All right, welcome back, everyone. This is another session of the 2024 Virtual Oncology Leadership Summit. My name's Yigal Nochomovitz, one of the biotech analysts here at Citi. As you know, the drill is if you have questions, just email me, yigal.nochomovitz@citi.com, and do my best to monitor the email and relay the questions to the management team. So it's my great pleasure to have with me, the President and Head of Research, Juan Jaen, of Arcus. Juan, welcome. Thank you very much. Obviously you had some important updates yesterday on the call, and so let's start with those.
But before we do that, if you could just give maybe just a, you know, 2-3 minute overview of the company, what are the key assets, and then as I mentioned, we'll start with the new data on the HIF-2α. Thanks.
Absolutely. So first of all, thank you, Yigal. Thanks for the opportunity to spend a few minutes here today. Arcus is an oncology R&D company. We presently have about 8 different molecules in clinical development. It's the most advanced of those programs is our Fc-silent TIGIT antibody, which is presently being investigated in 3 phase 3 pivotal clinical trials. All 3 of them in major areas of clinical need, an all-comer frontline metastatic non-small cell lung cancer population, stage 3 inoperable lung cancer, and frontline upper GI adenocarcinoma. We over the next 12 months anticipate opening a 4th phase 3 study together with our collaborator, our partner, Gilead, in the perioperative non-small cell lung cancer space.
We also have a very promising small molecule inhibitor of HIF-2α, a space where we believe that we are primarily competing with Merck's belzutifan, and if we have an opportunity, we'll I'll share some of the specifics for why we think we may be developing a better, differentiated molecule. We anticipate that molecule to also be in a phase 3 study in clear cell RCC within the next 12 months that will make our 5th phase 3 study at that point. And finally, we are pretty much, I think, at this point, the leaders in the adenosine space. We have a small molecule inhibitor of CD73, a molecule, quemliclustat, for from which for which we presented data at ASCO GI earlier this year with some really, really promising data in frontline metastatic pancreatic adenocarcinoma.
We're moving as fast as we can towards the initiation of a phase 3 study with that molecule. We hope that that will occur towards the end of this year, early next year, at which point that'll make our sixth registrational study with four of our own molecules moving forward. We're very well capitalized. At the end of January, following Gilead's latest equity investment, we were sitting on $1.2 billion. But we're also very fortunate to have partners like Gilead, Taiho, AstraZeneca, Exelixis that are helping us operationally in some cases but also financially move forward each one of these registrational studies. We also have a very active research engine that continues to feed the pipeline. And if we have an opportunity, we can talk a little bit about some of those earlier stage assets. So I'll stop there and take another question.
Okay. Well, the obvious focus today, given the market is, is HIF-2α. So let's begin there. For those that maybe didn't have a chance to listen yesterday or didn't see the slides, if you could just give us a quick recap of what you've shown, casdatifan or cas for short. You showed some initial early efficacy data. So can we go through that? And then, as you mentioned, the arguments around why you believe this could be differentiated, from the Merck drug, from belzutifan.
Absolutely. So, belzutifan that just a couple of months ago received its first approval in advanced clear cell renal cell carcinoma is an inhibitor of HIF-2 α . HIF-2 α is a transcription factor that for many years now has its profile, its pharmacokinetic profile in humans has been well publicized. So we set out to identify a molecule that could be as potent and selective, if not more, than belzutifan, but one that might not suffer from the pharmacokinetic limitations of belzutifan. In a nutshell, the limitation stems from the fact that once you reach a certain dose, it happens to be 120 mg, it's very difficult to achieve greater absorption, greater amounts of belzutifan in circulation in humans. And that's what's supported by the publicly available data from Merck.
So, given that the molecule across a number of settings and different studies appears to provide broad benefit to patients with clear cell RCC, as demonstrated by some of the single agent studies where the large majority of the patients experience some level of benefit, yet very consistently, the objective response rate is in the low 20%. In the most recent study, LITESPARK-005, that supported the recent approval as a single agent in advanced clear cell RCC, the median PFS, which are just under 6 months. So we believe that there was an opportunity to do better, perhaps, if you could get more drug on board, if you could hit the target harder in a tumor type where it's generally accepted that the large majority of clear cell RCC tumors are being driven by an overactive HIF-2α mechanism.
