Exelixis, Inc. (EXEL) Earnings Call Transcript & Summary

Welcome to the Exelixis virtual event. Please welcome Executive Vice President of Public Affairs and Investor Relations, Susan Hubbard.

Welcome, everyone, to the Exelixis 2025 R&D Day, building next-generation oncology franchises. We very much appreciate you taking time to join us today. As you can see, we have a very busy agenda and are delighted to be joined during the disease focus areas by 3 guest speakers, Dr. Shwari, Dr. Saeed and Dr. Chan. But let me just start by saying that during the course of this presentation, we will be making forward-looking statements regarding the future events and the future performance of the company. This includes statements about possible developments regarding discovery, product development, regulatory, commercial, financial and strategic matters and potential market and growth opportunities. Actual events or results could, of course, differ materially. We refer you to the documents we file from time to time with the SEC Commission, which under the heading Risk Factors, identify important factors that could cause actual results to differ materially from those expressed by the company verbally and in writing on the slides today, including, without limitation, risks and uncertainties related to product commercial success, market competition, regulatory review and approval processes, conducting clinical trials, compliance with applicable regulatory requirements, our dependence on collaboration partners and the level of cost associated with discovery, product development, business development and commercialization activities. And with that, I'm going to turn the presentation over to Mike.

All right. Good morning, everybody, and welcome to our 2025 R&D Day. We are really excited to have you join us, and we're certainly grateful for your time and attention and interest in Exelixis. We have a very packed agenda, as you heard from Susan, I'm going to give a brief intro. You hear a lot from me during the year, and I want to make sure that we have a lot of time today for the discussion between Dana Aftab and P.J. Haley and the clinical experts that are joining us today to really get a sense of our strategy, our focus and the intent we have in terms of building Exelixis into a multi-compound, multi-franchise company. Several important key themes today are on this first slide. Again, we're going to focus on strategy. This won't be a typical R&D day data dump. We're going to get into the weeds about what we're doing, why we're doing it and how we're doing it from a strategic point of view. So you can understand how we'll move forward from where we are today with cabo to again, this franchise approach building out for patients and shareholders. The focus is really on pipeline and franchises, right? We're not looking at one-off indications. We're not looking at small populations. We're really going for it from the standpoint of building and enhancing our ability to play the franchise game really, really well, as you see in big pharma, so that we can be successful for patients and shareholders. Bottom line here is a guiding principle is that we have to prioritize well, we have to allocate capital well and make sure that we're always making the tough decisions in terms of picking the winners and maximizing our chance of success. Our goal overall is to -- again, as you've heard me say many times this year, improve the standard of care for patients with cancer. That's how you move the needle for patients and shareholders and to become and really build upon the leadership position we have in solid tumor oncology today to go to that next echelon of leadership in terms of patients we impact tumor types we attack and then obviously, the commercial side with revenue. All right. So let's start by taking a quick step back and just looking at what we've done since the last time we met in December of 2023. Obviously, cabo has been a huge success for us and for patients and for shareholders, we continue to see outsized growth of the cabo franchise. We're projecting more than 30% growth cumulatively looking at full year 2023 to full year projections for 2025 in terms of cabo net product revenues, it's very exciting. We're pleased to have 2 new indications for CABOMETYX in the net space as well, and we think that will help drive revenues in 2025 and '26 and beyond. Certainly, as you'll hear a lot about today, as we've talked about throughout the year, zansa is now at center stage for our next potential franchise molecule. Very pleased with the positive top line results that we had in STELLAR-303 and now having a filing in place with the FDA based upon that trial. So a lot of progress there, a wide variety of pivotal trials either ongoing or planned -- you'll hear about that today in great detail. We think between cabo and zansa we have very good opportunities to drive near-term and midterm growth from the pipeline. In terms of early stage work, again, it's been a very productive couple of years. Our early-stage pipeline is very fill, 3 IND candidates that you'll hear about today, XB010, XB628 and XB371 all important new molecules that are accruing rapidly. We're really excited about both as monotherapies, but also in combination and then some new molecules that are advancing rapidly towards IND status as development candidates that you haven't heard a lot about it in the past, but that we're super excited about especially XP773, our DLL3, warhead ADC and then XL557, which is an oral SSTR2 agonist for neuroendocrine tumors. So again, this next wave coupled with what's happening and in discovery, we really expect to drive long-term growth with both first-in-class and best-in-class potential. All right. So I went too far. Can you go back one, please? Thank you. So bottom line here is that our goal is to really drive the company with our science, with our clinical development work, with our commercial expertise to become a top 5 solid tumor oncology company, not be able to do that. We have to have multiple blockbusters franchise molecules in important indications with important combination partners to be able to drive that revenue growth to help more patients than we currently are right now with cabo. Where we stand today, it was a pretty good spot, obviously, right? We're -- in 2024, we were a top 10 solid tumor oncology company in the U.S. with a single blockbuster molecule and cabo with 8 indications. So we have a lot of success in the past, and that lens of why we were successful with cabo drives us forward. And that is to really build franchise molecules, franchise indications from our pipeline. We look to establish those in the context of getting on the beach, if you will, to be able with our first indication, say, with the TKIs to be able to build dominance in GU and GI and our first ADC launch that will happen sometime in the near future, hopefully, and then to expand upon that in terms of other indications, other combination partners, other tumor types as we -- as the pipeline moves down field and then finally to entrench and really make sure that we have the best possible options for patients best combination partners, et cetera, that will help us move forward as an organization. So large aspirational goals. We're swinging for the fences here. We're very excited about that, and we have the conviction we have the culture and we have the team to be able to get that done as we go out in the coming years ahead. So we talk about and we think about franchises really in 3 dimensions, right? Think about them in terms of compounds, right? Like compounds like cabo, compounds like we hope zansa will be, where you can build the pipeline within the compound by itself. We think about a [indiscernible] expertise. Obviously, we're very strong in small molecules. Over the last few years, we've been investing in biologics and ADCs and bispecifics, and we think we can double down there as time goes on as well and then importantly, tumor franchises. We want to make sure that we are strong in areas of high unmet medical need. We want to be able to, again, move the bar for patients by improving standard of care for those patients with these different tumor types and doing them with single -- with monotherapies with combination approaches that are potentially best-in-class because that's the only way to move the needle commercially is to move the needle for patients themselves. Our pipeline, as you've seen throughout 2025, is advancing nicely. We have a lot going on with zansa. You hear all about that today. We have 7 either ongoing or planned label-enabling studies. Go here obviously is to right shift all those while we're bringing up new indications and new combination partners in Phase II. Our early-stage pipeline goal here is to, again, advance those through Phase Ib into Phase II and Phase III through proof of concept, proof of developability, picking the right combinations and the right overall approach. So we have the opportunity to, again, pick the winners, maximize success and move these important molecules into full development. So here's our pipeline, looking at those 3 dimensions around products, around modalities, around tumor franchises. Again, lots of room to maneuver. You'll hear a lot about this today from the team and our external advisers and collaborators, certainly, we're going to focus heavily in the kidney cancer space in the net face and in the colorectal cancer space as our main short-term focus to building tumor-type franchises with a variety of different compounds, combinations, myotherapies that will help move the needle. So finally, I'll leave you with this slide as a road map I think you'll hear very, very clear details and a very clear summary of how we're going to do this in terms of establishing, expanding and entrenching franchises across kidney cancer, colorectal cancer and neuroendocrine tumors. So should be a great day. I'm really excited to have the opportunity to move forward now and invite Dana and PJ to join us at the stage, and we'll -- they'll be having a dialogue with Dr. [indiscernible] and Saeed and Chan, very grateful for these clinical experts and longtime Exelixis collaborators to join us today and help us tell the story of how we're going to make this pipeline work for patients. as we go forward. So with that, I'll turn the podium over to PJ and Dana. Thank you.

All right. Thank you, Mike. First, it's my pleasure to start us off with our kidney cancer or renal cell carcinoma franchise discussion by welcoming in Dr. Tony [indiscernible], Dr. [indiscernible] is the Director of the Lank Center for Geo Oncology as well as the co-leader of the kidney cancer program at Dana Farber, Dr.[indiscernible] great to see you. Thank you for joining us today, and maybe we'll start out -- just to give you a chance to tell everybody watching a little bit about yourself about your clinical practice and about your research. So thanks for joining us, [indiscernible]

Thanks P.J. Pleasure to be here with you and Dana here, our journey. I can't believe it's been over 15 years now. It started with a bit of hope and the hope continues and the survival is better and better. So -- this journey actually started with cabozantinib and will continue through zanza, like I like to say it, and thank you for the investment in kidney cancer, 1 of the top 10 cancers in the U.S. and in the Western world.

Great. Well, we'll move on to the landscape discussion now so you can help us kind of set the stage here. So as you mentioned, it's hard to believe we've been working together for over 15 years. Throughout that time, the landscape has evolved dramatically with new MOAs, multiple treatment options for patients. As you mentioned, certainly CABOMETYX has become a mainstay of treatment in renal cell carcinoma. You've really led many of these trials, which establish this current landscape. So hoping you could maybe give us your thoughts on the current landscape, but also with the mind towards really tell us about what the importance of overall survival has been to establish this landscape and how you see the importance of overall survival going forward as we look to continue to evolve the landscape.

No, thanks, P.J. I think I've I personally do not compromise on overall survival at all. There is nothing that capture benefit the plus and minus more than overall survival though even if we do not reach out overall survival, other endpoints are also important. I'm happy how we started with cabozantinib with METEOR, if you remember, we had an overall survival against an active agent that was the first TKI to have as a single agent, an OS benefit against an active control. And after that, I'm happy how we continue exploring cabozantinib and we moved it to the first line, if you remember, with the Alliance study, the academic study versus [indiscernible]. This is the first time that TKI beats another TKI had to have. We had progression-free survival response rate, both investigator and center review. We did not have OS simply because this was a very small randomized Phase II study of less than 200 patients. But then immune checkpoint inhibitor came in first line, and we combined cabozantinib very well. It did actually combine very well in terms of toxicity and activity and beat sunitinib hands down with all the endpoint you can imagine, progression-free survival response rate OS even quality of life, et cetera. So that regimen continues to be one of the most used regimen in first line and what I say that keep on giving despite the fact that I always want more and better and to cure patients.

Great. Well, thank you for that overview. I think now it would be interesting to get your thoughts on this perspective. So I think there's a new evolving space in the first-line metastatic setting as we now have pembro available in the adjuvant setting for RCC patients. So could you talk to us a little bit about how do you think about and how would you characterize these patients whose disease recurs after adjuvant pembro what's the unmet medical need for these patients in this setting?

I mean, look, one of the embarrassment of riches was having drugs like cabo is that an adjuvant pembrolizumab, which has been adjuvant treatment, we waited for, for decades. And finally, we have a drug that prolong overall survival in the adjuvant setting. But patient do recur, and they can recur once you finish pembrolizumab or they could be refractory. And that creates a setting, which we did not have before, and is those patients that experienced progression, not a first-line metastatic disease, but in the adjuvant setting. And that unmet need was addressed in a study that hopefully will start accruing by the name Light Spark 033, which randomized patients to cabozantinib versus zansa plus HIF-2 inhibitor. I think it's also important to take into consideration whether patient progress or experience progression on therapy after a therapy for a while or years down the line for that, we had nice piece at ASCO to define this. It's a new area that we are embracing, created by the availability of good choices.

That's great. Thank you for those thoughts, Dr. [indiscernible]. And now I want to kind of shift gears slightly and think about non-clear cell RCC. So nonclear cells we know, represents roughly 1/4 of all RCC, but these patients traditionally haven't been included in Phase III studies. So I'd love to hear from you if you could tell us a bit about non-clear cell patients what they look like, how they may differ from your standard clear cell patients as you think about that?

