Nuvalent, Inc. (NUVL) Earnings Call Transcript & Summary

Good morning, and welcome to Nuvalent's conference call. [Operator Instructions] Please be advised that this call is being recorded at the company's request. I would now like to turn the call over to Chelcie Lister, Senior Director of IR at Nuvalent. You may begin.

Thank you all for joining us today. Earlier this morning, we issued a press release announcing top line pivotal data from our ongoing ALKOVE-1 trial of neladalkib for patients with ALK-positive non-small cell lung cancer. The press release and the slides that we'll be using during today's call are available on the Investors section of our website at nuvalent.com. On the call with me today is our CEO, Jim Porter; our Chief Financial Officer, Alex Balcom; Chief Medical Officer, Dr. Christopher Turner; and Chief Development Officer, Darlene Noci, will join for the Q&A session. During this call, we will make forward-looking statements related to our current expectations and plans, which are subject to risks and uncertainties. We will also make certain forward-looking statements about the potential attributes and benefits of our product candidates and the format and timing of our development activities and clinical trials. Actual results may differ materially due to various important factors, including those described in the Risk Factors section of our public filings, including our Form 10-Q filed in October. These statements represent our views as of this call only and should not be relied upon as representing our views as of any date in the future. We undertake no obligation to publicly update any forward-looking statements. Let me now turn the call over to Jim.

