All right. I'm Marc Frahm from the TD Cowen Biotech team, welcome to the next session of the Oncology Innovation Summit that we're hosting over these two days. We're really happy to have with us the team from Nuvalent for the next session here. We've got Jim Porter, the CEO, as well as Alex Balcom, CFO. I and my team have come up with a list of questions that we will go through with Jim and Alex, we would like this to be interactive and make sure we get the questions that investors are most interested in answered. Please either submit questions that you may have through the web portal in the text box at the bottom of your screen, or you can also email me directly at marc.frahm@tdcowen.com I'll layer those questions in to the question list. Maybe to start off, Jim, you want to kind of just provide a high-level overview of Nuvalent and what you view as kind of the key value drivers over the next 12 or maybe as much as two years for the company including there, obviously, you had an important update this morning around the ALK submission. Sure. First of all, thanks, Marc. Thanks for the opportunity to participate in this virtual conference. A little bit about our company. We're about eight years old. We just passed our eighth anniversary. At the foundation of the company is a deep expertise in chemistry, structure-based drug design. We focus on validated biology, so kinases are an obvious place to focus. Over 100 approved kinase inhibitors, and we can learn from the precedent and run small focus studies to understand if our drugs are working as intended. Where we try to make an impact is to learn from the physicians. Talk to the physicians that have developed the earlier generation inhibitors, understand from their perspective what are the needs of the patients they treat, what are the limitations of the therapies that they use for their patients that they helped develop, and that we can try to solve for them through innovative chemistry. A pretty simple concept. We made a lot of progress building the company, and Alex can walk through some of the milestones ahead of us. Yeah. Thanks, Jim. Made a lot of progress over the last several years, and this progress set us up to deliver on our on-target 2026 operating plan with line of sight, as of this morning, to two potential U.S. commercial launches later this year. At the beginning of the year, we outlined all of our milestones, which included submitting our NDA for neladalkib in TKI-pretreated ALK non-small cell lung cancer, and we were excited to announce earlier this morning that the NDA has been accepted with priority review, and our PDUFA date is November 27th, 2026. Importantly, this positions us for not one, but two potential U.S. commercial launches later this year. The team has been preparing for potential launch of zidesamtinib in TKI-pretreated ROS1 with launch readiness efforts well underway. Additional milestones include submission of data to FDA for indication expansion of zidesamtinib in TKI-naive ROS1. We'll continue to progress the ALKAZAR phase III study for TKI-naive ALK. Beyond the two lead programs, we'll progress the HEROEX-1 phase I-A/I-B study for HER2 altered non-small cell lung cancer. We are on track to disclose a new development candidate by year-end as well. All right. Thanks for the overview. Maybe we'll start with neladalkib, where, as you mentioned, now the ALKOVE-1 data has been submitted to the FDA. Maybe, Jim, you want to kind of, one, summarize the high-level data that was released to investors a handful of months ago, but then what are kind of the significant aspects of that data set that you'd kind of point investors to that they still need to learn about probably at ASCO, where maybe a few more details are going to be disclosed? Sure. Thanks, Marc. I'll take the first part. Maybe I'll turn it to Alex for the second part. The two themes that emerge from the ALKOVE-1 data set are enrollment and durability, right? I'll touch on each one of those. On the enrollment side, just massive enthusiasm for the differentiated profile neladalkib. As of November of last year when we presented the update, 781 patients in the ALKOVE-1 study. This is an original trial that was designed for 250 patients, and we more than 3X'd the enrollment. That doesn't happen in drug development, right? Here it's happening for a reason, right? Physicians are excited about the differentiated profile. The patients we collaborate are excited about the differentiated profile, and we're incredibly fortunate to partner with both groups to advance neladalkib in drug development. Those 781 patients allowed us to quickly generate data to learn the profile of neladalkib, and that's where I come to the second part on durability. What we heard from physicians, what they were looking for was a compound that addressed the medical needs of their patients, specifically can hit the original ALK fusion to cover ALK single and compound resistance mutations, have excellent CNS penetrance, and importantly, be