All right. Can everyone hear me? Yes. Okay. I think we're gonna get started. All right, thanks, everyone, for coming tonight, and for those online, thanks for being patient as we let people get in and take their seats. I know we're starting a little bit late. My name is Jake Van Naarden. I lead the oncology unit here at Lilly, which, in the case of oncology, actually spans our discovery efforts all the way through our commercial medicines, and you'll see that reflected actually in what we walk through here tonight. Over the past couple of years, we've been working to modernize the portfolio and strategy in oncology here at Lilly, and we're doing this event tonight because I, I, I think we're really entering a new phase. And, and so tonight, we're gonna tell you a little bit about how we think, our philosophy about medicine creation, what we've been up to over the past couple of years in these efforts, walk through the portfolio itself, and importantly, actually introduce you to a bunch of members of the team who don't do as much IR, and don't do as much media, but are actually the ones doing all the hard work, getting our medicines built and bringing them to patients. So I'm excited, for you to meet them, here tonight. This is the safe harbor provision. So in terms of agenda, I'm gonna start and kick things off, talk a little bit about our strategy, our vision, the kinds of medicines we make, tell you a little bit about the changes in both the research and development portfolio and philosophy over the past couple of years, give an update on the commercial performance of our approved medicines, and then hand it over to my teammates, my colleagues, who are gonna walk through a bunch of the actual medicines in the portfolio that we're excited about. And then we'll take some Q&A at the end. Speaking of the team, really excited about the team we've built here in Lilly Oncology. This is a group of people who... The vast majority of whom are new to the company over the past couple of years. Many of them are new to industry. I just couldn't be more thrilled with the kind of talent that we've been able to attract, which I think is a big reflection, actually, of the medicines we're working on. Great people wanna work on great medicines. We've had the ability to bring a really great team together that I think rivals the best, frankly, among our peer set. And so you'll hear from them tonight, as we talk through the portfolio. So, a couple of years ago, in 2019, Lilly bought Loxo, and, you know, I came to the company from that acquisition, and in the ensuing year, a bunch of us had the opportunity to take on increasing roles in leadership, and we were afforded an opportunity to reshape what oncology looked like here at the company. But, you know, Lilly's had a long history in oncology. This is not our first gambit. Some of the first chemotherapies ever invented were Lilly products. Many of them are in use today as still standard of care in tens of thousands, hundreds of thousands of patients globally as generic medicines. Some of the first monoclonal antibodies in oncology are Lilly products still in use today. And of course, Verzenio is a Lilly medicine that has made a huge impact and continues to do so for people with breast cancer, and has, of course, been an important business contributor as well. But putting Verzenio aside, the past, call it, decade of oncology research at Lilly has not been as successful. And that was the opportunity we had a few years ago to change what that looked like. So starting with strategy, how do we think about oncology medicine creation and delivery? It's really three things, and it starts with a conviction in biology. The entire effort is biology-oriented. It's not around where the tumor arose in the site of the body. It's not around some categories of biology. It's about it starts with identifying targets, proteins, or other parts of the cell in, on, around a cancer cell, that we think that if you build the right medicine, step two, that you can actually get the tumor cell to die, and you can observe that both preclinically and eventually, you can observe that clinically on conventional imaging. Monotherapy activity clinically is what we're looking for in the right patients. We beat these medicines up a ton preclinically. We build them to pretty exacting standards. Of course, they're not always gonna be perfectly replicable when you put them in the clinic, but we think that through this approach, we can build a portfolio with a reasonably high probability of delivering medicines, come the end of clinical trials. So when we enter the clinic, yes, we're looking for monotherapy activity. Sometimes it's gonna be robust enough to allow for an accelerated approval in a late-line population where there's a significant unmet need. We've done those. Sometimes it's just enough to tell you, you have something real that you can invest more capital into in randomized trials and prove out the benefit through other endpoints. We've done that as well. And so this is the approach we take. And it really centers on biologic conviction, target selection, and building the right medicines. How do we do it? We do it through a combination of our internal discovery efforts and business development. You know, a couple of years ago, we recognized that we really needed business development to help accelerate this modernization effort, and so we've done a lot of deal-making since the Loxo acquisition. We've purchased companies, both public and private. We've done discovery partnerships. We've done licensing transactions. We've gravitated towards earlier-stage deals. That's where we think the biggest opportunity is to actually create value. And I think we will continue to be active in business development. It's really a philosophy of agnosticism as to where good medicines come from. Our discovery teams are actually at the table with our business development professionals in identifying these opportunities. We don't sort of have a first principle about where a good medicine come from. We have a lot of smart people here. There's a lot of smart people out there in the external environment, and if we can find programs that we otherwise wouldn't have the ability to make or can de-risk things we're already working on, forward integrate things we're already working on, we love to be able to bring those things in from the outside world. So let's talk about the portfolio. So in late 2019, early 2020, this was the portfolio of approved and investigational medicines, that we inherited and, had to decide what to do with. Unfortunately, most of the medicines, certainly in the first two columns on this slide, were either sort of already failing or we thought were destined to do so. And so, we took the bold initiative in the first couple months of assuming these roles, to terminate nearly the entire pipeline. We made a bet that in the ensuing years, through a combination of internal discovery efforts, leveraging the philosophy I just talked about, through business development and through extreme focus, we could build back to a pipeline of size that would rival what we inherited, if not larger, with a portfolio probability that had a much higher chance of delivering real medicines that made a big impact to patients come the end of their journey. While at the same time, taking the handful of medicines that did look real and actually progress them through the development portfolio and get them approved, launch, et cetera. And I'm excited tonight to report in this way that I think we're well on our way to doing that. Now, do we yet have the portfolio of clearly working medicines in the clinic, to... That, that resulted from these efforts? No, we're not there yet, but I think we're entering a new phase of what that could look like. Importantly, as you can see on this slide, that dotted box on the upper left represents entirely new projects since that 2019, 2020 timeframe. These were literally like ideas on a sheet of paper that we either brought in from the outside world and perfected or we built from scratch. And of course, we've moved important medicines from the left to the right. You'll hear about a lot of those later this evening. We've also diversified the modalities. A couple of years ago, if you wanted to make a cancer medicine at Lilly, you could make a small molecule, or you could make a naked antibody, and that was basically it. Our observation in looking at the increasingly complex landscape, patient need, and biologic opportunities, was that we needed the ability to diversify the modalities for which we could make cancer medicines, which meant diversifying the technology toolkit that we actually had. I'm proud to say we've been doing this. Of course, we're continuing to make selective, potent, oral small molecules. We'll hear about a bunch of them tonight. We're putting our first antibody-drug conjugates into the clinic. We're... We'll have our first T-cell redirector into the clinic next year, and by way of, at least initially, the POINT Biopharma acquisition, we're now making radioligand therapies, with our first one of those in a wholly owned way in the clinic now as well. So, I expect over the ensuing years, the color diversity will continue, in fact, perhaps even get more balanced over time. But I'm excited that we, when we identify a target now, we identify a product profile that we think can work in a patient and be differentiated, we now have a technologic toolkit that we can apply in a diverse way of how to make that medicine. While we were retooling the discovery portfolio, we, of course, were trying to jumpstart pivotal development for the medicines that we thought warranted late-stage development. We kickstarted a suite of late-stage development for a handful of different programs a couple of years ago when this all happened. And interestingly, this resulted in a pretty concentrated clustering of readouts. 