Good morning, everyone. Thank you for joining us. Really pleased to have with us the Arcus team. We have Terry Rosen, CEO, and Jennifer Jarrett, COO. I guess to start here, it'd be helpful to get a high-level outlook. You've shared a number of encouraging data sets over the past few quarters, which we'll dive into shortly. But to start, can you give us an overview of how the company's positioned for the second half of this year? And where you're most focused on in the near term, and when we might start seeing registrational data from your pipeline portfolio?
Sure. So thanks, Shelby, and thanks anybody who's listening in. Obviously, I know I'm gonna go quickly, so we can leave a lot of time for Q&A. We just had the two oral presentations at ASCO just within the last week, and I think those are really important for us and the field. I'll tick through those quickly at a high level. We had the EDGE-Gastric data. I'll remind you that's upper GI cancers. It's frontline. And what we showed there, the new data, was median PFS on the order of 13 months. That's a median PFS that hasn't been seen anything like it in that field. There's been three registrational studies done. The most notable is CheckMate 649. That's the standard of care nivo chemo, but there's been Keytruda chemo and tislelizumab chemo.
They all come in about 7 months -8 months. So that 13-month PFS that we showed is actually in line with what's known to be OS in that field. The other thing I think that was important data there was that the molecule performed similarly in both the high PD-L1 and low PD-L1 populations. I'll remind you, in our study, we actually had a bit of our arm tied behind our back compared to CheckMate 649, so we were 40, 60 high PD-L1 to low. CheckMate 649 was 60, 40 high. So, what's, to your point, exciting about that study, more than just the data per se, is that on Monday, we just announced that the corollary phase III study to that, STAR-221, over 1,000 patients, is fully enrolled.
So that really starts the clock ticking towards registration, you know, hopefully, launch and commercialization, years ahead of anybody. So we're gonna have a great first mover opportunity there. The second study that we reported on really pretty exciting data, especially, you know, everyone talks about patients. This is about patients. This was in third line colorectal cancer, one of the most dismal settings out there. This is with etrumadenant and, you know, some standard chemo regimen in colorectal cancer. And in that third line setting, we saw in a very rigorous study, you know, a study arm of 70 patients, control of 35. In OS, that's never been seen with any combination in that setting, any regimen in that setting of around 20 months.
In fact, when you break out the data, we saw that even in liver met patients, and by the way, some studies even exclude liver met patients, which is kind of ridiculous, given that they're about 70% of their population, we saw that same benefit of around 20 months. So that's another program we're quite excited about the data, and we'll be moving forward there. The final catalyst that I'll talk about is one that I think there's a lot of excitement in the world, and probably that excitement is most generated by, you know, call it technical validation proof of concept. So that's our HIF-2 inhibitor program, molecule called casdatifan. We would say casdatifan is drug waiting to happen. Merck's belzutifan has validated the target.
We clearly, demonstrably, and in the clinic, have shown that we have a better molecule. The point now will be to show that that actually manifests itself clinically. We have a 100-milligram cohort that's fully enrolled in clear cell RCC. We'll be sharing data from that at a medical conference later this year. We've also fully enrolled the 50-milligram cohort. We did a 150-milligram cohort in dose escalation. There's so much excitement in the investigative community. An expansion cohort with that is almost fully enrolled. That'll fill out our Project Optimist dataset. So we'll have a steady flow, you know, starting later this year with those 90 patients. We've also started a cohort combining with Cabo, which will ultimately support where we're going with these, this program, which will be in combination therapies.
So lots of opportunity to differentiate from Merck, and we feel like we have a molecule that is already showing those signs. So I'll stop there and jump into your questions.
Great. Let's start with the TIGIT update at ASCO and gastric cancer. Walk us through any feedback you received from the physicians at the event, and also, you know, your confidence that you can repeat this in the phase III study, STAR-221.