I mean we, in the past 20 years and other brought this issue heads on that the RCC that we know about where anti-angiogenic Asian works very well in HIF2 inhibitor. And VEGF multi-tyrosine kinase inhibitor like zansa are the ones that are driven by VHL driven by the story that led to the 2019 normal price. But there is around 10-plus more types of renal cell cancer that sometimes are not -- they are distinct histologically. But sometimes the histology overlap, molecularly, they are certainly different. They have a different story, different prognosis. Sadly, we still treat them with the same drugs we use in clear cell RCC largely with some exception, I would say. So that presents a total unmet medical need that we need to address. What we have is mostly data from single-arm trials that justify using a combination that we know it's been used in Phase III clear cell RCC.

Yes, that's great. Thanks, Dr. [indiscernible]. Thanks for talking a bit about the unmet need there. Maybe you could talk about historically the challenges of conducting a Phase III study in that setting and how important it is to do that to address this unmet need you're talking about?

Well, it's always hard to be first. It's very easy to copy. But there hasn't been, at least to my knowledge, a Phase III trial that is done in non-tier cell subtype powered enough. And I know you guys either finished accrual or finishing accrual and STELLAR-304 which combine nivolumab with zansa against sunitinib in international trial in non-clear cell RCC. Hopefully, you will be adding to the standard of care level. I think the fact that hasn't this concept hasn't been done and these tumors are rare, and there hasn't been a consensus. What to do was led to the fact that today in 2025, almost 2026, we treat non-clear cell RCC almost the same clear cell RCC just because we don't know what to do.

Great. Well, thank you for your thoughts on that, Dr. [indiscernible] and on the landscape in general. So at this point, that gives me the opportunity to bring Dana into the conversation. So Dana, can you now talk to us about kind of as Exelixis is thinking about the future and our plans in RCC, how we're thinking about the pipeline advancing there.

Sure. Great. Thanks, P.J. And thanks for joining us, Tony. It's great to see you. Again, as always. So yes, so let me just take the opportunity to talk about sort of what we're thinking about as we look to the future, especially with zansa in this space. So as Mike set up in the beginning, the GU franchise and kidney cancer, in particular, are very important to us, and it's especially important for us to continue to reinforce and maintain our leadership position here and our commitment to this space with our pipeline. So obviously, zansa is going to be a crucial part of that. It is a crucial part and will continue to be a crucial part of that strategy. And we see zansa as potentially serving as really an ideal TKI backbone for a number of different novel combinations across settings and lines of therapy. We're also excited about the potential for another molecule in our earlier pipeline shown on this slide, XB-628. This is a novel bispecific IO-focused molecule that has 2 different mechanisms of action. We'll speak to that in just a moment. But looking at this molecule potentially as a single agent, maybe in the adjuvant setting and then also in combination, perhaps an adjuvant or especially in later lines of therapy, we see as having some high potential in this area. So we're also continuously evaluating other opportunities that perhaps lie outside of our own pipeline. We're always evaluating new targets new modalities that look like they're showing promise or could show promise in the RCC space, again, with an eye to maintain our leadership here and focus on really building a robust pipeline and approach to bring the best benefit to patients overall. So again, we'll have the opportunity to talk about these -- all of these aspects in the next few slides. So let's now focus a bit more specifically on zanzolitinib. And before I engage you, Tony, and some of the discussion around this, I just wanted to set up the discussion a little bit by introducing zansa and especially how we pursue discovering and positioning this molecule after we brought cabozatinib 4. So based on our experience with cabozantinib, we essentially, I would say, fell in love with the target profile of that molecule, targeting MET, targeting the TAM kinases in addition to targeting VEGF receptors was really sort of a perfect sort of trifecta or nexus of targets in a range of different tumors, but especially in renal cell carcinoma. So we wanted to bring forward a next-generation tyrosine kinase inhibitor that maintained that target profile but was able to perhaps differentiate from cabozantinib based on what we knew about cabozantinib and some of the challenges we had developing it. So perhaps the biggest challenge for managing the use of cabozantinib was managing tolerability and how to dose reduce for adverse events and having a long half-life became a challenge, having to discontinue dosing and wait for plasma levels to reduce over days, if not weeks, to achieve lower exposures, have the AEs resolved and then begin therapy really set up the potential for patients to progress. So we wanted to have a molecule that had much shorter half-life to really drive better management of those AEs. So that's what we achieved with zanzolitinib, but then what we came to discover later was that it had a bunch of other benefits that further differentiated from cabozantinib, and those are shown on this slide namely in the PK, PD and ADME realm. So zanzolitinib, along with having a shorter half-life compared to cabozantinib also has lower plasma protein binding, more potent pharmacodynamic against the MET target. As you can see on the left side of this slide, it has about half of the IC50 for inhibiting the target in vivo in a preclinical model compared to cabozantinib and it also has a preferred tumor to normal tissue distribution profile. Again, something we very sort of serendipitously stumbled upon when we were doing some of the ADME development work on the molecules, but using radio labeled compound, we found much less radiolabeled zanzolitinib was penetrating into normal tissues and preclinical models than we were seeing with cabozantinib. So that really set up in our minds, a very strong hypothesis and potential for differentiating zanzolitinib as really a best-in-class TKI across the spectrum, not just within our own pipeline, but across the entire treatment landscape for these patients. So turning back to you now, Tony, what do you see as some of the specific advantages of a compound like zanzolitinib? And specifically thinking about a VEGFR targeting TKI that also builds in these other targets like MET and the TAM kinases in the setting of RCC?

No, I love how you said that you fell in love. Well I fell and love with the science and with the alternative pathway of resistance. We talk about resistance all the time. So if you think that zansa or cabozantinib or another VEGF TKI, develop -- the tumor develop resistance, how do they develop the resistance. And this is why MET and EXEL play an important role as alternative pathway that drive angiogenesis and proliferation. Now this is in multiple tumor models, and this has been established. So that combination of keeping the -- keeping the brakes on the VEGF receptor and also targeting Methanexl is very beneficial in terms of strategy to combat resistance and keep patients as long as possible, benefiting from VEGF TKI. In addition, I think also now is antitumor immunity and immune checkpoint inhibitor at the center stage for combination I can tell you that Matt and especially the EXEL family of receptor plays an important role in this evasion of antitumor and immunity. So this is also a double whammy quite beneficial. So that's from a scientific perspective, what not to love and then comes the half-life that is very, very short and very important compared to cabozantinib. I mean cabozantinib helped many patients, but it had a prolonged half-life. So if you are to have toxicity, you have to hold the drug, maybe sometimes go down on the dose. But a lot of us physician and patient are anxious, despite that the patient does have a therapeutic dose level with cabozantinib when you hold, but the side effects don't come down in general, very quickly. Now with the shorter half-life with zansa, we can address adverse event in a more nimble way. And I love the slide here the part on the right, where actually, probably you call it serendipity, I call it less politically correct way of luck. You're stumbled on a molecule where the penetration into tumor tissue is simply higher than normal tissue. So I imagine side effects like PPE, which could be severe on all TKIs, okay? We started seeing with sorafenib long before zansa or cabo existed. We see it with cabo, we see it with other TKI. But that going to be, I think, a differentiator when you have a drug that entered tumor tissue more than normal tissue. So I think a lot of room to hope and to optimize what we know about the science and small molecules.

Great. Thanks very much for that overview, Tony. I think that really sets us up quite well to discuss our plans for bringing forward zansa in the RCC setting. So looking to the next slide, you can see that we've got quite a few trials planned in this space. We actually have 3 Phase III trials either ongoing or initiating soon. So the STELLAR-304 study is is underway, and that's in the non-clear cell renal cell carcinoma setting. This is looking at zansa plus nivo. And then we have 2 Phase III trials in the setting of clear cell both looking at zansa compared with belzutifan. And those are studies that we're collaborating with Merck on that they're actually executing on. So we're excited to discuss one of those studies today, and this is the one you already mentioned earlier in your earlier remarks, Tony. This is the Light Spark 033 trial. Again, this is looking at zansa plus Belzudifan versus cabo in the frontline setting in patients who progressed on adjuvant pembro. So Tony, let's go back to you now to go over some of the data that we've generated in the Phase I studies with zansa. On the left side are the data from the STELLAR-001 trial, looking at single-agent anzalitinib in RCC patients. And then on the right data from the STELLAR-002 trial looking at zansa plus nivo in RCC patients. Tony, would you mind just taking us through, first, the left side data, what are some of the, I guess, key features and highlights of these data that you think point to potential differentiation of zansa?

No. I mean this is good -- if you look on the left, first at the monotherapy data, this was in patient previously treated patient had VEGF PKI and you can see when you look at the responders that this drug zanzalintinib, which we are calling zansa is active period. I'm very interested since you said how much zansa could be an improved version of cabo in the many underlying properties you mentioned, both chemically and now you're going to see clinical wise. I was very interested to look at the patients who had prior cabozantinib and did experience progression on prior cabozantinib. And here we go, we have patients that respond over 20%. That's a very strong signal here while continuing the tradition of cabo, which one of the thing about cabo, the low rate of PD as best response. To me, as a clinician, it's very important when I put a patient on study and in 6, 8, 9, 10 weeks get scans is not to immediately burn through therapy I need to hold their disease. A lot of these patients have disease that can be intermediate for [ res ] and still hear the rate of PD as best response. Even if you had a prior cabozantinib is very low. The majority -- the vast majority of patients do respond and have tumor shrinkage and disease control on single-agent zansa, 32 patients. And I think the follow-up is is good. Now even the next question is, what can we do first line? And of course, it will be hard to justify first-line TKI in this day and age. So that combination with nivolumab is very reasonable. The first thing I look at, and I think you're going to mention tolerability later that it's combinable. Third thing is combinable. The second thing, if you work at this waterfall plot, besides 2 patients here with PD and one of them barely at the 20%, every patient had some form of tumor shrinkage with a response rate that reached 63% and a median PFS to be loaded at 19, 18.5 months overall. So there are a benefit here if you look at single agent that we're seeing from zansa beyond cabo to differentiated molecules since patients can respond, and that's not just one case, but more than one case, even if you had prior cabozantinib. And in the combination, it's doable and the response rate of 63% with only 2 patients here, experience PD is quite intriguing.

Thanks for those insights, Tony. And I just wanted to reiterate something that Monty Powell had mentioned when he presented the data on the left side from STELLAR-001 that a number of the patients who had experienced prior cabozantinib and then went on to have benefit on zanzolitinib included kind of the range of of sort of prior response that you might expect. Some patients have been doing well in terms of disease control with cabozantinib, but then they ultimately had to come off due to AEs. They went on to zansa and tolerated the drug well and had a great response. But there are also patients who couldn't even tolerate cabo to begin with. They went on and had to come right off, didn't really have a chance to experience benefit went on to the Phase I trial with zansa and then receive benefits. So we think that's fairly strong evidence that zansa truly is a best-in-class TKI to really serve as the backbone for any therapy in this space. So now just in the spirit of a balance and as you mentioned before, it's always good to talk about tolerability. So moving on to the next slide, we have some of the tolerability data, again, on the left side from the STELLAR-001 trial looking at monotherapy zansa, and then on the right side, zansa at the 100-milligram dose. And I just want to reiterate, these studies are specifically at the 100-milligram dose, but we have recently initiated some randomized cohorts in the Phase I studies looking at lower doses of zanzolitinib and so far, seeing very encouraging activity as we've lowered the dose, which we certainly expected to see in real cell carcinoma. So our goal is to really understand the ideal dose in that setting as we move forward. So getting back to the AE profile, Tony, tell us what you see here in terms of -- is this consistent with what you would expect for a TKI either in the single agent or combination setting?