8 randomized trial readouts in the span of 12 months. It's probably the most concentrated number of late phase readouts in oncology that Lilly's ever had. And most of them have been successful. Of course, they're never all gonna be successful. That's just not the way this business works. I wish it were, but it usually isn't. But most of them have been, and that's really great for patients. It's really great for advancing our medicines towards approvals and new indications. There's still one more coming very soon. This is the imlunestrant EMBER-3 phase 3 study, the first phase 3 study for the oral SERD in second-line, ER-positive metastatic breast cancer. You'll hear a little bit more about that later tonight from Lillian. Important phase 3 study coming later this year for that medicine. Of course, all of the discovery retooling has led to an unusually active agenda for new clinical trial starts in calendar 2024. Eight new clinical trial starts for new molecular entities this year, three of whom have already dosed their first patients. The rest are still on track to happen throughout the remainder of the year. It's perhaps not, not coincidental that this is such a robust year for new clinical starts. We started this process, as I mentioned, about four years ago. That's roughly how long it takes in sort of a best case scenario, to make a new medicine from scratch against the standards that we hold ourselves to. And so it's really this bolus of early phase momentum that I think allows us to feel like we're starting a new chapter for oncology R&D here at Lilly. While we've been doing this on the R&D side, of course, we've been busy, launching new medicines, launching new indications for, other medicines, and, it's been going pretty well, especially as of late. The growth that we've seen commercial in the portfolio has been, pretty robust, especially across our three key growth brands, Verzenio, Retevmo, and Jaypirca. Verzenio, abemaciclib, a medicine that, we all know well, has really, had a tremendous couple of years, for patients, particularly those with high-risk early breast cancer. We're about two years into the launch of that indication for this medicine, and it is very clearly now the standard of care for these patients. It's a 2-year regimen, and then patients are finished, that I think has really bent the curve, for patients with high-risk EBC, especially with the increased follow-up that we've had on the monarchE study, and the duration and frankly, expansion of benefit even when patients have finished the regimen. Uptake in this indication has been fairly brisk. We estimate that about 60% of the eligible population now receives this regimen, which is sort of, an interesting Rorschach test of how you think that is. If it were any other therapeutic area, 60% 2 years, 2 years into a launch would feel pretty good. Unfortunately, in oncology, especially in a curative setting, we're not satisfied with that. So, we have work to do to make sure that every eligible patient in the curative setting of high-risk EBC has the potential to benefit from this regimen. And, you know, we're gonna continue working until we get as close to 100% as we can. Jaypirca, pirtobrutinib, is our newest approved medicine in oncology. This is the non-covalent, non-covalent BTK inhibitor. We have two indications under accelerated approval that were both approved last year. First in relapsed mantle cell lymphoma, second, in relapsed CLL. Both admittedly small indications to start, although interestingly, we found that the CLL indication, which is for patients who've already received at least a covalent BTK inhibitor and venetoclax, or BCL-2 inhibitor, it's probably a larger indication than we initially thought. The growth in those medicines over the past couple of years have led to an increasing population of patients who've now relapsed on those medicines and have extremely poor outcomes that Jaypirca can really offer nice durable disease control for them. So, we're continuing to execute commercially to bring this medicine to patients. It's been interesting. We've gotten a lot of anecdotal feedback from patients and from physicians about their initial experience with this medicine, particularly those who weren't involved in the clinical trial program. So this is really their first experience, and just great things to say about what the medicine has been able to do for patients in terms of both efficacy and tolerability. I say that because we're still really in the earliest innings of the overall life cycle of this brand. You'll hear from Jeff a little bit later tonight about the large development portfolio here, most of which hasn't actually read out yet. So there's a lot more indications to come for this drug, and the early signs of its adoption, as well as just the experiences that patients and physicians have had, I think bode really nicely for the medicine's potential future. So you're gonna hear now from the team about our investigational portfolio for the most part. You know, as we've been working over the past couple of years to speed our medicine delivery to patients, we have worked tirelessly to squeeze out every ounce of efficiency from every part of the drug development cycle. And yet, we still face a pretty significant bottleneck, which is actually clinical trial enrollment. It remains by far our biggest bottleneck to getting our medicines to patients. Our trials just do not enroll as quickly as we want them to. And yet, ironically, particularly in the United States, clinical trial enrollment is not a priority for the healthcare system. 7% of U.S. cancer patients ever enroll in a clinical trial, despite it being a great way to access great care, to access standard of care, oftentimes to access new investigational medicine. So I mention it here tonight because you're gonna be hearing more from us in the future about this. We've initiated a new effort this year to try and change perceptions about clinical trials in the United States in particular, and really do more to broaden clinical trial access for patients in this country. You'll hear a little bit later tonight about the first phase 3 trial for olornarasib, our KRAS G12C inhibitor in lung cancer, which is really the first study where we're piloting actually a lot of new ideas for trial implementation to try and broaden access. So I'll just give you a flavor for what that's like, and you'll hear about the study from Jeff in a bit. We're allowing entirely local biomarker testing, so whatever patients and providers are using to identify, let's say, PD-L1 levels or KRAS mutations, that liquid biopsy or solid tumor biopsy makes them eligible for the study. We're allowing a cycle of standard of care medicines prior to even coming onto the study, because we recognize that for patients who are newly diagnosed, they may be waiting for those biomarker results. They may be nervous about a clinical trial and not know how to think about it. They may be going through the study screening procedures. We're allowing a cycle of standard of care before coming on to our program. Interestingly, we're doing something that I think is a first, actually, certainly a first at Lilly, I think a first for industry, which is that we're actually paying for all standard of care procedures on the study, in addition to the medicines themselves. So CAT scans, labs, all of the things that would normally just be billed to insurance, we're actually paying for. This is actually the normal course for every other disease, that we work on at Lilly. We probably should have implemented this in oncology years ago, but we're doing it now because it's the right thing to do. And if we're gonna change the way that patients and providers think about clinical trials, particularly in the community, we really need to eliminate every barrier we possibly can. So, you'll be hearing more about this from us over the coming months and years. I hope we're able to make a dent here. And, in the meantime, I'm gonna hand the- ... mic over to my colleague, Dr. Lillian Smyth, who's going to walk us through our breast cancer portfolio. Thanks, Jake. Hi, everyone. Good to see you. I'm Lillian Smyth. I am a medical oncologist. I was previously on faculty with the Breast Medicine and Early Drug Development Service of Memorial Sloan Kettering, so I used to see breast cancer patients in my clinic. I was also a clinical trial investigator, enrolling too many studies. In the last few years, I joined Lilly, and now I lead development of our breast cancer medicines. So let's jump right into Verzenio. So as you know, abemaciclib is our oral potent CDK4/6 inhibitor with greater selectivity for CDK4 than CDK6, which allows us to continually dose this medicine due to less myelosuppression. Shown here are the pivotal studies that we've conducted across the entire hormone-positive, HER2-negative breast cancer continuum that have led to key indications for abemaciclib. We know that abemaciclib is approved in advanced breast cancer as monotherapy and in combination with endocrine therapy, and abemaciclib is the first and only CDK4/6 inhibitor approved for the treatment of patients with high-risk early breast cancer. I'm also going to talk to you a little bit about the postMONARCH study, which you may have seen, was presented at ASCO yesterday, addressing a very important question for the community about CDK4/6 inhibitor sequencing with fulvestrant and abemaciclib after progression on a CDK4/6 inhibitor. So obviously, there's been a lot of noise about the evolving adjuvant CDK4/6 inhibitor landscape, so I just wanted to remind you about the data that we have with monarchE. As you know, monarchE was it... was the only adjuvant CDK4/6 inhibitor study designed exclusively for patients with high-risk disease, and we now have a very mature data set with all patients off therapy and in long-term follow-up. Shown here is the 5-year outcome data, which is a really important landmark for this disease, and you can see clear separation of the curves well beyond the treatment period. This is what we call the carryover effect that we're seeing from abemaciclib. Ultimately, at 5 years, we have seen a 32% reduction in the risk of developing an IDFS event, which translates to almost an 8% absolute difference in the risk of IDFS at 5 years. abemaciclib and endocrine therapy is the globally approved standard adjuvant therapy for high-risk early breast cancer, with a Category 1 NCCN designation and a strong ASCO guideline recommendation. Now, let's touch on the postMONARCH study. So we saw these data presented by Kevin Kalinsky yesterday. To remind you, the postMONARCH study addressed a question about continuing CDK4/6 inhibition beyond progression on a CDK4/6 inhibitor first line. Patients received abemaciclib plus fulvestrant, or fulvestrant alone. You can see here at the primary analysis, abemaciclib added to fulvestrant improved investigator-assessed progression-free survival, with a hazard ratio of 0.73. Just to put these data in context, we know that there is a really high unmet need to optimize therapy in that post-CDK4/6 inhibitor setting. When you look at these data, and when you consider that the standard of care is quite fractured, actually, in this second-line post-CDK setting, targeted therapy options are limited and are associated with varying toxicity. fulvestrant and abemaciclib offers a simple treatment solution with an observed treatment effect that is at least directionally similar to what we've seen with approved targeted therapies. The conclusions from this study is that postMONARCH is the first phase 3 randomized, placebo-controlled study to demonstrate the benefit of continued CDK4/6 inhibition after progression on a CDK4/6 inhibitor. In this trial, abemaciclib improved progression-free survival, despite the control arm performing better than expected, with a 27% risk reduction for developing a PFS event, consistent benefit across multiple pre-specified and clinically relevant subgroups, including key biomarker subgroups, and a consistent improvement across key efficacy endpoints. Safety in this study was consistent with what we know about abemaciclib, and discontinuation rate, importantly, was low at 6%. abemaciclib and fulvestrant offers a targeted therapy option after disease progression on a CDK4/6 inhibitor for patients with hormone-positive, HER2-negative advanced breast cancer, not selected for biomarker status. We think that these results really have the opportunity to complement EMBER-3, as Jake mentioned, which is our phase 3 study, which we'll read out later next year or later this year with our oral SERD imlunestrant. Now, talking about imlunestrant, this is our brain-penetrant oral SERD designed for continuous ER-target inhibition, including in ESR1 mutant breast cancer. As I mentioned, there is no clear standard of care after receipt of a CDK4/6 inhibitor in the first