All right, thanks everyone for continuing to join us here at the Stifel Virtual Oncology event that we were hosting over two days. My name is Brad Canino. Really delighted to be hosting Nuvalent for the next fireside. We've got Jim Porter, CEO, and Alex Balcom, CFO. Jim, Alex, thank you so much for joining us. Thanks, Brad. Great to see you, and thanks to Stifel for the opportunity to participate in the conference. Let's just kick it off. Can we get a little intro to Nuvalent for those unfamiliar and talk about the state of the business as we're about one quarter and a few days into 2025? Sure, sure thing, Brad. I'll start. Maybe I'll kick the milestones over to Alex. Nuvalent started in 2018. We are focused on building a company that can discover, develop, and deliver a portfolio of precisely targeted therapies for patients with cancer. We do this through a deep expertise in chemistry and structure-based drug design. I'm a trained chemist. Our scientific founder is a trained chemist. We're trying to bring innovative chemistry solutions to patients with cancer. We focus on clinically proven kinase targets. The rationale there is clear. There are 90+ kinase inhibitors approved, over 70 of them approved for patients with cancer. You're working on validated biology to sort of take that target risk out of the equation and to make an impact in the space. We went from the beginning to talk to the physicians that have developed the earlier generation kinase inhibitors, learn from them, what are we solving for, what are the needs of the patients they treat, what are the limitations of those therapies, and then we try to use innovative chemistry to come up with those solutions. Fast forward to today, we have a portfolio of interesting compounds. Maybe, Alex, you can share some of the milestones ahead of us. Sure. Yeah, thanks, Jim. To start, you know, at the beginning of last year, we had announced our OnTarget 2026 operating plan, and that guides our efforts towards having our first approved product in 2026. Towards that end, we have a number of milestones coming up this year, including, you know, first, we expect to report pivotal data for TKI- pretreated ROS1 patients from the ARROS-1 trial in the first half of this year. We plan to submit an NDA for TKI- pretreated ROS1 mid-year, and then we're expecting to report pivotal data for TKI- pretreated ALK patients from the ALKOVE-1 trial by the end of the year. We're also planning to initiate our ALKAZAR phase III trial for TKI-naïve ALK non-small cell lung cancer in the first half. We are planning to progress the phase I-A/1-B HEROEX trial for HER2 non-small cell lung cancer. Importantly, we are also well capitalized to support these initiatives with runway into 2028, and that is not including any revenues from sales. All right, excellent. I had the biggest data update of Nuvalent's history at ESMO of last year. Maybe give us some of the quick highlights for how you think that has shown the profile of your portfolio. Jim, you mentioned the ethos of the company is to listen to physicians and get their feedback about what the unmet need is. What has been the feedback from the physician community over the past six months since ESMO? Yeah, so ESMO seems like a lot has happened in the world since ESMO, Brad. Yeah, it was an exciting conference for us. You know, there were three objectives we were trying to accomplish, and I think we did accomplish each one of those. One was just to share the momentum we've had on the programs. You know, we had started these programs by listening to the physicians and trying to design solutions for what we've heard. What we had showed is that the enrollment has been massive on the programs. I forgot the specific numbers at ESMO, but in December, we had updated them that on the ROS1 program, we enrolled 430 patients, 330 in the phase II. In the ALK program, we enrolled 600 patients, 460 in the phase II. That was like in the first 10 months of the ALK trial. It's one of the most impressive enrollment rates I've ever seen in oncology drug development. Truly humbling to be working on a program like that. It reminds the Nuvalent team that we're doing something that's important, that physicians are excited about this differentiated profile. They're excited about, you know, the opportunity that it has to address the medical need. It starts to paint a pretty compelling commercial opportunity. The second key area for ESMO was sharing that we had aligned on the ALKAZAR study. This is our global phase III study for frontline metastatic ALK non-small cell lung cancer, comparing neladalkib to the standard of care alectinib. We aligned with regulators and we're in the process of getting that study up and running in the first half of this year. The third area was we showed data updates for each of our parallel lead programs targeting ROS1 and ALK non-small cell lung cancer with both zidesamtinib and neladalkib. The data continues to showcase that these drugs solve for our target product profile that we heard from the physicians. It's active beyond all the other therapies. It's active against the mutations. It's active in the brain, and they're well tolerated. They can keep patients on therapy and drive deep and durable responses. That is what we saw with both of our data updates. Those were the three areas. I think the feedback to your second part of your question