Morning, everyone. My name is Emily Shtulman. I'm a Vice President here on the Targeted Oncology team at Leerink, and I'm super happy to have with me Andrew Peters, senior Vice President of Strategy and Investor Relations at Exelixis. Thanks so much for being with us today.
Yeah, happy to be here.
Great. Yeah, maybe we could start out, you know, ASCO GU happened very recently. You know, I was thinking we could start with RCC and talk about some of the dynamics within the HIF-2 alpha space for RCC. You know, the results from LITESPARK-011 for belzutifan and lenvatinib and second-line RCC were just presented. I believe it showed a PFS benefit without a stat sig benefit in survival, at the time of the second interim analysis. All that said, I'm just kinda curious to understand your perspective on this data set, you know, and where you think this regimen may ultimately fit in versus CABOMETYX and second-line RCC.
Yeah. You know, thanks again for the invite. Happy to be here in sunny Miami. You know, as we were talking about before, you know, the West Coast in California has been quite a nice winter, but I understand from a lot of people that coming from the Northeast, it's quite a treat.
Yeah.
Before I begin, we'll be making some forward-looking statements today. Just as a reminder, please see relevant risks, disclosures around risks in our business and SEC filings. Yeah, ASCO GU kind of, you know, pretty common topic these days. I think, you know, from our perspective, you know, the conference overall was as expected. What we mean by that is, you know, kind of before, during, and after ASCO GU, a lot of the conversation among clinicians is really this idea of, is it better to combine modalities or is it better to sequence? The LITESPARK-011 data kind of in our view, and I think what a lot of the KOL feedback has been really kind of is aligned with that.
You know, if you look at, say, TKI monotherapy in the second line, followed by, say, belzutifan monotherapy in that third line segment, you know, the overall PFS benefit is similar, if not a little bit longer, than kind of the data that was seen in eleven. Adding to kind of the additional talks that you saw, and the fact that, you know, roughly 20% of either belz or len discontinued. You have somewhat of a sequential treatment anyway, given that a lot of those patients are functionally just on a single agent anyways. You know, as we think about kind of the overall impact of the data, it's probably, you know, pretty benign to our business.
If anything, where we do see some len/belz use kind of in that second line space, it'll probably drive incremental CABOMETYX-NIVO use in the front line. You know, obviously, patients tend not to see individual treatment retreatment. If someone's, say, gonna get len/belz second line, they probably won't get len first line. That's where we'll see some incremental CABOMETYX-NIVO use. Kinda net-net to us, as expected, you know, pretty overall, not a lot of robust enthusiasm for the data, let's say, given that lack of survival. On balance, kind of if it does get used, we'll probably see some incremental share in the first line.
Got it. Okay. No, no, that makes sense. Yeah, we also did some, you know, KOL calls on this topic, and something that they emphasized that's really important is ultimately seeing that sort of stat sig OS benefit pan out. I guess what are your sort of thoughts on that dynamic? Like, what's the likelihood that you think the OS could eventually be stat sig or what are the pushes and pulls to think about there?
Yeah, I mean, really hard to kinda speculate without knowing a lot of the you know intricacies of the statistical plan, so to speak. Really kinda hard to speculate, but you know at this time I'd say it's you know it would be you know hard to see that they'll have a very very robust survival advantage, let's say. You know if anything we'll just have to see the data.
Yeah. No, that makes sense. I think that's consistent with, you know, what we've heard too. Especially some KOLs I think are nervous that not really too much works after LENVATINIB in that setting, whereas there are more options after CABOMETYX, which could be something that could influence the OS as well.
Yeah. We'll just have to see.
Yeah, for sure. That makes sense. Maybe could you speak a little bit about, you know, the quality of life and toxicity data that we saw for that doublet versus CABOMETYX ? I think you touched on it a little bit, but, you know, that's something that's definitely risen to the surface in our KOL conversations as, you know, being really highly relevant in this setting, in addition to survival.
Yeah. I mean, one of the dynamics to consider, again, in this question of combination versus sequencing is what's the added tox that you're giving as part of the combination. And then I think importantly, you know, hopefully it's not being glossed over, the adverse events that you see, particularly around, say, hypoxia and cardiac dysfunction, those can be especially problematic from a clinical dynamic perspective as both for patients and physicians. Is you have to think about, you know, baseline characteristics of patients. You know, hypoxia, how do you monitor that? You know, what's the potential implications of, you know, higher grade hypoxia over a particular amount of time? Is that what's driving kind of that increased cardiac dysfunction? All those different dynamics are certainly in play.