line setting, although I've shown you just some evidence for abemaciclib from postMONARCH in this setting. There was also no SERD approved in combination with a CDK4/6 inhibitor or indeed in the adjuvant setting. The thesis of our program was twofold: to develop an oral SERD that could differentiate in the advanced breast cancer setting by combining with abemaciclib, including in that pretreated CDK4/6 population. And then secondly, to displace standard of care adjuvant endocrine therapy in the adjuvant setting. In terms of the phase one data that we've generated from our EMBER phase one study with imlunestrant, we've seen encouraging clinical efficacy, particularly in that second-line post CDK4/6 inhibitor setting, which is the subject of our ongoing phase three EMBER-3 study. And we've seen efficacy of imlunestrant alone, but also in combination with standard-of-care targeted therapies. Shown here in the far right panel, we've evaluated imlunestrant with abemaciclib, with everolimus, and alpelisib, all therapies that we use in the clinic. From a safety perspective, imlunestrant as monotherapy is well tolerated, and importantly, it safely combines with standard-of-care targeted therapies. As I mentioned, our pivotal registration studies are ongoing and include EMBER-3, which is our first phase 3 study in the advanced breast cancer setting. This study enrolls patients who have received an aromatase inhibitor with or without a CDK4/6 inhibitor across three study arms: imlunestrant alone, investigator's choice endocrine therapy, or imlunestrant in combination with abemaciclib. We have dual endpoint evaluation in both the ITT and ESR1 mutant population, and this study represents the first evaluation of an oral SERD in combination with a CDK4/6 inhibitor in a phase 3 study in the second-line setting. This should position us for dual approval, both as monotherapy and in combination with Verzenio. Although we are aware of the risks of studies like this, we are looking forward to seeing the data later this year. If positive, this study positions imlunestrant to be the second oral SERD to market and the first in combination with the CDK4/6 inhibitor. EMBER-4 is our adjuvant study, enrolling early breast cancer patients who have already received 2-5 years of adjuvant endocrine therapy, which may have included a CDK4/6 inhibitor. We are randomizing 6,000 patients across two study arms, 5 years of imlunestrant or 5 years of continued standard adjuvant endocrine therapy. This trial evaluates a sequencing strategy for patients who are at increased risk of recurrence and really positions us to address the full continuum of the adjuvant treatment journey. You can envisage a future state, if EMBER-4 is positive, where patients are sequencing from upfront abemaciclib and endocrine therapy, then to imlunestrant to complete their adjuvant therapy journey, which for many patients is 7-10 years, particularly for those at increased risk. This is the largest oncology trial we have ever conducted at Lilly, and we're looking forward to see this study complete in 2027. So finally, ending on LOXO-783, this is our highly mutant-selective H1047R allosteric inhibitor. And just to ground you in the landscape, we know that these H1047R mutations, they're actually the most common PIK3CA mutations that we see in our clinic. They occur in 15% of breast cancer. And the limitation of current therapies, current Akt and PI3 kinase inhibitors are not wild-type sparing or not mutant-selective, same thing, meaning that they lead to wild- type-mediated toxicities, particularly hyperglycemia, skin toxicity, and GI toxicity. And so the thesis of our program was to develop a mutant-selective inhibitor that spares wild- type entirely and would lead to superior tolerability and efficacy in the clinic. 783 preclinically, shown on the far right panel here, achieves significant tumor regression as monotherapy when compared to alpelisib, but importantly, does not lead to increases in insulin or C-peptide. We've also generated other preclinical data of 783 in combination with endocrine therapy and CDK4/6 inhibitors, and here we see additive efficacy with those combinations. Our phase 1 study, the PICASSO trial, is ongoing, and we're looking forward to sharing data later this year. Important to say that LOXO-783 is part of a broad discovery campaign that we have against this target. In fact, we're continuing to advance next-generation molecule to be clinic-ready in 2025 as we continue to refine the clinical profile of 783. As you know, we've been in clinic for a little while now, evaluating 783 as monotherapy and in combination, and continuing to refine our understanding of the efficacy profile. Really, the first important goal of this program was to establish: Have we developed a truly mutant-selective inhibitor that spares wild type and avoids hyperglycemia? We have. LOXO-783 does not cause hyperglycemia in the clinic. From an efficacy perspective, this medicine has efficacy, and we're continuing to refine whether that efficacy is good enough in the context of the evolving therapeutic landscape and also the advances we've made in our own discovery campaign with molecules that are near clinic-ready for 2025. So with that, I'll hand you over to Dr. John Pagel to continue the portfolio review. Good evening, everyone. I'm the guy that brought the water up because I'm struggling a bit with my voice, so bear with me if you could. Thanks for joining us. I am the Global Head of Development for Hematology here at Lilly. I'm going to give you a little bit more about the development of Jaypirca, although, of course, Jake's introduced that a little bit for us tonight, and I'm gonna tell you about a new drug that's just entered the clinic, targeting the folate receptor using a novel antibody-drug conjugate. About 2.5 years ago, I joined Lilly, but before that time, I spent more than 20 years in academia doing translational research. I had a research lab, and I saw patients with blood cancers. It was during that time where I was an investigator on the phase I/II BRUIN study, exploring the use of Jaypirca in patients with relapsed B-cell malignancies. I saw firsthand what this drug did for patients, and because of that, I wanted to be closer to its development. Of course, you know, say a lot about Jaypirca. I'll remind you that it is a Bruton tyrosine kinase inhibitor, but it's a different type of BTK inhibitor. It is very highly selective, but importantly, it is a non-covalent BTK inhibitor, and it's really been designed to overcome the limitations of the covalent BTK inhibitors. As you have heard, and based on our strong efficacy and well-tolerated safety results from the phase I/II BRUIN study, the FDA approved Jaypirca for relapsed mantle cell lymphoma patients after two prior lines of therapy, including a BTK inhibitor, and in CLL, after two prior lines of therapy, after both a BTK and a BCL-2 inhibitor. You can see on this slide, we have a comprehensive suite of phase III studies, and I'm gonna mention a little bit more in detail in just a subsequent slide. But first, I wanna tell you a little more again about the efficacy of Jaypirca. These are the waterfall plots showing tumor size reduction in patients. On the left was CLL. All of these patients had received prior covalent BTK inhibitor and in mantle cell lymphoma, which is on the right, and again, all these patients had received prior BTK inhibitor. These patients are very difficult patients. Not only had they received prior BTK inhibitor therapy, but many other classes of therapy. And in particular, if you see on the left, those CLL patients, all again, who had received a covalent BTK inhibitor, many of them had received as well a BCL-2 inhibitor, Venetoclax, and that's represented by all the asterisks that are at the bottom of those vertical bars representing individual patient tumor size reduction. That's important because that is a patient population that historically has been of high unmet need due to actually very poor survival. Similarly, on the right, we see a pattern of patients treated again with a covalent BTK inhibitor, but also many other lines of therapy, including lines of chemoimmunotherapy as well. This is also a patient of high unmet need. This patient population historically has had survival of six months or less. We have built on these robust responses from this study to develop a comprehensive advanced series of phase III studies, and those are shown here. We have tried to explore the use of Jaypirca through multiple different treatment settings. This includes first line, second line, using continuous therapy, as well as fixed-duration therapy. We recognize that there's a need for improving on the therapies and as well as improving on the tolerability profile of, of the medicines, and therefore, we are comparing Jaypirca to globally established combination therapies, including covalent BTK inhibitors or chemoimmunotherapy. Also, we recognize that there are some patients who where a fixed-duration approach might be important for them. So we are enrolling patients in a relapsed CLL trial of using Jaypirca in combination with venetoclax. That study is now continuing to enroll. The other four company-sponsored studies shown here have all completed enrollment. We expect to enroll about 2,200 patients over these company-sponsored studies and look forward to them reading out over the next couple of years. I will note the BRUIN 321 study. That will be our first readout of a randomized phase III study. That's our study comparing Jaypirca to idelalisib and rituximab or bendamustine and rituximab, and we anticipate those results being reported again later this year. Lastly, I wanna point out on the far right, the BRUIN CLL18 trial. We're excited about this trial. This is a trial that will be run through the German CLL Study Group. It's anticipated to begin later this year. This is a trial using Jaypirca in combination with venetoclax in a fixed-duration approach in the first line. Overall, I think you can see that these studies show the confidence, not only in relapse refractory CLL of Jaypirca, but also in the first line and with fixed-duration therapy. Okay, I told you that I lead development in hematology. However, we have lots of medicines that are entering the clinic, as you can see, and many of them simultaneously. So I do lead other programs, and this is one of them. Of course, we also are very aware that recently, the FDA approved an antibody drug conjugate targeting the folate receptor for patients with relapsed ovarian carcinoma, and that's Elahere. Elahere was shown to be superior to investigators' choice of chemotherapy in third-line ovarian cancer patients, but only those who have high folate receptor expression. We also know that Elahere has some significant toxicities, including ocular toxicity. So we recognize that there's an opportunity to establish a new standard of care, not only targeting those patients who might have a high folate expression, but low and moderate expression levels as well, and hopefully, that would be relatively well tolerated. This is an antibody-drug conjugate that uses a topoisomerase payload and has a drug-antibody ratio that's high, and we have significant excitement around this product, and it's actually now just entered the clinic. I just want to show you a little bit of preclinical data to support our conviction that this