The question stands out as, well, if that is true, and we all pretty much across the field, that's taken as a given, then why is it that only 22%-24% of those patients reached that objective response threshold? And could you do better if you could only hit the target in the tumor harder? So we think we've accomplished that. By now, we've evaluated our compound Cas in a healthy volunteer study where we've defined, with a lot of precision, the PK and PD effects of the drug. And when I talk about PD in healthy volunteers, obviously, I'm not referring to PD on the tumor, but the PD in normal effects on normal physiology. HIF-2 alpha happens to be present in healthy kidney, but where it regulates the production of erythropoietin.
So, before we even went into the cancer trial, we already understood a fair amount about the PK and peripheral PD of our molecule. The study that I think caused that that drew so much attention yesterday and today is a study that we refer to as ARC-20. It's a study; it's our first study in patients. The study is made up of two stages, the dose escalation portion, and three different expansion cohorts. In all cases, the population in all three expansion cohorts is the same. The only difference is the dose that's being evaluated in each one of those cohorts.
and so the data that we shared yesterday was, we spent a lot of time talking about the PK-PD advantages of our molecule and the early observations of very promising clinical activity, both in some of the patients in the dose escalation cohorts that obviously have been on drug longer, as well as some very, very comments about the early signs of clinical benefit that we're seeing in the expansion cohorts.
Okay. Well, that's great. Let's, if we—you mentioned the PK-PD arguments, and I think that would be a good point just to go through that. I know it's a bit technical, but I think it would be helpful. You know, you made the point around the EPO as a biomarker, not related to the tumor. And if you could just kind of go through that argument, because, as you've shown in the slides, you know, you see a saturating effect on EPO as you move from 20mg-100 mg of your drug, Cas.
But I believe your point is that while you're seeing the saturation on EPO, because you have much, much higher doses as compared to what belzutifan achieved on the EPO curve, that you would have a potentially outsized impact on downstream genes being controlled by HIF-2α that are relevant in the tumor. So maybe I'm just if I've characterized that right, tell me, but that's kind of what it's trying to happen.
Yeah. Yeah. I think it's generally correct. I mean, it's a well-accepted principle in pharmacology or, you know, in biology that the amount of drug present in the blood of a subject is what feeds whatever amount of drug is gonna make it to different tissues. But that extent of penetration into different places doesn't have to be identical. In fact, quite often it's not, you know. So you're used to hearing people talk about brain penetration of a drug or concentration in the liver. The tumor happens to be the one place where drugs, in general, tend to have the hardest time getting in. And in the case in the situation that we're discussing, primarily, we have tumors that are highly dependent on this one transcription factor for growth and survival.
So we talk about peripheral PD, as measured by the amount of erythropoietin, EPO, that the healthy kidney can produce. And we've known from the Merck data that about 2/3 of the EPO produced in healthy kidney is controlled by HIF-2α, right? Once you reach a level of inhibition, a certain level of inhibition, and you reduce it by, you know, 65, 70, 75, something in that range, going higher in dose, having more HIF-2α inhibitor is not gonna move that needle any further, because, just empirically describing the observation, is that the rest of the EPO seems to be controlled by other mechanisms that are not HIF-2α. Okay? So that's a measure of peripheral pharmacology. It takes Merck, or belzutifan, 120 mg in a certain amount of drug in the blood.
It takes us. We've now demonstrated this in the healthy volunteers, as well as in our dose escalation patients. It takes us only about 20 mg of Cas to achieve the same level of peripheral, by peripheral, I mean, in the blood, in the healthy kidney, the same level of EPO reduction that belzutifan achieves at 120. We do it with significantly lower plasma levels, because our compound just empirically, I'm just restating the empirical observation, our compound appears to have better partitioning from the blood into tissues than belzutifan does. So that's sort of a normalizing point. 20 mg of our drug, 120 of belzutifan.
Okay.
The second part of our premise is that we've shown this in the updated corporate deck, is that, unlike Belz, we can continue to go up in dose of Cas and continue to see dose proportional increases in the amount of drug that's in circulation, right? So the question on the table, which Belz is unable to do, is, is the dose of Belz, which was selected primarily based on the pharmacokinetic limitations of the molecule, does that also happen to give you maximal inhibition of the target in the tumor, or is there room for more? Right? We think about that dose of Belz almost as not being random, but it wasn't selected based on any biological endpoint. It was just selected on, gee, you know, can't go any higher.
