ARCUS BIOSCIENCES - ARCUS BIOSCIENCES INC

All right. Good morning. Welcome, everybody, to our Castatapen Investor Day. We will be sharing some exciting new data across first, second, and late-line kidney cancer. Before we begin, I'd like to remind you we'll be making forward-looking statements, and please review our SEC filings where the risk factors are laid out in detail. Today, you'll be hearing from a number of members of our management team, as well as our guest speaker, Dr. Raina McKay, who will be joining us virtually. After Dr. McKay's section, we'll stop for a short Q&A with her, and then we'll take more questions at the end after the full presentation. So I'll turn it over to Terry to begin. I'll repeat that. Thanks again for all of you who are joining us, including those of you who are online. We have a lot to share today. It's a pretty exciting day for us. We're obviously here to talk about Kazdatafam, but before we jump into that, we just wanted to spend two minutes on the background of the company, even though it looks like a lot of familiar faces. For those who are out there and know less about the company we just want to give you a drop of background. So Arcus was founded in 2015. We've been around for about a decade. The company was founded with both a focus and expertise around small molecule drug discovery. We're a very R&D-centric organization. You can see we had that goal of advancing one to two molecules into the clinic each year. I think we've done a quite good job of that. We built up quite a portfolio of programs. Castatafan is sort of right down the middle of the fairway, really reflects the paradigm of Arcus. We have our molecule, QEMLY, that's in frontline pancreatic cancer. We're actually doing an interim analysis of its registrational trial this quarter. That'll read out. On the other end of the spectrum, we have a portfolio of very early programs that are just into the clinic or earlier. Those are mostly in the immunology area. The reason we point that out is because as CasDataFan approaches commercialization, we feel we have a very sustainable pipeline to continue to grow the company with other molecules, both addressing similar opportunities and of similar quality. So I'm going to use this slide somewhat as an executive summary as we talk about casdatofan, high-level, you should think about what we're laying out for the day. I think the first thing that I wanted to talk about is our holistic approach here. So we recognized some time ago that casdatafan represented a true, unique molecule, dramatically different from And so, in thinking about the opportunities, what we did is we looked across each line of therapy in Clear Cell RCC at what were the vulnerabilities of the standard of care. And I'm going to talk a little bit about that on the next slide. But essentially what we're going to lay out today is the plans that we had, the data that we've generated in the plans we have going forward but suffice it to say I think when you walk out of this room that you will believe that cast data fan hands down is the best molecule best drug in clear cell RCC bar none we think you'll recognize that it does have a five to ten billion dollar commercial opportunity and we have a lot of tailwinds in our development program so essentially we're going to talk about first line second line in late line what we're gonna share today it's not just totality of the data in each of those modules we think you'll walk away thinking we have the best molecule to address each of those. So for those who like the minimalist version where everything can be done in five minutes and feel like you have to be able to say everything in five months, this slide has it. So those are real curves. We'll be talking about more specific data as I go along. But what I want to do here is just lay out those vulnerabilities in each line of therapy. So when you think about the front line, the most commonly used regimen is ipinivo. So ipinibo has about 30% of the front-line market. The reason that ipinigo is used, you know, number one, is because it provides the best overall survival. So it's used 30%. Why isn't it used 100%? And its limitations are very clear and very simple. It's its rate of primary progression, which is almost 1 in 5, and then just PFS in general. Landmark PFS for epinevo is 50% at 12 months, so 50% of the patients have progressed. So the clear message, and this is a theme you're going to hear throughout the day, everything we're doing is highly aligned with how physicians want to treat clear cell RCC. So as we're going to change the paradigm, we're essentially going to give an umbrella of a casdatafan-based regimen on top of the regimens that they already like to use. So the idea on ipinevos, get that disease control to where it can take that 30% to maybe 50% or more conservatively. The second line is a very interesting one. So second line has two vulnerabilities, two limitations. So the first one, we've now had LightSpark 011 done. Merck with Belzudafan is 0 for 3 on hitting overall survival. So one thing that we've been told in second line, if we could achieve an overall survival signal, that would be game-changing. You'd essentially take the whole market. Now, the other thing about the second line is that includes a patient population that probably has the worst prognosis of any population in clear cell RCC. And that's the group of patients that come out of the front line having experienced a second-generation TKI. So I'll talk a little bit more about this in detail a little later on. But that's 60% of the patients coming into the second line that you'd say miscellaneous. So two clear, simple opportunities, overall survival, and then also it would be great to address that patient population that's very underserved by the second generation agent. And what we're doing there is we're going on top of Cabo. So just like ipinivo is most commonly used regimen in the front line, CABO is the most commonly used regime in the second line. It's 40%. In terms of monotherapies, it's actually 80%. So it's very favored by the clinical community. Finally, the late line. You generally look at this late line as almost like a salvage therapy population, a new lease on life. extraordinary overall survival. So a picture's worth 10,000 of my words, and I won't give you 10, 000 words. This really, everything that sort of describes castatofan's advantages over belzutifan can be described as coming from this property of the molecule. So we have a better quality molecule, and the first thing that we recognized where you could really see dramatic difference is when you look at the effect of casdatofan on the biomarker for HIF-2-alpha inhibition in the human, and that's the ability to suppress erythropoietin. So not only does casdatafan more deeply suppress that production, but you can see it's incredibly durable as far as we know it goes on in perpetuity. Whereas the V-shaped curve, which was published by Merck, what you see is somewhere between one week and 13 weeks, you lose essentially all effect on that biomarker. So the thing I'd like you to keep in mind is that whether you're taking those three 40-milligram tablets, your effect on erythropoietin production beyond that 13 weeks looks very minimal. particularly important when you start to think about biologies that are interacting when you're thinking about combination therapies. So the left-hand side will show more specific data but the left hand side represents what we'd shown with our late line patient population about a year ago. So basically much better data compared to Belzudafan about half the rate of primary progression, 50% higher ORR, a two-plus-fold improvement in PFS, and what we're going to show today is a very strong OS signal in that same population. So the key point here, as I mentioned before, these two molecules are completely different. This is not an incremental difference. And what we will show you today, as you see our data, is that Belzudifan doesn't define what HIF-2-alpha inhibition does. It defines what Belzodifan does, and essentially Casdatofan squeeze all the water out of the stone of what you can get of the true promise of HIF2-Alpha inhibitions. I think when this target first came into recognition, there was a lot of hope. There was a sort of promise as to what robust inhibition could deliver for patients. And I think what you're going to see today is how that manifests itself when the curve looks like the bottom curve. So we've looked to be in the lead in science of HIF-2 biology and studying CasDataFan. This highlights a recent Nature paper, and I just want to point out two key aspects of what we showed in this Nature publication. So the first one is we were able to correlate efficacy with pharmacodynamic biomarkers. So, basically what we showed was that you could correlate ORR or PFS with that ability to suppress erythropoietin production. So when you think about the previous slide, given that correlation, you could see how important, you know, the difference between those two curves is. The second thing that we showed is that patients that had higher HIF-2-alpha activity actually did better. So why is that important? Well, HIF2-Alpha activity is one of the most negative prognostics you can have in RCC or cancer, for that matter. So what that tells you is it's not only correlative, but it's causative, given that we're having the best effect in the patients that have the worst prognostic. This is another very important aspect of durable, robust TIF2-alpha inhibition. So this is the spider plot for the 120-patient monotherapy cohort that we've been talking about. And I'd like this to kind of get imprinted in your head because I'm going to show three spider plots today. And they're just at various stages, but I don't really love the metaphor if you've seen this movie. But this movie tells you how the other spider plots are, you know, going to play out with time. And so what you can see, and this is remarkable when you look at this mechanism. So keep in mind, this is a late line patient population, third plus line of therapy and 25% or more that are fourth plus line of therapy. So if you look at that x-axis, you're out past 30 months. So what you can see is not only do you get early disease control rate of primary progression, ORR, but these patients just go on and on. Whether you're a yellow stable disease or whether you're green or blue responder, all of these patients are getting tremendous benefit. If you look up there, 25% of the patients are still on therapy after two years. So basically what you're talking about, this drives obviously patient life benefit, but also it drives hazard ratio for both PFS and OS. So very critical to see that basically once a patient is on control, they're essentially go on and on. I would emphasize, you know, you can see this is out past 30 months. You're going to see like an amazing OS signal. When people first started to see this even a year ago, they, you Know, they suggested, hey, maybe you're going to see a strong OS. So this just calls out two particular patients to amplify the last point. So what you can see from these two patients is here are two patients that were stable disease in out past two years they actually became confirmed responders so again it's a very very durable mechanism of action and it's probably no more benefit to these patients but it just illustrates the point that you can even see deepening of the tumor response out past 2 years so I'm not going to say much about the slide, you're going to see it way too many times. Both Raina and Richard are going to comment on this. But as I was talking about, when we thought about our strategy, it's a very integrated strategy. These patients, some of them are going be on therapy for over 10 years. So the sequencing of all of the different opportunities is a very critical aspect to how these patients are managed. And as I said, the way we thought about approaching this was to ensure that we're going to change the paradigm for treating clear cell RCC, but we're going to do it in a way that's highly aligned with how physicians want to treat clear cell RCC. So the brass ring therapy, again, that we are building on, the reason I say it's brass ring that's the ipinevo so frontline it's the largest patient population it's going to give the greatest durability when i showed that spider plot that also drives commercial opportunity it's also there's no competition in the front line so as most of you know uh belazudafan failed in the front line, so our only competition in front line is to improve upon ipineivo the second line as i I mentioned, we're going on top of Cabo. In late line, we are going on top of TiVo. So these are three regimens that are all favored already by physicians. Essentially what we're doing is putting an umbrella over them. We're going to have a cast data fan enhanced opportunity for them to use those therapies. So I'm going to switch now to, I have about a half a dozen data sites. I'm basically going to steal all the thunder from Juan and Richard, and then they'll put a little bit more meat on the bones. Juan will talk more about the translational aspects of this. Richard will give you a few more details about the clinical aspects, and also he'll tell you a lot more about the development plan. So a year ago, I think it was basically in this room, this is the data set that we were focused on. And if you look on the left, that was last year. On the right is the Merck data set. And now in the middle, we have similar maturity to that of the Merk data set, and I'll just run through this quickly. This is, as I talked about before, you can see the confirmed ORR, it's about 50% better than what