Yes. I think if you look at monotherapy, consistent with TKI, Hypertension is the most common. It's on target. It could be manage. We have 20 years plus experience with managing blood pressure, and we play very well that all of the primary care physician here and we do it well. I do not remember recently anyone, I had to stop the drug because I couldn't control hypertension. If you look at high grade, they're in the single digit beside hypertension, which is fine. Usually, even if it's Grade 3 or 4, it's asymptomatic. So the single digit is good. The one that actually is quite interesting brings me back to what I was saying about this potential drug distribution tissue versus normal tissue versus tumor, the low rate of PPE. I think that's important. I don't think it's as common as people think or with TKI, but certainly can be debilitating. I've seen cases with cabozantinib, I've seen case with other TKI where PPE was a reason to stop even a dose reduction, even if sending to dermatologists or a podiatrist. The rate of PPE here is quite low. So I'm pleased with that. Now when we combine on the right, there is always possibility that the TKI rather than the TKI exacerbates immune-related AEs. I don't think we know enough about the science to roll that out. But then when I look at the combo of nivo and zansa, I do not think that the rate of potential immune-related AE or toxicity that are common to both drugs like LFTs and the area is way worse. Again, beside hypertension, everything in the single digit, everything is expected of anything, actually, the 4% for grade 3, 4 is low. Remember, those patients, those 40 patients had a median follow-up of 20-plus months. This is not a short data cut where half of the population had just one scan and you presented the response with more follow-up, more likely of is to happen. And even with that, all in the single digit, the Grade 3, 4 and the PPE is 4%. This to me is reassuring.

All right. Thanks very much for those insights, Tony. So let's move on now to discuss some of the clinical trials we have planned with zansa first being STELLAR-304. So as you mentioned earlier, Tony, there's quite a bit of high unmet need here. and lack of high-level evidence in the non-clear cell renal cell carcinoma patient population. Can you just walk us through the trial design and specifically point out how you think this could be impactful for this patient population if the trial reads out positively?

Yes. First, congratulations in launching the first Phase III trial, seriously powered to answer your question and not clear cell RCC. So this is, to my knowledge, against the only randomized Phase III study against an active comparator, sunitinib, it addresses unmet medical need that include the most common type of non-clear cell RCC, the second most type is papillary. And then it includes translocation, which is a really unmet medical need non-clear cell RCC in younger patients. It includes also unclassified. I think the randomization also is favorable 2:1 to the experimental arm and the endpoints are really quite reasonable. And over 300 patients are enrolled. So we have enough power to answer this question, hopefully, once for all.

And this -- I think this is a great example of how we're really trying to just really strongly reaffirm our commitment to advancing standards of care in this setting, no matter what the patient population we really want to bring as much benefit to patients in this setting as possible. So now let's move on to the other study that we kind of teased a little earlier. This is the Light Spark 033 trial. Tony, can you walk us through this design as well?

Yes. So again, we talked about the advances in the adjuvant setting with pembrolizumab, but I wish, but that every patient will be cured with adjuvant pembrolizumab, but that's not the reality patients do experience progression. Remember, that study was against placebo. So this creates a new niche a new unmet medical need, it's postadjuvant pembro. The biology of the disease may be different than treating patients with strong line metastatic RCC, which usually also you use 2 drugs. And in Light Spark 033, we are trying to address this unmet medical need. So patients with progression after adjuvant treatment with clear cell RCC, where we were randomized to the standard TKI. Here the standard used by most, including myself, is cabozantinib or to add to the VEGF TKI here, a HIF2 inhibitor to [indiscernible] and to improve, hopefully, the profile of cabozantinib using zansa. So zansa plus bell versus cabozantinib. It's a very reasonable study. And what I like about it is we're taking in this 900-plus patient study, we're taking OS as another call primary endpoint in addition to centrally reviewed progression-free survival. I think this is the first non-IO combination to address a totally new treatment setting in renal cell cancer, the first line post adjuvant treatment and a whole patient #1, subject #1 will be enrolled before December 31.

Yes. As do we. And we're very happy to have Merck as our collaboration partner executing this trial with us. So -- thanks for your insights here, Tony. Now let's shift gears a bit and move into our earlier pipeline and speak a little more specifically to the molecule I introduced a little earlier, XB-628. This is our novel immunotherapy targeting 2 different immune checkpoints. So this slide just shows the design of the molecule. This is in our view, a very innovative biotherapeutic molecule. It's in our early clinical stage pipeline, and we think it really has a strong potential to be impactful for patients with renal cell carcinoma as well as in other tumors. So Again, XV-628 is a bispecific, which targets PD-L1 and NKG2A. We're excited about these targets for a number of reasons. So PD-L1 and the PD-1 axis are well validated. -- with a lot of agents targeting that pathway as an immune checkpoint in renal cell carcinoma and other tumors. This molecule builds in another I/O mechanism targeting the innate immune pathway. NKG2A is expressed on NK cells. So we have the ability with a single molecule to target 2 different important immune checkpoint pathways. But also since these binders are on the same molecule, the molecule can actually act as an immune cell engager. So because this is the only molecule that we're aware of that builds these mechanisms into an MOA like this, we believe we're in a great position to really have first-in-class potential with this molecule. So Tony, this slide shows a little bit more around the mechanism of action. Can you just lead us through a little bit about what you think is interesting or exciting about this MOA or the potential for multiple MOAs in a single molecule to potentially bring benefit to patients in renal cell cancer?

No, I'm excited about this immuno-oncology drug because of target, if you want both sides of the immuno-oncology question. So there's a potential that like you, Dana, I might only might fall in love with this. Why? Because it addresses something we know very well, the adaptive immunity through targeting the PD-1, PD-L1 access, but also the innate immunity that's coming back really now at the front stage with targeting the NK cell access, I would say, overall. So while these 2 binders on the same molecule and an antigen expressed on tumor cells and antigen expressed on immune cell, this approach gives us the ability potentially to co-localize these cells. So when you co-localize that's the old principle of bispecific we have with VEGF PD-1 that launched of this $1 billion acquisition. So perhaps the immune cell has a better chance to kill the tumor cell. I'm a believer here and I like now that the NK cell becomes center stage. We've done work, specifically in clear cell RCC with David Brown and Rizwan Romie, where we did single cell sequencing on Stage 1, 2, 3, 4 renal cell cancer. And we found the NK cell initially are quite functional in early stage. But a bit with early -- with later-stage disease, they can become quite dysfunctional. So reinvigorating the NK cell in the advanced setting and the cell at the same time, make a lot of sense. And that's why I think 6% to 8% has potential, not just in frontline, 1 day, but in IO experience. And I would argue also in IO-refractory patients in these patients where PD-1 inhibitor resulted in complete refractory disease. So I'm excited. Again, there is potential for falling in love and relationship here remain to be seen based on the clinical data.

Yes. Yes, for sure. We, too, are super excited about this molecule. And as you're well aware, the Phase 1 is well underway. We're now at dose levels that are predicted to be well within the target range for activity based on the preclinical modeling. So we're really excited where we're at now. The Phase I trial has moved along quite quickly. So we're hoping to get to the expansions quite quickly and especially combinations with zansa in the renal cell carcinoma setting. So looking forward to our future potential collaboration with that trial as well, Tony. So let's talk about some of the opportunities for our pipeline beyond zansa-628. So as I mentioned before, we're really committed to pursuing new targets and modalities and other approaches that we think are really helping to drive innovation in this setting. So looking beyond the approved modalities that are shown on the top -- on the upper part of the slide and then also beyond zansa-628. We're looking at some of these other potential modalities, other bispecifics, some cell therapies, personalized neoantigen therapy and also ADC approaches and others. Tony, in your view, what do you think are some of the more exciting possibilities for these new future combination opportunities, both with zansa and with 628 with some of these other modalities that are outside of our pipeline.

Yes. No, one of the things I like working with you and Mike and everyone for 15-plus years, and we continue to have relationship of respect and love, of course, now is you do have molecules that have alternative mechanism of action in real cell another tumor that potentially you can combine. And then you reach out to the investigator that have alternative, if you want, strategies and research that can -- I wouldn't say, but in large part, can start an academic setting, although you guys have been great. So for example, with Dr. Katy Wu, who is my dear colleague at Dana Farber, we have embarked on a journey 10 years ago was personalized neoantigen vaccine. Neoantigen therapy, I would say. This is more in neoantigen therapy, P&Ts, which I'm a big believer and has actually led to adjuvant studies in renal cell cancer randomized study after our paper in nature. But here, I don't think people using neoantigen therapy, have introduced a TKI, especially in the metastatic setting or high-risk setting where it can downsize the disease completely as an neoadjuvant, if you want a strategy, control it in a way to make the personalized neoantigen therapy and give that to the patient. And for that, we are collaborating with Exelixis and MyLab and the app to introduce zansa with this neoantigen personalized therapy, both in the metastatin and adjuvant setting in clear cell and non-clear cell because in these 2x2, it makes sense. A lot of correlative also to learn from this. I don't think anyone has explored that strategy in renal cell before.

Yes. We're excited about that, too, Tony. And especially given the potent inhibition of the MET and TAM kinases, we think a TKI like zansa with all of its immune modulatory effects because of the inhibition of those targets really set it up to be the ideal partner with a vaccine approach or a personalized neoantigen therapy approach like we've discussed. So certainly, very exciting times for us. Again, we're really focused on moving the needle for patients in the RCC setting and looking for all possibilities to explore and improve standards of care for these patients. So at this point, I'd like to now turn the podium back over to PJ to close out this section of our discussion. .

Great. Thank you, Dana. That was great. Well, first and foremost, Dr. [indiscernible], I'd just like to take the opportunity to thank you very much for joining us, say, for your time and your insights. And obviously, your partnership over the many years, we're very appreciative. And I'll just turn it over to you if you have any final words for the audience as we conclude the RCC section.

No. For me, it's a personal thing. I mean, for me, I've been over 20 years in the field of renal cell cancer. And I love the continuity. One of the issues I always have, in general, you let me it with industry is how things change overnight. Sometimes it's not great for us, not great for patients, all this. But with Exelixis, we've been since day 1, we talked P.J about METEOR, you and Dana [indiscernible] METEOR. But before METEOR there was the earlier study, the Phase I dose, I think food -- and those dose interaction study with rosiglitazone, that led to METEOR Mike remembers that. So even at this 15, 18 years relationship at 3 other yields with renal cell cancer, and you stayed on track with continuity with expertise, with focusing on 1 disease. Patient survival now is not 1 year, is 5 years and more. And maybe with all your novel strategies, 1 day, we can cure in answer, so I can move and do something else in my life.

That's great. Well, thank you very much, Dr. [indiscernible]. Have a great day. Building on that, I mean, I think Tony couldn't have highlighted better Exelixis collaboration and commitment to RCC. If you look at this, this is a market that in 2015 in the U.S. was about $1.5 billion. CABOMETYX played a very large part in helping patients and making this a $6.8 billion market in 2024. But as you heard today, our ambitions really go much further than that. We're excited about zanzolitinib in the variety of studies going on there. We're excited about new modalities coming forward. We see the RCC space continuing to grow in the coming years, and we are very committed to continuing to work across modalities to hopefully raise the standard of care, raise the bar for patients with RCC. So with that, that concludes the RCC portion of the day. So I'd like to shift gears and we're going to focus on another very exciting tumor type here at Exelixis right now, which is colorectal cancer. So to kick off the colorectal cancer franchise portion of our discussion, I will turn it back over to Dana.

All right. Great. Thanks, P.J. And to start off this section, I'd like to introduce our next outside expert. Please welcome Dr. Anwar Saeed. Anwar, thanks for joining us today. Anwar is the Section Chief of GI Oncology at the University of Pittsburgh and also Director of the GI Disease Center at the Hillman Cancer Center. So welcome, Anwar. Thanks for joining us. Before we get started, would you mind just telling us a little bit about yourself, your research interests and the patients you treat in your practice?

