Hello, everyone, and welcome to Oppenheimer's thirty-fourth Annual Healthcare Conference. I'm Jay Olson, one of the biotech analysts at Oppenheimer, and I want to thank you all for joining us here today. It's my pleasure to welcome Exelixis to our conference, and it's an honor to introduce Varant Shirvanian from IR, and Andrew Peters, Head of Strategy. If you guys have any questions during this discussion, please feel free to submit them using the Q&A function. With that, we'll get started. Thank you so much, Andrew and Varant, for joining us today. Yeah, thank you. Thanks for the invitation. It's our pleasure. So maybe for those in our audience who aren't fully up to speed with the Exelixis story, do you want to get us started with kind of maybe some updates on some of the key milestones from last year and anything that you'd like to highlight? Yeah, happy to. And, before I get started, just as a reminder, we may be making some forward-looking statements today, so please see any relevant, disclosures in our SEC filings for risks, to our business. Yeah, so, Jay, as a little bit of an overview to Exelixis, we're a commercial-stage biotech company, focused primarily in GI, GU, thoracic, lung oncology, kind of the solid tumor space, with our lead product CABOMETYX, approved in several tumor types, but really kind of the main driver there being in renal cell carcinoma or kidney cancer. For Cabo, we've issued financial guidance for net product sales this year of $1.65 billion-$1.75 billion, and we're really using that kind of financial success that we've had to, one, both kind of run the business in a very disciplined way, as we showed earlier this year with kind of the announcement of our second set of share buybacks that will total $1 billion between last year and this year, and then also investing in the future. I'm sure we'll get to it later on, but we have 2 or 3 now clinical stage pipeline products including zanzalintinib, a next-generation VEGF-targeting TKI that really builds upon the success and kind of the uniqueness of Cabo, but makes some improvements upon it as well. Then there's XB002. That's a tissue factor targeting ADC. Again, kind of a next-generation version, which we think, builds upon kind of the, the predicate molecules, that are out there. And then, XL309, that's a USP1 inhibitor, that, we announced is now in the clinic. That's again, you know, a molecule we're really excited about. We think is, is certainly best in class. From an overview perspective, I, I'd really kind of point to two additional things. We held an R&D day in December, which I'm sure, you know, you're very familiar with. You were, you were there. But for those in the audience who didn't listen, I certainly think it's worth an hour or two of your time to really understand everything from a science and strategy perspective, kind of what's involved in our early-stage portfolio. You know, where we're going with Zanza, where we're going with XB002. And then I think Mike did a particularly good job earlier this year at the J.P. Morgan conference to kind of set up kind of the business side of the company. So we have two kind of bookended presentations over the last several months, kind of first with the science side and then second, you know, about how Exelixis runs the company like a business, which I think certainly separates us from a lot of our biotech peers. Great. Thank you so much for that overview. And yeah, those—I totally agree with you. Those are two excellent reference points with a lot of... packed with a lot of information. So with that, maybe we'll jump into Cabo. Congrats on a solid full year 2023 performance, as Cabo continues to be the top TKI in renal cell carcinoma. I guess the question is, when you're growing off of such a large base, how do you sustain that growth, especially given the several years you've had of a very high growth? And how do we think about the market opportunity for Cabo in the established indications in the next few years, especially with potential impact from the IRA? Yeah, so that's actually something that we focused a lot about, especially kind of coming out of the J.P. Morgan conference, where we gave net product revenue guidance for the year. I think unsurprisingly, you know, mentioned—you mentioned kind of the two biggest dynamics there is, you know, growing off a larger base, the success of Cabo. Obviously, the bigger the denominator, the more incremental revenue you need to you need to grow. But secondly, you know, if you look at most oncology launches, they tend to start to plateau around quarter 5, 6, 7 or so, and we're now 12 quarters in plus, post 9ER. That's the phase III data of Cabo plus nivo in first-line RCC. And so unsurprisingly, we're starting to see a little bit of the slowdown. The good news is when you look beyond kind of this year, we're excited about two new potential indications, one in the NET side, the neuroendocrine tumor opportunity, as well as in CRPC. So, you know, Cabo growth going forward as the RCC opportunity is starting to slow, is really going to be driven by new indications. Most oncology products grow that way. Cabo is no different. And really kind of the data sets that we presented with NET at ESMO last year, and then earlier this year at ASCO GU with the CONTACT-02 trial in CRPC, you know, that's really what we're excited about, kind