Okay, great. Thanks, everyone, for continuing to join us at the Stifel Healthcare Conference. My name is Brad Canino, Senior Biotech Analyst here. Really happy to be closing out the show with Nuvalent. We've got Jim Porter here, CEO. Alex Balcom, CFO. Thanks so much for joining us.
Thanks, Brad. Thanks to the Stifel team for the opportunity to participate in the conference, and excited to see that we're closing out the show. That's cool.
It's because we have faith that you can close it out strongly.
Oh, there we go. We'll live up to the expectation.
So we're two months out now from what was, I would say, the biggest medical conference for Nuvalent at the ESMO Conference. What were the highlights for your portfolio, and how does that position the company into next year, where you've indicated first registrational data are expected?
Yeah, I agree, Brad. It was a really exciting, important conference for Nuvalent and the team. I think there were three objectives we were looking to accomplish. I think each one of them were accomplished. One, the first and foremost, is showing the progress we've made on each of our pivotal studies: the ALKOVE-1 study and the ARROS-1 study. Enrollment has gone incredibly well, and it's gone well for a reason. We had formed relationships with investigators years ago when we started the company, understanding from their perspective what to solve for. And if we could deliver that, they would be excited to run the experiment and to enroll those clinical studies. And enrollment has been significant on both.
We enrolled 230 patients in the ROS-1 study over a year, and we enrolled 230 patients in the ALK study over six months, and that's in the first six months of the study, so it's gone quite well, and it sets us up to have pivotal data readouts in 2025 for both programs. The second objective was describing the ALKAZAR study. ALKAZAR is a randomized study in frontline TKI-naive ALK non-small cell lung cancer, comparing 655 to the standard of care alectinib. We have been working with global investigators and regulators on that study design over the past year, and we are excited to roll that out, and that's going to start in the first half of this year, 2025 coming up, and the third objective was sharing the updated phase I data we had for both our ALK and ROS-1 programs, where we had already shared the punchline.
The drugs are active where all the other therapies do not work. They're active against ALK or ROS1 resistance mutation, active in the brain. They're well tolerated, but we hadn't really shown the extended follow-up. So getting a chance to look at durability was really the first opportunity. And we shared that drugs were showing durable responses, even in these late-line patients and patients that have exhausted available options. And it speaks to why ALK and ROS1 are excellent drivers and very interesting targets for precision oncology drug development.
Okay. Can you spend a minute to break down the phase II registrational strategies you have for both ROS1 and ALK?
Yep. So we'll start in ALK. ALK, their standard of care is alectinib. Patients progress on alectinib, they get lorlatinib. When they progress on lorlatinib, nothing works. We have breakthrough in that third-line setting where nothing else works. We have data that shows the drug is active, it's driving durable responses, it's well tolerated. We have a registrational cohort specifically for that third-line patient population. It's pretty straightforward, and second-line, lorlatinib's the standard of care. We believe that's a limited drug in that patient population. We believe our drug can hit ALK mutations harder, drive deeper and more durable responses than lorlatinib because it was designed to do so. It was designed to hit the ALK mutations with a wide index versus TRK, which is the dose-limiting tox for lorlatinib. It leads to inefficient target coverage of lorlatinib.
We're seeing in our phase I data, patients progress on lorlatinib with either single mutations or compound mutations, and they respond to 655. We also have TKI, I'm sorry, lorlatinib-naive patients in our phase I that are doing quite well on 655 as well. We designed a phase II registration cohort for second-line lorlatinib-naive patients, and that's enrolling well. We're going to use that collated data, the second-line and third-line data, to have an informed discussion with regulators around a broader previously treated ALK indication. The benchmark in third line, there is none. The benchmark in second line, it's lorlatinib, it's 31%-39% response rate with a seven-month duration response. That's the ALK strategy. We have a frontline strategy in ALK, but I'm sure we're going to get to that.