Yeah. So, the feedback could not have been more positive. So at ASCO, we met with well over 100 KOLs to talk about gastric CRC, as well as our RCC program, but probably at least a third of those were gastric. Everyone was extremely impressed by the data, said it's unlike data that they've ever seen in gastric. So as a reminder, Terry was saying we saw about 13 months PFS in the overall patient population, almost 14 months, in the PD-L1 high patient population. That compares to 8 months for the benchmarks. So getting to your second question, we're well above anything that's been seen from a historical benchmark perspective. So even though you always assume there may be some degradation as you go from phase II to phase III, we obviously have a huge amount of cushion there.
The other thing that you might ask is: Well, OS is your endpoint for STAR-221, your phase III study. You just reported PFS data. PFS and OS tend to be very, very highly correlated. If you look at CheckMate 649, which was the phase III study that Bristol conducted in gastric, the hazard ratio for PFS and OS was almost identical. So those two things seem to be very, very correlated. Also, the OS for the benchmark studies was 13 months, which is what our PFS was. So obviously, we're going to see an OS that's well beyond 13 months, in our phase II study, so well beyond, what you would expect with, with comparator drugs for the primary endpoint.
Remind us as to the size of the addressable population here.
So it's north of 40,000. It's a huge patient population. Some people think of gastric as being very Asia-centric. There is a large Asia patient population, but for the adenocarcinoma markets, so gastric, GEJ, esophageal adenocarcinoma, there's also a lot of patients in the U.S. and Western world. It's actually, I think, the fastest-growing tumor type in the U.S. and Western world right now, you know, related to diet and other things. So it is a very large market. We think it's $3 billion plus overall. It's probably $2 billion plus just in that PD-L1 high segment. And, you know, we'll see what we see with our PFS and how long patients stay on treatment.
But obviously, if we're keeping patients on treatment for 12 months -13 months, you know, it's going to be a much bigger market opportunity than $3 billion.
When could we see the phase III data set here?
So we haven't said. If you look at our investor materials and Gilead's, that we've had it out there for a while, very consistently, we've shown 2025 plus, which means we could have the data as early as 2025. We did just announce completion of enrollment. You know, we know OS, at least, for nivo chemo, is 13 months. You know, we obviously want to do a bit better than that with our regimen, but you can kind of do the math and start to get a sense for, when we could see our data. But, you know, obviously, as Terry was saying, you know, it's now around the corner.
Is there a mechanistic reason that the benefit that was seen here might be more meaningful than, than what we've seen in lung? Maybe help put that in context for us.
Yeah. So I would just say, actually, you might expect by the time these trials run, seem similar types of benefit. And I like the way that you asked the question because we tend to look at whatever we're doing, is you're treating biology, not an organ. And the biology that you're treating here is the same, and these are both high CD155 tumors, particularly when you bring on the chemo. So that brings in the PD-1 component, but they are high CD155. And so we think, you know, we're extraordinarily excited about our PD-L1 all-comer non-small cell lung trial, which really is going at, you know, the largest patient population, 100,000 patients, and that study is going to be fully enrolled this year as well.
So we think mechanistically, the two go hand in hand, both in terms of the role of PD-1, the role of chemo in driving that to lower levels, and that they're high CD155 tumors, which is, you know, what drives the, the TIGIT activity.
At ASCO, you and Gilead also presented interesting data from etrumadenant in colorectal cancer. Could you walk us through the highlights from this data set and what next steps are for that program?
Yeah. So the headline for the data set was median OS of 20 months, which is unlike anything that's ever been reported, probably in second-line colorectal, but certainly in third-line colorectal. And that's something, going back to what we were hearing from investigators and KOLs, that they very consistently said that, you know, 20 months is well, well above anything you would expect in the third-line setting. The other thing that was very interesting about the data is that we saw just under 20 months in patients with liver mets. Usually, that's a patient population with a very poor prognosis that tends to progress much more quickly. You know, actually, the trend has been from some other studies that are looking at third-line colorectal to actually exclude those patients, even though it's about 70% of the patient population.