So, and we're seeing some tumors shrinking, so cannot be a bad dose. And so that's what we're trying to do, is say, okay, is there more room for more biology, clinical benefit, if we can go to a higher level of a very effective HIF-2α inhibitor? And what we've shown now, in our PK profile, as I said, is that we can dose proportionally. So at 100 mg of our drug, we have 5x as much as what is required to completely shut down all of the HIF-2α dependent EPO in the periphery, right? And now we're really just at the beginning, and some of the data that we shared yesterday, and I think you could sense Terry's excitement, is the very early signs that start to suggest that our hypothesis may, in fact, be correct.
We're starting to see with still relatively mature, you know, very early looks, particularly at the expansion cohorts, we're starting to see a profile that suggests to us that, in fact, we may be onto something. So at Belz tends to be a slow onset of benefit. The median time to response in the most recent study is just under 4 months. The majority of our patients in our expansion cohort at 100 mg daily have only had 1 or 2 scans. That for our in our study is 6 weeks-12 weeks. In spite of that, we're already at a place where we're seeing response rates that look pretty much in line with what Belz recorded after a couple of years of follow-up. So, you know, the question on the table is, are we bringing in the responses earlier?
Are we gonna continue to see more and more responses, or, you know, that's, I think, what we will continue to accumulate data on over the coming months and intend to present that more mature data, in the second half of this year. The other thing that we talked about yesterday is that if you look at the, LITESPARK-005, data that led to the recent approval of Belz, about one-third of the patients progressed by the time of their 1st scan. So, you know, literally 33% almost 34% of the patients in that study, their 1st, by 2 months, had progressed. And the early indications from our expansion cohorts is that our, let's call it, primary progression rate is significantly, and our CMO would argue clinically meaningfully lower. That's a number that's not gonna change.
You know, everybody that we have in the expansion cohort has already crossed that threshold. They've already had at least one or two scans. So we pretty much know what the ultimate PD rate will be in that expansion cohort, and it's gonna be meaningfully different than what LITESPARK-005 reported. That number isn't gonna change in this study.
So you're saying it's around the 20%-22% from their trial. And now, some of them, you said, some had one scan, some had two. So you're still waiting for some of these early responses to be confirmed. Is that correct?
Correct. So we're seeing some responses, even in the early scans. But the majority of the patients in the expansion cohort have only been on study. The majority of those patients are still on study. but the, you know, a good half of the cohort hasn't made it past the 3-month mark yet. And so even with a very, very early look at the expansion cohort, we can already see response rates that are very much in line with what Belz has reported. Very, very consistently, there are 4 separate cohorts that you can look at, at Belz, the original phase 1 expansion cohort. a recent study that was also described that, the most recent ESMO comparing 2 different doses of Belz, and then, the 4th data set is LITESPARK-005.
The objective response rate is uncannily consistent across those 4 groups, right around 22%-24%. So it's a very solid objective response benchmark against which we can compare what we're seeing in our expansion cohort.
Okay. And then on the, so that's what just so we know, when the next update you said. Are we gonna get the more detailed data on those 30 in the expansion in the second half of the year? Are we gonna see the typical data plots, like the waterfall plot and the swimmers plot, things like that? Should we expect?
That's our intent. That's our intent. Definitely, objective response rates that will probably almost certainly not be the final number, because I anticipate many of the patients will still be ongoing. And, both for Belz and even some of our, one of our patients in the dose escalation, we've seen that those late delay responses do occur. Don't get me wrong. It just may very well be that we continue to see responses, much later. But we definitely will be presenting fairly mature response rates in the second half of this year. Our intent is to share some aspect of PFS. We should be so lucky as to not have mature PFS data. The median PFS in LITESPARK-005 was just under six months. You know, you can do the math. We may be able to infer that we're doing better than that.
But our intent is to be fairly generous with the data that's available from ARC-20 in the second part of this year. And we haven't communicated yet the venue for that.
Okay. And then, can we touch on the safety side? Are there what are you seeing in the early safety that would suggest a different profile versus belzutifan, specifically on the anemia, for example, and hypoxia?