of the Cabo growth profile going forward. Okay, great, and thanks for mentioning NET and metastatic CRPC. Those are two areas that we wanted to dig in a little further. Maybe starting with NET, we saw the super impressive data from CABINET at ESMO. Can you just talk about the next steps as you prepare for filing? And also, if you could just help contextualize the market opportunity for pNET and epNET, especially as Lutathera moves to earlier lines. Yeah. So I think this is one we're especially excited by, and it's probably a little bit under the radar for many investors. NET is kind of a reasonably large indication, in part driven by kind of a large prevalent population of, you know, patients who tend to have a reasonably kind of slow-growing disease, but, you know, fairly high burden. There are effective therapies out there, but unfortunately, patients do become resistant and refractory, and so you see them over time, kind of running through several options. And so the CABINET study was one that really showed kind of the substantial and very robust benefit of Cabo, in a patient population who really doesn't have many options beyond that. I'm glad you highlighted Lutathera. We think, you know, that's a drug that does around $400 million plus in the U.S. in kind of a somewhat later line opportunity. And, you know, we think that's a reasonable approximation of kind of what the market could look like. Obviously, we're still doing a lot of work there from a market research perspective to kinda get a little bit more understanding of the nuances and specific dynamics of the NET market, but really shows that there's an opportunity there. And that's what kind of drives our excitement about the potential for additional Cabo growth in the future. The NETTER-2 data that was presented earlier this year for Lutathera certainly looked quite interesting to us. You know, we'll leave that to others to kind of better define that. But certainly, as Lutathera has the opportunity to move up in the lines of therapy, you know, patients will be looking for effective therapies to kind of help their disease burden. And certainly, the CABINET data would be suggested that that Cabo could fill that role. Okay, great. That's super helpful. Thank you. And then, maybe moving on to metastatic CRPC, congrats on the CONTACT results. We know there was a lot of interest in that study at ASCO GU last month. So I guess, look, you guys ran a really difficult and successful study, so kudos to you for designing that study and executing it. Showed for the first time a positive clinical benefit with a checkpoint inhibitor combination in metastatic CRPC. So super exciting. And could you maybe just highlight some of the key points of the study and maybe share some of the feedback that you heard from ASCO GU? Yeah. So, you know, certainly, we've been getting a lot of questions and feedback from the KOL community, from the patient advocacy groups, from the investment community about that study. And, I really think it's it one, our CMO, Amy Peterson, did a really good job on our last earnings call, framing a lot of the specifics, so won't want to repeat everything kinda that, that Amy went through, more in the interest of time than anything. But I think she went almost kind of point by point to really frame and reference a lot of the differences and nuances about CONTACT-02, that I think maybe got lost in a little bit of that conversation, after the conference. So this, you know, I’m glad you highlighted kind of the uniqueness of the study. It’s a patient population that truly does have a real unmet need. 100% of patients enrolled in the study had visceral metastases at baseline or extra-pelvic adenopathy. That’s kind of a much higher risk, more high unmet need group, compared to a lot of other contemporaneous trials being run in the space. You know, certainly there’s a lot of debate and discussion around the appropriateness of, excuse me, a second NHT as the comparator in the study. And again, Amy kind of framed that as well. But really, if you look at other contemporaneous trials, both prior to CONTACT-02 and those that are ongoing right now, really, in practice, second NHT is the best option for patients because there really is a desire to kind of delay chemotherapy, just given all of the issues from a tolerability perspective that many of these patients can have. And so, coming out of the study, it makes us even more excited about the data, looking at, you know, both the ITT population, the overall population, but then we think there's really compelling data coming out of some of those important subgroups, such as those with visceral metastases, where you saw... It has a ratio around 0.43 or so, and that's, you know, just really goes to show that the treatment effect here is substantial. You know, a tripling of the medians in that population. A lot of people haven't really picked up on it, but again, kind of doing all of the problematic cross-trial comparisons and caveats related to that. But if you look at kind of that liver met population as a subgroup in PSMAfore, for example, with Pluvicto, you know, they had a HR of around 0.41, I believe. And so really, kind of the two data sets are quite similar there. I think the big difference is we were looking at a distinct and defined population, really to understand and provide kind of the