Welcome, everybody, to the second day of TD Cowen's Oncology Summit here in advance of ASCO and EHA, where we'll be getting a lot of updates. We're really happy to have with us the team from Nuvalent for the next session, Alex Balcom, CFO, and Jim Porter, CEO. Of course, Nuvalent will not have their own presentation at ASCO. Jim gets to enjoy his birthday for the first time in, I don't know, in how many years, Jim? But we will, they'll be getting some competitive updates there, and then also some large updates from the company later in the year that we definitely want to discuss today. So maybe just to start off, Jim, do you wanna just level-set everybody, kind of give a high-level status update of Nuvalent and kind of what you see as the key milestones over the next year or so? Yeah, sure. Happy to, Mark, and thanks so much for the opportunity. Always a pleasure to speak with you. So, you know, a little about Nuvalent. We're about a six-year-old company. We focus in precision oncology. We're the company's founded on a deep expertise in chemistry and structure-based drug design. We focus on clinically proven kinase targets, and we talk to physicians that have developed the earlier generation inhibitors to understand what are the needs of the patients, what are we solving for through innovative chemistry? We've made some progress in building the company, and Alex can walk through that, as well as how we're thinking about the path forward. Yeah. Thanks, Jim. And thanks, Mark. Pleasure to be here. So we've made a lot of progress over the last several years, having emerged from stealth mode just in 2021, and now having presented clinical proof of concept data for 2 programs and enrolling the pivotal studies for those programs. So we've also been fortunate to bring in additional capital along the way. We have runway into 2027 to continue to advance our program. So as we look ahead to the next 3 years, earlier this year, we set out our On-Target 2026 plan, which lays the groundwork for the Nuvalent team to begin to deliver on our mission, which is to bring new best-in-class medicines to patients with cancer. So in 2026, we're planning for at least one approved product, in 2025, pivotal data from at least one of our programs, and that means this year will be a critical year of execution for us, and we have a number of milestones across the pipeline. So we've initiated our ALCOVE-1 Phase II study, and we plan to launch our frontline ALK strategy later this year. We anticipate interim data updates for both programs in the second half of this year, and we'll initiate the Phase I trial for our HER2 program as well. Great. Great, thanks for that. Maybe Jim or Alex, just... There's a number of drugs approved for ALK-positive, sorry, in ALK-positive lung cancer. And I should mention, for the investors online, welcome to add in your own questions. I have my own list that I'll go through, but I'd love to keep this as interactive as possible. So you can submit them either through the portal or email them to me at mark.frahm@tdsecurities.com. But, Jim, maybe on ALK, there's several drugs approved. There continue to be drugs moving towards the frontline, you know, lorlatinib, you know, where we'll get an update of long-term outcomes from the CROWN study at ASCO, where it does seem to be moving the bar from an efficacy perspective, at least. Just what do you... You know, kind of like the key unmet need remaining in ALK, and how much of that unmet need is really kind of on target versus, you know, people developing bypass where, you know, a new ALK inhibitor probably isn't gonna help a lot? Yeah, yeah. It's... You know, there are good options for patients, but, you know, the reason we started this program is listening to the physicians that have developed those other options, and clearly hearing from them that the needs aren't being served for all patients. So, there's five approved therapies, but really think about it in two buckets. In frontline, patients mostly receive alectinib. When patients progress on alectinib, the only drug that works is lorlatinib, and the reason lorlatinib works is it has some coverage of ALK mutations, and it's highly brain-penetrant. And when patients progress on lorlatinib, none of the drugs work. So the third-line patient population, it's a clear need, where the disease is still driven by ALK. It's driven by, in many cases, ALK compound resistance mutations. You know, we saw that as the immediate need we're trying to solve for through innovative chemistry, and 655 showed in both our preclinical and clinical data, that we are, you know, active in that patient population. You know, but, you know, although we want to be an option for third-line patients, we want to develop the best ALK drug for all ALK patients. So if we look across the other two lines of therapy, most physicians would tell you lorlatinib is the more active drug than alectinib. However, it doesn't get as much of the frontline use, and the reason being, it hits a specific off-target called TRK, and it causes a broad spectrum of nervous system disorders when TRK is inhibited in the brain. And lorlatinib, being brain-penetrant, you know, over half the patients experience these CNS cognitive issues. And so physicians have, for the majority, stuck with alectinib as a standard of care. Now, we recognize that as a, you know, an interesting opportunity. If we could make a drug as active or maybe even more active than lorlatinib without that safety challenge, meaning selective for ALK versus TRK, that's a chemistry problem, then we would have a better drug than lorlatinib in second line and potentially a better drug than alectinib in frontline. And, you know, our early data suggests that we do indeed have that