Nuvalent, Inc. — Call Transcript 2025

Hi, everyone. I'm David Dai, one of the biotech analysts here at UBS. Thank you. Thanks for joining our inaugural virtual oncology day today. We continue our session with Nuvalent. It's our great pleasure to welcome Jim Porter, Chief Executive Officer, and Alex Balcom, Chief Financial Officer. Alex and Jim, thank you for joining us. Thanks, David. It's a real pleasure to be with you, and sincere thanks for the opportunity to participate in the conference. Excellent. Great. Jim, maybe you can just help us understand Nuvalent at a high level. For anyone who is new to the story, can you give us just a quick introduction of what Nuvalent is and some of the key programs in development? Sure. Nuvalent Inc is about seven years old. We're founded with a deep expertise in chemistry and structure-based drug design, and we like to apply that chemistry to discover, develop, and deliver a portfolio of precisely targeted therapies for patients with cancer. At the foundation of the company is that core chemistry expertise. We focus on validated biology, and the rationale there is clear, that we can accelerate the discovery phase and the development phase by focusing on validated targets, running small focus studies to understand whether your drugs work or not. To make an impact here, we partnered with physicians that had developed earlier generation kinase inhibitors. We want to learn from them. They are the experts in the space. What are the needs of the patients they treat? What are the limitations of those therapies? Let's use innovative chemistry to try to solve for that. In about seven years, we've quickly advanced the portfolio of compounds. The first program, we just completed our first NDA submission for. The second program has pivotal data reading out soon. They both have breakthrough designation. They both address medical needs, and we think they both have an opportunity to make a significant impact for patients. Beyond that, a broad portfolio of compounds in our discovery portfolio, that same idea, listen to physicians and see where we can apply innovative chemistry to it. Happy to go deeper into any of those areas, David. That's a great overview. Yeah, you guys are definitely one of the leaders in innovative chemistry here, and you have two very exciting programs, actually three very exciting programs in development. Maybe let's focus on sort of the near-term, you know, a program that has some near-term kind of updates. Zetacentenib, right? It's for ROS1-positive non-small cell lung cancer. By the way, just completed an NDA submission two weeks ago. Congrats on that. A big milestone here. On that front, how has your experience with the FDA engagement been so far? Has there been any kind of changes in the FDA interactions, given all the things that are happening at the FDA? Thanks, David. Yeah, the completion of our first NDA submission is a massive milestone for the Nuvalent team. As I mentioned, the company is only seven years old, and from scratch, we invented a new compound, developed it, and now have completed our first NDA submission. Clearly a sign of outstanding execution by my colleagues at Nuvalent. To answer your question directly, no, we haven't seen any impact, really. In my 20+ 25 years in the industry, mostly in the oncology space, I found the interactions with the FDA, you have to bring your A-game. They're very good at what they do. They're thorough. They're diligent. They know the landscape. They know the needs. They're very good at looking at, they're diligent about looking through the data, understanding. You better make sure that when you interact with them, that you are up to speed on all aspects, because they're going to bring their A-game. You need to bring yours as well. We've seen no drop-off or changes in any way that impact that perception, and we look forward to continuing to collaborate with them to get these drugs to patients as fast as possible. Got it. Just on the interaction with the FDA, you know, of course, the OR and DOR has been the primary endpoint you're using for approval. Any signals that you got from the FDA in terms of using survival endpoints for approval? You know, anything you can share on that front? Yeah. In the ROS1 space and in the ALK space, actually, we're greatly aided by the fact that other drugs have been developed in the space. We can learn and understand from those other approaches how those development strategies were tackled and how they were viewed by the regulators. In the ROS1 space, there's actually four approved therapies. Each of those four approvals came off of single-arm studies that utilize ORR and DOR and safety as the primary measures to understand the benefits and risks of the drug. With each of those approvals, they received full approval off of those single-arm phase II studies. We took a similar approach, understanding that precedent and also aligning with the FDA. We have a previously treated cohort that we followed for six months. We aligned with the FDA on that approach. We cut that data, and we submitted that data in our recent NDA submission. For TKI naive patients, the precedent has been to follow those patients for 12 months. We're still letting that data mature, and we're going to work with the regulators to get that data submitted as possible as that data continues to mature. Got it. Since you already have breakthrough designation for Zetacentenib, curious, you know, what's the chance of receiving a priority review for Zetacentenib in ROS1, you know, TKI pretreated non-small cell lung cancer patients? Yeah, we do believe there's a medical need. We do think that Zetacentenib has a chance to address that medical need. As you mentioned, we do have breakthrough designation, which is often, you know, regulators are going to look at what are the needs and how in the data available to address that need. As far as the type of review, that's out of our hands, right? That's something that the regulators will decide. We will work with them to make sure that we can do whatever is necessary on our end to get the drugs reviewed and approved as fast as possible. As we learn more about how the FDA is viewing our submission and the review timelines, then we'll provide more clarity on that. Got it. OK. Talk a little bit more about the data here. Maybe, Jim, can you just maybe help us understand the data you recently presented? You actually saw it in the data presented at WCLC recently, too. Maybe just help us understand some clinical data there. Give us some perspective around what we're seeing in TKI in pretreated cohorts, and what's sort of like the benchmark that people are looking for in this particular population. Yeah. You know, the target product profile that we've been working towards really came from the physicians in the space. They had said, you know, based on what was the standard of care at the time, crizotinib, that drug worked reasonably well, but it had some limitations. The drug was not highly brain penetrant, so patients would progress with CNS disease, or patients would progress with ROS1 resistance mutations. We needed to solve for those two things. Other drugs have tried to solve for one or more of those things, but with each of those other drugs, they bring in other off-targets that they also inhibit in addition to ROS1. Inhibition of those other off-targets has held back the development of those other drugs, because it leads to these off-target toxicities, these dose-limiting toxicities. It's been difficult for physicians to manage the patients on those therapies, and they've largely stuck with crizotinib as the standard of care. The goal for Zetacentenib was to develop a drug that can hit the mutations, can get into the brain, but importantly, was selective for ROS1, so that we did not bring in those off-target dose-limiting toxicities. Zetacentenib is the first and only drug that has that profile. What we showed in our top-line data was, even beyond all the other therapies, our drug was active. It was active beyond those other therapies in patients with ROS1 resistance mutations. It was active in the brain. Even when patients are progressing on CNS-active drugs, like entrectinib or repatrectinib or talotrectinib, our drug is still active in the brain, which really is a high bar that no other drug has shown. Most importantly, it has that ROS1 selective tract-sparing safety profile that's been lacking from the other drugs in this space. We're quite encouraged by that. What it's resulted in is we're seeing activity that's driving these responses that look to be durable, right? As an example, in patients that have progressed on one prior TKI, what we're seeing is at the year-and-a-half landmark or 18 months, 93% of those patients are still in response. That's quite encouraging, because these patients have already progressed on another line of therapy. It bodes well to, as you push the drug up earlier in the treatment paradigm, their responses might become even more durable than that. I think it's definitely trending in the right direction, and we're excited about the path forward for Zetacentenib. That's really, really interesting and helpful here. One thing that we noticed at WCLC was that we had a conversation with some physicians. Of course, they were impressed with the overall efficacy and durability data, but they were also surprised to see some of the onset of the peripheral edema, which, you know, to them indicates some tract inhibition. They worry about the long-term toxicity associated with tract inhibition here. Jim, can you just help understand, you know, what are your thoughts around the peripheral edema here, and what are some of the long-term safety kind of issues you're thinking about? You know, thanks, David. Yeah, we actually see the Zetacentenib safety profile as very favorable and differentiated compared to any other ROS1 TKIs out there. I think most physicians agree with us. I think that's why you see the massive enrollment momentum we've had in this study. We used to get asked, like, how are you going to find these patients? We just enrolled 540 patients in really, you know, very limited time. That speaks to the enthusiasm that investigators have for this differentiated profile, as well as the patient advocates, which are very active in this space and have pushed a lot of patients towards our study. The peripheral edema signal, that's something that's due to excessive fluid accumulation in the extremities, and it's not associated with tract inhibition. The exact etiology of edema is not fully understood, but I will tell you that many TKIs in oncology drug development have this associated edema signal. These include drugs like lorlatinib, crizotinib, alectinib, brigatinib, lezertinib, repotrectinib, entrectinib, the MET inhibitors, tepotinib, capmatinib. These are pretty common signals for kinase inhibitors. Many of those drugs I just mentioned are perceived to be well tolerated, and they're also not tract inhibitors. This is not a tract-related signal. We are not seeing those safety signals that are commonly associated with the tract inhibitors like repotrectinib, entrectinib, talotrectinib, lorlatinib, et cetera. Got it. OK, great. Thanks for providing that perspective here, Jim. Moving on to the TKI naive cohorts, we have seen 35 patient data that shows some impressive OR and DOR. Of course, we are eagerly waiting to see the updated pivotal data. Maybe just help us understand, Jim, when should we expect to see the frontline data in TKI naive cohorts, and help us understand what kind of expectations should we be looking for in terms of the OR and DOR? Yeah. We had a cohort directed towards registration in TKI naive patients. As of the data cut back in June, we basically announced that we had enrolled 104 patients already in that cohort, more than we actually needed. As I mentioned before, David, the precedent has been to follow naive patients for 12 months, whereas we cut the data for previously treated patients at six months. We need a little bit more follow-up on those patients. We showed how the first 35 were trending, and it clearly was favorable, 89% response rate. The 12-month landmark of duration response was 96%. We're seeing deep responses in the brain, right? That's by design. We had designed a highly brain penetrant drug, and five of the six patients with CNS disease responded. Four of them had an intracranial complete response. That's different than any other drug in this space. Those drugs have not demonstrated intracranial complete responses. Importantly, it has that differentiated safety profile. We're going to continue to follow that cohort and work with the regulators to consider a line agnostic extension as that data continues to mature. Is there a bar or benchmark we should be looking for here for the OR and DOR side of things? You know, most of the patients, most of the drugs in the ROS1 space in the frontline are going to have high response rates, right? If you have ROS1-driven disease, it's likely the patient's going to