My name is Pia Eaves. I'm Vice President of Investor Relations for Arcus Biosciences. Welcome to our October 2025 Investor Event. Thank you for joining us this morning. Today you'll hear from multiple members of our management team, as well as two independent KOLs, Dr. Raina McKay and Dr. Bill Kaelin, who are preeminent experts in RCC and HIF-2α biology. We will also have two Q&A sessions, about 20 minutes each, where we can take questions from the room. I will be running a mic around the room for that. If you are watching on the webcast and have a question, please feel free to email me directly, and I will do my best to ask the question on your behalf or get back to you as soon as possible. This event is being recorded, so please, if you're in the room, keep background conversation to a minimum and keep your phones on silent. I'd also like to remind you that, as always, we will be making forward-looking statements, so please review our SEC filings that review the risks and uncertainties in excruciating detail. With that, I'll turn it over to Dr. Terry Rosen, our CEO, to begin. Thanks, Pia. Thanks everybody for joining us today. The main event is casdatifan. Also, Juan is going to be talking about our I&I programs. Before we get started, I think most people here have been following Arcus for some time. We've been around for 10 years or so, but some people are newer. We thought we'd spend about 10 minutes or so to just provide a little context, say a little bit more about the company. As you know, we're not a one-trick pony. It's not just one program. It's not just casdatifan. In fact, we have five and soon to be six phase III studies that are ongoing. casdatifan, though, is the highest priority program. If you'd ask why is casdatifan the highest priority, it's a number of reasons. The first thing is validation. It's validated scientifically, it's validated clinically, and it's validated commercially, most notably by belzutifan, Merck's HIF-2α Inhibitor. You'll know that that's approved. It's approved just as a monotherapy and in late line settings. Even with that, it has a run rate already now of about $700 million a year. That's really the tip of the iceberg in the field. Secondarily, from our Arcus' standpoint, we own casdatifan 100%. With that in mind, it gives us enormous strategic optionality, particularly when you combine it with the rest of our portfolio. Perhaps most importantly, and I think as you'll really see today, the molecule has a best-in-class profile. We feel we can fully leverage the opportunity offered initially by clear cell RCC. I'd like to spend a bit of time on dom, our anti-TIGIT, as well as quemli, our CD73 inhibitor. Next week, you'll see our abstract published for ESMO. We have an oral presentation on dom from EDGE Gastric. EDGE Gastric is the phase II study in upper GI cancers looking at dom zim. Those will be the first time that we share overall survival data. I think what you'll find exciting about those data is that they foreshadow what will be our first registration readout next year from STAR-221. Same setting, same combination, was fully enrolled in June of last year. We think those data are exciting. Again, they'll foreshadow the potential of what STAR-221 can deliver. That's a very broad program. We also have our frontline non-small cell lung cancer, PD-L1 all-comers. That's going to be fully enrolled by the end of this year. That will be 1,000 patients. Keep in mind that's going against Keytruda, and that's probably the largest segment of the Keytruda market. Finally, quemli, which is a little bit under the radar. That's our CD73 inhibitor. You'll recall that we reported overall survival data from our study of quemli on top of gemcitabine/nab-paclitaxel, pretty unprecedented, 16.4 months overall survival. Now, that trial is fully enrolled in about nine months. It was fully enrolled in September, about a year ahead of schedule. Keep in mind that the OS for the standard care there is fairly dismal. It is pancreatic cancer. That should be reading out in the not too distant future. I want to mention that today, for the first time, we'll be talking about our immunology programs. We've really been working in immunology since the outset of the company. These programs have finally reached the state of maturity where we're comfortable wanting to say something about them as we think about, in 2026, our first molecule going into the clinic. In fact, we expect in 2026 and 2027 that those will be our INDs that are next to come. The final point on this slide is the $900 million+ that we have. That enables us to get through initial readouts from all of those late-stage programs that I just got done discussing, and it takes us through multiple value inflections for the company. Today we're talking about casdatifan. Why today? We just did a data cut, largely to provide the data that will underlie our first clinical publication on casdatifan. We've had a lot of tailwinds on this program. There's investigator enthusiasm for the target. There's investigator enthusiasm for casdatifan based upon the data that we generated today. We feel with our phase III programs getting up and going, most notably PEAK-1, as well as our collaboration eVOLVE with AstraZeneca, these sort of provide the tailwinds to the tailwinds. We keep that momentum going. What specifically are we going to talk about today? Today, there's a number of firsts. We'll have 120 patients that represent our four monotherapy late-line cohorts: 50 mg b.i.d., 50 mg, 100 mg, and 150 mg once a day. Those latter three doses aren't random. They're Project Optimus doses. What you've got is three doses that are at the upper end of the dose response curve. We feel while we're going to break out the individual doses, you'll see the 100 mg tablet, the go-forward dose and formulation in phase III. We've also combined the data because we feel with 120 patients, that's a huge data set, and it gives you a sense of what truth is. We'll have 120 patients. The other first that we'll have today, you'll see our 150 mg data. Now it's been about eight months since ASCO GU, so we have much more maturity. You get a chance to see how PFS is looking. It's clear at this point that casdatifan has a black and white best-of-class profile. The number one reason to get these data out is to drive enrollment as these phase III studies get up and going. They're already doing well. Secondarily, as I mentioned on I&I, the last two years, we've quietly been working. Our discovery effort has been about 50% on I&I. What you'll see today are the most mature data. In fact, we expect to take an inhibitor, MRGPRX2, or RX2 program into phase I, and we'll talk about the advantages that we think we have. What I want to emphasize is that as you look at the portfolio of I&I programs, which I think you'll be impressed by the breadth, they're a lot like the HIF-2α Inhibitor program where there's a lot of validation, but there's not a good molecule yet. We feel with our discovery organization, what we built, that's playing to a sweet spot. We wanted to assemble this little table here just because as an early-stage company embarking on PEAK-1, it's not our first global study. When we talk about how one might think about our ability to enroll, we want to just put these out there. STAR-221, the trial I already mentioned, we enrolled over 1,000 patients in 18 months. As I just mentioned, we enrolled the quemli trial in nine months. In fact, even ARC-20 is a global study. It's in five countries. We've enrolled over 240 patients. We think holistically, we've got the experience and track record and understanding that we'll be able to enroll this trial. On top of it, with extraordinary investigator enthusiasm and strong data going into the study, we're going to be able to enroll this in a very efficient and rapid manner. This is another important aspect of Arcus Biosciences and our ability to execute. We've been well-funded, and we've particularly been well-funded by our collaborators. That's been not only the capital, but also on the execution front operationally. I would use as an example, sort of almost forward-looking, the eVOLVE study with AstraZeneca. Here we have probably as good or better than anybody collaborator to run the eVOLVE program. That'll be our study in frontline clear cell RCC. You got a great team executing it. We have experience with them from our phase III studies with our anti-TIGIT. We're cost-sharing, but we maintain 100% of the economics and commercial rights to casdatifan. We think you couldn't come up with a more efficient way to execute an important study. Similarly, with dom, Gilead has been a major player, both operationally and from a funding standpoint. Sometimes it gets lost, but Taiho has been a great partner in that as well. Taiho not only executes the trials in Japan, but they pay for them. Taiho is also going to be making a decision very shortly, within the next few weeks, about potentially opting in to the casdatifan program. They'll be a valuable collaborator if they do so. Finally, I'll point out on quemli, you'll recall that Gilead made an equity investment in Arcus Biosciences in 2024 that more than fully funded the quemli registrational trial. Now, on the other part, sort of your numerator-denominator, what I'd like to emphasize is that our investment in dom, zim, quemli is really peaking this year. In fact, next year, our investment in dom, zim is going to be probably on the order of 50% of what it was this year. The majority of our clinical investment will be in casdatifan. As I suggested, it's that funding that's really enabled. When you look at the breadth of what we're doing and the depth of what we're doing, all of these programs are in major markets, huge medical need. We're competing with Merck. We're competing with Roche. We're even competing with our collaborator, AstraZeneca. We're able to do that because we're well-resourced. I think this just emphasizes what may be obvious. These are all big markets. If you just think about our initial two, and we have bigger visions on this, our initial two forays into clear cell RCC, the frontline and second line settings, probably about $5 billion market opportunity. Dom, zim, between the upper GI and the non-small cell lung, obviously that gets you into double-digit billions of dollars. Pancreatic cancer, with the dearth of anything good, is probably approaching a $5 billion market. These are all huge market opportunities where we have real, real opportunity for Arcus Biosciences. Now let me transition from overview of the company to overview of casdatifan. We thought we'd start with a bit of a review of the field to give a bit of context. It was in the 1990s that what I'd call Nobel Prize-winning quality biology on HIF-2α was generated. In fact, we're fortunate enough to have one of those Nobel Prize winners, Dr. Bill Kaelin, join us today to answer some questions about HIF-2. Now, given that HIF-2 is a transcription factor, there wasn't sort of an immediacy that this would immediately lead to therapeutics because transcription factors are notoriously difficult to drug. However, there was some very elegant work done by structural biologists at the University of Texas Southwestern that actually revealed a potential small molecule binding pocket in HIF-2. Scientists at Peloton, a company called Peloton, most of you are probably aware of them, came up first with a first-generation molecule where they generated clinical proof of concept. They then came up with what was to become belzutifan, which was good but not great. It's got a number of clear limitations that it's had all along. That molecule was a good drug. Merck acquired Peloton pre-phase III for about $1 billion upfront and another $1 billion in contingent payments. With a recognition of the limitations of belzutifan, we began work. We took casdatifan into the clinic in 2023. We stand here now, I think, poised with a very robust phase III plan and beyond. This highlights some aspects of our program. There's going to be a lot more depth here, so I'm just going to make a few points here. If you go to that second bullet, it kind of hits on some of the key points. When you think about belzutifan, we've got about twice the PFS, 50% higher objective response rate, and that's confirmed response rate. It's all driven by probably the most important number. That's the 50% lower rate of primary progression. As Jen's going to talk about, we have a clearly better development plan. Jen's going to spend some time. This will really be the first time that we're doing this. Since the program is so tangible now, I think she's going to do a good job of linking our development strategy together with the commercial strategy to tie all of the story together holistically. This is something that we believe will be growing to a $10 billion + market because one of the things that I think you'll be most impressed by is the duration of therapy. When you take the patient population and you look at how long these patients are going to be benefiting from casdatifan, I think it's going to get you to some pretty big numbers. I'd like to spend a bit of time on this slide because to me, this is one of the most important slides in the deck. It's one of the most important sets of data because it really gets at the underlying advantages of casdatifan. The left-hand panel, we basically had those data even from our healthy volunteer studies. This relates to our PK and PD profile. What's known about belzutifan is it has absorption-limited pharmacokinetics. They would love to get more drug in than they get with their 120 mg dose. However, if they go higher, they don't get meaningfully higher exposures. We get about the same level of suppression of the biomarker. The gold standard biomarker here, I think you're all familiar with, is the suppression of erythropoietin production. The casdatifan at 20 mg gets what Merck gets at their 120 mg dose, except our clinical dose is 100 mg. We're at five-fold the PD equivalent of the Merck drug. If you go to the panel on your right, what you have are data that Merck published at the end of last year, along with Arcus data. That blue curve, which is a time course for suppression of erythropoietin, the blue curve are Merck data. What you can see is not only do they not get quite as deep a response, deepest suppression that casdatifan achieves, but they lose that effect on the biomarker roughly 9 - 13 weeks. What you can see is we maintain our effect out past the year. What's even more exciting and probably more important, and Juan's going to get into some real detail here, is now we've been able to correlate that ability to suppress erythropoietin production with clinical outcome. That's whether you look at objective response rate or whether you look at PFS. That's extraordinarily important because when you think of these types of data, as you look at them, they're highly quantitative and highly reproducible. Essentially, those data are your smoking gun that correlates with the very different clinical outcomes that we're seeing. You can feel confident that those clinical data are meaningful. You'll especially get that when Juan shares those data. Our communication strategy on this program has been purposeful. It's been intentional. We recognize the enthusiasm for the mechanism. We recognize the advantages that we had with casdatifan. We started presenting early. You see, we've had multiple presentations, including most recently an ASCO presentation on our combination with cabo. The thing I want to emphasize, though, is that we promised at the beginning that this mechanism would lead to improvement over time. Oftentimes, companies, people present data sets, and the data degrade. We promised that the data would get better. I think today we'll have the receipts on that. Let me go to this slide. Let's focus on the today column and the 100 mg once-a-day tablet that's our go-forward formulation. What you can see is, just as we saw at the beginning, that rate of primary progression has been consistent. The confirmed ORR, as we sit here today, is 35%. What I can tell you is we've had two additional responses. In fact, to emphasize, I make this point primarily to emphasize that the data continue to get better. Since the data cutoff, there's been another response. These data, even out at this time point, continue to get better. Most importantly, though, we now can move on from ORR to median PFS. Durability is the approvable endpoint. This is what we really care about. We're at a stage today where you'll see data on median PFS, which I'll remind you, even though it says not reached, for a combined data set, it's fairly stable. It's over 12 months. With the 100 mg tablet, we have a median time on treatment of over 12 months. We are quite confident that the median PFS is going to be over 12 months for that tablet. This will be my last slide for now. I just want to emphasize, we do feel that we're poised to have the HIF-2α Inhibitor of choice. Not only does the molecule have across every endpoint better properties, but we think we have a better development strategy. Even on the pill burden front, patient convenience, we've got a one tablet, great formulation, once-a-day drug. We feel we're really well positioned. With that, I'm going to turn things over to Richard, and he's going to walk you through the data in quite some detail. Let me take the clicker. Sure. Great. Am I gone? Yep. Great. All right. Thanks, Terry. Thank you all. I have the pleasure this morning of sharing some great data with you and updating you from what we've seen before. Let me get to my slides. I think this data really supports casdatifan as a best-in-class HIF-2α Inhibitor. At ASCO GU in February, we previously shared early data from three of the monotherapy cohorts from our ARC-20 