Today, our 44th Growth Stock Conference. I'm Andy Hsieh, one of the biotech analysts here. So with me today is Andrew Peters, Senior Vice President of Strategy at Exelixis. We've been covering Exelixis for a long time, really seeing the complementary growth and now pipeline growth with the baton passing to Zanza, some ADC assets, which we'll spend time talking about. Before I get started, for a full list of disclosures and conflicts, please visit our website. So Andrew, thanks for joining us today.
Yeah, thanks for the invitation. Yeah, exactly.
Yeah, so maybe to get people started, kind of brief history of the company, especially with Cabo, how we got here, and then in terms of the indications, right? So RCC, HCC, DTC, how should we think about kind of the revenue breakdown of those contributors?
Yeah, happy to get into it. Again, thank you for the invitation to present here in Chicago. Capping off what was a great ASCO for us, certainly busy, certainly hear it in my voice about all of the great conversations we had over the course of the week in Chicago over at McCormick Place. Before I start, just let me add my list of relevant disclosures around the risks related to our business. Please see relevant SEC filings around those. Exelixis is a commercial stage oncology-focused biotech company with our core product, CABOMETYX, approved, as you said, in a couple of different or three different indications, but really kind of the bulk of that revenue coming from RCC or kidney cancer.
Cabo has kind of had a long and storied history of development, and it's one that I think provides a really good example of kind of the trials and tribulations of the industry. Biopharma is a tough business, but ultimately also shows that good data really helping patients live longer, better lives can really translate to success and build value commercially and build value as a company. So the CABOMETYX business really in RCC started off with second line plus in the METEOR trial as a monotherapy, then CABOSUN as a monotherapy and front line, and then finally in combination with nivolumab in the CheckMate 9ER study. And so that was launched in early 2021 and has really helped grow the business. We've given guidance for product revenue this year between $1.65 billion and $1.75 billion. That's U.S. revenue.
We're partnered with Ipsen and Takeda and the rest of the world in Japan. Cabo is really a success story in the biopharma business and just kind of shows what great data can do. Behind that, we have zanzalitinib, which we developed as essentially kind of a third-gen VEGFR targeting TKI. If you think about Cabo as a second-gen VEGFR targeting TKI, which improved upon some of the limitations of those first-gen agents. Similarly, Zanza improves upon, we hope, kind of the limitations with Cabo, notably its long half-life. So Cabo has around a four-day half-life. We engineered a metabolic liability into that kind of core Cabo scaffold where we're able to phenocopy the kinase inhibition, kind of the secret sauce, so to speak, of Cabo's efficacy and really improve upon that PK profile that's been one of the limitations there.
So Zanza is currently in three phase three studies in colorectal cancer, non-clear cell RCC, and head and neck cancer. And then beyond that, we have an additional pipeline of both biotherapeutics, ADCs, antibodies, and small molecules, notably USP1, XL309, in kind of the synthetic lethality space. So excited to get into kind of lots of questions today. Certainly an interesting time for Exelixis, an exciting time for Exelixis, waiting for clarity and resolution of the ANDA with MSN, which has certainly been an overhang on the stock on the company over the last several years now. And we're just looking forward to getting clarity there.
Great, great. So maybe we can dig a little bit deeper into the Cabo expansion opportunities in the very near term, right? You have the NET trial that could potentially expand the growth, also the prostate cancer. So maybe talk about those two and where you are in terms of the regulatory queue.
Yeah, so when we gave guidance, revenue guidance earlier this year, we really framed it as kind of a 2024 and then a 2025 and beyond story. When we talk about 2024, unsurprisingly, if you think about most oncology launches, it takes between 5-7 quarters on average to kind of hit steady state per indication. We're now 12+ quarters in post-9ER. And so unsurprisingly, we're starting to see kind of a maturation of that frontline RCC market. Still seeing incredibly strong demand. Cabo is still the number one TKI, both as a monotherapy as well as in combination with a checkpoint inhibitor. But really, guidance reflects kind of the maturation of the market.