drug will be active in those patients with perhaps low and moderate folate receptor expression levels. On the left, you can see a model of high folate expression, but in the middle two are moderate and low folate expression tumor models, where Elahere is much less sensitive, and even in a model on the right of a non-ovarian cancer, here colorectal, where we see significant activity with our folate-directed antibody-drug conjugate. As I said, this program has now entered the clinic, and we're excited to see where this goes over the next many months. I think with that, I'll turn it over to my colleague, Dr. Geoffrey Oxnard. Thank you. John. Good evening. I'm Geoffrey Oxnard. I lead Lung Cancer Clinical Development at Lilly. I'm gonna tell you about a couple of molecules focused in GI and thoracic cancers. I'm a lung cancer doc myself. I still see patients part-time at Boston Medical Center, a safety net hospital in Boston. I joined Lilly last year. I previously was on faculty at Dana-Farber and Harvard Medical School for about 10 years, where I was deeply involved in targeted therapy development and biomarker development. I was one of the lead investigators of the first in-human trial of Retevmo and got to see this patient in many of my own RET-positive patients over the years and to see its impact. That's one of the reasons I joined Lilly last year. Retevmo, I think, nicely demonstrates the three principles that Jake told you about earlier. Find a target that is important in cancer, RET, develop a drug that differentiates compared to the available therapies. We know multi-kinase inhibitors had their limitations in terms of tolerability and potency limitations that Retevmo overcomes, and three, develop the drug into the need. Retevmo has been exhaustively developed. This drug has tumor-agnostic approval in RET-positive cancers in the U.S. and in the E.U. It recently received pediatric approval in the U.S. It's the only RET inhibitor indicated in patients age two and above with RET-positive cancers. It's under development in adjuvant lung cancer, a timely space for targeted therapy development. And finally, we've just described two positive first-line trials in RET-positive non-small cell lung cancer and RET-positive thyroid cancer. These are those two trials. Both were reported last year at ESMO. Both were co-published in the New England Journal of Medicine, and both demonstrate the impact of this drug when given first line compared to standard of care. PFS hazard ratio of 0.47 on the left in lung cancer, of 0.28 on the right in RET-positive thyroid cancer. Now, this is the activity one would expect from an effective RET-targeted therapy. But these were difficult trials. People said these trials couldn't be done. We are proud to have completed these first-line trials in rare biomarker-positive populations to demonstrate the impact of the drug and to enable access to this drug globally, where randomized trial data is really important. Of course, a RET inhibitor only works if you test for RET, and so enabling access and adoption of molecular testing is critical for this molecule and other molecules in our programs, and we continue to advocate for this. If you do send molecular testing, the most common result you get back is KRAS. I'm gonna tell you about our KRAS portfolio. These are three drugs on the left, olornarasib, a second-generation, potent KRAS G12C selective targeted therapy. In the middle, KRAS G12D targeted therapy, an orally bioavailable drug. This drug is more focused in GI cancers. G12D is the most common KRAS variant, and finally, a pan-KRAS inhibitor, an ambitious drug, also orally bioavailable. olornarasib is entering late-phase clinical development. The other two drugs are entering the clinic later on this year. I'll tell you more in a moment. Let's start with G12C. G12C is 15% of non-small cell lung cancer. The discovery of G12C inhibitors created enormous excitement about the ability to target KRAS. The FDA approval of these has moved the bar, and yet some of that optimism has not come to fruition. These drugs are mostly making an impact in previously treated non-small cell lung cancer. First-line lung cancer remains a meaningful, unmet need where we think we can make a difference. Our thesis was that by developing a selective, potent, tolerable drug with a wide therapeutic index, would allow us to do the difficult thing that has not yet been done in lung cancer, combine a targeted therapy upfront with immunotherapy, something we think we are well positioned to do. On the upper right, I'm showing you the target inhibition or target occupancy of this second-generation G12C inhibitor, compared to first-line first generation inhibitors, where we see more consistent and more effective target inhibition. And on the bottom right, I show you pan-tumor activity we recently showed at ASCO, demonstrating the effect of this drug. But the real reason to believe is data like this. This is new data of olornarasib after treatment with a prior G12C inhibitor. What you see on the left is patients who discontinue due to toxicity, or on the right, patients who discontinue due to progression. Most of these patients, their immediate prior therapy was a G12C inhibitor, and we see a response rate above 40%. We see a median PFS of eight months in this heavily pretreated population. We don't think this drug is overcoming resistance. We think this drug is overcoming the target inhibition and PK limitations of first-generation drugs. Importantly, it has differentiated tolerability. The predominant AE range is grade one. One patient discontinued due to treatment-related adverse events. Even in patients who had intolerance to prior drugs, we see tolerance of this drug. My colleagues, investigators in the study, tell me that this is a drug people can be on for durable periods. We think this is a differentiated tolerability that will enable first-line combination with immunotherapy. This is CNS activity we've just reported. As we know with Retevmo, CNS activity is important to enable durable response and durable impact in advanced non-small cell lung cancer. Developing drugs with CNS activity, you can imagine, is a principle across all of our early phase programs. And so this is the data then combining olornarasib with pembrolizumab. We reported at ASCO 64 patients combined pembrolizumab plus olornarasib of two drugs undergoing ongoing dose optimization development with pembro, 50 milligrams and 100 milligrams. This is efficacy data in the first line. You see a 77% response rate across a range of PD-L1 levels. You see a favorable median PFS. We acknowledge this is an early cohort, but nonetheless gives us enthusiasm that this is a regimen that can make a difference in first-line lung cancer. And here is the tolerability profile. We are pleased to see that discontinuation due to treatment-related adverse events are infrequent. Fundamentally, this is a tox profile we think is consistent with first-line development, motivating the SunRay-01 trial that I'll tell you about now. Jake alluded to this study earlier. This is a study that's been designed for, fundamentally, phase 3 success across a wide range of phase 3 sites. It is a master protocol. Sites love this, right? You start with a dose optimization experiment. When that is completed, the trial seamlessly transitions then to two parallel phase 3 trials. We expect that transition to phase 3 later on this year. Those two trials are meant to represent real-world practice in KRAS positive lung cancers. You get a local biomarker result that comes back, you can either put that patient onto an immunotherapy-based regimen or a chemo-immunotherapy-based regimen based on your own clinical judgment and their biomarker results. As Jake mentioned, this allows enrollment after one cycle of standard of care therapy to give time for that patient to get started urgently on treatment, get biomarker results. We've got enormous positive feedback from sites of how that enables them to enroll effectively. We really think this is designed for rapid enrollment. It's already active across a wide range of global sites. I'm gonna move on to the two other drugs in the KRAS portfolio. First, KRAS G12D. KRAS G12D is the most common KRAS variant. It is more prevalent in GI cancers, especially colon cancer and pancreatic cancer. This is potential for a big impact, but the development of an orally bioavailable KRAS G12D inhibitor has been challenging. In our R&D unit, we have been able to learn from the development of olornarasib, and so through persistent iterative R&D, we have identified an orally bioavailable G12D inhibitor, a drug that has excellent PK properties, so far as we can tell in our preclinical models, and motivates us to get this quickly into patients. We think this, this can make a real impact, especially in GI cancers. Here you see the selectivity for G12D compared to other KRAS targets. On the right, you see activity across a range of cell line models. This drug is potent. This drug we expect to be highly selective, and our hope, getting into the clinic later this year, we will quickly get to effective and tolerable doses, thus allowing the kind of creative combination regimens that we've seen and we've been trying with olornarasib. So again, hoping to make an impact quickly here into the clinic later this year. Finally, I'll end with the pan-KRAS inhibitor. We realize that this is more ambitious. At the same time, this is one in seven cancers, so if we can develop a drug across all of KRAS, there's a potential for broad impact. There are a lot of ways to target KRAS. There is a unique thesis to this molecule, which is that we can target KRAS activating alterations, wild-type KRAS dependency, but spare HRAS and NRAS. By sparing HRAS and NRAS, we believe we can get around the rash and other intolerance that other multi-KRAS inhibitors have exhibited. We see this already in preclinical molecules, making us hopeful that this drug will be able to get to potent, effective doses without the toxicity challenges. Again, on the left, you see selectivity, selectivity for a range of G12 and G13 mutations, activity in wild-type KRAS dependency, but sparing HRAS and NRAS, motivating our thesis, and on the right, activity across a range of cell line models. Again, this is also going into the clinic later this year. Our expectation is this drug will have a slightly more measured dose escalation and a slightly more narrow therapeutic index as compared to the selective G12D inhibitor. But nonetheless, with this KRAS portfolio, we think we'll be positioned to make an impact across a wide range of cancers. And at that, I'm going to hand off to Dr. Arjun Balar. Thanks so much, Jeff. So my name is Arjun Balar. I'm a medical oncologist by training, much like my colleagues. And after 10 years in the clinic at NYU Langone Health, leading the GU Cancers program there and also the clinical trials office, I was really thrilled to join Lilly about 2 years ago to lead development programs across a variety of different modalities. I wanna focus on two programs, LOXO-435, and also our Nectin-4 targeted ADCs, which are really poised to change treatment options for patients with metastatic urothelial cancer, which is a personal area of research interest for me.... Let's jump right in. So LOXO-435, this is our isoform selective FGFR3 inhibitor. A little bit of background. FGFR3 