you see with Belzudafan. The PFS is about 2x that. And very importantly, you see that progressive disease that's about 50%. That's hugely enabling. That's why we're able to go into the front line with, again, what physicians wanted to see was a TKI sparing regimen. So building on top of ipinevo where you don't have the baggage of the TKI. So you've got the opportunity to give patients years of life before they ever see that TKI, So with that high rate of primary progression, that's why Merck always needed to combine with a TKI to control, to get that early disease control. So while these data, as always, this is a theme for this target, and particularly for Casdafin, the data always get better with time. That was one of the first points that I wanted to illustrate when I showed you that spider plot. Similarly, you can see bits of improvement. But the real sort of home run now on this is the overall survival. So you could see the opportunity inherent in the spider plot. But basically, I'd emphasize that yellow oval, we're seeing a median OS of three years at this point. When we saw these data, it kind of was mind-blowing that you're going from something that was, If you look what Belzudafan was, Belzutafan showed a 5.6-month median PFS and basically did not improve upon the OS of Everolimus. And here you can see, if you look at the confidence interval, when we come back and look at this a year from now, it's going to be even better. Look at all the tick marks of patients still on. So, three-year overall survival. Importantly, this is really important. One is going to show you data where, as I mentioned in the Nature paper, where we showed that PFS and ORR were correlative with pharmacodynamic markers. We're going to show the same thing for overall survival. So these are real and they're highly likely to read through to other lines of therapy. In fact, I'm going to show you in the second line, we're already seeing a strong OS signal. To put With this number in context, in second line, CABO monotherapy has an OS of about 20-something months, low 20s, so almost the same as Belzudafan late line. So we're already doing better. The other thing I'll just tell you here, when I show you curves for the second line CasCABO, we've already put them on top of this OS in the late line monotherapy PFS. those second line data are looking better. So you can expect that the second line data, as they continue to mature, are going to mature similarly. And I'll show you the spider plight that points to that. So now let's turn to the second line. So the first thing I want to do is briefly address the patient population coming into the second life. So as I mentioned, 60% of the patients that come into the second line have received the second-generation TKI, and those patients have the worst prognosis of any patient group in this particular setting. Now, for second podcast data fantasize, and I just want to illustrate what Merck just recently published in the Lancet publication describing the patient population in LightSpark 011. And what you can see is there's a couple of unusual things about that. So first of all, they have zero CABO patients, obviously. They have zero limvatinib patients as well. And then they have about 25% or more patients that receive a first-generation TKI like sunitinib. That's very rare, particularly in the U.S. that's almost not used anymore. So the point we just want to make here is to illustrate that this patient population looks nothing like the real world patient population that's delivering 60% of either Axi, Cabo, or Lenva priorly treated patients into the second line. So why is that important? Well, it comes back to what I mentioned about those patients who are underserved a little earlier. If you look at that upper blue box, Lenva is the most notorious in that context, and basically real-world data that were published this year illustrates if you got Lenva Pembro in the front line and then you get Cabo monotherapy, you're basically going to have 5% ORR, a median PFS of four to five months and change, and most devastatingly, in eight months, overall survival. So keeping that patient population in mind, that's illustrative of differences in the patient population between LightSpark 011 and the ARC-20 Cascavo cohort, as well as our Peak 1 registrational trial, which is going to include plenty of those Lombatin patients. Now, we actually felt, for a number of reasons, Juan will share them, that we had an opportunity to completely change the trajectory for those patients that had those second-generation PKIs, and I'll get to that in a few slides. So what this actually shows now is the waterfall plot and the spider plot for those patients that received Cas-Cabo in ARC-20. And what I want to emphasize, not only the depth of response, the number of patients still on study, but that spider plot should look really familiar to you. And basically, when you get Cas-DataFan, if you get past that second scan, you're going to be very well served by the drug. You're going be on it for a long time, whether you're a responder, whether you're a stable disease patient you just get incredible durability as I emphasize all of these patients are contributing to the hazard ratio for both PFS and OS and as Bob speaks to you and he'll be pretty conservative on our estimates they're also contributing for the commercial the commercial opportunity. So you can see, again, we have something that a year from now is only going to get better, and all of that's contributing to, you know, the implied hazard ratio, the shape of that Kaplan-Meier curve. So now this actually compares Cas-Cabo to Bell's Lemva from LightSpark 011, and then you see the control arm of CABO from LightSpark 011. So despite those patient population differences that we talked about, we're overlapping on our PFS curve, but what you can see is there's already a dramatic separation on overall survival. What you can say is that the curves are separating at six months. Now, to just give this some context, if you look at the two lower curves, those represent the Bell's-Lenva versus Cabo from LightSpark 011. And they actually did start to see some separation about 16 to 18 months out. At this time point, when they had the same maturity data that we have now, Bell's Lenva had a hazard ratio on OS of 0.9. It actually improved over the ensuing year to their final analysis to about 0.85. So interestingly, they almost hit on OS. So given what you're seeing here, this is sort of the first piece of evidence to suggest, in addition to what we've shown for the molecule as a single agent, Casdata-Fan-Cabo is going to hit on overall survival. And I'll show you more on this topic. Now, this emphasizes the point that we talked about, those TKI pretreated patients. This is another one that probably had us just staring at the data. So the first thing is, on the left, what we've basically shown are the PFS curves for patients that did receive a TKI in the prior treatment and those patients that Did not receive a PKI in prior treatment. What you can see is they're overlapping. Now, on the right-hand side, we've shown swimmer plots for the subpopulations. So those reds are all Lenva patients. The yellows are other TKI patients, and the blues are those patients that received IO that didn't receive a TKI. The remarkable thing about those Lenva patient, recall the data that I said, those patients had four to five months expected median PFS, eight months expected median OS. If you look at that right-hand oval on the reds, that's out past 600 days, 20 months. So those patients that prior to casdatafan, really in a devastatingly poor situation, Now you've got basically looking just the same. So if you look down those swimmer plots, what you basically see is all patients have equal opportunity when you come on to cast DAPHN. The second and probably most important aspect of this is those ovals that we've highlighted. All of those patients are going to continue to contribute you to the PFS curve, as well as then that PFS curve feeds into the OS curve. And this is just going to be a dramatic hazard ratio as you think about how this therapy will mature. And, this slide is meant to make the point of how our registrational trial is going to look. So, what we have here is cascabo is the teal colored curve. And what we've shown here are the corresponding PFS and OS Kaplan-Meier curves from every registrational trial that's involved Cabo, including LightSpark 011. And the important takeaway message from this is peak one control arm will be the first that ever includes meaningful levels of any second generation TKI other than AXI. AXIs are probably the most gentle. So basically what's absolutely the case is that the control arm for peak one should be, it's going to be a worse population, it's gonna perform worse than any of these Cabo curves. And you can already see how strong we're looking. Again, I would emphasize, if you look at the OS curve, this is going to hit on OS. And like I said before, when we look at this a year from now, those curves are only going to be more separate. You've got a lot of patients that are contributing to these curves. Now I'm going to show you what's, I think that last slide emphasized where you had a patient population that has the highest medical need. This is the brass ring patient population where the commercial opportunity is huge. So in the last six months, as we've been talking to people, everyone's been wondering, what are we going to be able to show that tells them that we're going to be successful in the front line? And I think, if anything's been a home run, these data are going to be a grand slammer. So what this shows is, again, same theme. We've shown you a waterfall plot. You see all those all those patients that are still on. Keep in mind, this matures, this doesn't have a TKI in it. So, this is basically Casdatafan plus anti-PD-1 without the IPI. So, ipinevo is 12 weeks of ipinebo, and then it's nevo for the rest of the time. So this is just the Cas anti-pd1 component. So the first thing you can see is waterfall. Like we said in January, we didn't show it, but we said it looked amazing. It only looks more amazing now. There will be more responders. So we've had two more confirmed responders probably in the last month or two. And you can se all of those patients with asterisks still on. Secondarily, look at the spider plot. So think about, basically when you think about the spider plots I've shown you, They're nice in terms of predictive ability because we're going from patient population that's most advanced, single agent, towards a healthier patient population and in a therapy that includes an important combination. So again, a pretty amazing spider plot. If you look, you do not see 45-degree angles shooting up. So, what does that tell us? Well, this is probably, this is nice, like if I was only going to have one slide, it would be this slide. So, What this shows you is basically how does CasDataFan anti-PD-1 compare to ipinevo, so the middle curve on the right is from Checkmate 214. Its control purpose, actually and it's summarized in the far right column of my table, it's the lower curve on the Kaplan-Meier curves. That's PEMBRO in the same patient population. So, what you can see is PEMBROW kind of gives you just what does anti-PD-1 alone do. You can see 30% rate of primary progression, 30 and change confirmed ORR, and then it has a median PFS of about seven to eight months. But the real takeaway is in the left-hand side of the table. So first off, remember, with Ipnevo, you get about one in five patients are primary progressors. Now, we had shared, we saw a 7% rate of primary progression, two out of 30. We're already at a 50%. A lot of people kind of during the course of the last six months said they'd love to see a 5 in the ORR. So for the ORRR lovers, we're at a 15% confirmed ORR, we think that will continue to get better. Most importantly, the landmark data. So we knew we were going to have 11 and a half months of follow-up with CAS anti-PD-1. We were excited about that because we know landmark PFS for IPI-NEVO is basically 50%. So when we plant our PFS curve on top of Checkmate 214, you can see yet another set of curves where you can drive a truck between those two curves. And in fact, when you look at our 50% landmark PFS, it's 69% compared to that 50%. To put that 69% in context, it is a small print under the graph. It should be in big print. That is essentially, it Is better than what you get with anti-PD1 plus TKI in the front line. So whether it's Axi or Cabo, and it's essentially the same as what you get with Lemba, Pembro. So this builds on a theme that we've seen. We've said this to you a number of times. Every single time we've looked at Casdatafan as monotherapy, it performs in terms of disease control and everything thereafter like a TKI, but without the baggage. So, what you're seeing here is a PFS curve that would be just as competitive with anti-PD-1 plus TKI, but without that TKI baggage. The other yellow oval that is important to highlight, so you've wondered, people have asked, we've been running a cohort of 30 patients for a safety data set of the triplet. This is IPI, anti-PD1 CAS. Richard's going to show you the safety data on that, but I'm going to give you the spoiler alert. It looks fine. As a matter of fact, that safety data set already fulfills. We had our discussion with the FDA and EMA in terms of the safety data set that we need to start our registrational study at the end of this year, and we already have the data in hand that meets those specifications. So, what you also see, though, is out of the 25 patients that have made it to first scan, one primary progressor. So, very