Thanks, Chelcie, and thank you all for joining us today. It's my privilege to represent the Nuvalent team today as we present top line pivotal data from the ALKOVE-1 trial of our ALK selective inhibitor, neladalkib. Over the past 15 years, tremendous progress has been made for patients living with ALK-positive non-small cell lung cancer. Before we dive in today's top line results, it's worth grounding in the broader context of the current treatment landscape and where we see continued opportunity for patient impact. As detailed on Slide 3, alectinib, a second-generation ALK TKI is well established as a standard of care in the front line where it demonstrated a 79% ORR and median progression-free survival of 25.7 months by independent central review at the time of FDA approval. Patients progressing on alectinib and other second-generation ALK TKIs often have ALK single mutations conferring resistance of therapy or brain metastases. Lorlatinib, a third-generation TKI, was designed with the goal of addressing the limitations of second-generation inhibitors through coverage of ALK single resistance mutations and improved CNS penetrant. Today, it is the only approved therapy with demonstrated activity following the second-generation ALK TKI and is the preferred second-line treatment option for patients following alectinib. No approved therapies have demonstrated activity following treatment with Lorlatinib, where a clear medical need remains. Experience with Lorlatinib has identified 2 additional limitations. First, insufficient coverage of ALK resistance mutations by Lorlatinib following prior treatment with second-generation TKIs has resulted in the continued presence of single ALK mutations and the emergence of compound ALK mutations conferring treatment resistance. In addition, Lorlatinib is a brain-penetrant dual TRK ALK inhibitor and CNS adverse events associated with TRK inhibition in the brain are observed in more than 50% of patients receiving Lorlatinib. The impact of these limitations can be observed in the modest activity of Lorlatinib for TKI pretreated patients. Following at least one prior second-generation TKI, Lorlatinib delivered an objective response rate of 31% to 40% with a median duration of response of 7.1 to 9.6 months. Experience with Lorlatinib has also clearly demonstrated that both activity and tolerability are of critical importance to physicians and their patients. Lorlatinib is approved for use in the frontline and has demonstrated the potential for improved activity, reporting 2024 that median PFS was not reached with 5 years of follow-up. However, many physicians, particularly in the community setting, continue to express reluctance to use Lorlatinib for their newly diagnosed patients due to the risk of CNS adverse events. We believe that due to this limitation, alectinib remains the frontline market leader today. With this understanding of the current treatment landscape and limitations of available therapies, we saw 3 clear areas of opportunity for meaningful patient impact. First, for patients in the third line and beyond who have exhausted the available therapies, a compound that demonstrates any activity is needed to bring new hope to patients. For TKI pretreated patients who remain Lorlatinib naive, we believe there is opportunity to meaningfully improve on the 7.1 to 9.6 month durability of response available today with Lorlatinib. Lastly, for TKI-naive patients, we believe a therapy that could deliver comprehensive activity against drivers of disease progression, inclusive of ALK resistance mutations as well as brain metastases and be well tolerated would have the potential to demonstrate superiority to alectinib and potentially become a new frontline standard of care. Turning to Slide 4. From these learnings, we designed neladalkib with the goal of delivering the first and only ALK selective compound designed to address the combined medical needs of hitting the ALK oncogenic driver, addressing or preventing ALK single and compound resistance mutations, having excellent brain penetrants and avoiding TRK-related neurotoxicities. We confirm these goals with the leading physician scientists who had developed the currently available ALK TKIs and continue to treat patients today and set out to operationalize a global development plan that could evaluate neladalkib across each of the 3 areas of opportunity we have identified. Our global development strategy summarized on Slide 5 is anchored on 2 clinical trials, each designed with registrational intent. Our Phase I/II ALKOVE-1 study was designed with the potential to support an initial indication for TKI pretreated patients, where we believe there is a clear medical need in the third line and an opportunity to differentiate from the second-line standard of care of Lorlatinib in both durability and tolerability. Today, we're reporting top line pivotal data from this trial and plan to discuss these data with the FDA at an upcoming pre-NDA meeting. Our ultimate goal is to establish neladalkib as a best-in-class drug for all patients with ALK-positive non-small cell lung cancer, including those who are TKI naive. Each of the currently approved ALK TKIs achieved line-agnostic label expansion through demonstrating superiority over the standard of care at the time, crizotinib in the Phase III head-to-head trial. Consistent with this regulatory precedent, in July, we initiated ALKAZAR, our Phase III randomized controlled trial designed to evaluate neladalkib versus the standard -- current standard of care alectinib for TKI-naive patients with ALK-positive non-small cell lung cancer. Global site activation and enrollment are ongoing. Turning back to the focus of today's data announcement, an overview of our ALKOVE-1 trial is provided on Slide 6. The Phase I dose escalation portion of our ALKOVE-1 trial enrolled heavily TKI pretreated patients, many of whom had exhausted all available therapies and was designed to determine the recommended Phase II dose. Preliminary data from the Phase I portion of the trial was first presented at the AACR-NCI-EORTC symposium in 2023, with updated data presented at the European Society of Medical Oncology Meeting in 2024. These data demonstrated preliminary clinical proof of concept supporting each component of our target product profile in a heavily pretreated patient population. Enrollment in the global open-label multi-cohort Phase II portion of ALKOVE-1 began in February 2024 with a recommended Phase II dose of 150 milligrams once daily. The multi-cohort design allowed evaluation of neladalkib within various pretreated subpopulations with the intention to demonstrate activity broadly across the TKI pretreated advanced ALK-positive non-small cell lung cancer population. Additionally, the trial included a cohort designed to enable preliminary investigation for patients with ALK-positive non-small cell lung cancer who are TKI naive as well as a cohort for other ALK-positive solid tumors. We have been encouraged by the support from investigators and patients for our ALKOVE-1 trial, as evidenced by the robust enrollment shown on Slide 7. In January of this year, we announced that we had enrolled 596 patients across the Phase I and Phase II portions of our ALKOVE-1 study. Following that update, we transitioned enrollment of adult patients with advanced ALK-positive TKI-pretreated non-small cell lung cancer from our Phase II cohorts to our expanded access protocol. At the time of cohort closure on March 25, 2025, 762 patients had been enrolled in ALKOVE-1. Enrollment remains ongoing in ALKOVE-1 for adult and adolescent patients with ALK-positive solid tumors other than non-small cell lung cancer and for adolescent patients with ALK-positive non-small cell lung cancer. As of the pivotal data cutoff date of August 29, 2025, a total of 781 patients have been enrolled across the Phase I and Phase II portions of ALKOVE-1. This enthusiasm has been incredibly humbling and reinforces to us that a clear need remains for patients with ALK-positive non-small cell lung cancer. Importantly, it also enabled the inclusion of a substantial number of TKI pretreated patients with ALK-positive non-small cell lung cancer in today's top line pivotal data set. These patient populations are detailed on Slide 8. Of the 781 patients with ALK-positive non-small cell lung cancer treated at any dose level by our data cutoff date of August 29 of this year, 656 patients received a recommended Phase II dose of 150 milligrams once daily and comprise our pivotal safety population. The pivotal primary efficacy analysis population includes 253 patients with measurable disease by blinded independent central review or BICR. These patients must have received neladalkib at the recommended Phase II dose by September 30, 2024, to allow for at least 6 months of duration of response follow-up for nearly all responders by the data cutoff date. Beyond our top line data in TKI pretreated patients, we're also sharing preliminary data from 44 TKI-naive patients with advanced ALK-positive non-small cell lung cancer from the Phase II exploratory cohort of ALKOVE-1. With that, let's dive into our top line data results. ALKOVE-1 is a multiregional trial with Phase I and Phase II patients enrolled across North America, Europe, Asia and Australia. Key characteristics of the pivotal primary efficacy analysis population are described on Slide 9. Overall, the population was heavily pretreated with a median of 3 prior lines of therapy and a range of 1 to 11 prior therapies. 51% of patients had received prior chemotherapy and 78% had received 2 or more prior ALK TKIs, of which 91% had received prior Lorlatinib. This population is unique to ALKOVE-1 as no other ALK studies have included Lorlatinib experienced patients. Additionally, 19% of patients had a secondary ALK G1202R mutation, 17% of patients had compound ALK mutations and 40% had active CNS disease at baseline. Notably, the pivotal primary analysis population also included 63 patients that were Lorlatinib naive, offering us an opportunity to evaluate neladalkib's activity earlier in the treatment paradigm. All of these patients have received at least one prior second-generation ALK TKI with or without chemotherapy, of which 70% received prior alectinib only. No patients in this subset received crizotinib as their only ALK TKI, further highlighting the differentiating nature of ALKOVE-1 from other ALK studies in TKI pretreated patients. 19% of patients in the Lorlatinib naive population had a secondary ALK G1202R mutation and 35% had active CNS disease at baseline. The top line efficacy results observed in the overall TKI pretreated primary efficacy analysis population are detailed on Slide 10. Objective response rate, or ORR, and duration of response, or DOR, were evaluated by blinded independent central review. In the 253 patients that have received any prior ALK TKI with or without chemotherapy, the ORR was 31% and the estimated probability of continued response or DOR rate was 76% at 6 months, 64% at 12 months and 53% at 18 months by Kaplan-Meier estimate. The median DOR was not reached, which is encouraging as we think about the potential for durable responses even in the most heavily pretreated of patients. In Lorlatinib-experienced patients, where no approved therapies have demonstrated activity, an ORR of 26% was observed and the median duration of response was 17.6 months. It is our belief that any activity in these heavily pretreated patients who may have exhausted all available therapies indicates the potential for differentiation and improved activity in earlier lines of therapy. The overall TKI pretreated population also contains 47 patients with the most common ALK single resistance mutation, G1202R, which is present in approximately 35% of patients progressing on a second-generation ALK TKI. In this subset of patients, the ORR was 68% and median DOR was not reached. DOR rate was 84% at 6 months, 80% at 12 months and 70% at 18 months by Kaplan-Meier estimate. Notably, responses were also observed in patients with compound ALK resistance mutations following treatment with 2 or more prior ALK TKIs. In these 43 patients, the ORR was 58% and DOR rate was 69% at 6 months with median not reached. These data support the potential for Neladalkib to provide an option for all TKI pretreated patients, including those who may have progressed on earlier lines of therapy with ALK resistance mutations. In addition, we believe that using a brain-penetrant TKI with broad coverage of ALK resistance mutations in earlier lines of therapy has the potential to extend the durability of response by preventing the emergence of on-target resistance in the periphery