best perspective of, does cabo plus an IO have a benefit here? You know, obviously, Exelixis has a history of development of cabozantinib in prostate cancer. And so the learnings from the COMET studies certainly played into kind of, you know, our decision to really focus on this defined group first and then understand what are the areas that we can go in prostate afterwards with something like a Zanza, for example. Okay, great. Thank you for that, and I'm glad you mentioned patients with visceral metastases at baseline. Do you know what percentage of these patients fall into that category? And then, I guess, can you just talk about where you-- atezo plus cabo can fit into the treatment landscape for metastatic CRPC? Yeah, so we haven't really framed out exactly what that population looks like, other than I think P.J. at the R&D Day and then at our earnings calls has really said that we think the opportunity is still quite substantial. If you look at the unmet need and the number of patients with, you know, CRPC, it's quite substantial and quite large. And so that's a lot of what's driving our excitement and our belief that CRPC plus NET is really gonna be kind of the two key drivers of continued cabo growth, you know, going forward through the end of the decade. And so, you know, it's an opportunity that as we continue to do the work to understand what a potential label could look like, that will have a better understanding of kind of more specifics around what that is. So kind of stay tuned there, but, you know, needless to say, we think it's substantial. Okay, thank you for that. I think you mentioned that you would have a final OS analysis later this year from CONTACT-02. Do you-- are you planning to wait for the final OS before filing, and have you had any resubmission meetings with FDA? Yeah. So kind of, again, stay tuned there as we're kind of finalizing our regulatory plans. You know, somewhat of a statement of the obvious that conversations with FDA are, you know, continuing and have occurred. You know, what we've said in the past is the agency wanted to see additional, more mature survival data prior to filing, and so as we continue those conversations, we'll get a bit more final with our plans for filing. So stay tuned there, but the survival data are continuing to mature, so we're looking forward to seeing those outcomes. Okay. And then, is there a scenario where you could file prior to having final OS if you were to target a subpopulation with visceral mets? Yeah, again, don't want to kind of get into the specifics ahead of time, but we're continuing to kind of dig into the data, have a lot of conversations about it to really understand what's the best path forward for us. Okay, got it. So, I was actually planning to shift gears over to Zanza, but an audience question coming in about COSMIC-313, and when do you expect the next OS analysis? Yeah. So again, that's an event-driven study on survival events, and so we've talked about, I believe, the next or the final survival sometime this year, but don't really have any details beyond that. Okay, understood. So with that, we'll shift gears over to Zanza, and, I guess based on the, the pioneering success that you've had with CONTACT-02 and, increasing excitement about IO combinations in metastatic CRPC, interestingly, you've got metastatic CRPC patients in, in both STELLAR-001 and STELLAR-002. So I guess how are you thinking about the metastatic CRPC opportunity with Zanza? And, since you've got different combinations, how will you determine the best combination to move forward with? Yeah. So, for those in the audience who aren't familiar with Zanza, it's really a next-generation VEGF-targeting TKI that we're quite excited about. So the background on it is, with cabo, one of the key liabilities, as they say, of cabo is its relatively long half-life, around a four-day half-life, which can have pretty significant implications from a patient management perspective, especially when it comes to adverse events. So if you think about that long half-life, the accumulation in plasma, and necessary washout period as patients do ultimately face adverse events, and the adverse events can be on the order of 10 days to two weeks. And so what can happen during that time? You know, one drug is obviously on board, and two, kind of the inertia to get back onto Cabo or CABOMETYX, whatever, can be quite significant. And so, what we wanted to do was really phenocopy the kinase inhibition profile of Cabo, kind of that, you know, the very specific combination of VEGF plus the TAM kinases, that we believe contribute to its unique and kind of best-in-class profile, but really mitigate a lot of the complications and related things around that longer half-life. And so, what zanzalintinib has is kind of that same chemical scaffold for Cabo and kinase inhibition profile, but we were able to engineer a unique metabolic liability that has changed the half-life from around four days to a little under 24 hours. And so we present a lot of data now for zanzalintinib, which established that, and really shows that we've been able to do exactly that, kind of, recreate that efficacy profile for Cabo, but really improve upon both the kind of combinability through the shorter half-life. But a lot of the emerging data also shows that the tolerability profile seems to have been