All right. Good afternoon, everyone. I'm Stephen Willey, one of the senior biotech analysts here at Stifel, and glad to have with us for the next session, Andrew Peters, who's the Senior Vice President of Strategy and IR at Exelixis. Andrew, thank you for the time. It's always appreciated.
Yeah. Glad to be here.
Maybe we can jump right into Zanza, which obviously remains the focal point of an expanding development effort across a lot of different tumor types and lines of therapy. You've got this December PDUFA date that's approaching in third line colorectal based on the STELLAR-303 data. Just how do you think about the value proposition of this regimen in this setting, and do you think that there's a subset of later line patients for whom this regimen might be best suited?
Yeah. Hey, Steve. Glad to be here. Just as a reminder, I'll be making forward-looking statements today. Everyone online, please see our disclosures around risks to our business and our regulatory filings. It's an interesting place to start, and I'm glad you started the discussion on Zanza that way. Highlighting the breadth of what we're doing with Zanza is really how we think about the business. Mike talked about on the last earnings call, and we certainly highlighted at R&D Day, this idea of franchises is really what we're trying to do. The breadth of development with seven ongoing or planned pivotal studies with Zanza, and certainly, one of those core areas, is not only the Zanza franchise, but the CRC franchise as well. The foundation of that is the 303 data, with Zanza, and it's one that we want to continuously build on.
I'm sure we'll get to STELLAR-316 later, in that post-adjuvant, post-definitive therapy CRC space. Really this idea that we want to establish a leadership position in CRC and really build from there. We think that the STELLAR-303 data certainly enable us to do that. On the heels of that positive data that came out at ESMO of last year, showed a survival advantage against a very active standard of care. It's something that as we've done market research and are really starting to ramp up a lot of that launch prep, we're finding that the patient community, physician community's especially excited about having another option. I certainly wouldn't frame it as we're thinking about it as only targeting a segment of patients. The way we see the landscape is it's actually quite fragmented. I think we've talked about this before.
That third-line plus CRC is about a $1.5 billion addressable kind of market today, with about 1/3 in that SUNLIGHT regimen, 1/3 in TKIs, and 1/3 kind of a mix-match of a bunch of others. Our job, and I think something that we've been especially good at in the RCC space, is just focusing and being competitive and trying to gain as much market share across all of those segments as possible. If you look at our data, the forest plot shows that there's no real patient population that drives that activity. It's actually pretty robust and consistent benefit across all of those different subtypes. Layering that on top of zanzalintinib, atezolizumab offers a chemo-free option, an IO-containing option.
Those are the sorts of messages that we think are starting to resonate in a lot of the market research that we're doing, and we're certainly excited, if approved, to go out and have those conversations with providers about having another option for their patients.
Okay. One of those subgroups is this non-livermet subgroup.
Right.
You've got this pre-specified OS analysis, from which we're expecting data sometime, I think, the middle of this year. How, if at all, would you expect this data to impact regulatory discussions or labeling discussions? Again, I know this was pre-specified as a dual primary endpoint, but you did hit stat sig in the ITT population. Why does this analysis, I guess, even matter to that extent?
The simplest answer to the question is the more data, if positive, that we're able to share with providers and patients to kind of complement the story that we've already generated, the better. If we're able, again, if the data are positive, having a label say, Kaplan-Meier curve for the ITT, Kaplan-Meier curve for the non-livermet, that just adds to the robustness of that conversation that we can have with providers and patients around this option for patients. Certainly as it relates to how the NLM data will impact our ongoing discussions with regulators, we certainly see this as par for the course. It's pretty standard in any ongoing review for the agency to ask for updates to data, especially on something like survival. We think that this is just something that will fit in with that normal course of review.
You did highlight that this is part of that dual primary endpoint. Factually speaking, part of the reason that data at ESMO, data mid-year is really about the time course of disease for these patients. Patients who have, unfortunately, liver metastases just tend to see events much faster. This is much more of a standard update than anything.
Maybe just continuing on zanzalintinib for a bit here. We get a lot of questions around safety tolerability at the 100 mg dose. Just given that if you look at median dose intensity from STELLAR-303 and some of the other phase II data sets that we've seen, it's a fraction of the specified dose. Can you just talk about the dose optimization work that led to the selection of this dose for this initial suite of phase III studies? Then I know that you've talked about other or additional dose optimization efforts that have been initiated to inform dosing in other combo-based trials and earlier lines of therapy. Is there anything you can say about how those additional efforts have kind of informed zanzalintinib dose selection for the next suite of trials that you're looking to enroll?
