Good morning, everyone. Bright and early in Times Square. The Elmos have not come out to Times Square yet. They will be there in a couple of hours. Do not engage with them. That's my only advice. My name's Akash Tiwari. I am a farm and biotech analyst here at Jefferies. It is my pleasure to host Exelixis. Andrew, thanks so much for joining us. We are both fresh off our trip from Chicago, at ASCO. It's been a really great, probably one of the best stretches for Exelixis as a stock. Andrew, why don't I hand it over for you for some brief opening remarks, and then we'll get started with more Q&A?
Yeah, thanks. I'd echo the sentiment, kind of bright and early this morning, but, candidly, just excited to be here, excited for a great day of meetings and for the conversation. You know, as a reminder, we've been making some forward-looking statements today, so please see relevant risks and disclosures in our regulatory filings. Yeah, as you mentioned, coming off the heels of ASCO, which is, you know, always an exciting time for an oncology company, certainly an exciting time for Exelixis, presented what we think is some pretty interesting data for our lead pipeline program, Zanzalintinib. You know, I think taking a step back, Exelixis has kind of been on this cusp of a breakout for quite some time.
You know, as you can appreciate, you know, prior to October 2024, we were a little bit of a holding pattern externally as a company as we kind of waited, you know, for some of the ongoing patent issues to resolve. Really kind of we came out of that October timeframe with a favorable, you know, outcome in that we signed a big clinical collaboration with our, you know, partners and, frankly, biggest competitors, Merck, and really just found ourselves at the point of about to break out. The underlying business of Cabo is certainly doing well, kind of humming along, and we're executing on all cylinders there. We have six pivotal studies up and running or soon to be running with Zanza, and two of them actually, you know, expected to read out later this year.
Kind of the early pipeline progressing and just, you know, kind of everything from a capital allocation, from an investment, from, you know, an Exelixis execution perspective, you know, really a lot of momentum behind it. It is an exciting time to be at Exelixis. It is an exciting time to, you know, be in my seat where I have an opportunity to both look internally on kind of how we're focused, whether it's Cabo, Zanza, or the pipeline, but importantly, externally as well.
I get to go to a conference like ASCO and just understand where's the future of oncology going, how do we play there, what are the sorts of things that we can do as a company to be opportunistic with our balance sheet, to be opportunistic as a big small company preferred partner for a lot of smaller biotechs, and really just understand, you know, how do we grow Exelixis. You know, one of the things we talk about is drug, you know, our business at the end of the day is simple. The more patients you treat, the more patients you help, the more value you can create. We think about it in drug one, Cabo is doing really well. Drug 2, Combo, Zanza is really poised for, you know, the key readout.
Drug 3, 4, 5, whether it's in our internal pipeline or external, that's what we also need to focus on.
Right.
Kind of going forward. Looking forward to the discussion today.
Awesome. I, as am I. Why don't we start off with, and I think this is probably where I get the most questions and what we're working on. So CRC, obviously you're going against regorafenib, not particularly the best, it's a good comparator to go against. It's a very tough disease. Obviously on the Q1 call, the dual endpoint changes, I think, a question people have. The way I kind of see it is a company generally does not split their alpha if they're worried about the powering for their trial. Then you also have kind of two distinct populations, liver mets and non-liver mets, that might have two different event rates. It's a bit complicated, I think, for investors to understand. I'd hand it off to you, Andrew. How should we think about that dual endpoint change? Is that a sign of confidence?
Is that a sign of speed? Is that a sign of, well, we want to put this drug in the best position to be stat-saving, and we might be concerned about powering in certain populations?
Yeah. So, you know, Amy Peterson talked a bit about this, on the earnings call. I mean, you know, taking a step back, one of the things we always talk about is ultimately we and everyone in our industry is in the business of P-values.
Right.
We want to run successful studies. We do not want to run studies. You know, there is an important distinction there that I think oftentimes a lot of companies, a lot of investors may miss.
Yeah.