Again, contrasted with this sense of, okay, physicians are comfortable with how they currently treat kind of in that second-line space, very comfortable with kind of that third line, belz monotherapy use. You know, on the AE side, one of the things that we've consistently heard is that sequence approach offers patients the benefit of kind of what we think of as like a TKI break with belz. For patients who have been on either IO TKIs or TKI monotherapy for, you know, two-plus years prior, all drugs have adverse events, but the difference between, say, a TKI and a HIF is a little bit different.
Mm-hmm.
Having that opportunity to be on as a monotherapy, an active modality with a slightly different AE profile, that's something that we've heard is actually important to patients and clinicians. That dynamic, I think, is important to consider in that overall, you know, just framework for how patients get treated as part of their journey with kidney cancer.
Yeah, definitely. Yeah, thanks for that color. Sort of, yeah, adjacent to that, I wanna talk a little bit about your collaboration with Merck, the BELZUTIFAN You know, like the LITESPARK-033 trial just started. Maybe, yeah, you could talk a little bit about where you see ZANZALINTINIB and BELZUTIFAN fitting into the sort of evolving treatment paradigm.
Yeah. 33, I think, is an interesting study, because, you know, when we first started talking with Merck, you know, one of the questions that came up, and at least how we think about it, is, you know, Cabo's the TKI of the 2020s. How do we define ZANZALINTINIB as the TKI of the 2030s? And part of that is just how the evolution of patients with RCC will be treated and how that changes over time. With pembrolizumab, with adjuvant PEMBROLIZUMAB especially now that they have an OS advantage with treatment, our expectation is that that dynamic of the number of patients who will be treated with PEMBROLIZUMAB over time increases and changes.
One of the questions that we asked and we're hoping to answer with 033 is really not what does the market look like today, but what does it look like in 2030, 2031, 2032. Our expectation is kind of that % of patients who have received prior adjuvant pembrolizumab will be much higher.
Mm-hmm.
033 is designed to really, again, define what the standard of care is, should be in those patients. With that data being so new, the pembrolizumab adjuvant data, it's really kind of an unanswered question right now. You know, a lot of things are used, Cabo's used, kind of more by default than anything. 033 is a chance to say, "Okay, with a, you know, we think truly best in class next gen TKI combined with a HIF like BELZUTIFAN, do we have a chance to kind of redefine and, you know, functionally answer that question?" you know, well, hopefully the answer is yes, but, you know, we'll see.
Got it. Yeah. Can you comment on, I guess, what % of patients get adjuvant pembrolizumab today, and where you see that going?
Yeah. It's kind of a, you know, still somewhat early days. I think our sense is just, you know, with the overall survival data, our expectation is that's gonna continue to grow.
Got it. Yeah. No, that makes sense. You know, the space, the HIF-2 alpha space is pretty dynamic now in RCC, the number of competitors. There's one trial called the PEAK-1 trial, which is testing another HIF-2 alpha agent CASDATIFAN in combination with Cabo in post IO RCC. I think it might be helpful if you could talk a little bit about the key differences between LITESPARK-033 and PEAK-1, as well as, you know, any thoughts you have on the differences of the potential profiles of these combinations based on what we know about, you know, these different agents today.
Yeah. You know, I think kind of a statement of the obvious that oncology is competitive, it's dynamic. It's always been competitive and dynamic, and it's just kind of the nature of how we think about our business. You know, LITESPARK-033, as I said, kind of is really designed to specifically answer that question of that post-adjuvant treatment. As I understand it, I think PEAK-1's a little bit of a broader study kind of looking at you know, more of just a generic post IO, which is a slightly different patient population. You know, as it relates to, say, the differences between CAS and BELZUTIFAN, you know, candidly, it's probably too early to say.
