Is a commercial stage company that is in several different tumor types and is a leader in renal carcinoma, but then also has ambitions to really think about VEGF inhibition in a broader subset of diseases, and that's what they're looking at with Zanza. Andrew, why don't I hand it off to you for some intro remarks, and then we'll get started. Yeah. Thank you. Thank you for the invite. Always a great conference. Great set of meetings today. Always good to meet with investors. Just as a reminder, we'll be making forward-looking statements today. Please see relevant disclosures in our regulatory filings for risks related to our business. Would certainly agree with you. Exelixis is, I don't know what generation of the company it is at this point, we're kind of in that important transition point from going from our first franchise product in cabozantinib to our next franchise in zanzalintinib. That's kind of the lens that we view the world of drug development, the world of oncology is kind of through this franchise mode, where not only are we investing broadly in each molecule, but within each tumor type, for example, we're also broadening our investment there. Whether it's RCC, we're going to continue to be the leaders in RCC, or a newer area like colorectal cancer with Zanza, not only this later line setting with the STELLAR-303 study, but investing, say, in the 316 study in the earlier line, and then layering on our pipeline as well, say XB371, our tissue factor ADC, which we really view as a colorectal asset as well. It's that franchise mode that we're really using to define our 2026 and beyond. Happy to get into a lot of the details there. I want to start with more of a conceptual question. It's interesting, I still remember back in 2020, I think Mike had put up the $4 billion number on Cabo, and obviously, okay, Cabo didn't get there. Fine. It still became a multi-billion-dollar product. There were a lot of successes. I think, and I don't know if Michael will ever admit it, but I do feel like you guys learned from that second wave of drug development with Cabo, and you're applying a lot of those learnings to Zanza, and I think that's actually quite interesting, right? When I don't see a lot of studies like COSMIC-313, right? I see a lot of studies where you're looking at adjuvant settings, post-maintenance settings, areas where there's really defined clinical unmet need. Can you talk about, is that perception correct, right? What learnings did you have from that development you had with cabo that you're now applying to zanza that you feel like maybe investors are missing? I would certainly say, taking a step back, everything we do at Exelixis is through what we call the Cabo lens. Learning what's been successful, learning what to do right, learning areas that we should avoid in the future. I would correct one thing. We certainly continue to be excited about the growth profile for Cabo going forward. It's something that as we look ahead to, say, 2030, we're still certainly excited about it. That Cabo lens is really a couple of different things. Cabo's been successful commercially because we've been able to define a new standard of care in the areas that we've developed it, whether it's 2nd-line RCC, first with the METEOR study, then as a monotherapy and 1st-line RCC, and then in combination with nivo. The reason Cabo's used is because it helps patients live longer, and helps patients live longer without their tumor progressing, and all of the important decisions and drivers for utilization there. What that means is that we're in the business of running studies that we think have the potential to really define that new standard of care. The second piece is we're also in the business of running successful studies. We're not in the business of just running trials for the sake of doing it. We try and be particularly thoughtful around probability of success, trial design, statistical powering, understanding appropriate comparators to really make sure that the data we're generating enables physicians and patients to really drive those treatment decisions. That Cabo lens is really when we apply it to Zanza, it's what are areas of unmet need and large market opportunities? What are studies that we can run to help define and plant a flag in the ground for Zanza to be the new standard of care? Can we do it in a way that's capital efficient? I'm sure Chris will talk about this later. One of the models that we really liked with Cabo was working with clinical collaborators. Whether it's Bristol, Roche Genentech, or now Merck, splitting costs, splitting risk, splitting expertise, splitting capability, and being efficient in how do you run pivotal studies. Bristol sells a lot of nivo in RCC. We sell a lot of Cabo. That same dynamic with zanza is certainly an approach we want to do going forward. Taking a step back as we think about that Zanza franchise approach, it's about all of those learnings and lessons in that Cabo lens, and applying it to what we think is a best-in-class molecule in areas of high unmet need where we can define a new standard of care. I think maybe let's start with first line RCC. Again, you mentioned you go where the puck's headed. Can you give us some perspective about really what your overall long-term strategy is in