consistent picture. We're delivering on both of what were those key things that investigators, not our narrative, what investigators wanted to see, basically dramatic improvement in PFS and, most importantly, Dramatic improvement on the rate of primary progression. A very consistent feature of CasDataFan. It performs just like a TKI, but it doesn't come with the baggage of TKI. There's two baggage with the TKI So the first is the quality of life. The second is, and you're going to hear this particularly when Juan speaks, TKI drives HIF-2-alpha activity. So that's why those TKI pretreated patients do so poorly in the second line. So sparing that patient a TKI has both a quality of life feature and a future feature in terms of driving their efficacy going forward. So let me just elevate for a second here and summarize what I've shared. We've looked at the front line, we've looked at the second line, and we've look at the late line. We've contextualized our data with limitations in each of those lines. I think we've shown unequivocally that in each line we dramatically address those limitations. Our second line study, we expect to be fully enrolled by the end of this year. Our front line study will be starting at the end of this year, and we're starting the work to enable that late-line phase 3 study combining with Tevo. So, I think you'll see some more meat on the bones, but I think when you put this all together, you see that not only do we, in fact, have the best drug for treating clear cell RCC, but it generally will be a $5 to $10 billion drug. So the next thing I'd like to do is turn things over to Raina McKay. Raina is a phenomenal clinician. She's worked with Gazdatofan. She's working with Belzudafan. As you can see, she's a leader in everything in her field. It says she's rising star. I say she is a star. She's a superstar. And the second thing I'd really point out, in this world where you all the time, It's such a misnomer you hear K-O-L. Raina actually has both. Most of them are just O's. She's emphasis on the K and the L. So we really appreciate having Raina here to share some perspectives on the current treatment paradigm and how she would expect that to evolve. So welcome, Raina. Thank you so much for that really kind introduction. And it's really such a pleasure to be here with you all this morning, really showcasing the evolution of the data around CasDataFan and the tremendous opportunities in renal cell carcinoma with this agent that we are all super enthused about really for our patients to ensure that they live longer and live better. Because that's really what's driving everything that we're doing here with the program. Let's go to the next slide. And just to showcase the patient journey, I think Carrie alluded to this as we talked about the different landscapes, you know, the evolution of kidney cancer treatments have really changed with the introduction of IO therapy in the frontline. And in the front line setting now, we largely have two key options, an IO-IO option in the context of nivolumab plus ipilimumab, of which 30 to 40 percent of patients will receive that combination, and it is actually the most commonly utilized combination if we think of things at the regimen level, or the combination of PD-1 TKI, which is the remaining share of individuals, but PD-2 therapy, anti-PD-1 therapy is the backbone of frontline treatment for patients with modern-day RCC. For the individuals that progress onto the second line, which is actually the bulk of individuals go on to develop the disease progression. So there's tremendous opportunity in the frontline setting. We are not curing the bulk of patients with metastatic disease, and many go on the develop resistance, which is a huge vulnerability. The bulk of the options for patients that are IO experienced now includes either TKI monotherapy or recently TKI HIF-2-alpha inhibitor, which has really proof of concept to the strategy behind the PQAN program and opportunities in the second line space. And then there are some individuals that, many individuals that go on to develop disease progression that receive third plus treatment options of which we're basically cycling TKIs with TKI monotherapy, HIF-2-alpha monotherapy can also be introduced in that context. And we are seeing that there is growing utilization of Belzodifan, which actually is a good thing as we think about the opportunities for Castatafan and MOA and developing a best-in-class HIF-2-alpha inhibitor. Next slide. And now when we break it down into those individuals that are actually receiving TKI-based treatments, which we think there's tremendous opportunity here, when we look at the PD-1, anti-PD-1 TKI regimens in the frontline space, There's almost an even split between pem-lenvatinib, nivolumab, cabozantinib, and anti-PD-1 combined with AXI, the bulk of which of that is pem-AXI. In the second-line setting, again, we see TKI monotherapy as the predominant backbone, and I think what's striking here is the astounding utilization of cabozanthinib in this front line, in the second line setting. It is the go-to workhorse in the second line. People know it, people go to it, people use it, clinicians and practitioners alike. And then when we look at the later line setting, Tavazanib is an agent that can be utilized. Cabozantinib can also be utilized in that context later on or other TKIs. And I think what Terry highlighted really so beautifully in his talk is that across every single line here, there's also an opportunity for integration of castatafan targeting the vulnerable opportunities that are present in existing modern day treatments. Next slide. So we've chatted a lot about the frontline setting and what Nevo IPI brings to the table and what it doesn't bring to the table. As a regimen, it is one of the most widely utilized regimens for frontline RCC, particularly in the academic setting. And the tantalizing piece about the use of NEVO-IPI is that in a small subset of patients, looking around, you know, approximately one in 10 patients, if you will, there can be long, durable remissions that can be observed with needle IPI frontline. And that is an opportunity that we want to continue to expand about. Unfortunately, one in five patients develop primary disease progression and have no response to treatment. And, that is the number from clinical trials. When we look at actually real-world data sets, that number is likely much higher. And so, there's a huge opportunity. There's no biomarker that exists to try to identify who these individuals are. And so this is where CAS can have a dramatic role with potentially reducing the high rate of primary PD and expanding the PFS in the frontline setting in the context that also spares a TKI. This is something that clinicians desire, patients desire, and is a huge opportunity. And from the early data that we're seeing from ARC-20, even just with the CAS-SIM combination, we are already seeing progress being made in that space with the introduction of castatidine in the frontline setting with decreasing primary PD rate and expanding the PFS rate. Obviously, the data will continue to evolve, but this is incredibly exciting, and we're incredibly excited about the triplet in this combination. Next slide. so as we think about second line opportunities and i think this is the workhorse right now with the peak one study cascavo really has the potential to improve pfs and potentially os and provide dramatic benefit in tki pre-treated populations you know what's striking about the data around cabozantinib is in the post-IO data sets from LightSpark 0101, from CONTACT3. The performance of cabozaninib has been pretty consistent, right around 10 and a half months for immune PFS in that context. When we also integrate all patients who have been exposed to prior tki we do see reduction of the activity of cabo's antonym as is highlighted the key here is cabo point where we see a drop off in the pfs um you know for those uh tki exposed individuals so i think the opportunity here really lies in that you know the cast cabo could improve upon this pfs cabo is the most commonly utilized most commonly prescribed tki in the second line setting So anchoring to that agent that clinicians know well and are utilizing very well, I think is a really strong play. There's significant comfort with utilizing this drug, managing toxicities, but then also an opportunity to dramatically improve upon the benefit and potentially build with expanding the response rate, expanding the PFS, and also the overall survival in this context. Next slide. And then when we think about the late line setting, where there's a tremendous opportunity as well, and not, you know, with every line of therapy, there are patients that drop off and are not able to receive a subsequent line of treatment. I think there is a tremendous, you Know, opportunity here as well. When we look at the drugs that are utilized, Belzodifan monotherapy, Tavazanib, other TKIs that patients may cycle through, the rates of primary progression are high, and almost a third of patients who receive Belzotifan greater than that have primary PD in the later line setting. And those are tough odds to stomach when you're facing potentially your last and final line of treatment potentially in RCC is that, you know, one third likelihood that the treatment is not going to respond at all. And we're sitting on a PFS that's less than six months, meeting it with both Tavazanib and Belzodifan. So there is tremendous opportunity to build upon this. Actually, the bar is quite low. and castatafan, we view it as a best-in-class agent from the data that Terry has shown regarding the pharmacodynamic properties of the agent. So I think there's tremendous opportunity with the combination in the later line setting. Next slide. And this is that slide that I think Terry had alluded to that myself and Richard are going to really talk through. So there's a lot of opportunity to color the entire landscape of rcc treatments from front line second line and third line with castatafan combination treatment options that leverage the vulnerable opportunities of the already existing standard of care agents in this context there's opportunities for a tki free regimen with peak 20 of cast nevo ipi that i think is going to potentially be a game changer in this context, lowering primary PD and expanding PFS. And basically, I love Terry's phrase of the benefit of a TKI without the baggage of a GTI. Then there's also opportunities to combine with a TGI. There may be people that have rapidly aggressive disease and need that dual inhibition where we look at P21 of Cas-Axi PD1 versus Axi PD1. And then also thinking about novel combinations, as we've seen many of the bispecifics entering into the testing landscape across the board. There's multiple agents, and I think tremendous opportunity there as well. In the second-line setting, you know, the most robust data coming from, you Know, the R20 combination and providing rationale for dual complementary targeting of the HIF-VEGF pathway with the combination of castatafan and cabozantinib there. And, you know, that's going to be a tremendous opportunity there in the second line. And then later line, thinking about peak 30, you Know, as I said, the bar is low with Tivo monotherapy in the later line setting and looking at a combination option in that context as well to decrease primary pd expand pfs will be a tremendous win for our patients let's go to the next slide i think that is the final one thank you dr mckay we'll pause here for a quick q a session with dr mackay if you can please direct your questions to her to maximize her time we'll take more questions with the management team at the end let's start with start with hi dr mckay thank you this is dana graybosch from lyrinc partners and i have a question about frontline because we're going to go into esmo and see the light spark 12 data set and in that abstract my read similar to what we saw with cosmic 313 is reduce treatment exposure of all three drugs in the triplet may have contributed to the lack of benefit there. I wonder if you agree, and as we see ARCUS move in the front line, if there's anything you can do in these trials to better keep patients on all three of the triplete therapies to avoid the negative outcomes we saw in LightSpark 12? Yeah, no, thank you so much for that question. It's incredibly timely. I think it's very different when you have agents that have overlapping toxicity. And I think this is what was the Achilles heel of 313, also 012. I think when you run into issues with hepatitis, you're not sure if it's IO-mediated. You're not sure if its TKI-mediate. Patients end up stopping both agents because you're kind of trying to tease it out. 313 was also a blinded study. And so you didn't know what patients were on and just stopped everything. You know, so I think that this is very different when you have a side effect profile that is very distinct and unique from that that you experienced with the IO. So, you know, the IO mediated itises that you see are, you Know, we're not seeing hepatitis with, you You know, castatophan, pneumonitis, colitis, diarrhea, these things that we know happen with TKIs don't really happen with castatophan. And so I think that is a real beauty of the agent. The other thing that I will highlight is, you know, when thinking about a TKI sparing regimen, you Know, the backbone of LenPem is a high bar actually in the frontline setting. And so I think that is also another reason why the 012 study failed, because I think there are more vulnerabilities with NEVO-IPI that can be leveraged with combination strategies when we're looking at the frontline. Lee from Dr. McKean. I