One of the challenges that we all have is trying to understand and tease out early kind of phase I unrandomized data, and how that'll play out and influence in larger randomized phase IIIs. You know, the challenge is that functionally a lot of times phase I patients can be different than phase III patients and you know, almost a truism in oncology, you tend to see a degradation of benefit when you go from phase I to phase III just because of how those patients are functionally different. So really kind of early days there. One of the things I'll say is, you know, we're really excited to be working with Merck. You know, there's no better oncology development company in the world than Merck.
You know, with them operationalizing the two studies that we're working together, along with kind of the financial partnership that we have, in terms of kind of the co-funding arrangement, it's something that we're really excited for.
No, absolutely. I believe based on the collaboration agreement, Merck is also expected to announce a second phase III trial for ZANZALINTINIB and RCC. I know this is in Merck's hands, but just kinda curious if you could comment at all on, you know, when this announcement could be or what the trial might look like, how it might be different than LITESPARK-033. Any color you could provide.
Yeah. You know, I think at this point, kind of the best way to say it is just stay tuned there.
Yeah.
We've agreed with our partners to, you know, not talk about specifics of the study until it's up and running. You know, excited to talk about it when that is, but for now, I think kinda the best way is just to stay tuned.
Okay. Yeah, fair enough. Maybe transitioning to non-clear cell RCC, top line data for ZANZALINTINIB and NIVOLUMAB, you know, in frontline non-clear cell RCC are expected in mid-2026. Maybe you could talk a little bit about this opportunity, you know, the trial and just sorta the broader thesis behind this combination.
Yeah. You know, we have had really great meetings so far this morning and obviously, with the latest data, you've been a topic of conversation. As we've discussed many times in the past, one of the really striking things that always jumped out to me as we were thinking about running this study was the fact that there's never been a large randomized study in non-clear cell. You know, by default, all of the approved agents in RCC are approved for both clear cell and non-clear cell. Utilization is driven by kind of guideline recommendations, which themselves are a bit of a hodgepodge of single arm, unrandomized, sometimes single center, IIT type studies that define how agents get used.
As a consequence, market share and utilization, when we can tease it out, is a little bit of a hodgepodge and mismatch of everything. What STELLAR-304 does is it provides an opportunity to define with level one evidence, with a large randomized pivotal study, what a new standard of care could be. You know, it's a chance with ZANZALINTINIB and Nivo, randomized against Sutent to exactly define that. If you think about kind of the opportunity set, non-clear cell from a pure EPI basis is, say, 15%-20% of RCC.
That's kinda how we're thinking about the market opportunity overall is, you know, do we have a chance to really draw a line in the sand and say, "This is the new standard of care," based on robust evidence, as opposed to, you know, kind of reading through some pretty limited data sets.
Mm-hmm.
You know, Cabo included, that define the market right now.
Got it. Yeah, that makes sense. I guess maybe could you set some sort of guidelines around, like, or what, yeah, what level of efficacy you're hoping to see in this study?
Yeah. I mean, kinda tough to speculate ahead of the data, but, you know, somewhat of a statement of the obvious, we wanna see robust benefit, you know, across response rates, PFS, and ideally survival. The way that, you know, our experience is the way that drugs are commercially successful is if they define a new standard of care and shift how patients are treated. The way that that's done is to have differentiating data, and so, that's kind of the goal.
Got it. Yeah. I guess, are you hoping to see better efficacy than what Cabo plus NIVOLUMAB or TECENTRIQ has shown in the, you know, phase Ib, phase II experience? I think, you know, there's some early data sets showing ORRs in the, you know, 30s to 40 range, PFS north of 10 months or so, 10 to 12 months. Is that something that you're looking to see?
Yeah. I mean, again, that's almost the point of the study is to kind of show the limitations of those small unrandomized data sets. I mean, depending on which study you look at, you tend to see pretty wide ranges of outcomes. It just inherently shows the limitations of cross-trial comparisons between small N data sets, which themselves have pretty wide error bars. I think there's some inherent challenges of saying, you know, 304 versus 20 patient data set here is a little bit of an apples and oranges comparison. You know, I think our goal is to define with a robust data set what that could be.
Mm.
Because obviously within non-clear cell, there are a bunch of different subtypes, and depending on how those were enrolled in these smaller studies, it can certainly influence it. I think, you know, our job is to just define what that is and answer the question definitively, how should patients get treated?