selective for ALK versus off targets that are dose-limiting, right? They helped us understand the landscape. Alectinib had traditionally been the standard of care. When patients progress on alectinib, the only drug that works is lorlatinib because it has some coverage of ALK mutations. When patients progress on lorlatinib, nothing works. What we saw in the ALKOVE-1 study, because we have the first and only drug that broadly covers ALK mutations, has excellent CNS penetrance, and avoids these off targets that are dose-limiting, we could drive durable responses even in that third line setting where nothing else works beyond lorlatinib. What we saw was a median duration response of 17.6 months. This is more than double the durability of lorlatinib. Beyond lorlatinib. That doesn't happen in oncology either. Typically, the duration of response will get worse and worse in subsequent lines of treatment, and we sent it in the opposite direction with neladalkib, which was really encouraging and speaks to the differentiated profile here. What we also saw is in patients that have yet to receive lorlatinib, we saw durable responses. We saw excellent CNS activity. We saw broad activity against ALK mutations, both single and compound mutations. Because of that, we can drive alectinib-like durability in that second line. We think it clearly differentiates neladalkib from the available therapy, lorlatinib. That portends well to what neladalkib might do in the front-line setting, where we have an ongoing randomized phase III comparing neladalkib to the standard of care, alectinib. We think there's a reason to believe that you can drive much more durable responses than alectinib in that front-line setting, and with a well-tolerated drug like neladalkib, keep patients on therapy and really be a game changer for this patient population. All of that together represents a compelling commercial opportunity as well. Based on that update, what's going to be different at ASCO? Maybe I'll just turn that over to Alex. Sure. Yeah, thanks. In terms of ASCO, we haven't provided specific guidance on what additional data points would be included, we'll take a similar approach to the presentation of our ROS1 pivotal data at World Conference on Lung Cancer last fall. It's the same data cut, we'll just look to illustrate some further data points from the top-line announcement in November. Looking forward to the presentation on Friday and discussing it at that point. Right. Completely understand, you need to be very methodical about when you take data cuts and present those for the portion of ALKOVE-1 that is pivotal and is now in front of the FDA. There's also the first-line cohort. Will that also be the same data cut, or is there an opportunity to maybe have a little bit more updated first-line data? What we shared on the first-line data back in November was that in the first 44 patients, we were seeing excellent response rates. The durability looked intriguing. We saw high intracranial activity, including intracranial CRs. This is a potential patient population where we hope to drive years of progression-free survival. An incremental update just a couple months after November doesn't necessarily meaningfully change that story. Really, it's about what do we see over the next several years with neladalkib. Truly, the best experiment to really understand that is the ongoing randomized phase III comparing neladalkib to alectinib. That's how we think about that update, Marc. Okay. That NDA is now in and accepted with priority review. Can you just remind us what is the kind of indication statement that you're really seeking in that label? How specific do you expect it to be around exactly which TKIs, in what order, how many of them have been seen? Yeah. Obviously, we submitted all the data we've generated from ALKOVE-1. Again, 781 patients enrolled in the study. When you submit a new drug application, you're including a comprehensive non-clinical and clinical assessment of what you've learned on this program. We've, of course, provided that in this submission. Our goal all along has been to use the ALKOVE-1 datasets to tell the story around pre-treated indication. Right? We start in third line, where patients have progressed on sequential alectinib and lorlatinib. Nothing works in that setting. neladalkib is active in that setting, is driving durable responses, double the durability of lorlatinib beyond lorlatinib. We also received breakthrough designation in that patient population, and speaks to the medical need and speaks to the value, the data that's been generated here with neladalkib. That's a pretty straightforward story. We also posit that neladalkib is a better option than lorlatinib in second-line. There's a scientific reason for that. We knew that lorlatinib was ineffective at covering ALK mutations. We see patients progress on lorlatinib with inefficient coverage of single mutations, and neladalkib is active in those patients. We see patients progress on lorlatinib