respond if there is a, you know, you're using a ROS1 inhibitor. What's key here is how durable those responses can be, right? I mentioned before, crizotinib was a standard of care. 40% of those patients are progressing with known ROS1 resistance mutations. If you cover those ROS1 mutations, you're going to take away that pathway as a potential disease progression pathway. In addition, if you're highly brain penetrant, you're going to take away that pathway as a potential source of disease progression. Zetacentenib does that. What Zetacentenib also does is it's, you know, well tolerated, so patients can stay on therapy. We only saw in our full data set only 2% of the patients discontinued due to any adverse event. Keep in mind, this is a very advanced patient population, and only 2% of the patients are discontinuing due to any adverse event, whether it's related or not. That is what we think is the recipe for keeping patients on therapy and driving more durable response. What we're going to want to understand is how durable are these responses, and how does that compare to a drug like crizotinib that has those liabilities? I think that's the real variable here. Understood. Let's assume that the TKI naive data is going to be positive next year. How soon should we expect, you know, NDA filing, given that you already, you know, did the NDA filing for Zetacentenib in TKI pretreated patients? What should, how should we think about potential approval timeline here? I can take that one. We haven't provided the guidance on timing just yet. Jim mentioned the precedent of following patients for 12 months post-response. We'll continue to follow the data from the TKI naive cohort and then engage with the FDA on a potential line agnostic expansion and look to provide updates in the future on timing. Do we expect the review to be shorter? Because this is going to be a, you know, it's an sNDA instead of, you know, actually a full NDA. Do you want to take that one? Yeah. It's really something that we haven't commented on at this point, David, of exactly what the submission strategy will be for the naive patients, other than that we're going to do whatever we can to collaborate with the FDA on getting that data reviewed and getting the drug approved for all ROS1 patients, including frontline patients. Once we have the data and we've aligned on that submission strategy, it's probably a more appropriate time to talk about what review timelines might look like. Yeah, understood. Your competitor, Nuvation Bio's talatretinib, the launch was pretty impressive, right? Does that strengthen your confidence in Zetacentenib's market potential in ROS1, either naive or pretreated non-small cell lung cancer populations? Yeah. I mean, we believe there's clearly a need for ROS1 patients. As I mentioned before, crizotinib is a standard of care, and a number of other drugs in the space were designed to address some of the limitations, whether it be CNS disease or the emergence of ROS1 resistance mutations. All of them brought in additional challenges in that they hit off targets, including, you know, the most recently approved drugs. We've seen with the enrollment on our study that clearly these patients exist, and clearly there's enthusiasm for new options that address those needs of ROS1 patients. We remain, you know, enthusiastic about, you know, our path forward with Zetacentenib, and we're looking forward to delivering this for patients. Got it. Great. Let's move on to nanodelcub, the ALK inhibitor in ALK-positive non-small cell lung cancer here. It looks like you will be presenting a poster at ESMO for nanodelcub in pretreated ALK-positive non-small cell lung cancer from the ALKOV1 study. Just curious, is this the pivotal data we should be expecting here? Maybe you can also provide some detail around data expectation for this ESMO update. Yeah. There are actually two data readouts we have for our ALK program in the second half here, and maybe we'll walk through each one of them. Alex, do you want to start first on our top line? Sure. Yeah. For our top line data, we're on track to deliver that by year-end, and we're planning to take a similar approach as we did for our pivotal data that we reported for Zetacentenib. Our preference has been shared data at a medical meeting, but it can be difficult to time the top line data with the abstract submission deadlines. We're planning to share our top line data as a standalone press release, and then we'll look to share the full data set at a future medical meeting. The other update is we do have a poster that's been accepted for presentation at ESMO. This is around tumors outside of non-small cell lung cancer. ALK is a driver in a number of different tumor types, probably like a dozen or so. The challenge there is to get physicians to sequence those patients for drivers like ALK, right? Then to try TKIs as compared to whatever the standard of care is in that particular indication. We had an exploratory cohort in our phase II to enroll patients with those other tumor types. With a compound like nanodelcub, which broadly covers ALK mutations, which has excellent CNS penetration, and we believe is designed to have a good safety profile, this could be an attractive option for patients in these other tumor types. We are going to share what we've learned so far at ESMO in that exploratory cohort. That's interesting. These are ALK-positive solid tumors. Maybe, Jim, can you just level set some of the market opportunity for the ALK-positive solid tumors? What % of the solid tumors will actually have ALK-positive mutations? It really ranges, David. It also is limited by the lack of good options for those patients. I think if you go back 20-something years ago, this is how the development in lung cancer started, right? All patients just used to get the standard of care, like chemotherapy. Scientists and drug developers established that there are actual drivers to target, like EGFR. EGFR therapies were developed and shown that they actually work much better than the standard of care. Today, the standard of care is to give a targeted therapy, like an EGFR therapy for patients that have EGFR-driven lung cancer, right? Not chemotherapy or chemoimmunotherapy. That is what we're looking to do across other tumor types. If you can show that you have an oncogene-driven cancer in, let's say, pancreatic cancer or colorectal cancer or something else that typically you give a tumor-directed therapy, then potentially you can start shifting the way physicians think about treating that disease. We are happy to participate in trying to push the field there if we have a drug that could potentially address that, such as nanodelcub or Zetacentenib in the ROS1 space, where the same theory is true. Got it. Yeah, that's just really helpful. In terms of the data update, the pivotal top line data update, we should be expecting this in the second half of this year or by year-end. Could you maybe just set some expectations for the potential benchmark we should be looking for in terms of OR and DOR? Right. The standard of care is alectinib. When patients progress on alectinib, they get lorlatinib. When they progress on lorlatinib, nothing works, right? We wanted to design a drug for any line of therapy, right? We'll start in that third line. Nothing works. That was the majority of our phase I patient population. We had enrolled patients that had progressed on all the available therapies, including lorlatinib. Nothing else works there. Our drug was active. It drove durable responses. It was active against mutations, both single and compound, active in the brain, and it had that well-tolerated safety profile. We received breakthrough designation in that population, demonstrating that there's a clear medical need. I imagine the way our phase II is going to be viewed is, how does it translate from phase I to phase II? There are no other relevant data benchmarks to point to, because, as I said, nothing else works in this patient population. In the second line, we also have a cohort directed for this patient population. This is where lorlatinib is the standard of care. Lorlatinib can drive responses in this patient population because it has some coverage of ALK mutations, and it has good CNS penetration, right? However, we believe lorlatinib is limited in this patient population in that it hits off-target tract very close to where it hits these ALK mutations, right? It's difficult to hit these ALK mutations hard. We see patients come on our phase I that have progressed on lorlatinib due to inefficient coverage of ALK single mutations, or they actually develop a second mutation called compound mutation, and lorlatinib is not active against those either. Our drug was designed to, it was optimized to cover these mutations broadly. We think there's an opportunity to clearly differentiate from lorlatinib on durability in the second-line patient population. The response rates are in that 30%-39% range, but the durability is only seven months in this setting. In our phase I, we saw more than double that in a patient population that had already progressed on lorlatinib, right? That's meaningfully different than what lorlatinib can do. If we see anything in that same ballpark, we think there's an opportunity to use that second-line data in conjunction with our third-line data to have discussions with regulators around a broader previously treated ALK indication. In addition to that, we have a front-line study compared to alectinib, randomized phase III ongoing. That's our approach to front-line ALK non-small cell lung cancer development. Hopefully, that makes sense. Yeah, that makes a lot of sense, Jim. We have about three minutes left. I just want to spend the next couple of minutes talking about your HER2-altered non-small cell lung cancer program. Maybe just give a quick update on the NVL-330 trial for HER2-altered non-small cell lung cancer and any kind of timeline toward data expectation here. Yeah, that's a tricky name. Heroics. Heroics is how we pronounce it. Although, I don't know if that's proper English, but that's how we pronounce it. Yeah. Let me tell you about our NVL-330 HER2 program. HER2 is obviously a well-known cancer target, a couple decades' worth of drug development in the space, small molecules, antibodies, ADCs, you name it. There's been lots of drug development across tumor types for patients with HER2-driven cancers. HER2 lung cancer is a little bit different in that the main driver is something called exon 20 insertions, HER2 exon 20 insertions. They are not the driver in those other tumor types, right? Some of those other HER2 drugs were repurposed for HER2 lung cancer, and the outcomes were not very favorable, right? Poor response rates, poor durability. There's a reason for that, a scientific reason, in that those drugs do not have a wide index for inhibiting HER2 exon 20 compared to wild-type EGFR. It's well known that wild-type EGFR inhibition causes skin toxicities, GI toxicities. It's difficult to keep the patients on therapy. You get a lot of interruptions, poor response rates, poor durability. That's a chemistry problem, one that we wanted to tackle, and we did with NVL-330. In addition, because this is lung cancer, patients will get brain mets. It's very important to have a compound that has excellent brain penetration. NVL-330 does have that. We think that positions it quite uniquely in this setting as a TKI that can broadly cover HER2 exon 20 with that wide index versus wild type and have that good brain penetration. That's a pretty attractive profile for HER2 lung cancer patients. That's where our phase I focus is. The compound is broadly active against HER2 cancers, HER2 immunes. You can imagine all the other places where HER2 drug development has happened, including where HER2 ADCs have been developed. You know, having a HER2 brain penetrant TKI is a very attractive option to consider in the treatment arsenal for those other cancers as well. That's a future development opportunity we can consider with this program as well. Got it. This is really, really helpful discussion here, Jim. I don't have any more questions. I think we're almost on the top of our hour here. Maybe just one quick sentence to highlight some of the key catalysts we should be watching for over the next 6-12 months. Want to take that, Alex? Sure. Yeah. We're looking forward to sharing the pivotal data from the ALKOV1 study by year-end, and then continuing to follow progress for our HER2 program as well. We haven't shared timing just yet, but we'll look forward to providing updates in the future as we watch the data there. We talked about the solid tumor data for the ALK program as well that we'll have at ESMO coming up. Excellent. Great. Thank you so much for taking this time to speak with us. You know, we're definitely looking forward to more exciting news over the next 6-12 months from Nuvalent. Thank you again for attending the virtual oncology day. Thanks for inviting us, David. Really appreciate it. Thank you.

