Okay. All right. Thanks, everybody. I'm Seamus Fernandez, the global biopharma analyst here at Guggenheim Securities. This is our fifth annual oncology conference. Really pleased to be joined by Eli Lilly. To my far left is Jake Van Naarden, CEO of Loxo Oncology at Lilly, and President, Lilly Oncology. Dr. David Hyman, immediately to my left here, is Chief Medical Officer of Lilly Oncology. You know, Jake, maybe just to kick us off, you can give us a little bit of the sense of key drivers. I think we were just talking about how impressive a quarter we just saw out of Verzenio, but maybe I'll leave it for you to take it away from there. Yeah. Happy to. Thanks for having us. You know, as I think about the key drivers of the oncology portfolio, maybe I'll split it up into the commercial portfolio and then the investigational ones that sort of still have more, you know, more to prove. On the commercial side, obviously, you know, growth of the overall oncology business is in the very near term driven by Verzenio, predominantly in early breast cancer in the adjuvant setting. To a certain extent in metastatic too, we can get into that. As you mentioned, the launch in the initial indication in early breast cancer has gone incredibly well on the back of what are just very compelling data that I think increasingly becomes hard for physicians once they know the data to not use in the appropriate patients. We're in the process, we hope, of expanding the labeled indication beyond the high Ki-67 population in light of the MONARCH-E data. I think, you know, we said publicly that we've submitted that to FDA, you know, hopefully that's something that'll happen later this year that we can then market against. You know, we can get into it more, you know, the next leg of the Verzenio story is obviously in prostate cancer, which could be a very meaningful opportunity for patients and for the brand. The other program that we hope will be a commercial driver, though perhaps not this year, but in the future, is Jaypirca, the recently approved BTK inhibitor, pirtobrutinib. We're in the midst of the very, very earliest days of launch right now, for the initial indication in relapse refractory mantle cell lymphoma. Very small initial indication. I think this year will be very modest. You know, as we expand the label and indications over time, it's a medicine that has a lot of potential for patients and for us. Obviously, there's other things in the commercial portfolio, but I think over the next five years, let's say, I think we'll see the revenue growth being driven by Verzenio and by Jaypirca. On the investigational side, I think, you know, we have imlunestrant, the oral SERD, which is in late stage development and, you know, could be an approved product in the next couple years. I think the two sort of mid-stage programs that I think are on the cusp of sort of proving to us what they are this year are our KRAS G12C inhibitor and our mutant selective PI3 kinase alpha inhibitor, both of which could be very meaningful opportunities and differentiated ones. We just have to see if they can de-risk themselves in the context of their clinical studies that are ongoing right now. We can get into that. Great. Maybe just as a follow-on to the sort of de-risking events, what are the sort of key catalysts this year that you're most focused on? Across the portfolio. Just the datasets. Yeah. You're most interested to- So again- to see. I'll sort of start backwards and then sort of go in reverse. On the sort of randomized phase III trial front, we have a clustering of studies that are all of course event driven, but are forecasted to potentially read out right around the end of the year. Of course that's a little bit nerve-wracking because it could be this year, it could be next year, you don't know, depending on how the events roll in. You know, EMBER-3, the first registrational study for imlunestrant, the CLL monotherapy study in relapsed CLL for pirtobrutinib, and CYCLONE 2, the castration-resistant prostate cancer phase III study for Verzenio, all three of those are sort of cusping right around the end of the year from event projections. All three really important for each of those brands. The other one that we haven't really touched on is the first line lung cancer randomized study for RETEVMO, where we're going up against the KEYNOTE-189 pembrolizumab regimen. That one should read out comfortably this year. I don't know exactly when, but also event driven. You know, important, not a label expanding study for that medicine since the drug is already approved for the treatment of first line RET fusion-positive lung cancer. In a world where not enough patients are biomarker tested and not enough of those who are tested are even acted upon, I think to the extent we can comfortably beat a PD-1 containing regimen in the first line, I think that does start to change some of those dynamics, especially 'cause no other targeted therapy of lung cancer has ever done that. Those are the randomized studies, and obviously, you know, on the earlier stage or mid-stage portfolio, those are a little more fluid because we're seeing data sort of over time and sort of