Again, I think it'd be helpful to set the framework around how we think about just dose in general, dose in 303, and dose for the other studies. At Exelixis, an incredible amount of work goes into that process, not only around generating a significant amount of early data, but we have an incredible PK team that does exactly this, focuses on a lot of in-depth modeling around exposure response, understanding tumor sensitivity, line of therapy, combination partners. Those are all of things that really play a role in how we determine dose selection, not only for 303, but other studies as well.
One of the things that we talk about at Exelixis is this cabozantinib lens helps inform everything that we do at the company, and the learnings and the process of development at cabozantinib certainly followed the same path where we started, say, at a monotherapy to higher dose as we moved in later lines, as we moved into earlier lines of therapy or different cancer types. Certainly in combinations, we evolved that to really focus on clinical benefit risk, tumor sensitivity, combination partner, what the biology really tells us and what the modeling really tells us. We're following that same playbook, so to speak, with zanzalintinib. We don't necessarily say, "Okay, there's one dose across all indications." We have a lot of in-depth work that goes into dose selection for each individual study, and we think that that's the best approach we should take.
One of the dynamics that we talk about a lot is we want to make sure that our job ultimately at the end of the day, to create value for all stakeholders in the company, is to run successful trials, not just run studies. Dose selection and optimizing dose for each of those kind of components and incorporating a lot of that exposure response modeling and all of the other things that the PK group does, that all fits into how we think about. Is this going to be a positive study? Is this a study we want to invest in? Is this study going to have the ability to shift standard of care? The only way that we're going to be successful commercially is if we're able to define a new standard of care for patients and help them live longer.
That's certainly what we're aiming to do.
Okay. Another near-term zanzalintinib catalyst that we're anticipating is top-line data from STELLAR-304, which is in non-clear cell, in combo with nivolumab. I know that there hasn't really been any perspectively generated data in this setting from a phase III perspective, but IO-TKI regimens, they're already listed as preferred treatment options and NCCN treatment guidelines. What kind of commercial opportunity do you see this 304 data unlocking, and how do you think these data will then change the prescribing narrative going forward?
Yeah. 304 is an important study for us and importantly for patients as well. Candidly, I think as we were starting to strategize around what we wanted to do in RCC, this idea of really no standard of care in non-clear cell, honestly surprised me a little bit. The fact that there's never been a large randomized study in this space, is somewhat unique in oncology, it's really a fact of all drugs, all combinations that are approved in RCC have a label for both clear cell and non-clear cell. Use is, as you mentioned, is really driven by guidelines. Again, those guidelines are informed mostly by single-arm, unrandomized phase I/II type studies, which we all can appreciate the challenges of interpreting that data because so much patient selection can oftentimes go into that.
From the physician and patient perspective, understanding, well, how does this data set apply to the patient that's in front of me, can be challenging. What we wanted to do with 304 was really plant a flag in the ground and say, "Okay, with level 1 evidence against an active standard of care, is zanzalintinib nivolumab able to show a benefit?" That's what we're hoping to read out, looking forward to reading out later this year.
Again, the feedback we've gotten from the RCC community is exactly that, is that they've been waiting for something to help inform a lot of those treatment decisions because from their perspective, reading the guidelines, you're basically trying to pick, well, do I trust this small phase II study or this small phase II study, or this small phase II study and all the caveats with cross-trial comparisons. Single site versus a few sites. What are the patient characteristics of these? Were they pre-selected? All of those dynamics are certainly important, and so 304 offers a chance for us to really define a standard of care, and again, with level 1 evidence, if positive, hope to move up and become that clear recommended combination.
Okay. Maybe just sticking to RCC. We just learned about the second phase III zanzalintinib trial that you are running in collaboration with Merck. I think it's LITESPARK-034. We just saw phase III data from LITESPARK-011, which was generated in pretty much the same kind of patient population. How do you think LITESPARK-034 creates a second line foothold for zanzalintinib in the context of this 011 data that we saw, I think at ASCO GU earlier this year?