We certainly have that kind of dynamic of we're in the business of P-values, as a through line for every study we design, everything we do. When we were looking at the 303 study, we've actually amended that trial several times now. If you recall, that first amendment was when we got, you know, a pretty significant kind of update for the industry about how, you know, IO-TKI behaves in that later line colorectal population. We made certain changes to that trial to essentially, you know, in our mind, maximize the probability of success, understand what are the really key drivers there. Is it RAS status?
Right.
Has that been kind of our hypothesis before, or was it more related to this emerging kind of view in the colorectal clinical community that, you know, patients who have liver metastases and patients who do not are functionally two different, you know, patient groups? You know, it actually makes a lot of sense. If you think about, you know, patients who unfortunately have tumors that have gone into their liver, you would expect compromised liver function. Given the role physiologically of the liver, you know, they tend to die faster, expire faster. You end up seeing kind of this difference in accrual of event rates.
As we were seeing these events coming in on a blinded basis, one of the things that we realized is given the size of the study, given the, you know, the number of patients that we had enrolled, we had the ability to, on a temporal basis, take an earlier look at a much bigger population. Anytime that we're able to do something which we think, one, increases the probability of success for the overall study and be able to look at a much larger population, we think that's a good thing.
Right.
You know, to me, the best way to think about it is more of a temporal shift than anything that allows us to also look at that broader ITT group as opposed to just the non-liver mets, for example. One of the things we have said is from a market opportunity perspective, CRC is probably about $1 billion, you know, but it's actually roughly split 50/50 between the NLM and the patients with liver metastases. That's in part because the NLM patients tend to live a little bit longer. They tend to be on drug longer. Kind of the.
Yeah.
The market opportunity is about the same. You know, from our end, if we're able to kind of left shift, get to market earlier in a bigger population, that's a dynamic that we tend to favor.
Bottom line, sign of confidence and speed rather than necessarily worry about how events are accruing. Would you agree with that or disagree with that?
Yeah. I mean, ultimately, the cosmic truth always comes out.
Yeah.
When that envelope is read, so to speak. I think, you know, it's a change that we're excited about and again, kind of tend to see it as more, you know, how do we do what's best for patients?
Got it. I like the cosmic pun given that's your study too. Okay, got it. Now maybe just stepping back and, you know, this is a conversation I have with investors. I'm like, I feel relatively confident on CRC given you probably know what the event rate on regorafenib is. As events come in, you can kind of figure out what the delta is. Non-clear cell, again, I feel pretty confident there. To me, where our team's doing the most work is really head and neck and then RCC. You know, it's interesting. Everyone's like, well, is Cabo differentiated versus Zanza? I look at your clinical development plan. Where are you directly testing that is I don't see those studies.
What I do see is what you kind of mentioned earlier, which is Zanza with novel targets and synergy where we maybe have not explored with VEGF TKIs and maybe potentially a better therapeutic window. That is the case study in RCC. Why did you choose Merck as a partner, your biggest competitor? What did you see with belzutifan, which intrigues you in terms of its potential in RCC? Can you give us at least some outline of what that study design looks like given that could make Zanza not just a plus one in indications where Cabo did not work in, but really a full switch?
Yeah. I think the best way to think about it is to maybe take a little bit of a step back because that Cabo Zanza dynamic is, you know, probably one of the most frequent questions we get as a company as well. I think you framed it appropriately is that we've been very thoughtful, we've been very strategic and specific about how we've thought about Zanza development. Given, you know, the original hypothesis around Zanza or XL092, is that the main liability, so to speak, of Cabo is its relatively long half-life.
What we sought to do with Zanza is really to phenocopy the kinase inhibition, kind of that efficacy profile of Cabo with a more combinable, potentially safer version, that we could say, okay, here is all of the 10-plus years of data that we have accumulated with Cabo across these various indications. Look across that landscape and say, okay, where are the areas that we can be pointed in the direction of where a drug like this would be active, but would be more favorable with a kind of more user-friendly, more combinable drug. You mentioned the six studies that we have up and running, you know, 303, 304, 305, frankly, all of them are certainly informed by our Cabo experience.