making judgment calls about, like, is this good enough to advance yet? Yeah. Okay. You know, David, as you look at the overall portfolio, we hosted a breast cancer conference call with a couple of physicians yesterday, and, you know, I think there was some really interesting feedback on the trade-offs between Verzenio and Kisqali. Interested to just hear your thoughts on, you know, how you think should MONALEESA succeed at the final analysis, you know, what that might mean for the overall category. Obviously one of the things that they talked about yesterday was that separation that continued in the data after, you know, the full two years, and now kind of you guys hold five years of data. They sort of seemed pretty convinced by the Verzenio opportunity. You know, just love to hear your thoughts there. Yeah. I think you're pointing out, I think something really important, which is it's not just about whether MONALEESA is a top line statistically significant positive study, what really matters to physicians is effect size and then the demonstration of persistence of benefit. We hear that very clearly from every physician we talk to. The things that they value about Verzenio in the early breast cancer space is the magnitude of benefit and the fact that that benefit is now proven durable. I think it's really obviously up to Novartis to demonstrate that. I think you are pointing out that, you know, we're well ahead in that process, I think we're really pleased with the inroads we've made. Again, I think it's really been a matter of just education. I think once people understand the data, they want this for their patients in the current, you know, indicated population and as Jake alluded to, hopefully future expansion there based on the data we presented at San Antonio. You know, I think it's really our market to define here. I think we're getting great feedback from physicians, and we'll let Novartis run their clinical trials and speak to their own data. Okay. I'll just add that I think that obviously there's been a lot of chatter about MONALEESA over the past couple of months, let's call it. I think that at least my observation is we're sort of conflating ideas a little bit. Mm-hmm. You know, there's one idea about, like, will the study be successful or not? I'm not sure how relevant sort of in a vacuum that question actually really is. David alluded to that. Because there's already a regimen that's approved and being used out there that has an effect size, that has a durability of benefit off therapy. I think the question has changed now. Right. For MONALEESA. It's not about whether the study is successful or not. Right. It's what are the texture of the data? Right. How competitive is the hazard ratio? How long will it take to see an extended period of time after a three-year treatment regimen? Ours are two-year treatment regimen. However long it took us to get follow-up post two years, it's gonna be longer to find follow-up post three years. I think we need to sort of integrate the idea that the landscape has actually changed. A successful study is not sort of just the ticket to entry. Right. Yep. The only other thing that I would ask is that ability or the opportunity to expand into the immediate low-risk patient population. Yeah. Is that an important question from your perspective that needs answering for CDK4/6? Or do you think it's just a very challenging area to reach into, and expand the overall market, for CDK4/6? Well, maybe I can take that. You can. I think there's a couple of things there. What really resonates about the MONARCH data with prescribers is the idea that we're intensifying treatment for the patients who really need the intensification based on their risk of recurrence. Obviously, when a physician is sitting in front of a patient, what they want or what the patient wants to know is, "What is my risk of recurrence, and what can I do to decrease that?" As that risk decreases, their willingness to take on any added risk or toxicity of treatment, any addition of a CDK4/6 inhibitor doesn't matter who's gonna be associated with the increase of side effect burden and toxicity. That has to be justified. In a treatment intensification setting like this, you need to identify patients that warrant that. I think that was actually why MONARCH was designed the way that it was. Yeah. It wasn't designed to maximize the kind of commercial opportunity. It was to maximize where patients actually need improved outcomes. Yeah. The second thing I just mentioned is that you can design a study that has broader patient eligibility, but if those lower-risk patients don't generate events, you actually haven't learned about the efficacy of your treatment in those lower intermediate risk patients. I think it's really. It's not just. When you say events, you're really talking about primary endpoint events. We know how FDA's position on overall survival trends as well, which are gonna take even longer for that population. Yeah. So... I think this idea of what is the benefit of CDK4/6 inhibitors in patients with lower risk of recurrence isn't really even a primary readout idea. It's gonna take years of follow-up with