Yep, ASCO GU. Yeah. I think one of the dynamics that informs how we think about zanzalintinib development is this idea of CABO's the TKI of the 2020s and RCC. How do we make zanzalintinib the TKI of the 2030s in RCC? Certainly a big part of that, and I'm sure we'll get to it later, is how the way patients are treated can evolve over time. A lot of that is understanding, okay, let's not run a study for how patients are managed today. Let's run a study for how we think patients will be managed in the future. What the LITESPARK-011 data show us is, HIF VEGF TKI combinations certainly can play a role in the patient's journey with RCC.
What we want to define with both LITESPARK-033 and LITESPARK-034, as well as other studies that we're planning with zanzalintinib, is how can we improve and iterate on that. The totality of the data that's been generated so far across all of these different regimens, all of these different combinations, whether it's 05, 11, 12, 22, those inform a lot of those decisions. We ask questions like, every patient who's coming in and trying to understand how they're going to be treated, is it better to combine? Is it better to sequence? This dynamic at ASCO GU that came out after that data were presented was, well, if there's no clear survival advantage based on what we've seen so far, the absolute PFS for, say, a TKI monotherapy followed by what we've seen, say, with LITESPARK-005 with belzutifan, how does that compare with what the combination does?
It's going to be on us and generating data with LITESPARK-034 to more robustly answer that question, and that's really our goal. As I mentioned before, our job is to right shift that standard of care. The question is, if LITESPARK-011 shows that this combination can have an effect and positive impact on patients, can an optimized TKI like zanzalintinib, best in class TKI, further improve upon that? Similarly with LITESPARK-033, as that treatment dynamic changes and more and more patients get treated, say, with adjuvant pembrolizumab on the frontline, what does that treatment option, say, should be for patients? It's that, what's the expression in hockey? Skate where the puck's going. That's how we think about development of zanzalintinib in RCC.
Okay. You mentioned LITESPARK-033, which was the first RCC collaboration that you announced with Merck.
Yeah.
A couple of questions on that, because that's looking at belzutifan and zanzalintinib as post-adjuvant IO frontline therapy. I guess number one, we know from LITESPARK-022 that belzutifan added to pembrolizumab can improve outcomes. I guess first question would be, what is your expectation for belzutifan uptake in adjuvant? The second question is, we've known that adjuvant pembrolizumab has been around and available and approved, I think, since 2021. An IO TKI is still considered to be standard of care frontline therapy following pembrolizumab in the adjuvant setting. That's still the tailwind that you're benefiting from 9ER. Wouldn't a more, I guess, appropriate comparator arm for this trial, should it have also included an IO TKI arm as frontline?
Yeah. There's a couple of different questions there.
It's a very long-winded way of my question.
So one of the-
That's me. We tend to be.
Yeah. Always. As a former sell-sider, I can certainly appreciate that. One of the dynamics that we've seen, and I think the industry has seen, is the challenges, frankly, across tumor type of IO retreatment, and so understanding the actual contribution of that IO piece, if you've received pembro in the adjuvant space, it's not really seen as being contributing a lot. We certainly feel that 033 is well designed to answer that question of if IO retreatment's not really expected to be successful, what should that standard of care be? This is the first study to help answer that question. We want, again, want to be involved in defining what that is. This comes back to this dynamic around TKI of the 2020s versus TKI of the 2030s. We see the world of adjuvant checkpoint use only expanding in the future.
One of the dynamics that we've seen is now that pembro does have a clear survival advantage, it's driving increasing and accelerated adoption. Beyond that, as the number of de novo versus prior diagnoses change as well, we expect that number to increase over time. It's this matter of, if our view is that the number of patients who are treated with pembro and the adjuvant is expected to grow over time, we want to make sure that we're helping to define the answer on what's that standard of care. As it relates to the adjuvant bel- pem use, our observation has been that hockey stick acceleration of adoption for pembro in the adjuvant space was really when they saw survival advantage. Again, these early-stage patients, as I mentioned before, it's always going to be about clinical benefit risk.
When you're adding on an additional mechanism, you generally see additional tox and understanding, well, if I'm adding on additional tox, what is the actual benefit that I'm getting? Especially with the 5-year survival rates of RCC continuing to improve, especially relative to, say, when Cabo was first introduced, understanding the combination versus sequence dynamic is always going to be important. That's something to consider, again, as we think about not how are patients treated today, but how will they be treated in 2030 and beyond.
Okay. STELLAR-311. This trial is evaluating single agent zanzalintinib versus everolimus as first TKI therapy in neuroendocrine tumors. I think unlike the other STELLAR trials, you're characterizing this as a phase II/III. Is there a formal phase II portion of this trial? If so, what is it actually assessing?