I think that was something else that KOL found very striking about the data.
You, you noted the potential for a second signal-seeking Phase II trial, where you could determine which drugs within the combo are driving most of the activity. How necessary is this? And then speak to which drug you would potentially drop from the regimen and when you'd expect to move into a registrational trial.
Yeah, so we're working through those exact questions, and we're going to do it expeditiously with both Gilead and the FDA. But to give you some insight, the molecule that we have question marks about is whether we really need the anti PD-1. So I'll remind you, what you've got is sort of the standard there is the chemo bev, so the FOLFOX-Bev , and then we've added etrumadenant anti-PD-1. There are very rational designs that could either be registrational, phase II, or where you might do some component. We have an ongoing platform study that was the, you know, ARC-9 nomenclature itself. We'll know very shortly, again, through conversations with Gilead as well as the FDA.
I'll note that, again, coming back to that concept that we're treating biology, not an organ, this is not unlike the pancreatic data set where you're going on top. By the way, we think this is a very favorable aspect of just the general strategy, that you're enhancing a standard of care that physicians are used to, as opposed to displacing something in the field. Those are the physicians are comfortable with the other regimen. But you see the same sort of thing where we actually did in the Gem-Abraxane pancreatic setting. We did a randomized trial that looked at the effect of anti-PD-1, and in fact, we saw that the anti-PD-1 brought nothing. The other thing that is known from this field is that Atezo, on top of the FOLFOX-Bev , does not bring any advantage.
So we haven't made a final decision on that, or whether we might generate some additional data, before we went forward. But the biggest question mark for us is whether we need the anti-PD-1 or not, based upon all the totality of the data that we now have that we didn't have when we started this study.
Could you also speak to mechanistic reasons as to why we are seeing a benefit, targeting the adenosine pathway here in colorectal cancer versus the prior setting, I think in prostate cancer, where it did not add as much therapeutic value?
Yeah, absolutely. So, it comes back to that same concept, where our original hypothesis as to where we thought the adenosine pathway would have its greatest utility was in the context of immunogenic chemotherapy. So by definition, briefly, immunogenic chemotherapy produces a ton of adenosine, and that adenosine inhibits the action of, if you can generate a T cell response, those T cells are inhibited by that adenosine. So to get the benefit of that, the hypothesis was remove that adenosine fog and let that immunogenic chemotherapy play out. Now, if you think about, we've actually generated 3 data sets in, like, the last 6 months that have shown that. Our ARCADE pancreatic data set, again, profound OS. The Genentech Morpheus-Pancreatic data set, also with the Keytruda, profound OS, 16+ months OS versus around 10 months for gem/abraxane alone, and now this molecule.
If you actually go back and look at our prostate data, what's interesting is we had multiple arms in there. They were relatively small. It was the early days, and the ones that did not include chemo, we basically saw no signal. Interestingly enough, there was one arm in later line with docetaxel, and if you look at those data, there actually is somewhat of a signal there. It would be something that you may or may not convince yourself, as a 17-patient or something, whether you might go forward. But if you were to look, that was we saw PSA decreases. We didn't have bone measurements on all of them. We didn't have tumor reduction on all of them.
So I would say the key thing to keep in mind in terms of mechanistic differences, and if you look not only at our studies, but across the field, where you will see some benefit, we think, is where you have that immunogenic chemotherapy. I'll remind you of a data set that, again, it's under the radar for most people, it's not under the radar for AstraZeneca, is their COAST data set. And they just presented updated data that ASCO continues to look quite good. And I'll remind you what that is, is that's in stage three lung, where you're treating with CRT and then you're treating, in their case, with their CD73 antibody and I know they were anti-PD-L1 durva. So they're actually running a registrational trial there. It's the same sort of thing.
You've got the CRT, the chemo. The other thing I'll point out is that these are also in colorectal and pancreatic. Our poster trials were in high CD73 settings as well. So you are definitely getting those high production of adenosine in the combination with immunogenic chemotherapy.