We actually see that as kind of a big point of value creation in that we've essentially enabled us to accelerate development because we can learn a lot from Cabo.
Sure.
Point us in the direction of Zanza. As it specifically relates to kind of the HIF-2α in the RCC space, we do, we've agreed with our partners, Merck, obviously it's a competitive area, not to get into the specifics of the design of the study until those are up and running later this year. What I can say is there's been a lot of intriguing early data of Cabo and Belzutifan that we can use as kind of a starting point to understand how those sorts of drugs behave in patients. Importantly, the signal is clear. The combination is very active.
Mm-hmm.
The combination is tolerable. If we think about Zanza as a potentially best-in-class TKI and we see the success that Welireg has had, as a monotherapy and in some of those early combinations, we and our partners have been intrigued about the potential for the combination of those two mechanisms, being able to benefit patients. Again, you know, the way we think about it, Cabo will never have a label in combination with a HIF-2α, with belzutifan.
Yeah.
We want to develop Zanza in a way that maximizes, you know, its opportunity, but also has the potential to candidly establish a new standard of care.
Right.
Because at the end of the day, drugs are successful because of that. Cabo's successful not because it's approved. It's successful because we were able to generate a dataset with 9ER that establishes the new standard of care in frontline RCC.
You know, what's most interesting there, 'cause I think when those studies got announced, my head was like, okay, you had those IPI, NEVO, Cabo studies, lot nice response rate, durability not there because, you know, the side effects weren't working. And then I would thought, okay, you can plug in HIF-2α, but it doesn't necessarily seem like you guys think about this as a triplet. You think about this almost more like a doublet. Is that, is that fair to say?
Yeah. Again, without kind of getting into the specifics of the trial design ahead of kind of the launch of those studies, I think the more important dynamic is to think about Zanza in combination with the HIF-2α, and kind of stay tuned on all of the specific details there.
Cool. Looking forward to it. Now maybe just on Zanza and differentiation, the way we kind of think about it is it's not like, okay, if you have a table and at any point did a patient have grade three proteinuria or did they have hypertension, it's Zanza's a shorter half-life drug, right? I don't think you're going to have a patient not have a grade 3 adverse event. The point is once that grade three adverse event occurs, how quickly can you down-dose a patient and keep them on a very high dose of VEGF inhibition while still being adherent on the medication? To me, this might be not a safety, in terms of just absolute safety differentiation, it's more about discontinuations and then a better translation from PFS to OS. Is that the right way to think about this?
Like how, if Zanza will differentiate in some of these indications, is that the angle you're going after?
Yeah. I mean, you know, I think one of the dynamics there, you're kind of spot on. You know, imagine a patient who's on Cabo Nevo for frontline RCC and they develop an adverse event and kind of the treatment algorithm, the, you know, AE management algorithm basically suggests dose hold to resolution of symptoms, down-dose to a lower dose. Given Cabo's half-life that I mentioned before is roughly 100 hours, and given its accumulation in plasma over time at steady state, that washout period towards resolution of symptoms can often be 10 days, 2 weeks, even longer. Imagine you have a patient who has an adverse event, and all patients with TKIs get them, that has potential overlap with a checkpoint as well.
Mm-hmm.
As a physician and as a patient, you have to try and understand, was this Cabo related? Is this Nevo related? Do I hold one? Do I hold both? If the patient is, you know, has metastatic cancer, it's a challenging just dynamic to kind of work through. Obviously, you know, Cabo's successful and it's something that physicians have learned to kind of do. Our perspective was if you can impact that half-life, that period of time where you're kind of in that dose reduction, dose management, AE management phase, that's the more important thing because simplistically, patients generally don't benefit from drugs that they're not on.
Right.