affected as well as one would expect. And so what we're doing with zanzalintinib, beyond the three pivotal studies that we've announced so far, is really continue to interrogate you know, additional indications and opportunities that we can look at through the STELLAR-001 and STELLAR-002, and now the STELLAR-309 studies. And regarding prostate or any other indications going forward, what we really are is a data-driven company. So if you look at the 303, 304, and 305 studies, those leverage both prior Cabo data to help inform areas of unmet need or areas that we think Zanza could be effective, but also layering in a lot of those learnings from the STELLAR trials to help understand where we can go next. And so stay tuned there on what the data begin to emerge, say, out of those prostate cohorts. But that's probably a good way to think about Zanza going forward in general, is we're using a lot of the experience in, you know, the 20+ tumor types that Cabo has shown real, you know, RECIST 1.1 activity, and then layering in those learnings from the STELLAR trials to really see where we're going to go next there. Okay, that, that's super helpful context. Thanks for providing that. And then, maybe just to follow up on zanzalintinib, since you already have 3 phase III studies running, and I think you previously indicated that, one of the priorities for zanzalintinib this year is to expand the, the clinical opportunity by working with, in partnership, with potential collaborators. Can you just talk about the cadence of initiating additional phase III studies this year for zanzalintinib? And how, how would you describe the, the strategy behind this first wave of, of, of phase III programs versus the, the next wave? Yeah. So kind of to tackle the latter question, you know, 303, 304, 305, really, we've framed as kind of the first low-hanging fruit, so to speak, and ones that we felt that we could execute with a reasonably high probability of success, in tumor types and areas that we know well. First, 303, you know, obviously a clear unmet need in late-line colorectal cancer. You know, the comparator in this study, regorafenib, is unfortunately not a great option for patients, and building upon, you know, what we think are really exciting data for Cabo in that dataset, as well as learnings from other kind of VEGF targeting TKIs, like the LEAP-17 study with lenvatinib, we're really able to kind of hone in on and understand, you know, what's the unmet need, what's the study that we could potentially run truly to be successful and kind of shift the standard of care for patients. And so you know, that was the first one that we initiated. Three or four, again, that's the second study, builds upon the success that we've had in RCC, and really some compelling datasets from Cabo, both as monotherapy and in combination in non-clear cell patients. This is again a patient population that, while there are therapies that are used, really there hasn't been a dataset that has a pivotal study that has been done to kind of definitively say: This is better, this is a better option than one or the other. And so it's an opportunity for us to really kind of define the standard of care there and really kind of cement zanzalintinib as kind of the standard there. And then the third one, 3 or 5, again, builds upon some pretty compelling data of Cabo plus pembro in a head and neck population, that we think again is still quite underserved. You know, if you look at the pembro monotherapy data, you know, the response rate's sub-20%. And if you compare that to kind of the pembro plus Cabo data that we reported at ASCO a couple of years ago, certainly much better. And so, those three studies build upon a lot of the success from Cabo. And then again, as I said, kind of the emerging learnings from STELLAR. Going forward, and kind of our desire or decision strategically to move to clinical collaborators, really comes back to some of the learnings we had from Cabo. So if you think about, say, the 9ER study or even the CONTACT-02, where through our clinical collaborators, say, in the case of Bristol, and then with Ipsen and Takeda, we were able to kind of fund those studies, for, you know, frankly, pennies on the dollar. And it really provides a good return opportunity for us to be disciplined with our expenses. Kind of share some of that clinical risk, but also share a lot of that upside as we're able to help kind of define and shift standards of care for what those combinations could be. So that's kind of big picture, how we're thinking about it. You know, obviously, we're talking to all of the major players in the IO space. We know Cabo and Zanza play well there, and so the idea is a more user-friendly and a more combinable VEGF TKI, you know, third-gen TKI that builds upon the success of Cabo. That's what drives our enthusiasm, and frankly, that's what drives a lot of the enthusiasm from our potential partners. You know, coming out of the IKCS meeting, where we presented that zanzalintinib monotherapy data in RCC, can certainly say that there was a lot of interest and enthusiasm from the IO players there. Recognizing that having that kind of best-in-class, potential best-in-class TKI that combines well really opens the door to a lot of combination possibilities. And so it's really about understanding what are the unmet needs, what are the