Speaker 1: Hi, everyone. I'm David Dai, one of the biotech analysts here at UBS. Thank you. Thanks for joining our inaugural virtual oncology day today. We continue our session with Nuvalent. It's our great pleasure to welcome Jim Porter, Chief Executive Officer, and Alex Balcom, Chief Financial Officer. Alex and Jim, thank you for joining us. Hi, everyone. hi everyone I'm David Dai, one of the biotech analysts here at UBS. i'm david dai one of the biotech analysts here at ubs Thank you. thank you Thanks for joining our inaugural virtual oncology day today. thanks for joining our inaugural virtual oncology day today We continue our session with Nuvalent. we continue our session with nuvalent It's our great pleasure to welcome Jim Porter, Chief Executive Officer, and Alex Balcom, Chief Financial Officer. it's our great pleasure to welcome jim porter chief executive officer and alex balcom chief financial officer Alex and Jim, thank you for joining us. alex and jim thank you for joining us

Speaker 2: Thanks, David. It's a real pleasure to be with you, and sincere thanks for the opportunity to participate in the conference. Thanks, David. thanks david It's a real pleasure to be with you, and sincere thanks for the opportunity to participate in the conference. it's a real pleasure to be with you and sincere thanks for the opportunity to participate in the conference

Speaker 1: Excellent. Great. Jim, maybe you can just help us understand Nuvalent at a high level. For anyone who is new to the story, can you give us just a quick introduction of what Nuvalent is and some of the key programs in development? Excellent. excellent Great. great Jim, maybe you can just help us understand Nuvalent at a high level. jim maybe you can just help us understand nuvalent at a high level For anyone who is new to the story, can you give us just a quick introduction of what Nuvalent is and some of the key programs in development? for anyone who is new to the story can you give us just a quick introduction of what nuvalent is and some of the key programs in development

Speaker 2: Sure. Nuvalent Inc is about seven years old. We're founded with a deep expertise in chemistry and structure-based drug design, and we like to apply that chemistry to discover, develop, and deliver a portfolio of precisely targeted therapies for patients with cancer. At the foundation of the company is that core chemistry expertise. We focus on validated biology, and the rationale there is clear, that we can accelerate the discovery phase and the development phase by focusing on validated targets, running small focus studies to understand whether your drugs work or not. To make an impact here, we partnered with physicians that had developed earlier generation kinase inhibitors. We want to learn from them. They are the experts in the space. What are the needs of the patients they treat? What are the limitations of those therapies? Let's use innovative chemistry to try to solve for that. Sure. sure Nuvalent Inc is about seven years old. nuvalent inc is about seven years old We're founded with a deep expertise in chemistry and structure-based drug design, and we like to apply that chemistry to discover, develop, and deliver a portfolio of precisely targeted therapies for patients with cancer. we're founded with a deep expertise in chemistry and structure-based drug design and we like to apply that chemistry to discover develop and deliver a portfolio of precisely targeted therapies for patients with cancer At the foundation of the company is that core chemistry expertise. at the foundation of the company is that core chemistry expertise We focus on validated biology, and the rationale there is clear, that we can accelerate the discovery phase and the development phase by focusing on validated targets, running small focus studies to understand whether your drugs work or not. we focus on validated biology and the rationale there is clear that we can accelerate the discovery phase and the development phase by focusing on validated targets running small focus studies to understand whether your drugs work or not To make an impact here, we partnered with physicians that had developed earlier generation kinase inhibitors. to make an impact here we partnered with physicians that had developed earlier generation kinase inhibitors We want to learn from them. we want to learn from them They are the experts in the space. they are the experts in the space What are the needs of the patients they treat? what are the needs of the patients they treat What are the limitations of those therapies? what are the limitations of those therapies Let's use innovative chemistry to try to solve for that. let's use innovative chemistry to try to solve for that In about seven years, we've quickly advanced the portfolio of compounds. The first program, we just completed our first NDA submission for. The second program has pivotal data reading out soon. They both have breakthrough designation. They both address medical needs, and we think they both have an opportunity to make a significant impact for patients. Beyond that, a broad portfolio of compounds in our discovery portfolio, that same idea, listen to physicians and see where we can apply innovative chemistry to it. Happy to go deeper into any of those areas, David. In about seven years, we've quickly advanced the portfolio of compounds. in about seven years we've quickly advanced the portfolio of compounds The first program, we just completed our first NDA submission for. the first program we just completed our first nda submission for The second program has pivotal data reading out soon. the second program has pivotal data reading out soon They both have breakthrough designation. they both have breakthrough designation They both address medical needs, and we think they both have an opportunity to make a significant impact for patients. they both address medical needs and we think they both have an opportunity to make a significant impact for patients Beyond that, a broad portfolio of compounds in our discovery portfolio, that same idea, listen to physicians and see where we can apply innovative chemistry to it. beyond that a broad portfolio of compounds in our discovery portfolio that same idea listen to physicians and see where we can apply innovative chemistry to it Happy to go deeper into any of those areas, David. happy to go deeper into any of those areas david

Speaker 1: That's a great overview. Yeah, you guys are definitely one of the leaders in innovative chemistry here, and you have two very exciting programs, actually three very exciting programs in development. Maybe let's focus on sort of the near-term, you know, a program that has some near-term kind of updates. Zetacentenib, right? It's for ROS1-positive non-small cell lung cancer. By the way, just completed an NDA submission two weeks ago. Congrats on that. A big milestone here. On that front, how has your experience with the FDA engagement been so far? Has there been any kind of changes in the FDA interactions, given all the things that are happening at the FDA? That's a great overview. that's a great overview Yeah, you guys are definitely one of the leaders in innovative chemistry here, and you have two very exciting programs, actually three very exciting programs in development. yeah you guys are definitely one of the leaders in innovative chemistry here and you have two very exciting programs actually three very exciting programs in development Maybe let's focus on sort of the near-term, you know, a program that has some near-term kind of updates. maybe let's focus on sort of the near-term you know a program that has some near-term kind of updates Zetacentenib, right? zetacentenib right It's for ROS1-positive non-small cell lung cancer. it's for ros1-positive non-small cell lung cancer By the way, just completed an NDA submission two weeks ago. by the way just completed an nda submission two weeks ago Congrats on that. congrats on that A big milestone here. a big milestone here On that front, how has your experience with the FDA engagement been so far? on that front how has your experience with the fda engagement been so far Has there been any kind of changes in the FDA interactions, given all the things that are happening at the FDA? has there been any kind of changes in the fda interactions given all the things that are happening at the fda

Speaker 2: Thanks, David. Yeah, the completion of our first NDA submission is a massive milestone for the Nuvalent team. As I mentioned, the company is only seven years old, and from scratch, we invented a new compound, developed it, and now have completed our first NDA submission. Clearly a sign of outstanding execution by my colleagues at Nuvalent. To answer your question directly, no, we haven't seen any impact, really. In my 20+ 25 years in the industry, mostly in the oncology space, I found the interactions with the FDA, you have to bring your A-game. They're very good at what they do. They're thorough. They're diligent. They know the landscape. They know the needs. They're very good at looking at, they're diligent about looking through the data, understanding. Thanks, David. thanks david Yeah, the completion of our first NDA submission is a massive milestone for the Nuvalent team. yeah the completion of our first nda submission is a massive milestone for the nuvalent team As I mentioned, the company is only seven years old, and from scratch, we invented a new compound, developed it, and now have completed our first NDA submission. as i mentioned the company is only seven years old and from scratch we invented a new compound developed it and now have completed our first nda submission Clearly a sign of outstanding execution by my colleagues at Nuvalent. clearly a sign of outstanding execution by my colleagues at nuvalent To answer your question directly, no, we haven't seen any impact, really. to answer your question directly no we haven't seen any impact really In my 20+ 25 years in the industry, mostly in the oncology space, I found the interactions with the FDA, you have to bring your A-game. in my 20+ 25 years in the industry mostly in the oncology space i found the interactions with the fda you have to bring your a-game They're very good at what they do. they're very good at what they do They're thorough. they're thorough They're diligent. they're diligent They know the landscape. they know the landscape They know the needs. they know the needs They're very good at looking at, they're diligent about looking through the data, understanding. they're very good at looking at they're diligent about looking through the data understanding You better make sure that when you interact with them, that you are up to speed on all aspects, because they're going to bring their A-game. You need to bring yours as well. We've seen no drop-off or changes in any way that impact that perception, and we look forward to continuing to collaborate with them to get these drugs to patients as fast as possible. You better make sure that when you interact with them, that you are up to speed on all aspects, because they're going to bring their A-game. you better make sure that when you interact with them that you are up to speed on all aspects because they're going to bring their a-game You need to bring yours as well. you need to bring yours as well We've seen no drop-off or changes in any way that impact that perception, and we look forward to continuing to collaborate with them to get these drugs to patients as fast as possible. we've seen no drop-off or changes in any way that impact that perception and we look forward to continuing to collaborate with them to get these drugs to patients as fast as possible

Speaker 1: Got it. Just on the interaction with the FDA, you know, of course, the OR and DOR has been the primary endpoint you're using for approval. Any signals that you got from the FDA in terms of using survival endpoints for approval? You know, anything you can share on that front? Got it. got it Just on the interaction with the FDA, you know, of course, the OR and DOR has been the primary endpoint you're using for approval. just on the interaction with the fda you know of course the or and dor has been the primary endpoint you're using for approval Any signals that you got from the FDA in terms of using survival endpoints for approval? any signals that you got from the fda in terms of using survival endpoints for approval You know, anything you can share on that front? you know anything you can share on that front