first line? A, is there ambition to ultimately run that CheckMate 9ER trial, and what would that look like? You've alluded that you might go with maybe even partnerships outside of Merck. Number two is, what is the opportunity in the post-pembrolizumab setting, right? If you were to think about that commercial opportunity to what you have currently in first line RCC, is there an argument to be made that actually the post-pembrolizumab maintenance is a larger commercial opportunity? I think both of those questions are somewhat related to one of our core strategic principles is basically, again, through this franchise lens, we're the leaders in RCC, and we want to continue to be the leaders in RCC. Our view on it is, if Cabo is the TKI of choice in RCC for the 2020s, we want to run a series of trials to define Zanza as the TKI of choice in the 2030s. You mentioned our efforts so far. We have the three studies ongoing in RCC, and I think just to answer your question on market opportunity, given rough guidance for a little over $2 billion in that space across those three studies. The way we think about it is where you said, how is standard of care evolving over time? How is that patient's journey in kidney cancer evolving over time? As more patients are diagnosed earlier, as more patients who are diagnosed in that more localized setting get adjuvant therapy, adjuvant pembro, this question of what should they get afterwards starts to come up, and that's the LITESPARK-0 33 study. We really want to define what that is. Similarly, as the treatment journey gets redefined for patients in that later line setting, the combination of Zanza and BELS we're evaluating versus BELS monotherapy. Both of those, we think we have reasonably high likelihoods of being successful, again, to define the new standard of care. On the question of frontline, we think we have half of that covered right now, that frontline, but post-pembro adjuvant. That's like 15,000 patients? Yeah. Plus, minus. I think it depends on how we see and how someone views the evolution of that utilization over time, as well as the evolution of when patients are diagnosed. Does the advent of improved diagnostic modalities change some of that time course of metastatic diagnosis versus prior? It's a multifunctional kind of dynamic. When we think about that kind of de novo metastatic first line space, it's certainly an area that we want to invest in, but it's one that we want to be thoughtful about how we invest in. Our own experience with COSMIC-313, as you mentioned, as well as the recent LITESPARK-012 data, show that you have to be particularly thoughtful and careful about rational combinations. Where does the biology suggest that what are those combinations that have the potential to shift the standard of care? Say, going back to COSMIC-313, that was a successful study on PFS, but as we looked at the opportunity and the lack of survival data and, again, this patient journey dynamic in RCC where there are now multiple lines of therapy. understanding the trade-offs between PFS benefit with additional tox, without survival versus sequenced therapies, that's just a dynamic that's relevant for every patient who has kidney cancer. Mike talked about it, Dana talked about it. One of the dynamics that we're certainly thinking about is we think Zanza is a best in class TKI. We think it has the potential to be a backbone therapy. Its shorter half-life and all of its profile lend itself to being that sort of backbone, and the question becomes, what are the sorts of mechanisms, orthogonal mechanisms in particular, that you can come at the cancer from multiple different angles to try and really drive the most robust benefit? Because at the end of the day, we don't want to run a study to generate similar data to what we've seen before. We want to run a study to be successful. That's where we're being really thoughtful about, but I think as Mike has said, we tend to view Zanza in terms of waves of development in that next wave in RCC, we're excited to share. Look, to that point, I guess the nuanced question there is, do you think it'll ultimately be a triplet regimen or a doublet regimen, right? You'll talk to maybe some of your peers in the space that are more on the HIF-2α side, right? Where they're like, "Look, we want to go with a doublet regimen, and ultimately we think that would be beneficial", and Merck ultimately went with the triplet, and that was really the error. Really, that doublet combo is good enough to be better than, let's say, CheckMate 9ER, the LEAP trials. There's another view of like, "Well, no. You are going to need three different therapies here. They need to all be combinable, and they need to be tolerable so that you can actually get that DOR. We're not comfortable with just, let's say, a HIF-2α TKI combo first line as better than CheckMate 9ER. What's your team's internal thinking there, doublet or triplet, when you do ultimately go into that frontline setting? I guess the answer candidly is it kind of depends on what those are. The reason I mentioned the orthogonal mechanisms before is if you think about the HIF space and VEGF TKIs, we think that the secret sauce, special sauce for Zanza is that it hits this whole other neighborhood of MET, AXL, MER, the TAM kinases, et