study. That was the 50 mg b.i.d., 50 mg q.d., and 100 mg q.d. cohorts. Today, I'll update you on those three cohorts where we now have seven to eight months additional follow-up. We'll also share the data from the 150 mg cohort. As Terry said, importantly, we've now combined those four cohorts to now have a data set of 120, well, specifically 121 patients that we can look at. We can interpret that much more stable in numbers because we are no longer trying to interpret relatively smaller cohorts of 30 patients each. We'll focus today on the 100 mg q.d. cohort because that's the dose going forward in phase III, or the pool data set, which is the larger data set of the four cohorts with 120 patients. You'll see we have a substantially higher tumor response rate compared to belzutifan. We also have a much higher or longer progression-free survival. We have a lower rate of primary progressive disease as well. I think all this data, every FT marker we look at is favorable when you look at casdatifan compared to the only other drug in the class, which is belzutifan. I think we have a lot of tailwinds going into our phase III study, PEAK-1 as well. A quick reminder here of the study design in ARC-20. We've enrolled over 240 patients now in the study overall. It had a dose escalation component and then eight separate cohorts, about 30 patients each for expansion in different settings. We're focused today on this four in the middle. These are late-line patients. That is all the patients previously have had a checkpoint inhibitor and a TKI. Late-line patients, about 30 patients each cohort, again, and this is monotherapy casdatifan data. Since we're talking about potential best-in-class, let's face the only other real molecule in the class is belzutifan. Many times when I compare our results, I'll set it against the belzutifan benchmark, usually using LITESPARK-5 because it's the most contemporary study of theirs. I want to be very clear, we're not cherry-picking. We aren't just picking LITESPARK-5 because of the results and that they had better results. In fact, LITESPARK-5 is very consistent with all the other trials of belzutifan. When we look at the data sets from their earlier studies, again, looking, trying to compare apples and apples with the patients that had prior checkpoint inhibitor and prior TKI, which is what we pulled out here. For example, if you look at the second column from the right, the tumor response, it's very consistent across these data, 19% - 22% for tumor response rate. The median progression-free survival is generally 5.5 months across two of the studies. LITESPARK-13 had the longest progression-free survival of 7.3 months. Note that that study only enrolled patients with one or two prior lines, and about 30% of those patients did not have a prior TKI. Regardless, even their progression-free survival is generally 5.5 - 7.3 months. Looking at the patients enrolled in ARC-20, they're very consistent with what you'd expect in a later line population in clear cell renal cell carcinoma. The distributions are consistent across the four cohorts that we enrolled. You can look at the pooled and compare that to the belzutifan on the far right. All very consistent data, typical of what we expect to see. Maybe I'll call out, focus on the IMDC, for example, to show that that also is very consistent with the patient populations we'd expect in a later line setting in this disease. There might be just two differences when we look at our ARC-20 population compared to belzutifan. One is highlighted on the bottom here, where we included about 25% - 30% of the patients having four or more prior lines of therapy. Later patient population with regards to their treatment journey. Those patients would have all been excluded from the belzutifan trials. The second is given the timing of the enrollment from our studies comparatively, all of our patients or almost all of the patients have had either cabo or lenva. The second-generation TKIs, in fact, about 85% of our patients had either cabo or lenva in prior lines. That's probably different than the belzutifan studies, where a large number of patients had the first-line TKIs like sunitinib. All right, enough of the setup and background. We'll get to the good stuff, the efficacy shown here on this slide. There are a lot of numbers, so I'll go a little bit slower here to walk you through the key elements. You can see we do have the four cohorts presented and then the all pooled. Again, I'll focus on the 100 mg daily cohort in the first gold box and the all pooled in the second gold box. If you look at time to response in the 100 mg cohort, the median time to response is 2.6 months with a confirmed overall response rate of 35%. That compares to belzutifan, whose time to response is 3.8 months, and they had a 22% confirmed response rate. Importantly, also in that first column, we can look at the progressive disease rate in the 100 mg daily cohort, and that was 16%. That compares to belzutifan's 34%. This is more than half of a reduction in the rate of primary progressive disease. If we look at the 120 patients now as a combined cohort towards the right, again, the median time to response is much more rapid at 2.8 months and a 31% confirmed tumor response rate. The primary progressive rate is 19%. That compares to the 22% for belzutifan for a tumor response and 34% primary progression. I think these data are very strong, clearly pointing to faster activity. More patients are able to stay on drug and avoid primary progression and, of course, higher confirmed response rate. I like to look at the data side by side, as I do here with both a spider plot and a waterfall plot. It really tells the story of each of the patients. On a spider plot on the left, each line represents a patient and their tumor volume. On the right side, the waterfall plot, each bar also represents a patient, and that's their best overall response or the maximum reduction in their tumor volume. Let's start on the left, looking at the spider plot. You can see the patients with stable disease are represented in gold, and the patients in blue are the partial responders. The green triangle shows all the patients who remain on therapy, which you can see almost all patients continue on therapy. What I also like to see when I look at a spider plot is what's the trend or the slope in these lines. Are the lines truly flat? Are they drifting upwards or drifting down, showing tumor volume? I think you can look at this plot here for the 100 mg q.d. cohort. If anything, the lines continue to trend down even at 12 months of duration. They continue to trend down where the tumor volume continues to shrink over time. On the right side in the waterfall plot, you can see almost all patients do have reduction in tumor volume, whether that's stable disease or the responders. You can see we've circled a number of patients in the middle there that are currently stable disease as far as their maximum response, but they're very close to that -30% threshold where they would then be determined as partial responders. As we said, and you can look at the spider plot where these lines are continuing to go down over time, there's a very good chance that those patients that are stable disease and close to that line can cross the line and add to the responder rate. This slide is really to emphasize or highlight that duration or the improvement of tumor volume reduction over time. The figure on the left is the waterfall plot we shared at ASCO GU for the 100 mg cohort with about five months of follow-up. On the right side is the current data with about 12 months of median follow-up. We've added that gold dashed line at -50% just to make it easier to compare because now I'm talking about depth of response, how deep or how much of the tumor reduction. That just is another extra anchor or reference point. I think if you compare the left to the right, you can see there are indeed deepening responses, both for patients that were stable disease, and they're still continuing to become deeper responses in those patients. Those who started out as rapid responders, meaning they still had partial responses even within the first five months, those tumors also continue to shrink and have deepening responses over time. Now, I'm going to flip back to another look at the spider plots. Here on the left is the 100 mg cohort I just showed. You can see here I've circled the stable disease patients because, again, these are long-lasting stable disease, right? We're at 12 months, still very flat or possibly still decreasing in tumor volume. That's the durability of the effect. These stable disease patients plus the responders are what contribute to the patients with progression-free survival, which is the endpoint for the phase III study. We look at both stable disease and responders, and the duration or longstanding effect is what's going to lead to the long progression-free survival for all these patients. On the right side, I show the 50 mg b.i.d. group. Of note, that's obviously 50 b.i.d. It is still 100 mg daily, just broken into two. I show that data because it's the first cohort we enrolled, and it has the longest follow-up. The same story holds. These patients have longstanding stable disease and longstanding benefit, whether it's stable disease or responders. You can see now we have a large fraction of patients that are well beyond 18 months of clinical benefit. In fact, we're now approaching two years for this cohort of sustained clinical benefit. One more way of looking at the same data: this is the 100 mg cohort now in a swimmer lane plot, which tells you a few different things because each of those tick marks or these colors are different effects of the measuring of the tumor volume. Importantly, you can see with the green arrows, we still have more than half the patients still on treatment, so still progression-free. All the patients who've had tumor response are confirmed responses in that they've had multiple scans showing significant reduction in their tumor volume. Now for a new look at data, we get progression-free survival. This is the Kaplan-Meier curve for the 100 mg q.d. cohort. First observations: this is a very flat curve, right? Going out a long period of time, we're now out at 12 months of median follow-up. We have not hit a progression-free survival median. We're very confident to say the PFS for this group, when we get to a median, will be at least 12 months because that's where we are in time today. Since we can't determine the median PFS yet, we can look at the 12-month landmark. We have 60% of our patients at 12 months that are still progression-free. That compares to LITESPARK-5 if you look at the landmark of progression-free survival at 12 months in that study, and it was only 34%. If we look at the pooled cohort of 121 patients, this is the Kaplan-Meier curve there. Again, you can see it's also still a long-lasting flat progression-free survival curve. We do have a median of 12.2 months, and that's with a median follow-up of 15.2 months. I think it's important here to also look at these landmarks for the durability and what happens even beyond the median PFS. You can see at 18 months, we still have 43% of the patients that are progression-free. That will compare to the belzutifan LITESPARK study where their 18-month progression-free rate was 20%. Again, we have more than twice as many the percentage of patients progression-free at 18 months. We looked at what might be driving these longer responses, both higher tumor ORR rates and also PFS. We look most likely, it could be the favorable risk or the IMDC risk, looking at favorable versus intermediate or poor. It's not. We have very much the same performance regardless of their IMDC risk score. That's not the driver. Basically, all the patients are getting this type of enhanced benefit with regards to tumor response and progression-free survival. If we look at the ORR rate, for example, in the all pooled group, in the favorable risk, that was 32%. In the IMDC intermediate or poor group, the ORR rate is still 31%. Very consistent still regardless of that risk score. Looking at PFS for the favorable risk patients, we can't yet determine the PFS, but in the intermediate or poor, that group has a 9.7-month median progression-free survival. That compares to the LITESPARK-5 study, looking at the intermediate or poor risk patients from that study, which was 5.3 months. What I've shown so far now is we have a more rapid time to response, a higher overall response rate, a lower rate of primary progressive disease, and a longer PFS compared to what we've seen with belzutifan. Happy to be able to say that it's not coming at the expense of increased safety risks. We see a safety profile very consistent with what's known from belzutifan across their studies. Here, a lot of numbers are on the slide, so I'll focus on the 100 mg q.d. cohort since that's what's going forward in phase III. If we look, for example, at the serious treatment emergent adverse events or SAEs towards the bottom there, 31% of patients had SAEs. As far as SAEs related to casdatifan, it was 6%. That, again, compares to what we see in belzutifan with their 43% all-cause or 13% treatment-related. A very comparable safety profile with what we know based on the class or based on belzutifan results. Here I'll highlight the one other slide about the safety of this molecule. The two known events of interest for the HIF-2α as a class are anemia and hypoxia. Anemia is easy to identify, of course, but also easy to manage these days with EPO, with green peripheral EPO or recombinant EPO, transfusions when needed. Patients can also have a dose hold or a dose reduction as needed. If we look at the anemia, for example, that's related to casdatifan in that 100 mg cohort, again, it's about 28% of those patients had high grade, but importantly, no patients discontinued treatment due to anemia. That bodes well in what I said with the anemia is easy to manage for these patients, and they can stay on treatment for long periods of time. Hypoxia is the other known on-target event of interest. The data here for hypoxia is very consistent with that from belzutifan. You can see the casdatifan-related hypoxia is very low, ranging from 3% - 10%. In fact, only 3 out of 121 patients discontinued casdatifan due to hypoxia. A very low rate of discontinuation is associated with this event. I'll summarize here. Let me just verbalize for you the summary so you don't have to read all the words on this slide. I think we've been able to clearly show both across the cohorts individually, which are consistent, the 100 mg q.d. cohort that's going forward dose, and the pooled data set now with 121 patients. The data are consistent with a higher rate of confirmed tumor responses, a longer PFS. In fact, more than twice the PFS has been seen with belzutifan. These are long, durable responses. As Dr. Terry mentioned, importantly, the responses are coming faster, meaning the time to response is earlier. Only about half the patients have primary progressive disease compared to belzutifan. All of that efficacy difference is very consistent, but at the same safety profile as we see with belzutifan. There's no increased risks or tolerability that we're seeing with this molecule by comparison. With that, I also have the pleasure now of introducing Dr. Raina McKay, who's been on a steering committee for our PEAK-1 and an advisor to Arcus for a long period of time. She's a Professor of Medicine and Urology at UC San Diego. She's an author of many publications and an expert in treating patients with clear cell renal cell carcinoma, in addition to a winner of many awards for her treatments here. I'll hand it off to Dr. McKay, who can talk about treating patients with renal cell. She has a lot of experience both with belzutifan and casdatifan to share with you. Thank you. Thank you so much for that kind introduction, Richard. It's just really been a pleasure seeing the development of casdatifan. We'll go to the next slide. Raina McKay, I'm a GU medical oncologist at UC S.D. I treat largely kidney cancer and prostate cancer with a very small smattering of bladder cancer patients in my practice, largely about 50/50 split between prostate and kidney. The typical patient that I see in the clinic that has renal cell carcinoma actually is generally an older male individual that has been found to have a large renal mass, either incidentally because they came in needing to get imaging for something or had some hematuria and then got some imaging. At the same time, inadvertently found to have metastases, whether that be spread to lungs or other parts of the body, and have tremendous experience with treating patients with belzutifan, both on trial and in clinical practice, and casdatifan on trial as well. I'll go to the next slide. It's important to reflect on the RCC patient journey as it is today based off of the approved therapies that are available for patients. For those individuals that present with metastatic disease up front, the two backbone strategies are either IOIO or IOTKI for these individuals. Anti-PD-1 therapy is the backbone of all frontline treatments. There are a smattering of patients who are receiving IO therapy in the adjuvant setting and then going on to progress at a later time point, but that's a very small proportion of patients. When we think about IOIO versus IOTKI, there's pros and cons of each strategy. With IOIO, while the response rate is about 40%, primary PD rate is about 20% with that regimen. It's been the only regimen that has shown long-term durability, and likely about one in five patients will experience that long-term durability with a pure IO strategy. With the IOTKI strategies, the response rates are quite high, greater than 50% across the