Speaker 2: Yeah. In the ROS1 space and in the ALK space, actually, we're greatly aided by the fact that other drugs have been developed in the space. We can learn and understand from those other approaches how those development strategies were tackled and how they were viewed by the regulators. In the ROS1 space, there's actually four approved therapies. Each of those four approvals came off of single-arm studies that utilize ORR and DOR and safety as the primary measures to understand the benefits and risks of the drug. With each of those approvals, they received full approval off of those single-arm phase II studies. We took a similar approach, understanding that precedent and also aligning with the FDA. We have a previously treated cohort that we followed for six months. We aligned with the FDA on that approach. Yeah. yeah In the ROS1 space and in the ALK space, actually, we're greatly aided by the fact that other drugs have been developed in the space. in the ros1 space and in the alk space actually we're greatly aided by the fact that other drugs have been developed in the space We can learn and understand from those other approaches how those development strategies were tackled and how they were viewed by the regulators. we can learn and understand from those other approaches how those development strategies were tackled and how they were viewed by the regulators In the ROS1 space, there's actually four approved therapies. in the ros1 space there's actually four approved therapies Each of those four approvals came off of single-arm studies that utilize ORR and DOR and safety as the primary measures to understand the benefits and risks of the drug. each of those four approvals came off of single-arm studies that utilize orr and dor and safety as the primary measures to understand the benefits and risks of the drug With each of those approvals, they received full approval off of those single-arm phase II studies. with each of those approvals they received full approval off of those single-arm phase ii studies We took a similar approach, understanding that precedent and also aligning with the FDA. we took a similar approach understanding that precedent and also aligning with the fda We have a previously treated cohort that we followed for six months. we have a previously treated cohort that we followed for six months We aligned with the FDA on that approach. we aligned with the fda on that approach We cut that data, and we submitted that data in our recent NDA submission. For TKI naive patients, the precedent has been to follow those patients for 12 months. We're still letting that data mature, and we're going to work with the regulators to get that data submitted as possible as that data continues to mature. We cut that data, and we submitted that data in our recent NDA submission. we cut that data and we submitted that data in our recent nda submission For TKI naive patients, the precedent has been to follow those patients for 12 months. for tki naive patients the precedent has been to follow those patients for 12 months We're still letting that data mature, and we're going to work with the regulators to get that data submitted as possible as that data continues to mature. we're still letting that data mature and we're going to work with the regulators to get that data submitted as possible as that data continues to mature

Speaker 1: Got it. Since you already have breakthrough designation for Zetacentenib, curious, you know, what's the chance of receiving a priority review for Zetacentenib in ROS1, you know, TKI pretreated non-small cell lung cancer patients? Got it. got it Since you already have breakthrough designation for Zetacentenib, curious, you know, what's the chance of receiving a priority review for Zetacentenib in ROS1, you know, TKI pretreated non-small cell lung cancer patients? since you already have breakthrough designation for zetacentenib curious you know what's the chance of receiving a priority review for zetacentenib in ros1 you know tki pretreated non-small cell lung cancer patients

Speaker 2: Yeah, we do believe there's a medical need. We do think that Zetacentenib has a chance to address that medical need. As you mentioned, we do have breakthrough designation, which is often, you know, regulators are going to look at what are the needs and how in the data available to address that need. As far as the type of review, that's out of our hands, right? That's something that the regulators will decide. We will work with them to make sure that we can do whatever is necessary on our end to get the drugs reviewed and approved as fast as possible. As we learn more about how the FDA is viewing our submission and the review timelines, then we'll provide more clarity on that. Yeah, we do believe there's a medical need. yeah we do believe there's a medical need We do think that Zetacentenib has a chance to address that medical need. we do think that zetacentenib has a chance to address that medical need As you mentioned, we do have breakthrough designation, which is often, you know, regulators are going to look at what are the needs and how in the data available to address that need. as you mentioned we do have breakthrough designation which is often you know regulators are going to look at what are the needs and how in the data available to address that need As far as the type of review, that's out of our hands, right? as far as the type of review that's out of our hands right That's something that the regulators will decide. that's something that the regulators will decide We will work with them to make sure that we can do whatever is necessary on our end to get the drugs reviewed and approved as fast as possible. we will work with them to make sure that we can do whatever is necessary on our end to get the drugs reviewed and approved as fast as possible As we learn more about how the FDA is viewing our submission and the review timelines, then we'll provide more clarity on that. as we learn more about how the fda is viewing our submission and the review timelines then we'll provide more clarity on that

Speaker 1: Got it. OK. Talk a little bit more about the data here. Maybe, Jim, can you just maybe help us understand the data you recently presented? You actually saw it in the data presented at WCLC recently, too. Maybe just help us understand some clinical data there. Give us some perspective around what we're seeing in TKI in pretreated cohorts, and what's sort of like the benchmark that people are looking for in this particular population. Got it. got it OK. ok Talk a little bit more about the data here. talk a little bit more about the data here Maybe, Jim, can you just maybe help us understand the data you recently presented? maybe jim can you just maybe help us understand the data you recently presented You actually saw it in the data presented at WCLC recently, too. you actually saw it in the data presented at wclc recently too Maybe just help us understand some clinical data there. maybe just help us understand some clinical data there Give us some perspective around what we're seeing in TKI in pretreated cohorts, and what's sort of like the benchmark that people are looking for in this particular population. give us some perspective around what we're seeing in tki in pretreated cohorts and what's sort of like the benchmark that people are looking for in this particular population

Speaker 2: Yeah. You know, the target product profile that we've been working towards really came from the physicians in the space. They had said, you know, based on what was the standard of care at the time, crizotinib, that drug worked reasonably well, but it had some limitations. The drug was not highly brain penetrant, so patients would progress with CNS disease, or patients would progress with ROS1 resistance mutations. We needed to solve for those two things. Other drugs have tried to solve for one or more of those things, but with each of those other drugs, they bring in other off-targets that they also inhibit in addition to ROS1. Inhibition of those other off-targets has held back the development of those other drugs, because it leads to these off-target toxicities, these dose-limiting toxicities. Yeah. yeah You know, the target product profile that we've been working towards really came from the physicians in the space. you know the target product profile that we've been working towards really came from the physicians in the space They had said, you know, based on what was the standard of care at the time, crizotinib, that drug worked reasonably well, but it had some limitations. they had said you know based on what was the standard of care at the time crizotinib that drug worked reasonably well but it had some limitations The drug was not highly brain penetrant, so patients would progress with CNS disease, or patients would progress with ROS1 resistance mutations. the drug was not highly brain penetrant so patients would progress with cns disease or patients would progress with ros1 resistance mutations We needed to solve for those two things. we needed to solve for those two things Other drugs have tried to solve for one or more of those things, but with each of those other drugs, they bring in other off-targets that they also inhibit in addition to ROS1. other drugs have tried to solve for one or more of those things but with each of those other drugs they bring in other off-targets that they also inhibit in addition to ros1 Inhibition of those other off-targets has held back the development of those other drugs, because it leads to these off-target toxicities, these dose-limiting toxicities. inhibition of those other off-targets has held back the development of those other drugs because it leads to these off-target toxicities these dose-limiting toxicities It's been difficult for physicians to manage the patients on those therapies, and they've largely stuck with crizotinib as the standard of care. The goal for Zetacentenib was to develop a drug that can hit the mutations, can get into the brain, but importantly, was selective for ROS1, so that we did not bring in those off-target dose-limiting toxicities. Zetacentenib is the first and only drug that has that profile. What we showed in our top-line data was, even beyond all the other therapies, our drug was active. It was active beyond those other therapies in patients with ROS1 resistance mutations. It was active in the brain. Even when patients are progressing on CNS-active drugs, like entrectinib or repatrectinib or talotrectinib, our drug is still active in the brain, which really is a high bar that no other drug has shown. It's been difficult for physicians to manage the patients on those therapies, and they've largely stuck with crizotinib as the standard of care. it's been difficult for physicians to manage the patients on those therapies and they've largely stuck with crizotinib as the standard of care The goal for Zetacentenib was to develop a drug that can hit the mutations, can get into the brain, but importantly, was selective for ROS1, so that we did not bring in those off-target dose-limiting toxicities. the goal for zetacentenib was to develop a drug that can hit the mutations can get into the brain but importantly was selective for ros1 so that we did not bring in those off-target dose-limiting toxicities Zetacentenib is the first and only drug that has that profile. zetacentenib is the first and only drug that has that profile What we showed in our top-line data was, even beyond all the other therapies, our drug was active. what we showed in our top-line data was even beyond all the other therapies our drug was active It was active beyond those other therapies in patients with ROS1 resistance mutations. it was active beyond those other therapies in patients with ros1 resistance mutations It was active in the brain. it was active in the brain Even when patients are progressing on CNS-active drugs, like entrectinib or repatrectinib or talotrectinib, our drug is still active in the brain, which really is a high bar that no other drug has shown. even when patients are progressing on cns-active drugs like entrectinib or repatrectinib or talotrectinib our drug is still active in the brain which really is a high bar that no other drug has shown Most importantly, it has that ROS1 selective tract-sparing safety profile that's been lacking from the other drugs in this space. We're quite encouraged by that. What it's resulted in is we're seeing activity that's driving these responses that look to be durable, right? As an example, in patients that have progressed on one prior TKI, what we're seeing is at the year-and-a-half landmark or 18 months, 93% of those patients are still in response. That's quite encouraging, because these patients have already progressed on another line of therapy. It bodes well to, as you push the drug up earlier in the treatment paradigm, their responses might become even more durable than that. I think it's definitely trending in the right direction, and we're excited about the path forward for Zetacentenib. Most importantly, it has that ROS1 selective tract-sparing safety profile that's been lacking from the other drugs in this space. most importantly it has that ros1 selective tract-sparing safety profile that's been lacking from the other drugs in this space We're quite encouraged by that. we're quite encouraged by that What it's resulted in is we're seeing activity that's driving these responses that look to be durable, right? what it's resulted in is we're seeing activity that's driving these responses that look to be durable right As an example, in patients that have progressed on one prior TKI, what we're seeing is at the year-and-a-half landmark or 18 months, 93% of those patients are still in response. as an example in patients that have progressed on one prior tki what we're seeing is at the year-and-a-half landmark or 18 months 93% of those patients are still in response That's quite encouraging, because these patients have already progressed on another line of therapy. that's quite encouraging because these patients have already progressed on another line of therapy It bodes well to, as you push the drug up earlier in the treatment paradigm, their responses might become even more durable than that. it bodes well to as you push the drug up earlier in the treatment paradigm their responses might become even more durable than that I think it's definitely trending in the right direction, and we're excited about the path forward for Zetacentenib. i think it's definitely trending in the right direction and we're excited about the path forward for zetacentenib