that develop a second mutation. It's called the compound mutation. We designed our drug to be active against those compound mutations. It's not a surprise that we can drive more durable responses on lorlatinib, because we can broadly cover these ALK mutations, and we can keep patients on therapy. We hope to use that combined dataset, both the second-line data, where we can drive deep, durable responses in patients that are lorlatinib naive, as well as the third-line data to tell a story around a previously treated ALK indication. Where this indication ultimately ends up is obviously something that we'd have to work with the FDA on and too early to discuss that at this point. Okay. It said it's extremely straightforward in that third-line setting, post, say, alectinib and lorlatinib, where there's absolutely nothing for them. I guess, what are the regulatory precedents you'll be pointing to in that discussion with the FDA as to why the delta you're seeing in that second-line setting versus what's expected with lorlatinib in that setting is enough to justify an approval where there is a full approval? Lorlatinib is a fully approved TKI-experienced agent, right? Yeah. It's a comprehensive dataset, Marc. Yeah. It's a third-line population where nothing works. It's a second-line population where we can drive durable responses. Our job as drug developers is to generate a robust dataset, tell a clear story. We believe we did our best job in that in the New Drug Application. We'll work with the FDA on trying to make sure we can, one, articulate and defend why this is a good option for all patients that have been previously treated with ALK TKI. Okay. What is the size of the population that you think flows through and actually, is being treated in that second-line and beyond setting, in terms of patient population and then maybe we can get to TAM later. Yeah. The ALK opportunity is very interesting because this is typically a younger patient population. They're relatively healthy. They're younger in their journey. They have many professional and personal milestones ahead of them, and a patient population we've actually had the tremendous privilege to collaborate with over the years and understand the needs of this patient population. When patients progress on alectinib, nothing works very well. lorlatinib has a six to nine month duration response. What today's previously treated market is less relevant to what the market could become. By keeping patients on therapy, driving more durable responses. Again, I mentioned before, we're seeing alectinib-like durability in patients that have already received alectinib. alectinib, remember, keep in mind, it expanded a half-billion-dollar ALK market when crizotinib was a standard of care to 4x that, just by keeping patients on therapy longer. We are seeing durable responses in previously treated patients. Today's previously treated ALK market, which is already interesting, which don't have drugs that can drive durable responses, now we have an option that we think can drive durable responses, can expand that patient population just by building up a prevalent patient population for patients that continue to drive durable responses. That's the general strategy. Too early to put a number on it of what that number could become, but what we do know is it's definitely interesting, first and foremost for patients, and two, as a commercial opportunity for Nuvalent. Okay. Recognizing, particularly in that second line setting, it's still a little bit of a moving target. Hey, in the third line, we are getting relatively increasingly mature duration of therapy type of data. How should investors think about how to translate durations across lines as you move up the line? Yeah. With the patient population we enrolled, it's the most advanced ALK study that has ever been done from our understanding. There are no other data sets in patients that have progressed on all these sequential therapies. What was intriguing is that our drug was still working, still active, in these very heavily pre-treated patients. No doubt some of these patients have progressed through many other therapies, and it's a difficult patient population to treat. It is not easy to tell a very clean story of how that data translates to durability in the earlier lines. What we are encouraged to see is when we do treat patients in earlier lines, the durability is trending favorably. That's the best way I can answer that question. I can't definitively define to you what a fifth or sixth line ALK durability translates into a commercial opportunity at this setting, just because there is no precedent in this space to draw those comparisons. Okay. How should we think about pricing? I know it's early in the FDA review, and obviously the exact label you get informs it a bit. Is lorlatinib a good comp? Is this one, the efficacy differences we've been talking about, but also the safety that we've been not talking quite as much about, do those justify a much different