and in the brain. This belief is supported by the potential for differentiated durability observed by Neladalkib in TKI pretreated patients who are Lorlatinib naive as outlined on Slide 11. In the primary efficacy analysis population, 63 Lorlatinib-naive patients with advanced ALK-positive non-small cell lung cancer had received Neladalkib as a second-line therapy or beyond. As Lorlatinib is the only approved option with demonstrated activity after a second-generation TKI, we believe the evaluation of activity in this population is of high relevance for physicians and their patients. In this subset, an ORR of 46% was observed. The median DOR was not reached and the DOR rate was 89% at 6 months, 80% at 12 months and 60% at 18 months. We are highly encouraged by the durability of response observed in this Lorlatinib naive population. As I mentioned earlier, in the separate study of Lorlatinib for patients who had received at least one prior second-generation TKI, Lorlatinib delivered an objective response rate of 31% to 40% with a median duration of response of 7.1 to 9.6 months. Recognizing this is a small sample set, we're also encouraged by the activity observed in the 12 Lorlatinib-naive patients with G1202R mutation. Here, the ORR was 83% and DOR rate was 90% at 6 months and 77% at both 12 and 18 months. Similar activity was observed in the subset of patients that had received one prior second-generation ALK TKI with or without chemotherapy. In these 46 patients, an ORR of 48% was observed with DOR rates at both 12 and 18 months of 74%. Overall, these findings support Neladalkib's potential to provide more durable responses for patients previously treated with second-generation ALK TKIs. Slide 12 shows Neladalkib's potential for durable responses in patients with CNS disease. Looking first at the 92 patients with measurable CNS lesions by blinded independent central review at baseline that received any prior ALK TKI with or without chemotherapy. The intracranial ORR was 32%, including 12 intracranial complete responses or CRs for a CR rate of 13%. The intracranial DOR rate at 6 months was 81% and 71% at both 12 and 18 months. Notably, this included CNS responses in patients who had previously received Lorlatinib. Lorlatinib has demonstrated what we consider to be impressive CNS activity, and we believe any signs of clinical activity in the CNS beyond Lorlatinib treatment is encouraging. In this population, Neladalkib was still able to deliver an intracranial ORR of 21% with an intracranial DOR rate of 71% at 6 months and 55% at the 12- and 18-month landmarks. Intracranial activity was also observed in the subset of patients who were Lorlatinib naive and received Neladalkib as a second-line therapy or beyond. In these 24 patients, the intracranial ORR was 63%, including 5 intracranial complete responses or CRs or a CR rate of 21%. The intracranial DOR rates at 6, 12 and 18 months were all 92%. These data support the potential for Neladalkib to address active CNS disease, both in earlier lines of therapy and beyond the brain-penetrant Lorlatinib, where no other TKI has demonstrated activity. As shown on Slide 13, Neladalkib was generally well tolerated and the safety profile remains consistent with prior data. Treatment-emergent adverse events, or TEAEs, occurring in 15% or more patients were reported by preferred terms for 656 pooled patients with ALK-positive non-small cell lung cancer treated at the recommended Phase II dose. TEAEs above this threshold were ALT increase in 47% of patients, AST increase at 44% of patients, constipation in 28% of patients, dyskinesia in 23% of patients, peripheral edema in 18% of patients and cough and nausea, both in 16% of patients. The most common TEAEs were transaminase elevations. Most were asymptomatic lab abnormalities and observed to be low-grade, transient and reversible with dose interruptions or reductions. Preliminary data suggests increased incidence in less heavily pretreated patients. Therefore, we implemented enhanced monitoring and prompt dose interventions in the protocol for the Phase III ALKAZAR trial. Across the 656 patients treated in ALKOVE-1 at the recommended Phase II dose, dose reductions due to TEAEs occurred in 17% of patients. Importantly, treatment discontinuation due to TEAE continued to be low, occurring in 5% of patients. Our ultimate goal is to bring Neladalkib to all ALK-positive patients. And today, we are excited to also share the first look at preliminary data from the exploratory TKI-naive cohort of ALKOVE-1 that further supports the potential for Neladalkib to improve outcomes in earlier lines of therapy. Preliminary findings are highlighted on Slide 14 for the 44 patients treated in our exploratory TKI-naive cohort of ALKOVE-1 with a data cutoff date of August 29, 2025. For these patients, treatment with Neladalkib delivered an ORR of 86%. Durability of response ranged from 1.7 plus to 14.8 plus months with a 91% DOR rate at 6 and 12 months and only 2 progression events among responders. Additionally, an intracranial ORR of 78% was observed in 9 patients with measurable intracranial lesions, including 4 CRs for a CR rate of 44%. Intracranial DOR range from 3.1 to 7 months with no CNS progression among intracranial responders. Taken together, we believe these data continue to support the potential for Neladalkib to be a generally well-tolerated therapy that can drive deep durable responses for patients across the treatment paradigm. Turning to Slide 15. We're incredibly encouraged by these top line pivotal data for TKI pretreated patients with ALK-positive non-small cell lung cancer and preliminary data for TKI-naive patients. We believe these data confirm the clinical proof of concept previously reported in our preliminary Phase I data sets, including meaningful clinical responses for TKI pretreated and TKI-naive patients, clinical activity in patients with key drivers of disease progression and a generally well-tolerated safety profile consistent with Neladalkib's ALK-selective TRK-sparing design. Importantly, we believe these data demonstrate that combining activity against key drivers of disease progression with tolerability and convenience to keep patients on target therapeutic doses has the potential to translate to transformative durability across all lines of therapy, avoiding the need for treating physicians and their patients to choose between efficacy and tolerability. As encouraging as these results are scientifically, they also remind us of why we built this company. We founded Nuvalent with a commitment to patient impact. Today, it continues to be the value that defines who we are as a company and reminds us that behind every data point is a person living with this disease, placing their trust in clinical research inspiring us to push further every day. Earlier this summer, our team was fortunate to attend the Annual ALK Positive Summit in San Diego. An event designed to unite patients, caregivers, health care professionals and researchers in the fight against ALK-positive non-small cell lung cancer. During the meeting, we were privileged to witness the celebration of several patients reaching 10 years of survival with ALK-positive non-small cell lung cancer, a milestone that was once unimaginable. This is truly a testament to the tremendous work by the ALK-positive organization and the larger biopharma communities advancement of therapies that are making a meaningful impact for patients. Celebrating those survival milestones alongside others in the community was profoundly moving for our team, many of whom have built personal relationships with members of this community over the years. In every conversation with these inspiring patients, caregivers and advocates, they continue to remind us that new treatment options are needed to help them spend more quality time with their loved ones. So when we look at these top line results reported today, we don't just see data. We see the potential for more quality time for more days living well with cancer and for more patients and their families to celebrate milestones of their own. We also see the courage and conviction of each one of the over 1,000 patients that has already chosen to receive Neladalkib through either our ALKOVE-1 trial or our global Expanded Access program and the support of the ALK-positive community that has made this level of awareness possible. While our work is far from being done, I know I speak on behalf of the entire team when I say that getting to work on a program that has reached this many patients in so short of time is both inspiring and a true privilege. The work also extends beyond ALK as we believe each of the clinical stage programs offers us the same opportunity to make a meaningful impact on the lives of patients. As summarized on Slide 16, today's announcement represents the culmination of a transformative year of achievements across our pipeline towards that goal. In just 1 year, we have reported the pivotal data for both of our parallel lead programs for ROS1 and ALK-positive non-small cell lung cancer and have submitted our first NDA application as a company in support of our investigational ROS1 inhibitor, zidesamtinib for TKI pretreated ROS1-positive non-small cell lung cancer. We plan to discuss the top line data presented today with the FDA at a pre-NDA meeting with the goal of aligning on the NDA submission plan and timing to support a potential indication for Neladalkib in TKI pretreated patients with advanced ALK-positive non-small cell lung cancer. We also plan to present detailed study results at a future medical meeting. Beyond their initial TKI pretreated indications, global development paths are now in place to support potential line-agnostic label expansions for both zidesamtinib and Neladalkib. We reported preliminary data for zidesamtinib from the ongoing Phase II TKI-naive cohort of our ARROS-1 Phase I/II study, which is designed to support potential line-agnostic label expansion. In parallel, global enrollment of TKI-naive patients with advanced ALK-positive non-small cell lung cancer is ongoing in our Phase III ALKAZAR trial, which we initiated in July of this year. Beyond our predefined milestones for this program, we also presented preliminary data for Neladalkib in patients with ALK-positive solid tumors beyond non-small cell lung cancer. We are pleased to see that Neladalkib demonstrated encouraging activity across a diverse set of ALK-positive solid tumors with a generally well-tolerated safety profile consistent with its ALK-selective TRK-sparing design. Enrollment continues in an ongoing Phase II cohort of our ALKOVE-1 study. Finally, we also continue to progress our third clinical program for HER2-altered non-small cell lung cancer. We presented new preclinical data for our third clinical stage program for HER2-altered non-small cell lung cancer at the AACR-NCI-EORTC Symposium supporting NVL-330's potential for differentiated intracranial activity. Our Phase Ia/Ib HEROEX study for NVL-330 is ongoing and progressing well, and we look forward to providing updates on that trial in the future. In closing, on Slide 17, our mission is to establish Nuvalent as a sustainable company with the ability to discover, develop and deliver a portfolio of precisely targeted therapies for patients with cancer. For the past 2 years, our progress towards this mission has been guided by our OnTarget 2026 operating plan, which targets our first potential product approval in 2026. This plan is ambitious and requires consistent achievement of critical milestones across our pipeline. In this industry, the achievement of any one of the milestones we outlined for 2025, bringing a drug to the pivotal readout, submitting an NDA or initiating a global Phase III trial, all while progressing a third program to clinical development is no small feat. With today's announcement, we have successfully achieved all of the milestones outlined in our OnTarget 2026 operating plan for the second year in a row, and our goal of having a first potential product approval in 2026 is in clear sight. This is a truly remarkable accomplishment that was only made possible by the tireless dedication of our team, collaboration with physician communities and patient advocates and most importantly, the patients and caregivers that participate in our clinical trials. Thank you for your support at this remarkable time in the evolution of our company. We look forward to sharing more in the months and quarters ahead as we continue building towards our mission of bringing new potential best-in-class medicines to patients with cancer. This concludes our prepared remarks, and we would be happy to take your questions.