have two quick questions. First, can you talk about your TKI sequencing decision, especially around lambda using front line versus second line in light of the light spark 11? And then for bells, how would you choose between the mono versus lambda plus balancing second line? Very good question. So I think in my context, I tend to be a dramatic user of nevo-ipi. I want my patients, if they are able to experience a long, durable remission, if they have the opportunity to experience that. For those individuals that have really rapidly progressive disease and really need a TKI. They're either in visceral crisis, have high volume of, you know, lung, liver, what have you, metastases, and really needs a TGI, cannot, you knows, afford them to have that one in five primary PD rate. I'm predominantly using limbatinib pembrolizumab in the frontline setting. And so when I do use a TPI in the front line, it tends to be Lembatinib. We've seen really high response rates with that combination, low primary PD for so for the person who needs it, that's the combination that I go to. Cabozantinib is my go-to second line, you know, agent. And I think that by using either Nevo IPI or, you now, Lempem front line I think it opens up the opportunity for Cabozanthinib second line. And so I think the data around monotherapy use versus the combination of belzodifan plus lenvatinib, I think a lot of it is, you know, TKI toxicity, what's the fitness of the patient, you know. And, you Know, that regimen was just recently approved about a month or so ago. And so I Think it's just being kind of considered in practice and trying to identify who is the right individual for that. But generally, my TKI sequencing is Levatinib front line, Cabozantinib second line, and then depending on the fitness of the patient, Belzudifan, and, you know, the underlying kind of distribution of metastases, you know, even profiling selection of either Belzutifan or Tabazinib in later line. Great. Thank you so much, John Miller from Evercore ISI. You just mentioned that you're an enthusiastic user of EpiNevo in the frontline, but it remains a minority regimen. In your opinion, what does it take to drive use in the first line off of TKIs, and is there a realistic possibility of expanding TKI-free regimen use with HIF-2? Absolutely. I think if you decrease the primary PD rate, you will increase utilization of hemoglobin. People don't want to get burned. They want to start somebody on a regimen, and they want them to do well at their first scan assessment and not have to be faced with making a treatment decision or having the patient have primary PD. Primary PD is not a good thing. And it can taint an individual's experience with utilizing that agent. And so I think if we can decrease the primary PD rate with a well-tolerated agent with non-overlapping toxicity with the backbone of Nivo-IPI, that's going to be a huge win and it's going drive up utilization. And, you know, as individuals are utilizing Belzodifan and Lateline, it's a not great monotherapy. And it's, you, know, again, that primary PD experience is going to taint utilization. I think to integrate it in the front line in a TKI-free sparing strategy will be a win. Hi, Tara Bancroft from TD Cowen. So I'm wondering if I could build upon one of the previous questions of, you know, when making prescribing choices, would you base your choice more on hazard ratio or absolute numbers, like which numbers actually matter most to you? And also then in those considerations, when you're comparing data sets, how much would you consider baseline differences in the different patient populations that are enrolled? How important are those nuances to you in prescribing? To me, they're very important because I'm very granular, very detail-oriented. And I think thinking about broadly how a community oncologist may interpret the data, I think there's a lot of education. I think it's all the above. It's not just the hazard ratio because the hazard ration is reflective of, well, what is the performance of your control arm? and if your control arm is underperforming or over performing that is basically going to be an interpretation of the hazard ratio yes absolute numbers matter but it's it's a combination of the two i think the absolute numbers can be um you have to think about the patient population when you look at that if there's more favorable risk patients that have low volume disease that don't have an intact primary your objective response rate is going to to be automatically higher. We see that the likelihood of somebody achieving an objective response that has an intact or like a complete response or with an intact primary is incredibly low when they still have their primary intact. So these are all the things that I think matter. All these trials are, you know, different. They enroll different populations. And I think the other thing too is we also have to think about the timing of when the trial's enrolled. You know, 214 was the first foray of challenging the standard of care of student in its front line with NEVO-IPI being utilized in a large phase three in RCC. And there's a learning curve that happens with actually being able to familiarize yourself with how to treat AEs, how to manage AEs. And if you actually look at contemporaneously these trials that we're enrolling later on, people learned how to use the medications and how touse combinations and howto mitigate tox. And AND WE LEARNED HOW TO ADJUST AND MODIFY THE CRITERIA AND MANAGEMENT ALGORITHMS. AND SO I THINK THAT THESE ARE ALL REALLY IMPORTANT THINGS WHEN WE ARE CONSIDERING INTERPRETATION OF THE DATA. COOL. THANK YOU, DR. MCKAY. THANKS FOR YOUR TIME THIS MORNING. CHARLES ZOO FROM LIFE PSYCH CAPITAL. have one question here. Based on your experience, as well as any available clinical literature out there, how would you describe patient outcomes segmented by whether or not they're able to receive all four doses of CTLA-4 during the induction phase relative to those who receive three or fewer cycles? Thank you. Yeah, very good question. And actually, not to say we don't know the right number. But the question to ask is, why are the patients not able to receive those regimens? And is it truly driven by an IRAE that we think could potentially be suggestive of an enhanced effect to treatment? So, you know, I don't know that, you know, whether patients received one to two, you know, I think the dichotomy is kind of in the one to two versus the three to four. But it all depends on what is the reason that the treatment was stopped. Was it for an IRAE? And how was that IRAE treated with steroids or other, you know, agents that could potentially blunt the activity of the immunotherapy? So this is why it's actually really critical to not have overlapping tox because you're stopping that you know you've got hepatitis that comes on from uh you know a tki that has a long half-life and you wait a couple days and still have you know high lfts and nobody feels comfortable with that and then you're you know layering in um you know steroids or tacrolimus and other things like that that are basically blunting the immune response you know that's not a good thing Thanks for the color, Dr. McKay. One from us on the second line data granularities here, we're getting some questions just on the 14 and a half months medium PFS that was presented today. I was wondering if you could put that into context. I think some people were expecting a slightly higher number for that Cascavo second line, especially when you look at the the late line 13 months medium pfs i'm wondering if you could put that into context for us especially as it relates to the os data that was presented today where we are seeing separation earlier than what we saw in light spark 11 and over light spark 11 bells lenva how do you how do put this into context your overall thinking here and then second to that could you comment on just your thoughts around 52 alpha having a greater contribution on the back part of the curve versus a tki yeah very good question so i think regarding the 14 months um first off i'll say this is a very respectable and very um you know uh encouraging PFS that we're seeing greater than a year in the second line setting in a very heavily pretreated patient population with, you know, multiple, you know, prior exposures. So I am certainly not discouraged by that. And when we think about the bar for approval and the bar for utilization, as we stated, you know, from, you know, Cabo's Anthony has been sitting in that eight to ten month range, depending on degree of TKI exposure. So I think that's actually quite encouraging. I think the latter part of your question about integration of HIF-2-alpha, I think we're seeing post-VEGF progression, there's upregulation of the pathway, and And castatafan really has the tremendous opportunity to overcome that expression and pathway upregulation probably much better than we're seeing from our pharmacodynamic studies. And valzudafan quite obviously dramatically suppresses, you know, EPO and blunts the pathway. And so I think the complementary aspects of VEGF and, you know, HIP in this context, and specifically with CAS, is going to be a really good thing in the second line. Hi, Dr. McKay. This is Jane from Goldman Sachs, and I'm asking this question on behalf of Rich. So my question is, how do you think CAS will translate in a TKI containing regimen first line, given the first line data here is without TKI? Is there anything you see from the second line CAS plus CABO that could be read through? So basically, is there any concern for using a first line in a TKI-containing regimen with AXI based on TKI combo data in second line? Is there any thing you see in the first line presented today? Thank you. Yeah, very good question. You know, I think the thinking here is in every way that a clinician could think about utilizing a modern day regimen, there is an opportunity with CAS being added. that's really the take-home message and while we haven't shown you today the combination of you know um a frontline regimen that includes cast with a tki with a checkpoint inhibitor i think that is the strategy the strategy is targeting in in every way that a clinician may think about okay i'm going to use nevo ipi for this well i'm gonna add cast to it i'm going to use um you know iotki for this well there's an opportunity to potentially test cas in addition to that i'm going to used cabo second line or i'm gonna use a tki second line okay add cas to that I'm going tki monotherapy uh later line I'm gonna add cas to this the the data is pretty dramatic and robust that across the board uh with an agent like cas who works uh pretty well or, you know, beautifully as a HIF-2-alpha inhibitor and, you Know, is likely best-in-class agent of combining. We'll take one last question. Hi, this is Sephora Tante from Truer Securities. Dr. McKay, just as a clarification to your earlier comment, so with Bells and LandNow approved, if CAS and CABO were also approved, what would drive your choice between the two? would it be primarily the profile the pfs and os profile we've seen today or the ease of integrating um cas plus cabo given that cabo is already a backbone and and secondly what do you think of peak one's probability of success you know having seen the results that we've seen today thank you yeah very good question you know i actually think that it's uh a little bit the latter and for like the fact that cabozantinib is already being wildly utilized as the go-to, you know, second line agent. Like Meteor really set the bar high. It was actually one of the first studies ever in kidney cancer on its first analysis to improve all three objectives of objective response rate, PFS, and OS, statistically significant improvement across all three of those parameters, the utilization of cabozantinib in the later line setting is anchored in high-level phase 3 data. There is no data for lenvatinib monotherapy. The best data that we have for lenvatinib utilization later line is from 150 phase 2 trial of lenvatinib everolimus and so and lenvatinib in people's experience and in the data has a lot of toxicities that's associated with it and so I think to anchor with an agent that has a really high bar with regards to the rigor of data that led to its utilization and also comfort and ease of use is going to really be an excellent thing. So I think that the data here really, I think, foreshadow what we hope to see in peak one. I am incredibly optimistic about this study being positive from the data that we've shared with you thus far and being integrated into the landscape. Thank you, Dr. McKay, for your time today. We'll let you get on with the rest of your day. I know there were some more questions in the queue, but the management team will take questions at the end. So I really appreciate you joining us today, and we'll let you get to it. Thank you. The next section, Juan will talk about the translational science. Thanks, Reina. Good morning, and thank you for your attention. I'm going to take about 10 minutes. My job today is to walk you through a couple of key points. The first one is I'm going to link the biology, the PD changes associated with cast treatment with every relevant clinical endpoint in our combined 121 patient late-line monotherapy cohorts. So I'm gonna link the PD Changes with Primary Progression, I'mma link the changes, I am introducing a new PD marker today. I want to link both of them with objective response rate, with PFS, and with OS. And the reason that I think the monotherapy cohorts are the ideal place to do this is because we have one single agent, we don't have confusing multiple mechanisms of action potentially pushing some of these