cetera. That's kind of why we think it's different. At the end of the day, one of its core efficacy drivers in RCC is that VEGFR kinase inhibition. Well, HIF and VEGF are on the same axis, so you're kind of doubling down there. From a cancer biology perspective, it certainly makes sense to want to bring in an alternative mechanism to make sure that you're attacking the tumor from as many different angles as possible. Your question of whether it's a doublet or a triplet, I would say it's somewhat semantic because take, for example, XB62A, our PD-L1xNKG2A bispecific. A theoretical combination of that brings in adaptive immune system, innate immune system, and then the kinase inhibition piece. That's probably a doublet, but it's incorporating multiple mechanisms of action as well. That's an example of the sort of thinking that we have around let's let the biology make the decision, drive the decision. Let's let the data drive that decision and really understand how do we really, again, run a study to right-shift that survival curve, right-shift that PFS curve, all while doing so in a way that's not adding additional tox for these patients. Again, in RCC, patients are living longer and longer, and it's the best part of our job to be part of that. You have to understand that clinical benefit risk trade-off as well. Understood. I couldn't agree with you more, the tricky question becomes, well, okay, there's three options here in my mind. You have something where it's a next-gen IO approach. You have T cell engagers, you have ADCs, right? I don't think I've seen anything early on right now, whether it's in a pharma pipeline or in a mid-cap pipeline where I'm like, "This is a step order improvement." Maybe I'm wrong here. Yeah When you think about those three modalities, when adding onto Zanza, where do you feel like there is this kind of natural synergy in first-line RCC? Maybe what are investors missing about how this market's actually evolving over time on the pipeline side? Yeah, I think the latter question is really, we're the leaders in RCC, and we're going to continue to be the leaders in RCC. Invest appropriately to do so. That Cabo-lens dynamic that I mentioned before is also that we want to make sure we're appropriate stewards of shareholder capital, and so we're going to run the right study. We want to run positive ROI studies that have a high probability of success, that have that opportunity to be commercially successful. Whether it's one of those modalities or others, that's kind of TBD. I think I probably am a bit more optimistic on what's out there. Especially what's out there in potential combination with Zanza. One of the challenges that I think the industry has, and certainly folks like you have, is trying to extrapolate the potential for later line data for modality X into an earlier patient population. I certainly think that we have the ability through the Exelixis lens to understand some of those risks a little bit differently. We're excited. We're having a lot of conversations right now about what those combinations could look like. I think it suffices to say the two key points are, we're going to make appropriate investments, and we're going to make sure that we're really having a thoughtful, strong opportunity in that frontline space. Are there any targets that you think you might call out, whether it's emerging in China or otherwise? I know there's ENPP3 bispecific data that's getting generated. There's next gen ADCs out there. Anything that you think is particularly interesting? Yes, I won't call them out. All right. Worth asking. Okay, understood. When we think about LITESPARK-001, and obviously, Merck is going to have a regimen that will, let's say, it looks supportive of displacing Cabo in a second line setting over a period of time. I also find it notable that Merck, right after that data, is also running the exact same trial with you, with Zanza, but now displacing belzutifan. How do you think about, what does Merck see with Zanza, especially in that second line setting where they feel like maybe there's room left on the table from the LITESPARK-001 data to actually improve the standard of care for patients? How do you expect to show that case with, I know you have a phase III trial that recently started there. Yeah. I think honest answer is, don't really want to put words in Merck's mouth. From our perspective I think we certainly view Zanza as a best-in-class TKI, and the totality of data generated for any of those combinations would suggest that tolerability is really important. Combinability, dose selection is really important. Can the combination of Zanza as a best-in-class TKI and BELS as a highly efficacious, very good HIF inhibitor, can that have the potential to generate strong data? Both from an efficacy perspective, also from a safety and tolerability perspective. Again, how you combine, how you double down on that VEGF axis is really important. Understanding the differences, say, between lenvatinib and Zanza is particularly important. Again, I think it's also in part on how patients will be treated in the future. As I mentioned before, that's one of the key considerations that when we have conversations with our now partner, that's where a lot of that begins. Just closing the loop on second line. My