Yes. So thank you so much for having me. And I'm a GI oncologist, ATI oncology at University of Pittsburgh and -- my -- I have been doing the i oncology for over 10 years, focusing mainly on combining VEGF targeted therapies, particularly working with you guys on VEGF tyrosine kinase inhibitors with the parent drug, cabozantinib and then now with anzalintenib in combination with immune checkpoint inhibitors or other immune modulators. So the focus of my research has largely been in new modulation with TKIs in the GI setting, colorectal cancer as well as noncolorectal cancer. And this is the population that I mainly see in my practice. A large portion of [indiscernible] practice are focused on the colorectal population as well as [indiscernible]

Great. Thanks for sharing that with us. So let's start off by discussing the landscape. And more specifically, focusing on patients with colorectal cancer who have microsatellite stable or non microsatellite instability high tumors, where chemo is really entrenched across lines of therapy, especially in places like the U.S. and other developed countries. In combination with anti-VEGF therapy. It's really been the mainstay of treatment for well over a decade. So my first question to you, Anwar, is as you think about the strong reliance on chemo in combination with anti-VEGF therapy across multiple lines of therapy, especially going into later lines. How do you think this potentially impacts outcomes for patients, especially as they get into later line treatment?

Yes. So as you highlighted, Dana, within the colorectal cancer space, we have a very strong evidence for the fact that colorectal cancer rely on the angiogenesis pathway for response. So it's a hallmarked pathway when it comes to colorectal cancer signaling and we have strong evidence for VEGF clonal antibodies with bevacizumab in the frontline setting, we have evidence for continuation of fat beyond progression in second line setting with bevacizumab as well [indiscernible] and then with the 1 posted based on the Sunlight data evidence that continuation works in the third line. However, digging deeply into the data and looking at the subcu analysis of this large sunlight trial that looks at longer plus BEV in the third-line setting. We know that the portion of the patients that went on that trial where patients who are naive. And it turns out, when you look at that data and dissect the subgroup, the overall survival based on sub groups, most of the benefits are actually derived from patients who were bevacizumab-naive, the population of patients who received prior -- the business number progress on prior bad before going on the study did not derive a lot of benefit. So the median survival for patients who with prior [indiscernible] was 9 months as opposed to 15 months and patients with BEV naive. And so this highlights that really the need for novel agents with new mechanical actions or -- as in the third line space. As I would say, particularly, we're returning to the western population and our U.S. patients, almost 90% of the patients, if not more, are be-exposed patients.

Great. Another important point to make here, I think, is the fact that immunotherapies have made really a significant impact across the tumor landscape in oncology. But a big exception here is with the patients we're talking about today, namely those with microsatellite stable colorectal tumors -- can you share your thoughts on why that has been the case? Why haven't we really seen much advancement of immunotherapy-based regimens in this setting?

Yes. So yes, that's a very great question. As we know, immunotherapy, particularly with immune checkpoint inhibitors have revolutionized the solid tumor outcomes in many tumor types, including, for example, RCC, which is a hallmark tumor that you guys are focusing on. But as opposed to RCC and many other tumors that are immune responsive within the GI cancer space, on cancer is considered we're referring to the microsatellite stable colorectal cancer consider as the cold tumor. And so there has been a lot of studies either with historically going back to the old studies with pembrolizumab monotherapy -- and there's also durvalumab that was explored either molecular or in combination with another checkpoint inhibitor CPNA4. And then there has been a number of smaller- to medium-sized studies that look at IO-IO combinations in the space and all of them have failed to show a benefit or a survival advantage in the MSS colorectal cancer population, including recently the Phase III LEAP 017 study, which explored a budget multi-bag tyrosine finance inhibitor lenvatinib in combination with PMR in this particular population and have failed to show survival benefit. And so it is a cold tumor and requires a very strong precision-oriented a new modular that could switch or modulate the tumor micro environment to turn it into an immuno receptive environment. And I see we're going to come up with the slides that your assets and valintinib is a great candidate that have proven itself in the [indiscernible].

Right? So those are excellent points Anwar. And it's certainly important as we begin to focus on really how to improve outcomes for these patients with immunotherapy-based regimens, helping to warm up tumors and make them more amenable to an IO-based therapy. So let's now shift our focus to early-stage disease. This is a neoadjuvant or adjuvant setting -- so looking at current options for definitive therapy in these early-stage settings, how would you characterize the unmet need here?

Yes. So well, let's get the perioperative setting in patients with colon as well as risk set cancer as we treat [indiscernible], we treat rectal a little bit different than colon as we do chemoradiation in the rectal setting while we do chemo alone in colon setting and one of them we do [indiscernible] therapy in some adjuvants. As well, while in the colon space, we use mostly adjuvant chemotherapy. That was unmet needed here is that despite all of this improvement as far as doing chemo or chemo radiation or rig cell space would surgery despite this definitive therapy, 15% to 30% of the patients with Stage I to II colored cancer develop recurrent disease in per -- and we'll see within the first 2 to 3 years, post-completion of definitive therapy. And right now, we really don't have any anything to offer those patients. However, there has been a lot of advancements into biomarker development. And over the last, I would say, 5 to 7 years, there has been really urgent development of TDD and ASAs to monitor minimal residual disease. So this has been started in heme malignancy that they moved into solid malignancies and really validated very well within the color to space. For example, Denentera minimal residual disease assay is very strongly validated in the colorectal cancer space in many studies that we're going to touch on later, but the highlight is that this assay is able to identify the high-risk population that would develop recurrence within the next 2 to 5 years with high accuracy and sensitivity above 19%. And so having that I say here is a great opportunity -- but to highlight the unmet need here is that we have an SA, we know who are at high risk to develop recurrent disease, but there is a great wound-up opportunity to offer something to those patients as finely there's no standard of care options. So if we do those assays in our reward practice, all what we can tell the patient that, hey, you are at high risk to develop recurring disease, and we have to continue to observe meaning do the CT Ken, to the serious assays until we see something pop on this kit, which could be an audible in the lung or a stage 4 disease. So it leaves those patients with a lot of anxiety and and really it makes the physician or reach that position with the feeling of being helpless and have nothing to offer. So it does await a need to develop strategies -- and to me, it's a great wind of opportunity for drug development and for industry move drugs, particularly that show -- drugs that showed evidence of late or speak setting to this exploration of the space.

Yes. Thanks very much for those insights, Anwar. As you know, we're really excited about the possibility of tracking minimal residual disease with circulating tumor DNA-based diagnostics a way to identify patients with high unmet need, which we'll be getting to in just a moment. So let's talk now a little bit about our pipeline strategy in colorectal cancer. So as we think about this treatment landscape, we're really firmly committed to developing differentiated therapies that we hope or think will address unmet needs for these patients across settings and lines of therapy. So our first big step in that direction is obviously the positive readout from STELLAR-303, which compared the combination of zanzalintinib plus atezolizumab versus regorafenib in patients with non-MSI-high colorectal cancer who had received multiple prior therapies. So Anwar, you recently presented the results at ESMO 2025 in Berlin. And I have to say the momentum we had going into ESMO and especially now coming out of ESMO has really been energizing for our team to not just stop at STELLAR-303, but really kind of bring it across the treatment landscape for these patients. So STELLAR-303 is really just the first of several opportunities now that we're considering across this landscape are -- and zanzalintinib, in particular, but our earlier pipeline also includes additional molecules that we think can potentially be beneficial to these patients, including both the immunotherapy, we just discussed XB-628 and an ADC XB-371, which we'll talk about in more detail in just a moment. But let's first focus on zansa because that is really kind of right in front of us right now. As Mike mentioned earlier, we've now submitted the NDA based on the findings from STELLAR-303 and are excited to have taken that step. The franchise strategy really starts with 303, which met one of its dual primary endpoints, demonstrating 20% reduction in the risk of death with the combination in the ITT population at the final analysis, which is one of the dual primary endpoints. In the next few slides, Dr. Saeed will briefly summarize the rate and the key findings. But before I turn the podium back over to you, Anwar, actually now, I am going to turn it over to you now to discuss some of the highlights from the 303 trial. Sorry, take it away.

So we can -- yes, definitely provide an overview here of the study design for STELLAR-303. It's a Phase III colorectal cancer study tailored to patients with tumors that are not in a side and not mismatch [indiscernible]. And the trial enrolled patients who are -- who have metastic or advanced unresectable disease, that progressed or were intolerant to prior standard of care therapy that included fluoropyrimidine, arotecan and oxybate with or without anti-VEGF targeted therapy and the patients with actionable molecular profile need to receive the standard of care molecular therapy, for example, trash patients should have received anti-EGFR antibody and then the VERA P6 mutant patients should have received or failed prior VERA targeted therapy. So the patients were randomized once we went to either the combination of zanzaletinib plus atezolizumab versus regorafenib dosed at the regulatory approved labeling. And we stratify the patients based on geographic region, based on our [indiscernible] as well as presence and absence of liver metastasis. The study had dual primary endpoint of overall survival in the intention to treat population as well as overall survival in patients without liver metastases there that I presented at the ESMO meeting where the fine overall survival analysis of the intention to treat population. And I also presented interim analysis of overall survival in patients without liver metastasis. Next slide. So looking at the final overall survival analysis in the ITT population here. So this study, as we all know, has met its primary end point with household ratio of 0.80 translating into a 20% reduction in that waste benefiting or favoring the combination of dental antibatezolizumab as opposed to regorafenib with a p-value of 0.0045. The median overall survival was 10.9 months with the combo versus 9.4 months with regorafenib. As you see in a couple of marks here, there's a very clear separation of the care from the get go. So some techs minimal. Clear early separation of the care that maintains the separation with time, which speaks to the attacks of the immunotherapy in the setting. As you see at the 12 months overall surge estimates, versus 38% with rigorous and the overall survival seen at the 24-month mark was 20% with a combination versus 10% a with monotherapy. And would ever I evaluate meaningful results in Phase III trials despite more overall survival stems very important. So if there is a 10% difference at the 24 months overall survival estimate -- that speaks to the meaningful outcome that the combination is really doing something as an improving outcome compared to the monotherapy arm. Next slide. So looking at the subgroup analysis from STELLAR-303 for overall survival, we have seen and looking at the key subgroups that you see in this slide here, we have seen consistent overall survival benefit favoring the combination as opposed to [indiscernible] and that benefit was seen regardless of the geographic region, Asia versus rest of the world. Regardless of the [indiscernible] benefit was seen in wise as well as mutant tumors. And the benefit was also seen regardless of the liver metastasis, which is something that we have actually not accounted for like when we've designed the study we were thinking that the benefit might be either restricted or more in patients without liver metastasis as seen in early phase trials that tested immunotherapy combinations in colorectal cancer space. However, the zansa data really surprised us, and this is very impressive to me, like, I would say, a believer in this agent because I have used it heavily in my clinic and in my own trials in collaboration with Exelixis here, and I have seen results in the liver metastasis in patients with poor tech cancer develop metastasis, which is something you, I would say, never seen with other [indiscernible]. So I think this speaks to the data. So -- and then also, -- more importantly, the patients who have prior product EGF targeted therapy also showed benefit with significant sellout ratio as you see here. So patients who had products for drug tomato targeted therapy had a hazard ratio of 0.8 or 20% reduction in risk of debt which also speaks to the combination here when comparing or contracting the results with the data from the sunlight. So talking about the safety for this -- for the combination versus Figo, the patient -- the treatment-related adverse events in general was slightly more with the combination versus regorafinib, we're referring to Grade 3 and above. But most of the side effects were grade 3 rather than 4 56% with the combo versus 33% with regorafenib. But 1 important point to point here is that the adverse events leading to the -- despite the higher at investments with the combination versus Rigo, the adverse events leading to discontinuation has been I would say relatively the same between the 2 between the 2 arms, 18% with a combo versus 15% with regorafenib, which speaks to the fact that modulation of the dosing works, meaning that those patients likely have modulation of the doses dosing and stay on the therapy. So effective dose modulation is what I'm inferring from this table. And next slide.