PED markers in opposite directions. So HIF-2-alpha regulates probably hundreds of genes, many of which are relevant for clear cell RCC biology. EPO doesn't really play a particularly important pathological role, but it has the advantage that it's something that we can measure easily in the periphery, and it gives us a really good integrated sense for how much HIF 12 activity a particular patient is experiencing and the changes associated with HIF-2-alpha inhibition. I'll remind you that at the approved dose of 120 milligrams, BELS reaches a maximal level of inhibition, the median being has been described more than once around 64 percent. Terry already alluded to the published data whereby the EPO levels in serum revert back to baseline after about three months. In the case of CAAS, we can reach that level of 60-some percent reduction in EPO at a dose of 20 milligrams daily. As we continue to go up in dose, and the figure to the left represents an integrated assessment of maximal level of EPO reduction as a function of daily dose of Cas. By the time we get to 50 milligrams daily, we pretty much reach the maximal level of inhibition, and it doesn't get any, in a meaningful way, any higher. We've gone all the way up to 200 milligrams in the dose escalation. Not only do we achieve, in general, a higher level of EPO reduction with a median of 84-85 percent, that PD effect is sustained for the duration of treatment as Terry reminded you that is shown here for the 100 milligram cohort, but pretty much the same for any of the other dose levels. This is a graphical illustration of where each one of the 121 patients is represented by one bar. And what we've done is illustrate each patient's maximal reduction in serum EPO levels and color coded to illustrate best overall response. What you can see very clearly is that they're, well, maybe you can't see it on these screens, but if you turn around, you can very easily see that there are way more blues and greens towards the right than towards the left. Patients with better objective responses tend to be associated with deeper EPOR reductions. The dashed line running horizontally represents the median of 84 percent. You've seen versions of the figure shown here to the left, the PFS comparison. is simply updated with the latest clinical data cut. There's no attempt to do any kind of patient selection here. All we've done is split the population down the middle using the median of 84 percent. You can very clearly see that those patients that experience greater than the median in terms of maximal EPO reduction tend to have a longer PFS than those in the lower than the meeting have. The representation to the right, still immature because many of the patients are still alive, fortunately, but it shows you a similar segregation when you look at the OS curves. Patients with deeper EPO reductions tend to live longer. Now, this is, I think, remarkable. This PD effect is first noted a couple of weeks into treatment and sustained, but nevertheless, It starts to be detectable right at the beginning of treatment. It's reading through to a clinical outcome two, maybe three years later. Now if you're not convinced of that relationship, I'm going to introduce PI1 as another marker of systemic HIF-2-alpha activity. In this case, we could spend an hour talking about the potential pathological role of this protein. It may be more than just a PD marker. But for today's update, we'll just use it as just another independent measure of systemic HIF-2-alpha activity. Illustrated here, and going back, combining both the EPO and PI-1 relationship between the extent of reduction of these markers and the best of all response. You can see here that, similarly to what we've shown previously for EPO, shown here now for Pi 1, is that patients with an objective response tend, in general, to have deeper Pi 1 changes than those with stable disease or those with primary progression. In the case of Pi 1 the average or the median level of reduction is 45%. tells you is that, and it's independent of cast dose, what that's telling you is that when it comes to systemic circulating PI1, about half of it is transcriptionally regulated by HIF-2-alpha. The other 50% of that protein is obviously regulated by other pathways. When we do the same median split and look at the deeper versus less deep reduction in PI1 levels, you see something very similar to what I showed you a second ago. Patients that experience the deeper reduction tend to have longer PFS and longer OS than those in the lower half. Again, not an attempt to select patients, just an attempt link biology, the efficacy or the activity of CAS with the clinical outcomes. Now here, this is I think one of my favorite slides. What we've done here is said, let's now make an attempt to identify a natural breaking point. Let's identify that 15 or so percent of the patients, they have a lower level of reduction on either biomarker or both, and let's separate them. When we do this, a couple of things happen. First of all, you see the majority, that darker upper curve that contains about 80 or so percent of the total population does pretty darn well. You also notice that it barely has any primary progressions left in it. If you look on the other hand to the three curves towards the lower part of the figure, those represent patients that are in the worst 15 or so per centile of either biomarker or or both. And you see what we've done is essentially taken out all of the primary progressors out of the 121 patient pool. So what this is telling us is that those patients roughly, and this ties in with some of the work that we published in the Nature paper where we define high HIF-12 activity in different ways. We did it using immunohistochemistry, the amount of protein. We did a looking at the transcriptional signature of HIF-2-alpha. There's always, we always come back to the same place, but roughly 15 to 20 percent of tumors that don't appear to have a lot of Hif-2alpha activity, and they really don't care that much about Cas intervention. The other 80 percent of the population that has meaningful levels of HF-2 alpha tend to do pretty darn well. So before I move on to the second part of my update, which is introducing the concept of adaptive HIF-to-alpha activity, I'd just like to recap what I hopefully have convinced you given the limitations of time. There's a link between the extent of HIF to alpha inhibition that we can achieve with CAS as measured by two completely independent circulating PD markers. There's a relationship between the rate of primary progression, objective response, PFS, and OS. So the numbers that Terry, the curves that Terry showed, and Richard's going to come back to, are clearly reflective of biology and the strength of HIF-2-alpha inhibition that CAAS is able to reach. Now Shung here, I'll remind you that the figure to the right is taken from a Merck poster. It's breaking down, in this case, we could have done something similar with the LysPARC5 data except that the LYSPARC13, the phase two data, was broken down more granularly. What you can see here, the three curves represent the number of prior TKI regimens that those patients that were treated with BELS had experienced. You can see that there's a very clear degradation of BELs performance as a function of prior TKI treatment, and as a function of the number of TKI regimens. If you look at our monotherapy data shown in the left of the slide, you see that there's absolutely no daylight between patients that received one prior TKI, two prior TKIs, or three prior TkIs. We think this is a reflection of both the biology that sets in as a result of the treatment with the TKI, but also the strength of HIF-2-alpha inhibition associated with Cas. We're working on a paper that should be submitted pretty shortly here that pretty much integrates a whole bunch of data that leads us to propose that anti-angiogenic treatment results in an increase I won't call it up regulation because we don't think it's necessarily transcriptional they're just an increase of hip to alpha activity in tumors they have been treated with anti-angiogenic agents so that the evidence comes in two forms in the tumor we see increased protein stabilization we've developed probably the world's most sensitive and specific immunohistochemistry assay for HIF-2-alpha and HIF1-alph for that matter. So we see increased levels of HIF2- alpha protein. We see increased transcriptional signature of Hif2-Alpha in patients that have received prior TKI treatment. In the periphery, we see increase levels of EPO and PI-1 in patients who have received TKI within approximately about eight months, sorry, six months. There's sort of a window of time after which that prior TKI exposure is no longer clearly detectable in the periphery. This is my last slide, just trying to introduce the concept. It's not really all that complicated. We all know that patients, the first, clear cell RCC is a tumor that comes into existence under the pretense of being hypoxic when in reality it's not so that translates into a tumor that's probably one of the best vascularized solid tumors that there is and they're the first time they see a blood supply drying agent the TKI they do relatively well you dry up the blood supply tumor shrinks there's no doubt no doubt about it and maybe the problem is what happens after that through hypoxia sets in. Evolutionarily, the tumor and the non-tumor cells are pre-programmed to respond, among other things, by relying on HIF-2-alpha activity for survival. That probably means that outside the tumor, there's an upregulation of HIF2-Alpha, but also the tumor may undergo selective pressure to identify clones that are perhaps more dependent on Hif2-ALpha, better able to thrive through a condition of true hypoxia. Now, the model explains why after a pretty good response on a first round of TKI treatment, you really don't do very well on second and third TKIs. Whatever benefit you're getting from the second or third line of TKI may have just as much to do with a non-VEGF inhibitory activity of that TKI, They're probably not getting much from an anti-angiogenic effect after the first round. But secondly, you've now set in motion something that if you're a borderline HIF-12 inhibitor, it's not particularly good. You now have a bigger foe to fight against. There's more HIF12 activity. And so how well you do with your HIF2-alpha inhibitor probably depends on how strongly that HIF1-2-Alpha inhibiter is able to fight against that increased, that adaptive HIF to alpha activity. We think this explains why BELLS is so dependent or performance is so degraded by prior TKI treatment, while CHAOS appears to be unaffected by that. I don't want to leave you with the impression that CHAOS works better in prior TGI-treated patients. It simply does well against people that have never seen a TKI, and it performs, the data supports that it performs just as well in patients that have seen multiple rounds of TKI treatment. So with that, I'll turn it over to Richard. I was told I should try and be brief. We've been here for a long time, so I'll try and move fast, but there's a few key points I'd like to make. so there we go you've seen this before it's the development plan but it's really important to understand and Dr. McKay I think highlighted that when you see a molecule with the impact of castatafan it really needs to be developed and available to all patients with clear cell RCC and I mean all patients in the front line and subsequent lines of therapy so as we put together the development plan it is to add castatofan and two, the preferred existing regimens, across each line of therapy. In the front line, the key here is to be TKI-free. And we know that the physicians, and good for the patients, they can now live 5 to 10 years and hopefully longer survival with adding castatafen. So they have to decide what to use in the front lines. And then also thinking about what they'll use in subsequent lines of therapy and being TKI free with long-term survival. That's the ipinevo regimen. And the only region it's not used by far more is the liability of that primary progression, as Dr. McKay said, where one in five patients actually show progression at the first scan, which is very disheartening for the patient and the treating physician. So the key here is to meaningfully reduce that rate of primary progression which would drive the ipinevo plus Casuse far higher even than it currently is. And then importantly, there are going to be patients that are highly symptomatic, so they do need a TKI up front for early inhibition there. And that, we have selected Exitinib and PD-1 as the partner for Castatafan. And Exitnib was deliberately selected because it, I'll say, is a kinder, gentler TKI from a tolerability perspective for the patient. And that's because it's a much more selective anti-VEGF TKI, so better tolerated. And that theme will continue. But importantly, we also have three different partnerships for additional potential frontline treatment of patients. That's our partnerships with BMS, Pfizer, and Summit, all testing their VEGF PDX bispecific with castatofan in frontline patients. So those will be additional frontline opportunities. Quickly moving to the second line, everyone's familiar with peak one, our Cas plus Cabo versus Cabo. I think very high probability of success. And the key here is we selected Cabo, again, deliberately, because it's by far the most preferred choice in TKIs in the second line setting. So very easy for the prescribing physicians who already use CABO predominantly in that space to just add Cas-Tatafan to the current algorithm. And then lastly, look at the later line setting there. We're