But on the ARROS-1 study, the ROS1 study, the strategy is both TKI-naive and previously treated ROS1 registration cohorts. We have a frontline, a second line, and a third line. Third line, we already have breakthrough therapy designation, nothing works there. Second line, there's no real clear benchmark either. It's pretty straightforward. Frontline is where there's three approved therapies. Those approved therapies each have limitations. crizotinib, the standard of care, not very active in the brain, and patients can also progress with ROS1 resistance mutations. Other drugs that have been designed and approved there are actually repurposed TRK inhibitors. They have a broad spectrum of nervous system toxicities that physicians have been reluctant to displace crizotinib with these drugs. Our drug, zidesamtinib, solves for all these issues. It was specifically designed for ROS1 patients. We expect to drive deep and durable responses across any line of therapy.
The TKI-naive cohort is designed to support registration, and the previously treated cohorts are designed to support registration.
Yeah, so on that for ROS1, are you going to wait for maturity for the frontline interim durability to file a dual label of TKI-naive and pretreated?
Not necessarily. We're going to do whatever we can to get the drugs approved as fast as possible. We think our drug works really well in previously treated patients. In addition, we hope it works well in frontline patients. But whatever data is available first is what we're going to use to guide our discussions with regulators. We will not wait for one data set to catch up.
Okay. And do you think the regulatory path could change for TKI-naïve, a.k.a. frontline ROS1? We've had the approval of repotrectinib. There's another compound from Nuvation Bio progressing towards registration.
Yeah. None of the other drugs in this space, as far as we can tell, are designed for ROS1 patients where they selectively target ROS1 and ROS1 mutations. They're active in the brain, and they avoid specific off-targets that drive these dose-limiting toxicities. That includes the dual TRK ROS1 drugs like repotrectinib and entrectinib. It also includes development stage compounds like talotrectinib, which has been designed for both TRK and ROS1 patients, but also brings in other toxicities beyond those as well. So I think with everything we've learned thus far on our ROS1 program, we think we're on the right track, that we have a differentiated profile, and we're just now executing on the experiment and hope to use that data to guide regulatory discussions.
Okay. And now what is the Nuvalent view of the market opportunity for ROS1? And do you think that is a shared view?
I think the shared view is getting more alignment, particularly around our ESMO update. Our view has been consistent for the last several years, and that is there's clearly an opportunity for a drug that's designed for ROS1 patients. None of the other drugs have. Like even crizotinib, the standard of care, it's a repurposed MET inhibitor for ROS1 patients with limited brain penetrance. crizotinib used to be the standard of care in ALK non-small cell lung cancer, and four other drugs have showed they're significantly better than crizotinib. For example, lorlatinib in ALK, as it has a ratio of 0.19 compared to crizotinib in ALK non-small cell lung cancer. The reason it's better is the same reason crizotinib's a limited drug in ROS1. crizotinib in ROS1, patients progress with ROS1 mutations or CNS disease.
And if you can solve for those things, what if you can generate data that's comparable to a hazard ratio of 0.19? You can take what is a year and a half duration response and make it significantly longer than that. So crizotinib today is about $400 million in sales as a limited drug. If you can drive much more durable responses for patients there, not only is it a game changer for those patients, it also represents a pretty interesting commercial opportunity where it becomes less of an incidence story and more of a prevalence story where you're treating these patients with a drug that's designed to be well tolerated and drive deep durable responses. So that's how we view the commercial opportunity. I don't want to put a number on it, but I think starting at $400 million a year, it could potentially be significantly better than that.
Okay. Now for ALK, you touched on this a little bit, but outline why you believe you do have a viable regulatory path to get a second-line label on single-arm data rather than through a randomized study versus the current approved drug, lorlatinib?
Yeah. The benchmark for a second-line is 31%-39% response rate and seven-month duration response. We completely agree that if we come in at roughly those numbers, there's no opportunity for a second-line label. We do not anticipate our drug to perform like lorlatinib. We're seeing even in our phase I, even beyond lorlatinib, deep durable responses. And we would expect when we treat lorlatinib-naive patients that our drug can do much better because it can prevent or delay the emergence of on-target acquired ALK resistance and drive more durable responses. If we could generate that, then I think that the strategy is to take that data in conjunction with the third-line data where nothing works and talk about a previously treated broader label as opposed to a only take this drug beyond this sequence of therapies because we're showing it works everywhere, right?