What we have also said is following two positive Phase 3 readouts last year, one in prostate cancer and two in neuroendocrine tumors in the CABINET study, we're looking forward to filing and potentially launching in those new indications to really re-accelerate and reinvigorate the Cabo growth kind of in the mid- to long-term. And so both of those opportunities both reflect candidly data sets that really show the unmet need for that population, the strong data that Cabo was able to generate. First in prostate cancer is the first study kind of post-NHT looking at truly a high unmet need, high-risk population.
Patients in the CONTACT-02 study, that was the study that we read out in prostate cancer last year, all had visceral metastases at baseline or extranodal adenopathies, which is really kind of a different patient population than most prostate cancer trials just because a good chunk of prostate cancer is actually kind of bone-only or bone-predominant. The reason we enrolled this study, not only because there's such a high unmet need in this group, but it really enabled us to ask and answer the question, does the addition of Cabo to atezolizumab have the ability to shrink tumors there and allow us to really look at something that's quite clear, like a RECIST response?
And so that data read out positively on primary endpoint of PFS, and we've guided that we're planning to file for approval later this year once the final overall survival data are available and mature. Similarly, with neuroendocrine tumors, the CABINET study also read out actually in the same week as CONTACT-02, a good week for Exelixis and importantly, a good week for patients. That's another one that the more we've kind of dug into the NET opportunity, I think the more we've been excited, not only like prostate where there's a real unmet need for patients, but it has the potential to be kind of the first new small molecule approved, I think, since 2016.
Right now, kind of there's obviously the radiotherapies that have been quite successful commercially, I think despite some of the challenges as limitations of that modality, just given the logistical complications of giving radiotherapy, as well as just from a patient practical management perspective. Certainly been eye-opening to me when I hear patient and physician experiences with these sorts of patients and these sorts of therapies where a woman or a physician described one of his patients where she was a kindergarten teacher and had to make a decision about whether or not she wanted to receive treatment or not because their patients are practically or functionally radioactive when they're receiving therapy. And so we view LUTATHERA as basically an example of indicative of the size of the market that we're potentially launching into.
So the NET data, it's not every day you can see an HR with a 2 in front of it, we like to say, and it really just shows kind of the benefit we can have with Cabo and those sorts of patients. So both of those we're excited about. Kind of obviously, number one, operational priority internally at Exelixis is getting those filings in as soon as possible so P.J., our head of commercial, can go out and try and sell and help as many patients as we can.
Great, great, great. So I guess maybe let's talk about some of the bottlenecks, as you will, before submission to the FDA. So for the NET, let's talk about the transfer of data, right? Because this is basically conducted by an external collaborator. So there are some things that need to be verified, QC'd, and things like that. Could maybe talk about that dynamic and how long that's going to take?
Yeah, so without kind of giving specific guidance on when that's happening, I think one of the advantages we have as a company is CABINET or not CABINET, CABOSUN was actually filed and approved similarly through a cooperative group. And so going through the process of designing the CABINET study, we certainly took a lot of those learnings from CABOSUN and incorporated them into the protocol, into just how kind of the study was run. And so we have experience kind of making that handoff, that transition, so to speak, knowing what to look for, what some of the hurdles and challenges can be. So I think Exelixis as a company is and was as well prepared for that process as we could be.
Obviously, there's a lot of things just that take time and need to get done in terms of central review and BICR and all of this stuff. But I think, as I mentioned before, operationally, it's certainly been our priority this year. And it's an all hands on deck process. So we're certainly focused there.
Okay. And then moving on to the prostate cancer space, right? Novartis basically had a hazard ratio greater than one. Now it's below one, and then they said they're going to submit to the FDA. It's a little bit different dynamic because you do have hazard ratio below one already. So maybe how do we think about that dynamic?