board for the three life-prolonging combinations. The primary PD rate is low on the order of around 10% or lower with a respectable PFS, but there's a question of long-term durability. When I have a patient before me in the clinic, I'm constantly asking myself, do I have to play the short game or do I have the luxury of playing the long game? Most patients want to play the long game if they get that chance. Usually, unless somebody is having rapidly progressive disease, high burden of disease, I'm generally reaching for an IOIO strategy as opposed to an IOTKI strategy. In the subsequent line setting, the standard of care continues to evolve, largely including sequential TKI therapy. What they have seen in the frontline space is switched around to the second-line space. For example, if somebody received lenvatinib in the frontline, they may receive cabozantinib in the second-line setting. Later on for third line, this is where we also see belzutifan as a novel mechanism of action, alternate treatment option. I think in clinical practice, this strategy has kind of largely fallen into the later line setting, given its alternate mechanism of action. However, I think one of the Achilles heels of this regimen too is that primary PD rate, about a third of patients are going to have no response at all at a time when you really can't afford to have them have no response at all. There is a lot of opportunity to improve upon that for patients throughout their treatment journey. Next slide. Here I want to highlight just a level setting where belzutifan stands. Belzutifan has established itself as a standard of care in the third line for patients with clear cell RCC, despite the fact that there are limitations. You've seen the data that have been presented, the response rates on the order of about 22%, the primary PD rate, which I referenced at around 34%, a primary PD rate that's even worse than everolimus. When we look at the PFS, it's sitting right around 55.6%. The median is equivalent to that of everolimus, but you can see that the curves cross and there's a little bit of a tail that emerges with belzutifan, which is why the data ended up demonstrating that there was statistical significance with that agent. I think there's a lot of opportunity, and this is really why I'm super excited about casdatifan because I think we can definitely build on what has been established with belzutifan. Let's go to the next slide. I know that Richard had demonstrated these data, but I want us to take a look at this waterfall plot. Every single one of these patients, as Richard, or every single one of these columns, as Richard said, is an actual patient. You can see that the bulk of these patients have had some regression of their tumor. Even those patients that didn't actually achieve an objective response, you can still see that they're having regression. They just haven't hit that 30% threshold, and their primary PD rate is quite limited. This is really fantastic, especially as we think about the ARC-20 100 mg cohort. This is a refractory patient population that has seen multiple lines of prior therapy. When we think about the PEAK-1 cohort, the ARC-20 data are even later than what the PEAK-1 cohort would be. Also, to draw your attention to the PFS, these data continue to evolve as we continue to follow patients over time. Now we have follow-up of over a year, and what's striking is that the median has not yet been hit with one year of follow-up. If you were to draw a line at this 12 months mark and draw it up to this curve, we haven't even hit the 50%, that's why it's not valuable. This is really quite striking. PFS, obviously you have to interpret with caution in the context of a phase I study, but we haven't seen PFS this long in this refractory patient population. Over a year PFS in a later line setting is really quite remarkable in this patient population. We're super excited about that, and that speaks to the low primary PD rate, the sustainable responses, and even in stable diseases. Patients are deriving benefit when their disease is stable. All right, let's take a look at the next slide. Just to level set, with the 12-month and likely greater PFS with casdatifan, this is just level setting where ARC-20 puts us against all the other later line studies, both the phase III studies and the phase II of LENVA-EVE. Also looking at CONTACT-3 and CANTATA, looking at the control arm of cabozantinib in the context of those studies, you can see that across the board, the PFS in later line is ranging on the order from five to upwards to seven months. The LENVA-EVE data here, this 14.6 month, this is a pure second-line population, and this does not reflect modern-day practice. This study was done in 2013 and is a small phase II with about 150 patients. If we look at the ARC-20, this is a much heavier pretreated patient population. Super exciting to see that in the context of these data. Let's go to the next slide. I think what's also really exciting about casdatifan, as we think about other TKIs and we think about checkpoint inhibitors, is the lack of overlapping toxicities with the TKIs and actually with IO treatment. The three key AEs, as you've heard about them, anemia, which is actually now pretty well managed, I think with belzutifan being the first kid on the block, clinicians have learned how to manage anemia, checking for baseline iron studies, B12, folate deficiency, those sorts of things, treating, watching the hemoglobin closely, utilization of ESAs to prevent hemoglobin decline. I think that learning that has happened with belzutifan is only going to be expanded with casdatifan, hypoxia and fatigue. Patients don't experience these chronic TKI toxicities like the decreased appetite, diarrhea, nausea, rash, hand-foot syndrome that are just very, can be very gnawing on any given individual. When we think about pairing with a PD-1 or CTLA-4 inhibitor, we think about the overlapping toxicities with regards to elevations of LFTs, colitis/TKI diarrhea. I think that it is an excellent agent and combination partner with not only TKIs, but also checkpoint inhibitors. Next slide. Super excited about PEAK-1 because it is evaluating casdatifan on top of the most widely utilized TKI, really globally, which is cabozantinib. Cabozantinib is the gold standard in IO experience, clear cell RCC. It's very easy to titrate, 60 mg, 40 mg, 20 mg. There's significant experience with managing the cabozantinib toxicities. There have been multiple registrational studies of its efficacy across the board and it has tremendous utilization within the U.S. and outside the U.S. as well. Despite it being an excellent TKI, I think there is still opportunity for improvement. The longer you can keep somebody's disease at bay, preventing them from progressing, the better that you're going to do for them in the long term. These are the level set data from CONTACT-3, METEOR, and CANTATA. You can see PFS ranging on the order of 7 - 10 months across these different cohorts with cabozantinib. I think there's tremendous opportunity to build upon that. What we've seen already with casdatifan alone in the later line setting, hopefully we can achieve that goal. Next slide. As you've seen, this is the schema for the PEAK-1 study that's really targeting IO-experienced, clear cell RCC patients. It does include patients who have progressed after adjuvant therapy. Patients have to have measurable disease, not having received prior cabozantinib or any HIF-2α Inhibitor. It's enrolling clear cell RCC patients. Patients will be randomized 2 to 1 to the combination of casdatifan plus cabozantinib at the 100 mg dose versus placebo plus casdatifan plus cabozantinib, with a primary endpoint of PFS. This trial is actively enrolling patients, and we're super excited about the study. I think the legwork that's been done in presenting the ARC-20 data and building up a drumbeat around this agent and this trial is really going to promote accrual. Quite honestly, when we think of the national and international scale, there's a very limited number of studies that are accruing in this context and on the international level currently in RCC. Next slide. Just to kind of also highlight that our anticipation is that PEAK-1 is going to enroll pretty rapidly. You can see the months to enroll across the landmark second-line and later-line studies. You can see the studies that were impacted by COVID, particularly CONTACT-3 and LITESPARK-005. In general, just over a year to accrue in this context, a little bit longer in the first-line studies. Those, in general, also tend to be a little bit larger trials if we think about their enrollment. Next slide. We chatted a little bit about the frontline treatment strategy and sort of the decision tree between IOIO versus IOTKI and how IOIO is really associated with that long-term durability. However, 1 in 5 patients have primary disease progression and can't realize that long-term durability that's associated with IO. There's tremendous opportunity to build in the frontline setting and also think about a TKI-sparing strategy in the frontline setting. I've highlighted the toxicities that are associated with TKI. Patients can be on therapy for quite some time in the frontline, and that TKI tox can also negatively impact their quality of life. There's really an opportunity with casdatifan and volrustomig, which is an anti-PD-1, anti-CTLA-4 inhibitor in the frontline setting, to build upon the backbone that's already been established with NEVO-IBBY. You know, I think casdatifan has the potential to reduce that high rate of PD, improve PFS with minimal added toxicity, and hopefully improve long-term outcomes for patients. I am super excited about the eVOLVE RCC study. Let's go to the next slide. This is the schema for eVOLVE RCC. It is a seamless phase I-B/III designed to evaluate casdatifan plus volrustomig in the frontline setting for patients with advanced clear cell RCC having received no prior therapy. The phase I-B will be looking at two different doses of volrustomig plus casdatifan with a primary endpoint of safety. We will move seamlessly into the phase III, where there will be a one-to-one randomization to volrustomig plus casdatifan, volrustomig monotherapy. We will look at the contribution of components versus the standard of care, which is nivo-ipi, with a primary endpoint of PFS and OS. Currently, phase I-B is actively accruing patients and I am super excited about this study as well. Next slide. casdatifan is also being evaluated in other early line settings, being looked at in the neoadjuvant setting through an IIT called NeoShift. I think there is tremendous excitement about perioperative treatment for RCC. We now have the one and only life-prolonging adjuvant therapy with pembrolizumab, but we have certainly seen data evolving in the context of melanoma that timing does matter. At least in the melanoma world, neoadjuvant therapy seemed to be associated with improved outcomes compared to adjuvant therapy. I think there is tremendous opportunity there. Also, there are various cohorts within ARC-20 that are looking at frontline combinations of casdatifan with IO, also looking at casdatifan monotherapy in the favorable risk population. In the post-IO TKI naive, casdatifan is being looked at in a monotherapy there to delay TKI use. I think we are going to learn a lot in the context of other studies that are being conducted in other cohorts within ARC-20 around placement of casdatifan across these different settings. Next slide. Okay. All right. Thank you, Dr. McKay. We'll pause here for a Q&A session. If you have a question, please raise your hand and I'll get you a mic. Please state your name and institution. If you have a question for Dr. McKay, if we can get her video up, that would be great. Please do so. Please ask your question now because she will not be able to join us later. We can start with you, Gal. Hi, yes. For Dr. McKay, I was wondering, you know, given everything you know about casdatifan today and given that you use belzutifan, I'm wondering, you know, if you had casdatifan available, what would be your relative usage of one versus the other today in the third line monotherapy? Honestly, we always want to go with the best-in-class agent. We want to go with the agent that's demonstrated the greatest efficacy, manageable toxicity profile. We certainly see that. We've seen that evolution in the context of the TKIs. As next-generation better TKIs have entered into practice, there's been adoption of those better next-generation agents. I think this is the evolution of developing a best-in-class agent. Next question from Lee. It's over there. Lee, you want to talk from Cantor? Congrats on the data. I guess just looking at 100 mg versus 50 mg BID, it looks like the data are perhaps better at the 100 mg dose. When we look at the EPO suppression, you know, PD biomarker looks like these two are pretty similar. Do you have any thoughts on what might explain the better outcome for the 100 mg dose and how much of that is driven by perhaps patient selection versus the dosing frequency, the Cmax here? I'm happy to take that, Lee. I think at this point, we would look at the 50 mg BID. As you know, it was also a different formulation. The reason we did that was almost more a proof of concept. There was five. This is when we had the 10 mg capsule, so we didn't want to give people 10 capsules at a time. With that said, drug on board is very similar. I think the way to look at it is just that it represents a 30-patient snapshot in time. We'll continue to generate more data with the 100 mg tablet. When you really want to focus again, like I tried to emphasize at the beginning, I think we will pay very close attention to the 100 mg tablet, which will get more and more and more data. At this point, probably truth, if you were to sit here today, is more represented by the 120 patients than any of the individual 30 patients. They're all a similar place on the dose response curve. Peter Lawson from Barclays. I guess the first question really for Terry, kind of why did this data get better over time? The different sequential cuts you had for casdatifan, it kind of improved. What gives you the confidence that the phase III is going to kind of hold up as what we've seen so far? Your question exactly on the, like we've seen. You showed a data set of over time of casdatifan and kind of improving. The reason we had the confidence in the beginning, it seems to be playing out, was both based upon what we know about the biology, what we know about the safety profile, and what we also learned from belzutifan. If you start just with the belzutifan data, they actually had observed about 60% of their responses came in the first six months, then another 20% in the next six months, and another 20% in the next six months thereafter. There's some element of that that no doubt involves, in our case, we're able to hit the tumor harder, faster, so we get more patients into sort of that conveyor belt of they've gained some benefit. What's become very clear, and that's where you see that, what we show with the stable disease patients, that they go on long term. It looks very much like IO. A big part of that is, in fact, that this mechanism, unlike so many in oncology, is very well tolerated. As the patients are, you know, fighting cancer, as the mechanism's kicking in, they're also not getting sicker. Because of the drug with time, to some extent, that informs the continued benefit, the continuing strengthening of the patient. We felt confident, based upon the casdatifan data, that that would be the case. We recognize that we were benefiting more patients. When Juan shows you the data with the EPO suppression, we really feel that we're benefiting essentially all patients where they have some HIF-2 component to driving their cancer, and that is roughly somewhere in the 80%- 90%. That's why you see that incredible disease control rate. Between the safety and the efficacy in more patients, we expect that duration of therapy to just continue, to get better. I think the confidence for phase III then comes from what we've already generated, even in the early stages in our combination with cabozantinib. The important thing there being that the AEs essentially didn't overlap. It looked like you were getting cabozantinib, and it looked like you were getting casdatifan, but nothing synergistic in toxicity. We, in fact, had a very early good response rate. We'll see, by ASCO next year, hopefully, we'll be at a stage where we can start to talk about durability there. Everything points to the same phenomenon: safe combination, and this mechanism to kick in. I'll make one last comment because it also applies to the, as Raina was talking about, our study with AstraZeneca. One of the reasons we got married was what she mentioned. If you look at ipilimumab/nivolumab, it's a great regimen in terms, and it's the most frequently used in the frontline. They still see 20%- 25% primary progression. You bring in another mechanism, orthogonal biology, that, by the way, is enrolling already ahead of schedule. We think we can come in with a safe mechanism that not only brings the efficacy, but enables more patients to get the full benefit because we think we can cut down on the rate of primary progression. Daina Graybosch with Leerink Partners. For Dr. McKay, and then secondarily for the company too. You mentioned there's a lot of different ways that we're exploring placement of HIF-2α for these RCC patients. I wonder if you have a hypothesis on where the ultimate best placement will be, and also what do we know about retreatment with HIF-2α, so continuing it across lines and switching out the combination partner? No, very good question. I think when we think about where we place HIF-2α inhibition, and