[Operator Instructions] Our first question comes from Brad Canino with Guggenheim.

Congratulations on great execution to this milestone. Two questions for me. First, I'd like to hear how you describe how you think this demonstrated neladalkib profile can lead to an expansion of the TKI pretreated market opportunity, especially relative to historic ALK inhibitors that launch in that setting? And then second, can you provide a bit more commentary around the liver enzymes and what you're hearing from investigators about the management of those relative to their experience with LFTs of alectinib?

Thanks, Brad. Yes, I'll take the first one first. that how do we view the opportunity? This is really -- honestly, for the Nuvalent team are privileged to work on a program like this. There are 2 things that jump out. One is just the massive enrollment, greater than 1,000 patients treated, overwhelming majority in the last 18 months. I'm not aware of a single oncology trial in the history of oncology drug development that has that type of enrollment. And it's clearly supported by the patient community, the investigator enthusiasm. It speaks to the medical need, and it speaks that we're doing something right here. So that really jumps at us. And then the durability that we're seeing, we're able to drive durable responses across all lines of therapy, right? And that's really saying something. It's speaking to the interest of this target. ALK the tumors are highly dependent on ALK signaling. And if you can hit the key drivers of disease and progression, meaning those resistance mutations, singular compound, get into the brain, importantly, keep patients on therapy, that is the formula for driving these durable responses. So that's really interesting because your question here is around what is the commercial opportunity. First and foremost, we care about making a meaningful impact for patients. And with the massive interest in enrollment and the durability we're seeing, we think we have the opportunity to do that. We're also trying to build a business around this and more time -- more durability means more time on therapy. More time on therapy means that we have the potential to grow the market. So across our couple of programs here, ROS1 and ALK, we've shown durable responses in these patients, which means more time on therapy. The current ROS1 market with more time on therapy, we think could look something like the current ALK market, which is very interesting. Meanwhile, the current ALK market, which is around $2 billion currently, we think would significantly grow, maybe looking something approaching what the current EGFR market is. That's a game changer for Nuvalent. So we're excited about the update. We're excited about what we're learning and the potential to grow these market opportunities. The second question you had was around the safety update. And Chris, do you want to take that?

Yes, happy to. Thanks for the question, Brad. As we previously mentioned, transaminase elevations that are seen with Neladalkib are similar to what's seen with most TKIs and all of the ALK TKIs. They're typically just asymptomatic lab abnormalities that are picked up by blood draws. They're not even noticed by patients. When they do occur, they typically occur in the first 1 to 2 months on therapy. And because of this, oncologists are really used to monitoring for this, typically monitor weekly in the first month on therapy and then every 2 weeks for the second and third month and then typically follow up with monthly thereafter. So it's something that oncologists are really familiar with testing and most patients don't even know that the labs are going up.

Operator, I think we're ready for the next question.

The next question comes from Marc Frahm with TD Cowen.

Congrats on the data as well. Maybe first off, just given the data you're showing today, can you maybe confirm what the kind of initial indication statement that you think you intend to seek with the FDA? And then can you put the efficacy in that Lorlatinib naive population into the context of what other times the FDA has granted single-arm accelerated approvals in a setting where there is some activity reported with alternative therapies. And then I'll likely have a follow-up.