Yeah. No, absolutely. Yeah, I guess, I mean, beyond like the efficacy and, you know, the fact that this is the first, you know, robust phase III data set and on clear cell, what are other sort of qualities of ZANZALINTINIB that you think would drive usage over Cabo in this setting? You know, KOLs that we've spoken to comment a lot on the titratability advantage over Cabo. That seems to really resonate with treating physicians. If you could maybe speak to that and some other sort of, you know, advantages.
Yeah. I mean, I think it gets to kind of the heart of why we developed Zanza in the first place. Cabo is a great drug. You know, everything we do at Exelixis, we say we kinda do through the Cabo lens.
Mm-hmm.
One of the dynamics that does come up with Cabo is, it's around its half-life. It's around 4 days. What that translates to from a kind of clinical practice perspective is all drugs in oncology, all TKIs patients inevitably develop AEs that are needed to manage. The challenge there, if you kinda go by the treatment algorithm is, dose hold to resolution of symptoms and symptoms, and then rechallenge at a lower dose. Because of that relatively long half-life that Cabo has, that dose hold period can be 10 days, 2 weeks, sometimes even longer. That can be challenging from a patient management perspective. That can be challenging from a combination perspective if patients are on multiple modalities.
It can be challenging just from a, you know, the perspective that the longer someone's not on drug, especially at subtherapeutic doses, does that give the cancer an opportunity to kind of regain a foothold, so to speak. Zanza was really designed to take that same kinase profile that Cabo has, which we really think is the sweet spot that differentiates it relative to some of the other VEGF targeting TKIs, and then improve the PK profile. Zanza's half-life is a little under 24 hours, and that makes it more user-friendly, so to speak, from a combination perspective, from a down titratability, all of those sorts of things.
You know, as we think about kind of ZANZALINTINIB not only in that non-clear cell space, but across the seven pivotal studies that we're running, that's one of the most important dynamics because our view is, while monotherapy certainly has a role and we're developing it in signet ring cell and meningioma, if you look broadly at kind of what we're hoping to do with ZANZALINTINIB over time, it's certainly around investing in combinations as well.
Yeah. No, definitely. That's helpful color. I wanna talk a little bit about CRC. I know that the phase III STELLAR-303 trial for ZANZALINTINIB Tecentriq read out positively at ESMO this last year. I think you have a PDUFA in December. Could you maybe talk a little bit about this data set and some of the features of this regimen versus, you know, regorafenib standard of care versus the SUNLIGHT regimen, which is a standard of care in this setting as well.
Yeah. You know, we're really excited about kind of the potential ZANZALINTINIB launch later this year in CRC. You know, that third line plus CRC segment is a really interesting opportunity because if you think globally, how patients are treated in the US, say, given the relative dynamics between, say, KOLs and the community and just how patients are managed over time, share is, you know, roughly 1/3, 1/3, 1/3, kind of that SUNLIGHT regimen, TKIs and chemo. Importantly, one of the things that historically hasn't been available to patients in CRC is kind of the checkpoint inhibitors in immunotherapy.
What the STELLAR-303 data provide is, you know, data to show with an overall survival advantage that patients live longer taking the combination of ZANZALINTINIB, ATEZOLIZUMAB compared to kind of the current standard of care. As we've gone out to the market with research, and that's one of the things that jumps out, is an opportunity to provide patients an option to have treatment with a checkpoint. You know, we all watch the Super Bowl and see all these ads for PEMBROLIZUMAB and OPDIVO and all this stuff, and it's a dynamic that we've observed that, you know, patients come in to talk with their oncologist and ask about these checkpoints. Up until now, you know, the answer has been, unfortunately, you know, these aren't available for your type of cancer. We think, one, that's a powerful message.
Too, you know, showing a survival advantage versus standard of care is certainly kind of the gold standard historically in oncology. You know, we think the 303 data that we showed at ESMO and was concurrently published certainly demonstrate that ZANZALINTINIB, TECENTRIQ should be a new standard of care. Then kinda lastly on your question on the SUNLIGHT regimen, you know, one of the dynamics that again has kinda come up in our research is if you think about how patients are treated in the U.S., the vast majority of them will have prior BEVACIZUMAB use, you know, either once, sometimes even twice.
