Good afternoon, everyone. Thanks so much for joining us. I'm Salveen Richter, I cover the biotechnology sector at Goldman Sachs. Really pleased to have with us the Arcus team. With us, we have Terry Rosen, CEO, and Dmitry Nuyten, CMO.
In the audience, Jim Jarrett.
Maybe to start here, you know, ASCO, you recently presented updated data at ASCO. Maybe walk through kind of the key takeaways from that data set, and you know, how we should put that in context of kind of the overall outlook here at the department.
That's an awesome question. Just reminding everybody, specifically, Salveen is talking about our ARC-7 data set, which is looking at the, you know, first Fc-silent, the anti-TIGIT, venetoclax. We were actually. It was a very awesome data set. It was presented by Melissa Johnson. She did a 6-minute presentation because it was part of the ASCO plenary format, and then we had a follow-up data set that we put out. I'll hit the real highlights. The first key thing is, in this interim analysis, the molecule continued to perform as it had in the past, most evidenced by the Kaplan-Meier curve.
If you look, the hazard ratio when you compared the doublet containing Anti-TIGIT versus simply Anti-PD-1, there was a 0.67 hazard ratio, so roughly a 33% reduction in events occurring. The other thing that emerged with this data set, is that we start to really get a good feel for durability, and I'll point to a couple endpoints there. First off, the DOR, very substantial, although immature, but basically a doubling of what we see with the Anti-PD-1 alone, with the DOM-containing doublet.
The other thing that really stood out, if you look at now that when you can look at patients that are out in, let's say, the 18 month to 24 month period, and you look at those patients still on therapy, dramatically more remaining on the doublet than the singlet, which really bodes well as you start to think about what's the approvable endpoint, what's the meaningful thing for patients, which is overall survival. On the other end of the sort of the bookend of the late versus the early, one of the more profound observations, this was pointed out, we had an event, and Tom Marron, who's one of the KOLs in this field, really emphasized this point. If you look at Anti-PD-1 therapy alone, you see about 25% early progressors.
In the domvanalimab-containing arm, we saw that with zimberelimab alone, the domvanalimab-containing arm, again, dramatically less early progressors. The other point we would make is that if you looked at the spider plots, you would see that a number of the stable disease patients, no longer stable disease before they actually progress. In fact, we have 1 pretty remarkable patient where it was after 21 months, they'd been stable disease, and they had a pretty deep response, and then a couple of weeks after the data cut off, they'd actually confirmed. That differential in the Kaplan-Meier curves of about 20% is really meaningful, and from a physician standpoint, almost gets to be like in quotes, like, those you're getting that much more of a curative effect.
Beyond just the clinical observations, one of the things that we highlighted was we're doing a very extensive biomarker analysis. One piece that we felt we could talk about early, because we felt it was important from being a smoking gun in terms of the mechanism, is that it's known, and this was known even before we did our study, that high CD155, which is the ligand for TIGIT, is a very negative prognostic for this particular setting when you're on anti-PD-1 therapy alone. Let me just real quickly talk about a couple of the key aspects of the biology. CD155 is the ligand for TIGIT. It's highly expressed on tumor cells. When CD155 engages TIGIT, it causes immune cells to essentially become quiescent. When you disrupt that interaction, that CD155 can now bind to another receptor on immune cells called CD226.
CD226 is immune activating, essentially, you convert a foot on the brake of the immune system, the foot on the gas pedal immune system. It's a very well-established biology. It's the reason why people got into Anti-TIGIT. It's the reason why it's such a safe mechanism, because that CD155 is so highly expressed in the tumor environment, so that when you get that switch over, you don't get a whole lot of autoimmunity type of side effects, and that's been borne out across studies. The reason we pointed out those data is that in our study, we actually validated what had been reported in that literature before.
If you look at the patients that were on Anti-PD-1 alone, those who had high CD155 above the median versus those who were below the median, the hazard ratio was 0.38. Very meaningful difference. You have a very negative prognostic if you have high CD155 and you get Anti-PD-1. What we also showed is that in the domvanalimab zimberelimab arm, that was reversed, and you could essentially take those high CD155 patients and turn them back into patients that would look like they had low CD155. We feel that's a very important observation for the field, because it's a smoking gun that links a mechanism and a molecular endpoint to the clinical observation. The final point that I would highlight about our data set is you continue to see really attractive safety profiles.