pricing strategy relative to lorlatinib? Yeah. Probably a little premature to comment on pricing for neladalkib, but we are, of course, able to leverage learnings from the other drug launches in the space and would consider the profile of neladalkib, as well as patient access when making our decision. Look forward to sharing more in the future as we get a little closer. Okay. When we get to a label, a number of TKIs have testing requirements and things, and some monitoring, particularly in the early stages of dosing. Just what are you expecting to be in the FDA label from that type of perspective? This is a patient population and a mechanism of action that's not novel. The first ALK drug was approved 15 years ago. We are developing the seventh ALK drug. If you just think about that, it's very tried and true indication. We don't have to go educate physicians on the, one, the value of sequencing their patients for oncogenes like ALK. Two, the benefits of an ALK TKI. They already are well aware of this. All we have to educate them on is the attributes of this differentiated profile, the broad mutational coverage, the excellent CNS penetrance, and keeping patients on therapy. We can build off what they already know about this patient population and the other available treatments. What we are encouraged by with our activity and safety profile is we think there's clear advantages to neladalkib. I don't expect something completely different to what's compared to the other ALK drugs as far as monitoring and management of patients. Would that include likely some liver monitoring? I know you're implementing it in the first-line trial, but second line it didn't seem to be needed. Not quite sure why that difference exists. Yeah. One of the findings from the phase I/II is that just like all the other ALK drugs, including almost all the other kinase inhibitors, transaminase elevations do happen with neladalkib. These are typically lab abnormalities. They are generally asymptomatic. They happen early in treatment. They typically don't recur, and they can be managed by either holding the dose or reducing the dose, and that we've certainly found that with neladalkib. All of the other ALK drugs have this same signal. Physicians are quite knowledgeable of this. To put it in perspective, alectinib, generally perceived to be a well-tolerated drug. This is something where physicians know that alectinib has these transaminase elevations. They very much know how to monitor for this and keep patients on therapy. Nothing really different here with the neladalkib profile. Okay. Then the first-line ALKAZAR trial, that you alluded to earlier, does the footprint of trial sites differ for ALKAZAR versus ALKOVE-1, and what's driving that? How much of that is maybe some of the adoption of lorlatinib in the first line? Oh, actually, that has nothing to do with it. We had always intended to press on the gas. This is a potentially practice-changing study. This is taking the standard of care, which is already a good drug. alectinib, let's be very clear, drives great outcomes for patients. I personally know many patients that have taken alectinib for many, many years. Unfortunately, about 40%-50% of the patients will progress on alectinib with ALK mutations, and neladalkib addresses those ALK mutations. There's an opportunity to have better outcomes for patients. Together with the collaborating physicians, we designed the ALKAZAR study comparing neladalkib to the standard of care, alectinib. It's a pretty straightforward study. It's 450 patients, and it's randomized one-to-one. It's progression-free survival as an endpoint. We are planning about 190 sites. That's not too uncommon for a large randomized phase III study. Our team is excited about the study. They're knowledgeable of how to execute. I would say our experience in the phase I/II with ALKOVE-1, that was the fastest enrolling oncology trial in the history of our industry, right? That's saying something, right? There's fastest enrolling oncology trial in the history of our industry. There's clear enthusiasm for this differentiated profile and clear recognition that the patient communities we collaborate are interested in neladalkib, and we expect that to carry over to the ALKAZAR study. Big picture, it's going exactly according to plan. It's enrolling well. We have not provided any specific updates other than it's all going according to plan. We keep ClinicalTrials.gov up to speed. I think today you'll probably find it, we're in that around 140-150 sites that are activated of the 190. All going according to plan. When do you expect to complete enrollment, and what does that mean for when data is likely to be available? Obviously, it's event-driven, so you don't know for sure. That's right. Data availability for a trial such as this, it's influenced by three different things. One is the actual enrollment rate, so how fast do you enroll the patients that you're targeting for the study? Second is the event rate. Here