alterations that are activating are present in about 15%-20% of patients with advanced urothelial cancer. There is an approved available agent, erdafitinib, responses, and also survival benefit against single-agent chemotherapy. However, it comes with a little bit of baggage, a lot of toxicities. These include things like alopecia, fatigue, hand-foot syndrome, diarrhea, ocular toxicity, and these are due to the fact that it's essentially a pan inhibitor. There are other isoforms of FGFR that we need to know about, such as FGFR4, but in particular, FGFR2 and FGFR1. Targeting these off targets is what drives these toxicities. So our core hypothesis here was that let's develop a truly isoform-selective molecule, focuses on the target of interest, and avoids those other targets that we really don't like. That enables us to have a better safety profile, but also captures the full benefit of patients receiving therapy, staying on therapy long, long enough, and not needing dose reductions. These are some of the challenges that patients on erdafitinib have, so that we can actually maximize the benefit. We've been in the clinic since 2023, early 2023, but I want to share with you a little bit about the preclinical profile that gives us a sense of how this drug will perform in the clinic. On the left is an enzyme inhibition assay that measures IC50 and looking at nanomolar concentrations. The first four rows there, just to make things simple, are representative pan inhibitors, erdafitinib, obviously, at the top. The nanomolar concentrations, they are essentially about the same, and that really defines what a pan inhibitor is. At the far bottom, you'll see LOXO-435. At 0.3 nanomolar, you have exquisite potency against FGFR3, but then if you look at the other concentrations, we're obviously very much sparing those other targets that we don't like. On the far right, you'll essentially see how we look at selectivity, which is basic arithmetic. Pan inhibitors are doing what they should be doing, which is really nonpreferentially targeting FGFR3 and the other isoforms. But we've shown exquisite sensitivity in these in vitro models. Selectivity in these in vitro models, again, for FGFR3 over FGFR1, and also FGFR3 and FGFR2. The last thing I'll mention is that middle column, FGFR3 V55M. What is that? So this is an acquired gatekeeper resistance mutation. It develops in the context of progression on pan inhibitors, such as erdafitinib. And these drugs lose their effectiveness, and that's represented in the IC50s there. We maintain potency, even against the gatekeeper resistance mutation. Pharmacodynamically, one of the things that we measure are things like hyperphosphatemia. That's actually specifically due to FGFR1 engagement. erdafitinib, comparator, causes hyperphosphatemia in preclinical models, and all the dose ranges that we tested showed no hyperphosphatemia for LOXO-435. In the middle, you've got representative examples of tumor growth inhibition, what we expect to see preclinically. I'm excited to report that after a little over a year of in the clinic, we've hit therapeutic exposures, showing really nice responses and also a safety profile that's consistent with our thesis. I'll continue on with our Nectin-4 program. Nectin-4 is a well-validated target in metastatic urothelial cancer, but also some other solid tumor types that we're learning about. Padcev has demonstrated, you know, meaningful transformation in the metastatic urothelial cancer, in particular, when combined with Keytruda, has displaced platinum-based chemotherapy in the first line setting. But what we know is that treatment resistance will develop, so patients will need options in the post-Padcev space. We've shown preclinically, and I'll talk about this in our two programs, that the primary mechanism of resistance is actually the payload, primarily through drug efflux pumps. And Nectin-4 remains the most important target in urothelial cancer, even after progression on Padcev. We have two programs that are entering the clinic. You'll see them on your bottom right. LY4101174, which I'll call 1174 for simplicity, and then LY4052031. I'll call that 2031. 1174, we acquired last year as part of our acquisition of a biotech in Western Europe called Emergence. They were developing antibody-drug conjugates with technologies that we really liked. And internally, by coincidence, we happen to have an internal program that looked very similar, but had some unique differences that I'm gonna walk you through. Let's zoom in on these two programs. On the left, you have 1174, and on the right, you have 2031. What's common? IgG1 antibody with an Fc gamma receptor silent structure here, primarily to avoid things like anti-drug antibodies. And let's talk about where things are different. And also, actually, both are DAR 8, highly homogeneous, and in vitro studies we've shown excellent, you know, linker payload stability. But what's different here? On the left, it's a novel PSar linker, cleaved by beta-glucuronidase. This helps us concentrate this drug more in tumors. The payload, however, is tried and true. It's exatecan, well-known, Topo I class inhibitor. And on the right, you have 2031, a conventional GGFG linker, cathepsin-mediated cleavage, but a novel payload, Camp- 98. It's not been tested in the clinic, but preclinically has shown higher MTD and perhaps more potency. So as you can see, we like both assets, and this reflects our conviction in this target, in putting this in the clinic. I'm excited to report that 1174, we treated our first set of patients, and we're proceeding through escalation. And And with 2031, we just received our safe to proceed letter from the FDA, and we'll soon treat our very first patients, later this month. So I'm gonna hand it off to Barry, who's gonna do his best, Mariano Rivera, and close us out. It's all downhill from here, that introduction. Good evening, everyone. My name is Barry Taylor, and I am the Chief Scientific Officer of Oncology at Lilly. I joined Lilly in the summer of 2020, having served as an academic faculty member running a translational cancer research laboratory, first at UCSF, and then for many years at Memorial Sloan Kettering Cancer Center in New York City. It's a pleasure to be here. I guess this is technically the anchor leg of our team's relay tonight, and I'm looking forward to walking you through a few additional clinical stage projects that are emerging from our portfolio this year. The first of these is our selective B and SMARCA2 selective inhibitor program. This is actually a collaboration with a partner, Foghorn Therapeutics. The thesis of this program is to exploit a so-called synthetic dependency in cancer cells. So what do I mean when I say that? SMARCA2 and its closely related partner, SMARCA4, together comprise the catalytic engine that drives a large multi-protein complex called the BAF complex. And the BAF complex is what rearranges and remodels chromatin to facilitate gene expression in every cell of our body. But tumor-specific loss of that partner, SMARCA4, which arises in approximately 10% of lung cancers through loss of function and truncating mutations, forces a lung cancer cell to then rely on SMARCA2 to mediate the BAF complex function, and that creates a therapeutic opportunity for us. If we were to be able to engineer a potent and selective SMARCA2 inhibitor, we could exploit a synthetic lethality created by SMARCA4 loss. I say selective because the inhibition of both SMARCA2 and SMARCA4 is not particularly well-tolerated in normal cells, and we'll get back to the selectivity piece in a second. But this synthetic lethality owes a debt to the pioneering work of PARP inhibitor therapy in patients with BRCA 1 and 2 mutations, a very similar concept. In fact, over the last, oh, say 10 years of academic research, cancer genomic profiling, as well as functional genetics, the SMARCA2, SMARCA4 synthetic lethal relationship is among the strongest associations in all of cancer. So we're keen to test this mechanism in patients. As such, we developed a molecule called LY4050784, again, with our colleagues at Foghorn Therapeutics. This is an oral SMARCA2 selective inhibitor. It has about a 30-fold margin over SMARCA4 in vitro, and so it demonstrates potent antiproliferative activity in SMARCA4 mutant, but not SMARCA4 wild-type lung cancer cell lines. Here on the right, you're seeing just an example of that. We've now profiled this in vitro over a much larger panel of SMARCA4 mutant lines that really represent the mutational diversity of human lung cancers. And most exciting of all is that this result has translated in vivo, and I wanna spend a moment on this slide to give you a historical perspective. These are three xenograft models of lung cancer, murine models of lung cancer, and on the far right, we see something we actually saw a lot of as we were canvassing the academic literature and the work of our peer companies when we embarked on this project, which was tumor growth inhibition. But we really embarked on this journey not knowing if we could deliver on the kinds of single-agent tumor regressions, but suspected that if we were able to engineer the right molecule with the right properties, that would be on the table, and that's what you see in the two in vivo models on the far left and in the middle. These are two SMARCA4 mutant lung cancer models, where we can observe single-agent regressions at multiple dose levels. And actually, these are quite aggressive models of the human disease. Multiple of these models have co-mutations like p53, KRAS, and actually, maybe most notably, STK11 and KEAP1 mutations, which actually define a particularly poor prognosis subset of lung cancers and one with particularly poor outcomes to immunotherapy-containing regimens. So with these attributes and this molecule's excellent oral properties, we're excited to test this clinically late-stage starting later in the year, and this has pride of place in our larger portfolio of mechanism-based therapies in lung cancer, as typified by the mutant selective and isoform selective KRAS inhibitors that Jeff was walking us through a little bit earlier. Switching gears slightly and entirely consistent with something Jake mentioned at the front, which was a very deliberate path toward therapeutic modality diversification in the oncology pipeline, we're incredibly excited to bring radiopharmaceuticals into the portfolio in oncology at Lilly. This began with our acquisition of POINT Biopharma a little less than a year ago. This is a deeply experienced team with a current clinical presence of next-generation molecules, which I'll talk about in a second, but also deep radiochemistry experience, a robust isotope supply chain, as well as internal commercial-scale manufacturing capabilities. We've supplemented that subsequently with our recently announced partnership with Aktis Oncology, which is to bring a novel targeting moiety to the development of RLTs, and we're excited about that as well. But we've also devoted a substantial effort internally in our own discovery labs for the development of RLTs, and this helps let us take advantage of the deep experience we have in structure-guided small molecule design, as well as to tap into the broader Lilly capabilities, be they therapeutic peptides or otherwise. Of course, the thesis with radioligand therapy is highly tumor-specific targeting of