additional event generation of recurrences, disease, you know, distant relapse-free recurrences, and even overall events, overall survival events, I think, to really convince prescribers and maybe even regulators about what the opportunity is there for patients. Got it. Apologize. There's a little bit of feedback in the room. Whoever has a speaker on, if we can just fix that. Pirtobrutinib. You know, we'll come back to the opportunity for Verzenio in prostate cancer. Let's talk about pirtobrutinib and go to Jaypirca. Is it Jaypirca? Jaypirca. Jaypirca. Okay. Got it. You know, relapse mantle cell, fairly small opportunity. You know, what does that sort of set from, you know, the ability to establish the, I guess, the really the improved tolerability profile of this product and the potential for improved efficacy, which, you know, do you really feel starts to set the bar? When we saw CALQUENCE launching, we started to see the early indication really from feedback from physicians was, this is definitely better tolerated than ibrutinib. What are sort of the characteristics of this product that you think really need to reveal themselves to physicians, you know, to drive use? Yeah. I think there's a couple things going on here. As you mentioned, you know, the initial indicated population is about 1,000 patients in the United States. Unfortunately, even with Jaypirca treatment, duration of therapy isn't terribly long. This is a modest sort of beginning for us. That being said, relative to the available therapy options for patients with relapsed mantle cell who've already seen a covalent BTK inhibitor, Jaypirca adds a lot of value for those patients 'cause their natural history outcomes are unbelievably bad, unfortunately. Yeah. Hence the reason to bring this to market quickly, and I think why regulators, you know, were amenable to that. You know, small population. I think what's critical though, with the medicine and the sort of what we're conveying with the medicine to prescribers is the ability to reestablish BTK inhibition in patients for whom previously they were under the impression that BTK inhibition was sort of over for that patient. Yeah. Yeah. That's what's different about Jaypirca relative to the covalent inhibitors, and that's a message that, or a concept I should say, that is true in mantle cell lymphoma and of course true in CLL as well. I think, you know, we spent, and we're spending a lot of time educating on the idea that a non-covalent BTK inhibitor, in this case Jaypirca, can do something different for their patients than what they've come to accustom from the covalent drugs, and that's an efficacy proposition. It's worth me saying sort of emphatically that the proposition of the drug is efficacy. Yeah. It just so happens, and this was not something that sort of we saw as imperative, but of course we're very happy about it. It just happens that the tolerability profile of Jaypirca is very, very good. Yeah. We continually hear that from physicians that it's sort of on par with whatever they perceive today to be their most tolerable covalent inhibitor. Okay. We don't, you know, we don't talk a lot about tolerability in part because we don't have comparative evidence yet. I think anecdotally, particularly in those physicians who've used the drug in the context of the clinical trials, they already have a sense for that. You know, we're right-sizing this launch, which we're in the middle of right now, for the indicated population, but recognizing that, you know, this is, this is sort of the first inning of this commercial journey, given the wealth of evidence generation that's gonna be coming with the randomized trials reading out over the next couple years and, you know, over time addressing, bigger patient populations. Yeah. Maybe I just add briefly, like the initial framing of your question kind of put Jaypirca in kind of direct near-term competition with the covalent BTK inhibitors. Whereas there may be, you know, some future state where that is a relevant question, and we actually are running head-to-head clinical trials, we can talk about that. Really the near term opportunity, and I think both from a regulatory and just from a clinical need, is actually to extend the benefits of BTK inhibition in those patients whom either couldn't tolerate or the covalent BTK inhibitor stopped working. I think in general, physicians understand that Jaypirca is really establishing a new line of therapy for those patients. Mm-hmm. Obviously, I think the reason that so many of the questions we get about Jaypirca are in direct comparison to the covalent inhibitors is because they've all been fighting for the same population of patients in the same market. Yeah. We really are establishing a new line of therapy for patients that we think could be incredibly beneficial. You see that in the mantle cell indication now. Hopefully we can mirror that in larger patient populations. When we think about the addition of additional indications, obviously the relapse refractory CLL opportunity is probably the largest of the group, or at least that's how I think about it. The most, to David's point, I think it's the most natural home