Absolutely, Marc. Thanks for the question. So the goal is to submit for previously treated ALK non-small cell lung cancer. Let me explain the rationale here. The general sequence that most physicians follow, they treat with alectinib in frontline. When patients progress on alectinib, the only drug that works is Lorlatinib. When they progress on Lorlatinib, nothing works, right? And the overwhelming majority of the data we presented today are for patients in that third line plus setting where there's no available options. In Phase I, we showed deep durable responses. We received breakthrough designation in that setting. And the data translated from Phase I to Phase II. We see deep durable responses in patients that previously received Lorlatinib, the second-line standard of care, which has a 7- to 9-month duration of response, we are seeing double the duration of response of Lorlatinib beyond Lorlatinib. And that simply does not happen in oncology drug development. When you give successive lines of treatment, the duration of response will go down. We are seeing double the durability of Lorlatinib beyond Lorlatinib, which really speaks to the attributes of Neladalkib and affirms our design goals for the program. Now we also think this is an opportunity to pursue a second-line indication, meaning patients that have yet to receive Lorlatinib. So in that setting, our drug is driving 46% response rates at the DOR landmark of 18 months, 60% of the patients are still in response. We are seeing alectinib durability beyond alectinib. It's really amazing. We're not really -- we're sort of thrilled about that. As you know, in this space, crizotinib used to be the standard of care and alectinib really changed the dynamic here by driving deep durable responses, took over as the standard of care, can drive a couple of years of durability. We're seeing that kind of durability in the previously treated setting. So we think if we take that second-line data, where we're driving these deep durable responses and you combine it with that third-line data where nothing else works, we think we have a compelling argument to be made around a previously treated non-small cell lung cancer indication.

Okay. That's helpful. And then maybe to follow up on Brad's earlier question on the liver testing. Just in the Phase III now, can you maybe describe the testing paradigm for patients and how it fits into -- Chris, I think you described a minute ago what's essentially in the label for alectinib. I mean is that the protocol that you're now following? Or is it something different?

Yes. So a lot of physicians even do beyond what's in the label for alectinib. As I described, it's pretty common to do actually monthly -- or sorry, weekly in the first month and then every 2 weeks for the months 2 and 3 and then monthly thereafter. I think what we did in -- what we've implemented is some additional blood draws early in treatment to be able to detect and intervene earlier to ultimately reduce the number of higher-grade events and minimize the impact to patients in the long run.

And the next question comes from Laura Prendergast with Stifel.

Congratulations on the data. I wanted to zone in on that comment you had in the press release that over 1,000 total patients across the Phase I have been treated with Neladalkib. So tracking out the Phase I/II patients, it seems like you have well over 200 patients enrolled in the [ EAP. ] Can you provide any additional commentary here, whether these patients are coming from U.S. or ex U.S. and how they could convert to commercial patients upon approval?

Yes. Thanks, Laura. The program is just between the ALKOVE-1 and the expanded access, there's just been a lot of interest in Neladalkib. It has a differentiated profile Physicians are excited about it. I think they're having good experience with their patients. The patient communities are excited about the opportunities. And we wanted to make Neladalkib available for all patients that need it. So we significantly over-enrolled the ALKOVE-1 study. The original protocol called for around 300 patients or so, and we enrolled more than double that, 781 patients because of the enthusiasm for the trial. Honestly, I think all of us at Nuvalent recognize this is like a career-defining opportunity for us to work on a program like this. And I'm just proud of the team rising to the occasion to meet that challenge. The expanded access was something we put in place because we wanted to continue to provide access patients with Neladalkib, but we wanted to work on closing the actual non-small cell lung cancer cohorts in the Phase II study. And I think your math checks out, yes, it's well north of 200 patients that are on the Expanded Access program. This is a global Expanded Access program. So it's across geographies, North America, Europe, Asia, and we're seeing excellent interest across all those geographies. And to your point about conversion, maybe, Alex, do you want to speak to that?

Sure. Yes. So on the conversion, we would expect that upon potential approval in the U.S. that those patients on the EAP would convert to paid drug.

Got it. And then just one follow-up. Are these patients exhausting standard of care, both alectinib and Lorlatinib -- or is it possible that some of these patients have moved on to the EAP access because of tolerability issues with like CNS issues with Lorlatinib, for example?

Yes. Thanks, Laura. So the protocol is typically for Expanded Access program, the patients do have to have exhausted available options or the physician has deemed the patient not acceptable for any other approved therapies. So I think that addresses where we're going, like if a patient was intolerant to another therapy, then yes, they would be eligible for the Expanded Access program.

And the next question comes from Anupam Rama with JPMorgan.

Congrats on the update. Just a question on the 17% of patients that had dose reductions. Were those mostly due to transaminases? And I guess, what type of activity was observed after the dose reduction?

Yes. So maybe I'll start on the activity, and then Chris, you can speak to the dose reductions. So one thing about the Neladalkib profile, what we learned in Phase I is we had activity across the entire dosing range, Anupam. So we chose 150 milligrams as our recommended Phase II dose. But if you go back to our Phase I data, you can see that our responses were pretty consistent across all dose levels. the 100 mg dose level, so the dose level below 150 mg also provides excellent target efficacy threshold coverage. So it does allow us to do dose reductions and still maintain patients at appropriate target efficacy thresholds. And I think that really helps with the activity. Chris, do you want to speak to the second part?

Yes. Happy to. Overall, we're very encouraged by the overall low rate of dose reductions of 17% regardless of the adverse event. I think you were specifically asking about the transaminase. There's only 11% of the patients who had dose reductions due to transaminases and only 3% discontinued due to that. What -- this is very similar. If you look at something like alectinib, which is considered a well-tolerated drug, they have 23% dose reductions and 6% discontinuations. So we're very pleased with our safety data overall.

The next question comes from Andrew Berens with Leerink Partners.

Congrats on the big milestone for the company and also for outpatients. It seems the premarket may be reflecting some concern, the modest erosion in efficacy between this trial and the prior Phase B. I think there's some key differences like the fact the Ib excluded concomitant oncogenic drivers and also the Ib with local reads versus BICR in this trial. Do you actually have any data from this trial that more closely reflects the Ib results for an apples-to-apples comparison? And then we noticed that all the prior ALK drugs received broad labels that allowed usage in patients intolerant to prior ALK agents. Wondering if you think that's still something the current FDA would consider and if so, the potential implications? And then if I could just sneak a third one about the LFTs. I think you said in the slide deck that the rate was higher in naive patients. That seems a bit counterintuitive, but does it suggest that it goes down with time and is not cumulative.

