogenic chemotherapy, but I think you could expand that to immunogenic backbones. So a study that we find also very supportive of our hypothesis is the COAST trial that AZ disclosed. Now it's going on almost two years. And that was what they showed is that CD73 inhibition with oleclumab enhances the PFS in Stage III non-small cell lung cancer patients following chemoradiation therapy. That was the basis for their ongoing phase III study, PACIFIC-9. And we actually think that, that, that study and that setting really, again, reaffirms the our mechanistic understanding of what we're seeing in colorectal and pancreatic. So that would be, in principle, another really interesting type of combination, not just immunogenic chemotherapy, but in, in combination with chemoradiation.
Mm-hmm. Interesting. Well, the time we have left, if we could talk to HIF-2a.
Great.
... You know, I think earlier this year, you, you generated a lot of excitement with fairly compelling PK/PD data. You know, there's, there's been a lot of hope that the, the increased potency here should drive faster responses than Belzutifan. How, how fast do you think you could get, you know, again, given kind of these molecular parameters?
So I'll tell you, we kind of have broken the opportunities for differentiation to few. There is a kinetic. Interestingly, when we had an ad board there, one of the endpoints that was most highlighted as a limitation from LITESPARK-005 was the rate of primary progression. So that was like 33%, which was actually even poorer than everolimus. So we're already seeing, since that's one of the earliest things that you're gonna pick up with immature data, you know, those patients that progress prior to first scan, we already have seen very good data there.
We'll have more data because not only do we have our 100-milligram cohort, that's will be quite mature by the time we present on it later this year, but the 50-milligram cohort, which we're doing for dose optimization, we'll also have a feeling from that. So then we have the opportunities, you said, for kinetics. And then importantly, you know, do all those things translate into not only a response rate, but PFS? So that's where we really see important potential differentiation. So it is multiple, and then recognizing that we're gonna go into all of this in combination. So we also see that we think we're gonna be going with a better TKI than lenvatinib.
So I think by the end of this year, we're gonna have a very mature, full data set around that 100-milligram cohort. People will get a really good feel for those multiple points of differentiation. We're clearly hitting the target harder, and to your point, is exactly how and where does that manifest the kinetics, depth of response, response rate, PFS, primary progression, and we'll have really good data set to inform those.
Sure. And then, have to ask on this. One of the PD markers you were looking at, EPO, looks like you can suppress it more than Belzutifan, but that brings up concerns about safety. Obviously, you know, it's an on-target effect. So, you know, as you move forward, what's the concern that you'll see similar sort of rates of, if not greater rates?
Yeah. So actually, that concern is diminished every day. So what we have just started to share, that we've actually even dosed in our dose escalation, 150 milligram cohort, did not see any DLTs. What it seems to play out, to your point, is that the maximal inhibition of HIF-2 that you can get in the kidney, roughly 60%-80% of that, depending on the patient, depending on the rounding errors, is HIF-2 mediated. So nature's built in this really nice block that you can hit the target harder, presumably and hopefully doing something that's more meaningful in the tumor, but we've yet to see anything across our studies that suggests we're seeing anything more on the anemia front. And in fact, the physicians love the profile, and they feel they understand how to, you know, manage that.
Great. As we wind down, you did mention that you have an upcoming update on the 100-milligram dose. You know, what should investors focus in when the data come out? Is it safety at this point, or do you think we're gonna see you know, enough of an efficacy enough about the efficacy to feel confident?
You wanna take the last word here?
Sure, yeah. So it's just to recap what Terry's already commented on, you'll get a really clear, complete final sense on primary progression rates from the 100-milligram cohort. You'll have an early but very encouraging look at objective response rates, and you'll probably get a... Not probably, almost certainly, you'll start to get a developing picture for the kind of PFS associated with 100 milligrams, as well as safety, of course.
So I think that what investors will be able to come away from this is that, and you, and you can almost infer this from what we know about belzutifan. Casdatifan is a drug, and the real question is going to be: How are we gonna do when we're competing against Merck? How are we gonna do with a different TKI, other mechanisms that we combine? It's gonna be about execution and competing with Merck.
Got it. Well, thank you so much, both of you, for joining us. You know, you said this is a very catalyst-rich-
Yeah
... period coming up for the company and certainly a very exciting one as well. So looking forward to the readouts.
Thanks, and thanks for the invitation. We appreciate it.
Thank you.
Thanks, Jason.