That SUNLIGHT data, there's actually a pretty stark difference in how patients respond to that combination, whether or not they had prior bevacizumab. Kind of overlaying that with treatment patterns in the U.S., there's kind of another dynamic at play, especially when you consider kind of looking at our own data, there's no real difference, say, between, you know, prior bevacizumab use or not, and no real difference between liver mets and non-liver met. We just had a robust result, you know, across all the different potential stratification factors.
Yeah. No, that's definitely come up in our KOL conversations as well, and I think, yeah, that was one of the more, you know, positively surprising aspects of that data set for us, was the robust benefit in liver mets patients. I guess, yeah, could you maybe comment a little bit on any hypotheses you have for why there was such a strong benefit in liver mets patients when historically IO/TKI combos, you know, haven't been able to show a benefit in that segment?
Yeah. I mean, I think candidly speaking, you know, just is a good example and highlights why WELIREG is different.
Mm-hmm.
You know, taking a step back and why we focused initially on this dynamic between patients with liver mets and not, you know, physiologically, these patients are very different. You would expect if there's metastases in the liver, they have a much poorer prognosis, and that's been clear. But one of the things that we've observed in the industry is observed empirically across all of these, you know, relatively contemporary studies in late line CRC, is that patients behave differently, especially on checkpoint inhibitors with and without liver metastases. Kind of the most recent study, LEAP-017, that Merck ran looking at LENVATINIB plus PEMBROLIZUMAB, functionally speaking, if they would've just looked at non-liver met patients, that probably would have been a positive study.
that kind of drove a lot of our interest around designing the study to specifically, from a statistical perspective, look at those two different groups. Kind of fast-forward the clock and when we read out the top line and then full data at ESMO, you know, we were pleasantly surprised and encouraged that we saw a robust response across both of those cohorts. You know, to me, to us, that just shows that WELIREG is actually different, and it's not just that VEGF inhibition that's driving activity, but it's, you know, hitting the TAM kinases, hitting MET, AXL, and MER , all of the things we think that are unique and differentiated about WELIREG , kind of myeloid cell biology, you know, tumor microenvironment, all the stuff that, you know, we think historically has benefited Cabo, say.
You know, all that holds true, and we think kind of derive a lot of that difference. You know, it shows that the combination is very effective and highly encouraged to see that activity across, you know, broad range.
Got it. Yeah, no, that makes sense. I guess sort of, yeah, related to that, the final OS analysis in non-liver mets patients is expected in mid-2026. I think that one initially wasn't positive at the interim, but the liver mets OS was. I guess sort of in that context, how are you thinking about, you know, this upcoming non-liver mets analysis and kinda curious if you think that, you know, the benefit in liver mets will that de-risk the non-liver mets to some extent, or how are you guys kind of-
Well, I think, just to clarify.
Yeah.
The data that we presented at ESMO and top line, so that was the ITT population.
Right.
We showed a benefit across all patients. It's inclusive of patients with and without-
Yeah.
Liver metastases, but given the dynamic that I talked about earlier around, you know, patients with and without just functionally, you know, can be different, the relative maturity, the number of events, survival events, for that non-liver met group was still early.
Yeah.
That's kind of what we're waiting for later in the year. Certainly kind of directionally, we're encouraged by the early look, but we'll see, you know, in the middle of the year. That's just kind of a dynamic to consider. You know, overall, when you kind of squint and look at the detail of the curve and all of that, we're certainly hopeful that we'll see a benefit.
I mean, again, a statement of the obvious, one of the better case scenarios or best case scenarios from our perspective is if that data is positive and we're able to get in a label or show clinicians kind of that benefit in the ITT, benefit in the non-liver met, and benefit in the liver met group that helps really drive, hopefully, uptake and utilization and show that the combination really is a new standard of care in that space.
Got it. Yeah, no, that's really helpful. Maybe just for our last minute, talk a little bit about, you know, 2026 guidance. I think, you know, it's like contemplates 10%-12% growth year-over-year. Could you talk a little bit about what's driving that in 2026?
Yeah. I mean, as we talked about kind of in the last earnings call, you know, continued momentum in the base business in RCC and then kind of additional momentum from the MET business. You know, the guidance reflects kind of both of those drivers, which, you know, we expect going forward. Kind of, yeah.
Got it. Okay. Well, thanks so much for joining me.