profile. We have a broad coverage of ALK mutations, we have excellent CNS penetrance, and we have a well-tolerated safety profile. So we think we designed a drug that can move up to those earlier lines and drive deeper and more durable responses. You know, you mentioned that there'll be updates from lorlatinib, and, you know, this is, this is actually all working out according to plan. What we heard from physicians years ago is that this is the more active drug, lorlatinib, as compared to alectinib. However, with the safety challenges, you know, that's something you can't really manage away from. You know, the more, you know, data that emerges from lorlatinib, it further supports that cause, that it can drive deep, durable responses. And we think that 655 has been designed to do the same, to keep patients on therapy now, 'cause it's well-tolerated, but drive those deep and durable responses. So we're really emboldened about the path forward, and really, it's, it's working out according to plan. ... Maybe in the third, starting with that kind of third line opportunity that you laid out as, like, the most, you know, acute need maybe. What do you view kind of the meaningful, maybe response rate, although we already kind of have that data from you, but duration of response maybe is at least as importantly in that population? Yeah, yeah, and third line, nothing works, right? So, like, any, any responses that are durable are going to be immediately interesting to physicians because they have no options for those patients. And you saw in our phase 1 data update, you know, we treated a very advanced patient population that have exhausted the available options. They've taken alectinib, they've taken lorlatinib. In many cases, they tried other TKIs and chemotherapy. So it's a difficult to treat patient population, but the drug was still active. You know, roughly 40% of the patients still responding, and, and much higher response rates when patients actually had ALK mutations. You know, at the time of the data cutoff from August of last year, that was an early look. But what was encouraging is that every single patient that responded remained on treatment and, you know, did not progress. That's quite encouraging. If you think about these late-line patients that have no options, and that if they have, if they have a response, they can tolerate the drug, they can, and none of them progress. Which really speaks well to what we're trying to do is, you know, push this drug up to the earlier lines and delay the emergence of those resistance mutations. So that's how we're viewing that later line data set. Yeah, as the trial population, your trial evolves a bit, I'd imagine maybe some of that prior use of, you know, random off-label TKIs probably wanes in terms of the population, just as you, they'll come straight to your trial once they've failed alectinib and/or lorlatinib. Are those really the only drugs we should think of as impacting the efficacy we'll see, or do those other ones, you know, also have their impacts when you get to a fifth-line patient on both a response rate and a duration of response basis? Yeah. You know, the other drugs, the second generation and first generation drugs, like crizotinib, ceritinib, brigatinib, they really don't have good broad ALK mutational coverage, so they're limited in addressing that patient population. And crizotinib is also limited in its brain penetrance. So, they're really not ideal options for these later-line patients that have progressed on alectinib or lorlatinib. So, I think 655 is the only drug we're aware of that's, you know, been designed to have this broad coverage of ALK mutations and be highly brain-penetrant and be selected for ALK inhibition. Should we expect, you know, as the patient population becomes a bit less heavily pretreated, should we expect response rate and/or duration to improve? Or, you know, is that, are some of those other drugs like that not gonna impact those numbers very much? Yeah. You know, less heavily pretreated patients, all the ALK drugs are pretty active. So in front line, each of those five drugs I mentioned all have roughly about a 70%-80% response rate. So if you're an ALK inhibitor, it's a good chance that if patients receive that in the front line, they will respond. It's really about the durability, and there is a broad difference between what crizotinib can do, roughly about 10 months PFS, to what alectinib could do, which is, you know, about two years median PFS. And we're gonna see updated data for lorlatinib, and, you know, we expect, you know, at ASCO, we expect that to be even years beyond what alectinib can do. And it really speaks to, you know, what, you know, the other earlier drugs were not really optimized to, for broad, you know, ALK mutational coverage. And this represents an interesting opportunity for 655, 'cause we designed a drug to, you know, potentially delay the emergence of on-target ALK-acquired resistance and drive deep, durable responses for patients. You also recently received Breakthrough Therapy Designation for the third line and beyond. Is that based on the data we've all seen? Is there updated data? Is that more of the data we're gonna actually see in the fall? Yeah. So maybe I'll speak to the breakthrough, and then Alex can talk about what's, you know, what's forthcoming this fall. You know, the data we presented in October at the Triple Meeting was based off an August data cut. Now, that was roughly 93 patients that were treated over 6 dose levels over 13 months, from June of 2022 until August of 2023. It was a preliminary look, but, you know, the data, you know, I think we believed addressed each key area of our target product profile. And, you know, we think that