areas that we're able to shift the standard of care for patients and really drive and really drive that next wave of trials, so to speak, for zanzalintinib. Okay, great, and maybe just one quick zanzalintinib follow-up question. Is Exelixis planning to retain worldwide commercial rights to zanzalintinib? Yeah. So that's kind of the base case for now. You know, obviously, a lot of what we do and, you know, frankly, what we talked about on the scientific side at the R&D day is, you know, kind of everything through the Cabo lens. Base case is obviously keeping global rights, but, you know, we continue to evaluate opportunities as they come up. So, you know, if there's something from a strategic or tactical perspective that we're faced with zanzalintinib, you know, we're obviously always having those conversations internally. We're obviously talking to a lot of partners on combinations, and so how that evolves over time, TBD, but as of now, kind of our base case is to kind of retain global rights because we do understand and believe that Zanza is differentiated and has real value there. Okay, great. Super helpful. Thank you for that. And then, so maybe shifting gears over to XB002, especially since we spoke to Zymeworks earlier today, and we're all super excited about that program. Can you just talk about different combination strategies with, with XB002, and how are you seeing combination versus monotherapy opportunities? Yeah. So I think that's a really interesting question, and kind of underlying that is, you know, what we think is really what's so special about XB002 is that it's differentiated from a lot of the predicate molecules that can help define and drive indications of interest, but are likely limited by some of the, you know, molecule-specific issues, say, with Tivdak. So if you think about an ADC, it has really kind of three components: the binder, the antibody, the linker, and the warhead. We think XB002 is differentiated across all three components. Obviously, you know, with tissue factor and its role in the coagulation cascade, the fact that our antibody is not competitive with factor VII, whereas Tivdak is, we really think differentiates and has the potential for differentiation on something like bleeding risk. And then, on the linker warhead side, you know, a lot of the hallmarks of kind of earlier gen ADCs where, you know, stability, free warhead can be an issue that can drive things like neuropathy, cytopenias, et cetera. You know, what we've shown with our data that we've reported is that, you know, equivalent doses, we reach about twice the exposure at about one-tenth the amount of free drug. So we think that's a really good starting point, from one, an ADC perspective as a monotherapy, but two, in potential combination, when you start to have to think about, you know, overlapping toxicities and things like that. And so, you know, one of the things I think that's interesting and you may have picked up on, is we're certainly interested in looking at internal combinations. You know, obviously, tissue factor expression is across a wide range of tumor types. Something like zanzalintinib also expressed or has activity across a wide range of tumor types. And those are the sorts of things that I think we're going to be increasingly interested in going forward, especially as, you know, when we start to layer in a lot of the earlier programs, that Dana talked about at the R&D Day. So those sorts of combinations with XB002 and the rest of our portfolio, will be areas of interest going forward. Okay, great. Thank you so much. We're just running up to the end of our time. Maybe one last really quick question on XL309, since you mentioned it in the introduction. Can you just talk about what you're doing there with PARP inhibitor refractory patients, and what are the timing and milestones that we should expect this year? Yeah. So we're just getting that program up and running, kind of as the IND is cleared and patients are starting to enroll. It's really another program that we're excited by that I think again fits through kind of this Cabo lens, in that it's not the first USP1, but we think it truly has the potential to be best in class. And so as you think about the biology of USP1 and the potential, you know, especially in combination with the PARPs, it has the ability to kind of broaden the activity beyond, say, just the BRCA population. But even the even in the BRCA, the ability to deeper responses, lengthen duration, those are the sorts of things that really benefit patients, but really kind of drive a lot of opportunities. You know, if you think about the PARPs as a globally $3.5 billion category or so, as we're able to kind of potentially, with that combination, deeper responses, longer duration, those are the sorts of things that make us excited about that, as we think a lot of the, the properties from some of the other USP1s make it best in class. Excellent. Thank you so much. That brings us to the end of our time, so we'll wrap things up there. Really appreciate your bringing us up to speed on all the impressive progress you're making at Exelixis across so many innovative programs. So thank you, Andrew, and thank you, Varant. Really wanna thank you for your time here today, and appreciate it. Yep. Thanks, Jay. Thanks. Jay, take care. Thanks. Good to see you. Bye-bye. Bye. See you.