Just, shifting back to TIGIT before we move to the rest of the pipeline. Now, we've seen a number of data sets in addition to yours, from Roche and Merck. Can you share your thoughts on the potential for targeting this pathway and where you're most confident and where you see the most risk?
Yeah. So you know, we feel like, lung and gastric, we've probably seen the most supportive data, and so we have a lot of confidence in our lung and gastric studies. And just as a reminder, you know, Sky One data was obviously inadvertently leaked. The takeaway from that data set was that we'll probably end up with a hazard ratio from that study, you know, somewhere between 0.76 and 0.81. So depending on their stat plan, you know, it will be a successful study. If they don't have their stats exactly right, they may just miss. But that in addition to all the data we generated internally, both from ARC-7 and then as a reminder, we had the ARC-10 study, which was a phase III study of dom plus zim versus zim versus chemo.
We shut down the study for, you know, a whole bunch of strategic reasons, but we obviously have the data from that that is also supporting what we're doing in lung and gives us more confidence around our phase II studies in lung, of which there's now II. On the gastric side, Roche has also reported some really supportive data sets both at esophageal adenocarcinoma as well as squamous cell. Most recently, at the end of last year, I think it was maybe ESMO IO or ESMO, but they reported data sets in both those esophageal tumor types that were both very, very encouraging. And then we have our own data set, EDGE-Gastric month PFS. That also gives us a lot of confidence in what we're doing in gastric.
So we think we've picked the right tumor types, the right settings, the right combinations. The other thing that I think is really unique about our program versus others is we have the only Fc-silent TIGIT antibody. So if you look at some of the data sets from the Fc-enabled TIGIT antibodies, there's definitely signs of more toxicity, particularly with the BeiGene and the Merck data sets. I think most interestingly, Merck just reported that they did not meet an interim analysis for a study they were running in melanoma, where they were looking at their coform of their TIGIT antibody plus PD-1 versus Keytruda. They said very explicitly in their release that the reason they were unlikely to hit the endpoint was because so many patients had to discontinue due to immune-related AEs.
We think the fact that we have a more mild or could have a more mild immune AE profile and we'll be able to keep drug on patients longer, will be a huge advantage for us and should result in better data sets.
I think that, I mean, just to call it out, I think that Merck press release read exactly what we've been saying for some time, including the fact that with the coform, so not only do you see the AEs, but then you have to take the patient off of both drugs. So it's not only you're having an AE difference, but it affects efficacy. The other tagline, I think, and this is implicit in what Jen said, is the settings that really you want to go, and this is. I won't go through the biology, but anti-PD-1 and anti-TIGIT are not orthogonal mechanisms. They're related to each other. So a lot of things in anticancer combination therapy, you're combining two things and, you know, almost quote, unquote, "hoping." In this case, the anti-TIGIT activity is facilitating the intrinsic activity that you can get out of anti-PD-1.
So the settings that will make the most sense are settings where anti-PD-1 actually works. So a lot of the studies where people might have just done things, they say, "Hey, there's high medical need, it's strategic, it makes sense in a PD-1 refractory tumor," are pretty much destined for failure. So, we think we've picked strategically not only the right sort of market opportunities and need opportunities, but also scientifically and feasibility. It doesn't work, it doesn't matter how, you know, how big of an opportunity it is.
One other data point is AstraZeneca had an investor presentation or meeting, I think it was either right before ASCO or at ASCO, but one of the programs that they highlighted was their PD-1 TIGIT bispecific, and they called out lung and gastric as the two areas that they were likely to focus on. So, you know, still again, it reinforces our strategy with our own TIGIT antibody.
You clearly have a lot of enthusiasm for the HIF-2 alpha program. Maybe help us understand the confidence here as you think about not just, you know, having that—hitting that clinical benefit, but also in the context of competitive dynamics.