Yeah, just I think a lot of that really comes out of just a broader FDA perspective around wanting a mature data set when evaluating kind of the clinical benefit of any new therapy or any new combination. Certainly, I think you could point to lessons learned, say, from the PARP class where maturation of data pointed towards perhaps maybe a detriment in overall survival kind of as that early data matured. And so I think a lot of FDA's general guidance, not even specific to CONTACT-02, is around kind of wanting to make sure that that survival data is as mature enough to really have an understanding. Is the effect size that you're seeing, say, either on response rates or PFS, is that translated in at least not to have a detriment to overall survival?
You mentioned kind of Novartis in their recent messaging around kind of their HR going below one. Certainly, the data that we've presented so far, trend towards overall survival, certainly well below one is a good starting place. And so what we've said is we want to wait for kind of the more mature final survival data before we submit just so we have kind of that data in hand. But everything that I talked about before in terms of the patient population, the high risk of that group, high unmet need, certainly we think there's a strong compelling rationale for having the Cabo-Atezo combination for patients.
And maybe this is kind of a hypothetical question. I think you've done a lot of work back in the Cabo days looking at, hey, what are some preceding treatments and what's the outcome if you get on Cabo treatment? For the NET opportunity, did you kind of break out some of the preceding treatments, either radioligand, either long-acting octreotide, and see if there's any sort of response?
Yeah, so a lot of that data kind of stay tuned hasn't been presented yet. But if you look at kind of the data as it's presented in CABINET, I think really kind of goes to the multiple prior therapies that patients had there across everolimus, SUTENT, LUTATHERA, etc., and really shows that it can be NETs, NETs, epNET, pNET. CABINET was actually two separate studies. It's a pretty heterogeneous disease to begin with, and treatment options are somewhat limited, but patients get a little bit of everything over time, in particular in the SSAs. And so I think kind of the data as it's presented right now really show kind of compelling opportunity for Cabo. Don't really want to get ahead of what a potential label could look like and how that's sliced and diced.
I think, as I mentioned before, a lot of my scratchy throat is in part having a lot of conversations with KOLs and a lot of that enthusiasm about the data set and the opportunity in NETs really kind of came through this weekend in Chicago.
That's great. Very encouraging signs. So moving on to Zanza, the next generation TKI. So three potentially pivotal studies. Do you mind kind of walking through all of them and where they are in terms of the enrollment status?
Yeah, so as I kind of laid out earlier, Zanza really kind of builds upon kind of the Cabo foundation. We used and really have the benefit of having Cabo data inform where we're going with Zanza. I think that's something that is probably underappreciated. I spent a lot of my time looking externally on the potential to bring in new assets into Exelixis. I think kind of that dynamic where we can really use not only kind of the Zanza data that we've generated so far, but the years and years of experience with Cabo to help kind of de-risk and inform where we're going with Zanza. So the first of the pivotal studies is STELLAR-303. That's in third line plus colorectal cancer. That's comparing Zanza plus Atezo versus regorafenib.
As Amy mentioned on the last earnings call, that's the most mature of the studies, and we would expect enrollment to complete sometime soon. Generally, we'll give guidance once we complete enrollment on kind of when to expect the next updates. Obviously, overall survival is a primary endpoint, so it's event-driven. A little bit challenging to kind of give specific guidance on when to expect data, but once enrollments complete, I think that kind of starts to narrow those timelines. One of the things that I often talk about when discussing 303 is really kind of informs the Exelixis strategy and perspective on Zanza development, where not only are we able to use everything we've learned about Cabo, but we can also look to other IO plus TKI combination studies and really use those to inform, say, trial design.
303, we amended the protocol once the full data from the LEAP-017 study of pembrolizumab plus lenvatinib was available. Really what that showed us is a way that we think we can increase the probability of success of that study being successful, not only first in the primary analysis looking at the non-liver met population, because data are increasingly coming out that in colorectal cancer in particular, there's a real distinction between the liver met and non-liver met population. Similarly, in terms of effect on regorafenib versus TAS, that dynamic certainly kind of plays into our amendments and then some of the powering assumptions there. So 303 study we're excited about, again, based on some pretty compelling data from Cabo previously and really designed with an eye towards trying to maximize the likelihood of a successful study.