We haven't broken out the specifics around what that Phase II, III gate is. In general, like all Phase II, III studies, it's a way to be reasonably efficient from a timing perspective to understand, is the study likely to be successful? What are some of the metrics that we can take an early look at and then continue to enroll? It's just a mechanism that we can use to really be efficient, both from a risk perspective, but importantly from a time perspective.
how to get that completed as quickly as possible.
Okay. Maybe the last, or maybe second to last zanza question. STELLAR-316, right? This is the trial you referenced earlier where.
Yep
You're looking at zanza and zanza plus PD-1 in early-stage colorectal. Conceptually, I think it's a very interesting study. There's certainly a lot of observational data supporting worse outcomes in these MRD positive patients. I guess when we've talked to KOLs about therapeutic intervention in these MRD positive CRC patients who don't have evidence of clinical progression, the feedback there has been pretty mixed, and maybe that's just a byproduct of some of the historical data that's been generated in that setting to date. How do you just think about the mixed opinions that seem to be out there around slotting something like zanza into treatment here, and whether or not that could have an impact on the pace of enrollment and just how you think about the market opportunity?
Yeah, this is one that I'm particularly excited about. We're particularly excited about it. This is a study where Exelixis is really defining a new standard of care. When we've done our pretty robust KOL work and really understanding that opportunity, I would frame it a little bit differently. If you look at the data that Natera has generated and published, those Kaplan-Meier curves for that MRD negative versus MRD positive are striking. The current standard from the patient's perspective is watch and wait. These patients who are MRD positive, ctDNA positive, know that they're in exceptionally high risk of their disease recurring, and can't really do anything about it. What we're offering is a potential intervention, where we know that Zanza is active in a much later line population, showing a survival advantage, so it's a sensitive tumor type.
We're offering them either zanza monotherapy or, as we've announced, zanza with pembrolizumab. Offering that opportunity to really right-shift again that DFS interval, which is unfortunately very short for these patients, that has the potential to be quite meaningful. I think you've heard Dana on the last couple of earnings calls talk about our view on potential enrollment being particularly brisk. That's one informed by this high unmet need from a patient's perspective around what do I do if I am ctDNA positive? Two, operationally, the benefits of working with Natera and working with Merck to help identify those patients and really accelerate operationally what that could do. I'd actually frame it the other way. This is one where we're really excited to enroll.
As we reflect on the STELLAR-303 data, what we've observed is KOLs who are really excited about STELLAR-303 start learning about STELLAR-316 and get even more excited about Zanza as a franchise in CRC. Similarly, as those docs who are interested in that STELLAR-316 post-definitive therapy CRC space, they start to learn about Zanza in the later lines, it's that echo chamber that we're hearing a lot about that really, I think is getting us excited about what we could do as having a real franchise in colorectal cancer.
Okay. Maybe the last question here. The pipeline behind zanza. You've got a few different modalities. There seems to be a bit of a building concentration on biotherapeutics, right? I think you've got ADCs that now represent the majority of these earlier stage pipeline efforts. Should we expect to learn anything about the four assets that are currently in phase I development? Will we learn anything about those things before the end of this year or maybe first half of next?
Yeah. I think the way that we view it, and again, as you can appreciate, you've known us for a long time, we're a little bit atypical for a biotech. One, we're profitable. Our focus candidly is on execution, and so we're not going to dribble 10 patients' data here and there.
Yeah
to try and raise money or juice the stock or anything like that. What we want to do is once we have mature, stable data that reflects this is what the profile is versus what the profile could be, that's when we'll present it. I think what we've shown ourselves to be really able to do is to prioritize. If any of those early stage programs aren't going to potentially define a new standard of care, we'll move on to the next thing. We're going to kill things quickly is one of the mantras that we have here, and that's how we can be efficient, is just this really stringent prioritization across the board.
Whether that's moving to the next, seeing us start a pivotal with one of those programs or seeing us cut it, that's the sort of thing that you'll see. We'll present when that data really is mature, and you guys can get an understanding of it's not just a couple of patients here or there. It's really a robust data set to help inform why we're making these investment decisions.
All right. That's all we have for time. Andrew, always appreciate it.
Yeah.
Good to see you.
Good to see you.
Thanks for listening, everyone.
Yep.