sense is it's maybe like a $300-$600 or somewhere in that range. Let's say it's about $500 million in second line RCC for Cabo. Your team's been kind of, A, I know you guys have never admitted that, so that's me. Number two, you've said like, look, as use in second line goes down, there's potential uptake in first line, and doctors are really thinking about stratifying different therapies. When you think about the absolute impact on the LITESPARK-001 data as that regimen gets onto the market, as we think about to the end of the decade, do you think there will be any impact on absolute Cabo sales? No, you're going to see this natural switch of as second line use declines in a subset of patients, there's going to be offsetting increase in first line usage. Without getting into guidance on guidance. Yeah long term outlook, I think that's probably directionally consistent. The most simplistic way to think about it is if a physician has come to the conclusion that LEN PEM is probably their go-to treatment of choice in second line, what it probably means is they would no longer use LEN PEM or LEN BELS second line. They would no longer use LEN PEM in the first line because you wouldn't. use LEN twice. What that means, functionally speaking, is for those patients who are likely to get an IO TKI, Cabo nivo becomes that frontline modality of choice. If you think about, generally speaking, over the last three to five years, that dynamic of trying to drive every additional market share point in frontline RCC, that's been our primary focus anyway, because the frontline market, just factually speaking, tends to have longer duration, longer time on drug, so tends to drive incrementally higher revenue, first line versus second line. Still TBD, a little bit early to see how all of these new combinations get adopted in the market, whether share is coming from single agent TKIs or LEN EV, which is another regimen that's used right now. There's a lot of moving pieces, but directionally speaking, that's probably a reasonable way to think about it, at least right now. Understood. Now, can you touch a bit on, I know there was data at ASCO presented with Cabo, actually running something similar to what you're running in non-clear cell against a sunitinib in first line. A, can you talk about your early thoughts on that data set obviously was phase II an academic run. How do you think a clinician will look at that data? Number two, what's your level of confidence? I know you have a phase III in non-clear cell that's reading out later this year about whether your drug will differentiate there or what's the magnitude of improvement you're expecting over sunitinib. Yeah, it's a good example of one of the unique dynamics around the non-clear cell space in that, honestly, when we first started thinking about it, I was surprised that there had never been a phase III done in that setting. Yeah. The way that I conceptualize it is utilization in part is essentially driven by this idea of which small unrandomized Phase I, II do I trust more as a physician and a patient? We all know the caveats and limitations of these smaller studies, patient selection. at identifying and selecting certain patients for these trials, which is a dynamic that you don't see and really can't do in large randomized Phase III studies. It's group over here of utilization being all over the map because it's defined by a bunch of different ISTs or single arm studies. Sure. STELLAR-304 being the opportunity to plant a flag in the ground and say, "This is the standard of care potentially in the non-clear cell space." They're two different things. I think the way that we look at it, and certainly our market research is emerging in that direction, is that physicians will be comfortable using what drug or what combination has level one evidence of showing an advantage over a standard of care. It's just that non-clear cell for a variety of historic reasons, utilization is driven by inference and Driven by the fact that all kidney cancer drugs are approved for both clear cell and non-clear cell. Right. Understood. Stepping back, and Andrew, this is a conversation you and I have had about how much you think buy-side and sell-side analysts, of the Zanza indications, you have eight trials announced. How many of them are actually in people's models? I think it's probably two or three. Relative to the trials that you actually have ongoing, for us who haven't modeled those other five indications, what are your favorite children? What are those markets where, again, it fits that profile of really clear unmet need, point and shoot? You have high confidence that Zanza will get established into standard of care, and then number two, you think the commercial opportunities are really underappreciated. Yeah. It's an honest answer in saying I think we've been particularly thoughtful around each of the studies. Our goal for 2026 and beyond is to really show that Zanza's a franchise molecule. We're certainly excited about 303 and the launch, and priority one A as a company, but it's really setting the foundation for Zanza as an opportunity. We think about it as a franchise and collectively across all of those studies, where individually we think they're all reasonably sized, if not very large market opportunities