Essentially, domvanalimab has created something that's pretty unique in our field, where you're creating a combination therapy, adding a new agent on top of the standard care, getting improvement in efficacy with no added safety barriers. That's due to both the mechanism, but also the fact that we have this Fc-silent Anti-TIGIT. What's clearly emerging across the field is that those antibodies that are anti-TIGIT, that are Fc-enabled, cause depletion of T regulatory cells. This isn't just theoretical, it's been shown multiple times by multiple companies. What you also see associated with that is higher adverse event, particularly immune AEs. Things like rash, pruritus, Genentech even reported pancreatitis, that all could be Treg linked.
We feel that the Fc-silent anti-TIGIT, which was there were some questions about for some period of time, is clearly emerging to have safety advantages compared to the IgG1 wild type antibodies. Final thing I'll just highlight is that in addition to our own data set, there were a couple of other important data sets, I think, important for the field. Genentech presented data in HCC, clearly a meaningful signal. Whether or not you want to ascribe quantitative truth to it, definitely from a qualitative sense, it's another very strong signal. BeiGene presented data in the GI setting. Interestingly enough, that's with chemo, and we also see there a high degree of AEs, which again, points to that Fc-enabled anti-TIGIT.
Finally, a company that's been developing their anti-TIGIT a little less under, a little more under the radar, and they only had an abstract, not a full presentation, but Innovent shared data in the same setting, high PD-L1 non-small cell lung, with a very similar hazard ratio to what we see. I think the field as a whole, KOLs, investigators, those who've been working in this field, clearly came away from ASCO with the, you know, clearly seeing that the signal in anti-TIGIT is looking very real.
Since your last interim analysis, we did see the median PFS pull back a bit by about three months. Put that in context for us with regard to your confidence, and particularly as you look to, you know, OS being kind of the more meaningful measure here.
Sure. As Salveen said, you definitely saw that point estimate for median PFS drop. What we come back to is really PFS. What you want to think about is the hazard ratio, and you want to think about those Kaplan-Meier curves. If you look at the Kaplan-Meier curves from interim analysis 4 and interim analysis 5, they're indistinguishable. The other point that we made is we did roll forward. We took the full patient population that had been enrolled as of IA4, and then just rolled those forward as if that was the last patient in, and did the same analysis. The data looked very similar to IA4. Between IA4 and the most recent analysis, you have two things happen.
Additional patients come on to each arm that affected the contemporary PFS. Again, you kept the Kaplan-Meier curves looking similar. Then everything in terms of OS, which by the way, to remind people, from the FDA is black and white clear that the only approvable endpoint in front line non-small cell lung cancer with an IO therapy is OS. All of the data, the DOR, those patients still on study in the doublet versus the monotherapy, point to what could be a very strong signal when it comes to OS. We, you know, we think the data are pointing towards a very positive outcome on the OS front.
As you know, with IO therapies, this is what we're seeing in terms of that tail, that tends to be the strongest part, where you get once patients have responded, that IO tends to really prolong their survival, and that's at least as we sit here now, how those. If you were to look at the spider plots, for example, what you would see.
Great. You know, clearly, you'll have to see the data, but tell us how you're thinking internally about the impact to your trials on the forward based on, you know, Roche's study and the outcome in the second half of the year, if it's positive or, you know, if it's negative?
Yeah. We think that it, like, in terms of positive, negative, it's less binary than that. We think that based on everything they've said and what we know, and they've talked about numerical differences between the arms, that we expect it to be positive. If it isn't positive, if we're positive, as measured, is approvable, we think it is more likely than not, and we'll have to see the data, would have something to do with their design or their statistics plan, et cetera. One thing about SKYSCRAPER-01 , it's been a topic for some time, we think probably overstated, because it for a while, it was sort of the only game in town. We think there's so much data out there that not only is public, but when you know, Merck clearly has a lot of data.
BeiGene has data. We have data. Genentech have data. They shared the HCC data, which was a, you know, pleasant surprise to their community. We think there's no doubt that anti-TIGIT is going to be important. It's going to be important in this setting, we will look with, you know, the same anticipation as everybody else towards SKYSCRAPER-01 , but we really don't see that it's likely gonna affect anything that we do going forward. Obviously, we'd rather see a positive signal, and it'll be good for the field than something that's perceived as negative. Again, we don't think it's gonna be negative, positive. We think it's gonna be the degree of positive and whether it actually hits statistical significance.