Yeah. So we're seeing an incidence of anemia and hypoxia that appears very, very similar to what's been reported for Belz. Now, remember, our premise is not that we're gonna be safer. It's that we're gonna be equally safe and more effective. That peripheral safety signals is the direct result of pharmacology on the healthy kidney. And so if you inhibit 2/3 of the production of EPO in the kidney, human physiology dictates that that's gonna translate into X% incidence of anemia. And so we don't anticipate.
Now, what we're seeing so far is that, as we predicted, that once you reach that point of saturation of peripheral saturation, we're not seeing a big difference in safety profile from 20mg- 100 mg, which is, again, consistent with the fact that, okay, you turn this figure down to, you know, by 2/3, and it stays, you know, you go up in dose in the periphery, it's the same number. So you would expect a very similar safety profile pretty much across the dose range.
Okay.
It's the tumor where we are anticipating more and more greater and greater inhibition. And the fundamental hypothesis that at that low dose, where you can max out the effects in the periphery, in those tissues that are, you know, that are easily vascularized or well vascularized, that it'll the tumor requires a higher level. We used an analogy yesterday in some of our calls of everybody knows that at every. I'm sure everybody can relate to this. Everybody knows that Pembro saturates PD-1 in the blood probably at a dose of 20 mg-30 mg. It's saturated or oversaturated. Yeah, the current thinking in our field is that in the tumor, it may require, and this is probably it's a rule of thumb that we all apply to, antibodies.
It probably is gonna take 10x higher to get to a complete inhibition in the tumor because it's harder for the drug to reach. And so we don't dose people at 20mg every 3 weeks. You give Pembrol at 200mg every 3 weeks. And so you can go down the list of, you know, a lot many, many different kinds of class of types of drugs where the stuff that you measure in the lungs or the kidney or in the blood itself, where drugs have an easier time reaching, you still go up in dose and associated plasma levels of the drug in order to get complete pharmacology in the organs that are harder to reach. And the tumors, you know, a metastatic lesion is the extreme of difficult to reach by any drug.
So that's pretty much what we're trying to squeeze out of this mechanism of action.
Okay. And then, you know, given you mentioned that example, and then, of course, you mentioned EPO as the biomarker in healthy tissue. Are there tumor-specific downstream genes that are controlled by HIF-2 α that at some point you could interrogate and show, you know, obviously, in addition to the tumor control data, but just show that you're like your thesis is that you're hitting the target harder and having a differential impact at the level of the renal cell tumor?
Absolutely. That is an excellent question and one that we're working very hard on. And, I hope, if we're lucky with some of the experiments that we're doing, that we'll have some numerical information at that point later this year. I suspect, as the clinical program is moving, that we will actually have the clinical, you know, that we'll be talking about the clinical, the numerical data that supports our hypothesis, possibly before I can show you the biomarker data. So I suspect it's gonna be a case where it's gonna be after the fact that I'm showing you how, you know, HIF-2 α regulated gene X, Y, and Z went up or down as a function of dose, but already with full knowledge of what the clinical activity is.
Sure. Sure.
It's a program that's moving very, very, very quickly. It's enrolling like gangbusters.
Well, we know, you know, drug development isn't necessarily a linear process. So we understand that. And then speaking of the plans for the phase 3, can you provide any thoughts as to, you know, how you would structure that phase 3? What would be the potential design, or what are the different scenarios for how you could combine belzutifan with approved, you know, or other molecules that are already approved?
Right. So as you know, Merck is now talking about belzutifan as a blockbuster or a drug with blockbuster potential. So they're already very active in a number of settings, including the one that the only clear cell RCC setting in which they just obtain approval. So we're trying to be, obviously, as you would expect, as very careful about selecting combinations and settings where we can either be best or first. When we announce later this year, I anticipate when we announce the specifics of what our first phase 3 study will be, hopefully, you will agree with me that you can check both of those marks. But at this point, we're definitely looking at a combination with a standard of care. It's public knowledge that we started a study in collaboration with Exelixis called the STELLAR-009.