Yes. Thanks for providing that overview, Anwar. Just to take the safety discussion a little bit further, we wanted to point out the profile in more detail for the combination from the STELLAR-303 trial in context with other recent I-O plus TKI combinations that read out in large population Phase III trials across a range of different tumors. So this table shows the most common any grade A rates on the left for zansa plus atezo from STELLAR-303. And on the right, we're showing a range -- or the range that were observed across the same any grade AEs that were reported in 5 different Phase III trials that read out either in renal cell carcinoma, endometrial cancer as well as in colorectal cancer with the LEAP 17 trial. So Anwar, just acknowledging the challenges of making comparisons across trials. Can you speak to how you view the safety and AE profile for the combination of zansa plus [ itezo ] in these patients in third line plus colorectal cancer? And how that compares to what's been observed with other IoT KI combinations?

Yes. Thanks, Dana. So I think one important fact that I have to -- when talking about the safety data from STELLAR-303 or this combination is that -- this is the first Phase III trial testing zanzalintinib in any disease type. And so this is -- I believe that those, which is very common when designing Phase III trials is that we take what we think has recommended Phase II dose to Phase III -- but then with more exploration, we figure that maybe a lower dose might lead to the same effect. And so knowing that this is the very first Phase III zanzalintinib with 100-milligram dosing I think the profile that we have seen and despite, in my opinion, it is probably higher than what's needed. The profile that we have seen is actually very consistent with the experience with our experience with other Bet FTKI-IO that's currently commercially available in the market for other disease types like RCC, like other disease types where this combination is approved. And so contrasting my experience with using [indiscernible] using rigorofenib in the GI space, and my experience with an zanzalintinib, I think I have -- I would say with confidence that I have favorable experience using zanzalintinib reward practice or [indiscernible], but in trial setting in my own practice, and comparing zanzalintenib with the current drug. So I have a very large, I would say, investigator trial around 100, 117 patients combining cabozantinib with [indiscernible] , in cabozantinib being the parent or the earlier generation better TKI for zansa and I have seen more hanfosyndrome with cabozantinib as opposed to zanzalintinib. I feel like the GI toxicities with having a little bit more nausea and some loose stools and diarrhea, is more [indiscernible] and so I feel like this drug -- we're talking about the side effects as well, what is dose limiting toxicity. And what is -- what are the toxicities that are manageable, right? When we talk about dose limiting toxicities, handful syndromes stand out as dose limiting toxicities in this family of etfTKIs. And so if the tostoxicitis like hand for syndrome is so high, it becomes a limitation to use sat in patients because you have to stop the drug, you have to do the dose hall, you have to reduce the dose, you have to hold [indiscernible] then wait for resolution before you resume, which could impact efficacy. And tentatetinib, the handout, which is a dose limiting taxis is very low compared to we have a very clear and in our STELLAR-303 study being 16% with 9% -- or less than 10% being rate 3 as opposed to much higher with regorafenib alone. And so it's is appealing, the -- and Mike, I can give you the numbers, like, for example, in more than 100 patients that I use cabozantinib, the handful syndrome was around 20% to 30%. with zanzalintinib, I probably have 20 to 30 patients that are treated with zanzalintinib and my own practice that none of them developed [indiscernible] syndrome. And so I think this is very, very appealing when it comes to us waiting for the regimen to be available commercially and [indiscernible] practice for community oncologists to know that they don't have to deal with the [indiscernible] syndrome issue is very, very important. The other side of it, we're talking about GI side effects like nausea, vomiting, diarrhea, most of those are grade 1 and 2. And if there is a grade 3, it's very manageable with the symptomatic management. We have really good agents to control diarrhea nowadays as well as nausea vomiting, and I have never had any issues with adjusting, for example, a tiara educations if the [indiscernible] is an issue. Hypertension is very easy to deal with nowadays. There's a large profile of antihypertensive drugs available in the market. And I really don't even need a primary care position to help me manage that I have a lot of patients who don't regularly follow their primary care physician, and I feel confident just managing their block pressure when I use a TKI. And so yes, so overall, this is my experience have been very, very favorable using this combination as opposed to other VEGF-TKI. And I think overall, the profile is really consistent with other VEGF. I don't see any red flags here. It's actually more appealing when it comes to, as I say, dose in toxicities like [indiscernible].

Great. Great. Thanks for all your insights there, Anwar. So if the zansa plus Atezo combination were to be approved what would you anticipate the impact would be for patients in the third-plus line setting?

Yes, I think it would have a huge impact. There is -- colon cancer is one of the most common cancer malignancies, and there was a large population of patients who with colon cancer, microsatellite stable who are failing or progressing on front line to second line and have really no meaningful options in the third-line setting. Also knowing that the third-line population 10% of them are beating video chemotherapy. A lot of those patients are really seeking new mechanism of actions, we do novel agents, immunotherapeutic combinations in combinations that doesn't go cytopenia fatigue and needing to wear a pump or need to come in frequently for transfusions or holding the doses and all of those complex measures, knowing that we can -- we are introducing a chemo-free Beament into rework practices a huge in my opinion, a huge asset to this population and hopefully will change the horizon. They -- the likelihood of them staying on a regimen like this is way higher than staying on chemo long term. The I feel like there will be a capture for this combination and more than 50% of the population is our line setting. That's my calculation, but it could be lower than that. But I feel like knowing the patients we are treating, how they think what they want. It's based on the data from STELLAR. I don't think it's convincing to continue with the VEGF TKI monotherapy. -- and between a chemo regimen versus a non-chemorefracto always lean toward using an non-chemo option.

Great. So thanks for those insights, Anwar, it's certainly our hope and intention to bring this as a potential option to patients pending review and approval by regulatory authorities. So now let's turn the podium back over to P.J to continue the conversation, focusing more on the potential market opportunity for zansa in the colorectal space.

Great. Thanks, Dana. We're certainly thrilled as you've heard with the results of STELLAR-303 and I appreciate the great discussion there from Dr. Saeed pending regulatory approval, we do believe that these data would provide us with a very compelling commercial opportunity in colorectal cancer, which is exciting. This is 1 of the big 4 tumors. You heard from Dr. Saeed many patients here. We've done a little work. And as we look at the third line plus CRC market opportunity, we see it's about 23,000 or so drug-treated patients in the United States. And when we think about that -- well, first off, start our market research indicates that, that population is roughly broken into 3 groups, approximately 1/3 each. One of those segments is receiving a TKI. So Rego or fiquitinib, 1/3 is receiving the Sunlight regimen, so [indiscernible] Bev and the final 1/3 is receiving either chemo or that could be a variety of chemos or Lonsurf monotherapy or a targeted therapy for a biomarker-driven disease. So that said, when we took that market opportunity, we looked at it in terms of sort of contemporary drug pricing, we see that as an approximately billion overall market opportunity. As you know, Exelixis and our team, we've been in the GI space for some time with our prior approval for CABOMETYX in hepatocellular cancer with our recent approval in neuroendocrine tumors, which certainly a large portion of those arise from the GI space. So we have experience in the GI setting already. We've been building our commercial capabilities for really a decade now. So we'd be excited to bring them to bear to help colorectal cancer patients in this space. Really, the physicians we talk to with our sales force currently, the vast majority of them overlap and would treat colorectal cancer in the community. So we feel this would be an exciting opportunity should we be approved. So with that, I'll turn it back over to Dana as we can shift gears now and talk about the future of zansa.

Thanks, PJ. So building on the positive STELLAR-303 results, we're now planning another trial of zansa plus an immune checkpoint inhibitor. But this time in colorectal cancer patients with early-stage disease. So Anwar, thanks for setting up the case for this population. So STELLAR-316 is the trial we're proposing to address unmet need in the adjuvant space for colorectal cancer patients. This is a Phase III trial design to evaluate zansa plus an immune checkpoint inhibitor or without an immune checkpoint inhibitor to zansa alone in the adjuvant setting in colorectal cancer patients who have a high risk of recurrence due to the presence of minimal residual disease based on a positive circulating tumor DNA test. Before we dive into the details of the STELLAR-316 design, we'd like to also discuss this past population in a bit more detail and also focus in a bit more on the outcomes for these patients. who have not yet recurred after definitive therapy and are ctDNA positive. So first, P.J., can you provide us an overview of this patient population and then we'll go on to Anwar to share a little bit more around the data supporting this patient population having high unmet need?

Sure, Dana. So I'll just draw your attention to the left side of the slide here. As we mentioned, colorectal cancer is a very large malignancy in terms of the epidemiology in terms of Stage I, II patients, again, in the U.S., it's approximately 90,000 patients here. About 2/3 of them will go on to receive chemotherapy in the adjuvant setting. And when we look at those patients, the estimate is approximately 20% of them will have MRD based on ctDNA test. So this yields approximately 12,000 patients at high risk in this setting. And I think maybe importantly, Dr. Saeed to give us a little context on these patients, you could talk about the bespoke data and again, how you see this patient population.

Thank you, P.J. So yes, this population, as we highlighted already to earlier there's a wait unmet need for this particular population. So as you see from the biodata here that around 20% to 30% of the patients with Stage 23 colorants are post definitive posted hetotherapy that includes the current standard of care chemo, chemo plus radiation, surgery, have an MRD-positive assay. And those 20% to 30% of patients that you see here, cercrogation of those patients, the patients who are positive versus the patients who are negative in MRD SA there is a huge a clear signal that the patients were positive in RSA doing worse. It's works with a very high risk of returning disease approaching 90%, if not more within the first -- within the first 18 months. And so it's great -- there's a great unmet need to tailor new novel agents and new therapeutics in this particular population. And why I'm saying this is because these patients were already explored and exposed the standard of care chemo standard chemotherapeutic agents. And so there is a great need for manipulating the tumor micro environment or approaching the disease using other novel mechanism of actions. And one of the really great assets to utilize in this population in combination with other novel agents that could modulate the tumor microenvironment. And the reason we're thinking that is because there is more and more trials now showing that if you go to early stage setting, including colorectal cancer in the peri-op setting, for example, Denise trial and the NIS trial that explored immunotherapy and immunotherapy nations in the neoadjuvant space, patients with colorectal cancer of Phase 2 and 3. My [indiscernible] a like stable. They are seeing really good responses with some pathology complete responses in both pathologic responses overall. Those are small studies, but they're seeing the message, a clear message that moving immunotherapy to early-stage setting in a tumor that is typically immunoresistant leads to benefit and so knowing that this MRD setting or mineralogical disease study post definitive therapy, is a disease that does not have [indiscernible] disease on CT scan. There is no debar metastasis on the CT scan. It is a situation where immunotherapy, even how we would check on the [indiscernible] alone might work -- and so the fascinating idea here is, I think if we find a combination that works in later chemorefractory setting and move it to this particular population that chances and or we're going to see a benefit is very high.

All right. Great. Thanks very much for that setup Anwar. So now let's move on to the next slide, which gives an overview of the design of the proposed trial STELLAR-316. So as you already discussed, there's quite a bit of unmet need in this setting. Please walk us through the trial design and how you see zansa with or without an immune checkpoint inhibitor being meaningful for these patients, especially patients with microsatellite stable disease.