radionuclides. The beauty of this theranostic approach, which pairs an imaging agent with a therapeutic agent, is if you can see it and you can deliver high-dose ionizing radiation locally, those cancer cells will die. That's because this is fundamentally not indexed on the often intractable, nuanced, and heterogeneous biology of individual cancer cells. So this process is schematized here on the slide. On the far left is a patient with advanced metastatic prostate cancer, whose tumor expresses PSMA. If you take a PSMA ligand, and through a linker and a chelator, deliver an imaging agent, be it gallium or otherwise, you can do PET imaging baseline and identify, in this case, widespread metastatic disease. But now, if you replace that imaging agent with a therapeutic isotope, leveraging the exact same PSMA ligand as your targeting agent, you can deliver potentially transformative anti-tumor activity in the patient, as indicated on the far right, while really sparing normal, healthy organs. It's this kind of result that got us excited and really built our conviction in the therapeutic modality, and we're keen to work as part of a community to really develop radiopharmaceuticals as a pillar of cancer care across therapeutic indications, in the future. And so I was mentioning about, a current clinical presence. This is our active phase I program called AcCel. This is currently enrolling in Canada, though we hope to bring it to the US quite soon. This is testing a novel PSMA ligand to deliver an alpha-emitting actinium isotope, so this is a shorter range but higher energy isotope. The fundamental thesis with this program is really one of biodistribution, because in prostate cancer, unfortunately, these aren't the only cells in the body that express PSMA. In fact, PSMA is expressed in the salivary gland, and what we and others in the community have seen is significant off-target uptake in the salivary gland of first-generation PSMA-targeting radioligands. And so the question here was, can we develop a PSMA ligand that not just improves its affinity and leads to increased internalization, but fundamentally increase the tumor uptake of the radioisotope, thereby sparing salivary and renal toxicities? And so here is just a summary of those key characteristics. PSMA-62 is that novel ligand, juxtaposed here to two additional first-generation PSMA ligands, both I&T, which is part of the lutetium-based PNT2002 product, as well as PSMA-617, which is the ligand in Pluvicto. And here, this just encapsulates what I was mentioning before of improved affinity, greater degree of internalization, leading to a significant increase in tumor uptake and what we hope will be reduced normal organ uptake. And so we're incredibly excited that this study is enrolling metastatic, castrate-resistant prostate cancers now, though, after initial safety data, we hope to expand enrollment to even earlier-stage hormone-sensitive prostate cancers in the not-too-distant future. Hopefully, this reflects an effort on our part to really build out a rich portfolio of RLTs at Lilly and really establish this as a mainstay of oncology care for patients in need of transformative therapies. And so I just wanted to end, and this circles back to something that Jake was describing at the beginning. We are enormously excited by the large number of clinical starts that we're embarking on this year. But I think when you combine that with our advanced assets, we hope this reflects, and we believe it does, a significant expansion in our R&D capabilities. Again, through the deliberate diversification of our therapeutic modalities and new technologies, it allows us to remain focused on the highest conviction areas of cancer biology in disease indications in need of real, fundamental, transformative medicines. And so to bring this back to something that Jake said, this big bet we took four years ago to refactor the oncology pipeline at Lilly, we hope this is at least an initial down payment on the output of that process, though we're keen to continue that work with a rich discovery engine for years to come. So with that, I'll give it back to Jake. Thank you, Barry and team. Before we go into Q&A, I think, you know, when you look at this slide, you look at particularly the new clinical starts. You know, in addition to... Hopefully, we've convinced you about our conviction in the biology ideas here, but really, the theme that connects a lot of these, that I think actually connects back to some of our initial successes with that are now approved medicines, is the idea of bringing what I think we're-- we were used to calling precision medicine to larger populations. I think, you know, when we think about these great precision medicines in oncology, drugs like larotrectinib Vitrakvi from the original Loxo experiment, drugs like selpercatinib or Tagrisso, drugs like alectinib, and at this meeting, even lorlatinib, you know, these are medicines that have huge effect sizes for the patient populations that they deliver for. But unfortunately, like, for the universe, those patient populations are not large relative to the global impact that cancer diagnoses have. And so we tried to learn from those efforts and say: How can we choose targets? How can we make medicines that can deliver that kind of benefit risk, but for larger populations and make a much bigger impact on cancer care? So, thanks, everyone, for joining tonight. I think we'll now take some questions, and I'll ask my colleagues to come back on stage. I think they're the Lilly IR team is floating around with some microphones, and we'll answer your questions. Thank you. ... I'm ready. Oh, thanks. Hi there, Evan Seigerman from BMO Capital Markets. Thank you for the fantastic presentation today. I wanted to touch on KRAS G12C, really kind of diving into a little bit on, not the commercial challenges of sotorasib and adagrasib, but mainly what really gives you excitement about the profile of olornarasib, especially given the challenges we've seen in developing these two assets and really getting them to the front line. What's differentiated about the profile, and how can you accelerate that development to get this to patients more quickly? Thank you. Jeff, do you wanna take that? Sure. I mean, we're unaware that there are a lot of these KRAS inhibitors, right? And so, you know, there are needs that are adequately addressed perhaps by some of the drugs. But there is a need every lung cancer doc acknowledges that first line, we give these treatments, and they're just unreliable. Like, sometimes the IO works, and sometimes it doesn't work. You know, and sometimes chemo IO works two cycles, and the patient progresses. And so I think in breast cancer, we've learned to, like, build and do more, and in lung cancer, we've kind of been slow to do that, but we're starting to do it. So I think we, as lung cancer docs, are ready to build and do more, and so these, these combinations are built to make that impact upfront, make that impact durable, and fundamentally bent the curves, and get more patients onto the flat part of the curve where they can benefit durably from these drugs. I, I think the trial is designed to enroll. I won't deny that tolerability is the key barrier, and we've heard very clearly this drug has overcome that barrier. We've identified efficacy, CNS activity, activity in previously treated patients, and now tolerability, that together allow us to combine with immunotherapy. We see that in our data, and that, and that's what motivates the first-line trial. I think it's gonna be... I mean, it's a worthy experiment. We can enroll this trial, and I'm hopeful it'll play out. Yeah, you're on. Seamus Fernandez from Guggenheim Securities. So, just a couple of questions. Jake, when you think about pirtobrutinib and the sort of magnitude of the opportunity for that product, can you just give us a sense of kinda your vision, and Lilly's vision for, you know, how far that product can go? And, you know, relative to some of the sales that we've seen of ibrutinib, Calquence, et cetera, where do you really see that product positioned? And then just the second question is on the folate-targeted ADC. I think we had the Eisai folate-targeted ADC, and it saw some fairly meaningful toxicity following a partnership with Bristol. Is there toxicity risk associated with folate ADCs in general that you guys are trying to avoid, or have you studied some of those molecules to really see, you know, what those issues potentially were and so that, you know, you really view that as a well-targeted therapy? Thanks. Yep. So yeah, I can start with the Jaypirca commercial question. It's interesting, we as folks who followed that program have probably seen, we've been on a journey with this, with this medicine that, you know, well, we started thinking it was sort of a niche product in previously treated patients, maybe those only with C481S resistance mutations. And over time, just as we've grown, or I should say, as we've gathered more clinical data, we've seen the medicine can be a lot bigger than that. And so, you know, I think in our space, it's probably true for, like, all drug development, but it's definitely true in oncology. It's pretty hard to project out to, like, what will be the ultimate peak opportunity for any medicine in its early innings, and that's really what this one is. In this class, in particular, we've seen sort of early winners and later winners, and I think it's still an evolving class, actually, with some of the recent data that's emerged. So where does that put us? Well, as John talked about, we're just trying to develop the medicine in all the right places, with all the right combination partners, to result in positive data readouts that are label-enabling so that physicians can use the medicine however they want. And that actually is increasingly a theme we hear from physicians when we talk to them about the medicine, especially now that they've had the chance to use it commercially. They just say, "I... Oh, I, I wanna use it continuous dosing in the first line," or, "I wanna use it post-BTK in the second line. I wanna use it, you know, after BTK and BCL-2." I think there are a lot of different potential ways this medicine can benefit patients, and there's a lot of variety, frankly, in how physicians, both in the United States and elsewhere, may wanna use it. Our job is just to enable that use, and I think if we can do that, this medicine will make a big impact for patients and probably be a meaningfully large product for the business. On the folate ADC question, I may actually have Barry answer that 'cause it sort of has a lot to do with linker payload design as much as anything else. Yeah, thank, thank you for the question. You know, I think what we're learning, and even as evident from today and the last several days at ASCO, is that the devil is in the details with ADCs. It's really a three-component system. And so is your question, is this really a fundamental attribute of the target? Is this a toxicities associated with the release of the payload in circulation, not necessarily in an antigen-mediated way? Is this pharmacology related to the linker? I think all of those things for different products have sort of reared their heads, I think, in many ways. You know, I think we're integrating all of those lessons, not just studying molecules preclinically, but even sort of the first principles