When we thought about why we wanted to develop Zanza, it was really about that combinability, that dynamic around having a more user-friendly, a more patient and physician-friendly TKI that acts as a backbone. That was really the dynamic that kind of shaped a lot of it. You know, again, we'll see in the cosmic truth on how this reads out in phase 3 studies. You know, that ability to have a more kind of user-friendly experience because of the shorter half-life is something that, you know, we always sought out as kind of the core driver around development. All of the other stuff on the margin of, you know, maybe we're seeing some differentiation in certain areas, some safety, you know, certainly potentially intriguing signals.
You know, one of the common themes I have is I look externally at a lot of these kind of smaller company assets. The caveats and challenges of interpreting small and unrandomized clinical data is, you know, significant. We got a lot of questions coming into this weekend around what's gonna be at ASCO. We're excited to share the data, really think that it shows that Zanza's an active molecule. At the end of the day, the much more de-risking events for us as we think about Zanza longer term are the phase three studies.
A couple to, one that sounded like head and neck, but, number two, I just wanna put a finer point on this. It seems like the safety differentiation should manifest in terms of efficacy because patients are gonna be on a higher dose for a longer period of time. Like if, again, if you're just asking an investor, like, 'cause it's not like you don't say, you're not, when I, when I talk with you, you, you don't say Zanza's not differentiated. You're just saying it's too early. Is that fair to say it's gonna be PFS and OS and discontinuations that we should be paying attention to, or is there something else?
I certainly think there's a point of that dynamic. Again, taking a step back, you know, to where we started, we again don't really think about it as Zanza versus Cabo and the differentiation.
Gotcha.
Because it's really about how is Zanza different and/or better than Rego.
Got it.
How is Zanza different or better than Sunitinib? How is it better than pembrolizumab therapy and 305? How is it better than everolimus and NET for 311? To me, that's actually the much more relevant dynamic. Certainly there's gonna be a lot of comparisons, across the, you know, cross-road comparisons, all of this stuff. When we on the third quarter call talked about Zanza having a $5 billion market opportunity across all of the six studies that we're running, that's actually in reference to, you know, all of these standards of care that we're comparing it against and not, you know, this.
That makes sense.
Yeah.
And by the way, for that $5 billion, what are the, is it fair to say the Merck studies are the two biggest contributors to that number, or are we maybe underestimating Zanza in NETs? You know, how do you break down that figure?
Yeah. We think about it roughly as about 45% GI, 45% GU, and 10% head and neck. The GI piece, if you think about our business right now, it's probably 90-10 GU, GI. Our aspirational goal over time, if we think about Zanza and Cabo growth and net, is a much more balanced dynamic between those two categories. The GU piece is obviously the three RCC studies. It's the two Merck studies and the non-clear cell. Non-clear cell's about 20%.
Right.
Of all of RCC utilization right now is a little bit of a hodgepodge across all approved therapies in kidney cancer, just a, you know, because of the dynamic around labels are inclusive of that. Then, use is driven by kind of guidelines around, you know, unrandomized single-arm data, things like that.
Yeah.
but the GI piece is then kind of the 311 study and 303. And as I mentioned before, kind of a billion-dollar opportunity across CRC. and we framed at least kind of that later line current net opportunity at around a billion dollars. And as we think about moving, earlier, tend to have more patients, tend to be on drug longer, that sort of dynamic. so it, it's kind of that 50/50 balance or plus minus that.
I think the most interesting thing about the breakdown you gave there is you would think head and neck would be bigger, right? I mean, if you think about what are the darlings in oncology, and there are not that many, there's a few of these bi-specifics. And, you guys have a frontline study you're running, right? And I, you know, I've talked to Mike about this before, and he is like, "Look, Akash, like you talk about single-arm uncontrolled data, you'll often have, you know, sites enroll healthier patients." I mean, and this is not just a comment on this line in specific, specifically you see this in oncology across the board. You have a 53% response rate with Cabo and Nevo, right? You have a lot of N in that, in that indication. so when you think about the Merck partnership, it sounds like Zanza plus Pembro.