we think about clear cell RCC, and the fact that it's really the driving pathogenesis for clear cell RCC is a VHL mutation that ends up resulting in HIF-2α accumulation. When patients become resistant to VEGF-based strategies and develop alternate resistance pathways outside of that driver alteration, I actually feel that this drug is best positioned earlier on, likely in a VEGF-naive cohort or in a frontline cohort, or even localized for people that have never seen prior therapy. Just given the mechanism of action and the fact that you don't want to be having to contend with mechanisms of resistance that are alternate to what your target is. With the question regarding retreatment, it's all going to be about timing and exposure and in what context that patient may be developing progression and needing retreatment. If you're thinking about localized disease and they had a response, had a long durable RPFS or RFS, recurrence-free survival, I would say, for localized disease interval or EFS interval, and then at some time point X, they ended up recurring, that maybe is beyond a year, then yes, I think rechallenge is something that can be considered and discussed. If that individual is progressing during or shortly after finishing a course of therapy, you really have to think about rechallenging. Daina, a couple thoughts under the umbrella of what Raina said. I think one thing we probably haven't emphasized as much, the data speak for themselves, but we should probably point out in our mind and based on the data, we actually think for the first time now that we have some durability that casdatifan is looking better than TKI monotherapy. One very informative cohort that I think we shared was that group of patients that now I think is fully enrolled, if not it needs another patient or so, where we're treating patients with casdatifan monotherapy who basically have progressed on IO but haven't seen a TKI. I think we do believe in a real way in our development strategies geared this way to have a paradigm shift in this field. It comes from, you know, Raina was one of the biggest sort of in our ear on this about trying to drive the TKIs down in therapy and bring HIF-2 up earlier from purely a quality of life. We think the biology, it's not just a nice to have. I think that the biology and the clinical push is taking us in that direction. I'm going to make one comment on the retreatment because I think the most interesting, we get questions, we would normally say, you don't treat a patient with mechanism A and then tomorrow treat them with mechanism A when they progress. What would be interesting, in particular when you see Juan's data, I think this speaks to this. We believe that the delta in primary progression comes from hitting the target harder, faster. What would be interesting is in that late line, patients that primary progress on belzutifan, at some point I think we need to take a look at taking those patients who probably haven't developed any resistance to HIF-2, but just needed to have it harder. Take that group of, let's say, what's 35% of their patients, we would expect that about half of those patients should be susceptible to HIF-2 intervention, and that would be a very interesting patient population to explore with casdatifan. Hey, Claudia, guys, Salim Syed from Mizuho. Just one quick clarification and then also just one on the revenue or the market potential that you put up. On the clarification, maybe Richard, I think the waterfall plot had 28 patients. Just to confirm that's three patients without scans or without scans that progressed. That's the delta between the 28 and the 31. That's right. In that, we have the eligible population, which basically means they had a pre-scan and a post-scan. We included in the overall data set, called 30 patients, the patients that maybe had clinical progression even before a scan. We would still count them as progressors, but they didn't have a scan, so we can't show them on a waterfall. Okay, thanks. Just on the market potential, those are the same numbers that you guys had, I think in your 2Q, like the $2 billion and the $3 billion. Yeah. The patient population, we just annotated our DRG data, and so we now have the IO experienced patient population at 21,000 and then first line at 24,000. We'll get to the dollars in a bit more detail, but that is the change from the last presentation as the patient populations are a bit higher. Thanks, Jen. Are you assuming a different PFS in those numbers, or are you planning to update that as well just given...? through all that in more detail, but you know we're assuming a longer PFS and time on treatment in the first-line patient population versus second-line. Yes, in the current deck, and we'll go through some more precise numbers later. We'll have another Q&A session later this afternoon. Okay, thank you very much. Any other questions? We have time for probably one more. Yes, one right there. Hi, this is Karina for AstraZeneca. I had a question for Dr. McKay. Since belzutifan is a frontline, LITESPARK-012 trial, it's about alleviating a triple combo of pembrolizumab plus TKI, do you think a similar triple study for casdatifan could be possible with the TKI as well beyond eVOLVE? Yeah, no, very good question. I think it's definitely something worth thinking about and worth exploring. What's the beauty about eVOLVE is that you are sparing the TKI and integrating the CTLA-4 inhibition, which we believe is driving the long-term durability. O12 is building on the backbone of Lenpem, and everybody gets Lenpem, and you either get Lenpem plus a HIF-2α Inhibitor or Lenpem plus a CTLA-4 inhibitor, but you don't get the pure dual IO combo. I think that's the beauty of eVOLVE, and I think what is going to be the differentiating aspect. Certainly, there's opportunity to think about building with a TKI strategy, but then, you know, the question is about long-term durability. Any other questions? Lee Watson from Canter. Maybe just a follow-up question on the frontline, in a combo trial, just given what we have seen from COSMIC-313, obviously that combination didn't show OS benefit, and that was a TKI in a combination. Maybe Dr. McKay can talk a little bit about your confidence about adding casdatifan to IPNEVO. Yeah, there was a lot of issues with the way 313 was designed. 313 was a blinded study, and the tox that was associated with cabo combined with the IO strategy, I think actually did, in fact, in the long run, end up affecting the impact of that trial. The average daily dose for cabozantinib in the context of that study when given with Nevo IPI was around 20 mg, or it was around 40 mg in the, or not 40 mg, but the placebo control arm didn't actually have the cabo lab, obviously. Dramatically lower doses than what is the standard for cabozantinib, and then when we think about the number of patients that were actually able to receive all four doses of IPI was dramatically decreased. I think even though the study was positive for PFS and actually met the objective of dropping down primary PD, many patients required dose reductions and dose modifications that I think ended up impacting the long-term efficacy of that combo, which we do not anticipate is going to happen. This is the beauty with belzutifan. It's not going to cause hepatitis. It's not going to cause colitis. It's going to cause anemia, which we know how to manage. It's going to cause hypoxia, which we know how to manage. It's going to cause fatigue, which we know how to manage. There isn't going to be this, oh my God, I have to stop both drugs because I don't know which is causing what, and have these long treatment holds. That's not going to happen. This is what I think is going to be so great about eVOLVE, and what is also the Achilles heel for 012. We're going to have to see what ends up happening because everybody got a TKI in 012. Time for one more question. Hi, Daina Graybosch from Leerink again. I wonder if you could talk about PEAK-1 excluding prior cabozantinib exposure. If that has any risks or benefit, are we in virtue for a certain baseline prognosis by excluding that, and do we know what cabozantinib looks like in that setting? We have to exclude cabozantinib just because obviously we're including cabozantinib for everyone on PEAK-1. If they, as Dr. Raina McKay said, if they just progressed on the prior line having prior cabozantinib, then cabozantinib now would be inappropriate for them by definition. It would be unethical, right? Because the control arm is cabozantinib alone. You can't have had patients receive cabozantinib. Yeah, by nature we have to do that, but we also think that there won't be a lot of patients who've had prior cabozantinib. It's a post-IO treatment fundamentally, right? This is usually where cabozantinib is given, is the patient population. We're really going on top of where the patients would get cabozantinib as a standard of care, and they all still get cabozantinib as they would, and then we randomize on top of that two to one for casdatifan? Yeah. Last question, seriously. Okay, thank you guys. I guess two for Raina, if I may. First, there have been questions on belzutifan when it may be generically available and the relevance of the Arcus program when that happens. I guess my question would be, belzutifan never attempted a PD-1 CTLA-4 plus HIF-2 trial. To what extent does that limit any utility of that considering Arcus will have that data from the ongoing eVOLVE study? Secondly, on eVOLVE itself, would you have wanted to have a fourth arm where a PD-1 plus a TKI is in there and you could speak to the tox differences on hemorrhage, on thrombotic events, etc., which it currently doesn't have? Finally, would a PD-1 plus HIF-2 arm have made sense as well? Thank you. Okay, I'm going to try to remember those three questions. I think the first question was around the combination of PD-1 and HIF in the frontline setting. Is that sort of what I'm gathering? I want to keep in mind there's the LITESPARK-022, which is the adjuvant study of pembro with or without belzutifan. I can't speak for others, but I suspect that there's some strategy around that to spare a PD-1 HIF frontline in the context of knowing that there's an adjuvant study that is testing that combination. I hope that answered your question. Maybe you can repeat that second one. I just want to make sure I get to your exact questions. Just on eVOLVE. Yeah, it's on. Yeah, I mean, the beauty about eVOLVE is that, you know, you wouldn't want to leave out the CTLA-4 inhibition. There's a lot of meat on the bone with CTLA-4 inhibition. That's the long-term durable strategy that you've already set as your benchmark. I think you want to build upon what you've already established as opposed to just, we're a better me too. You want to build upon, like, we've set this benchmark of PD-1 TKI, we've set this benchmark of PD-1 CTLA-4, and we want to build upon those benchmarks that have been set. I think to add a fourth arm, we also have to be pragmatic, and at the end of the day, there's going to be one winner, and we need to sort of understand what that is going to look like. To address the first part of your question, Zumer, first of all, you know, belzutifan's patent life goes into, I want to say, mid-2030s, maybe a little bit later, now we're into the 2040s. I think what's really important to keep in mind here is this is a more potent drug and much harder acting and faster acting. Clinicians are going to want to use this drug in frontline, particularly given that we know that belzutifan has a high rate of primary progressive disease. This isn't like drugs that are targeting a specific mutation, and you might be fine keeping that as your second-line drug or third-line drug. To us, I think people are really going to want to use casdatifan first before belzutifan. We think that, you know, belzutifan going off patent, which is not for a while, by the way, is going to have very little impact on us. The second part of your question on them combining with anti-PD-1/CTLA-4, in their study where they're combining with PD-1, for example, they actually have a PD-1/CTLA-4 arm. They just decided to combine it with TKI, which we think was the wrong decision because of all the toxicity. In fact, AstraZeneca was first combining volrustomig with lenvatinib, but because they saw so much toxicity, that's why they decided they wanted to pair HIF-2α inhibition instead, and that's why they approached us. They have not chosen to combine their anti-PD-1/CTLA-4 with HIF-2α, but they kind of ran a different study, and I think that's to our needs. Thank you, everybody. Thank you, Dr. McKay, for joining us. We are going to transition to the new EPO suppression data that Dr. Juan Jaen will present for us. You can come up to the front. Great, thank you. We've generated the last half a year a phenomenal amount of translational data. Today, I'm only sharing the tip of the iceberg, specifically focused on the aspects of that analysis that I think provides a context for why numerically we're seeing casdatifan outperform belzutifan. To the extent that Merck hasn't seen fit to share a lot of translational data as to what's happening in their tumors, primarily we rely on this serum EPO change to provide the benchmark that is bridging to what the two drugs are doing in this patient population. I should point out in a couple of weeks we have an abstract at the triple meeting. It's a more in-depth analysis, a more in-depth version of what I'm doing, still using an older clinical data set, six months older, but still I think if you find what I'm going to share with you interesting, then you should be looking out for that. The bulk of the analysis that we have performed so far we're saving for sometime early next year for publication of the monotherapy data. If you ask the right question, I'll share some of that with you. As you know, HIF-2α is a transcription factor. It regulates the expression of hundreds of genes in a cell-specific manner. EPO just happens to be one that we're very familiar with, and it's very easy to measure in the periphery. This regulation is taking place in the healthy kidney as well as in clear cell RCC. We noticed a while back that when looking at baseline samples from the patients, the first 170 some patients enrolled in ARC-20, as you can see here, we saw that those baseline levels of serum EPO were significantly higher than what we had seen in healthy volunteers. We obviously went through and asked the obvious questions. Is that because those people are more anemic or are they receiving ESAs? The answer is no to those very logical questions. There's something reflective of the biology of clear cell RCC that's driving these patients to present with higher levels of serum EPO. The obvious question is, is some or any of that extra EPO spilling out from the tumor lesions? We started to get a glimpse of that by looking at a number of matched paired biopsies from ARC-20 patients receiving monotherapy. What I've illustrated here is data from a couple of such paired or matched biopsies, showing you on the left about a 20-fold reduction in the amount of EPO mRNA about two weeks into the beginning of treatment with casdatifan. Shown to the right are a couple of other well-understood, well-known target genes for HIF-2α, PTHRP, or the gene that controls for PTHRP and PI1 protein production. Very consistent, very quickly downward tuning down of HIF-2α transcriptional activity, beginning to suggest what you might expect, that at least a portion of that EPO that we measure in the periphery is the result of HIF-2α inhibition in the tumor. Terry already showed you this graph, just a few more comments. As you can see in the Y-axis, what we're showing here are average maximal reduction in serum EPO. Merck described that the maximal inhibition of about 63% actually represents a range of 18% - 100% reduction. It's a very heterogeneous response that they're seeing. What we're seeing with our drug is a much tighter level of inhibition, but still you're looking at averages. Our median level of reduction is at 85% reduction, but we still see a range from about 50% - 100% as the maximal change. It's not entirely surprising, like I said, that not everybody's giving you a 100% response, given that you're looking at a combination of things that are coming from the healthy kidney, and the same thing is coming out from the tumor lesion. You can also, as Terry pointed out, see a very sustained maintenance of this PD marker. If you could see the footnote, you would see that we've taken great care to censor any samples taken from patients that received an ESA within 28 days prior to the sample. That's a very easy source of confusion when you're doing this kind of analysis if all you're measuring is recombinant EPO administered to the patient to treat their anemia. This is all clean of that. This and the next slide are probably the most important parts of this section. What we've done here in this particular analysis is take the midpoint of 129 patients. This number is a little bit larger than what Richard alluded to because we've incorporated, just to have the largest number of data points, eight subjects from the dose escalation part of the study that received monotherapy. That's why the total, the denominator here is 129. If you add up all the objective responses that I'm going to be talking about in a second, you see that there are four more than what you can count if you look at the dose expansion cohorts. Again, we picked up an additional eight patients for this analysis and an additional four responses from out of those eight. You can do this analysis, and we have done it in a number of different ways, looking at quartiles, looking at best cutoff for that EPO suppression. The simplest analysis, what I'm showing you