the key is alectinib works reasonably well, so patients are not going to progress too quickly on alectinib, so you have to wait for those events to happen. The third thing is the stats plan. What are the individual stats that we're using that guide the statistical assumptions and hence the data readout for the study? We think the most critical thing in those three parameters is the event rate. That's likely to be the slow step, right? We can model based off of a standard enrollment rate seen with other phase III ALK studies. We can model a standard event rate based on the available alectinib data from the ALEX study. We can use our statistical assumptions. If we model that out, it suggests that end of 2029 is when the primary completion of this particular trial would read out. That is obviously an estimate. We don't know that. It could be faster than that. It could be right around there. It could be slower than that. That's our best guess today, end of 2029. As this trial continues to mature, if there are milestones to announce from it, we certainly will share that. Okay. I think in the ALK space, there is a history of randomized trials before ALKAZAR, as you mentioned, although those all compared against crizotinib. I don't think any of them have actually ever hit on survival, although as of the last update of CROWN, it seems like lorlatinib's getting close. Do you think that changes anything about what you need to show to drive adoption? Maybe not survival versus alectinib, at least some sort of trend in favor of it if CROWN ultimately does establish a survival benefit. My knowledge of the CROWN study is that there was no overall survival data shared in the update from the five-year. I'm yet to understand whether a survival update is included for this seven-year coming this weekend at ASCO. What I can tell you is that the alectinib has a median overall survival for 8.8 months. To show a benefit over something that takes 8.8 years, not 8.8 months. To show a benefit of something that takes 8.8 years is obviously a very long experiment, right? What the FDA is often interested in these types of studies, particularly when progression-free survival is an endpoint, that there's not a negative trend with respect to overall survival. That's critical in drug development. We'll continue to follow if there is a survival benefit in lorlatinib, the CROWN study, I'm not aware of any such data. Okay. Maybe ROS1, obviously, that review is ongoing. There is this guidance to update the available data to the investment community in the not-too-distant future to include the TKI-naive kind of pivotal cohort. Just mechanistically, how is this going to work? Is there a chance that that TKI-naive data can even be added to the ongoing review? Does it, no matter kind of when it comes, it's got to then wait till you have a label to then be submitted? In the ROS1 study, we had registration-directed cohorts for previously treated patients and for naive patients. The precedent was to follow naive patients for 12 months post-response for the other approved therapies. We had went to the FDA and asked for an opportunity to cut the data for the previously treated patients at six months post-response and got alignment there. That is why this was broken up into two different pathways. Cut the data last year for previously treated, submit that NDA. As Alex mentioned, we have a PDUFA date of September 18th for this particular previously treated submission. The naive patients, we were continuing to follow those patients. As of last year, June, we had already enrolled over 100 patients in that naive cohort. That's more than we needed, right? We did not have the appropriate follow-up at that time, again, a year ago. What we shared earlier this year is that we will be in a position this year to submit that naive data. We haven't got it on the specific timing, and your specific question you're getting at is, what is the case? Can one overlap with the other? What's the regulatory tactics we're going to employ? We've been very clear. We submitted for previously treated ROS1 lung cancer. There are different mechanisms we can employ for how to submit these updated naive data. We will share what tactic we employed once we've actually done it, but we're very comfortable that we have the right strategy in place. If it could be added to the ongoing review, I would assume that would be viewed as a major amendment, by the FDA, which would extend the PDUFA. Is that a good outcome to get a broader label at, say, three months beyond at the end of the year, versus having a more narrow label in September and then that broader label sometime in 2027? How do you think through that calculus? The goal as drug developers always, Marc, is to get the drugs approved for patients as fast as possible. That is a guiding principle in our industry and one that Nuvalent operates at in its basic credo, right? We have a commercial team all in place, ready to go. As soon as this drug is approved, we are ready