There we are evaluating primarily the safety and PK profiling of our drug in combination with their second-generation VEGF TKI, Zanza. But we're also within our own ARC-20 study, we are in the process of enrolling or evaluating the combination of our drug with Cabo. So we're keeping open the options. But you can see where that is going. It's gonna be we're evaluating the safety and initial profiling of combinations with 2 VEGF TKIs that are generally accepted, I think, as being probably your best choice when it comes to an agent in that class. As you know, Merck is, for better or worse, stuck with lenvatinib, an agent that in this setting is, yeah, I think a lot of practitioners have a problem with, that it's harder to manage the toxicity associated with it.
That's one of the areas where one might conceive that a better HIF-2α inhibitor combined with an equally effective but safer and better to manage TKI might, you know, be a combination that has the potential to be best.
Well, so okay. So STELLAR-009 is with Zanza, with the company you mentioned. But, why is the Cabo combo with 521 not part of that trial? You said it's you're just doing that yourself, right?
Yeah. Yeah. At this point, we're trying to generate foundational safety and early evidence of activity data with both combinations. Over the coming months, we'll settle on which of those two doublets we're taking forward, into a phase 3 study.
Okay.
Clearly, that's where Zanza is, at this point, an experimental drug. Cabo has been, you know, a well-accepted standard of care, in front line and later lines and clear cell RCC. So there's some pros and cons of going one way or another.
But so you'll tell us the design, I guess, later this year for the phase 3. And that's starting, I have in my notes, that's starting early 2025. Is that right?
Correct.
For the Phase 3?
Correct. And that's that, you know, that's about as much resolution, a level of time resolution as we should bring to that. We're still a year away from the most likely initiation of that phase 3 study. And I included it in my 12-month forward look of how many phase 3 studies we're gonna have. But that one is right. I would say it's probably right at the very end of that 12-month look.
Okay. Fair enough. All right. Well, we spent half an hour on HIF-2α. So let's try to hit some of the other assets. You mentioned Quiemli at the beginning. So there was some good data in pancreatic, the ARC-8 trial. So, can you walk us through that? And of course, I mean, I noticed and others noticed that Zym didn't appear to have much of a contribution there. So just wanted to walk through that aspect of the data too.
Absolutely. So, the study in question is ARC-8. It's a study in which we evaluated the benefit of Quemli, our small molecule CD73 inhibitor in frontline pancreatic, in combination on top of a gemcitabine Abraxane backbone, chemo backbone. And some of the patients in that study received that combination plus our anti-PD-1, Zym, and another portion of the study did not. The data that we presented at ASCO GI last month clearly demonstrates that any differences in clinical benefit, as a function of having Zym or not having Zym, is entirely the result of the percentage of patients with liver mets in each particular group. So we did a very detailed analysis of that aspect of it.
And when you look at patients with liver mets as a subgroup and patients without liver mets as a subgroup, the survival parameters for both of those cohorts is it's within days of each other. So our conclusion is that there's no benefit associated with the inhibition of PD-1. That's consistent with what we all know that in pancreatic, anti-PD-1s or PD-L1s really haven't had much activity, when combined with standards of care. So that's very consistent with our observation. And we were seeing the remarkable thing I think the most remarkable thing from that study is that, and it's very consistent with a immune-linked mechanism of action, is that numerically, the objective response rate was not indistinguishable from historical chemo numbers.
In fact, we conducted a synthetic control arm analysis, and we should talk about that for a couple of seconds. I think it's a really exciting new direction, not just for our study but for clinical trial execution in general. We saw that numerically, objective response rate, that's not where the benefit of inhibiting adenosine formation is gonna manifest itself. An interesting benefit on PFS and an unbelievable level of benefit when you look at OS. So, we ended up with a median OS in our study of just under 16 months. Compare that; in the synthetic control analysis that we performed, the synthetic control arm came in just under 10 months, which is smack in the middle of recent large Phase 3 study sort of benchmarks, which range from 9-11.
Like I said, it has a ratio of 0.67. For the specific synthetic control analysis that we presented at ASCO GI, we conducted a total of four of those analyses looking at different subgroups. What and what we presented.
And can you explain to everyone how you did the synthetic? Because you used an external company that has expertise in this whole setup of external controls.
Yeah.
I mean, synthetic controls and how they picked the patients from other studies but in a very specific way to.
Yeah.
Density match. So can you go through?