combining Cas with TiVo. That's, again, a very selective, very well-tolerated TKI. And we think that combination will take over all of the monotherapy use in the third line and be the dominant regimen in the late line as well. So quickly, this is our ARC-20 study. It's our phase two with multiple expansion cohorts that generates all the data that we've talked about today. This is for data in the monotherapy as well as many different combination therapies, again, across first line, second line, and late line. And we have over 300 patients that have been on castatafan and over 200 patients that are discussed and described today in the data sets we're sharing. So quickly, I'll talk about the late-line setting with our, as you've seen, unprecedented overall survival. You've seen this before, so just to highlight the keys here is we actually at the 24-month or two-year landmark have two-thirds of the patients still alive and surviving. And I think what's more amazing is, as Terry said, that three-year landmark here is about 50% of the median, still alive at three years. This is late line. I'll remind you, this is generally a median of fourth-line use, meaning the patients had a median of three prior lines coming into this cohort. Not sure why it won't advance. So safety, we've shared the safety before. It generally looks like the safety profile of Belzudafan, and we've described it before, but now we have much longer follow-up and the safety profile has not changed despite having the much longer follow- up now. So late line setting, again, unfortunately for patients, there are three different monotherapies that are used or available. of them have a PFS of even six months, and none have shown an overall survival benefit. And so we think this is a very real opportunity to add CAST to TiVo and take over the entire third-line regimen, and we can meaningfully improve both PFS and OS for these patients. And we strongly believe this because of these data here. Here we overlaid our CAST monotherapy, Again, basically a median of fourth line, and that's compared to T-NEVO2 in the gray. Those are patients that received TiVo monotherapy in the second or third line. That trial enrolled both second and third line patients. Not hard to see the very clear difference in PFS on the left, but also a very clear difference in OS on the right. So these are the monotherapies. So now adding TiVo and Cas compared to TiVos should only further separate the curves. So we are enrolling now an arm in ARC20 that is a randomized arm, Cas plus TiVov versus TiVoz, and this arm is enrolling all patients that have had prior HIF-2 or prior Belzodifan experience. And our Phase III trial will enroll all comers that will be patients that have had or have not had prior HIF-2 experience. So quickly moving to the second line, Cas plus Cabo, we think this is really positioned to be the regimen of choice, particularly because we've started with Cabo which is the TKI of choice. You've seen this from Terry, the PFS on the left and OS on the right, where we meaningfully beat all prior benchmarks for ACABO and that's why we have such strong expectations and high probability of success since PFS is the primary endpoint of the trial. But I also think we can very meaningfully beat OS on the right. Keep in mind, LightSpark 11 had a hazard ratio of 0.85, so they almost had significance. So we only have to be a little bit better than what they were in in order to achieve a significance, and that would be a complete game changer. From a safety perspective, so far the experience really is looking like CABA's safety profile, plus the anemia and hypoxia associated with the potent HIF-2-alpha inhibitor. So the trial you've seen before, this is now enrolling. It's enrolled very well, and in fact, we're going to complete enrollment in the next few months. really to expectation. It's CASP as Cabo versus Cabo in a two-to-one randomization. And importantly, all the statistical power, or alpha, is on PFS as a sole primary endpoint. And then the other reason that we can probably win on overall survival is we then recycle the alpha. So the statistical test of OS has all these statistical power recycled from PFS to OS. So we don't have to split our alpha. So we have to be slightly better than 0.85, and we have more power or full power because all the alpha will be allocated to OS. So move to the front line where we've seen now the unprecedented early data. And you saw this, and I'll just highlight again that the main reason ipi and evo is not the regimen for every patient is the risk or concern of primary progression. And you can see we have two cohorts now in ARC-20. CAS plus ZIM, so without IPI, with 11 and a half months median follow-up, and we have CAS plus XIM plus IPI that recently fully enrolled, and that was for a safety set for the FDA and EMA, and I think Terry said we have all the data now, and it's packaged up ready to go to the agencies to start our phase three trial, but you can see now we have two separate cohorts, both showing single-digit primary progression, so that's going to be the meaningful element there that will really drive adoption. And I think enrollment in this trial is going to go very fast. You can also see the confirmed response rate of 50%. That's quite high, particularly compared to ipinevo. And on the right, you've already seen how the separation of curves there are. With the primary endpoint is progression-free survival. So that's where we are to win on this trial. And then, of course, ipineva already has the advantage on overall survival compared to all of the other regimens. So importantly, and there was a comment or question earlier about the safety, this could be, I think, clearly the first triplet that shows high tolerability for the patients. It really does look like ipinevo, that's the immune AE profile, plus the hypoxia and anemia associated with HIF-2-alpha inhibition. We don't have the overlapping toxicity, and as Dr. McKay said, predominantly that's the GI toxicities and liver hepatitis, colitis, pneumonitis, et cetera. None of that is associated with HIF-2 inhibition. So we've had, dose intensity-wise, about 78, well, exactly 78 percent of the patients that have been on the trial long enough to get through four cycles, meaning more than 12 weeks on the study, 50 percent of them did receive all four cycles of IPI along with the ZIM, and then an additional 28% got three of the four cycles. So quite high utilization to get, as Dr. McKay said, and that's, I think, how we all think about when we prescribe ipi and evo. The goal is to get them through at least two and ideally three or four cycles of ipi. And at that point, all the patients are off ipi, and they'll just be on the PD-1 plus Cas. And as I just showed you, our Cas plus Zim, we've gone out now 11 1⁄2 months of median follow-up, So we're very confident and comfortable with that safety profile. Otherwise, the immune-mediated events that we're seeing are very consistent with ipinivo, both in frequency, severity, but also timing. And that's the important thing, is when do these happen? And they've been happening very consistently with what we see generally with ipnivo. So as expected, CASP doesn't change the immune mediated events. So the frontline trial is CASP plus ipinibo versus ipinigo. It's an all-comers from an IMDC perspective. And another important point, you know, the PFS is the sole primary, so all the statistical alpha is on PFS. And as you can imagine, if we meaningfully reduce primary progression, that instantly elevates the pre-FS curve by that magnitude, and that will carry forward. So high probability of success on hitting on PFC. And then after the first four cycles of IPI is depicted on the bottom, for the continuation the trial, which can go years, it's really a test of Cas plus Nevo versus Nevo. So with that, I'll hand it off to Bob. Thank you, Richard. So we've had a chance to share a lot of data today, and we think that a clear picture has been painted, and that's the best therapeutic for the treatment of clear cell RCC in terms of castatafan. When you look at each of the key therapeutic attributes, we think that picture becomes super obvious. So let's start off with disease control. And Dr. McKay mentioned the importance of disease control and giving a patient an opportunity to succeed in each line of therapy. In our late-line monotherapy, our disease control is on par or better than a TKI monotherapy in any line of therapy. That's really been the gold standard when you think about disease control historically, and I think we showed you a lot of spider plots today across different lines of therapy, and you saw that sort of consistent theme around disease control, which we think is quite impressive for CasDataFan. Moving to survival, both OS and PFS, we've showed really exciting OS data, obviously, in the late line, and it's emerging very nicely as well in the second line, alongside very compelling PFS in every setting. Importantly, we've talked about the tail of the Kaplan-Meier curves here, and we think that that's going to continue to show through as all of our data matures over the coming years. Finally, tolerability is important. Dr. McKay talked about ability to combine casdatofan without overlapping toxicities across treatments, and, we think that's very unique having a treatment like casdatafan that doesn't have that overlapping toxicity. So Terry and Richard have already reviewed this slide. I just want to make sure that everybody's left with the impression that we are laser-focused on the first two commercial opportunities for CasDataFan. First of all, peak one is poised for success, and that's a $2 billion opportunity. And then perhaps even more importantly, we have a clear line to success in the front line with the IPINIVO combination, where we have a $4 billion-plus commercial opportunity. The plan obviously lays out additional opportunities both in the front line and the late line as well. So let me talk about how that development plan then translates into the commercial opportunity with a little bit more specificity. So starting with the second line, and this is important, I think Dr. McKay underscored this, we're building on the physician preferred regimen in the second line. In fact, when we spoke to 50 physicians and asked them the question, would they utilize the newly approved LightSpark 11 regimen or cabozantinib monotherapy, 50% of those physicians told us they were going to stick with cabozaninib therapy. And that's because of their preference for cabozinib. And we think that's really important in terms of how we built that regimen in the second line in the front line this is the largest commercial opportunity with no hip to alpha competition in peak 20 is richer highlighted we're combining with the regimen and dr. McKay made this point physicians reach for to provide patients with the best opportunity for long-term survival the weakness here obviously is disease control, where 50% of patients do not stay on therapy beyond a year. We've shown you data to support our belief that casdatafan can address that key weakness in the front line, and that it can be the dominant regimen in the frontline, which is a $4 billion opportunity. In addition to peak 1 and peak 20, we're also exploring opportunities that were regimens that address the VEGF pathway in the front line, AXI, and the PDX VEJF bispecifics, and a compelling combination with dominant later line share in TiVo. I think one of the themes that continues to emerge in our data across lines of therapy is the incredible durability of Casdatafan, and we think that that introduces a huge upside to the overall commercial opportunity and duration of therapy, and we thank that story will continue to play out over the next few years. So with that, I'm gonna turn it back to Terry to wrap up and then we can take your questions. Thanks, Bob. Thank you all again for your attention and we look forward to the Q&A. So I just wanna close. I'm not gonna go through these in detail. You can look at them, but we have a lot of milestones coming over the next few years. And I'll just bucket them. We're gonna continue, as you've seen, we've done medical conference after medical conference after medical conferences. We'll be continuing to do that. We do that not only to share the data with you, but to generate that sort of investigator enthusiasm. We work, I think, with amongst the best investigators in this field, and we feel it's important to get all of our data out there. So what you're going to see is the data that we share today. Obviously, as they continue to mature, we'll be sharing them on a fairly ongoing basis, and we'll continue to publish as Juan was mentioning. I think then the next, probably most important aspect, Richard talked about fully enrolling peak one, that's coming shortly, starting peak 20. That's going to enroll gangbusters, and as Richard suggested, not only is it going to enroll quickly, but it's going read out quickly given that primary endpoint of PFS. And then you should expect to see a continuous flow of information around these other studies that we're doing. We barely touched on it, but obviously everyone was looking at all the various ESMO abstracts. You saw the exciting data with the anti-PD-1 VEGF bispecific. We think that could end up being an important, basically, version of TKI anti-PD-1 without the baggage of the TKI. So, we're well-positioned to have the one reagent that has the monopoly, and I think there's a large number of those bispecifics, and we're working with three of them, and we'll be executing the study that's in collaboration with Summit, so we're confident in how that will get done and enrolled. So, I think the