of what we're hearing from physicians since then is, you know, keep executing. Like, this is what they wanted to see. You know, you can see by the momentum of them putting patients on the trial that they like the outcomes that they're seeing for their patients. Our team is very motivated to get these drugs approved as fast as possible, which is a key 2025 objective. Right. Now, on that trial momentum, looking at ROS1 specifically, zidesamtinib, how does enrollment into the phase two that you've accomplished compare to the pivotal cohorts from what is now three precedent selective ROS1 inhibitors? I would argue we're the only selective ROS1 inhibitor. The other ones are repurposed multi-kinase inhibitors. You know, I don't actually know, Brad. I know that this is faster. I don't know how much faster because we don't pay too much close attention to the other ones. The other drugs were developed for multiple patient populations. In some cases, they were developed for ALK, ROS1, TREK inhib patients. This is the first and only drug that was designed selectively for ROS1 patients. It solved for what the needs we heard from the physicians were. I think because of that, it's enrolled quite well. We've also really benefited from relationships with the patient advocacy groups. They're very informed and motivated in this space, and they funnel patients to our studies, both ROS1 and ALK. We really, you know, appreciate that collaboration. How does it compare? I don't know. All I know is that we used to hear that it's going to be impossible to find these ROS1 patients. It's a rare patient population. It's competitive space. When we showed our enrollment, I think most saw like, okay, I see that Nuvalent's on the right track here. Now, you have potentially registrational single-arm zidesamtinib data coming in the first half of this year, which I now, I guess, what I will call 2Q of this year. Talk about the form of disclosure and extent of data you intend to release with that update. Sure. I'll talk about the forum, and then I can turn it over to Jim to talk a little bit about the extent of the data. We're very much looking forward to sharing top-line pivotal data from ARROS-1. You know, while our preference is always to share data at a medical meeting, it can be difficult to time the top-line data announcements with, you know, the timelines for abstract submissions. We're planning to share our top-line data in a press release, and then we'll look to share the full data set at a future medical meeting. As far as the expectations for the data, you know, like I mentioned that we enrolled 430 patients across the ARROS-1 program. We vastly over-enrolled what we needed, right? Basically, there was so much momentum that we didn't want to stop the access to the drug. So we over-enrolled the trial. At a certain point, we felt we had enrolled enough patients for, you know, guiding regulatory interactions. That being said, we wanted to follow those patients for a longer period of time. The precedent in the ROS1 space for TKI-naïve approvals has been follow those patients for 12 months post-response, right? So that's a precedent to think about in naïve patients. We believe in previously treated patients that you don't need to follow them for as long because there's a clear medical need. There was an opportunity for us to cut that data first, to use that data to guide regulatory interactions, and then have the TKI-naïve data soon thereafter. That guides our approach here, Brad, that let's cut the previously treated data first to get the drug approved as fast as possible, and then have the TKI-naïve data soon thereafter. What is the process to potentially expand the label? Are you thinking about these data being submitted all at once, data submitted as a major amendment to the NDA sometime during review, SNDA? Help us conceptualize how this might take place. Yeah, the immediate goal is to submit for previously treated patients. That's the goal. That's the first data set available. The TKI-naïve data I mentioned will be available soon thereafter. We will go through whatever mechanisms are possible. We're going to obviously work with the regulators to get the drug approved for all ROS1 patients, but it would be premature for us to guide what that exact process is. We will be doing whatever we can to get the drug approved for all ROS1 patients as fast as possible. All right. If and when it becomes available, what aspects of the data do you think will be the selling point to physicians to select zidesamtinib amongst what is, I guess, three or four other options as a TKI for ROS1 patients? Yeah, this one's pretty straightforward. It is the first and only drug that's been designed to address the combined medical needs of hitting the original fusion, being active against ROS1 mutations, being active in the brain, and selective for ROS1 versus other off-targets that are dose-limiting. It is the first and only drug that does that. The profile that we've seen both preclinically and clinically suggests that is the case. It drives deep and durable responses beyond all the other therapies. It's active against mutations. It's active in the brain. It's got a safety profile that's competitive with any oncology drug, let alone any other ROS1 drugs, right? It's got a safety profile that is really well tolerated. I think that's why the drug really, like the trials