Speaker 1: That's really, really interesting and helpful here. One thing that we noticed at WCLC was that we had a conversation with some physicians. Of course, they were impressed with the overall efficacy and durability data, but they were also surprised to see some of the onset of the peripheral edema, which, you know, to them indicates some tract inhibition. They worry about the long-term toxicity associated with tract inhibition here. Jim, can you just help understand, you know, what are your thoughts around the peripheral edema here, and what are some of the long-term safety kind of issues you're thinking about? That's really, really interesting and helpful here. that's really really interesting and helpful here One thing that we noticed at WCLC was that we had a conversation with some physicians. one thing that we noticed at wclc was that we had a conversation with some physicians Of course, they were impressed with the overall efficacy and durability data, but they were also surprised to see some of the onset of the peripheral edema, which, you know, to them indicates some tract inhibition. of course they were impressed with the overall efficacy and durability data but they were also surprised to see some of the onset of the peripheral edema which you know to them indicates some tract inhibition They worry about the long-term toxicity associated with tract inhibition here. they worry about the long-term toxicity associated with tract inhibition here Jim, can you just help understand, you know, what are your thoughts around the peripheral edema here, and what are some of the long-term safety kind of issues you're thinking about? jim can you just help understand you know what are your thoughts around the peripheral edema here and what are some of the long-term safety kind of issues you're thinking about

Speaker 2: You know, thanks, David. Yeah, we actually see the Zetacentenib safety profile as very favorable and differentiated compared to any other ROS1 TKIs out there. I think most physicians agree with us. I think that's why you see the massive enrollment momentum we've had in this study. We used to get asked, like, how are you going to find these patients? We just enrolled 540 patients in really, you know, very limited time. That speaks to the enthusiasm that investigators have for this differentiated profile, as well as the patient advocates, which are very active in this space and have pushed a lot of patients towards our study. The peripheral edema signal, that's something that's due to excessive fluid accumulation in the extremities, and it's not associated with tract inhibition. You know, thanks, David. you know thanks david Yeah, we actually see the Zetacentenib safety profile as very favorable and differentiated compared to any other ROS1 TKIs out there. yeah we actually see the zetacentenib safety profile as very favorable and differentiated compared to any other ros1 tkis out there I think most physicians agree with us. i think most physicians agree with us I think that's why you see the massive enrollment momentum we've had in this study. i think that's why you see the massive enrollment momentum we've had in this study We used to get asked, like, how are you going to find these patients? we used to get asked like how are you going to find these patients We just enrolled 540 patients in really, you know, very limited time. we just enrolled 540 patients in really you know very limited time That speaks to the enthusiasm that investigators have for this differentiated profile, as well as the patient advocates, which are very active in this space and have pushed a lot of patients towards our study. that speaks to the enthusiasm that investigators have for this differentiated profile as well as the patient advocates which are very active in this space and have pushed a lot of patients towards our study The peripheral edema signal, that's something that's due to excessive fluid accumulation in the extremities, and it's not associated with tract inhibition. the peripheral edema signal that's something that's due to excessive fluid accumulation in the extremities and it's not associated with tract inhibition The exact etiology of edema is not fully understood, but I will tell you that many TKIs in oncology drug development have this associated edema signal. These include drugs like lorlatinib, crizotinib, alectinib, brigatinib, lezertinib, repotrectinib, entrectinib, the MET inhibitors, tepotinib, capmatinib. These are pretty common signals for kinase inhibitors. Many of those drugs I just mentioned are perceived to be well tolerated, and they're also not tract inhibitors. This is not a tract-related signal. We are not seeing those safety signals that are commonly associated with the tract inhibitors like repotrectinib, entrectinib, talotrectinib, lorlatinib, et cetera. The exact etiology of edema is not fully understood, but I will tell you that many TKIs in oncology drug development have this associated edema signal. the exact etiology of edema is not fully understood but i will tell you that many tkis in oncology drug development have this associated edema signal These include drugs like lorlatinib, crizotinib, alectinib, brigatinib, lezertinib, repotrectinib, entrectinib, the MET inhibitors, tepotinib, capmatinib. these include drugs like lorlatinib crizotinib alectinib brigatinib lezertinib repotrectinib entrectinib the met inhibitors tepotinib capmatinib These are pretty common signals for kinase inhibitors. these are pretty common signals for kinase inhibitors Many of those drugs I just mentioned are perceived to be well tolerated, and they're also not tract inhibitors. many of those drugs i just mentioned are perceived to be well tolerated and they're also not tract inhibitors This is not a tract-related signal. this is not a tract-related signal We are not seeing those safety signals that are commonly associated with the tract inhibitors like repotrectinib, entrectinib, talotrectinib, lorlatinib, et cetera. we are not seeing those safety signals that are commonly associated with the tract inhibitors like repotrectinib entrectinib talotrectinib lorlatinib et cetera

Speaker 1: Got it. OK, great. Thanks for providing that perspective here, Jim. Moving on to the TKI naive cohorts, we have seen 35 patient data that shows some impressive OR and DOR. Of course, we are eagerly waiting to see the updated pivotal data. Maybe just help us understand, Jim, when should we expect to see the frontline data in TKI naive cohorts, and help us understand what kind of expectations should we be looking for in terms of the OR and DOR? Got it. got it OK, great. ok great Thanks for providing that perspective here, Jim. thanks for providing that perspective here jim Moving on to the TKI naive cohorts, we have seen 35 patient data that shows some impressive OR and DOR. moving on to the tki naive cohorts we have seen 35 patient data that shows some impressive or and dor Of course, we are eagerly waiting to see the updated pivotal data. of course we are eagerly waiting to see the updated pivotal data Maybe just help us understand, Jim, when should we expect to see the frontline data in TKI naive cohorts, and help us understand what kind of expectations should we be looking for in terms of the OR and DOR? maybe just help us understand jim when should we expect to see the frontline data in tki naive cohorts and help us understand what kind of expectations should we be looking for in terms of the or and dor

Speaker 2: Yeah. We had a cohort directed towards registration in TKI naive patients. As of the data cut back in June, we basically announced that we had enrolled 104 patients already in that cohort, more than we actually needed. As I mentioned before, David, the precedent has been to follow naive patients for 12 months, whereas we cut the data for previously treated patients at six months. We need a little bit more follow-up on those patients. We showed how the first 35 were trending, and it clearly was favorable, 89% response rate. The 12-month landmark of duration response was 96%. We're seeing deep responses in the brain, right? That's by design. We had designed a highly brain penetrant drug, and five of the six patients with CNS disease responded. Four of them had an intracranial complete response. That's different than any other drug in this space. Yeah. yeah We had a cohort directed towards registration in TKI naive patients. we had a cohort directed towards registration in tki naive patients As of the data cut back in June, we basically announced that we had enrolled 104 patients already in that cohort, more than we actually needed. as of the data cut back in june we basically announced that we had enrolled 104 patients already in that cohort more than we actually needed As I mentioned before, David, the precedent has been to follow naive patients for 12 months, whereas we cut the data for previously treated patients at six months. as i mentioned before david the precedent has been to follow naive patients for 12 months whereas we cut the data for previously treated patients at six months We need a little bit more follow-up on those patients. we need a little bit more follow-up on those patients We showed how the first 35 were trending, and it clearly was favorable, 89% response rate. we showed how the first 35 were trending and it clearly was favorable 89% response rate The 12-month landmark of duration response was 96%. the 12-month landmark of duration response was 96% We're seeing deep responses in the brain, right? we're seeing deep responses in the brain right That's by design. that's by design We had designed a highly brain penetrant drug, and five of the six patients with CNS disease responded. we had designed a highly brain penetrant drug and five of the six patients with cns disease responded Four of them had an intracranial complete response. four of them had an intracranial complete response That's different than any other drug in this space. that's different than any other drug in this space Those drugs have not demonstrated intracranial complete responses. Importantly, it has that differentiated safety profile. We're going to continue to follow that cohort and work with the regulators to consider a line agnostic extension as that data continues to mature. Those drugs have not demonstrated intracranial complete responses. those drugs have not demonstrated intracranial complete responses Importantly, it has that differentiated safety profile. importantly it has that differentiated safety profile We're going to continue to follow that cohort and work with the regulators to consider a line agnostic extension as that data continues to mature. we're going to continue to follow that cohort and work with the regulators to consider a line agnostic extension as that data continues to mature

Speaker 1: Is there a bar or benchmark we should be looking for here for the OR and DOR side of things? Is there a bar or benchmark we should be looking for here for the OR and DOR side of things? is there a bar or benchmark we should be looking for here for the or and dor side of things