to start delivering it to patients. No, I would not suggest that a delay in any way waiting for an approval would be a good outcome for Nuvalent. We always are working towards how do we meet the needs of patients as fast as possible. That's what we're ready to do. Okay. When you start launching, obviously, so if you have a little bit more narrowed label than previously been issued to other drugs with that TKI experience requirement, does that imply that initial part of the launch should maybe not do much better? I know you think peak sales are much, much different in ROS1 than the prior ROS1 agents for you. That initial kind of few quarters, it will be relatively slow until you can really get the broad label. Is that kind of TKI-experienced population large enough and compelling enough? Sure that you think you can really separate from other launches even before you get a broad label? Sure. Let's zoom out a little bit. Eight years ago, we wrote a business plan for Nuvalent. We had zero employees, never run an experiment as a company. This year, we're talking eight years, we're talking about two approvals for drugs that we've discovered, developed, and hopefully now will deliver, right? We see the next few years as transformational for the company, because we're not talking about just a previously treated ROS1 launch. We're talking about four launches. Previously treated ROS1, TKI-naive ROS1, previously treated ALK, TKI-naive ALK, right? That is a tremendous opportunity for Nuvalent, right? It's not a what does the next two to three to four months look like? It's not what does the next one to two to three quarters look like? It's how do we become leaders in the ROS1 and ALK space? We think launching in previously treated indications is the perfect opportunity. We designed our drugs to work well in previously treated patients, both ROS1 and ALK. In that setting. If we are fortunate enough to receive those approvals, the physicians get experience working with these drugs where the other drugs don't work well, and neladalkib and zidesamtinib were designed to work well. It sets us up beautifully for when the line-agnostic extension comes. That's how we think about it. It's not a month to month, quarter to quarter. I get that there are certainly going to be stakeholders that are interested in the month to month to quarter to quarter. Our job at Nuvalent is to build a leadership opportunity in the ROS1 ALK space. We think we have the strategy, we have the potential medicines, and the team to deliver that. Right. I know we're running over, but just real quick on HER2, there also is a pretty good drug. Maybe not quite as good as alectinib, but a pretty good drug that's been approved over the last year. What is the big unmet need there? How much do we really know about resistance mechanisms yet for that drug, since it is very new? Yeah. It's limited CNS penetrance. That is the need, right? If to go back to the EGFR and ALK space, when the earlier generation drugs that were game changers for those patients, because they could address that oncogene and drive durable responses for those patients compared to what the standard of care was, and the standard of care was chemotherapy-based regimens. That was a game changer for patients. Better drugs came along that addressed the liabilities of the first-generation drugs. In the ALK space, crizotinib was the original game changer. Patients were progressing on crizotinib with CNS disease. The only difference really between alectinib and crizotinib was better CNS penetrance. It doubled the durability of crizotinib. Doubled it. It took it from a half a billion-dollar market to a +$2 billion market, right? Just by building up that prevalent patient population. Yes, zongertinib is an excellent drug. I'm thrilled that that drug is available for patients with HER2 lung cancer. It's very clear from our preclinical characterization that that drug has limited brain penetrance. I think there's reason to believe that you can improve durability in HER2 lung cancer patients with a better brain penetrant drug, because unfortunately, lung cancer patients will develop CNS disease. That's where our program strategy starts with NVL-330. In addition, NVL-330 is broadly active against HER2 mutations and has excellent CNS penetrance, and we designed it to be selective for HER2 versus wild-type EGFR, which is dose-limiting toxicity. With that profile, there are a lot of other places we can take that potential therapy, and we can take that to other HER2 indications where patients might be prone to developing CNS disease. The longer patients stay alive on HER2 targeting therapies like HER2 ADCs or HER2 antibodies, the more likely they're going to get CNS disease. What better to combine it with than a highly brain penetrant small molecule? That's the strategy there. Unfortunately, we're over, so we're going to get cut off there. Thanks a lot, Jim and Alex, for joining, as well as all the investors on the line. Thanks, Marc. Thank you.