Yes. Thanks, Andy. So 3 questions there. So first of all, the differences between the Phase I and II, I think what we -- the general theme is we're seeing durable responses across all lines of therapy in the Phase II. Regarding the specifics of the patient populations, -- in Phase II, as is typical, you would report activity by blinded independent central review. It's a higher bar than a Phase I, which is investigator assessed for activity. Another difference, as you pointed out, there are about 10% of the patient population. So of the 253 patients, 25 that had other oncogenic drivers that were included in the analysis patient population. In Phase I by protocol, those were not included in the analysis patient population. So these patients could have had other oncogenic drivers like MET amplification, MET mutations, BRAF, KRAS, G12C. So we do see some activity in those patients, but you can imagine it's a harder patient population to treat because they have multiple oncogenic drivers. What is likely going to be needed for a patient like that is eventually combination therapy. And then your second question around are patients -- the registration strategy around a broader label progressed or intolerant. I think you're right to point out that other ALK drugs received such an indication where patients that were -- had progressed or were intolerant to crizotinib. That was the original indication statement for some of these second-generation ALK TKIs. We certainly noticed that and understand that. I think that the data we generated clearly supports that our drug can drive durable responses regardless of the line of therapy. And I think we have a lot of interesting data to share with regulators around a broader previously treated ALK indication. The third question was around the naive patients. Chris, do you want to take that?

Yes. Just to clarify, too, I think what we had indicated was preliminary data suggests increased incidents in less heavily pretreated patients. It's just not the TKI naive only. As we pointed out earlier, we -- this is a heavily pretreated population with 1 to 11 lines of therapy. And what we noticed when we just do look across all lines of therapy that there's a little bit of a trend with the less heavily pretreated patients across the board. We have a number of hypothesis there. We don't necessarily want to get into speculation at this point, but it is an interesting phenomenon we're noting.

And the next question comes from Charles Zhu with LifeSci Capital.

Congrats on this update. My first one is a little bit of a semi follow-up to Andy's question. What's the proportion of ALK mutant versus ALK wild-type patients that you'd expect to see out in the real world? I'm mostly asking because it seems like you had a lot more mutant patients last year at ESMO 56% relative to today's 36%. And we know -- we see, for example, the ORR and DOR differences between those 2 populations not only for you guys, but also for Lorlatinib. So I wanted to get your sense there in terms of real-world proportions.

Thanks, Charles. So the -- we believe the data supports post-alectinib, around half the patients are progressing with ALK mutations. And that can range from the ALK GR mutation, the most common, the [ LM ] gatekeeper mutation, the IX mutations. Neladalkib was designed to address all these mutations. In addition, Neladalkib was designed to address compound mutations. Compound mutations occur because of Neladalkib's inefficient coverage of the first mutation. The second mutation starts to grow in, patients will progress. Our drug was designed and optimized to cover those mutations. I think that's why we can see durable responses regardless of the line of therapy even beyond Lorlatinib. So I think that range of ALK mutations overall in previously treated patients, it's going to be somewhere in that 40% to 50% range. I don't think we have a large enough data set to really get more granular than that, Charles. But I think our data update here suggests that there are a decent amount of patients with ALK mutations, and our drug is working quite well in those patients.

And the next question comes from Joshua Schimmer with Cantor.

Congrats on the update. Just want to dive into the expanded access program a little further. Can you discuss the cadence of enrollment of patients in that program, specifically in the U.S., whether there are any restrictions to the number of patients you can enroll in the U.S.? And are these patients all TKI pretreated?

Thanks, Josh. Yes, all TKI pretreated. As part of Expanded Access program, patients would have to have exhausted available options or physicians have deemed them not appropriate for the available options, right? So they may have taken alectinib and Lorlatinib, they progressed on both or they might have taken alectinib, perhaps Lorlatinib is not an appropriate option for them and the physician could put them on. This is enrolling across all geographies. It's enrolling well across all geographies, including in the U.S. I don't want to know -- I don't think we can get into more specifics on what the enrollment is by geography other than it's going well across all.

Okay. And then any restrictions into the number of patients that ultimately can enroll?

No restrictions. No restrictions.

And the next question comes from Rich Law with Goldman Sachs.

Congrats on this achievement. In your TKI pretreated patients, have you looked specifically at only patients who were Lorlatinib pretreated? And what do the results look like? In the past, I think you guys broke out those details. So curious how that compares to your 31% overall and the 32% intracranial ORR. And then I have a follow-up.

Thanks, Rich. Yes, there are 190 patients that received prior Lorlatinib. That is a patient population where nothing else works. 26% of these patients responded and a median duration of response was 17.6 months. That's what really stands out to us. That's double the durability of Lorlatinib beyond Lorlatinib. And again, that just didn't happen in oncology drug development. I'm not aware of really any examples where that happens. We also saw really interesting intracranial activity beyond Lorlatinib. Lorlatinib is one of the gold standards as far as brain penetrants. And any activity in the CNS beyond Lorlatinib is encouraging. We saw roughly 21% of the patients that had activity in the intracranial compartment, IC ORR rate of 21% and those responses were durable, over half the patients still in response at that 1.5 years landmark. So very encouraging data beyond Lorlatinib. Was there a second part to that question, Rich? I'm drawing blank here.

No, that was it, but I have another question. In the exploratory cohort of the 44 TKI-naive patients, what was that median follow-up across these patients? And do you expect these -- the results to mature further? Or are they fully mature? And how do you think this compares to alectinib and , Lorlatinib data so far?

Yes. The 44 patients in the TKI-naive cohort, so this is an exploratory cohort. I think we captured it. The update across the entire population of follow-up was 11.6 months. I don't think we broke it out specifically for the TKI-naive patients, so I can't report on that data today. This is an early look. So we expect that Neladalkib could drive years of durability for these patients. right? At the 12-month landmark, 91% of these patients are still in response. We hope they have many, many more years to go on Neladalkib. So we'll be following these patients for a long period of time. What stands out from this update, 86% response rate, 79% intracranial response rate for those patients with complete responses, only 2 progression events total among the 38 responders. So very encouraging data. If we map this out, this looks as good or better than what a drug like Lorlatinib can do in this setting. So I think we all know that Lorlatinib has the potential to drive deep durable responses in this setting. And the challenge with Neladalkib has been the off-target toxicity. What we're seeing with Neladalkib is we're not seeing those off-target TRK-related CNS events. Therefore, potential to keep patients on therapy for long periods of time and drive deep durable responses create considerable value for patients with ALK non-small cell lung cancer.

Yes. Sorry, I meant to ask, do you think the ORR could continue to mature over time? Or do you think the ORR is pretty much mature at this point?

With the potential for some of those patients that are still on the drug that have yet to have a response could convert to a response. So it could get slightly better, yes.

And the next question comes from Kelsey Goodwin with Piper Sandler.

Congrats on the data. Two quick ones from me. First, I guess, could you just provide some more details on the dose reduction? I guess, to what dose are they reducing to? How many reductions are they getting? And then secondly, obviously, very impressive enrollment in the Phase I/II and Expanded Access program. Any commentary on the ALKAZAR trial enrollment? And are you seeing the same level of physician enthusiasm there?