enroll so well, is that physicians are seeing these positive outcomes for their patients. I think all those aspects of the TPP matter, and we need to continue to demonstrate that in this updated data set. How are you preparing Nuvalent to become a commercial company? Yeah, I can take that one. We hired our head of commercial late last year, and he's been, you know, building the team and setting the strategy. Launch readiness efforts are well underway. It's a big focus for the team. Importantly, with our raise, you know, last year, we're well funded to be able to build the commercial infrastructure. Okay. Moving to Nuvalent and the ALK inhibitor. One of the recent updates you had in the latest earnings press release was the announcement of an expanded access program. What is the strategy behind that? What would you like to say about the program? Yeah, so we had announced in January that we enrolled 600 ALK patients in our ALKOVE-1 study, 460 since we opened the phase II, like just 10 months earlier. You know, I like to study—I know you study the space, Brad. I like to study the space too. I'm not aware of too many drugs ever in the history of oncology drug-targeted development that have enrolled that quickly. It's super humbling for our team to know that we're involved in something that's potentially impactful like this. That being said, it's expensive, right? We can't enroll the trial forever. We want to make sure we continue to provide access to patients that need neladalkib in this differentiated profile. The expanded access was our way to do so, that we could, you know, focus our access to the drug through expanded access, meanwhile shut down enrollment in the actual clinical study. That was the driving purpose behind it. With the clinical trial, we now can continue to follow the patients that have already been enrolled and use that data to guide regulatory interactions in the future. Okay. Now, quick housekeeping question, because you have neladalkib, essentially pivotal data, single-arm, slated for year-end 2025. Will that encompass both the second-line and third-line plus cohorts? Yes. We would anticipate providing data for both of those cohorts, both second-line and third-line plus. Okay. Now, as we drill down to just the second-line ALK setting, one would assume post-alectinib, pre-lorlatinib for the majority of patients, what efficacy is required to ensure a single-arm approval in that setting, given that lorlatinib has a full approval in that setting? Yeah, sure. It's a question we get a lot, Brad. Just to orient folks to the landscape, patients in frontline get alectinib, in second line, they get lorlatinib. It's the only drug that works beyond alectinib. In post-lorlatinib, nothing works. We designed our drug to work in any line of therapy, right? The majority of our phase one data are those post-lorlatinib patients, those third-line plus patients, and the drug was still active and driving deep and durable responses. Your question was, what is needed in second line for a broader previously treated ALK label? I think in third line, it's pretty clear. That's where we have breakthrough. Nothing else works. You know, we just got to show the drug is active, durable, and safe. I think we can use that data to guide our regulatory interactions. In second line, lorlatinib delivers a 31%-39% response rate, approximately about a seven-month duration of response. Now, what we saw in phase I that gives us confidence here is we saw even beyond lorlatinib in our broader patient population, more than double the durability that lorlatinib delivers. That was beyond lorlatinib, right? When we push it up to second line, if we can show those deep, durable responses in that second-line patient population, together with a third-line data set that shows it's active beyond lorlatinib, we would use that collated data to guide discussions with regulators around a broader previously treated ALK label as opposed to a third-line only label. Yeah. Are there any good precedents, historic precedents, where a single-arm oncology approval has happened in the setting where another drug has a full approval? Yeah, I mean, there are. One of the examples that I actually remember vividly because I was involved in a competitive program is in the CLL space. I think venetoclax was given an accelerated approval, even though ibrutinib had converted to full approval in the relapsed CLL space. I remember the FDA making a case, well, this is doing something different than what ibrutinib can do. Just to double-click on durability, what duration of therapy do you think could be possible based on your phase one data for both the second-line setting and the third-line plus settings? Yeah. So what we saw in phase one was we saw roughly a 38% response rate in a 14.4 months duration response across all doses in the phase one. Now, when we looked at the phase II dose, where we got better coverage of the mutations, we actually only saw a single patient progress. If you think about that for a second, these are patients that have taken all the other therapies, and our drug is still driving deep, durable responses in these late-line patients. In second-line patients, you know, that have only taken lorlatinib, that yet to take lorlatinib, we only had a handful of patients. But in those patients, none of them progressed at the phase II dose. So it's too small of a