for the medicine. Yeah. If you think about the landscape and the unmet need that exists today, you know, relapsed CLL post BTK inhibitor is a space with real unmet need, and not a ton of great options. It's where I think Jaypirca is sort of the data show you that it's doing something truly different and meaningful for patients. Could it do something different and meaningful for patients in the first line? It could. We're running that experiment, we don't know that today, and we won't know that for a while. What are you guys seeing in the market now with regard to BCL-2 and what's your interest in, you know, whether it be marrying your own BCL-2 or BCL-X type mechanism to Jaypirca? Look, I think it's pretty clear that in the second line, so in this exact population we're talking about, the really only regimen that is out there that physicians have really any interest in using is the MURANO regimen, so Venetoclax Rituximab for two years. Obviously in certain geographies, it's widely adopted, like in more cost-centric countries like in Western Europe. In United States, you know, it's sort of a mixed bag. That, that regimen comes with some real complexity, which I think physicians over time have gotten used to figuring out. If they didn't have to do that, would they? What I'm really referring to is tumor lysis monitoring and inpatient stays on the front end. It's, you know, it's a different proposition from, let me stick with BTK as my target, switch to a different class of BTK inhibitor and send a patient home with a script for an oral medicine they take once a day. I think those are different phenomena. That having been said, we see over time the benefit of Jaypirca playing in both fields, and we're running a monotherapy study of Jaypirca dosed continuously until progression, and we're running a study that adds on to the MURANO regimen, where it's venetoclax rituximab plus pirtobrutinib versus venetoclax rituximab as a time limited two-year regimen, also in a BTK, or mostly BTK pre-treated population. I think we're gonna enable physician optionality and sort of country optionality for either of these two ideas. Right. In that relapse setting. Great. Maybe we can sort of shift gears to the opportunity to extend and life cycle manage a product like Verzenio. I'm sure you guys are already thinking about that. We know that there's a lot of opinions out there on oral SERDs. You know, just wanna hear where your oral SERD is today, and then also how PI3K might actually work into that, if it does work into that at all, or if it's more kind of a second line opportunity post-Verzenio that you see. Let me start with the SERD. Our oral SERD imlunestrant is currently in two global randomized studies. One we call EMBER-3, that's a study looking at the second-line endocrine therapy space in metastatic breast cancer. It's a study that's looking at imlunestrant versus fulvestrant or imlunestrant and abemaciclib, Verzenio, versus fulvestrant. Actually one of the things we've heard from prescribers we understand is that the outcomes of second line endocrine therapy following CDK4/6 inhibition is not what prescribers or patients want. Obviously one strategy to improve that is to bring a drug like imlunestrant to market. We know that physicians are also interested in adding targeted therapy onto the regimen. We're actually, to our knowledge, the only company exploring in a registrational manner a targeted therapy combination with an oral SERD right now in the second line metastatic breast cancer space. We also have a adjuvant program we call EMBER-4. This is a very large study, about 6,000 patients in the extended adjuvant setting. This is in patients that have received two to five years of initial adjuvant endocrine therapy that may contain a CDK4/6 inhibitor like Verzenio. There's still a need to further decrease the recurrence risk, and so we're looking at switching to imlunestrant versus continuing the current endocrine therapy they're on. We've also heard this is a highly relevant question, again, for people that are increased risk of recurrence. What you'll notice we don't have in that list of randomized experiments is a first-line metastatic breast cancer study. Right. You know, we've kind of looked at the treatment landscape and also the available clinical data, including the PARSIFAL study, and concluded that that study is, you know, very, very high-risk study and really arguably is not really addressing the area of greatest need right now to patients, that people feel pretty good about the first-line metastatic breast cancer therapy options they have, including Verzenio. Whereas it may have been natural to add on to our own CDK4/6 inhibitor, we made the decision not to do it. I think your kind of broader question about the oral SERD space is, the way we kind of look at it is really this is about adjuvant therapy. Oral SERDs or SERD as a class has not been able to access the adjuvant space because of the intramuscular injections. We've always thought that's the opportunity, we also see an opportunity to help women on an efficacy proposition, but also a convenience proposition. I think, you know, when we speak to providers and