next part that's other separate bucket is our studies with TiVo, our studies with AXI or studies with the bispecifics, and you'll see a continual flow of information. So I just would finish by summarizing, bring you back, elevate a second. I think our data show that not only across all lines, but in each line, we have the opportunity to completely win. The other thing that should not be lost on you, and this is something that Bob, why I would say everything he talks about is the conservative end of things. So this is a therapy. When you think about HIF-2-alpha drives this cancer in all of these patients that basically we're seeing efficacy, so whether it's 80% to 90% of these patient, it also may even be induced in those patients where the TKI is bringing some benefit and they were either lower HIF-2-alpha activity or no HIF 2-alph activity. So extraordinarily important in the setting. And the other thing to keep in mind, there is zero evidence of any meaningful resistance development to HIF2-Alpha inhibition. So we believe that you will be able to sequence Casdatofan with the other agents for the duration of their therapy. talk about backbone a lot of this discussion is sequencing this sequencing of that we actually believe all the evidence and we'll be generating more evidence ourselves that you will be able to have a backbone therapy of casdatafan much like you see Bev in colorectal cancer where patients will benefit from casdatofan throughout their five to ten hopefully plus ten plus years on treatment so I'm gonna stop there thank you all again thank the presenters thank Raina and her absence I think Raina did a fantastic job of both laying out the current treatment paradigm I evolved and rather have her answering the questions from you guys then then also appreciate that more we'll be happy to take some questions now all right will someone speak up One person raise their hand and everyone will jump in. Thanks very much. I'm wondering if you showed the data for OS for frontline broken out by TKI versus no TKI in the prior therapy. I know you showed that PFS broken out. I assume it was consistent on OS. So in the frontline? Yes, in the second line. Oh, okay. Second line with prior TKI versus no prior TKI. Did you show the OS broken out? Yeah, we need much longer follow-up to track OS, really. But we are already seeing the same type of separation. But to Richard's point, they're simply not mature, as you might imagine. It's very early. Okay, and then I'm just curious, with regard to the spider plots on HIF-2-alpha, maybe Juan can answer this. I gather the results would be similar based on the baseline HIF 2-alph, as well as the HIF2-Alpha expression. Did you look at that as well? You want to comment on that one? Can you repeat the question? Just I was curious if the spider plot conclusions regarding HIF-2-alpha expression were consistent when you looked at the baseline HIF2-Alpha data as well. Yeah, the thing with baseline Hif-2 Alpha assessment is that we don't have a sample for each one of those 121 patients. So when you start to get away from the PD marker, you're interpreting, you know, 40 as opposed to 121 but yeah generally it and again we publish this when you look at baseline HIF-2-alpha protein levels for transcriptional signature evidence that HIF 12 face firing the correlations that relationships that are described using the PD markers all hold up and then just the last one is obviously have amazing data with the single digit primary progression but is there any rationale to do a biomarker strategy to even even lower that so that you just don't treat the people that you know have extremely low if to alpha driving the tumor you know that's not really necessary I can take that I think short answer is no because even those with low still have benefit from cast it's just those with higher hip to or you know higher EPO well we can cover it with cast out a fan but even in the less deep suppression that's say stronger we've we've had stronger responses than Bell's would have. So I think it still treats everybody. You should just grab that from Hugo. You're a big guy. Terrence Flynn, Morgan Stanley. I guess the first one is just for Richard. You mentioned in peak one that OS was powered for 0.85. Just wondering if that's similar for peak 20. I know primary is PFS, but just can you tell us anything the OS stats and then Bob you mentioned a doc survey 50% stay on Cabo in light of the recent approval but did you ask about future casts and like what uptake would look like of those that are staying on Caboo or versus the when FEMA well a red regiment thank you yeah sure so me I guess clarify a little bit so we said I said light spark 11 had a 0.85 so we just have to be a little bit better to have a meaningful impact both statistically and clinical impact there and we are well powered because we'll have all our statistical power will go from PFS to OS so well in light spark 11 they split their alpha accordingly so I think we have both ways to win there on our both ways to improve and win on OS which I think is like the game-changer right I think that's an you know for those of you didn't catch that I think that's a really important point about the staff plan in terms of not splitting the alpha in basically getting a hundred percent of the output to go on OS so not only do we look like we're having a better role a signal but I think we're well positioned statistically the way our the way our survey was structured wasn't hopefully it's picking up there we go the way a survey was structure wasn't to ask follow-up questions I think dr. McKay made a particularly important point, which is that physicians are very aware of the weight of evidence for cabozantinib monotherapy in the second line, and it's their preference to go with that regimen. I think that's what's driving. So there's two pieces that drive probably the feedback when we did talk to a few of the physicians afterwards. One is the level of comfort with cabozaninib, and that is probably the primary driver. The secondary driver is that they didn't hit on overall survival. I think if they had hit on overall survival, there might have been a chance that you would see more uptake despite the fact that there's a hesitance to use lenvatinib. But separately, we have asked physicians the question, that same group of physicians, if we delivered a profile like what we believe we can deliver with casdatafan plus cabozantinib, would you use it? And the vast majority of those physicians indicated they would. Oh. Alethea Young, William Fleer, two questions. I wanted to follow up on your GALS question, but I wanted ask explicitly about third line and clarify that in your active dose, the 100, did you see kind of a similar trend versus the entire group on the 121 group where you saw 35 months? And then I have a second question. Survival for the 100? Yeah, so the data for the hundred is even less mature than the aggregate data, but it is trending very nicely. I think it might be in the deck. It's in the back of the deck I mean on the surface it may look better. We've tried to emphasize that we believe truth is best represented by the full 120 patients but the 100 if anything it looks better. The next one, the kind of two situations obviously there's the question as to whether Pico-1 is going to hit and then obviously there is a commercial question around whether that regimen is goingto be competitive because people like Capo so I think we kind of know the competitive But on the trial itself, can you just talk a little bit about the evolution of TKI use and cabozantinib and how it, you know, kind of how that might play out? I think you guys assumed 10 months roughly or so as a comparator, but just maybe give us a little more color. And then also tie that into how it seems that, you now, obviously with whatever's happening with, you, know, EPO suppression that you kind of have longer, your responses get better over time. Your PFS gets better over time? Yeah, I think the trial design assumed, I'd say, even a relatively conservative estimate for Cabo's performance. So we expect it to perform well by all prior benchmarks, and we're still very well-powered to have a win over that. So I think reality, and as we've seen going forward, is we expect the Cabo arm to perform less well than we assumed from the models, if you will, because of all the prior Lenva and second-generation TKIs for the patients coming into our trial. But from a trial design perspective, we were pretty conservative and assumed CABA would perform based on prior benchmarks on the higher end of the prior benchmarks. So I think that's a very high probability success that we would win on PFS from that. Lee Wasser from Cantor. I have two questions. First, for the PIC1 trial, do you guys have any sense in terms of percentage of patients that might have prior LENBA exposure or prior next-gen TKI exposure? Any reason to believe that number may look different relative to ARC-20? Yeah, I think the number would be similar to ARC-20 because they're, you know, enrolling near-term, let's say, to each other. The only thing we exclude by design, of course, is Cabo, right? So I think there's going to be very little first-gen TKI. There'll be some because it's a large global study, so there's still some first-generation use, but the TKI part will be predominantly Axie and Lenva, and my guess is they'll be somewhat split between the two depending on what part of the world you know lenva is not everywhere in the world compared to axi so i think axi will still probably be more than lenva by trend from that standpoint as a global trial and i still think that the io use and tki you know use will be maybe roughly equivalent at the end of the day from a split but we're still enrolling it so i can't say definitively but it's we're getting close to enrollment okay great um and then second question is around the front line just from a mechanistic point of view can you talk a little bit about your conviction level for the ioio combination versus tki um regimen based combinations light of light spark 12 and then also I wonder if you can comment on the biological interplay between IO versus TKI with cats I mean you share some pretty interesting data of the impact of TKI on the hip to activity I wonder if you have to look at you know I always impact on hip to so I'll speak at least to the first part and then I'll speak a little second in that one. We see the opportunity for CasDAF and much the way Raina talked about it given the orthogonal profiles of the AEs we see it as being quite well matched to also go with an Axi type of treatment. So the reason we picked Axi is for the reason that when Richard described it as kinder kinder gentler so we see that our therapy is dominated by the hip to alpha activity and perhaps there's a spark almost like with chemo that the TKI would bring to that so we want a TKI that does no harm actually selective it's well used it's time tested it's a It's a gentler TKI, and we feel like all the benefit that you get with Cas, we know you basically can even get benefit with monotherapy, Cas Datafan, that it will enhance the TKI. The other aspect of this, and this is an important part, when we talked about the OS signal, you're actually, the OS benefit is likely coming from both directions when you combine with the TKI. Then I'm going to come back to LightSpark 012 in this context. So if you think about it, those patients that come into the second line, for example, and I'll apply it to the first line. The patients that comes into the 2nd line, they basically, those that had a TKI have had their HIF2-alpha activity dramatically increased by the prior TKI treatment. So what you saw, and we didn't overstate it, but basically you bring those patients back as if they hadn't been treated with the TKI. Now the secondary piece is that while they're on the TKI plus the castatafan, same thing is going on that would have been going on the front line. The TKI is causing a push for that tumor that's already addicted to HIF-2-alpha to become even more dependent on HIF2-Alpha. But having Casdatafan that's there for the entire ride, those patients then move to their neck. when they progress on that other TKI, as they go on to their next line of therapy, they're in a much better position than if you think about a situation where you didn't have a TKI or if you had Belzutifan. So like think about Lenva plus Belzudifan, then think about that biomarker curve. So as you're tending to lose your effect on HIF-2-alpha with time, now those patients are starting to look like naked Lenva-treated patients. So as they go into the later line, they're basically deaths. So you're affecting the OS in both directions. Now, coming to the front line, the reason, and we've been stating this for probably six months when we heard about the light spark on to failure, is we attribute that to nothing to do with biology. We attribute it to the shorter effect of Belzodifan. So if you think about it, that was a perfect storm for not having a strong hazard ratio. You have the toxicity that's obvious even before we see the data, just from the abstract. It's dramatic when you think about you had a 37% rate of discontinuation from already known for Lemvapembro that was reproduced in this study, and then the combination drove it up to 50%. So that's the first thing. The second thing is for 24 months now, let's say if you took a median PFS, you're driving increased TIF2-alpha activity. And then you've got a molecule that's falling off in its F2L activity, however you want to define that, somewhere fairly early on. So all those things conspire to be that it's more the molecule than the biology. So we think the biology