emboldened us to, you know, push forward on the program. Now, we've obviously kept the Phase I ongoing since then, and then just a few months ago, we announced that transition into Phase II. So we've obviously, you know, learned a lot since then. You know, we're not gonna comment on the specific data set that, you know, was used to engage with regulators on the breakthrough designation. But I will tell you that, you know, what we presented back in, in October was, I think, a pretty robust data set. 93 patients that were treated across six dose levels, with a broad mutational coverage, broad activity, CNS penetrance, CNS activity, and a, a well-tolerated safety profile. So I think, in general, you saw the... you know, that data set looked encouraging. Alex, do you wanna speak about what's path forward is for this year? Sure, yeah. So for our ALK program, we shared we'll be at a medical meeting in the second half of this year with an update. And I think, you know, we did tell you the punchline for that program at, with the data set that was presented last year, but recognize it was an earlier look. So we know that follow-up and durability will be key areas of focus for investors, and so we'll provide an update on what we're learning from our Phase I study. And the Phase II portion of ALCOVE-1 is ongoing. Enrollment's been going well, and so we'll continue to evaluate progress there, enrollment rates, timelines to pivotal data in order to make a data-driven decision on, you know, whether or not we include any Phase II data in the second half update. And, you know, in opening that Phase II cohort, you there still had not been an MTD identified. You know, I guess, how did you settle on the 100 milligram recommended Phase II dose? And do you guys now consider you know, do you have agreement with the FDA that kind of Project Optimist has been satisfied, or is there still a bit more work that needs to be kinda done in parallel to fully satisfy that? Yeah, we fully align with the FDA on the dose. It's before initiating the Phase II, we settled on 150 milligrams as, as the recommended Phase II dose. 150, sir. Yep. No, it's fine. At that dose level, we had excellent coverage of ALK mutations, both single mutations, compound mutations. That was both in the periphery and in the CNS, which is really important, especially for these later-line patients, so that you'll be able to. You're able to treat these patients that might have developed resistance mutations on these earlier therapies. The drug was active at that dose level, and it was really well-tolerated. So it was. The safety profile was indicative of an ALK-selective TRK-sparing design. So we believe that was the best dose to take forward. You know, that's how we're... You know, I don't wanna go through this in more specifics on the regulatory interactions, but, you know, in general, we feel like we've, you know, we've met the standard that, you know, regulators have looked for, you know, before pushing forward into a Phase II pivotal study. You wanna walk through kind of the, those expansion cohorts that you have opened, the size of that, and then maybe kind of, given the enrollment you've been seeing, just, you know, what that kind of implies for, how long these may or may not take to complete? Yeah, you know, we've been really encouraged by the enthusiasm we've had from investigators and, quite frankly, patients, the patient advocacy groups that we collaborate on both of our studies. And it really speaks to, I think we're on the right track with a differentiated target product profile. You know, since we initiated both the ARROS-1 and ALCOVE-1 studies, we've seen robust enrollment on our programs, and that's both Phase I and Phase II. In the Phase II cohorts for ALCOVE-1, we have a third-line cohort where patients have progressed on, you know, front-line alectinib, second-line lorlatinib. There's no clear option for those patients. NVL-655 has been designed to address that patient population, and our Phase I data suggested it was indeed active. We also have a second-line cohort. This is where patients have received frontline alectinib, and lorlatinib is the current standard of care. Now, we designed drug for, we believe, for all outpatients, so we have other exploratory cohorts in that Phase II, including patients that don't meet the criteria for any one of those first two cohorts, including patients that have other tumor types outside of non-small cell lung cancer. So ALK is a driver in over a dozen different tumor types, so we wanna be able to treat those patients, and we think 655 could be potentially an interesting option for those patients. And then we opened a TKI-naive cohort in the Phase II as well. Now, I think as Alex mentioned, we're going to, you know, talk more about our frontline development strategy for NVL-655 later this year. The rationale for the TKI-naive cohort is, you know, it'd be nice to generate some data in an open-label setting, you know, over the next couple of years to, you know, be able to discuss and share with, you know, external stakeholders, you know, as our Phase III development strategy is ongoing, which obviously would be a blinded trial. So that's the rationale there. We're not necessarily waiting for data from that particular cohort to guide any decisions on the frontline strategy. I think we're pretty settled on what we want to do going forward there. And just in terms of initial approval strategy, you know, should we think of a label that looks kind of like the breakthrough designations? 