here, the median cutoff, and we've defined patients as being deeper versus less deep from a perspective of maximal serum EPO changes. You can see to the left the deeper EPO changers that in that half of the population, we have a response rate, confirmed response rate of just under 45% and a primary progression rate of just under 10%. On the other hand, if you look at the less deep half of the population, which still maintains that PD effect all the way out to a year, you see a diminished objective response rate of 20%, just about 20%, and a primary progression rate that begins to approach what we've been seeing all morning, the data from LITESPARK-5 with belzutifan. In other words, our worst half is somewhat similar to what you've seen for the totality of patients treated with the 120 mg dose of belzutifan. Our other half is obviously deriving much greater benefit. In my summary slide, I'll try to provide a summary statement about what we think the underlying biology is here. Still, our worst half is just as good as the totality of the belzutifan benefit. At the end of the day, response rate is just an intermediate assessment or to set an expectation about what we're going to see from a PFS standpoint. The same separation of those 129 subjects that received monotherapy into deeper versus less deep EPO responders, you see here that in the better half of the population, we have a median PFS just under 15 months. In the less deep population, which is clearly numerically different, less benefit than in the deeper responders, it's still just under 10 months, still better than the 5.6 months, 5.7 months that we've been talking about from LITESPARK-5. The take-home message here is not that we intend to select patients based on this marker. It's simply that the clinical benefit that we're seeing holistically, it's perfectly lining up with the underlying biology, what's happening in the tumor, what we measure in the periphery is a really good window into what's happening in the tumor. To sum it up, I want to read the first bullets, what I just said. One of the things that I haven't shared with you, actual numerical data to support, I'll just give you the conclusion for now, second bullet, is that there's a strong relationship between the amount of EPO mRNA that we find in tumor biopsies, the amount of EPO that we can measure in the periphery, and a relationship between the baseline level of EPO, the maximal extent of EPO decrease, and clinical outcomes as defined by best overall response, rate of primary progression, and now for the first time seeing a correlation with median PFS. We think that this really demonstrates the relevance of tumor HIF-2α biology and what we can measure in the periphery and what we can compare across molecules in trials with what belzutifan can do. The ability of casdatifan to hit the target harder may explain the numerically better clinical outcome profile that Richard described for you. Some of the stuff that I'm not showing you that you can look forward to, we've developed a HIF-2α immunohistochemistry assay that lines up very well with what everything I just said about tumor EPO mRNA, we've developed a transcriptional measure of how much HIF-2α activity there is in a tumor. It lines up beautifully with the degree of clinical benefit that we see associated with casdatifan treatment. We're also starting to get insights into how HIF-2α biology modulates the response of clear cell RCC patients to IO and anti-angiogenic TKIs. Like I said, a really strong foundation for the phase III studies that we're launching. Great, that's a great segue. The next segment will be a panel conversation. We're joined today by Dr. Bill Kaelin online. We can get his video up. And Jen will moderate the conversation. Juan, if you could please stay on the front as well, that would be great. I want to thank Bill for joining. Probably most of you have heard a lot about Bill over the years, Dr. Kaelin. I've been hearing about Dr. Kaelin since probably 2004. He's been around for a long time. He was one of the preeminent scientists out there. He just in the last few years won a Nobel Prize for his work on HIF and HIF-2α. We're really, really fortunate to have him here today. He's also been an amazing advisor to Arcus Biosciences, a lot of other companies in the HIF-2α field, and he's been super, super helpful to us. I'm going to ask a few questions. The first I'm going to ask, and Raina touched on this a little bit earlier, but there appears to be consensus that the majority of clear cell RCC tumors are associated with mutations in the VHL gene. What is your latest thinking on this point? Yeah, so I'm a bit of a lumper rather than a splitter. I look for commonalities. It's certainly the case that the vast majority of clear cell renal cell carcinomas have inactivated the VHL gene either because of mutations or hypermethylation. I think the actual numbers, whether it's 70% or 80% in terms of mutation frequency, depend a little bit on the technology used to detect the mutations, as well as my pathology colleagues tell me how much one is including tumors that actually have a mixed histology, meaning regions that look clear cell and regions that look like non-clear cell. Certainly, if you enrich for true clear cells, the percentages go even higher. Certainly, again, I'm a lumper rather than a splitter. When we look at transcriptional profiles, the vast majority of what we call clear cell renal cell carcinoma has a signature consistent with HIF activation. It sounds like based on that, that a significant percentage of patients with clear cell RCC should benefit from HIF-2α inhibition. That's our working assumption. Now, it turns out if you look at some renal cancer cell lines that have VHL mutations, some are HIF-2 dependent and others are not, and we're trying to understand that better. Mind you, these are often from patients who had metastatic disease, maybe late lines of therapy. We're very encouraged from the experience with belzutifan in the VHL population that most clear cell tumors initially are HIF-2 dependent. Great. What other tumor enhancing pathways may be relevant alongside HIF-2α? I'm sort of a dyed-in-the-wool cancer geneticist, so I try to let the mutations in different cancers inform what pathways and processes they really care deeply about. For example, you probably know that many clear cell renal cell carcinomas also have mutations that directly or indirectly activate the PI3K mTOR pathway, so we're thinking about that. Many clear cell renal cell carcinomas have mutations in one of two epigenetic regulators, namely PBRM1 or BAP1, but we're not smart enough yet to know how to translate those mutations into therapeutic targets. We're still learning the biology there. Great. Anything, Juan, you want to add or? I don't know. Exactly. In Arcus's first phase III study, PEAK-1, they're combining casdatifan with cabozantinib. What thoughts do you have on combining HIF-2α inhibition therapy with TKIs and specifically with cabozantinib? I think it's certainly the case that HIF-2, amongst other things, is driving the production of VEGF, but we also know that not all the VEGF in a tumor comes from the cancer cells themselves. I could certainly see benefits of trying to block VEGF that's coming from the host, if you will, rather than the cancer cells and getting an even better local inhibition of VEGF. I would also point out that we now know that VEGF not only promotes angiogenesis, but at least according to some, is also an immunosuppressant. I like the idea of trying to hit VEGF maybe a little bit harder. I think in terms of other targets such as MET, there's credible evidence that MET may play a role in clear cell renal cell carcinoma as well. Interesting. When you think about HIF-2α as a mechanism, and we've been showing some data earlier, I think it's consistent with this where it can be a little bit slower to kick in in patients versus what you expect with chemotherapy and TKIs. A lot of patients do get your responses, and then these responses are very, very durable. I'm just curious as to what you think the biological underpinning for that dynamic is. Yeah, I remember when this observation was even being made early on with casdatifan, and people sort of were up in arms about this. Why is it so slow? My response as a former clinician was, as long as the tumors are shrinking, I'm happy. Frankly, I think people's expectations were overly influenced by what we've come to expect with either classical cytotoxics or with kinase inhibitors that rapidly induce apoptosis or programmed cell death in the laboratory. I think this is a very different mechanism. Certainly, in the laboratory, HIF-2α Inhibitors don't induce rapid cell killing. We do see this much slower response where the cells stop proliferating. We imagine that part of what we might be seeing in the clinic is you've arrested the growth of the cancer cells enough that maybe things like the immune system can now start to kick in such that the equilibrium now favors regression rather than tumor growth. I actually think it's very heartening that if you watch these patients over time, more and more of them seem to hit a, you know, for what RECIST criteria responses. As you say, frequently the responses can be durable. Building on that point a little bit, you know, the other thing that we've noted is you don't see resistance like you do with the typical anti-cancer drug. You know, we see these really, really durable responses in stable disease. Why do you think you don't see resistance developing like you'd expect with other anti-cancer drugs? Clearly in late lines of therapy, the early indication where you can see de novo resistance if you look at some of the early experience with casdatifan, and we and many others are trying to figure that out. Similarly, although as you know, there have been case reports of resistance related to mutations in HIF-2α or its partner, I think in general we don't understand acquired resistance very well here either. I think we and others have looked to see whether any of the obvious candidates matter, such as mutations, and I just mentioned a moment ago genes such as PBRM1 and BAP1, but that doesn't seem to be the answer. I hate to tell you we're a bit ignorant here, but we're still learning. It's a good answer. Yeah, that we don't see resistance like you expect with other drugs. What do you expect to see in patients based on line of therapy? You know, we obviously started in late line. The plan is to move into earlier lines. Do you expect that patients will do better if they're treated with HIF-2α Inhibitors like casdatifan in earlier lines of treatment? Medical oncology 101 is that most cancer drugs work better in the front lines of therapy, where hopefully you have lower tumor burdens, hopefully you have less intratumoral heterogeneity, and in particular, hopefully you haven't been selecting for all sorts of resistance mechanisms through earlier lines of therapy. What I think is very unique here and very exciting is something I alluded to a moment ago. Even though it's not a perfect experiment, I think the experience treating 61 patients with von Hippel-Lindau disease, who had measurable kidney tumors that had never been treated before with casdatifan, strongly again supports the notion that if we can get these drugs into earlier lines of therapy, they'll be far more active. Again, I told you I'm a lumper rather than a splitter. I think in those 61 VHL patients, all of the patients had some measurable tumor shrinkage, I think save two where there was simply no change. Have any questions from the audience? Please raise your hand and I'll come back to you as well. Great. I'm now going to switch gears a little bit. Sorry, someone probably had a question. I'm just going to put one more in, which may be a good segue to questions. Juan just presented some data that was linking suppression in EPO levels to outcomes, and just would love to get your thoughts on that data. Is that what you would expect? What does that data tell you about casdatifan in particular? I used the expression medical oncology 101 a moment ago, so I'll use it again. I think medical oncology 101 is in general hitting the target harder and longer generally translates into more efficacy. Of course, you eventually can run into issues with tox, but in general, the ability to hit a target harder and longer is a very good thing in oncology. I think the data that we just saw from Juan are actually quite compelling. Now, some in the audience might be thinking, how do you know that the decrease in EPO isn't simply a reflection of a decrease in viable cell number? In other words, in that scenario, it would be a bit circular to say this predicts for response. A cynic might have said, maybe it's the consequence of the response. If you were looking closely, and of course, Juan and I have discussed this with his team at length, and they've already been doing a lot of good work here, the decrease in EPO is occurring very quickly. I think this is more consistent with a pharmacodynamic effect where you're looking at how hard you're hitting the target and not simply, of course, the EPO is going down because the tumor is responding. I think the EPO fall is probably happening too quickly for that latter explanation. Thanks, Bill. Hi. Thank you, Daina Graybosch from Leerink Partners. I think there's some evidence on HIF-2α that it might drive expression of retroviruses. I think, Dr. Bill, you did that. Yes. That might be what the immune system is recognizing. Yes. If it's HIF-2α, do you have any risk of limiting the immune response in humans? Yes, I think that is a theoretical, and I'm going to underline theoretical and put it in bold concern here, that in the simplest view, maybe downregulating the expression of endogenous retroviruses would decrease the recognition of the tumors by the immune system. The reason I put that caveat of theoretically is, first of all, HIF-2 turns on a number of genes, some of which you might argue would be pro-immunogenic. I would include the endogenous retroviruses there, but some would be anti-immunogenic. I mentioned VEGF a moment ago, but there are others. I don't even know what the net effect would be of suppressing HIF-2 in terms of the immune response with respect to HIF-2 target genes. You throw on top of it that HIF-2 probably has some effects on the tumor microenvironment and the immune cells themselves. For example, HIF-2 is expressed in tumor macrophages. I'm not smart enough to say the net effect of blocking HIF-2 here with respect to the immune system. Finally, as you probably know, I'll now do medical oncology 101 a third time, the benefits of combining two drugs that have distinct mechanisms of action are often profound because of the heterogeneity within tumors. I can imagine some tumor cells being perhaps more sensitive to HIF-2 blockade and others within the tumor being more sensitive to, for example, an immune checkpoint inhibitor. I'm aware that it's a theoretical concern, but I think the clinical experiment has to be done, and I'm not smart enough to tell you the outcome other than I just love the idea of combining two active agents that have distinct mechanisms of action. Only kicking and screaming when I decide that you can't do this because of the ERV story. What about, maybe I'll ask one more question and then I'll see if anyone else in the audience, but you know, along the lines of talking about HIF-2α as a transcription factor and all the different pathways that can be activated, like what other tumor types do you think HIF-2α inhibition could have potential in, and are there diseases even beyond cancer where HIF-2α inhibition may have activity? Yeah. First of all, genetics never lies, and you would have predicted from the patients with von Hippel-Lindau disease that a HIF-2α Inhibitor would be active in paraganglioma, and I think that's certainly going to prove to be the case. Certain neuroendocrine tumors such as so-called PNET tumors in the pancreas, as well as the blood vessel tumors called hemangioblastomas. I understand all of those are relatively uncommon diseases, but again, the genetics is not going to lie there. I think these are tumors that are HIF-2 dependent, or going to be HIF-2 dependent. After that, it gets a little more complicated because a lot of common cancers, cell lines don't express, and by common cancers, I'm meaning lung cancer, colon cancer, breast cancer. A lot of those lines don't express high levels of HIF-2. In fact, some of them don't express HIF-2 at all, and when probed genetically, they don't depend on HIF-2. That's looking for cell intrinsic HIF-2 dependence. I'm not sure there are going to be any other common cancers where there's going to be cell intrinsic HIF-2 dependence. As I sort of alluded to a moment ago, HIF-2 does play roles in the immune system, including in tumor macrophages. It also plays roles on the host, such as tumor-associated fibroblasts. I'm not smart enough yet to tell you what other common cancers this drug will be active in. We may have to do some empiricism here, frankly, because I'm not sure the laboratory is going to come to the rescue and tell you in a timely manner, this is the place to go. I think right now it's what I would have predicted based on von Hippel-Lindau disease. there any other diseases beyond cancer? I think there's a fairly strong, thank you for reminding me, I think there's pretty credible evidence that HIF-2 plays a role in pulmonary arterial hypertension, which is, of course, a terrible, terrible disease. Now, given that hypoxemia is one of the complications of a HIF-2 inhibitor, I don't know whether one would be able to thread the needle here in patients who already have lung compromise from pulmonary arterial hypertension. The preclinical studies, I