Thanks, Kelsey. So the dose reduction, we start at 150 and the dose reduction is to 100. As we mentioned before, in the Phase I, we saw excellent activity and coverage of the target efficacy threshold at 100. So that was one of the reasons we chose 150 as our dose. As you can imagine, patients with ALK non-small cell lung cancer, they're likely to have adverse events associated with their disease and having a flexibility of a dose reduction that still provides excellent target coverage is an advantage for Neladalkib. As far as the enrollment in ALKAZAR, it's going well. It's going according to plan. We're going to enroll this across the North America, Europe, Asia and Latin America. There's 160 sites that we're planning. The team is doing incredible work getting these sites open. We have broad enthusiasm from investigators and the patient advocacy communities that we collaborate with. We think this trial is going to enroll well, but no specific update we're providing today on what that enrollment metrics are. We'll look to maybe do that in the future.

The next question comes from Chris Raymond with Raymond James.

This is Sam on for Chris. Congrats on the data. One clarification and one question for us. So in the press release, I noticed that you said the median duration of exposure was 6 months from the whole 650-patient safety cohort. Could you just clarify what the duration of exposure was for the efficacy cohort that you were commenting on today? And then second, I don't think I see this spelled out in the data. Could you comment on the response rate that you're seeing in just the patients who have only had one prior TKI? And do you see any differences in response depending on what that first TKI was?

Thanks, Sam. So yes, just a clarification between duration of median follow-up as compared to duration of exposure. I think you cited the 6 months, that was from the broader safety population, the roughly 650 patients, 6 months of follow-up there. For the analysis patient population, 253 patients, it was a little over 11 months for median follow-up for those patients. Remember, we do a look back and cut the analysis patient population to have all patients have at least 6 months of DOR follow-up, and that's why we get more time on study for those patients as compared to the full safety set, which includes all patients with non-small cell lung cancer that received the recommended Phase II dose. As far as the one prior TKI, we saw in that -- in a patient population that have yet to receive Lorlatinib, I think we have called out that all those patients received at least 1 prior second gen. Some of those patients would have received alectinib plus crizotinib, some of them alectinib plus brigatinib, some of them maybe brigatinib plus crizotinib and all the combinations thereof. The response rate there was 46%. 60% of those patients were still in response at that 1.5 years landmark, which really is impressive. In that same slide, we did call out a subset that received only one prior second-gen TKI. So 44 of these patients received alectinib. 2 of these patients received brigatinib. I think the response rate was 48% and 74% of these patients were still in response at 1.5 years landmark. Again, that's incredible durability in a previously treated patient population. It's looking more or even better to what alectinib can do in the front line. And we're seeing that in a patient population beyond alectinib, which really speaks to the attributes of Neladalkib.

And the next question comes from Etzer Darout with Barclays.

On the data here. Maybe if you could comment on what you know about the real-world duration of therapy for Lorlatinib versus what's previously presented in the literature and your expectations for the durability for Neladalkib in the real world based on sort of those observations. Then have the FDA commented any particular subgroup of the data that it would be -- that they would like to see in terms of sort of efficacy durability, for example, look at the Lorlatinib experienced population where there are no approved therapies and if there's special interest from the FDA and maybe that subgroup or other subgroups that you'd want to call out?

Thanks, Etzer. So the Lorlatinib duration of response post alectinib is about 7 to 9 months. The PFS is even lower. I think it's around 6 months in that patient population. And you can imagine in the real world, it might be even lower. What we hear often from physicians is the challenges with Lorlatinib is keeping patients on therapy. ALK non-small cell lung cancer, unfortunately, is a disease that commonly impacts folks when they're younger. They're 30, 40, 50 years old. They're in the prime of their life. They have professional milestones. They have personal milestones. And Lorlatinib is a difficult therapy to tolerate. So many patients we hear from directly are scared of Lorlatinib. They don't want to go on that treatment, and they want more options that they can stay on therapy and still live their life, still do their job, still be part of their family and not have their therapy impact or dictate their day-to-day. So that's one of the reasons that we came up with this profile, working with physicians that had direct experience with Lorlatinib and the limitations that drug has in the previously treated ALK non-small cell lung cancer setting. So we are not seeing those TRK-related neurotoxicities. We are seeing patients stay on therapy, and we're seeing durable responses even in patients that have previously received Lorlatinib or in patients that have yet to receive Lorlatinib. So I think that really speaks favorably about us being on the right track here with Neladalkib. Your question about what do we expect the duration of therapy for Neladalkib to be in the real-world setting, difficult to know at this point. We obviously are encouraged by the massive enrollment we're seeing and the durability across all lines of treatment. We think that would translate well to time on therapy in the real-world setting, but that's to be figured out going forward. And then as far as like what our registration strategy is, maybe, Darlene, do you want to take that?

Yes, sure. So thanks for the question. We're super excited to share the data with the FDA and the next steps for our program as part of an upcoming pre-NDA meeting. We're planning to seek an all pretreated indication based on this ALKOVE-1 study. And as far as details regarding subgroups, we don't disclose the details of our discussions with the regulators. But again, we're super excited to be where we are today and for an upcoming discussion with FDA around the data.

And the next question comes from Roger Song with Jefferies.

This is [ Nabil ] on for Roger. Congratulations on the updates, the trial results. Just had 2 questions. Looking at that exploratory naive cohort and those 2 progression events and 38 responders, that's about a 5% rate. How do you contextualize that? And again, being that it's preliminary, how do we look at that when we look at escape mutations from other ALK TKIs? And then I had another follow-up.

Thanks, [ Nabil. ] So yes, listen, the TKI-naive cohort, it's early, right? It's -- we have -- we're reporting DOR landmark at one year. We want these patients to have years of progression-free survival, but only 2 progression events of the 38 responders, it's promising. It looks as good or better than Lorlatinib. And that's saying something, right? So we're thrilled about that, but we also predicted that. We predicted this drug would work better than all the other ALK drugs. It has a profile that the other ALK drugs have, doesn't have. It's the first and only drug that it can hit the oncogenic fusion, hit the mutations, single and compound mutations, has excellent brain penetrants and importantly, can keep patients on therapy because we're not hitting those off targets that drive dose-limiting toxicities. So we're not surprised that it looks great, but we're actually pretty happy to see it.