What also would help our case is that we would have a randomized study ongoing, which is the ALKAZAR study in frontline patients. So we could ask sometimes, well, why not just also do the second-line randomized study because we're doing the frontline randomized study and we're doing the ALKOVE-1 in the previously treated patients. That's our strategy. We're going to keep executing on it, and hopefully the data will guide the outcome here.
Yeah. Now you've outlined the benchmark for lorlatinib, but is there a clear understanding or bar of what would be a real therapeutic improvement over lorlatinib that would be so obvious it wouldn't require randomization? And also, is this a conversation that's just about efficacy with the FDA?
I think efficacy is the critical part of the conversation, for sure. We do hope to have a better tolerated drug than lorlatinib, but the tolerability is what enables you to actually hit those mutations. The drug was designed to have a wider index for hitting ALK mutations versus TRK when lorlatinib was in drug development. And we learned this from the physicians who did the lorlatinib drug development program, our collaborators. They recognized they tried to go higher in dose to cover the ALK mutations and unfortunately hit up against that TRK CNS toxicity and had to back the dose down. So we could learn from that. Drug development is a big part of it is learning from the precedent literature from the folks that have done great work before you.
We optimize that from the beginning where we can really hammer those ALK mutations and drive deeper and more durable responses. I don't want to put a number on what is significant as far as different, but the data we're seeing in phase I look pretty good as far as durability.
Okay. And now as you think about lorlatinib and its sales, what is the commercial opportunity for a better ALK inhibitor in the second-line setting alone?
Yeah. So lorlatinib did about $500 million in sales, I think, last year. And we think a majority of that was coming from previously treated ALK patients, and we think that's a limited drug in that patient population. So none of the approved ALK therapies are really that great for previously treated ALK patients. We optimized our drug for previously treated ALK patients. So we designed a drug to keep those patients on therapy, to drive durable responses by taking out the ALK resistance pathways. It's honestly, it's really interesting that the tumors for both ROS1 and ALK non-small cell lung cancer are highly dependent on the original driver. You don't often see that in oncology. Many times the original oncogene, it switches to a new mechanism early in treatment, right? So I know you know this well as well as anyone, like a KRAS, right?
So after a certain amount of therapy duration on a KRAS inhibitor, you're going to get some sort of bypass that happens. It happens less frequently or less early than an ALK and ROS1 for whatever. The original tumor is really dependent on that fusion protein that's driving the cancer, and you get on-target acquired resistance. So if you can broadly cover those resistance mutations, it makes it an attractive opportunity to drive very durable responses.
Okay. Now, like you said, you also announced the frontline ALK trial at ESMO. Can you sketch the design for us and then also update us on the progress towards getting that first patient enrolled in the trial?
Yeah. Do you want to start with the timing?
Sure. Yeah, so we're making progress there, and I would say we're on track to initiate the study in the first half of next year.
We've been working with physicians since we started the company on what the right trial would be here. We've always known that alectinib was that right standard of care to go against. What we needed was we needed a dose and sort of data to put in front of physicians to say, this is the right study to do. Over the course of this year, we arrived at both of those things, and we started talking to the global investigators and regulators to get this study up and running. It's called the ALKAZAR study. It's one-to-one randomization, 655 versus alectinib, progression-free survival as the primary endpoint. That's blinded independent central review. Pretty standard secondary objectives, 450 patients. It's not a completely novel approach. It's pretty cookie cutter. There are four other randomized frontline trials that have been done in ALK non-small cell lung cancer.
This is the same type of study. Just here's the standard of care. Show your drug is better. So we think this is a pretty interesting approach in that we can learn from the precedent studies in this space, right? There's no reason to take this giant leap of faith. There's actually data from the other drugs that helps convince us that a drug like lorlatinib could beat alectinib in a randomized study. And we think our drug is at least as active as lorlatinib in the frontline setting. So you don't often have that kind of conviction when you're running a large randomized phase III study. Here we have 15 years' worth of clinical research to lean on to guide our approach. We just think we happen to have the best molecule, so that helps us put the strategy in place.