'Cause we often see that they... You know, the statements about what you got breakthrough for is also very similar, if not identical, to the wording of what your indication statement ultimately says. Or so that would be third-line plus, or should we be thinking broader? Yeah, I mean, our development strategy is broader. So, it always will be guided by the data, but, you know, in our ALCOVE-1 study, we have cohorts both in Phase II that are designed for second-line and third-line, right? And the third line, it's, I think it's a pretty straightforward strategy. There's a relatively, you know, there's a medical need here. We designed a drug to address the medical need. If the drug is safe and drives durable responses, we think there's an opportunity to engage with regulators on that particular cohort. The second-line cohort, I think it's a reasonable question of why not do a randomized study versus lorlatinib, right? That is the current standard of care. Now, we know lorlatinib is a limited option for that patient population based on discussion with investigators. So, because it has, you know, a minimal window hitting ALK mutations compared to TRK, that was dose-limiting in that development program, that we are seeing patients that are progressing on lorlatinib in second line, with ALK single mutations and still responding to NVL-655. We're seeing patients progress with ALK compound mutations and responding to NVL-655, right? We think there's an opportunity to drive deeper and more durable responses than lorlatinib can do in that second-line patient population. The bar there is about 30%-39% response rate with a seven-month duration of response, right? Now, we think that there's an opportunity in this single-arm cohort to generate data to see if this hypothesis holds up. Can we drive deeper and more durable responses in the second-line patient population? We think if we can, in addition to having third-line data, we think there's an opportunity to engage with regulators around a broader previously treated ALK indication. Now, obviously, that's dependent on the data, and we think the single-arm cohort is the fastest way to generate that data and understand this opportunity. We also think it would help our case that, you know, having the, the discussion around a previously treated label is augmented by potentially having a randomized phase 3 ongoing, which we hope to be doing in the frontline setting. So that's our general strategy: randomized for frontline, single-arm cohorts for second and third line. Do you think you need to create a meaningful separation from that lorlatinib second-line bar in order to support approval? Or is kind of just being matching it to maybe, you know, very minimally better on a numerical basis enough, given the fact that that part of lorlatinib's use doesn't have randomized data, right? That's single-arm data. Yeah, yeah, totally. I think matching it with different safety is not good enough. I think the precedent in oncology drug development is pretty well stated by regulators in the past, that you need to show that your drug is, you know, can drive deep and durable responses in addressing a need that's not being met by the available therapies. And quite frankly, I don't think 7-month duration response is that, is a great option for patients in second-line ALK-non-small cell lung cancer. Keep in mind, this is a younger patient population; that's a motivated patient population. You know, driving a 7-month duration response, we think is, is a, you know, a rather dismal outcome for those patients. So if we can improve upon that, I think there's an opportunity to engage with regulators around, you know, driving more durable responses by keeping patients on therapy, by covering ALK mutations and driving deep, durable responses. Okay. And then maybe for the first line, I know you're going to unveil the, you know, the absolute specifics later this year, but you've also talked kind of in some broad strokes about that trial already. What should investors look at as kind of the key, you know, unknown questions that still need to be answered, at least for investors, maybe for you as well? Yeah. I mean, we've known the trial we wanted to do for years now. Alectinib is the standard of care. This isn't. There's good precedent in the ALK space. You know, there's three or four randomized studies that have already been conducted in frontline ALK non-small cell lung cancer. They've all been randomized 1:1. They've all been a PFS endpoint. They've all been roughly about 300 patients. They've all been roughly about 2.5 years-3 years from start of enrollment to the line extension approval. Now, our study is likely to be against a different standard of care. Crizotinib is no longer the standard of care. Alectinib is the standard of care. So, it will be slightly larger, slightly longer, but well worth doing. If you think about what we're trying to do in this space, I mentioned before, the ALK patient population is a relatively young, motivated patient population, and, you know, alectinib has done great things for that patient population, giving about 2 years progression-free survival. But if you're a patient in your 30s, 40s, or 50s, you know, 2 years is not good enough, right? Half of those patients are progressing with ALK mutations, and, you know, alectinib is not good at covering them. That's, and 655 is. I think that's why you're seeing some, you know, interesting data emerge from the CROWN study, where those patients aren't progressing with ALK mutations, right? They're driving deeper and more durable responses with lorlatinib in frontline, and it, it supports the theory that you could do this, something like this. Now, the hang-up with lorlatinib is that off-target tox of inhibiting TRK. Well, imagine you could do the same or better without that off-target tox. I think it really bodes well to the NVL-655 strategy. Is there—So obviously, median PFS is going to take a lot—a