Yeah. So, yeah, absolutely. I'm happy to do that. Before I do that, let me just sort of walk through some real basic math, okay? If you have a place or a setting like frontline metastatic pancreatic, where there are at least two, if not three, very well-known, hugely prognostic features, you know, the presence of liver mets, the geography of your, you know, the ethnicity of your patients, whether the disease is de novo or recurrent after prior locally advanced surgery, if you try to run a randomized study where you theoretically try to stratify for each one, even just a couple of those variables, you would need well over 100 patients in your experimental arm and similar number in your control arm.
You know, to try and run a randomized study with 50 patients versus 50 patients, yeah, you randomized them, but you really didn't control for these prognostic variables. And whatever conclusion you might draw from that comparison is subject to the most likely unevenness of these elements. The beauty of a synthetic control arm is that you can go into a much larger pool. You need to be careful about where that data is coming from. The dataset that we use, the Medidata that has accumulated, contains, as I understand it, over 100,000 individual patient records. These are patients that participated in recent Phase 2 or Phase 3 multinational studies and received the standard of care, not the experimental treatment. So there's single patient data accumulated from those studies that allow you to do what we did in collaboration with it.
You know, we went in and said, "How many patients that do you have in your database that were that received gem Abraxane in frontline pancreatic in but studies that read out in the last X number of years?" So that you're not reaching back to the beginning of time. And the answer was, "Over 500 patients fulfilled those conditions out of 100,000-patient database." Then they apply all kinds of statistical models that, honestly, I don't understand. But they went in, and they did this for us three different times. Looking at the totality of our cohort, they did the patients that received only the no-Zym combination, and then they did it for the patients that received the Zym, three completely independent analyses. And then went looking into that pool of patients for the ones that best matched all the prognostic features present in our study.
But they did it without while being blinded to the results. They didn't know what the, you know, there was a protocol for how this study was gonna be done. They didn't know what the right answer was. And so what we ended up with is in our the totality of the patients that received 100 milligrams of Quemli was 122 patients. They ended up with 122 patients that looked like the parallel universe, alter egos of our 122. I mean, down to the age, performance status, presence of liver mets, ethnicity. I mean, it's like you can go down the list of every one of these things.
At the end of the day, it felt like a much better way to sort of say, "Well, you know, in that parallel universe where these patients would have received only the back the chemotherapy, what would have happened?" That's the comparison that we ended up placing so much value on. We clearly beat out all the, you know, cross-trial comparisons. But, you know, there's always that question of, you know, are your patients different or whatever? So we were very happy with the results of those synthetic control analysis.
But, your argument is that, I mean, it's not obvious; it's not a prospective randomized trial. But your point is that, in some sense, the control is maybe even a better control in a certain sense because of the way you can select from a much larger database and find the more completely matched patients to what you actually enrolled in your active arm.
Correct. I think that from a decision-making perspective, the regulatory agencies are sort of gradually becoming more and more open to the possibility of, you know, maybe a mixed real-world randomization supplemented with some synthetic control analysis. But as a company, believe me, we try very hard to talk ourselves out of doing anything further. I think until we dug deeper into the last 10 years' worth of clinical trial development in pancreatic, we suffered from the same superficial, often-repeated, notion that, "Oh, pancreatic is so hard." We tried to talk ourselves out of going forward, and we tried to challenge the observations that I just described every which way.
At the end of the day, the data just kept coming back to, "No, you're looking at a very, very strong signal." And so, you know, part of that process of getting comfortable with the meaning of the data also requires us to dig very, you know, spent a lot of time looking at the last 10 years' worth of failed phase 3 studies in pancreatic. And our conclusion was that there were very few, if any, of those failed studies that were preceded by any kind of proper phase 2 data. In many cases, there was single-arm phase 1 data, 12 patients. It looks good. You know, launch a phase 3 study. But okay, fails. Okay.
Well, so I think we're probably the first. This, our study, is gonna be the first registrational study in the last 10 years that's really preceded by what we think is a very robust and strong signal.
So, then getting back to the clinical development, I think you said you're gonna be starting the phase 3 early next year. What's the plan then as far as the regimen? I mean, I have my guesses, but tell us, is it's gonna be the triplet or the quad for the phase 3?