You kind of have the same two components, maybe version 1.15 version of some of these drugs. When you're seeing all these other datasets and they're showing higher response rates, how, as an investor, can we feel like Exelixis has a plan to win in that head and neck arena? It almost implies you're going for subpopulations in head and neck, maybe not the whole pie. Help me understand that.
Yeah. I actually think it's not really about kind of that, that latter comment. If anything, when we look at that $5 billion market opportunity, it's a good example of, candidly us being public-facing and passing the red face test is kind of what, what, you know, when we talk internally about, you know, market opportunities or projections, what's realistic? Does the model need to have 65%, 70%, 80% market share to kind of make the math work? I think it's a relatively believable, reasonable, conservative assumption as to say, you know, the reality is, is that you can draw some comparisons between, say, RCC 10 years ago and head and neck.
Mm-hmm.
The RCC pie has grown over time because there have been drugs and therapies, to really help patients live longer. Hopefully we're successful in kind of growing that pie overall. I'd much rather be in the position of say, you know, we think it's a $500 million opportunity, but if we're wrong on the upside, that's great.
Right.
I'd rather not set an expectation that assumes, you know, very challenging kind of share or duration or pricing assumptions. I'd rather say, okay, let's start from a place that $500 million is reasonable.
Right.
Large market and hopefully we'll generate a dataset, to improve upon that. You know, it's just.
You're talking about like 10-15% penetration. That's what you're saying.
Yeah. It's, it's something that, you know, we wanna make sure that, we're realistic, in setting expectations. Kind of getting back to your point on the, the Pembro Zanza piece, again, we looked at Merck's prior dataset from LEAP-010 as a signal that clearly an IO-TKI is active in the space. They saw robust benefit on response rates. They saw robust benefit on PFS. Unfortunately, that didn't translate to overall survival. The question that we asked is basically using the lens of the prior Cabo Pembro data as a starting point. I'd certainly, you know, echo Mike's comment that, you know, there's inherent challenges in interpreting phase one data from here and here and here. You know, to us, they're probably more similar than different.
Right.
but we can look at that data as a starting point, layer in the learnings from LEAP-010 and ask the question, can a potentially more user-friendly TKI plus Pembro, you know, replicate a lot of that benefit on responses in PFS, but also translate to survival? That's really the question of 305. Again, we'll find out, you know, the cosmic truth is gonna come out when that card flips. It's really using all of that information we have at our fingertips to, you know, drive investment in a market we think can grow.
A couple things just to wrap on that. Number 1, there are 2 cuts in terms of head and neck where I feel like none of the companies are really thinking about. A, you've just seen Pembro get approved in first line. A lot of first line's gonna change. It's gonna be basically post PD1. You know, it's interesting, your datasets post PD1 might be much more comparable to some of these early bi-specific datasets. Is there any appetite to run studies post Pembro or given that the adjuvant approval's gonna really change what first line looks like? Number 2, we saw this with the Pfizer PD-L1 ADC that had data at ASCO, the HPV positive and HPV negative, there's different profiles that some of these treatments show in those populations.
Is that, so post Pembro and then HPV positive and negative, are those areas where you feel like a VEGF TKI combo could actually differentiate here?
Yeah. I mean, you know, a couple of dynamics within that. I think our experience with at least taking the learnings from LEAP-010 is probably HPV status is less relevant than, say, maybe the EGFR bi-specifics are trying to kind of frame that dynamic.
Interesting. Yeah.
Maybe it is, maybe it isn't. We haven't seen as much of a kind of clear difference, at least looking at the mechanisms that we're evaluating. As it relates to kind of other studies, other opportunities in head and neck, I think the way that we think about Zanza is wave one is kind of the 6 studies that we've outlined right now, expect a wave 2, expect a wave 3. We think that Zanza has the potential to be a broadly active, you know, backbone therapy, so to speak, across a wide range of tumor types. Head and neck certainly is one of them, especially if we're able to kind of read out positive data in 305. The other dynamic that I'd kind of layer in there is that, take the Merck collaboration as a model, or even going back to 9ER in Bristol.