Yes. Thank you, Dana. So this is the -- I think this is a study that is very timely. And I think as you see as far as the design, it's tailored to this and maybe population with the background that we just highlighted -- this is a population that already exhausted standard of care options in the period space. and have a residual disease seen in an [indiscernible], minimal do at the [indiscernible] and there's most standard of care as far as next line and what to do. And so those patients are sitting and seeing us sitting around us with a positive MRSA and us taking, hey, you have high risk, but we can't do anything, we have to wait. And so it's really addressing a huge unmet need population in this population, which is -- and this population constitutes around 20% to 30% of Stage I and II colorectal cancer. So as we see the design of the study is limited to patients with stage 2 and 3 who have ctDNA positive [indiscernible] therapy and obviously, have no prior exposure to immunotherapy randomizing to 3 arms, the combination of zansa, a new checkpoint inhibitor or zanzalintinib alone or placebo alone. So the design is very very appealing. And I think it will help us know whether it will address the proponent, the contribution of components whether he does and the work by itself or in combination with immune checkpoint inhibitor. And to me, I think this Phase III trial is very important too because it's it's moving something that's proven to be significant in a Phase III setting in a chemo refractory colorectal cancer to an unmet need in an early stage setting. So this is like a perfect scenario where you want to move and explore a combination in early stage setting. And this would be the first and only CTDNA guided treatment in the adjuvant MRD setting for colorectal cancer. So very excited to to help with this trial, let the trial and then looking forward to the launch of this trial in the second quarter of 2026.

Great. Thanks for these insights. Anwar, we're also quite excited about this. So our plan is to develop this concept further and then get the green light to launch and we're hoping to launch it actually in the second half of the year. But if all the stars align, we might get it into the first half is, we'll see. Okay. So now let's move on to discuss the earlier pipeline and the potential for some of our earlier-stage molecules to have an impact or benefit for patients in the colorectal space. So we previously discussed XB-628, our NKG2A PD-L1 bispecific antibody in the context of its potential in renal cell carcinoma. We're highlighting this molecule again here because we think that really does have strong potential across treatment landscapes, including in colorectal cancer, both in early-stage settings as well as later stage settings, either alone or in combination with one of our other favorite molecules, zanzalintinib. Okay. So this again is a slide we showed -- last time, it just as a recap of the design of the molecule, the fact that it's in Phase 1 investigation right now, and we're really pleased with how it's been progressing to date. So Anwar, given the profile of XB-628 as an adaptive plus in at immune checkpoint inhibitor plus potentially as an NK cell tumor engager. What are your thoughts around developing this molecule in the colorectal cancer setting?

I think -- yes, I'm very excited about this asset on new molecule because I think being a bispecific immune modulator targeting both innate and specific immunity here. This is very important in the Policinspace. I think that SLR have already laid the foundation that using a PD-L1 inhibitor with a better TKI is a positive way to treat patients. And with that foundation to capitalize on the results from STELLAR-303, I think considering also the toxicity profile and everything, the optimum partners with the other immune modulators, where you could further in moderate it to our macro environment without significant additional toxicity. And keeping that in consideration the bispecific [indiscernible] engagers come as high priority when it comes to partnering, if I would have a vision of what's next, that will be high or my last. And I think this molecule has all of those assets that we're talking about having a PD-L1 target as well as NK. So target, I think, both will address the immune system to stimulate immune cells infiltration into the tumor macro environment, in combination with zanzalintinib that have already shown an immuno moderator impact as well. So I think to build up on STELLAR-303 data, this will be a really good partner with zansa in future studies and follow on.

Yes. Great. It's so great to hear your support for this molecule. We're certainly super excited about its potential really based on all the scientific rationale and hopefully, as we now start to generate more data in the Phase I trial to really highlight its potential to become really the next preferred backbone I/O across tumors, but especially in colorectal cancer. So again, as I mentioned, we're well along the way in the Phase I trial through dose escalation. And hopefully, soon, we'll be expanding, including in combinations, including in patients with colorectal cancer. So hopefully, we'll be getting data as soon as possible and be able to share them with you and others as the data start to mature. So let's highlight another molecule in our pipeline now that we're particularly excited about for colorectal cancer, and that's XB-371. So again, just to give a brief overview, we see this as a potential -- as a high potential targeted chemotherapy option in colorectal cancer patients, given the fact that it is a tissue factor targeting ADC, with a topoisomerase inhibitor payload, which we know colorectal tumors are sensitive to bringing a molecule like this into colorectal cancer has a strong scientific rationale given that tissue factor is highly expressed in colorectal tumors. So let's go into a little bit more detail about this molecule. And really just briefly, this is a monoclonal antibody that targets tissue factor, it has top summary inhibitor molecules conjugated with a next-generation linker payload technology that requires 2 tandem cleavage events for a release of the payload inside the tumors -- it really has potential to be a best-in-class tissue factor targeting ADC in this space. So Anwar, what do you think about this approach? And what role do you think a molecule like XB-371 could have in the colorectal cancer treatment landscape?

Yes. So I'm also enthusiastic, I would say, equally to this molecule and when as to the previous molecule that we just discussed a bispecific is engager. I think having an ADC in colorectal cancer is very important. There's no -- currently we're referring to the bulk of patients will call the cancer, we don't really have an ADC approval yet. And I think this is concerning the standard of care therapeutics in colored cancer knowing that IoT kid is we'll have the standard therapeutics in first line and second line space, knowing that this ADC has a payload that took biases inhibitor and targeting -- using the tissue factor to localize the tumors, the tissue factor is over expressed in many solid tumors, but overexpressing call on as well. And so knowing that, I think this is an appealing asset and very relevant to the colorectal cancer population. And I also feel when looking at your assets anti I think this could also be a partner in earlier line setting as it will address [indiscernible] or replace ROTC in the current standard of care regimens and potentially replace an regimens and maybe combine it with antarlyorline in the Stage IV setting. So I think it has a high potential, and I look forward to to seeing the data from this -- from a safety early phase trials

Great. Thanks very much for that. So the molecule is well underway in Phase I clinical investigation, and we're hoping to get into expansion cohorts very soon, including, again, in colorectal cancer patients. So hopefully, we'll have more data to share as that trial matures. So I'd like to discuss 1 more program now that's really in the early discovery phase, but we're so excited about it that we really wanted to talk a little bit about it today. And this is a program designed with a particular strategy or vision in mind to discover novel molecular glues and glue degraders targeting KRAS and potentially other important dominant oncogenic drivers across different tumor landscapes, but especially KRAS and colorectal. So our ultimate goal with this program is to address significant unmet need for patients with KRAS-mutant tumors including colorectal, non-small cell lung and pancreatic tumors, but others as well. Our vision here is really driven by the current state of the field with short durations of treatment and rapid resistance occurring with the covalent mutation-specific binders approved in lung and colorectal indications, which really highlights the pitfalls of that mutation-specific approach. So while large macrocyclic cyclophilin A glues and protect degraders, are now showing promise. They still leave a lot of room for differentiation with smaller molecular wage glues and glutarators that target unique cryptic pockets on the targets. So over the past several years, we've assembled really a truly incredible team in discovery that has taken our vision to discover such molecules to the next level. And that happened with our recent discovery of a series of very small novel chemical structures capable of gluing KRAS to other proteins capable of impeding its function. So the figure at the top left of this slide is of a high-resolution cryo-EM structure generated in-house of 1 of those molecules gluing KRAS to an effector protein. Now we've intentionally masked the structural details for obvious reasons given the cryptic pocket identified by our team has never been described before and provides a real opportunity for us to rationally drive this program forward. using the structural information is our guide. So it's certainly still early days in the discovery process for this program, but we are super excited to share the information as a way to highlight how our commitment to patients with colorectal tumors really spans the breadth of our R&D efforts from the earliest stages of discovery through late-stage clinical development and on to commercialization. So with that, let's now turn back to P.J to wrap up this portion of the discussion.

Great. Thanks, Dana. Well, first and foremost, Dr. Saeed, I want to take this opportunity to thank you very much for lending us your time and your expertise and all your insights today. Very much appreciate that. Thank you for your partnership with us and certainly all you've done for colorectal cancer patients. With that, I just want to give you the opportunity to say any final words before you go on with your day.

Yes. We're -- thank you so much, P.J. and Dana for having me today, my pleasure to work with you guys and -- my pleasure to continue this research partnership and making a difference in the color teaser space and beyond. So really excited about the 1303 data and really cost of fingers and looking forward to seeing the regimen available on rework practice. I can't wait for that. And looking forward as well to STELLAR-316 and hopefully having an impact in area stages of the disease as well. And yes, thank you for having me. And I look forward to continuing this partnership. Thank you.

Great. Have a great day, Dr. Saeed, thank you. So as we conclude our colorectal cancer portion of the day, we'll talk about our franchise vision. As we've heard and as you've heard today, we're very excited about the STELLAR-303 data and certainly the submission of the NDA. But as we view this, this is only the first step that we want to take in colorectal cancer as a company. This is a market that's large. It was about $3.4 billion in the U.S. in 2024, and we see that more than doubling by 2035. And -- and as we think about moving zanza into earlier lines of therapy, such as STELLAR-316, as we think about novel mechanisms of action in our pipeline. We're very excited to continue to work with investigators to raise the bar and the standard of care for patients with colorectal cancer. So I will conclude now the CRC portion of our day. And that gives me the opportunity now to move on to the neuroendocrine franchise portion of our program, which I'm very excited about. And in particular, I'm very excited to have the opportunity to bring in Dr. Jennifer Chan, hi Dr. Chan, -- great to see you. Dr. Chan is the Clinical Director of the GI Cancer Center and the Director of the program in carcinoid and neuroendocrine tumors at Dana Farber and certainly been a great collaborator with Exelixis for many years. So Dr. Chen, welcome. And maybe to start us off, if you can give us a brief overview of yourself, of your clinical practice and your research interests.

Okay. Well, thank you so much. I just want to start off by thanking you for the invitation to join you today and to be part of this conversation. So just a little bit about myself. I'm a medical oncologist. As you mentioned, about Dana Farber. I've spent my entire career here. I specialized in the care of patients with gastrointestinal and neuroendocrine cancers. I have a clinical practice. I'm in clinic 2 days a week. Those are the busiest days of the week and probably the most satisfying days of the week for me. But I care for patients mostly neuropen carcinomas. About 90% of the patients that I see have in some form of neuroendocrine cancer and that can be a well-differentiated neuroendocrine tumor. The nets as they're referred to, I see patients with net start in all primary tumor sites, not just in the GI tract or pancreas, but also long unknown primaries and other rare sites. And then also on the other kind of more aggressive end of the neuron cancer spectrum care for patients with the poorly get franked retroincarcinema as the next -- my research really has focused on treatment of neuroendocrine cancers really aiming to investigate novel therapies to identify new treatments, ore treatment strategies to ultimately advance the care of the patients that we're seeing.

Well, that's great. Thank you, Dr. Chan, and it's a really nice segue for us now to talk about the landscape of the neuroendocrine tumor setting. So -- we're certainly pleased that CABOMETYX was approved in neuroendocrine tumors earlier this year in March, really the first new therapy broadly applicable in neuroendocrine tumors in terms of an oral small molecule therapy in 9 years. And Dr. Chan, this is based on your efforts and certainly partnership in terms of leading the cabinet study. So I'd love to hear from you a little bit about about your cabinet study? And then what you see is the impact of cabo now that it's been approved for patients with Nets.