sample set to really make too much out of. All of it together is trending in the right direction that we're showing deep, durable responses even beyond lorlatinib. You know, and hopefully that could, you know, translate into phase II, where, you know, broader sample set where we can show those deep, durable responses regardless of line, second line or third line. Now, moving to the front-line setting, what is the status of the ALKAZAR study startup? Yeah, study initiation processes are underway. We're planning to initiate the trial in the first half. Jim, do you want to talk a little bit about the study design? Sure. Study that it's pretty standard study design based on, you know, the 12 + years of ALK clinical development in this space. You know, other drugs have run randomized phase IIIs, all comparing their drug one-to-one to the standard of care. The current standard of care, we believe, is alectinib. Our drug is compared directly to alectinib in a one-to-one fashion, 450 patients, progression-free survival by blinded independent central review as the primary endpoint, standard secondary objectives. Not a lot of like novel stuff here. It's sort of a tried and true area, and we're just trying to show that our drug is better than the standard of care. Now, normally, how long has it taken for previous front-line ALK studies to enroll, read out PFS data, and get approved? Yeah, there's four, at least four that I'm aware of in the ALK advanced metastatic setting that have been run in this space. They've all been about 300 patients. They've all been approximately two and a half to three years from start of enrollment to that line extension approval. This is, you know, brigatinib, lorlatinib, alectinib, and ensartinib. You know, there's a lot of learnings there for us, like what, you know, what was seen in those studies, you know, how they were conducted, how the, you know, the control arm behaved, how the active arm behaved. Actually, those studies directly guided our approach with the ALKAZAR study. You're often not armed with that much data where you can take from the literature. We actually use that data to design, like, you know, that lorlatinib itself would probably beat alectinib in a randomized study, right? That study would probably look a lot like the ALKAZAR study, right? Because that's exactly how we used to design it, right? Now, we think our drug is as active, if not more active than lorlatinib. With that literature, we could, you know, take some of the risk out of, you know, a phase three study design with neladalkib. There are three things that influence data availability in a randomized study like this. It's enrollment rate, it's event rate in the statistical analysis plan. Enrollment, we expect to go well. Either way, it's unlikely to be gating; it's likely to be event rate, hopefully in the alectinib arm, that guides that data availability. We have to list on clinicaltrials.gov when we think that that primary completion might come. We estimate in October 2029. Just to be clear, that's a guess, you know, based on the variable assumptions. You know, we often get asked, will there be any earlier looks? Will this trial include an interim analysis? We have not taken anyone through the specific statistical assumptions for this study, other than to say, you can go back through the other studies and learn from them. Some do include an interim analysis, some do not. Yeah. Maybe to expand on that, what degree of PFS event maturity has supported historic approvals? How should we think about the ability to reach that threshold when you're using a comparator arm that's going to be much better in terms of its own PFS results with alectinib? Yeah, I mean, the—so let's go through a couple of examples here. lorlatinib had a CROWN study, brigatinib was the ALTA study, alectinib was the ALEX study. The ALEX study did not include an interim analysis. The brigatinib ALTA study actually had two interim analyses, IA1 and IA2. IA1 was about 33% of the events. The trial was positive at the first interim analysis. The FDA told them to keep going. They did, and they stopped it actually at IA2, which is around 55% data maturity. Lorlatinib also included an interim analysis. They did stop it at the interim analysis. I think that was around 45% data maturity. There is precedent of doing this and not doing this. We do think the control arm, you know, it's a higher bar to beat here in the ALKAZAR compared to those other studies. Crizotinib, as you mentioned, it's a little bit easier of a bar. Nonetheless, I think that the alectinib available data and the lorlatinib available data help convince us that this can be beat. We're excited for the experiment. Okay. Maybe just a final question to close out. How would you define your cash runway and what it encompasses in terms of milestones and what Nuvalent is able to do? Sure. Yeah. We're in a strong position. We ended the year with $1.1 billion in cash, and that provides us with runway into 2028, not including any revenues from sales. You know, importantly, that sees us through multiple catalysts, including what we've laid out in the OnTarget 2026 operating plan and bringing us to, you know, our first potential approval in 2026. Okay. Great. Jim, Alex, thank you so much. Busy year coming up. Looking forward to seeing all the data updates and progress as we go. Thanks, Brad. Appreciate you.