You're gonna have a number of readouts coming in the second half of this year and next year for TIGIT, including in other tissue targets, right, or like gastric and so forth. You know, help us understand what you expect to learn from each of these different studies and, you know, the outlook here, and also just based on what you mentioned earlier, you know, is liver going to be a focus on the forward?
You want to comment on-
Yeah, I can start with the different readouts.
Yeah.
Let's start with gastric cancer. In gastric cancer, we have the phase III trial going on, STAR-221. It's a phase III trial where the standard of care is nivolumab chemotherapy, FOLFOX or CAPOX, we are randomizing patients between the standard of care or domvanalimab zimberelimab with FOLFOX or CAPOX, the same chemotherapy backbone. The trial was started because we thought it was a really great opportunity. There's obviously clinical data to support it was relatively limited at the time, we felt this is a field where we can move fast and not only bring a meaningful trial to patients, but actually be the first ones in the setting.
In order to enable that trial for, let's say, regulators, for patients, for physicians, while the trial startup was ongoing with a lot of preparations, we started a phase II trial, that is now called EDGE-Gastric. In that trial, we examined the same regimen, so FOLFOX with domvanalimab and zimberelimab. That's done in a platform setting, that means there is a standard of care control arm in there, meaning it's zimberelimab plus FOLFOX, so we can use that for contribution of components, but it's also a rolling control arm in a platform study. In that particular, let's say, the first-line cohort, the domvanalimab zimberelimab FOLFOX, we are planning to present data later this year. That'll be the first presentation with the safety and response rate data.
It's probably too early at the time for PFS data. That is, as I said, it's basically a data set that we use for health authorities, for physicians, doing investigator meetings, to make sure people see data from that trial, right? If you start treating patients in a phase III , you can't look at the data, right? That's it's completely blinded, and you can't look at it until the trial reads out. That same trial, EDGE-Gastric, also has a second blind cohort in there for patients that either have or have not seen a checkpoint inhibitor, so it gives us the opportunity to explore different regimens. At the same front, where we are looking at the mid-stage development platform studies, phase II studies, we also have two phase II studies in lung cancer.
VELOCITY-Lung, run by our partner, Gilead. Then EDGE-Lung, run by us. Those are examining chemotherapy-based combinations with, let's say, domvanalimab and zimberelimab, but also with our CD73 programs. Those trials are really set up with the same purpose. They generate early signals of efficacy. They have flexibility to put in new combinations. While we are thinking about next opportunities, we are generating the safety and early efficacy data in order to move fast if we want to move into a different setting.
In the VELOCITY trial, are you stratifying by PDL-1 status?
We have different sub-studies in the trial, and different sub-studies, they look at either all comers, or they look at certain parts of, let's say, the PD-L1 spectrum. In VELOCITY right now, it's all comers. In EDGE-Lung , we do have a cohort with PD-L1 high separate, where we only explore immunotherapy combinations, and in the other cohorts in both trials, it's the chemotherapy backbone with experimental agents on top.
Outside of TIGIT, you also have a pretty vast portfolio, and you're also gonna have a lot of reads coming there. Maybe just help us understand what you're most excited about in terms of some of these programs?
Awesome. Love that question. First off, let me talk about HIF-2. HIF-2, to remind people, it's a transcription factor. There's an approved drug, Belzutifan, that Merck has, that they acquired from Peloton, that has well-documented, well-described limitation, and that limitation is that it's associated with its PK profile, so it has absorption-limited pharmacokinetic, basically above the 120 mg dose that's clinically used for Belzutifan. You can't get higher exposure. It's clear, as you think about clear cell renal cell carcinoma, we think there's a high probability that, you know, Merck is gonna get approval there, but we also feel like there's a high probability they're leaving activity on the table.
We've been in healthy volunteers. We just completed the dose escalation phase of a study in all-comer patients, and that's with the 100 mg dose. That's cleared. We're starting a dose expansion of phase of that study. We're also will be starting a phase II study in combination with another agent that we'll talk about later this year, that we think actually gives us an opportunity for a best-of-class combination. To describe what we already know and then what we'll be sharing later this year in terms of a data set. That 100 mg dose of AB521 is our molecule is called, achieves essentially a 3 and probably closer to 4-fold the activity that you get with that 120 mg dose of Belzutifan.