think, are quite provocative that a HIF-2 inhibitor might be helpful here. Great. Thank you, Dr. Bill Kaelin, for joining us today. We really appreciate you taking the time. I don't have the sharm. Oh, yeah. I'm baffled. Nice. It's great to see you. We will now take a short break. I'd like to get us back on time. If we can, we have some lunch outside. If we can get back into this room and seated by noon, that would be lovely. Thanks, Bill. Thanks, Dr. Kaelin. Thank you. Bye-bye. Thank you. Okay. We're getting started again. I'd like Richard to come up and review the casdatifan development strategy, and then we'll have Jen present. All right, thank you. I'm going to talk about our late-stage development strategy. To start off, there'll be a few slides that overlap with what Dr. McKay showed, but I can go through it again, and there'll be time for some more questions later if needed. Excited for our PEAK-1 study. It's our first phase III study for patients who've had prior PD-1 or prior PD-L1 therapy. This is really in the sweet spot where cabozantinib is currently used, as we discussed briefly earlier. All patients will get cabozantinib, and then they'll get randomized two to one for casdatifan versus placebo. That's two key features that actually start out with being an attractive trial for patients and the physicians, which is its standard of care. They just tell the patients you're getting standard of care, everyone gets cabozantinib. The mismatched randomization, meaning two to one to add casdatifan to it, is also a feature that's desirable for the patients and the investigators who offer. Importantly, the primary endpoint here is progression-free survival. We put all of our statistical power onto that endpoint, which gives us more probability of success versus splitting it between PFS and OS in regards to the statistics involved. The PFS endpoint is a much more near-term endpoint from a pure timeline perspective than waiting for OS. Those are the kind of key features here. I think this really differs substantially from, say, the Merck strategy, where they're in current clinical trial in the same space, meaning a post-IO setting, where they're combining belzutifan with lenvatinib, but comparing to cabozantinib. There you still, they still have the TKI plus belzutifan in the investigational arm, control arm being cabozantinib. I think adds a lot of heterogeneity or noise to the experiment, and that just changes their probability of success just from that aspect. You've seen this is our ARC-20 design, but I'm going to share with you some of the data we just shared a few months ago at ASCO, just to remind you of the data that we have that's really created the tailwinds for us going into this trial. We do have an arm in our ARC-20 study that's for casdatifan plus cabozantinib in the post-IO setting. We did a data cut for safety with 42 patients enrolled in that cohort, and we shared that, like I said, just at ASCO in June of this year. At that early cut with 42 patients for safety, we did have 24 patients that were evaluable for efficacy, so I'll share that as well. By the definition of a valuable for efficacy, it means either the patients were on study for at least 12 weeks, so they had the opportunity for two scans, and hence the opportunity to have a confirmed response, because I really am focused on confirmed responses. That's just the minimum time necessary to have the ability to have two scans. However, I'll be clear, any patient that progressed and didn't get a scan or a second scan because of progression, they were included in this as well. They were not eliminated from that analysis. This is the waterfall plot for these patients, and you can see almost all patients, again, had reduction in their tumor volume. Keep in mind, this is a very early look, so median time of follow-up here is just over five months. It takes three months to get your two scans. These are basically all patients who had tumor reduction in their second or third scans, basically, on average. You can see 46% of the patients had a confirmed tumor response, even this early in the study. As before, I like the spider plots, so I have to share one of those as well. You can see, again, similar to what I showed this morning for the monotherapy, now in combination therapy, you again see the rapid reduction in tumor volume, meaning by the first scan, it's generally going downwards. As you go out over time, again, general slope is very flat or slightly downward. Even as patients continue on beyond the three, four, and five months shown here, we can see that the tumors are maintaining control, still drifting towards tumor reduction. We expect this to be a long-lasting and durable story or picture, just like we showed with the monotherapy earlier this morning. As we briefly touched on, the real power or capability outside of the monotherapy we've shown is its ability to combine with other therapies because it doesn't have overlapping toxicities. I think Terry showed that earlier, and then it was discussed by both Raina as well. Here is the data for the patients. We look to say, how many patients stay on drug? That's really the only way they can get to therapy or derive benefit is staying on the treatment. Are patients able to stay on treatment and particularly stay on both treatments, which only really happens if you don't have overlapping toxicity? Here you can see the data for those patients leading to dose reduction, not even discontinuation, but anything leading to dose reduction. You can see, as we showed this morning, really the anemia and hypoxia are the two on-target effects of casdatifan that lead to dose reduction. The others are really associated with cabozantinib. There's not much overlap. The only one with potential overlap is fatigue, still predominantly attributed to cabozantinib, more so than casdatifan. Only two patients did discontinue treatment with either product, and no patients discontinued both products. That also bodes well for a combination therapy. You can hit the tumor, hit it hard, be prolonged staying on both therapies, and potentially, if you have to come off of one, you're still on the other therapy. The other study that Dr. McKay presented, which I would like to highlight because I'm very excited for this study, is our frontline study. This is to be TKI-3. We strongly believe that the best place for casdatifan and the HIF-2α Inhibitors are early, not just because you get higher tumor responses, as even Dr. Kaelin said in general, or oncology 101, the earlier usually leads to higher responses, but just the overall safety and tolerability of the product makes it a preferable therapy of choice for a longstanding treatment. We think this combination with volrustomig, the AstraZeneca bispecific for PD-1/CTLA-4, is a great combination. It is being executed or run by AstraZeneca as the sponsor of the trial. It's a seamless phase I-B/III study. phase I-B is actively enrolling. Here, we're testing two different dose levels of volrustomig. All patients get 100 mg daily. casdatifan in both those arms. We'll do a safety evaluation very quickly, pick the dose of volrustomig to go forward, and then seamlessly continue enrolling globally in this trial into the phase III. The phase III does have three arms to be randomized, but I'll be really clear. 3A, which is volrustomig plus casdatifan, is being compared to 3C, ipi nivo, the standard of care. That's where the statistics are going. That's the primary analysis is evaluating 3A versus 3C. 3B, the volrustomig monotherapy, is there really for healthcare agency interactions where we have to evaluate composition of components as well. Excited to add to our development program to really continue exploring casdatifan's capabilities again, early and TKI-3. We're looking at, we've been enrolling three new cohorts into ARC-20 to look at casdatifan in these settings, and we'll see how that can potentially inform further development activities. First, we have monotherapy for frontline patients that have favorable risk disease. The second cohort is an all-comers frontline, so all-comers meaning intermediate and poor IMDC risk patients as well. That's casdatifan plus our PD-1 zim. That again is just going to be the checkpoint inhibitor plus cas in TKI-3. Lastly, we're also looking at the post-IO setting and looking based on the data we showed you this morning, what does cas monotherapy do post-IO? We do see these results being very comparable to what a TKI does, but again, compared to a TKI, a much more favorable safety profile, and we are seeing very long PFS, even monotherapy. Those are three new cohorts that are currently enrolling. My last slide is we will have a continuous stream of information for you next year as well. We'll start with additional analyses from the data sets we looked at today, and we're working on a manuscript. These will be available in the first half next year. Mid-year, we look to update you on the cas-cabo cohort from ARC-20. We showed you the data at ASCO just a couple of months ago, and I just went through a few highlights from that just now. We'll have, in essence, another year of follow-up. We'll present that data sometime mid-year. These three new cohorts I just spoke about for ARC-20, first line and post-IO setting, we'll hopefully share that data with you later next year as those data become available. Lastly, for the eVOLVE study, phase I-B portion is enrolling. It should enroll quickly, and we'll be able to share that data later next year as to what happened in phase I-B portion of the study and what's the go-forward dose going into phase III. With that, I'm going to hand it off to Jen. Thank you, Richard. Now I'm going to talk a bit about how we're going to translate this development strategy into what we think is a multi-billion dollar market opportunity for casdatifan. I'm going to start with the slide that a lot of you have seen from us before. What this slide shows is market share by product and by line of treatment. The left-hand side is frontline, right-hand side is second-line. I want to make two important points on this slide. The first point is when you glance at this slide, it makes it look like the RCC market is highly fragmented. In reality, there's only two classes of therapies that are approved and used today in RCC. There's IOs, that's anti-PD1 or anti-PD1 in CTLA4, and then there's TKIs. There's four different anti-PD1s or PDL1s that are approved, and then there's six or seven different TKIs. It's really that high number of TKIs that are approved that gives that appearance of the RCC market being highly fragmented. In contrast, in the HIF-2α Inhibitor space, we only expect there to be two HIF-2α Inhibitors that are approved for the foreseeable future. That's all that's in development right now. There's going to be much less fragmentation and splitting of share in the HIF-2α Inhibitor market. The second point that I want to make, if you look at our development plan and our near-term studies, PEAK-1 and eVOLVE, they're going after the two largest segments within each of these markets. If you look at the second-line RCC market, we're going on top of cabozantinib. Cabozantinib currently has about 30% share of the market. It's about 2.5 x its next closest TKI, lenvatinib-everolimus, which you can see a little bit below, which is that 13% bar. If you move over to the first-line bar, you can see again, we're going right on top of the most widely used standard of care, in this case, anti-PD1 plus CTLA4, which has over 30% share. We also believe, and I think Raina affirmed that earlier today in her discussion, that this is the fastest growing segment of this market because both clinicians and patients prefer to avoid TKIs if they can in that frontline setting. Just to spend another moment on our development strategy and how it's different than what Merck is doing, and Richard touched on some of those points in his presentation. In the post-IO setting, us and Merck are both combining with TKIs, which is the standard of care in that setting. The major difference between what they're doing with belzutifan, what we're doing with casdatifan, is our choice of TKI. They're combining with lenvatinib, which is the TKI that they own. We're combining with cabozantinib, which as I just talked you through, is the most widely used TKI in the second-line setting. I was actually just going back and looking at the prior therapies that the patients had gotten in ARC-20. That was that 121-patient data set. 80% of those patients had actually gotten prior cabozantinib. In contrast, only 25% had gotten prior lenvatinib. It just shows you how much cabozantinib use there is out there and how it is a preferred TKI. The two primary reasons why we think clinicians like cabozantinib over lenvatinib is, first of all, we do think it's a better tolerated TKI. We've heard that repeatedly from clinicians. Interestingly, one of the toxicities that you see more of with lenvatinib than cabozantinib is fatigue. That is the one overlapping toxicity that we think we'll see with TKIs and HIF-2α inhibition. We like the fact that with cabozantinib, there does seem to be less fatigue. The other thing that people like about cabozantinib versus lenvatinib is it's much easier to dose and to choose the right dosage. Lenvatinib is available in dosages from 4 mg all the way up to 22 mg. One of the things that we hear from clinicians, including we've heard this from Raina a lot, is that a lot of clinicians don't know how to dose lenvatinib and what the right starting dose to use is. In contrast, cabozantinib, most clinicians start at 60 mg, and then if you do see toxicity, you just reduce to 20 mg or 40 mg. It's much simpler than lenvatinib. When you go to the frontline setting, our development strategy is even more different. Here we are leapfrogging what Merck is doing, which is combining with anti-PD-1 and TKI. They still have a TKI in their combination. In contrast, as we've talked about a lot today, we are combining with anti-PD-1, CTLA-4. We are going for a TKI-3 regimen in the frontline setting, combining with IO, IO. We think that gives us a huge advantage in the frontline setting. I want to spend a few more moments on this because I think the study that we're doing with AstraZeneca, eVOLVE RCC02, is probably the least appreciated aspect of our development program. First of all, this is a true clinical collaboration with AstraZeneca. A lot of times companies will announce clinical supply agreements. They try to dress them up as clinical collaboration, but they're really only getting free drug supply. This is very different. In this case, AstraZeneca, which is obviously a world-class drug developer in oncology, is operationalizing the study. That means a lot less resources for us, and we are sharing the cost of the study. They are making a huge investment in this study alongside us. We love the fact that they are all in on this study. They have been a great partner. We've actually worked with AstraZeneca for many years now. We are collaborating with them on another study called PAC8. It's a team that we know well. Like I said, they're equally excited about this study. On the choice of volrustomig, we actually spent a lot of time as a company thinking about the right anti-PD-1/CTLA-4 combination. This wasn't something that we just jumped into because AstraZeneca was there. We talked to a lot of clinicians about their thoughts on volrustomig, how it compares to ipilimumab/nivolumab, other anti-PD-1/CTLA-4s that are out there. What we're hearing very consistently is that there's a lot of excitement for volrustomig in the clinician community. We felt like this was the right combination partner for us for casdatifan. Now I'm going to segue a bit into actual numbers and try to help you guys all build your models. Here we show the largest tumor types in the U.S. by incidence. This is SEER data. I'm sure you guys have all seen this data. RCC is actually the seventh largest tumor type by incidence in the U.S. It's kind of neck and neck with bladder and just a little bit smaller than melanoma. It is a very, very large tumor type. Two things that I want to point out. First of all, when we go through these numbers on the next few slides, we're only talking about the metastatic setting right now. We think that there's a really big opportunity, as Raina was talking about earlier, in even earlier line settings, pre-metastatic. We are very excited about this IST that we'll be doing with Tony Choueiri at Dana-Farber. It is a large IST where we'll be looking at anti-PD-1 plus casdatifan in the neoadjuvant setting, pre-nephrectomy. We have designed a study so that it could potentially support guideline inclusions in the future. It will be a large randomized study. The second point that I want to make here about RCC relative to these other tumor types, and you guys all follow these other tumor types very closely, but it's a very clean competitive landscape in RCC relative to these other tumor types, particularly if you look at breast and prostate and lung, which are becoming very, very fragmented. In RCC, there's no chemotherapy, there's no ADCs, there's no targeted therapy, there's very few bispecifics. We feel very, very good about our opportunity in RCC because it is such a clean market and such a clean competitive landscape. This is one of the reasons why we think the PEAK-1 study will enroll as quickly as we do and why most RCC studies have enrolled so quickly. There's just so little competition out there for patients right now. Dollar-wise, what does this mean? The RCC market today is almost $10 billion in just the major markets. This is U.S., Japan, and the five largest countries in Europe. This doesn't even include places like China, South America, other European countries, etc. Obviously, a