Well, of course, I'm happy to share a little bit more about about [indiscernible]. It's been really a focus of mine for many years now. But the Cabinet trial was designed to evaluate the efficacy of cabozantinib in patients with advanced neuroendocrine tumors. And in particular, patients who had received a prior line of therapy and who are in need of something new to control their disease. This was a study that was designed and conducted by the Alliance for Clinical Trials in Oncology, 1 of the large cooperative groups part of the NCI's National Clinical Trials Network. And really from start to finish and even ongoing to date, it's been a really nice and very strong collaboration between the Alliance Exelixis, the NCI and our patients to speak more about the trial itself, it enrolled a very broad group of patients with neuroendocrine tumors. As mentioned before, all patients had received at least 1 prior therapy for their disease that could have been either ratinuclid therapy with lutetium-177 Dotatate or 1 of the targeted agents, whether it be evolution -- there were 2 groups of patients, pancreatic neuroendocrine tumors in this larger group of what we call extrapancreatic neuroendocrine tumors, where disease arises outside the pancreas and the GI tract in lung and unknown primary sites are the more common areas. But the results of this study showed compelling efficacy for cabozantinib. There was significant improvement in progression-free survival for patients receiving cabozantinib versus placebo. And this is ultimately what you mentioned, led to the approval of cabosamton earlier in the year. What I think is really interesting to note about the trial is that we saw efficacy really across the board in terms of all of the patients who are enrolled in the trial across the board in terms of primary tumor site in both extrapancreatic and pancreatic erendoconsumer cohorts really across all grades of disease that we see and treat whether patients had a functional neuron tumor or a nonfunctional tumor. Those are the patients who may or may not have any hormone symptoms related to their disease. And the efficacy wasn't really related to the prior lines of therapy that we received -- that the patients had received. So thinking back to patients that I'm seeing in clinic every day, this is quite relevant to all of our patients with their endocrine tumors. And I think it's going to be an option to consider for all of our patients at some point during the course of their disease, particularly when we get to a point where there is a role for an oral-targeted therapy, I think cabozantinib is the first targeted therapy that we're choosing for many of our patients.

Great. Well, thank you for your perspective on that, Dr. Chan. I very much appreciate that. And I guess as you think about the field, the setting now, the landscape where it is today, as you think about looking forward, unmet needs for novel targeted oral therapies in the space, perhaps in earlier line settings what do you see as those unmet needs?

Yes, I think as you mentioned, these oral target therapies are really important class of agents that we'll use for our patients. One of the challenges that we have in clinic as we're seeing patients is that we really lacked head-to-head data. So that helps us to make a decision between, for instance, a TKI versus mTOR inhibitors. So I think that's 1 area where has been some need for more data. The other thing I'll point out about the targeted agents is that the ones that we use in practice now, they do have a side effect profile that can be challenging for some patients. I think we, as clinicians, have gotten more experience with recognizing adverse events being able to dose modify and help to mitigate some of the toxicity these patients have. But ideally, if we had an agent where there was a better AE profile overall or toxicities that could be more easily managed. I think that would really go a long way into how we care for patients and how they're living their lives day to day. The other thing I will say is that we know the targeted agents work. We've seen from many trials that there is PFS benefit, but I think we're always aiming to do better. So I think ultimately finding an agent that has better PFS that can really raise that efficacy bar and put that in terms of something desired.

That's great. Well, thank you for your perspective on that. Really appreciate it. I'll switch gears slightly now -- and I want to talk about somatostatin analogs, which is obviously agents that you use throughout the course of this disease. Could you really just give us an overview of how you're using somatostatin analogs today?

Yes. This -- as you mentioned, somatostatin [indiscernible] are, again, 1 of the mainstays in the care of patients with neuroendocrine tumors. They are helpful for a number of reasons. They can help with reducing hormone secretion from tumors. So any symptoms, for instance, flushing or diarrhea whatever hormonal syndrome patients have -- they can feel better with use of somatostatin analogs -- we've also seen from other trials that the somatostatin logs, particularly for GI and pancreatic neuroendocrine tumors can slow disease progression -- so we are often turning to somatostatin analogs very early during the course of disease to treat our patients -- and what I will say, and I think what is important to recognize is that patients with well differentiated neuronconsumers. They have a very long journey with their disease. They are living years with their disease. And I think patients are on somatostatin logs for quite a long period of time, and that can be early on were -- and then maintained throughout their lives as news are added on to that somatostatin analog backbone.

Great. had guess when you think about the currently available therapeutic options in terms of SSAs. Could you talk about what are any potential challenges associated with them today?

Sure. Yes. I think even though the SSAs are really important and we use them quite commonly, they can help with syndrome, they can help with disease control. I think some of the challenges really relate to the administration and how they're given -- they are typically monthly injections, intramuscularly or deep subcutaneous injections that are given in the gluteus area, in the Bodick area. So patients really do need to come into clinic. They're seeing nurses or other health care providers who need to administer these injections. So patients are as we think about, again, years of therapy on the somatostatin b, they're really needing to plan their lives around these monthly injections. They're needing to take off time from work. They're needing to planned their schedule around treatment. Patients with again, a long time, and I think many people, particularly with indolent disease and no symptoms, they really are aiming to live normal lives. And having to come in and plan around treatment, I think makes that feel a little bit more cumbersome, a little bit less convenient. The other thing about this amount of standing analogs is that they -- while they can control carcinoid syndrome patients from month to month will perhaps have some breakthrough symptoms or big days where they might have more flushing more diarrhea more fatigue that is attributed to to break through syndrome. And I think some of that is particularly true in the days or even that week leading up to that next injection. So that, I think, can affect people's quality of life -- we wonder and I think even patients wonder because the administration of the somatostatin logs can be challenging in some cases, whether some of their symptoms might be related to an injection that wasn't appropriately given we do sometimes on stands, see that an injection that was meant to be intramuscular may not have actually ended up in the right place.

Got you. Well, thank you very much for your perspective on the landscape sort of as it stands today. So with that, I will bring Dana back in to talk about our future plans for zansa as well as the pipeline.

All right. Thanks very much, P.J. So our most advanced effort in this space in our pipeline right now is with the Phase II/III style Phase II/III trial STELLAR-311, which is evaluating zanzolitinib in patients with advanced neuroendocrine tumors. So this study really leverages the body of data that have been generated with cabozantinib in this tumor indication as well as feedback from yourself, Jen as well as other investigators who are really looking for additional safe and effective therapies to treat patients in earlier lines of therapy. With STELLAR-311, our goal is to really extend our leadership position in this area and establish zansa as the preferred first oral therapy for patients in this setting. Okay. So Jen, this slide shows the overview of the STELLAR-311 trial. Would you mind walking us through the trial design, please?

Yes, sure. Happy to. So STELLAR-311, as you mentioned, is a randomized Phase II/III trial that's designed to evaluate the efficacy of zanzolitinib versus everolimus in patients with advanced neuroendocrine tumors. The trial will enroll really all types of neuroendocrine tumors, pancreatic neuroendocrine tumors, extrapancreatic neuroendocrine tumors and all patients will have advanced or metastatic disease. Patients can have had up to 1 prior line of systemic therapy that's not including a somatostatin analog, no prior VEGFR targeting TKI or mTOR inhibitor therapy. There'll be a 1:1 randomization to anzolitinib or ralimus with the primary endpoint of progression-free survival. There are expected secondary endpoints for efficacy and safety and also assessments of quality of life during the course of the study. There's a targeted enrollment of 440 patients, and the study initiated in July of this year. And I think more and more sites are coming online. We just activated the trial at Dana Farber last week have already started talking about the trial to our patients, and I'm glad to have this as an option to review with patients who are kind of at a point where they will need a targeted therapy. I think there sorry, go ahead.

Sorry. No, no, go ahead, finish your thought.

Yes, I was just going to mention that. I think this is an important trial for a number of reasons. One, it really is the first trial that is going to examine on oral targeted agent versus another to try to kind of get at that question that I mentioned to you before. And I think also just with the safety profile of everolimus. We know that there are some challenges. Some patients have difficulty with tolerating ever lines. And I was encouraged by what I heard earlier in the meeting today from both Tony and are about the safety profile of enzolitinib. So it will be important, I think, interesting to compare these safety profiles.

Excellent. And just do us a favor and just highlight the key differences in the population for this trial compared to the cabinet trial that you ran? With cabozantinib.

Sure. Yes. I think probably the most important difference to note is that this is designed as a you don't count SSA as a first or second line therapy. If you look at the cabinet population, most patients enrolling on that trial were receiving cabozantinib in later line settings. There was a median of 2 or 3 prior lines of therapy and cabinet and some patients that even had up to 9 lines of therapy. I think do you anticipate, and I think what we see clinically is that disease may become more refractory as you receive more and more lines of therapy. So I think we may see better efficacy in this earlier line setting.

Great. And just again, to reiterate what do you think the impact would be for patients to get access to a new therapy like this that showed a PFS benefit compared to an active control like everolimus.

Yes. No, I think this is really an important study. I think this will have a huge impact. I think for patients, number one, if we see that there's better efficacy for zanzolitinib compared to ever lines, the standard of care. We'll actually now have a new standard of care to think about it will be kind of an obvious choice that in is the preferred oral targeted agent. And I think we'll be using it first and second line. So I think it will be a really important trial. And especially as we evaluate the adverse event profile of these agents, I think it's really the safety is better. I think it really is a win-win. I think there's no question that this will become the preferred agent.

Great. Thanks for all your insights there, Chan. And also thanks for continuing to be such a great collaborator of ours in helping to really move the needle for patients for this important disease. So -- let's shift gears now and just focus on one of our earlier pipeline opportunities beyond zazolitinib. So we're rapidly advancing a new molecule that we really think has strong potential to be highly impactful for patients in this area. So XL-557 is a small molecule orally bioavailable somatostatin receptor 2 agonist that was really designed to meet the unmet needs associated with injectable somatostatin analogs, or SSAs. Some of the key issues with these agents were highlighted by Jen previously, but they're also shown here on the next slide. Monthly in-office dosing requiring patients to kind of organize their life around these, given long durations of treatment on these therapies and also potential for incomplete target engagement as they reach the end of their cycle with the drug clearing, potentially losing benefit, losing -- experiencing breakthrough symptoms -- so we really see a lot of opportunity here with an oral agent that would require way fewer visits to the office and also due to the once daily dosing and continuous target engagement that you can get from that, really potentially dramatically improving therapeutic benefit and also reducing the potential for breakthrough symptoms. So this shows a little bit more about this molecule. Again, it's called XL-557 is an orally bioavailable SSTR2 agonist, which we really think has high potential for best-in-class differentiation here from other SSA competitors. It's highly potent with picomolar level potency for activating the receptor in vitro while also being highly selective for SSTR2 compared to a wide range of other targets tested, including other semastatin receptors as well as other G-protein-coupled receptors. So based on the preclinical studies, XL-557 really appears to have very low potential for drug-drug interactions. And again, that highlights the potential for giving it in combination with other therapies such as at 557 was nominated as a development candidate earlier this year and is currently in IND-enabling studies with IND filing expected next year. So Chan, turning to you now, I'm interested to hear your views on this profile and how you think XL-557 could be or would be received by the community of net treaters and patients.

Yes. No, I think it's really exciting to hear about this agent. I think for patients not having to come in every month, not having to get an injection in a really uncomfortable area. I think that will be really meaningful for patients and their quality of life. I think as you think about the mechanism of action and how it's working. I think that it really has the potential to overcome against some of the challenges that we see where we wonder about drug delivery and issues with not having adequate target engagement. So you might have some breakthrough symptoms or even some loss of disease control when it relates to progression. So I think it's really exciting to hear about this, and I'm looking forward to seeing how this gets developed.