One of the positive surprises coming out of the ESMO meeting was your enrollment rate, which you mentioned some of those numbers at the top for the phase II. How are you planning on carrying forward that momentum as you look towards the frontline trial?
Yeah. So I think the enrollment momentum is a function of a couple of things. It's starting from the beginning of the company, going to the investigators, and learning from them. They are at the front line. What do they want? They develop the other drugs. They're the ones they have just as much ownership in those drugs as the future drugs, right? They helped develop them. But if you ask them critically, what would you want to see better for your patients? What would you want to improve upon? And then hold Nuvalent team accountable to only put drugs forward that deliver that profile. And 655 and zidesamtinib, they deliver that profile that they set for us. In addition, at the same time, we were doing the same thing with patient advocacy groups. There are very informed, motivated groups in the ALK space. They're called ALK Positive.
In the ROS1 space, they're called the ROS1 ders. These folks are globally connected. If you have an ALK or ROS1 driven disease, there's a good chance you're a part of this group. They talk all the time. They all know who Nuvalent is because our goals are directly aligned with their goals. So our trials enroll like crazy. And I like to say it's because we're really good at our jobs, but I actually give the physicians and the patients the credit here. They find the studies, they're interested in the studies, they're enrolling the studies. Our team's very good at executing it, but they enroll really well. And I expect the same to be true in phase III, where we're going to globally use many of the same sites, many of the same physicians, and more to enroll these 450 patients.
Yeah. Now, lorlatinib is gaining some momentum as the frontline choice for certain institutions, certain patients. I do get questions how I think about the potential feasibility of enrollment of that study if you're only using alectinib in the control arm. So as we talk about enrollment momentum based on single-arm trials, do you see any friction as you move towards that control arm choice in the frontline setting?
No. We don't. We've talked to the physicians, and we know some of the physicians that prefer lorlatinib, but those same physicians helped guide us to design this study, that this is the right study to do. Because alectinib is a good drug. It drives years of progression-free survival. We're not giving patients placebo here. We're giving them a very good drug that is today's global standard of care, right? So there's not going to be a challenge or a reluctance to potentially get randomized to what is today's standard of care. Alternatively, you have the upside of getting potentially the best-in-class therapy. So I think it's going to enroll very well. And yes, we appreciate that a few physicians are excited about the five-year update from lorlatinib, but they already knew lorlatinib was the most active drug. It still wasn't getting the predominant frontline uptake because of the safety.
So if you would want that profile where you can drive those deep durable responses without those safety challenges, that's what we hope we have at 655.
Okay. Now, you mentioned there's a rich history of frontline ALK studies to learn from. All of those studies use crizotinib in the control arm, though. You're using alectinib, which is a much more durable drug for patients. So as we think about a timeline proxy relative to those studies, how close do you think you can be?
Yep. So all those studies were about three years from start of enrollment to the line extension approval. They were all about 300 patients. Ours is about 450, and it's a different standard of care, so it will be slightly longer than the three years. What drives the primary endpoint is a number of things. One is enrollment rate. Two is event rate. And three is the statistical assumptions that are going to the study. I don't think enrollment rate is the gating factor. Now, obviously, if enrollment took forever, it would be gating, but I think it's the event rate that will guide this. We often get asked about statistical assumptions. We don't necessarily go through them. We get asked about, is there an interim analysis? We don't comment on that other than to say other trials have used interim analysis here. We try to learn from them.
It is a pushback we get here and there. It's like, oh, this will take a while. Yes and no. Yes, it's going to be a little bit longer than three years, but it's not going to be forever, and thinking about what we're trying to do here, we're trying to change the game for ALK non-small cell lung cancer patients where they're often diagnosed when they're 40s, 50s. They're in the prime of their life. They're relatively healthy. They're informed. They want to live much longer. They have good outcomes with alectinib because a couple of years of progression-free survival, which is amazing, and amazing what alectinib's done for this patient population. But a couple of years when you're in your 40s or 50s is clearly not good enough, right? And 655 has the potential to give extra years there, and that's a game changer for one.
That's one that our team is so excited to be part of this to see if we can accomplish that. And if we do accomplish it, it represents an extremely attractive commercial opportunity, which is also good for the business. So this is the right experiment to do. We're excited. We made the molecule to do it, and we're going to go do it.