It's gonna be the triplet. You know, we would not be acting on the data if we ignore the fact that PD-1 inhibition seems to be adding nothing. It's not even close. It's nothing. So, yeah, it'll be the triplet. It'll be a population very similar to the one that we enrolled in ARC-8. I mean, that if not identical. And yeah, it's something that I should mention before I forget is that completely independently of our ARC-8 study, our adenosine receptor blocker, Etruma, was being evaluated by Roche in one of their Morpheus platform studies, pancreatic. The first read-out objective response rate differences was unimpressive. So we had pretty much written that study off, until Roche shared the results. It's a randomized study. So you're comparing gem Abraxane to Etruma on top of gem Abraxane.
In that study, they also have a Atezo in the experimental arm. At about the time that we were analyzing ARC-8 with Quemli, we saw the results, looking at both PFS and OS, results with Etruma, same mechanism of action, different drug, in completely different places. In that case, a control study, albeit relatively small numbers in each arm. And other one is Steel the Thunder from Roche. They'll be presenting that in the coming weeks at a major medical conference. But I think that you will see that it's very consistent with what we've been talking about for Quemli. And we find that very reassuring.
Okay. In terms of activity on the adenosine axis.
Correct. Yeah.
Okay. We did have one clarifying question from an investor. Just going back to the synthetic control arm, I think he referenced 100,000 in the database and then 500, you know, or 0.5% met the criteria. Can you just clarify? Was that 100,000 in the.
Oh, yeah. I'm sorry.
Or that was all in the database?
Right. And clearly, I'm not an employee of Medidata, so my 100,000 is it's a ballpark. But in my recollection from conversation, that refers to all tumor types.
Oh, okay. That explains it. Okay. Thank you. Got it. All right. Then, in the last bit of time we have here, we should touch on domvanalimab. So let's start with the expanded collaboration with Gilead. Can we walk through that?
Yeah. So at Gilead and Arcus are co-developing and have, you know, we share not only that molecule, but you know, at this point adopted into four programs, total of five molecules. So we're co-developing and which also requires us to pay for half of all costs. And then we share the commercial rights or financial benefit at the back end. Operationally, Gilead is in charge of some studies. We run others. In this case, they are running the PD-L1 all-comer frontline non-small cell lung cancer in lung, sorry, on top of chemo. We are operationalizing the frontline gastroesophageal adenocarcinoma study. AstraZeneca is operationalizing PACIFIC-8, which is a stage 2, 3 inoperable. It's consolidation after chemoradiation therapy. In that case, it's our TIGIT antibody domvanalimab plus durvalumab in patients that have not progressed after CRT.
The fourth Phase 3 study that we've talked about will be operationalized by Gilead. It'll be STAR-131. It'll be in the perioperative non-small cell lung cancer setting, a place where we believe we could be not only best but also first, given what our competitors are doing.
Okay. And then I believe you're gonna have an update from the EDGE-Gastric trial, I think, ASCO. And is that.
That is correct. Yeah. So that is.
What's the.
Yeah. So that will be an update following our presentation late last year in one of the ASCO plenary sessions.
Right.
So we described data from our platform study in gastroesophageal in upper GI cancers, where we demonstrated that a single-arm dataset, but where we demonstrated that don plus Zym on top of standard of care was looking extremely, extremely promising. So this will be an update on on that dataset. It'll have about five or six months greater maturity. But just to remind you of some of the data that we saw there, some of the data that we presented at the time, the progression-free survival at six months was north of about 93% in the PD-L1 high subpopulation, which we were and others were extremely excited about. Remember that in the pivotal study and, you know, you can go back and look at a couple of reference studies.
CheckMate 649, similar setting and backbone, the corresponding median PFS was just under eight months in that PD-L1 high population. And so we.
Yeah.
So it'll be an update on that. We'll have. I don't, you know, it'll be primarily an update on response rate and PFS. We haven't done the data cut yet. I don't know if there'll be enough maturity. I suspect not to say anything about survival. But definitely, it should be a really interesting dataset. And that'll happen at ASCO in early June.
There's also this other study, EDGE-Lung, which is the Quemli don Zym.
Yeah.
You had done the ARC-7. Everyone knows about that one from last year, Etruma don Zym. So what's the difference? Why are you doing the EDGE-Lung trial?