very, very large market. It's also expected to grow to $13 billion just in the next few years. A lot of that growth is coming from that turquoise bar that you can see on the top. That bar represents HIF-2α Inhibitors, and this is data that's straight from DRG. You can see there is a lot of expectation around the HIF-2α Inhibitor class. I think one very important point that I want to make, and this is consistent with what I was saying a few slides back, there's really only two classes of therapies that are approved in RCC, and you can see these very clearly on this slide. You have IO, which is that blue bar, TKIs, which are those yellow bars. Each of those bars are about $4 billion in sales. A very simplistic way to think about the market opportunity for HIF-2α Inhibitors is to think about that $4 billion, and there's no reason why HIF-2α Inhibitors should be less than $4 billion. On top of that, because this mechanism is so well tolerated and because we are getting these really long duration of treatments, we think that we can grow the market beyond that $4 billion. I'm going to talk a little bit more about that on these next few slides. We're going to start here and how we are estimating our time on treatment for casdatifan. Here we show the median PFS for prior RCC studies in second line and frontline. We are using median PFS as a proxy for time on treatment, as I'm sure you guys all do. When we look at the bars under second line, obviously the best proxy for us right now is the belzutifan plus cabozantinib PFS. This is from LITESPARK -03, where they showed a 13.8 month PFS. We obviously expect to do a little bit better. We're not going to show you the precise number, but you can probably make an educated guess in terms of what we'd ideally like to see in PEAK-1. If you go further to the right and you look at the first-line patient population here, we're obviously building on nivo plus ipi. With nivo plus ipi, you currently see about 12.5 month PFS based on CheckMate 214. We expect to build on this even further because it is the frontline setting. I think consistent with what Bill was saying earlier, he does expect casdatifan to be even more additive in these early line settings. Again, we're not going to show you the exact number that we're assuming for median PFS and time on treatment here, but it's a very nice number. Now just translating all of this into dollars. I'm going to start actually talking about belzutifan today. So belzutifan, as Terry pointed out earlier, is doing about $660 million in run rate sales, which is amazing. There are a lot of companies that would be very happy to have a drug with $650 million in sales. They're only about a year and a half into the RCC launch. The reason though it is not greater than this is that its use is almost entirely restricted to the third line setting. That setting has a patient population of about 15,000. The time on treatment we're estimating to be about 5.6 months based on the PFS that they showed in LITESPARK- 05. When we talk to clinicians, they are telling us this is very consistent with what they're seeing in the real world. There is a slide earlier that showed belzutifan as having about 40% share. You can run the math on those numbers, you know, get very close to that $650 million. We are not going in that third line setting. We are focusing on earlier lines, specifically the second line and frontline as we've been talking about. If you look at the second line market today or IO experienced patient population, today we're getting to 21,000 patients. To Sylvia's question earlier, we actually did just get some updated research from DRG. The numbers are even higher. Keep in mind that 21,000 includes not just patients that progressed getting treated in the first-line metastatic setting, but these are also patients that got adjuvant Pembro and progressed that would also be eligible for PEAK-1. This is a very large patient population. We talked a little bit on the prior slide about what we might be assuming for median PFS here. We're assuming belz-like pricing, and that gets you to about a $2.5 billion opportunity for this setting alone for HIF-2α Inhibitors. As you go to the right, to the frontline setting, obviously patient population a little bit bigger. We're assuming an even longer time on treatment. Here we get to $2.8 billion opportunity for the HIF-2α Inhibitor class. This to me is a really important point to make. Here we show the Kaplan-Meier curve for PFS for the 50 mg BID cohort. We didn't show it in the clinical data section because we wanted to save it for here. What you can really see in this cohort, and this was the cohort, as a reminder, we have the longest follow-ups. We have almost two years median follow-up in this cohort. Is that really long flat tail, which is very IO-like. You have about 40% of patients, actually over 40% of patients on treatment beyond 18 months. A lot of these patients are getting close to two years of therapy. Keep in mind the median PFS for this cohort, as you remember, several months ago, and it hasn't changed, is 9.7 months. Clearly with this kind of curve, 9.7 months is probably not the right proxy to be using for time on treatment. We could argue that you should be using a time on treatment that's several months higher than that 9.7, just given that long flat tail that you're seeing. For each additional month that you assume for time on treatment for the major markets alone, we get to $150 million - $200 million incremental revenue. We think that this is a huge potential source of upside relative to the slide that we showed you just before this. How are we going to convert cas plus cabo to a multi-billion dollar market opportunity? To us, it's very easy. We think the value prop is pretty exceptional. The first step is obviously just converting those cabo users to cas plus cabo. There's 30% of patients that are getting cabo today based on a better efficacy with very similar safety that we expect to see in PEAK-1. Next is converting those other bars. Patients that are getting TKI mono, PD-1 plus TKI, or even belz plus TKI to the cas plus cabo regimen. Finally, in terms of really optimizing the revenue opportunity for cas plus cabo, we do think that we can maximize and extend the time on treatment based on all the things that I talked you through on the prior slide. Another thing that really helps is just how well tolerated cas is. Even with TKIs, patients tend to have drug holidays. Even if a patient's doing well on a TKI, they may switch to another TKI just because they're getting TKI-related toxicities. The fact that cas is so well tolerated is really going to allow us to maximize the time on treatment. Last, longer term, we think the opportunity is much bigger than just PEAK-1. We talked a lot about eVOLVE, which we think is a multi-billion dollar opportunity in the frontline. That study, phase I-B portion, is going exceptionally well. It's already enrolling well ahead of expectations, which is very, very unusual for an oncology study. As Richard was just talking about, we are also starting to look at cas in some other early line settings where the goal is really to displace TKIs in early settings. Last, longer term, we do think that there's a potential for casdatifan in other tumor types, other diseases. Right now, we have our hands full with RCC. With a $5 billion market opportunity, we want to make sure we get every dollar of that. We are trying to think about longer term, what else we might want to do with cas. Just to wrap it up, and before I turn it over to Juan to talk about our inflamed portfolio, I just want to hit on three key points. First of all, I think the data that we showed you today makes the case very, very clearly that cas is a best-in-class HIF-2α Inhibitor. In fact, we don't even think of belz as the comparator anymore. We think TKIs are. As Raina pointed out earlier, this is the longest PFS that has been seen for any second-line plus TKI study, not just for belz, but for any TKI out there. That is something that's really, really exciting for us. Second, we believe that we have a better development strategy. We just talked you through that. We feel like we have the better TKI. We like the fact that we're going TKI-3 in the frontline. We're super excited about our development strategy. We believe it is differentiated. The third point is our goal is to take as much share as we can get. We should get well more than 50% share of the HIF-2α market. It's only us and Merck. There are no other competitors on the horizon. Very, very unique oncology market. We are laser-focused on really maximizing the opportunity that we have with casdatifan. That starts with PEAK-1. With that, we're going to switch gears and go to Implan. Right. My job now is to simply introduce you to a small number of very advanced programs in the inflammation space and to give you a sense for what might transpire over the next 12-15 months out of this. As Terry pointed out a couple of times, our group, our discovery group, really started as an immunology-focused organization. As you know, the first few years of our existence, we worked primarily on immune oncology targets, reflecting that strong immune expertise. Two or three years ago, we simply decided to shift the clinical focus, but not so much the type of discovery organization that we have built. We decided to pursue a two-pronged strategy, looking for small molecule improvements upon cytokine-targeted therapeutics that already have well-established clinical value and utility. In pair with that, we decided to work on pathways that revolved around two critical front-end defense, immune defense cell types that have been historically understudied in the pharmaceutical industry. We decided to pursue things that modulate mast cell biology as well as neutrophils. As I think those of you that know our organization, we love biology, but we hate the inherent risk associated with translating novel biology into clinical trials. We tend to prefer to let other people sort through all the science that doesn't translate into the clinic. At the end of the day, humans are not mice. We'd like to let other people do a little bit of the heavy lifting. We're very good at spotting. I think the HIF-2α story is a good example of that. I could mention TIGIT, actually, a way for other people to do the heavy lifting, spend their money illustrating where there might be an opportunity to come in and do better. The reality is that clinical proof of concept is hardly ever, if ever, generated by best-in-class molecules. That's just not how it works. With that as the backdrop, I'll tell you about a couple of things that we're really excited about. These are the five most advanced programs in the immune inflamed space. I'm going to have one slide each on the first three, which are more or less listed here on this table in order of maturity and readiness for the clinic. I fully expect that over the next few months, we'll select at least our development candidates against at least three of these, most likely the top three, a fraction of which will probably advance into the clinic next year. We make that decision as to the timing and priority urgency of moving things into the clinic, taking into account in real time the competitive landscape, the medical need as it exists at that time, and obviously competing priorities within the portfolio. I'm going to be talking to you today a little bit more in detail about X2, small molecule TNF modulator and RCCR6 program. The other two are very exciting. One of them is an antibody program against CD89, which we think has a lot of potential against a subset of patients with RA and a small molecule CD40 ligand disruptor. Very much along the same vein as the anti-TNF program, but at an earlier stage of maturity. You see there's a wide spectrum of potential clinical utilities ranging from allergic conditions like AD or CSU, all the way up to the big chronic autoimmune conditions. X2 is one of two main modulators of mast cell biology. As you know, mast cells represent one of the frontline defense against infections. Mast cells live in skin, lungs, the gut, places where they're waiting for some out of place foreign agent that they can literally self-explode against and kill in the process. There are two main known mechanisms that trigger a mast cell to explode, degranulate to be the more scientific term. IgE, of course, we're all familiar with that. That is relevant when being exposed to environmental antigens or food allergens. There's also, over the last few years, a second, we hope equally important mechanism in which endogenous substances like substance P activate this GPCR called MRGPRX2 that also leads to degranulation of those mast cells. It may play more of a role or an important role in itching and pain sensation relative to the IgE mechanism. Very recently, the clinical proof of concept has been generated by our main competitor, a company called Evommune, with an agent that I think is, on the one hand, really exciting because it's the first translation of the preclinical to the clinical observations. On the other hand, we think it's an agent that in typical form leaves something to be desired, and we think we can come in and do better. It's a molecule that has shown signs of activity in chronic inducible urticaria, a very easy place to move into to generate proof of concept upon which to build in some of the other indications that I've mentioned. They're reaching with the high dose that they evaluate. They're reaching plasma levels that we calculate to be north of 20 μM. There were some LFT signals associated with that. The twice daily administration of 50 mg twice a day, which should give you an exposure just a little bit under what you get at 300, appears to be clinically active as well. We think that those exposures are really not the kind of exposure that you should be building a program around. By contrast, our leading compound, we refer to it as 102, demonstrates in under fully physiological conditions. We tend to run all of our programs in under fully handicapped conditions, whether it's human blood or serum. In this case, we use serum. As you know, small molecules have a nasty tendency to bind nonspecifically to all kinds of proteins and lipids. The potency that you generate in the lab hardly ever predicts the true potency in a whole organism. That particular compound in 100% human serum can block 90% of substance P activity at double-digit nM, just below 50 nM. With the kind of human PK that we project for that, we should be reaching therapeutically relevant concentrations with a Cmax of a little more than 200 nM. That's almost a hundredfold less than the 20 μM that I mentioned that the competitor reached. We are very confident or excited about the prospects that this molecule has as we advance it towards the clinic. The second most advanced program is our small molecule TNF alpha disruptor. The commercial and clinical value of anti-TNF biologics cannot be overestimated. However, something that's perhaps less known is that TNF alpha signals through two different receptors, receptors one and two. Receptor one is the bad one, is the one that drives inflammation. Receptor two is the one that TNF relies upon to begin to orchestrate the recovery from that acute inflammation. This is fairly typical in inflammation. As the marines land and start destroying things, the bridge builders are right behind. They start to lay the foundation for the recovery operation. In the case of anti-TNF biologics, those agents block both the good and the bad signal. The beauty of these small molecules is that they only disrupt the ability of TNF to bind to the bad receptor R1, leaving the R2 biology intact. There is very, very clear preclinical evidence that we can recapitulate all of the anti-inflammatory benefit of anti-TNF biologics with the small molecules with none of the bad R2 receptor R2 mediated biology. In a mouse, for example, where you're, and we hope this will translate into the clinic, while you're treating RA, IL-17 levels in serum are going up. Tregs are starting to shift from being inhibitory in nature to be pro-inflammatory and start to develop a TH-17 profile, all under control of the R2 receptor. We are very much looking forward to translating that preclinical biology into the clinic. Similarly to the previous program, our main competitor here, Sanofi, just reported an early phase II study in psoriasis. The good news is that they're seeing clear evidence of clinical benefit. The bad news is that they're dosing twice a day, presumably because of the LFT and QTC prolongation observations at the next dose up at the once daily dosing. For us, it's an opportunity to come in with a better compound and hopefully steal their lunch. Finally, the last program that I'm going to be commenting on today is our CCR6 program. CCR6 is the signal, it's a chemokine receptor that certain inflammatory cells utilize to find their way into psoriatic skin. The therapeutic hypothesis here is that by blocking the recruitment of not just TH-17 cells, but also gamma delta T cells and other inflammatory signals, not only will we be able to recapitulate the therapeutic benefit associated with IL-17 blockade, but also some of the other pro-inflammatory cytokines like interferon gamma or TNF alpha that come on the back of these inflammatory cells will be alleviated if you prevent these cells from coming into the tissue. Our only competitor here, not the only one, the most relevant one would be Pfizer. They just started a phase I healthy volunteer study with a small molecule CCR6 antagonist. Here what we are counting on is the fact that historically the chemokine space is complete with clinical failures in our estimation because of underdosing of borderline molecules. If you look