patients about what they want, they love the idea of more efficacy in the second-line metastatic breast cancer setting, but they also find the kind of visits and intramuscular injections painful and inconvenient. If you can offer some improvement in efficacy and improvement in convenience, that's like an all-around win for patients. That's kind of the oral SERD proposition. In terms of PI3Kα, we already know these drugs. A drug like alpelisib is effective, very poorly tolerated, and that really comes from the wild type inhibition. We designed this drug called LOXO-783 right now to be exquisitely selective for the most common mutation, called H1047R. It's about 40% of the mutations in this gene or about 15% of breast cancer overall. We think we can deliver you know, improved tolerability and potentially improved efficacy to patients that have this alteration. Exactly where that fits into the treatment landscape, I think is still to be defined. Which has to do both with the clinical profile of 783 as it emerges. It also has to do with the sort of landscape of biomarker testing and breast cancer, which is not other than like ER, PR, HER2 is not really routinely done on a genomic basis in the first line setting. You know, we'll weigh those sort of considerations as we move forward. The only sort of bigger picture comment I would make is just latching on to how you framed the question is, you know, we tend not to make these decisions sort of around life cycle management, so to speak. We tend to sort of call our shots on a program-by-program basis. You know, can we make the medicine we wanna make? Is it gonna be differentiated? Is it gonna work? Can we develop it? It just so happens that we have a clustering of medicines in breast cancer. That's great. We didn't start with breast cancer and then say, where can we go? Right. You know, we've landed in prostate cancer with Verzenio. Like did we have any quote, right to be in prostate cancer? maybe not. I don't know that I even care. We have a medicine we think is gonna work in prostate cancer and improve patients' outcomes, so we'll figure out how to be in prostate cancer. Yeah. We don't let the kind of life cycle management drive us to do things that we think are like unnatural from a medical perspective. Right. Again, you can look at the kind of the fact that we're not running a first-line metastatic imlunestrant Verzenio study as a kind of example of voting with our feet on that. Yeah. That's great. Maybe just as a final question, you know, Jake, I know we ask this question to you a lot. You know, as you look at the landscape in oncology, and also some of the changes that are occurring in the landscape or could occur in the landscape from a legislative perspective, what would you say are kinda the, you know, sort of two or three strategic realities, whether it be from a business development perspective or from a commercial perspective as you look at the longer term, you know, opportunities for Lilly Oncology? I think it's forcing us to be even more disciplined than we were. I think when you look at the sort of combination of the Inflation Reduction Act, and some of the regulatory changes afoot, like Project Optimus and other things like that, and sort of what's going on with accelerated approvals in general, Jaypirca notwithstanding, I think, you know, it is overall forcing companies, and we're not the only ones in this respect, to accelerate and pull in sort of riskier and larger spend on any given program earlier in a program's life cycle than you normally would. Right. That's okay, but it forces, you know, people like us to sort of be willing to take on more risk rather than do sort of what would be a more typical sequential risk reduction. you know, in certain situations we'll have the conviction to do that, in other situations we won't. I do think though, like when I take a step back, I think this clustering of changes, I do think like in a zero-sum game world, definitely biases success towards large pharma. I, you know, having come from a small company, I don't, I don't know how, at least in oncology, small companies can really like take things to the finish line, like reliably anymore from a standing start. It's just, it's too capitally intensive. Yeah. Too complicated, and sort of too competitive. Now, what we haven't yet seen in many cases is sort of valuation reality in the context of business development actually recalibrate to that, to the new normal, which has been a little surprising. Yeah. I imagine over time that'll happen, but it hasn't yet. I think, you know, to develop new cancer medicines from a standing start, I think having the capital and the operational wherewithal of a large pharma is much more valuable now than it's ever been. Yeah. Great. Well, thanks very much. Unfortunately, I believe we are actually out of time. It's never enough, 25 minutes, but thank you so much both of you for joining us. Congratulations on the very impressive trajectory that we're seeing Verzenio on. Looking forward to the launch of pirtobrutinib and all the great catalysts through the balance of the year. Thank you. Thanks very much. Thanks for having us. Yeah. Yeah.