by which we design our own medicines, really have to solve the ternary problem of those three pieces simultaneously. I think these different medicines are reading out the answer to your question in different ways, actually. But if you don't mind, Jake, I- Yeah, please. Let me jump in on that, too. We actually do think, based on our preclinical data, of course, as well, that this drug we have in development will differentiate itself from... Well, here from an ocular toxicity standpoint, it's probably not- ... because of folate receptor involving the eye, it's really the payload. And I say that, here we're differentiating with the topoisomerase payload, but if you look at the MMAE payloads, they're typically associated with ocular toxicity, and I think that will be probably the biggest differentiating factor. And as I said, our non-human primates, and we don't see that type of toxicity. Of course, it's not the same experiment as we see in humans. We'll see, but we're pretty confident that we'll have a differentiated product there. Geoff Meacham at Bank of America. I had a couple for you, Jake. In the spirit of tonight, I wanted to ask you maybe a higher level. You know, you have a lot of newer technologies, you know, newer assets. You're developing, you know, clinical trials in a novel way, right? In oncology. I guess the question is: what is the appetite for taking target risk, you know, to do true basic discovery and to go after novel targets at Lilly? Is that something that, you know, you would say is a priority or not? And the second question is, when you look at lifecycle management for Verzenio, you know, down the road, I know you're studying the SERD in combination, but what's the appetite for looking at other CDKs like some of your other competitors are? Yes, sure. I'm gonna start on that on the first one and have Barry chime in, too. You know, when we started a couple of years ago, revitalizing the pipeline, I think the... One of the things we wanted to make sure is that the early wave of medicines had a higher probability than that which we inherited. And so part of the way to do that is to work a little bit more geared towards validated targets with what we think are better medicines. Coming from behind, the things we didn't talk about tonight are way less validated ideas. The other interesting thing that we didn't touch on tonight in the prepared section is the opportunity for novel targets, particularly in the context of radioligand therapies, because, you know, those are not targets that you need to have any biologic role in the cancer cell. And that's sort of a truism for ADC targets, too, except for RLTs, you can actually target intracellular proteins. So, you know, there's a whole suite of interesting ideas for targets that are overexpressed in cancer, but actually have nothing to do with the cancer itself, that if you can bring high energy radiation locally, too, you can actually kill the cancer cell. So the RLT portfolio actually is going to probably, over time, end up being very geared towards targets and ideas that, like, you don't see walking around the halls of ASCO or AACR at all. But, Barry, why don't you chime in further on the topic? Yeah, no, I mean, as exceptionally well said, I think, you know, outside of the radiopharmaceutical target space, you know, the pillars of cancer biology are unchanged. They've lasted for 25, 30, 35 years of cancer research experience, and that's, I think, at least partly why we see a lot of clustering around core target ideas. We are, in our earliest phase projects, taking on a little bit more target risk, but staying central to the sort of fundamental tenets of cancer biology for the non-radiopharmaceutical products in our portfolio. Cancer is a little bit different, I think, than many other indications, even both at Lilly and elsewhere, in this regard, in that there's a, quite a bit of biological clustering around core tenets that we're really planning the vast majority of our target work around. And then on the CDK work, Lillian, you should probably chime in here because we've- Yeah. Thought about this idea and looked at a lot of these programs. Yeah. I mean, I think that the postMONARCH data at least reinforced to us, right, the importance of cyclins in ER-positive, HER2-negative breast cancer. I mean, I think, you know, obviously there's a couple of others looking at CDK2, CDK4 inhibitors. I think, you know, as I think about the development of those kind of molecules, there probably is potential to build upon what we're seeing in postMONARCH with CDK4/6 inhibition. There's, you know, by adding on some synergistic mechanism of action agents. However, you know, the CDK4 piece is a little trickier in terms of development, right? Because you're looking at potentially head-to-head studies against very potent CDK4/6 inhibitors, like abemaciclib, which we already know is very CDK4 selective. So, you know, I think that really it's about integrating what the development path looks like for those molecules, into, you know, decisions there. Yeah. Hi, Steve Scala from TD Cowen. Jake, I believe consensus suggests Lilly Oncology will contribute a high teens% of Lilly 2024 revenue, and that likely will be a single-digit% in about a decade, so a relatively small contributor to the overall company. Now, you sit on the Lilly Executive Committee, so you're privy to the 10-year plan. Is that likely how it plays out, or are we underestimating Lilly Oncology or overestimating something else? Secondly, Dr. Smith, you might not have intended it this way, but you basically referred to the Novartis Kisqali/NATALEE data as noise. Novartis has a pretty formidable data package, so what are the weaknesses in it? Thank you. Well, then why don't you take NATALEE first? Sure, sure, sure. Thank you. The easy one first. Yeah, okay. So NATALEE, you know, obviously, it's great for patients to generate more data with more molecules, even in broader populations, so it's a positive study, and it's great to see that data. When you sort of talk about, okay, what are the weaknesses? Well, I mean, first of all, follow-up and maturity of datasets is crucially important in adjuvant breast cancer. You're talking about cure, which is clearly paramount, but you're also talking about toxicities. ... of these therapies, which are not insignificant. So that benefit-risk assessment is crucially important in the adjuvant setting. So maturity of dataset, degree of follow-up, crucially important. Clearly, there are differences between the monarchE study and NATALEE relative to that point of maturity of dataset, so that's number 1. Number 2, we need to evaluate the duration of the therapy, right? We know, that 3 years of therapy is what was evaluated in NATALEE. The question is, is that needed? Is the additional year of therapy, particularly for that high-risk patient population for which you already have a palbociclib available to you, is that additional year of therapy justified in that context? We need to see, with more maturity of data, how those curves are looking in that off-treatment period. We know that there are patients still on that therapy, still on the study, so that's important to see patients off therapy and see how those curves are behaving. The node-negative group that was presented at ASCO represents a relatively small group that was enrolled to the NATALEE study. Clearly, they had high-risk features, but I think particularly for that group, when you're considering three years of additional adjuvant therapy, it will be very important to see a mature dataset and how those curves look. Because we know those node-negative, although they're high risk, node-negative patients, they do need longer follow-up to see how those events come in. I would just add one other comment, which is I think that there are still a number of patients with high-risk breast cancer who are not receiving treatment today. And so in some ways, we welcome having another organization be talking about those patients and the need for therapy. I think if you want to also look at the ASCO guidelines that were recently released, I think they were pretty clear about how they view all of the issues that Lillian just talked about, but also the importance of the separation and deepening of the benefit over the course of time. Your first question, Steve. Look, Lilly is at an incredibly interesting moment in time right now. I think we all appreciate that. And the healthcare benefits that the incretin portfolio are delivering for patients is extremely significant and position the broader company, I hope, for a lot of success over the next decade. One of the knock-on effects of that is the financial strength of the company allows us to invest significant capital in the other disease areas that we focus in, including in oncology. When I sit around that table that you referenced, the success that we're having with the incretin portfolio makes me, not just, of course, excited for what it can do for society and for patients, but it really affords us, I think, a unique opportunity, sort of among our peer set, to invest in oncology, in addition to neuroscience, in addition to chronic immunologic diseases. So, I think, you know, as we think about accelerating clinical trials, doing things differently, taking more risk, putting lots more medicines into the pipeline, into clinic all at once, a lot of the reason we're able to do that actually is because of the success that the rest of the business is having. So, you know, I don't know if consensus 10 years from now is right or wrong, but I think the success the company is having right now really is a sort of rising tide that lifts the boat of all the other therapeutic areas we invest in, including oncology. Thank you. Chris Schott at J.P. Morgan. Just two questions from me. Maybe, coming back to the POINT acquisition, how quickly can you move those additional targets forward as you think about kind of building out a suite of these opportunities? And at this point, do you have all those capabilities in-house, or do we have to think about additional acquisitions to really get to the point you want it to be there? The second one was just a bigger picture question, more commercial. There's been a number of questions around the Part D redesign and some of the changing payer landscape. When I think about a drug like Verzenio or any oral kind of Part D potential medication, do you anticipate there'll be greater efforts from the payer universe to manage formularies in oncology differently than the past? Or do you think this will still be a category where that's less frequently occurring? Thank you. Barry, you want to take the RLT question, and then... Sure. I'm going to have Winslow Tucker, who leads commercial for us in oncology, take your second question. I think with regard to how quickly we can continue to move forward RLT programs that are in the discovery phase of our pipeline, the intense focus we bring to all of the other therapeutic modalities to get them to patients in a competitive timeframe, we apply to the RLTs. Several of those programs, depending on the specific question and feature of the molecule we're optimizing for, can be moved along quite quickly, actually. But I think it also gives us the opportunity to do something that perhaps radioligand therapy hasn't enjoyed per se to date and historically, which is to bring real professional molecule