is going to be just great. And for the reasons Raina suggested, we have very strong advocacy from the physicians that Even if you drive with Cas-Ipinevo to greater than 50%, certain physicians are still going to want to reach, particularly with fast-growing bulky tumor for TKI, and they should have a Cas-Data fan-inclusive regimen. Otherwise, I don't think there's anything biologically related to the immunotherapy alone, but Juan can comment on what is known. So we have baseline information on over 200 patients, not just the monotherapy ones. So we can interrogate baseline characteristics looking back, no prior therapy or IO only. And so I can clearly state that no therapy doesn't look any different than IO only in terms of how much HIF-2-alpha is there at baseline. And now, asking the question, your other question was in reverse, does HIF-2-alpha inhibition impact the response of the tumor to an anti-PD-1 or an IO regimen, aside from the clinical data that you just saw, we have a whole bunch of additional measures of cytokine changes occurring that have been described in the context of PEMBRO or NEVO. be showing a triple median that we see similar things in our combination of Cas with Xen. We also have a whole bunch of clinical data leading to the conclusion that HIF-12 inhibition should not impair the responsiveness of the tumor to an IO regimen. So in both directions, I think they're fairly independent. There's some data out there from some of our collaborators showing that the best predictor of a rapid response in a frontline patient treated with IO only is mRNA levels of EPO, presumably HIF-2-alpha indicating, which ties in very nicely with the fact that we sort of seem to take the head off those primary progressors, presumably Hif-2 alpha may be a key driver of non-responsiveness to IO only. Yeah, Jane asking for Richard Long from Goldman Sachs. So if you only compare the second line CAS, CAVO, PFS curve for patients without, for those patients, for patients with all the seven, sorry, for without those seven prior Lenva patients, and then compare those to like SPARC11's BELS curve, in a more comparable population, how would the PFS curve look compared to Bells plus Cabo? Sorry. Yes. Bells Plus Lanva. And then a follow-up question is that in peak one, since you allow Lanva use, how much worse do you believe the Cabo control will look relative to the Cabal arm in the Light Spark 11? Want to take all of that? Sure. Yeah. really is what we see is with patients who had Lenva in a prior or they had Axi in a prior, we just don't know about Cabo in a Prior by definition, basically look the same. So CAS is able to overcome whatever, I'll call it, damage the prior Lenva is doing with regards to that enhanced HIF-2 activity. So I think if conceptually you removed that seven patients from the TKI prior profile, then we're predominantly going to be an axi-profile. But the axi profile looks very consistent with or without the Lenvo subjects, and I think that's going to Be very different than, like you said, the Cabo control arm. We know that Cabo following Lenvo does very poorly on PFS and sadly on OS, probably because of that HIF-2 driver that Lenva really stimulates. So the CABO control arm, I'd say, would perform on the lower end of any prior benchmark for those patients that had prior Lenva by comparison, even though, like I said before, we assumed CABO would perform on the higher end of the prior benchmark, so we'd still win. I believe that actually in our deck, I think we showed the seven Lenva patients broken out As silly as it is, Juan told me it's silly to put it as a Kaplan-Meier curve. We wanted to illustrate the point. That's on slide 84. And secondarily, we did do, to your question, just in general, we pulled the seven out to look at the curve without those seven. And not surprisingly, it looked essentially the same. Those LEMMA patients performed quite well. John? Oh. Thanks. Charles Zhu from LifeSite Capital again. I had another question on your frontline triplet safety. So on slide 62, you highlighted, you know, for example, you had a few cases of hepatitis, colitis, so on and so forth. I wanted to ask, what's your true denominator here? Are all 31 patients in the ITT truly safety-evaluable? And how should we think about when IRAEs tend to occur, especially as patients receive subsequent cycles of IPI? Thank you. Yeah, no, it's a good call-out. because as I pointed out, maybe 18 out of the 30 had made it past the four cycles. The safety data includes all of them, so even if they were in their second cycle and they had an event, they were captured there because the average or median time to these immune-mediated events were kind of in that 10- to 12-week frame, so it's very typical. So I have someone that followed the third course of IPI, and that's why if they got three and not four, they probably had an immune-miadiated event, since they didn't get the fourth. Other immune events happened after the fourth or fifth cycle, you know, later on. And those are, I think, very typical time frames for an ipinevo immune-mediated hepatitis colitis picture. You're very patient in a public setting. I didn't know that. I saw you not used to that. More patient in public. John Miller from Evercore again. I have a question for the first line as well, Well, specifically on the doublet arm, which shows really nice-looking PFS, but you have a lot of favorable risk patients in that population. Obviously, Checkmate 214 didn't have it in that benchmark. We know favorable risk patient do a lot better on TKI, maybe not as much or have any difference at all for epinevo. How does risk status impact CAS efficacy, and how do you expect that to play out in the first-line trial? Yeah. But we broke them out. There's a slide somewhere in there that we broke out the tumor responses by favorable versus intermediate poor. And to me, they basically look the same. Cas and Zim performed the same, and so if you want to be, I'll call it, a skeptic and carve out the favorable and just focus on the intermediate and poor risk, Cas plus Zim still looks better than the comparison group from Checkmate and their intermediate and poor because you can break out their data as well. So I think breaking it out by favorable compared to favorable or intermediate poor compared to intermediate poor, we look better on either of those fronts. And then, of course, in the phase three study, we'll stratify by favorable, intermediate, or poor. It's an all-comer, but we'll make sure that the risk stratum are equal in the face three trial to make sure they're balanced for that comparison. You know, strategically, obviously, as you know, like, IPI-NIVO ended up just logistics timing everything in intent, used primarily in the intermediate poor because of the, you know... the great PFS you get in favorable risk with the TKI. But the intent here, obviously... is to have it sort of be an all-comers population. Just for the record, the one in that data set, the one complete response that we've seen to date is in the poor. And maybe I'll just quickly, you know, I know the approval originally was just intermediate and poor and not favorable, but the broad use today is across the spectrum, and that's probably why, as we enroll this cohort and enroll it fast, we have the distribution because the patients and physicians do like to use epinevo regardless of the IMDC risk, and that'S a global, you Know, Europe the same. There's a lot of use across all risk groups, despite the initial interpretation, which has evolved over time to appreciate its use across every group. It was interesting. It was subtle, but you remember when the question came up to Raina about her use of TKI, and she emphasized she's almost like 100% ipinevo, and a lot of the academic centers more and more go in that direction where they basically want to get that OS. So obviously bringing CAS in and lowering that rate of primary progression would be a big help. There's a disconnect between what they're doing, what she's doing in the academic setting and what the broader community is using where they're very, very hesitant to give up AI, especially in my sense, especially in the labor participation. That's right. We need data to turn it around. Hi, guys. I'm Priyanka from J.P. Morgan. So it was mentioned that in frontline there was no overlapping tox with the Zim-Ipi combo. So as we're thinking about the registrational data set, and given that these patients will be in the combination for a longer time, how does the anemia and hypoxia-related side effects, how do you think those could drive physician prescribing choices for castatafan in frontline versus second line? Yeah. I think the, I'll call it beauty of this combination as a triplet is it's barely a triplets if you will, right? Meaning the first four cycles or up to the first four cycles is all three. And then after that, it's really Cas plus PD-1 or in this case Nevo. And we're very comfortable with that profile. Like I said, in our Cas-Zim group, we now have nearly a year of median follow-up. So we have a lot of experience there. The anemia and hypoxia, we see that occurring regardless of line of therapy. It's clearly HIF-2-driven. I'll say that I'll expect all patients to have anemia to some degree when they're on castatafan, especially in a prolonged use. So we tell all the investigators, physicians, just expect it. Look for it. Treat it fast. Use an ESA if your institution allows an EASA, erythropoietin-stimulating agent. Otherwise, if they get anemia, depends on the degree, and if they're symptomatic, if symptomatic will get a transfusion, but they stay on Cas. That's the key, as we haven't seen discontinuations of Casdatafan due to the anemia. Hypoxia occurs similar rates as Belzutafan. Again, that's considered on target, but again that's kind of regardless of the combination partner, meaning Zim, a PD-1, versus Cabo from that standpoint. And hypoxia is obviously not a desirable event, but the higher-grade hypoxia is still quite low in occurrence, and that'll drive patients to take a holiday or lower the dose of Cas, but they generally are staying on Cas even with events of hypoxic. That's the AE that they'll end up lowering down to 50 milligrams, maybe. But the key, as you saw in the PDE data, even at 50 milligrams of Cas—that's a more potent HIF-2 inhibitor than the commercial dose, 120 milligrams of Belzudifan. So I'd say even though they dropped it down, they're still on, you know, conceptually full-strength inhibition of HIF-2. Last couple questions. Hi, I'm Sipo from Truist. Thanks for the rationale for why Cas plus Cabo could extend OSS by some more similar PFS. I'm just curious if we have post-progression of data of sequent therapy, post- Progression data in Act 20 to support the hypothesis. And related to that question, now BELS and LENS have been approved. I'm curious if it's potential use you know, in Progressive, in the peak one, study might alter or influence the OS outcome in peak one. Thank you. Sorry. Can you restate that last part? So presumably that bells and lands now approved, and I was wondering if it could be used, for example, in the CABO control arm in peak 1 and may change how the OS hazard ratio might look. Yeah, so the CABO arm in peak 1 is exclusively CABO, right? So there'll be no Len-Bell patient coming in. There's no prior HIF-2 alpha exposure allowed. Right, so there's no, yeah, so that's exclusion. So you're saying what will happen after peak 1 progression? Can a patient, after, so sure, after progression on peak 1, And a patient could go on BELLS, for example, if they were on the CABO arm. If they didn't have the treatment arm, that will be up to the physicians as to what to give. Now, it's a global study, and BELLs isn't really available outside the U.S. for these patients from an access and reimbursement perspective. So I would expect the majority in either arm really to go on to an alternative TKI, I probably, you know, or they can go on Len, Ev, Eve if they haven't had Len before. So I don't expect much Len Bell anywhere in PQAN, and it'll be Len, Eve, TiVo, or in the U.S. they could get Bells if they were on the Cabo arm. Last question. Hi. Excuse me. Dana Graybosh from Learning Partners. I'm wondering if BMS is contributing to funding PQ-20 and whether you allow patients to receive subcutaneous nivolumab, particularly when you go down to the doublet with Cas. I can comment on the financial arrangements first. So we haven't disclosed the financial arrangement, but I would just comment, and we said this previously, that if you look at the totality of our collaborations with BMS, with Pfizer, and with Summit, the aggregate of those is very financially attractive to Arcus. And in the aggregate, we're spending less than we would have spent on one arm for ourselves. I was asking about peak 20. Oh, sorry, for peak 20, okay. Yeah, no, and we haven't disclosed anything there yet. But the trial, just to be clear, if anything there, that would just relate to some sort of supply. So there's no collaborative aspect of peak 20 with EMS. It would just, if we did something, it would involve the, just supply. And we're planning on IV use, not sub-Q use, open-minded, but just for consistency in a global trial, which is very important that everyone knows how to use it, and we're picking centers that obviously have a lot of experience with the Penevo, but predominantly that experience is IV, and so we're sticking with what they know. Thank you, everybody, for joining us. we'll end the webcast now and we're happy to take questions one-on-one afterwards. I'll thank everybody too. We really appreciate engagement and not just today but on an ongoing basis. So thank you very much.