while to read out, right? You know, you're comparing against a drug that has a median of a couple of years. Is there an opportunity to kind of accelerate that, either through some sort of landmark analysis, early trend, you know, particularly maybe leveraging, like, the Project Frontrunner from the FDA that's trying to get some drugs, you know, to the frontline faster? Yeah. I mean, you know, we're, we're at the stage where I've mentioned already that we, we believe we know what we want to do, and we have the data to support the strategy, and we're in the process of, you know, aligning with investigators and regulators on that specific strategy. And when we do roll that out, I'm happy to go deeper onto that type of question, Mark, of how we think about the trial design. But, in general, I think this is a pretty straightforward plan. ... Okay, I know we're running up on time, but do you want to talk briefly about ROS1 as well, your other program? Maybe to start off, there have been a couple updates over the past kind of year in that space, right? We've had approval, we have had another approval. We will have data at ASCO from a competitor, as well as, you know, some of that data is already out in the form of the abstract and some updates that those companies have done. So just, how do you view the kind of landscape as having changed over the last year? What have you learned about the ROS1 market over the past kind of year from these? Yeah, when we started this program, working with physicians, when we started the company, it's worked out exactly according to plan. So at that point, crizotinib was the standard of care, and any other drug that was in development, and that included entrectinib, repotrectinib, taletrectinib, all those agents, what they had in common is they were dual TRK ROS1 inhibitors, right? And the physician feedback was, you know, we don't see these drugs displacing crizotinib as a standard of care because they had this off-target, you know, tox associated with, you know, TRK inhibition in the CNS. So cognitive liabilities that, you know, it's difficult to keep patients on therapy and drive deep, durable responses. And to address crizotinib's liabilities, you need to have excellent brain penetrance, which crizotinib does not have, and you need to have good, you know, resistant mutation coverage, which crizotinib does not have. And you need to be very selective for ROS1 versus TRK to minimize those off-target toxicities. And everything we've learned since then is, you know, entrectinib gets approved, has a poor update. Repotrectinib data emerges, and they're, you know, 75% of the patients have, you know, CNS issues. The other drug, taletrectinib, you know, I think one of the angles there is that it's a little bit less potent for TRKB, so that the nervous system disorders aren't as significant as entrectinib and repotrectinib, but they're still there. And that compound, interestingly, you know, over the course of development over a number of companies over the last decade, you know, they've tried to find different dose levels to minimize the GI toxicity that that drug may have. And, I don't think that, you know, that, that signal has really gone away. So none of those drugs really address the liabilities of what crizotinib and the other drugs have. And other than zidesamtinib, NVL-520, this is a drug that is highly selective for ROS1, has broad mutational coverage, has excellent brain penetration, hits each of those key areas that the physicians were looking for, and our preclinical data were very compelling, and our clinical data were quite compelling. We've received breakthrough designation in the third line, and we have pivotal cohorts ongoing in both first and second line and third-line patients. So you mentioned you have breakthrough kind of in that, in that third-line setting. I, I think at one point, Turning Point, I believe, had breakthrough designation for one TKI prior experience. Taletrectinib has gotten both first line and later line. Is there value to, as your data matures in some of those earlier lines, seeking breakthrough designation, or do you kind of have everything you need already, and it, it's really not gonna add anything? We'll use any, any method, any process to develop the drugs faster. You know, keep in mind, our, our Phase I data was in a, in a very advanced patient population where those other drugs don't work, right? We were treating patients beyond those other drugs, and our drug was still active. I think that bodes well for what our drug could do in earlier lines of treatment. And if our drug is active and safe in those, that patient population, you know, we will engage regulators to use any method to develop them and get them approved as fast as possible. So that's how we view it. Bristol has opened a head-to-head trial, repotrectinib versus crizotinib, in first-line setting. Or you don't think you need to do that, and they obviously didn't either to get FDA approval, with a broad label. But do you think that has value, a similar trial would have value to Nuvalent, maybe to support reimbursement, particularly ex US? Yeah. We think the immediate strategy of the single-arm cohort is the fastest path to approval and something that we're neatly focused on. You know, longer-term development strategies in ROS1 was something we can talk about at a later point, but we think the, you know, the focus is really on getting these drug approved for all ROS1 patients. And our current ARROS-1 study, which has been enrolling since September of last year, we think is the path to do so. Unfortunately, it's all the time we have, so we're gonna have to cut it off there. But, thanks a lot for joining, Jim and Alex. Thanks, Mark. Thanks so much, Mark.