Mm-hmm.
Frame the upcoming dose expansion data that's set to be released in the second half, I believe.
Yeah. So we could not be more excited about the casdatifan program, especially because it's progressing so quickly, and the data that we're seeing is everything that we'd hope to be seeing. So as a reminder, at our 100 mg dose, which right now is our going forward dose, we're getting 5 x the PD equivalent that you see with belzutifan's 120 mg dose, which is the dose that they're using. Belzutifan is Merck's drug. They're currently on a $500 million runway, just about 3 months or 4 months after they got their drug approved in RCC. So I think that really highlights the market opportunity and the unmet need in RCC. From a competitive landscape point, you know, we really think it's just us and Merck.
We are probably a few years behind, but we're doing everything that we can to catch up. At our Q2 earnings call, we'll shed a lot more light on what our phase III plans are, and we'll get to the specifics of our first phase III study, where we'll be combining our HIF-2 alpha inhibitor with a TKI. So we'll discuss what that TKI is and what exactly we're planning to do, and then probably talk about another phase III study later in the year, early next year. As far as the data sets that are coming in the fall, we will have our first data set from our first expansion cohort. So that's a 50-- a 30-patient expansion cohort from the 100 mg dose. So that will be at a medical conference in the fall.
That will be mature ORR. So you'll see waterfall, spider plots, et cetera. And we're right on the cusp, then, of having that 50 mg expansion cohort data set as well. So we may be able to talk a little bit about that. We'll certainly know what the progressive disease rate from that cohort is. We know what that is today. It looks very, very good. And, but we may have a mature ORR number for that as well. And then the 150 mg expansion cohort, so this is another 30 patients on top of the 60 from the 100 mg and 50 mg cohorts. We'll have that data set probably early next year at this point, so we're just about to complete enrollment of that cohort.
Originally, we thought we'd have data probably mid-next year, but that could actually move up a little bit just given how quickly that cohort enrolled. So it's going to be nice studies from a data. It'll be about 90 patients of expansion cohort data, all patients getting treatment in, second-line plus settings. So it's going to be exciting, very exciting time for the program.
You're clearly not very busy.
No, and I'll tell you the other thing about that is, from the competition standpoint, we clearly have a better molecule. We think that is demonstrating itself and manifesting itself clinically, not just from the pharmacodynamic and pharmacokinetic advantages. But we do feel also that our combination that will not involve lenvatinib, and that's where this field is really gonna, you know, be expanding and getting into that full population, that's certainly gonna be another advantage that we're gonna have relative to Merck.
And should we expect Gilead to opt-in post this? And what would those financial implications be?
I'm gonna ask them later today, but, I, I think they're excited about the program, and I think they would say that, you know, they do have a, a GU presence because of Trodelvy. So I mean, RCC isn't like squarely GU, but it, it's very adjacent to GU. So, you know, we think they'll be interested in the program. You know, we're seeing strong, yeah, very strong OR as a single agent. So like everything you want to see now today, with an oncology drug. If they do opt in, and it would be a $150 million upfront and then cost sharing. So, you know, it would be nice to get that capital.
I think, you know, if Arcus, we're just talking about another investor, you know, if Arcus was a standalone company today and, you know, we're just about to report 29, or sorry, 90 patients worth of data, in the single agent-like settings, and you'll have, I think, a pretty interesting OR. You know, I think that's the company that would be worth $3 billion. So we think a $150 million opt-in will be a pretty good deal for them.
Currently targeting CD73, you're advancing that next year into pancreatic cancer in a phase III study. What gave you the confidence to move this program forward, and help us understand why Gilead will not be joining you?
Sure. So, first off, the confidence primarily come from the data themselves. So this is like just under 16-month OS. When you have another study that's similar but different, the Morpheus-Pancreatic data set, that's also confidence-enhancing. They showed over 16 months OS against the Gem-Abraxane data set. And coming back to what I said, these three studies reinforce that their biology makes sense. I think the misconception about Gilead is they still have the option to that. They— When we did the $300 million equity purchase, that was keep in mind to fund, as part of what that did. It was to partially fund this study. So Gilead is involved. There's no interaction we have with the FDA, where they're not involved. There's nothing about the program.