with high probabilities of success. Honestly my view is look at each one of them individually and have a conversation, have an understanding, do whatever work you need to do to understand, is this study likely to succeed? If it succeeds, what is the commercial opportunity here? An example of that, say like STELLAR-316. That's another area where we're essentially defining a new standard of care. Right now, with the advent of Natera's Signatera test, there's this new patient population that if they're ctDNA positive, now finds themself at very high risk of relapse. Right. Until that kind of new diagnostic modality was available, that dynamic didn't really exist. We're looking at either Zanza monotherapy, Zanza in combination with subcutaneous pembrolizumab against watch and wait placebo. That's an indication where we've already shown a survival benefit in a much later, heavily pre-treated population that we know is sensitive to this sort of therapeutic modality. It's an example of where we're defining a new patient population. There are a lot of these patients- who really do need a therapeutic intervention because right now they're being told that there's a really high risk of their cancer recurring, but there's nothing you can do about it. That kind of anxiety, that kind of unmet need is very palpable. It's the sort of thing where, simplistically again, any time you can randomize a large global. large randomized study against placebo, it's probably an opportunity. The size of that commercial opportunity, let's say relative to RCC in first line, how should we think about that? I think at the highest level we've said there's 12,000 ± patients. How that number evolves over time is kind of that availability and utilization of the Signatera test improves. Similarly, if there is a therapeutic intervention. Is there a higher likelihood of, one, people getting tested, but two, people getting treated? It's a reasonably sized market. At the end of the day, the math's pretty simple. It's number of patients, times share, times price, times duration. Yeah. So. Chris, for you to wrap it up. It's funny, your stock has tripled. Not funny, credit to what you've done, but it's interesting. A lot of investors are like, "I don't get it. Why are they still buying back their shares?" Normally when a company buys back their shares, the obvious announcement is, "We think we're undervalued". You're also at this point, as you approach the Cabo LOE, where there is this question of, well, what's the allocation between external BD, buying back our own shares, and then also pursuing other kind of Merck partnerships where you can really divvy up the capital costs. What's the right balance for you now that you've gotten to this new level in terms of valuation and investor expectations? Should we continue to expect this level of share buybacks on a go-forward basis, or this is more of like a temporary dynamic? Yeah. From a capital allocation perspective, we look at it, not mutually exclusive in any way. I n three buckets: R&D expense that we have every year, potential BD, M&A, then share buyback. Like I said, they're not mutually exclusive. We've committed to spending $1 billion or less in R&D for the time being. We continue to look at assets from a BD M&A perspective. As our record has shown, we haven't found that many things that we really like, but we're continuing to look. Then we've been buying back shares for the last three years almost, since first approval March of 2023. You touched on the undervalued part. When you look at the how the analysts are modeling it and how the Street generally is modeling Zanza, which is our next potential franchise molecule, there are not a lot of the indications in there. The ability to continue to develop Zanza in a way that'll drive sales in the 2030s, as Andrew talked about, the TKI of the 2030s. We continue to think we're undervalued. That's one of the reasons. I know it's not going to be guidance. I will stick this question in. You think you're undervalued. You guys have given long-term perspectives on Zanza. This is a question you get, you're partnered with Bristol. Bristol gets this comment of is there a trough? Is there growth? It seems to me like a lot of the Zanza Phase III start to read out before the end of the decade. Yeah. You're going to start to get uptake. Is there a possibility you have just straight growth through the Cabo LOE? Is that how investors should be thinking about this? Yeah. I'm not going to give guidance on that. Yeah. I think we're very excited about the opportunity. Yeah Zanza brings, and the potential that at the end of this decade, the beginning of the next decade, that Zanza allows us to grow through that LOE for Cabo. To add maybe this, any potential of J.P. Morgan from a few years ago where you call your shot and give a four or five year commercial outlook on Zanza and the uptake. Is there appetite internally to do that any time in the near future? That's a tough question to answer. It depends. We did that back in 2020 because we weren't getting a lot of credit for 9ER. or the potential of 9ER, then the other indications we were developing. If we see that situation again, we'll evaluate everything. Okay. Understood. All right. Thank you so much. I really do appreciate it. Thank you.