Similarly, on the kind of favorable risk side, I would say 304 is a study of zanzalitinib in non-clear cell RCC. Obviously, this study builds on the success that Cabo has in the RCC landscape, but really is an opportunity to really define a standard of care in that exact subset of kidney cancer. So non-clear cell RCC, while all of the available small molecules have a label that's encompassing of the non-clear cell subset, there's actually no definitive kind of pivotal data to really define that. And so what 304 does is really kind of builds upon what we know is a particularly sensitive tumor type to this sort of combination and really allows us to kind of be at the forefront and define what a standard of care is. And then lastly, on 305, another IO-TKI combination of building upon some Cabo data in frontline head and neck.
That study is looking at Zanza plus pembrolizumab. And again, we can certainly take a lot of the learnings from other IO-TKI studies, notably LEAP-010 and LEAP-010 that Merck ran and can really help shape and define why we're excited about that. Certainly at this ASCO, a lot of data in head and neck, but we certainly think that between Zanza and the Cabo data, we certainly set a high bar. And we think that the improvements, if you think about kind of that spectrum of first gen to Cabo to Zanza, a lot of the improvements around tolerability, potential combinability, ease of use, titration, etc., helping patients stay on drug can potentially translate that robust response rate and PFS benefit that LEAP-010 saw into survival, which is, given the discontinuation rate, unsurprising that you saw their data. So those are the three pivotals.
We've also talked about kind of the breadth of the Zanza opportunity going forward, about novel doublets, novel triplets, but really excited about potential clinical collaborations. As I've said often, we kind of view everything through the Cabo lens. One of the experiences we had with Cabo is understanding the value from an investment perspective of having clinical collaborators contribute not only the other agent in a combination, but contribute financially as well. If you look back at the 9ER study, that's the frontline RCC study with Cabo and Nivo. Bristol paid half, we paid half, our partners, Ipsen and Takeda, paid half on our half. From a return on investment perspective, 25 cents on the dollar for a study like that, which more than doubled revenues, is something that we're certainly interested in and excited about exploring that sort of potential with Zanza.
Certainly, I think it's safe to say that the data we've presented with Zanza so far, notably at the IKCS conference last year, certainly has stood out to a lot of the leading checkpoint companies and really helped kind of define and generate a lot of that excitement. So again, I'll point to my scratchy throat as a lot of Zanza conversations over the weekend, so.
Yeah. Yeah. I remember on the first quarter call, it was discussed, Dana kind of talked about different compartmentalization. So maybe kind of talk about some of the hypothesis-driven work to really characterize why this compound could be used.
Yeah. So if you look at the data that we presented at IKCS, I think a couple of things jumped out. First, obviously the activity. We all hate to do it, but cross-trial comparisons, Cabo looks or Zanza looks just as good, if not potentially better than Cabo on the efficacy side. Not only are we seeing response rates with a six in front of them in that kind of non-VEGFR or naive population, but we're actually seeing durable responses in patients who are actually Cabo-experienced as well. So that's kind of the first bucket. But I think that the second bucket that you're getting at is around the tolerability. And that's something, while early and we need to see additional data as it matures, shows both kind of from a frequency and severity of adverse events perspective, Zanza actually looks reasonably differentiated.
And so the work that Dana talked about on the last call that you're describing really reflects trying to kind of tease out why exactly are we seeing that beyond just the obvious half-life differences. And one of the things that we're starting to see, unsurprisingly, when you change kind of a lot of those PK half-life dynamics, things like protein binding, tissue distribution can be different as well. And so if you think about some of the hallmarks of VEGFR targeting TKIs like PPE or hand-foot syndrome, if you have differential distribution between the tumor and normal tissue, skin, etc., unsurprisingly, you would see kind of less frequency and importantly severity of those sorts of adverse events.