Okay. Now, you've made the argument of why NVL-655 should be clearly superior to lorlatinib in second line to the point that you won't even need to randomize it to demonstrate that. In the frontline setting, do you think you need to go beyond the historical benefit that's been observed with lorlatinib to be a meaningful result in a trial that's versus alectinib?
I think what you're asking would be to beat alectinib or to compare to lorlatinib? Is that what you're saying?
Either/or.
So I would say that the available lorlatinib literature data suggests to us, and I think many others, that lorlatinib would beat alectinib in a randomized study, right? Because it's good enough at covering ALK mutations before they occur. Once those ALK mutations occur, it's not as good at treating them, but it's good at preventing them from emerging. And that's why it outperforms alectinib because half the patients that progress on alectinib progress with ALK mutations. Now, that trial has never been run. I'm willing to bet it never gets run. We think our drug is just as active, if not more active than lorlatinib. And we are going to run the study because we think it's going to clearly outperform alectinib. That's how we view it. How it compares to lorlatinib? Well, we think we've already shown lots of data of how our drug compares to lorlatinib.
Our drug is the only drug active beyond lorlatinib. And in second line, it's got very interesting response rates and durability. It's active in the patients that are progressing on lorlatinib with single mutations or compound mutations. And importantly, and maybe most importantly, because the reason physicians aren't as excited about lorlatinib is the neurotoxicity signals. And our drug is not showing that. So I don't think it's going to necessarily need how many years out on 655 do you have the data to make that switch for everyone to the frontline setting? Does that answer what you're getting at?
Perfect. Now, does the balance sheet allow Nuvalent to start to think about an ALK adjuvant study now?
So we're in a strong position with the recent raise extending our runway into 2028. And so I would say our near-term focus is on executing on the phase II studies, initiating the frontline ALKAZAR study, as well as continuing to advance our HER2 program and our discovery pipeline. And so I think, as you know, most patients, or the majority of patients with ALK, get diagnosed in the advanced metastatic setting. But the goal is to have a drug for all ALK patients. And so expanding the patient population is certainly of interest to us, but I would say near-term priorities and resources on the frontline ALK study.
Okay, and how are you thinking about business development strategy for this portfolio? Sooner rather than later it's going to be November next year, where we'll be sitting on the stage, hopefully with pivotal data closely in hand?
Yeah. So generally, I think lots of synergies across our pipeline with three programs in non-small cell lung cancer. And we have the capital and the team to continue to execute on the program, so we're in a strong position. Longer term, we think about how a partner could potentially help on the commercial side specifically as we think about XUS.
Okay. Maybe last question for me. So we can round out the portfolio. The HER2 asset, status of the trial there, and what do you hope to show about the profile of this drug in your first disclosure? Maybe compare it to how the ROS1 and ALK stories first unfolded with their initial disclosures.
Yeah. Let me touch on the strategy, and then Alex can talk about the timing here. The strategy, HER2, obviously a known target, two decades' worth of research, lots of drugs targeting HER2-driven cancers. In HER2 lung cancer, it's a little bit different. The major driver is something called exon 20 insertions. The other HER2 drugs were repurposed for this with dismal outcomes, poor response rates, poor durability because they lack a wide index for hitting exon 20 compared to wild-type EGFR. That's a chemistry problem, one that interested us, one the physicians pointed to, one that we solved with 330. In addition, because it's lung cancer, you need excellent brain penetration because patients with lung cancer will get brain mets. 330 also solves for that. So our HEROIC-1 study started in July. We're enrolling patients with HER2 lung cancer.
I think we're going to allow the data to accumulate before we give any guidance to what the benchmarks should be. But things like activity in the brain, activity in patients that have HER2-driven lung cancer, the safety profile, all those things will be important. Want to talk about the timing?
Yeah. We haven't shared specific timing just yet, but we'll take a similar approach as we did with our other programs. Want to ensure we have meaningful data and we can tell a clear story, and so we'll look to provide updates in the future.
Okay. Perfect. Well, thank you, Alex. Thank you, Jim. Always great to.