Speaker 2: You know, most of the patients, most of the drugs in the ROS1 space in the frontline are going to have high response rates, right? If you have ROS1-driven disease, it's likely the patient's going to respond if there is a, you know, you're using a ROS1 inhibitor. What's key here is how durable those responses can be, right? I mentioned before, crizotinib was a standard of care. 40% of those patients are progressing with known ROS1 resistance mutations. If you cover those ROS1 mutations, you're going to take away that pathway as a potential disease progression pathway. In addition, if you're highly brain penetrant, you're going to take away that pathway as a potential source of disease progression. Zetacentenib does that. What Zetacentenib also does is it's, you know, well tolerated, so patients can stay on therapy. You know, most of the patients, most of the drugs in the ROS1 space in the frontline are going to have high response rates, right? you know most of the patients most of the drugs in the ros1 space in the frontline are going to have high response rates right If you have ROS1-driven disease, it's likely the patient's going to respond if there is a, you know, you're using a ROS1 inhibitor. if you have ros1-driven disease it's likely the patient's going to respond if there is a you know you're using a ros1 inhibitor What's key here is how durable those responses can be, right? what's key here is how durable those responses can be right I mentioned before, crizotinib was a standard of care. 40% of those patients are progressing with known ROS1 resistance mutations. i mentioned before crizotinib was a standard of care 40% of those patients are progressing with known ros1 resistance mutations If you cover those ROS1 mutations, you're going to take away that pathway as a potential disease progression pathway. if you cover those ros1 mutations you're going to take away that pathway as a potential disease progression pathway In addition, if you're highly brain penetrant, you're going to take away that pathway as a potential source of disease progression. in addition if you're highly brain penetrant you're going to take away that pathway as a potential source of disease progression Zetacentenib does that. zetacentenib does that What Zetacentenib also does is it's, you know, well tolerated, so patients can stay on therapy. what zetacentenib also does is it's you know well tolerated so patients can stay on therapy We only saw in our full data set only 2% of the patients discontinued due to any adverse event. Keep in mind, this is a very advanced patient population, and only 2% of the patients are discontinuing due to any adverse event, whether it's related or not. That is what we think is the recipe for keeping patients on therapy and driving more durable response. What we're going to want to understand is how durable are these responses, and how does that compare to a drug like crizotinib that has those liabilities? I think that's the real variable here. We only saw in our full data set only 2% of the patients discontinued due to any adverse event. we only saw in our full data set only 2% of the patients discontinued due to any adverse event Keep in mind, this is a very advanced patient population, and only 2% of the patients are discontinuing due to any adverse event, whether it's related or not. keep in mind this is a very advanced patient population and only 2% of the patients are discontinuing due to any adverse event whether it's related or not That is what we think is the recipe for keeping patients on therapy and driving more durable response. that is what we think is the recipe for keeping patients on therapy and driving more durable response What we're going to want to understand is how durable are these responses, and how does that compare to a drug like crizotinib that has those liabilities? what we're going to want to understand is how durable are these responses and how does that compare to a drug like crizotinib that has those liabilities I think that's the real variable here. i think that's the real variable here

Speaker 1: Understood. Let's assume that the TKI naive data is going to be positive next year. How soon should we expect, you know, NDA filing, given that you already, you know, did the NDA filing for Zetacentenib in TKI pretreated patients? What should, how should we think about potential approval timeline here? Understood. understood Let's assume that the TKI naive data is going to be positive next year. let's assume that the tki naive data is going to be positive next year How soon should we expect, you know, NDA filing, given that you already, you know, did the NDA filing for Zetacentenib in TKI pretreated patients? how soon should we expect you know nda filing given that you already you know did the nda filing for zetacentenib in tki pretreated patients What should, how should we think about potential approval timeline here? what should how should we think about potential approval timeline here

Speaker 3: I can take that one. We haven't provided the guidance on timing just yet. Jim mentioned the precedent of following patients for 12 months post-response. We'll continue to follow the data from the TKI naive cohort and then engage with the FDA on a potential line agnostic expansion and look to provide updates in the future on timing. I can take that one. i can take that one We haven't provided the guidance on timing just yet. we haven't provided the guidance on timing just yet Jim mentioned the precedent of following patients for 12 months post-response. jim mentioned the precedent of following patients for 12 months post-response We'll continue to follow the data from the TKI naive cohort and then engage with the FDA on a potential line agnostic expansion and look to provide updates in the future on timing. we'll continue to follow the data from the tki naive cohort and then engage with the fda on a potential line agnostic expansion and look to provide updates in the future on timing

Speaker 1: Do we expect the review to be shorter? Because this is going to be a, you know, it's an sNDA instead of, you know, actually a full NDA. Do we expect the review to be shorter? do we expect the review to be shorter Because this is going to be a, you know, it's an sNDA instead of, you know, actually a full NDA. because this is going to be a you know it's an snda instead of you know actually a full nda

Speaker 3: Do you want to take that one? Do you want to take that one? do you want to take that one

Speaker 2: Yeah. It's really something that we haven't commented on at this point, David, of exactly what the submission strategy will be for the naive patients, other than that we're going to do whatever we can to collaborate with the FDA on getting that data reviewed and getting the drug approved for all ROS1 patients, including frontline patients. Once we have the data and we've aligned on that submission strategy, it's probably a more appropriate time to talk about what review timelines might look like. Yeah. yeah It's really something that we haven't commented on at this point, David, of exactly what the submission strategy will be for the naive patients, other than that we're going to do whatever we can to collaborate with the FDA on getting that data reviewed and getting the drug approved for all ROS1 patients, including frontline patients. it's really something that we haven't commented on at this point david of exactly what the submission strategy will be for the naive patients other than that we're going to do whatever we can to collaborate with the fda on getting that data reviewed and getting the drug approved for all ros1 patients including frontline patients Once we have the data and we've aligned on that submission strategy, it's probably a more appropriate time to talk about what review timelines might look like. once we have the data and we've aligned on that submission strategy it's probably a more appropriate time to talk about what review timelines might look like

Speaker 1: Yeah, understood. Your competitor, Nuvation Bio's talatretinib, the launch was pretty impressive, right? Does that strengthen your confidence in Zetacentenib's market potential in ROS1, either naive or pretreated non-small cell lung cancer populations? Yeah, understood. yeah understood Your competitor, Nuvation Bio's talatretinib, the launch was pretty impressive, right? your competitor nuvation bio's talatretinib the launch was pretty impressive right Does that strengthen your confidence in Zetacentenib's market potential in ROS1, either naive or pretreated non-small cell lung cancer populations? does that strengthen your confidence in zetacentenib's market potential in ros1 either naive or pretreated non-small cell lung cancer populations

Speaker 2: Yeah. I mean, we believe there's clearly a need for ROS1 patients. As I mentioned before, crizotinib is a standard of care, and a number of other drugs in the space were designed to address some of the limitations, whether it be CNS disease or the emergence of ROS1 resistance mutations. All of them brought in additional challenges in that they hit off targets, including, you know, the most recently approved drugs. We've seen with the enrollment on our study that clearly these patients exist, and clearly there's enthusiasm for new options that address those needs of ROS1 patients. We remain, you know, enthusiastic about, you know, our path forward with Zetacentenib, and we're looking forward to delivering this for patients. Yeah. yeah I mean, we believe there's clearly a need for ROS1 patients. i mean we believe there's clearly a need for ros1 patients As I mentioned before, crizotinib is a standard of care, and a number of other drugs in the space were designed to address some of the limitations, whether it be CNS disease or the emergence of ROS1 resistance mutations. as i mentioned before crizotinib is a standard of care and a number of other drugs in the space were designed to address some of the limitations whether it be cns disease or the emergence of ros1 resistance mutations All of them brought in additional challenges in that they hit off targets, including, you know, the most recently approved drugs. all of them brought in additional challenges in that they hit off targets including you know the most recently approved drugs We've seen with the enrollment on our study that clearly these patients exist, and clearly there's enthusiasm for new options that address those needs of ROS1 patients. we've seen with the enrollment on our study that clearly these patients exist and clearly there's enthusiasm for new options that address those needs of ros1 patients We remain, you know, enthusiastic about, you know, our path forward with Zetacentenib, and we're looking forward to delivering this for patients. we remain you know enthusiastic about you know our path forward with zetacentenib and we're looking forward to delivering this for patients

Speaker 1: Got it. Great. Let's move on to nanodelcub, the ALK inhibitor in ALK-positive non-small cell lung cancer here. It looks like you will be presenting a poster at ESMO for nanodelcub in pretreated ALK-positive non-small cell lung cancer from the ALKOV1 study. Just curious, is this the pivotal data we should be expecting here? Maybe you can also provide some detail around data expectation for this ESMO update. Got it. got it Great. great Let's move on to nanodelcub, the ALK inhibitor in ALK-positive non-small cell lung cancer here. let's move on to nanodelcub the alk inhibitor in alk-positive non-small cell lung cancer here It looks like you will be presenting a poster at ESMO for nanodelcub in pretreated ALK-positive non-small cell lung cancer from the ALKOV1 study. it looks like you will be presenting a poster at esmo for nanodelcub in pretreated alk-positive non-small cell lung cancer from the alkov1 study Just curious, is this the pivotal data we should be expecting here? just curious is this the pivotal data we should be expecting here Maybe you can also provide some detail around data expectation for this ESMO update. maybe you can also provide some detail around data expectation for this esmo update

Speaker 2: Yeah. There are actually two data readouts we have for our ALK program in the second half here, and maybe we'll walk through each one of them. Alex, do you want to start first on our top line? Yeah. yeah There are actually two data readouts we have for our ALK program in the second half here, and maybe we'll walk through each one of them. there are actually two data readouts we have for our alk program in the second half here and maybe we'll walk through each one of them Alex, do you want to start first on our top line? alex do you want to start first on our top line

Speaker 3: Sure. Yeah. For our top line data, we're on track to deliver that by year-end, and we're planning to take a similar approach as we did for our pivotal data that we reported for Zetacentenib. Our preference has been shared data at a medical meeting, but it can be difficult to time the top line data with the abstract submission deadlines. We're planning to share our top line data as a standalone press release, and then we'll look to share the full data set at a future medical meeting. Sure. sure Yeah. yeah For our top line data, we're on track to deliver that by year-end, and we're planning to take a similar approach as we did for our pivotal data that we reported for Zetacentenib. for our top line data we're on track to deliver that by year-end and we're planning to take a similar approach as we did for our pivotal data that we reported for zetacentenib Our preference has been shared data at a medical meeting, but it can be difficult to time the top line data with the abstract submission deadlines. our preference has been shared data at a medical meeting but it can be difficult to time the top line data with the abstract submission deadlines We're planning to share our top line data as a standalone press release, and then we'll look to share the full data set at a future medical meeting. we're planning to share our top line data as a standalone press release and then we'll look to share the full data set at a future medical meeting