creation to radiopharmaceuticals. We obviously have cut our teeth for many years, engineering medicines against really tough, complex and nuanced TPPs, to bind and inhibit targets, to avoid off targets, to solve challenging ADME and oral pharmacology. We are really looking forward to bringing the kind of dyed-in-the-wool professional drug development to RLTs, but do it at a cadence that's competitive. To move these programs along, we, I think, have every expectation we can deliver on exactly that. We do have the vast majority of the capabilities necessary in-house. I don't think that necessarily precludes additional external innovation, which, as Jake put at the very beginning, we're constantly looking for, as typified by the recent Aktis Oncology partnership. Thank you for your question. ...Thank you for your question. I think, when it comes to the Part D benefit redesign, there may be a desire for payers to do more managing. But oncology has had a bit of a protected class in some ways, and so we see that continuing over some time, like there may be some efforts, but I do think it's still gonna be one that's gonna be hard-fought for major change in that space. Excellent. Akash at Jefferies. So, all right, so a couple. In your earlier studies for your SERD, you had a six-month ET cutoff. You removed that in your phase 3 study. I think if you look at some of the emerging SERD data sets, it's clear that having patients on a CDK4/6 enriches for ESR expression. And then number two, you're kind of kicking out some of these ET fast progressors. How much of that is a risk with your upcoming EMERALD study, and what's your confidence that you're gonna be able to get both a wild type and ESR1 label? Number two, you know, when we look at the DESTINY-06 data, there's this kind of question, well, what's gonna happen with HR- positive going forward? I mean, you're showing a 13.2 benefit in HER2- low. There's a 75% overlap between, you know, HER2- low and HR- positive. Do you feel like that's gonna be kind of paradigm changing for your franchise? Thanks. Lilly, you want to take a stab at both of those? Yes. I want to make sure I remember all of them. Okay, so, first of all, with respect to minimum duration of prior therapy, yes, you're right. We have a requirement in there in terms of number of months on prior endocrine or CDK4/6 inhibitor, nor did the EMERALD study. So I think that, you know, we are in a position still, particularly given the sample size that we've designed here, you know, 860 patients enrolled. I think we will be in a position to be able to appreciate that benefit robustly. And to your point about ESR1 mutation acquisition, I think we expect that it should be in that range of around 30%. And as I mentioned, that endpoint is one of our primary endpoints. So I think that positions us well in terms of our statistical design to be able to see a positive study. The next question about- ESR1 versus ITT. Oh, yes. Okay. So, I mean, I think it's, obviously, we have to look at the data sets that have been generated thus far and across other programs, including the approved agent. There does appear to be an enrichment of benefit in the ESR1 mutants. Having said that, we would also hope that we can demonstrate at least that this agent is also equally efficacious without added tolerability issues in the wild type patient population. We appreciate that that was not the case in EMERALD, and that a restricted label occurred for the ESR1 mutants. However, we feel, and having spoken to a lot of physicians and patients about this, that that alternative route of administration is crucial for patients. We know that they want to be able to take medicines at home. So I think, you know, obviously, we need to see the data to enable that risk-benefit argument with the regulators, but, but certainly, that is, I think, an important attribute. With respect to then, I think you had a third question. DESTINY, DESTINY. DESTINY-Breast06. Before you get to that, let me, I just want to chime in on EMBER-3 for a second. Look, I think there's no question that seeing benefit over fulvestrant in the ESR1 wild types is a riskier proposition. I think we know that from all the other studies that, that we've seen. But, you know, over the past couple of years, in particular, we've had a lot of conversations as society about, like, access to medicine, access to care, equity in the, in the context of that. And yet, you know, we're demanding superior efficacy for an oral agent that patients can take at home versus a painful intramuscular injection that requires extra visits to the healthcare office, hours of lost time, lost wages, et cetera. I don't think that we, frankly, as a society, should be looking at this through conventional lenses of superiority on PFS endpoints for methods of administration that are so radically different. So we'll see what the data show, but we hear consistently from physicians that the oral route of administration is valuable, even in the event of the same PFS. And I don't think that's what we're going to show either, but just gives you a sense for sort of how the treating world is thinking about this. And Lilly, why don't you take the DB06? Yeah. I mean, it was great to see the DB06 data. Obviously, collectively for T-DXd, the DB06 and DB04 data tell you that you can offer this therapy for patients in that first or second line chemo appropriate setting. And I think that's the point. I don't, I don't think that the community will swing from maximizing and optimizing endocrine and oral therapy options for patients. We know it's important that they don't want to jump immediately to infusional therapy, nor in fact, do the data tell us that they need to do that. I think that, we're seeing in that first line chemo appropriate setting, obviously, the patient population that was enrolled to DB06 had a median number of two prior therapies. So most of these patients had obviously received; all of them had received a CDK4/6 inhibitor, and in fact, more had received a second line of endocrine therapy. So I do think there's opportunity for us to build in that second line post-CDK setting. PostMONARCH is the start. Hopefully, EMBER-3 builds upon that. We see nice data with imlunestrant in combination with abemaciclib, and I think that that second line setting is really where we need to intensify for patients to delay the need for infusional therapy. Thanks. Maybe just a follow-up on, on EMBER-3, I guess, you know, at ESMO last year, we heard about the, you know, diarrhea profile overlapping with Verzenio, so maybe just confidence in the tolerability profile as you think about EMBER-3 and then the adjuvant setting. And then the second question is just, if EMBER-3 only shows a benefit in the ESR1 population, what does that imply for EMBER-4 in terms of your confidence level? Thanks. ... Thanks for the question. So with respect to the tolerability profile of imlunestrant in combination with abemaciclib, we're pretty confident. We've generated a relatively robust phase 1 data set with at least 80 patients that have received the combination. And when we looked at the comparative adverse events in those patients compared to the MONARCH 2 population, it certainly appeared no worse. So our expectation is that imlunestrant will not have additional significant toxicity over what we see with fulvestrant abemaciclib. So from a tolerability perspective, we're confident that that will play out well in the phase 3 setting. With respect to your question about ESR1 mutant restriction, so I mean, I think that it's important to recognize that early breast cancer and advanced breast cancer do have meaningful biological differences. Obviously, ESR1 mutations are not seen in the early breast cancer setting, but ESR1 mutations are surrogates for ER dependency, and we know that most ER-positive breast cancer is ER dependent. So I think that the question still remains relevant, regardless if the, you know, label or study is confined to an ESR1 mutant benefit, I still think that that has important and relevant read-through to the adjuvant, EMBER -4 setting. And remember, in this EMBER -4 study, we're evaluating patients that have already demonstrated a degree of endocrine sensitivity. By definition, they've gotten past that two years of therapy, initial adjuvant therapy. So I think, the question still remains relevant and important. And also recognize that the EMBER -4 study is a different comparator arm to EMBER-3. The hurdle is to be improving upon standard of care, adjuvant endocrine therapy, not fulvestrant, which is obviously the comparator in EMBER-3. I think, I think we have time for one last question. Thanks very much. Dave Risinger from Leerink Partners. So, Jake, I was hoping that you could talk a little bit about postMONARCH in terms of the commercial opportunity, when you think guidelines might change and, you know, when we might see that added to the labels globally. Yeah. So I can start, and then Kara Winslow should really chime in. You know, the idea behind the study was not really motivated by commercial forces, so to speak. The medicine's already labeled in this population, and a lot of physicians have actually already been using the medicine for years now, sort of in this way, and they can, because it is labeled here. This was really an evidence generation question that we just had been hearing for years, that physicians wanted an actual robust phase 3 trial. And of course, now with imlunestrant, it complements that program as well. So you know, it's just, it's not been a main motivation. I think, you know, the feedback we hear at this meeting is that the results in many ways are what docs expected to see from this regimen. And so for those who are already doing it, they sort of feel validated in that approach. And for those who maybe weren't doing it, maybe they feel like they can have more comfort doing it now that there's phase 3 randomized data. But I mean, Kara, you should talk about guidelines. Yeah, I think a couple things. One is, I think that people still are largely unsatisfied for patients that don't have a biology-driven cancer and second-line metastatic breast cancer. So I think the enthusiasm has been relatively high, and people were really interested in answering this question in a randomized phase 3 setting. I think overall, we would anticipate that this information will be submitted to appropriate guidelines, and I would expect, because it's a positive study with a PFS benefit of 27%, so that will be included in the guidelines, and then they'll go through the categorization process for NCCN and others. But I think, like Jake had said, I think currently today, in most markets, not only in the U.S. but in the world, if people are choosing to do this, it's within a labeled indication. So, I wouldn't say there's a significant amount of commercial upside. Mike, are we at time? Yep. Take it away. Okay. All right. All right, thanks, everyone, for coming tonight. Hopefully, we give you a flavor of what we've been up to over the past couple of years, and as you can tell, like, we still have a lot more work to do. We wanna see these medicines start working against the profiles that we expect for these specific patient populations, and hopefully, we'll be doing another one of these events in the near future, and we can show you some of those emerging clinical data. So thanks, everyone, for coming.