So that's the sort of thing we're going to continue to evaluate over time, but I think is just frankly a good example of our excitement around Zanza and kind of the breadth of that platform and why we're investing.
Yeah. Yeah. All right. So I think it's a good segue to kind of ask some non-science, non-clinical questions. So one thing about you mentioned about the IP litigation, the verdict's coming imminently, hopefully. That would really clarify, remove an overhang. But on the peripheral side of things, there's 2 settlements on Cabo. I'm curious if there's anything that can be read through just because the proposed settlement date for generic entry is actually identically, right? January 1st, 2031.
Yeah. So I think it's a little challenging, candidly, to read across the Teva Cipla to MSN in that they're functionally different types of cases. And in general, given the ongoing litigation, we don't like to talk about a lot about MSN. But from the very highest level, I think Cipla and Teva were just straight Cabo generics, where MSN is slightly different and they're actually developing their kind of Form S, which is a different polymorph of Cabo. And so from a kind of settlement, just overall legal strategy perspective, they're just functionally different. And so getting the Teva and Cipla cases settled provides kind of that clarity and that certainty on those cases. And we're just waiting for that additional clarity and certainty on the MSN case, given that it's essentially around a whole separate set of issues.
Yeah. Yeah. All right. And then maybe a little bit about stock buybacks, right? First time in the history of company, $550 million buyback, followed by $450 this year. How should we think about the buyback topic going forward?
Yeah. So buybacks have been something that we've talked about, candidly, going back years and years and years and years. It's something that we always joke internally and externally that we run the company like a company, not like a biotech. And so we're always evaluating kind of what we can do best for the business. Obviously, we view our balance sheet and our profitability as strategic assets. I mentioned I spent a lot of my time looking externally to potential products and companies that we can partner with. And certainly, we've done a whole host of, candidly, smaller business development transactions over the last several years. But we're always kind of balancing that optionality with the balance sheet on what's right for the stock, what's right for shareholders, etc.
So last year and earlier this year, we decided that buybacks were appropriate given kind of our view on the company's valuation, our view on pipeline going forward, and everything like that. So we made the decision at the time to first do that $550 million and second that $450 million to bring it to $1 billion over this year and last. I'm not going to give guidance on what we're going to do in the future, but I think it suffices to say that we're kind of always evaluating opportunities and we're going to try and do what makes sense for patients, shareholders, etc.
Yeah. All right. And then one kind of macro topic as well. A lot of large companies are talking about Medicare reimbursement redesign on the first quarter call. So can you maybe qualitatively describe the potential impact for Medicare redesign, potentially in 2025?
Yeah. So just as practice, we don't talk about kind of next year until we're not going to Mike's comments always, we're not going to give guidance on guidance. But I think at a very high level, again, one of the unique positions or positions that Exelixis has is that we are kind of a small company still. We consider ourselves a big small company, but we're a single product company for the most part. And so a lot of those carve-outs and exemptions that were really put in place for IRA certainly are applicable for Exelixis. And so a lot of the dynamics around patient out of pocket, certainly we think are great for patients. And we've heard a lot of feedback as much.
But from our business perspective, we think we're a little bit shielded, at least given kind of a lot of those small company carve-outs without getting into any of the specifics.
I see. All right. And maybe one last question, which also related to some of the big macro things we've heard. A lot of crackdown on WuXi, and it's a big ADC player. You have a big ADC pipeline. Any sort of impact here as you kind of progress these assets potentially to late-stage development?
Yeah. I mean, I think as it relates to that specifically, very minimal to no exposure. So not something that kind of keeps me up at night going forward. I think, again, everything we do at Exelixis kind of is filtered through that Cabo lens. And so ideas around redundancy and supply chain and all of that certainly come from a position of experience that we have. And so no, not something that keeps me up at night.
Okay. Great. Well, thank you so much for joining us. Thanks, Andrew.
Yep. Thank you.
For sharing your perspective.