through that whole history of clinical trials run with chemotactic inhibitors, the only positive outcomes you will find are the ones that are associated with my group at a previous company that reflected the knowledge that we generated about the potency and dosing requirements for effective blockade of immune cells recruitment to inflamed tissue. We are counting that when the time comes, we'll have that competitive advantage relative to Pfizer. With that, I'll stop and I think we're all going to take questions. Yes. This concludes the bulk of the content for today. We'll take questions on casdatifan as well as the immunology pipeline. I'll ask Jennifer and Terry to come up to the front so that they can answer questions. Hi, Emily Bodnar from H.C. Wainwright. I guess maybe I'll ask one on casdatifan and one on the immunology side. Maybe if you could discuss the neoadjuvant trial a bit more. I'm curious, we've talked a bit about how HIF-2α is slower to lead to responses compared to some other therapies. How do you kind of see that playing out in the neoadjuvant space where typically treatment is like four to eight weeks? Maybe also just discuss how many patients might be eligible for neoadjuvant treatment. Yeah, I can start. I think one of the aspects of casdatifan that got Tony to where he was excited about this IST is that much faster time to response and the greater and faster tumor reduction that we seem to be seeing with casdatifan versus belzutifan. We do think that there's likely going to be tumor shrinkage, especially given, keep in mind, what we've been showing you is data from patients that have had three prior lines, four prior lines, five prior lines, et cetera. For patients that have not been pre-treated, we do expect that there could be meaningful tumor reduction and that it could really impact the nephrectomy, the ability to minimize what you need to do with the nephrectomy, and then the longer term outcome. I think because, as Bill was saying, HIF-2α is such a key pathway in clear cell renal cell carcinoma pathogenesis, that's the other reason why they were excited about hitting that pathway early and prior to surgery. We are also combining with PD-1, also using the benefit of ramping up the immune system prior to surgery. That should provide some benefit as well. What's nice about this is there's nothing that's used today for neoadjuvant. It's not like other settings, like lung, et cetera, where you do tend to have a lot of pre-treatment in the neoadjuvant setting. In this case, patients just go to nephrectomy. This is a completely new opportunity for casdatifan. We're running the study, it's randomized so that we'll get some really meaningful data out of it. It's an exciting opportunity. Could you discuss how you think about that pathway versus BTK inhibitors, which are the other oral therapy that's now approved for CSU? I think it's primarily an argument about safety. X2 does not play any normal role. You're not going to be missing a single B cell or a mast cell as a result of this. You're literally going to be blocking something I didn't mention. Our understanding is that it's the ends of peripheral sensory neurons that are putting out a lot of these substances that are interacting in a two-way communication with the mast cells in the skin. Inflammation is triggering the sensation of itching and pain. The nerve endings themselves are putting signals that are enhancing that signal and leading more mast cells to degranulate and keep driving that process forward. There's nothing that's going to happen as a result of a complete shutdown of X2 signaling other than a widening of that vicious cycle. If you have a question, please raise your hand. We want to hear from the center. Just two questions. First, can you just share your early thoughts on pricing strategy? Just give a couple of legal generics around 2030 to give you guys more pricing flexibility. Second, can you just comment on the potential to get a broad label on PEAK-1 to combine with any TKI, not just cabozantinib? Have you heard any feedback from physicians that once they get results from PEAK-1, they might just use to combine casdatifan with any TKI? Yeah, so for pricing strategy, right now we're assuming that pricing is essentially equivalent to belzutifan, maybe a tiny bit below. We also plan to use flat pricing, which is how cabozantinib and Lenvima are priced, which means that the 100-mg tablet would be priced the same as 50 mg and 25 mg. If a patient's dose reduced to 50, the price for that 50-mg tablet would be the same as 100-mg. As far as being on top of a generic TKI, it definitely helps. That is one of the things that we liked about combining with cabozantinib versus maybe a TKI that is going to have a much longer patent life than cabozantinib because obviously the price of cabozantinib is going to drop quickly. To your last question, it's a very good question. I don't see that happening as much. I think, first of all, just because cabozantinib is like the preferred TKI, so it's not like there's a lot of clinicians out there going like, "I'm dying to use Lenvima, I'm dying to use axitinib. I wish I could combine casdatifan with one of those." I do think in clinical practice, it could happen, especially if you start with cabozantinib, maybe you get some cabozantinib-related toxicities and it's like, "Maybe I want to switch to axitinib." I do think because with TKIs, the safety profiles are all different. They're all hitting different kinases, so they're not interchangeable like maybe PD-1 could be. I think it'll happen a little bit, but maybe not as much as you might think. One thing that I do think is going to happen, which I think is very interesting, and it goes back to somewhat what Dr. Bill Kaelin was saying and Dr. Terry Rosen was saying about the importance of keeping the patient healthy, but where the TKI is really helpful, and Raina made this point too, is patients that have high disease burden, rapidly growing tumors, really cooling everything down and getting tumors to shrink very, very quickly. I actually think one of the things that can happen is not so much switching out different TKIs, but maybe you have a patient on casdatifan plus cabozantinib for six months, and then you can wean them off of cabozantinib for a while and maybe tumor starts growing a little bit, you give them some more TKI. I think that is actually maybe the more interesting longer-term opportunity versus swapping out different TKIs, can you actually remove the TKI, maintain the patient on just casdatifan? I think it's a lot, what Jen just spoke about, the TKI is highly analogous to like chemo in certain regimens. I think that notion of hitting it early and then weaning off, like people often talk about with immunotherapy chemo, maybe that hasn't been explored as much as it should be. I think in this situation is they have a similar notion where you then, especially if we can demonstrate how well patients can do on monotherapy early on as well. Hi, Daina Graybosch with Leerink Partners. I have a couple related questions on PEAK-1. I wonder if you can tell us how many interim PFS analyses you've built in, and assuming FDA will ask for an ad hoc OS look per project endpoint as a safety endpoint, how mature will OS be at the interim or final PFS analyses? Maybe I'll add that. Short answer on the first question. We aren't really talking about the statistical plan in that way. As far as OS goes, OS is a pre-specified key secondary endpoint. We're collecting that in all the ways necessary and expected. We expect the OS data at the time of the PFS data, for example, if that's positive for submission, we'll have adequate OS data at that point in time to satisfy a full approval. I don't expect it to be an early approval, but it would be a full approval at that point. I think, you know, that PFS endpoint, having it so primary, is a key difference between what we're doing and what Merck is doing because they have dual. We're not sure why they did dual. Like most RCC studies have been approved just on a PFS endpoint, but you know, because of that, they probably chopped up their alpha a bit more. They may be waiting for OS right now, which may be why their timing has been pushed out. Any other questions? I know it's been a long day. It's just getting started. I guess what are your expectations on the O12 trial, especially as it relates to their Arm A versus Arm B, which is PD-1 plus Lenvima plus HIF-2α versus IO-IO Lenvima? What we're hearing anecdotally, this is the Merck phase III study that Umer's referring to that's evaluating belzutifan plus pembro plus len versus their anti-PD-1/CTLA-4 plus len versus, I forget what's the other one, I think just len. We will see, I mean, pembro len, sorry. What we have been hearing through the grapevine is that that triplet is giving patients a decent amount of toxicity. There was a slide in Reina's presentation. This is A. This is belzutifan plus pembro plus lenvatinib. I think that their anti-PD-1/CTLA-4 plus len, I would be shocked if they don't see the same problem that AZ, which was too much toxicity. I just think anti-PD-1 plus CTLA-4 plus TKI is going to be too much toxicity for a lot of these patients. For that first combination, back to the slide that Reina had on overlapping toxicity, anti-PD-1 and TKI have a decent amount of overlapping toxicity, more than people probably appreciate. It's hepatitis, colitis, GI, rash, et cetera. Even though HIF-2α inhibition doesn't bring a lot of toxicity, it may bring just enough that it sort of pushes patients over the edge. What we're hearing on that triplet is just concerns about the toxicity. We definitely think with their anti-PD-1/CTLA-4, which, by the way, they don't seem to be making a really big investment in, which probably tells you something, combining that with TKI is going to give a lot of tox. Like we said, that's what AZ tried to do with volrustomig and lenvatinib. The reason they wanted to combine with casdatifan is because they were seeing too much toxicity. We'll see what that study shows. If it's successful, it kind of doesn't matter, honestly, for us because, as we talked about, our strategy is different and we're going TKI-3. We think for anybody that prefers a TKI-3 regimen, which as Reina talked about, we think as most clinicians, we think they're going to prefer our combination. Got it. Jen, just so we're all on the same page, you're saying because of tox on the two TKI, so HIF-2α plus TKI plus PD-1 arm, too much tox, so it may not necessarily outperform because you may not be under optimal control. Exactly, yes. Are you also saying that PD-1/CTLA-4 Lenvima could outperform that arm? Anti-PD-1 plus CTLA-4. Plus Lenvima could outperform the HIF-2? No, I don't think it will. I think because, like I said, like AstraZeneca ran that combination, volrustomig plus lenvatinib. The reason they are not taking that combination forward is because they saw too much toxicity. That's why they decided that HIF-2α inhibition was a much better combination partner. That's why they actually approached us was because of the toxicity that they saw. I wouldn't be surprised if that combination does anything. I mean, they're probably honestly regretting having that combination in the study. It just created a much bigger study than they needed to run and a lot more expensive study. I may just add to that. I'll remind you that it's bispecific, which, you know, the reason why we think volrustomig may be effective and safer is that the PD-1 arm is pulling in CTLA-4 biology, presumably into tumor-draining lymph nodes. That's not the same thing as a co-formulation of a PD-1 and anti-CTLA-4, where you're trying to achieve this convenience, I guess, which I think is what Merck is using in that trial, co-formulated pembro plus CTLA-4. If it's successful, like I said, it doesn't really matter for us. I mean, we hope, you know, great for patients, and because our strategy is so different and because we're combining with IO-IO, we think patients and clinicians will prefer the TKI-3 regimen. Just give Umer a microphone. Maybe finally on the X2, Juan, is it your base case that it works in CSU only, or do you see utility in entire there as well? No, I think chronic inducible urticaria is a really easy way to generate clinical proof of concept. It's very predictable. You literally induce the disease with a five-pin scratch, and you know within a few days whether your drug has biological activity. The standard path would be to follow that up. The general wisdom is that there's no market in chronic inducible urticaria. It's an intermediate step towards chronic spontaneous urticaria. In parallel with that, I think at the right moment, you start to evaluate atopic dermatitis, which is the second equally obvious place for X2 biology. Again, you can follow the GAT roadmap to illustrate the places where mast cell biology is pathologically relevant. Are there any other questions? If not, I'll ask Terry to. Oh, we got one more. Hi, this is Corina for AstraZeneca. There's actually an IST study at MD Anderson in RCC looking at volrustomig, which is a PD-1 and CTLA-4 bispecific. Could that be potentially combined with casdatifan? You mean with HIF-2α with casdatifan? Yeah. Oh, casdatifan, so I should say with the cytokine. Yes, yes, that's something. I think, you know, the challenge with that is, you know, it's just a tough phase III study to run because anti-PD-1, REG F bispecifics are not approved in the frontline, nor is, and there's very little use of atezolizumab, Avastin these days. I just think the phase III study would be very complicated. I think that's why, you know, probably anti-PD-1 plus TKI combo is like a better strategy. It's something we've definitely thought about and could be something we do in the future. Yeah. Last Yeah. Last call for questions. Okay, I'd like to ask Terry to wrap up with some closing remarks. I'm going to say two quick slides. We know it's been long. Hopefully, it's been interesting. We tried to put a lot of meat in there. We appreciate you guys coming by and everybody online as well. It doesn't seem like there's anything happening. There we go. This is just maybe make a few key points. You heard a lot today and a lot about casdatifan, but to bring it all together, I would emphasize points that you've probably heard this start, middle, now at the end. We believe at this point we can clearly say black and white casdatifan is the better molecule, and we do think this is going to be a two-horse race. Obviously, you see that the profile is driven by the lower rate of primary progression. We have a confirmed objective response rate that's probably going to approach 40%. Most importantly, the PFS looks like it's going to well exceed 12 months. Even when you look at our landmark PFS, I think that becomes another important thing to recognize because that starts to tie in what Jen was speaking to, that that duration of treatment, patients that get any benefit, get long benefits. Hence what we were literally when we started this program, we had our first ad Board meeting in January 2024, that Achilles heel of the high rate of primary progression that Raina talked about, what was highlighted for us. Fortunately, hitting the target harder matters. I'll steal Bill's. He's got the Nobel Prize. I'll steal his oncology 101 for a chemist. Oncology 101 is well over my head. Bottom line, we think we have the improved molecule. Secondarily, we think because it's a two-horse race, because there's nothing else out there, we believe we're going to be able to execute our trials well, and we believe that we're going to be able to expand that market so that we get that duration of therapy in the AUC that's created with a number of patients. Finally, I don't think it can be overstated the clear, apparent trend that we look better than TKI monotherapy because I think that provides the genuine clinical scientific rationale for a complete paradigm shift where what we've been discussing today, you want to get away from, like in everything, people don't want to get away from chemo. They want to get away from TKI. When you think about patients, efficacy is everything, but if you can actually flip things around and get the efficacy and improve the quality of life and bring HIF-2α inhibition up to the front and push TKI down, that would be great benefit to patients. We think we've provided compelling data today, and you'll continue to see more data throughout next year as has been outlined by others. Coming back, bigger picture to Arcus, next week you'll see our overall survival data from gastric. That'll be an oral. The abstract will be out next week. As I suggested, we feel really foreshadows the potential opportunity in upper GI cancers with TIGIT. Beyond that, recall that you're not treating a tumor. You're treating biology. Our STAR-121 first non-small cell lung cancer PD-L1 all-comer study will be fully enrolled with 1,000 patients by the end of this year. We'll see how that goes. TIGIT's been a, you know, an interesting field. We're excited that we're finally getting to the point where the data will speak for themselves. Also importantly, as I mentioned, when you look at our cash position, the investment in TIGIT, the investment in quemli have maxed out. Next year, we'll be spending less than 50%. Importantly, these dollars fund us through multiple value inflection points. All three of these late-stage programs, most importantly, PEAK-1. You've got HIF-2α inhibition, you've got TIGIT, and you've got CD73 all covered with the cash we have. We think we'll be having a steady cadence of data, and we'll be having a steady cadence of phase III readouts for the foreseeable future. We thank you all for joining today and look forward to continuing dialogue with all of you. Thanks very much.