Speaker 2: The other update is we do have a poster that's been accepted for presentation at ESMO. This is around tumors outside of non-small cell lung cancer. ALK is a driver in a number of different tumor types, probably like a dozen or so. The challenge there is to get physicians to sequence those patients for drivers like ALK, right? Then to try TKIs as compared to whatever the standard of care is in that particular indication. We had an exploratory cohort in our phase II to enroll patients with those other tumor types. With a compound like nanodelcub, which broadly covers ALK mutations, which has excellent CNS penetration, and we believe is designed to have a good safety profile, this could be an attractive option for patients in these other tumor types. We are going to share what we've learned so far at ESMO in that exploratory cohort. The other update is we do have a poster that's been accepted for presentation at ESMO. the other update is we do have a poster that's been accepted for presentation at esmo This is around tumors outside of non-small cell lung cancer. this is around tumors outside of non-small cell lung cancer ALK is a driver in a number of different tumor types, probably like a dozen or so. alk is a driver in a number of different tumor types probably like a dozen or so The challenge there is to get physicians to sequence those patients for drivers like ALK, right? the challenge there is to get physicians to sequence those patients for drivers like alk right Then to try TKIs as compared to whatever the standard of care is in that particular indication. then to try tkis as compared to whatever the standard of care is in that particular indication We had an exploratory cohort in our phase II to enroll patients with those other tumor types. we had an exploratory cohort in our phase ii to enroll patients with those other tumor types With a compound like nanodelcub, which broadly covers ALK mutations, which has excellent CNS penetration, and we believe is designed to have a good safety profile, this could be an attractive option for patients in these other tumor types. with a compound like nanodelcub which broadly covers alk mutations which has excellent cns penetration and we believe is designed to have a good safety profile this could be an attractive option for patients in these other tumor types We are going to share what we've learned so far at ESMO in that exploratory cohort. we are going to share what we've learned so far at esmo in that exploratory cohort

Speaker 1: That's interesting. These are ALK-positive solid tumors. Maybe, Jim, can you just level set some of the market opportunity for the ALK-positive solid tumors? What % of the solid tumors will actually have ALK-positive mutations? That's interesting. that's interesting These are ALK-positive solid tumors. these are alk-positive solid tumors Maybe, Jim, can you just level set some of the market opportunity for the ALK-positive solid tumors? maybe jim can you just level set some of the market opportunity for the alk-positive solid tumors What % of the solid tumors will actually have ALK-positive mutations? what % of the solid tumors will actually have alk-positive mutations

Speaker 2: It really ranges, David. It also is limited by the lack of good options for those patients. I think if you go back 20-something years ago, this is how the development in lung cancer started, right? All patients just used to get the standard of care, like chemotherapy. Scientists and drug developers established that there are actual drivers to target, like EGFR. EGFR therapies were developed and shown that they actually work much better than the standard of care. Today, the standard of care is to give a targeted therapy, like an EGFR therapy for patients that have EGFR-driven lung cancer, right? Not chemotherapy or chemoimmunotherapy. That is what we're looking to do across other tumor types. It really ranges, David. it really ranges david It also is limited by the lack of good options for those patients. it also is limited by the lack of good options for those patients I think if you go back 20-something years ago, this is how the development in lung cancer started, right? i think if you go back 20-something years ago this is how the development in lung cancer started right All patients just used to get the standard of care, like chemotherapy. all patients just used to get the standard of care like chemotherapy Scientists and drug developers established that there are actual drivers to target, like EGFR. scientists and drug developers established that there are actual drivers to target like egfr EGFR therapies were developed and shown that they actually work much better than the standard of care. egfr therapies were developed and shown that they actually work much better than the standard of care Today, the standard of care is to give a targeted therapy, like an EGFR therapy for patients that have EGFR-driven lung cancer, right? today the standard of care is to give a targeted therapy like an egfr therapy for patients that have egfr-driven lung cancer right Not chemotherapy or chemoimmunotherapy. not chemotherapy or chemoimmunotherapy That is what we're looking to do across other tumor types. that is what we're looking to do across other tumor types If you can show that you have an oncogene-driven cancer in, let's say, pancreatic cancer or colorectal cancer or something else that typically you give a tumor-directed therapy, then potentially you can start shifting the way physicians think about treating that disease. We are happy to participate in trying to push the field there if we have a drug that could potentially address that, such as nanodelcub or Zetacentenib in the ROS1 space, where the same theory is true. If you can show that you have an oncogene-driven cancer in, let's say, pancreatic cancer or colorectal cancer or something else that typically you give a tumor-directed therapy, then potentially you can start shifting the way physicians think about treating that disease. if you can show that you have an oncogene-driven cancer in let's say pancreatic cancer or colorectal cancer or something else that typically you give a tumor-directed therapy then potentially you can start shifting the way physicians think about treating that disease We are happy to participate in trying to push the field there if we have a drug that could potentially address that, such as nanodelcub or Zetacentenib in the ROS1 space, where the same theory is true. we are happy to participate in trying to push the field there if we have a drug that could potentially address that such as nanodelcub or zetacentenib in the ros1 space where the same theory is true

Speaker 1: Got it. Yeah, that's just really helpful. In terms of the data update, the pivotal top line data update, we should be expecting this in the second half of this year or by year-end. Could you maybe just set some expectations for the potential benchmark we should be looking for in terms of OR and DOR? Got it. got it Yeah, that's just really helpful. yeah that's just really helpful In terms of the data update, the pivotal top line data update, we should be expecting this in the second half of this year or by year-end. in terms of the data update the pivotal top line data update we should be expecting this in the second half of this year or by year-end Could you maybe just set some expectations for the potential benchmark we should be looking for in terms of OR and DOR? could you maybe just set some expectations for the potential benchmark we should be looking for in terms of or and dor

Speaker 2: Right. The standard of care is alectinib. When patients progress on alectinib, they get lorlatinib. When they progress on lorlatinib, nothing works, right? We wanted to design a drug for any line of therapy, right? We'll start in that third line. Nothing works. That was the majority of our phase I patient population. We had enrolled patients that had progressed on all the available therapies, including lorlatinib. Nothing else works there. Our drug was active. It drove durable responses. It was active against mutations, both single and compound, active in the brain, and it had that well-tolerated safety profile. We received breakthrough designation in that population, demonstrating that there's a clear medical need. I imagine the way our phase II is going to be viewed is, how does it translate from phase I to phase II? Right. right The standard of care is alectinib. the standard of care is alectinib When patients progress on alectinib, they get lorlatinib. when patients progress on alectinib they get lorlatinib When they progress on lorlatinib, nothing works, right? when they progress on lorlatinib nothing works right We wanted to design a drug for any line of therapy, right? we wanted to design a drug for any line of therapy right We'll start in that third line. we'll start in that third line Nothing works. nothing works That was the majority of our phase I patient population. that was the majority of our phase i patient population We had enrolled patients that had progressed on all the available therapies, including lorlatinib. we had enrolled patients that had progressed on all the available therapies including lorlatinib Nothing else works there. nothing else works there Our drug was active. our drug was active It drove durable responses. it drove durable responses It was active against mutations, both single and compound, active in the brain, and it had that well-tolerated safety profile. it was active against mutations both single and compound active in the brain and it had that well-tolerated safety profile We received breakthrough designation in that population, demonstrating that there's a clear medical need. we received breakthrough designation in that population demonstrating that there's a clear medical need I imagine the way our phase II is going to be viewed is, how does it translate from phase I to phase II? i imagine the way our phase ii is going to be viewed is how does it translate from phase i to phase ii There are no other relevant data benchmarks to point to, because, as I said, nothing else works in this patient population. In the second line, we also have a cohort directed for this patient population. This is where lorlatinib is the standard of care. Lorlatinib can drive responses in this patient population because it has some coverage of ALK mutations, and it has good CNS penetration, right? However, we believe lorlatinib is limited in this patient population in that it hits off-target tract very close to where it hits these ALK mutations, right? It's difficult to hit these ALK mutations hard. We see patients come on our phase I that have progressed on lorlatinib due to inefficient coverage of ALK single mutations, or they actually develop a second mutation called compound mutation, and lorlatinib is not active against those either. There are no other relevant data benchmarks to point to, because, as I said, nothing else works in this patient population. there are no other relevant data benchmarks to point to because as i said nothing else works in this patient population In the second line, we also have a cohort directed for this patient population. in the second line we also have a cohort directed for this patient population This is where lorlatinib is the standard of care. this is where lorlatinib is the standard of care Lorlatinib can drive responses in this patient population because it has some coverage of ALK mutations, and it has good CNS penetration, right? lorlatinib can drive responses in this patient population because it has some coverage of alk mutations and it has good cns penetration right However, we believe lorlatinib is limited in this patient population in that it hits off-target tract very close to where it hits these ALK mutations, right? however we believe lorlatinib is limited in this patient population in that it hits off-target tract very close to where it hits these alk mutations right It's difficult to hit these ALK mutations hard. it's difficult to hit these alk mutations hard We see patients come on our phase I that have progressed on lorlatinib due to inefficient coverage of ALK single mutations, or they actually develop a second mutation called compound mutation, and lorlatinib is not active against those either. we see patients come on our phase i that have progressed on lorlatinib due to inefficient coverage of alk single mutations or they actually develop a second mutation called compound mutation and lorlatinib is not active against those either Our drug was designed to, it was optimized to cover these mutations broadly. We think there's an opportunity to clearly differentiate from lorlatinib on durability in the second-line patient population. The response rates are in that 30%-39% range, but the durability is only seven months in this setting. In our phase I, we saw more than double that in a patient population that had already progressed on lorlatinib, right? That's meaningfully different than what lorlatinib can do. If we see anything in that same ballpark, we think there's an opportunity to use that second-line data in conjunction with our third-line data to have discussions with regulators around a broader previously treated ALK indication. In addition to that, we have a front-line study compared to alectinib, randomized phase III ongoing. That's our approach to front-line ALK non-small cell lung cancer development. Hopefully, that makes sense. Our drug was designed to, it was optimized to cover these mutations broadly. our drug was designed to it was optimized to cover these mutations broadly We think there's an opportunity to clearly differentiate from lorlatinib on durability in the second-line patient population. we think there's an opportunity to clearly differentiate from lorlatinib on durability in the second-line patient population The response rates are in that 30%- 39% range, but the durability is only seven months in this setting. the response rates are in that 30%- 39% range but the durability is only seven months in this setting In our phase I, we saw more than double that in a patient population that had already progressed on lorlatinib, right? in our phase i we saw more than double that in a patient population that had already progressed on lorlatinib right That's meaningfully different than what lorlatinib can do. that's meaningfully different than what lorlatinib can do If we see anything in that same ballpark, we think there's an opportunity to use that second-line data in conjunction with our third-line data to have discussions with regulators around a broader previously treated ALK indication. if we see anything in that same ballpark we think there's an opportunity to use that second-line data in conjunction with our third-line data to have discussions with regulators around a broader previously treated alk indication In addition to that, we have a front-line study compared to alectinib, randomized phase III ongoing. in addition to that we have a front-line study compared to alectinib randomized phase iii ongoing That's our approach to front-line ALK non-small cell lung cancer development. that's our approach to front-line alk non-small cell lung cancer development Hopefully, that makes sense. hopefully that makes sense