That's an excellent question. So our EDGE-Lung or EDGE-Gastric studies are platform studies that we use for a number of purposes: signal generation, dose optimization, datasets. The main potential use of that combination may be one of the things that we have been intrigued for a while is the possibility of looking at Quemli in the stage 3 non-small cell lung cancer setting. There was a study run by AZ described a year and a half a couple of years ago called COAST, in which they demonstrated there was a fairly large randomized phase 2 study. They demonstrated that their CD73 antibody provided a very significant benefit over the DERVA control arm, Durva being the PACIFIC regimen standard of care in that setting.
In fact, they're currently running a phase 3 study, PACIFIC-9, evaluating their CD73 antibody, oleclumab, in exactly that setting. We believe that oleclumab is a really—I mean, if we find the results of that phase 2 study, COAST, actionable, then by definition, we believe that the drug, their drug, is active in that setting. But we've shown preclinical data that supports the thesis that quemliclustat, our small molecule inhibitor, is more effective than oleclumab. So oleclumab is unique amongst all of the CD73 antibodies in clinical development that it's primarily effective on CD73 that's still attached to a living cell. As soon as that CD73 sheds floating around in solution, and there's a lot of it, then the way that antibody binds to soluble CD73 is only about 50% effective.
So it's like trying to shut off a fire hose but only being able to close the opening by half. That's a well-recognized limitation of the drug. So we have a compound, quemliclustat. We didn't touch on this. It's a 5-picomolar inhibitor of CD73 that places one or two orders of magnitude, even though it's a small molecule, more potent than any antibody that I'm aware of against that target. Small molecule gets into the tumor more deeply, and so we think that we should be able to do better with quemliclustat relative to oleclumab or any other CD73 antibody.
and so back to your question, if nothing else, the data that we are generating in EDGE-Lung will generate a baseline of safety in combination with don and Zym that we may choose to use to build on and go in some of these directions that I've been talking about.
Just so everyone understands, when you say soluble, you mean extracellular shedding?
Yeah.
Is that right? Yeah. Okay.
Yeah. So CD73 is literally anchored to the plasma membrane in the cells where it's expressed. And there's a lot of it that just gets shed into the extracellular.
But your point is that your molecule binds the soluble, but it also binds the bound as well as better than the antibody.
Right. It's equally potent against both forms of the enzyme. Oleclumab is primarily effective at inducing internalization. It.
Yeah.
You know, so it binds to the CD73 that's still attached to a living cell and induces removal, let's call it that. And in doing that, it seems to be highly effective. But anything that's already been shed that's not continues to make adenosine, there's gonna be 50% of that adenosine generation that cannot be impaired no matter how much antibody you use. It's a.
Okay.
Has to do with how it binds to CD73.
Okay. We're running a little on time, but I wanna make sure we there is another program we don't talk about much. You have AB801, the AXL inhibitor.
Yeah.
What is the status of that phase 1, and when are we gonna get some data?
Right. So we just completed our dose escalation in healthy volunteers, which, again, we tend to do whenever we can, which provides a lot of information on what I would describe as nothing short of a spectacular human PK profile. We're very happy with that. Concurrent with that, we are in the dose escalation part of a study in cancer patients. At this point, we're still in the all-comer, you know, typical dose escalation type of population. And as soon as that's completed, we haven't really disclosed the specifics, but we will be expanding into a couple of different cohorts, slightly different patient subsets and slightly different combinations. But a couple of points I wanna make.
One is that the belief in AXL is that it's a common mechanism that cancer cells utilize, in connection with becoming resistant to various forms of therapy, the survivalist mechanism. The second one is that, no matter what anybody may claim, there are a lot of TKIs that list AXL as part of their many kinases that they hit. I don't think there's anything that's ever been tested in humans at sufficiently high levels to completely inhibit AXL. They're typically, you know, even we're talking about CABO. Yeah. You can quote, "inhibit AXL," but the doses tend to be defined by the toxicity associated with VEGF receptor inhibition.
We believe that we will have the first molecule anywhere that will allow us to test whether AXL inhibition is, in fact, effective at reversing that drug resistance profile of many, many types of cancer.
All right. I think we're gonna have to leave it there, Juan. We can probably keep going, but we have another session in a few minutes. So, thank you very much. Really interesting data across the platform, especially the recent data yesterday. So thanks again, and we will.
Thank you. Thank you for the opportunity.
Appreciate it.
Thanks, everybody, for listening, and appreciate it.