At the same time, there's a peripheral biomarker for that activity, it has to do with unrelated to the molecular mechanism in the tumor, it's associated with erythropoietin production from the healthy kidney. What you can see is that we would achieve at roughly 20 mg-30 mg dose, what Merck would achieve with the 120 mg dose. The good thing about that marker is that it essentially saturates at that, at that level. In going higher doses, you don't suppress any more of that erythropoietin production, but on the other hand, you're going to be hitting the tumor much harder. There's a number of reasons based upon the historical data.
Most notably, if you were to look at a second-line, RCC data set that Merck has in about 30 patients, essentially, almost every patient had some tumor reduction, but still you only had a 20 some odd percent response rate. Also, pretty substantial time in terms of the kinetics to see that response. We think it's pretty clear that there's an opportunity that activity was left on the table. We're very excited about having the opportunity to go with a molecule that's unquestionably better. We'll have the phase III data that we'll be starting the phase III study, we'll be sharing the dose escalation data prior to the end of this year.
You'll see that PK, PD and safety that you can compare to the Merck molecule, and we're pushing really hard to be in phase III by the end of next year, in looking at both the doublet combination as well as a monotherapy. The other thing that will be important readouts between now and the end of the year is if you think about our molecules in the adenosine ATP pathway, etruma, the A2 receptor blocker, and Quemly, the CD73 Inhibitor, we'll have in addition to the ARC-7 study, we have ARC-6, ARC-9, and ARC-8. As I stated, that would be Etrima in both prostate and colorectal, and ARC-8 is in a frontline pancreatic cancer. All of those are randomized studies. They all have had data where we've seen an interesting signal.
The one that we're probably most excited as we sit here today is our frontline pancreatic cancer trial. This was a study, just to remind briefly what we're looking at here. We did a dose escalation, dose expansion, where we saw an early signal. We started a randomized component, where what we're looking at is gemcitabine, the standard of care, plus Quemly, our CD73 Inhibitor, then plus or minus Zimberelimab anti-PD-1. Really what we're sorting out here is whether anti-PD-1 brings anything to the table. There have been a couple of studies with gemcitabine, using Nivo or Pembro that didn't show any benefit. In our case, we're looking in the context of CD73, that was an outstanding question. We ran this randomized study.
Mid the randomized study, we pointed out that we were not seeing a difference suggesting that the anti-PD-1 was doing anything, and it wasn't clear how exactly things would play out. We said that the next data cut that we would report on would be when we had OS. That's very near. I think it's going to be a very interesting data set. That's something we're excited about and something we'll be sharing prior to the end of this year. I think between all of those studies, that'll also define a lot about how our investment's going to look in both of those molecules going forward. A lot of readouts, and I think a lot of interesting readouts between now and the end of the year.
I think you mentioned on the last earnings call that with ARC-8, the event rate's been a little bit slower than expected. How should we think about this in terms of hitting the 6-month PFS goal?
Here's what I would say is out there. We described that the last patient in was the end of 2021, and we're looking at OS. If you think about what you would expect with gemcitabine's sort of been in numerous studies. As a control arm, of course, there was a phase III approval trial. In the phase III trial, the OS was about 8.5 months. There have been other studies. If you were to ask people, what would you expect with contemporary gemcitabine, they'd probably say 10-12 months. There's been other recent readouts where it showed up 9.5 months OS.
If you consider that last patient in was the end of 2021, and we've been, like, waiting to get to a good, meaningful, mature OS, it's a pretty positive, I would say, that you're waiting. It's a good sign.
... Right. You also expanded your partnership with Gilead recently to include immunology targets, I believe, four assets here. Could you just talk, even though it's very early, just discuss your work here and, what investors should take note of with regard to this partnership?
I think it's our entire Gilead relationship from day one, and I think you see this playing out, has been our focus has been to build a long-term, independent company. You know, something when we first mentioned that, I think, you know, people have questions. Okay, let's just see how that plays out. I think the first part of that is it's enabled us to really build not only a really strong portfolio of molecules, but a portfolio of molecules that are competing in major markets with major need, with major competitors. You know, look at us, we're running four registrational trials that are, you know, with huge. You're competing with Merck, you're competing with Roche, Genentech. We have a mid-stage pipeline, you know, with things like our HIF-2 Inhibitor, the adenosine modulators. We have early molecules.