One of the things that we've talked about is, you know, there's this through line or, you know, kind of tongue in cheek comment that we make sometimes is that we run Exelixis like a business and not a biotech.
Mm-hmm.
We are particularly thoughtful about expense management, how we think about new studies, how we think about just running the company. One of those dynamics is if you look at a lot of these studies that we are running, they are actually in combination with partners where there is risk sharing, where there is cost sharing.
Right.
As an example, the 9ER study, we ran that with our partners Bristol, or Bristol ran it. We paid for half, they paid for half. Actually, Ipsen and Takeda, who have ex-U.S. and Japanese rights, paid for half of our half. That was a really capital efficient way to develop and run a large pivotal study. You know, similarly with Merck, functionally we're running three studies with them where each paying for roughly one and a half.
Yeah.
Sharing free drug. I would say an important dynamic to look for going forward is we like that model and we wanna replicate it. It allows us to have a broader ambition for Zanza for that next wave and that next wave and that next wave while remaining capital efficient and, you know, candidly just thinking about spend in a probably more disciplined way than many of our peers.
Is it fair to say in terms of potential partnerships going forward, I mean, you've done mostly with large companies when we think about Cabo development. The Merck deal does not exclude you partnering with other large cap players in the space when you're exploring that kind of VEGF signal across the board, 'cause there's certainly other indications.
Yeah.
Okay. Let's just hit on commercial performance. I thought what was most surprising last year, your management, the management team was pretty clear. Their first line RCC, we're seeing uptake kind of start to plateau. We shouldn't expect that to grow much more come towards one year later. You're actively taking share in first line. I wanna understand, is that patients waterfalling or is that actually new patient starts are now starting to trend the other way? How does that occur so late into a launch? I think investors don't understand.
Yeah. I mean, you know, again, a little bit tongue in cheek, drugs are successful or drugs perform based on the data and based on the team. And the data, we obviously had a 5-year update to 9ER at ASCO GU earlier this year. I think it's a dataset that frankly continues to resonate with that physician prescriber base. On the team side, you know, I think we certainly believe that we have a best in class commercial organization, not only in biotech, but across pharma as well in that kind of GU landscape. We have the ability to do things from an analytics perspective that allow us to continue to kind of be very targeted and take share.
You know, certainly we see that stacking of patients of long duration over time, but our team continues to have their foot on the gas, continues to focus. I think one of the challenges that our bigger competitors, bigger peers have is that, you know, we have the ability to just focus on Cabo.
Right.
They do not. And so having a team that is completely dedicated and focused to maximizing the value of Cabo, that is an advantage.
All right. I'm gonna stick in one more question. I know we're out of time. NETs launch, I think the big question is there is obviously use of Cabo in that population already, but there's something about getting it reimbursed, getting it on the label. And you guys were pretty clear the increase in guidance was not necessarily NETs driven. Is there going to be a bolus on the NETs population once that approval gets online?
Yeah. PJ talked a little bit about this on the 3Q call. Given the later line and more advanced stage of disease that these patients, generally we do not expect a bolus with kind of these late line patients.
Right.
What I can say is that the dynamic that we have talked about around Cabo and NETs is that there's this inherent familiarity with Cabo that physicians have. And, you know, one of the things that we've seen early on that we've talked about is we're seeing scripts for the 40 mg dose. Approval's at 60, but 40 milligrams is indicative that these are physicians that use Cabo for, say, 9ER.
Mm-hmm.
Are familiar that that 40 mg dose is still very active, but more, uh, kind of more tolerable.
Sure.
More gentler. And so it's kind of an early sign that I think is really positive that those kind of NET physicians have this familiarity. And so, you know, we've said that we'll update the street when we have a better sense of that launch trajectory. But some of the early signs that we're seeing on KPIs are really encouraging.
Got it. Thank you so much. I really appreciate everyone for joining us early in the morning. Andrew, thanks.
Thanks.
Thanks. That's awesome.