Great. Thanks for your views on that. We're also really excited to see this move forward. And we see potential for it to potentially have impact really across the treatment continuum in this landscape. So let's see. So as we've heard from you and as well as others, many net patients will receive an SSA across their treatment journey and an orally available SSTR2 agonist, like 557 would potentially give us an opportunity to really broadly impact these patients and bring benefits. So outside of zansa XL-557, we're also very excited about the prospect for another molecule in our pipeline and its potential in neuroendocrine cancers. And this molecule is called XB-773. This is a novel and highly innovative antibody drug conjugate targeting DLL3, a target known to be expressed across a range of neuroendocrine carcinomas including small cell lung cancer. Now DLL3 as a target is known to be highly expressed in other neuroendocrine neoplasms, including neuroendocrine prostate cancer as well as other neuroendocrine carcinomas. Despite a lot of competition in this area, we're really excited about the potential for this molecule to show best-in-class differentiation in the clinic. The molecule has a smaller VHH Fc format compared to traditional ADCs and novel site-specific linker chemistry, which in preclinical models displays much more efficient payload delivery to tumor cells compared to ADC competitors in side-by-side experiments. So we've also observed an excellent safety profile in the preclinical models leading to, frankly, the best preclinical therapeutic index we've ever seen with any ADC to date in our hands, which we think sets this molecule up for success, both as a single agent and in combination potentially supporting use in earlier lines and settings. So just turning briefly back to you again, Chan. Can you please tell us a little bit about the unmet needs for patients with neuroendocrine carcinomas and also comment on the potential opportunities for differentiated ADC like XB-773 for these patients?

Yes. I think I'm really glad to see you with an interest in neuroendocrine carcinomas because this really is a patient population that is really tough to treat. I think it's aggressive disease. And I think the treatments that we have are really limited. We use chemotherapy. But I think what we recognize with chemotherapy is that benefits and the durability of control that we get from chemotherapy is quite short. We've been actually really desperate for new strategies to treat neurotrophin carcinomas and new targets. I think what we've seen building on what's been seen with small cell. DLL3 is really probably 1 of the most attractive targets that we've seen on our different carcinomas. And I think what we've seen in the small cell lung cancer base where DLL3 targeting agent can improve survival. That's really encouraging. And I think that gives us hope that we'll see something similar for the extrapulmonary neuroendocrine carcinomas. As you mentioned, there are different ways to target DLL3. So I think although there is, as you mentioned, a lot of interest in other agents being developed in this space. I think to hear about XB773 and how it -- they have a really good safety and efficacy profile that I think is really encouraging. I think it will be important to think about using agents together. I think given the biology and the aggressiveness of neurotophicarcinoma is, I think, being able to look at combination strategies and earlier line therapies is going to be really important.

Great. Thanks. We're certainly excited as well. And when we're really looking forward to filing the IND for that next year and getting the Phase I underway. So at this point, I'd like to now turn it back over to P.J. to close out this portion of the discussion with some insights on future commercial opportunities with our net franchise.

Well, great. Well, first and foremost, Dr. Chan, I'd like to thank you so much for joining us today for your valuable perspective and your feedback. And certainly, for your great collaboration over the years and your commitment and efforts that have moved forward the standard of care for patients with neuroendocrine malignancies. So I just want to give you the opportunity to say a few a few words before you go on with your day.

Yes. Well, thanks again. Thanks for having me with you today. And I think back to this long collaboration that I've had with Exelixis, and it's really, I think it's been great to see how things have evolved from the Phase II trial of just 60 or so patients in Boston to now kind of expanding across the world. So I've been glad to have your support for now many years. I appreciate the estate dedication you have to the neuroendocrine field, and it's actually really exciting for me to see about some of the agents that are in your pipeline. I think neuroendocrine tumors are -- they are not a common disease. So there's not a lot of interest in supporting the endocrine that we see in some of the other common cancers. So I really appreciate your commitment to the space and to us those investigators and to the patients.

Great. Well, thank you very much, Dr. Chan. Have a wonderful day. We appreciate it. Great. Well, now I have the opportunity to speak to our neuroendocrine franchise vision. Dr. Chan mentioned, it's not the most common malignancy -- but it's interesting. We kind of think of neuroendocrine tumors really the way we thought of RCC a decade ago. I think many didn't think that, that would grow so much as we saw in the previous section, the RCC market grew tremendously in the past decade. Currently, the neuroendocrine tumor market in 2024 was about $2.5 billion. We see that in the U.S. We see that as having the opportunity to grow to $7 billion in 2035. And obviously, excited to now be a part of that with CABOMETYX approved this year in net, but even more excited in terms of zanzolitinib going into earlier lines of therapy in terms of other pipeline agents because that's how we have the opportunity to really help patients and ultimately have commercial opportunities by raising the standard of care. And we see the neuroendocrine market really is analogous to RCC and Exelixis' ability to kind of tap into that and do that and really benefit patients, hopefully down the road with many different assets. So we're thrilled with that, and this kind of wraps up now the neuroendocrine portion of our day. And with that, I have the honor to turn it back over to Dana to share some -- a few more updates on the pipeline outside of these 3 core areas that we've discussed. So Dana?

Great. Thanks very much, P.J. So we've spoken a lot today in detail about our renal cell carcinoma, colorectal carcinoma and neuroendocrine franchises, which are really at the core of our portfolio strategy. So let's shift gears now and highlight a couple of areas of the pipeline that we think have great potential to advance standards of care in other areas of solid tumor oncology. So a key component of our strategy is to continuously assess the solid tumor landscape with the goal of identifying additional opportunities to build leadership in other tumor areas, prioritizing compounds and/or studies that can make the greatest impact for benefiting patients. So as a way to illustrate that strategic approach, I'd like to highlight 2 opportunities in our pipeline that we think have strong potential to really move the needle for solid tumor patients with high unmet needs. So first, I'll discuss a planned Phase II study to evaluate zanzolitinib in recurrent minigeoma. This is a high unmet need population where zansa has the potential to be the first and only approved systemic therapy. And then I'll shift gears and share some exciting early clinical data for XB-010, our 5T4 targeted ADC which may be broadly applicable for patients across several different solid tumor indications. So focusing first on Goma -- this is the most common intracranial neoplasm with an incidence of around 40,000 patients in the U.S. annually. Most of these tumors are barely benign or indolent but about 1/4 are aggressive and typically recur within 3 years. There is a significant unmet need in the recurrent setting with no approved systemic therapies available for patients. And while treatment guidelines recommend several targeted therapy options, none of those options have shown meaningful response rates in clinical trials in this setting. A key part of the rationale for investigating in this space really comes from some work done here as usual for us with zanzolitinib, work done with cabozantinib, an initial finding of regression of meningioma in a patient being treated with cabo for their thyroid cancer led to further investigation in an investigator-sponsored trial, where really a game-changing response rate has begun to emerge. That trial is still enrolling. But in the first handful of patients or several handfuls of patients the data have really captured our attention and really helped shine a light on the unmet need for us in these patients and the potential for a compound like zanzolitinib and with its target profile in this space. So this slide shows the design of the STELLAR-201 study, which is a planned single-arm Phase II study that will evaluate zansa in patients with [indiscernible] who have relapsed or progressed following surgery and radiation. The primary endpoint here is objective response rate, with secondary endpoints, including duration of response, progression-free survival and overall survival. We expect to initiate this study in the mid-2026 time frame and are also planning a confirmatory Phase III study to help confirm the benefit of zanzolitenib in this setting in a randomized trial. So if successful, this approach could lead to zansa becoming the first and only approved systemic therapy for this patient population really in need of better options. So let's shift gears now and briefly focus on 1 of our earlier pipeline assets, XB-010. So this is our 5T4 targeted antibody drug conjugate, which is conjugated to monomethyl auristatin E payload, which is currently being evaluated in a Phase I clinical trial. We like 5T4 as an ADC target because of its high levels of expression across a range of tumor types with limited expression on normal tissues. XB-010 comprises a high affinity 5T4 targeting monoclonal antibody that uses next-generation site-specific conjugation and linker payload technology requiring 21 cleavage events with enzymes expressed inside tumor cells. This gives us a very clean ADC approach with very little leakage of the payload in the systemic circulation. So we're excited about this molecule as it really represents another differentiated approach in our pipeline. And specifically, to this target, potentially leading to the first and best first and best-in-class status for targeting 5T4 expressing tumors. The Phase I trial for XB-010 initiated last year and is progressing quite well in the clinic with dose expansion now underway. So let's take a closer look now and an example of how XB-010 is performing in the clinic. This is a case study of a patient treated in dose escalation with XB-010. The patient was diagnosed with head and neck squamous cell carcinoma in 2017 and was heavily pretreated prior to enrolling in our Phase I study, having previously received numerous systemic therapies, including prior taxane therapy. In response to single-agent XB-010 every 3 weeks. This patient achieved a partial response at week 7, which was subsequently confirmed at week 13, with a substantial tumor lesion reduction shown in these scans. This is particularly interesting given that the patient had progressed on a chemotherapy with a mechanism of action similar to the payload on XB-010. So we think these early data really suggest that XB-010 has the potential to show benefit across 5T4 expressing tumors, and we look forward to presenting further data as the Phase I trial mature as the Phase I trial matures. So these are just 2 examples of how our strategy focuses our R&D efforts on compounds and studies that have the highest potential for moving the needle for patients. And hopefully, we will be able to show you more as compounds could continue to progress and trials continue to come into our our view. So with that, I'll now hand it back over to Mike for a few closing remarks.

All right. I'm back. Great work guys. Thank you so much really grateful to have the discussion between Dana and P.J and our clinical experts today give you a sense of where we're at, where we're going, the clinical nuances and the strategy behind how we're trying to build important new franchises to complement cabozantinib and take us to the next level of impact for both patients and shareholders. So a couple of brief remarks before we close, I'll just remind everybody following up on the last couple of comments from Dana, that we rigorously and stringently prioritize what we do, how we do it, when we do it, how much we invest in doing it to be able to maximize value for patients and shareholders, again, improved standard of care because that's the only way we'll be able to really monetize and create value for our shareholders from the standpoint of investing in the winter. So we have a lot of internal expertise there. As you all know, we've done that historically. We bet on cabo early when everybody else gave up back in 2014, 2015, and I think that's paid off handsomely in terms of approvals, very impactful label. You heard from our critical experts today, the role cabo can have in different tumor types in both GU and GI and we're certainly looking to do that again and again and again across the portfolio. So more of that's on the way. We're going to pick the winners. We're going to maximize success and continue to move forward. I won't spend too much time on this slide. It's kind of a lead behind from the standpoint of key upcoming milestones for the Pivotals, the Anza development program. You've heard this commented on and really opined upon today, so I won't read every line, I'll just, I guess, reiterate the obvious is that we're looking to do a lot here, both in terms of existing and soon to start pivotal trials, but a whole range of new potential indications kind of Phase II enabling trials that can get us into new indications, new combinations, areas of high unmet medical need with our strong focus of our commercial lens to be able to understand where we can maneuver and bring the most value to patients and shareholders. So again, as these trial starts, we will update you on that and certainly very excited to, again, move the needle and collaborate further across the GU, GI and net space. So our last slide today, again, has kind of a pictorial illustration of how we can achieve this aspirational vision for success going from where we are today with CABOMETYX to where we hope to be in the future with this pipeline of franchise molecules covering, again, 5x, 10x more patients than we currently cover with cabo across many, many more tumor types and across a portfolio of pipeline of franchise molecules. Again, keep in mind, we're going to establish, expand and entrench important new franchises across the pipeline as we build value for patients and shareholders. So thrilled to have the opportunity today to talk to you about our strategy behind building franchises. And now our job is to get back to work in the lab and the clinic and make that happen for patients and shareholders. So I want to close here. First, I want to thank everybody involved in putting on this production today. Certainly, Dana and P.J and our clinical experts Tony and Anwar and Chan did a phenomenal job of having a discussion around our strategy and our focus. I want to thank the entire Exelixis team led by Susan Hubbard and Andrew Peters, Deborah Leong and Alice Redick did a great job of helping us pull these slides together, pulling our messages together. Lindsay Treadway was intimately involved in making this happen on a minute-by-minute basis, and I want to certainly thank our friends at Wilson Dow for putting together a phenomenal production that I hope you enjoyed and I hope you'll have a chance to look at as we go forward in the future. So we'll stop there. Hope you all have a great holidays, and I look forward to seeing you in San Francisco in January, okay? All the best. Thank you.