Speaker 1: Yeah, that makes a lot of sense, Jim. We have about three minutes left. I just want to spend the next couple of minutes talking about your HER2-altered non-small cell lung cancer program. Maybe just give a quick update on the NVL-330 trial for HER2-altered non-small cell lung cancer and any kind of timeline toward data expectation here. Yeah, that makes a lot of sense, Jim. yeah that makes a lot of sense jim We have about three minutes left. we have about three minutes left I just want to spend the next couple of minutes talking about your HER2-altered non-small cell lung cancer program. i just want to spend the next couple of minutes talking about your her2-altered non-small cell lung cancer program Maybe just give a quick update on the NVL-330 trial for HER2-altered non-small cell lung cancer and any kind of timeline toward data expectation here. maybe just give a quick update on the nvl-330 trial for her2-altered non-small cell lung cancer and any kind of timeline toward data expectation here

Speaker 2: Yeah, that's a tricky name. Heroics. Heroics is how we pronounce it. Although, I don't know if that's proper English, but that's how we pronounce it. Yeah. Let me tell you about our NVL-330 HER2 program. HER2 is obviously a well-known cancer target, a couple decades' worth of drug development in the space, small molecules, antibodies, ADCs, you name it. There's been lots of drug development across tumor types for patients with HER2-driven cancers. HER2 lung cancer is a little bit different in that the main driver is something called exon 20 insertions, HER2 exon 20 insertions. They are not the driver in those other tumor types, right? Some of those other HER2 drugs were repurposed for HER2 lung cancer, and the outcomes were not very favorable, right? Poor response rates, poor durability. Yeah, that's a tricky name. yeah that's a tricky name Heroics. heroics Heroics is how we pronounce it. heroics is how we pronounce it Although, I don't know if that's proper English, but that's how we pronounce it. although i don't know if that's proper english but that's how we pronounce it Yeah. yeah Let me tell you about our NVL-330 HER2 program. let me tell you about our nvl-330 her2 program HER2 is obviously a well-known cancer target, a couple decades' worth of drug development in the space, small molecules, antibodies, ADCs, you name it. her2 is obviously a well-known cancer target a couple decades' worth of drug development in the space small molecules antibodies adcs you name it There's been lots of drug development across tumor types for patients with HER2-driven cancers. there's been lots of drug development across tumor types for patients with her2-driven cancers HER2 lung cancer is a little bit different in that the main driver is something called exon 20 insertions, HER2 exon 20 insertions. her2 lung cancer is a little bit different in that the main driver is something called exon 20 insertions her2 exon 20 insertions They are not the driver in those other tumor types, right? they are not the driver in those other tumor types right Some of those other HER2 drugs were repurposed for HER2 lung cancer, and the outcomes were not very favorable, right? some of those other her2 drugs were repurposed for her2 lung cancer and the outcomes were not very favorable right Poor response rates, poor durability. poor response rates poor durability There's a reason for that, a scientific reason, in that those drugs do not have a wide index for inhibiting HER2 exon 20 compared to wild-type EGFR. It's well known that wild-type EGFR inhibition causes skin toxicities, GI toxicities. It's difficult to keep the patients on therapy. You get a lot of interruptions, poor response rates, poor durability. That's a chemistry problem, one that we wanted to tackle, and we did with NVL-330. In addition, because this is lung cancer, patients will get brain mets. It's very important to have a compound that has excellent brain penetration. NVL-330 does have that. We think that positions it quite uniquely in this setting as a TKI that can broadly cover HER2 exon 20 with that wide index versus wild type and have that good brain penetration. That's a pretty attractive profile for HER2 lung cancer patients. There's a reason for that, a scientific reason, in that those drugs do not have a wide index for inhibiting HER2 exon 20 compared to wild-type EGFR. there's a reason for that a scientific reason in that those drugs do not have a wide index for inhibiting her2 exon 20 compared to wild-type egfr It's well known that wild-type EGFR inhibition causes skin toxicities, GI toxicities. it's well known that wild-type egfr inhibition causes skin toxicities gi toxicities It's difficult to keep the patients on therapy. it's difficult to keep the patients on therapy You get a lot of interruptions, poor response rates, poor durability. you get a lot of interruptions poor response rates poor durability That's a chemistry problem, one that we wanted to tackle, and we did with NVL-330. that's a chemistry problem one that we wanted to tackle and we did with nvl-330 In addition, because this is lung cancer, patients will get brain mets. in addition because this is lung cancer patients will get brain mets It's very important to have a compound that has excellent brain penetration. it's very important to have a compound that has excellent brain penetration NVL-330 does have that. nvl-330 does have that We think that positions it quite uniquely in this setting as a TKI that can broadly cover HER2 exon 20 with that wide index versus wild type and have that good brain penetration. we think that positions it quite uniquely in this setting as a tki that can broadly cover her2 exon 20 with that wide index versus wild type and have that good brain penetration That's a pretty attractive profile for HER2 lung cancer patients. that's a pretty attractive profile for her2 lung cancer patients That's where our phase I focus is. The compound is broadly active against HER2 cancers, HER2 immunes. You can imagine all the other places where HER2 drug development has happened, including where HER2 ADCs have been developed. You know, having a HER2 brain penetrant TKI is a very attractive option to consider in the treatment arsenal for those other cancers as well. That's a future development opportunity we can consider with this program as well. That's where our phase I focus is. that's where our phase i focus is The compound is broadly active against HER2 cancers, HER2 immunes. the compound is broadly active against her2 cancers her2 immunes You can imagine all the other places where HER2 drug development has happened, including where HER2 ADCs have been developed. you can imagine all the other places where her2 drug development has happened including where her2 adcs have been developed You know, having a HER2 brain penetrant TKI is a very attractive option to consider in the treatment arsenal for those other cancers as well. you know having a her2 brain penetrant tki is a very attractive option to consider in the treatment arsenal for those other cancers as well That's a future development opportunity we can consider with this program as well. that's a future development opportunity we can consider with this program as well

Speaker 1: Got it. This is really, really helpful discussion here, Jim. I don't have any more questions. I think we're almost on the top of our hour here. Maybe just one quick sentence to highlight some of the key catalysts we should be watching for over the next 6-12 months. Got it. got it This is really, really helpful discussion here, Jim. this is really really helpful discussion here jim I don't have any more questions. i don't have any more questions I think we're almost on the top of our hour here. i think we're almost on the top of our hour here Maybe just one quick sentence to highlight some of the key catalysts we should be watching for over the next 6- 12 months. maybe just one quick sentence to highlight some of the key catalysts we should be watching for over the next 6- 12 months

Speaker 2: Want to take that, Alex? Want to take that, Alex? want to take that alex

Speaker 3: Sure. Yeah. We're looking forward to sharing the pivotal data from the ALKOV1 study by year-end, and then continuing to follow progress for our HER2 program as well. We haven't shared timing just yet, but we'll look forward to providing updates in the future as we watch the data there. We talked about the solid tumor data for the ALK program as well that we'll have at ESMO coming up. Sure. sure Yeah. yeah We're looking forward to sharing the pivotal data from the ALKOV1 study by year-end, and then continuing to follow progress for our HER2 program as well. we're looking forward to sharing the pivotal data from the alkov1 study by year-end and then continuing to follow progress for our her2 program as well We haven't shared timing just yet, but we'll look forward to providing updates in the future as we watch the data there. we haven't shared timing just yet but we'll look forward to providing updates in the future as we watch the data there We talked about the solid tumor data for the ALK program as well that we'll have at ESMO coming up. we talked about the solid tumor data for the alk program as well that we'll have at esmo coming up

Speaker 1: Excellent. Great. Thank you so much for taking this time to speak with us. You know, we're definitely looking forward to more exciting news over the next 6-12 months from Nuvalent. Thank you again for attending the virtual oncology day. Excellent. excellent Great. great Thank you so much for taking this time to speak with us. thank you so much for taking this time to speak with us You know, we're definitely looking forward to more exciting news over the next 6- 12 months from Nuvalent. you know we're definitely looking forward to more exciting news over the next 6- 12 months from nuvalent Thank you again for attending the virtual oncology day. thank you again for attending the virtual oncology day

Speaker 2: Thanks for inviting us, David. Really appreciate it. Thanks for inviting us, David. thanks for inviting us david Really appreciate it. really appreciate it

Speaker 3: Thank you. Thank you. thank you