I think they are opted into the program. So I think there may be a misconception as to we're executing it, the way it was funded came through that funding, but they're definitely have retained their interest in the program.
You know, while you've recently had several positive early-stage readouts, investors continue to view the profile as high risk, high reward. What do you view as the most misunderstood aspects of your portfolio and the key debates here?
Sure. So we think the portfolio is really very highly de-risked, and I'll just start with, you know, if you, if you run through what we talked about today. The HIF-2 program, there's probably no program on this planet where being second, but having a molecule that's demonstrably better on a validated mechanism, that's a huge opportunity. So, you know, to the extent that someone doesn't see that is about as de-risked as you can get in an early-stage company, and we have the resources to run a phase III program there. I'd tick that off first. The anti-TIGIT field, for the reason Jen said, I think is extraordinarily de-risked. There's multiple data sets. The data sets make sense.
As we all know, there's been— There's all sorts of investor risk evaporates that somewhat has stemmed from all of the saga, if you will, of SKYSCRAPER-01 and how's that gonna affect investor sentiment. So I view that as a bigger investor sentiment risk than what we come to work every day, you know, which is patient-centric and investigator-centric, and obviously, we care about our investors. But, you know, from a long-term standpoint, I think that's gonna turn out to be great for investors. And when they look back at the time, the positive data, de-risking it, is staring them in the face, and it's from multiple companies with multiple different molecules and other companies talking about why they're gonna be best of class, but you still have some concern otherwise.
And then I think the adenosine front, we think we've generated quite compelling data that's de-risking, but we recognize it's still left over from what we would say were obviously inferior molecules. And I'll show you a really quick thought experiment to do. So Novartis just shared data from their HIF-2 inhibitor, which frankly are not good data. And frankly, they don't have a good molecule, and their properties of the molecule are out there. What I would tell you is if those data were the first HIF-2 data ever to be out there, and you didn't have Belzutifan, and you didn't have our molecule, from an investor sentiment standpoint, I think there'd be a lot of investors that would say HIF-2 is dead. And then they'd have a lot of skepticism about the next HIF-2 data set.
That's a thought exercise. I think it's actually very true, but it gets to true technical de-risking versus short cycle time investor mentality, which is part of the ecosystem, and it should be there or shouldn't be there. It just,i It is what it is. I think from a long-term perspective, our later stage programs are really, really, quite, well de-risked.
Great. So closing out, could you briefly walk us through the next key data sets for Arcus and any that you're monitoring as well from a competitive read-through standpoint?
Yeah. So the second half of the year for us will largely be around casdatifan, the HIF-2 alpha inhibitor, with that first data set coming in the fall, the 30 patients worth of data, maybe a bit more, if we're able to put the 50 data set in there. You know, also OS data from EDGE-Gastric, probably at some point early next year, so that'll hopefully be more validating data on TIGIT. We could also start to see some competitive data sets from the other anti-TIGIT antibody companies. Obviously, SKYSCRAPER-01 will be in the second half of the year. iTeos has a data set coming, I think, maybe at ESMO, for their anti-TIGIT antibody. We're also starting to get close, probably to Merck's first readout in lung. So that's all comer study, where they're combining their anti-TIGIT antibody, Keytruda, plus chemotherapy.
There's a lot coming in the TIGIT space. The other data set that's a little bit more off of the is our ARC-10 data set, which I alluded to here. So that was the phase III study that we're doing that we discontinued, but we have about 100 patients worth of data there, and we'll probably get that data set out at some point this year as well.
Great. So with that, Terry and Jen, thank you so much.
Thanks.
Thank you.
36 seconds to spare.
It was perfect.