Great. And then you mentioned you'll have updated data at a medical conference. Would that include more mature data cutoffs? And then could we also see subsets of like second line versus third line [ loratinib ] experienced and how do you see like the safety profile in an updated set? Would we see something similar or...

Sure thing, [ Nabil. ] So typically, what's done here in a pivotal data set is you go discuss that data with regulators. And ideally, these will be the data that we submit for an NDA. And a medical meeting presentation in the future will likely be the same data cut. There is an opportunity to present more data as we did for our ROS1 program. Just to put it in context, we presented top line for our ROS1 in June of this year. And then at the WCLC meeting in September, we presented at the Presidential Symposium, same data cut, just a more fulsome data presentation at the medical meeting. I think that same blueprint probably makes sense for the ALK program as well.

Just if I could sneak one more question in on that safety profile. How do physicians and investigators look at that [ AE ] profile when it comes to the CNS-related AEs versus an incremental increase in like LFTs, which, as you mentioned, are common in this class?

Yes. I would say the best evidence how investigators feel about the drug is that we've enrolled over 1,000 patients in the last 18 months. Again, I would challenge it like we've -- I've talked to several of our analysts about this. Can we find another trial in all of oncology drug development in the history that has this type of enrollment. And keep in mind, this is a rare tumor type. So I think that tells you all you need to know how physicians feel about Neladalkib. This is a differentiated profile. We know the patients are excited about it. I think that's why our trials enroll so well. I think that the best evidence that we can support your question.

And the next question comes from Charles Ramakanth with Stephens.

This is RK from H.C. Wainwright. Congratulations, Jim and team. A couple of quick questions. I'm just thinking through the median DOR, especially in the second-line setting, which is Lorlatinib naive patients. What's the longest these patients have been followed to date? I understand that you are not -- the data is not mature enough to show the median DOR. And the second question is, based on what you're seeing in the exploratory cohort of 44 patients in the TKI naive cohort, what would your expectations be for the ongoing ALKAZAR?

Thanks, RK. So the first question was around what's the longest these patients have been followed. So keep in mind, the analysis patient population includes any patients from the Phase I or Phase II that have non-small cell lung cancer that were treated at the recommended Phase II dose. So patients in this trial only started the Phase I in June of 2022. So just a little over 3 years total in the history of this oncology development program. So no patient could have been followed that longer than that because that's when the trial started. We don't have it broken out of how many of the Phase I patients started at the recommended Phase II dose that are in the analysis set. So I wouldn't be able to specifically answer your question, but the Phase II started in February of last year. And you can see that we saw massive enrollment right from that get-go. And so most of those patients are in that time frame where they started between February and August of last year. The second question was, what do we expect as far as durability on ALKAZAR? We expect to give years of progression-free survival. That's the goal here. alectinib is a game changer in the ALK space. Crizotinib was the original standard of care. It drove about 12 months of durability for patients. It created about a $500 million market at its peak. Alectinib came along, and it did great things for this community. It doubled the durability of crizotinib, right? And it quadrupled the market. We're looking to do something like that compared to alectinib. We think that with 50% of the patients progressing on alectinib, that's not good enough, right? And AK non-small cell lung cancer patients deserve something better. Neladalkib has that profile. It has been designed to keep patients on therapy for extra years. That would be a game changer for that patient community, and it will represent a very compelling opportunity for Nuvalent.

And the next question comes from David Dai with UBS.

And also my congratulations on the data here. Two quick ones for me. So first, just thinking about the filing strategies, can you maybe just give us some sense around what are some of the key questions you need to discuss with the FDA to get the second-line Lorlatinib naive on the label? And then secondly, just regarding the liver enzyme elevation. So you are now implementing more monitoring for the ALKAZAR trial. How do you think the drug reduction percentage will evolve in the Phase III ALKAZAR trial? And how do you think this might impact survival outcomes compared to alectinib?

Yes. So on the second -- I'll take the second question first, David. As we mentioned, the dose reduction provides excellent coverage of ALK and ALK mutations. So we're not concerned at all about any dose reductions. We're seeing durable responses even in the Phase I across the entire dosing range. So this was the luxury we had with a Neladalkib profile. Patients with lung cancer will have dose reductions based on their underlying disease and to have multiple dose levels that can cover that target threshold is an advantage, and Neladalkib has that. Regarding the filing strategy, as Darlene mentioned, we're going to bring this data to the regulators to discuss a broader previously treated ALK indication. Third line where nothing else works, we have breakthrough designation, second line where Lorlatinib is a standard of care, and we can drive significantly longer, more durable responses than Lorlatinib, excellent CNS activity, keeping patients on therapy. I think the data -- the collated data, we think presents a compelling argument around a broader previously treated non-small cell lung cancer indication.

And our final question comes from Colleen Kusy with Baird.

Congrats on the updates today. So I realize this is an early top line look at the data, but can you speak to any indication of benefit for those patients that did not achieve an ORR? And then can you just speak quickly to the filing strategy for global territories, any time lines for Europe and whether you'd expect a broad label there as well?

So thanks, Colleen. So these trials were designed to support global registration, right? So we certainly have an interest in getting these drugs approved for all patients across all geographies. I can tell you it enrolled well across all geographies. And we intend to -- once we discuss with the FDA, also follow that up with the global regulators. So that's the strategy there. As far as your first question, are there -- is there a benefit for patients that did not actually have a response? Yes, you can imagine that there are often going to be patients that do not have at least 30% tumor reduction, which is in the RECIST 1.1 response criteria, but still derive benefit for the therapy. You can imagine, particularly in a very advanced patient population where patients have progressed on so many lines of therapies that there could be heterogeneous disease and not all the disease is driven strictly on ALK at that time. It's an opportunity to still have benefit for patients, but not actually hit that 30% reduction threshold. So those patients likely to continue on therapy. Often that's measured by an endpoint of progression-free survival. So this update did not include PFS. We really tailored it around how regulators view a single-arm Phase II data set. They want to know, do you shrink the tumors and for how long and what the safety profile is. That's ORR, DOR and safety. But as you might know in the ROS1 program, that's how we tailored our top line update. And then at medical meetings, we considered PFS for investigators. So maybe more to come on that in the future. Big picture, we're excited about what we're seeing on the durability for these patients across all lines of therapy.

And that concludes our question-and-answer session. I would like to turn it back to Jim Porter for closing remarks.

Great. Thank you all for joining us today. We are really proud of the progress we have made across our pipeline and appreciate your continued support of Nuvalent. We look forward to speaking with you in the weeks and months ahead.

Thank you, presenters. And this concludes today's conference call. Thank you all for joining. You may now disconnect.