We have, you know, an excellent i nhibitor that'll be going into the clinic soon, CD39 antibody that started. We built a pipeline, you know, we have a very much something I think is unusual. We have a discovery group that is capable of creating something from nothing, it's not like we're just running around looking for the leftovers. We're basically looking at, you know, innovative targets with potentially best-in-class molecules. At the same time, we've built a very substantial development organization. If you look at what Arcus does, like, we have a very strong small molecule expertise, also from a biology standpoint, our group is primarily immunology. Despite the fact that we do so much in oncology, a substantial portion of that, because it's immuno-oncology, is studying immunology. We've always had the intent to get into immunology.
The dynamics of the relationship with Genentech, as many of you are aware, it's an extraordinary collaboration. It's not just tossing money over the transom. It's not just tossing molecules over the transom. Gilead has hundreds of people working on our programs. We're well capitalized, largely due to the relationship with them. It is sort of a soup to nuts type of collaboration. As part of the discovery effort, very organically, our discovery units since the arrival of Flavius Martin as their head of discovery, there's been very good dynamics, both at the oncology level and inflam level. Also, keep in mind that Gilead has built out a very substantial inflammation development group under the leadership of Mark Genovese.
There's a very good, you know, symbiosis there, where you can imagine they have a development organization. We want to get into oncology, into immunology in a bigger way. It enables us to do that without having to distract the development organization. Basically, Gilead enhanced our resourcing on the inflammation end. We have a strong immunology group. We pick the targets together. Jen's pointed out herself to a couple of groups. It enables us to be very aligned on the targets from day one. We're working together from the earliest, literally basic, discovery into the early phases of drug discovery and then ultimately clinically together.
Strategically, it really enables us to, in a very continuous way, continue with our oncology efforts at all levels, from discovery to, you know, phase III development, but to weave in these inflammation and immunology programs in a capital efficient and operationally efficient way. We're really excited about that, and we think it's, again, another aspect of building a sustainable drug discovery organization where, you know, we can start things and stop things based on their merit, not simply because, you know, you have to keep pushing something because it's the only thing you have.
Great. Well, with that, maybe we'll open it up to the audience for any questions. Can we just get...
For the PDAC study, I think before you've mentioned ORR of 40% is what you think is meaningful, PFS of greater than six months. It sounds like the OS is gonna be probably, I don't know, north of... I feel like 15 months would be meaningful in terms of benefit over that 10 months-12 months. Is that fair to say? What about you have both the quad and Quemly plus chemo? Have you seen anything different between those two subgroups?
What I, what we'll say, and I'm comfortable saying this now, is that the anti-PD-1 is not enhancing the activity. Your points on, like, what would be a good OS, certainly that would be fair to say. I think any KOL in the field would say something above that would be appealing. You know, we obviously don't have the full data set yet, but something along those lines would be exciting. We shared an update when we looked kind of interim. We haven't done a formal data analysis since that one, but we will be soon.
Just one last one here at the-
Sure. You have a couple.
Keeping you on schedule. There's the phase II EDGE platform study in lung cancer. Just remind us how that kind of fits in your overall strategy for lung.
The way we see the platform studies is, like lung cancer, obviously, is one of the tumor types we're very focused on. The platform study fits in the way that we have the ability to keep on putting new arms into the study with a running standard of care control. We're able to say, to benchmark early signs of efficacy. We're able to generate safety data that typically is needed when you want to start a phase III trial. For different combinations that we're interested in, we can basically amend it into the trial, have the flexibility, and then wait for the data to mature while we are making decisions about where the combination can go.
For example, if we think about, let's say, the CD73 pathway, we've done the experiment in ARC-7, but that's a an IO-only setting, and then etruma was added to domvanalimab and zimberelimab. I would say based on the research hypothesis, exploring adenosine targeting in the context of chemotherapy is a very different, and I personally think, more attractive setting to explore that. That's why we have a number of arms in the two platform studies, where we are combining, let's say, the adenosine modulation on top of chemotherapy with zimberelimab and sometimes with domvanalimab as well.
At some point, we have the safety data and efficacy data to make decisions, and especially when we want to move into earlier lines, for example, a Stage 3 setting in lung or, let's say, a purely adjuvant setting, meaning patients with curable lung cancer, it is even more critical to have some safety data and early efficacy data in order to start mature trials. It's really a very efficient way of being able to screen for efficacy. Also, if we have new agents that we are, let's say, that are coming out of the pipeline, they can also go in those trials. These trials can run for a very long time.
Great. With that, thank you so much. Really appreciate the time, Terry and Dimitry.
Thanks, Salveen.
Thank you.
Thanks, everybody.
Thank you.
Appreciate it.