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 Alex Balcom, CFO of Nuvalent. You may begin.

Thank you all for joining us today. Earlier, we issued a press release highlighting progress for our parallel lead programs zidesamtinib and NVL-655 and outlining updated data from the Phase I portions of the ongoing ARROS-1 trial of zidesamtinib and ALKOVE-1 trial of NVL-655. These data were presented during 2 oral presentations today at the European Society for Medical Oncology or ESMO congress 2024. The press release and the slides that we will be using during today's call are available in the Investors section of our website at nuvalent.com. On the call with me today are our CEO, Jim Porter; and CMO, Christopher Turner. Our 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 August. 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. We will also discuss case studies, which are not indicative of all the data or any results we may see in the future. Let me now turn the call over to Jim.

Thanks, Alex. And thank you all for joining us today. Nuvalent was founded with a bold mission to discover, develop and deliver a portfolio of precisely targeted therapies for patients with cancer. At the start of this year, we laid out our envisioned path to patient impact through our OnTarget 2026 operating plan, targeting our first potential product approval in 2026. As shown on Slide 3, we outlined several operational milestones for 2024 to achieve this goal, including initiating the Phase II portion of our ALKOVE-1 trial with registrational intent, which we announced in February; and initiating the Phase I trial for our HER2 program, announced in July. Our progress to date has not been limited to our predefined milestones. So far this year, we have also received breakthrough therapy designation for both of our parallel lead programs for ROS1 and ALK; presented new preclinical data supporting the target product profiles for our ROS1 and HER2 programs; and just yesterday, announced our second publication in Cancer Discovery, this manuscript outlining our approach to the design of NVL-655 for ALK-driven cancers. Today, we look forward to discussing the remaining 3 milestones for 2024, specifically: sharing updated clinical data for both of our ROS1 and ALK programs, providing insight into the progress of both our ARROS-1 and ALKOVE-1 Phase II trial and the announcement of our development strategy for front-line [indiscernible]. With today's updates, we have successfully achieved all of the milestones laid out for this year. This is a significant 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. As you will hear today, there is positive momentum in our parallel lead programs that has accelerated our development time lines, with the potential to provide multiple value creation milestones throughout 2025 and 2026. While we've made significant progress across the whole of our business, these updates are focused on our parallel lead programs targeting ROS1 and ALK-positive non-small cell lung cancer. At the outset of these programs, we worked collaboratively with the leading physician scientists who helped to develop the currently approved kinase inhibitors. We sought to craft well-defined target product profiles based on the medical needs they continue to observe in the patients they treat today despite available therapies. The learnings they shared with us are summarized on Slide 4. Beginning with ALK on the left. There are currently 5 FDA-approved therapies for patients with ALK-positive non-small cell lung cancer. Alectinib is well established as a front-line standard of care. Patients may experience disease progression on alectinib due to ALK single resistance mutations or CNS metastases. For these patients, lorlatinib is the preferred option due to coverage of ALK single resistance mutations and CNS penetrance. When the patient's disease progresses on lorlatinib, it's often due to the emergence of ALK compound resistance mutations. Despite having disease that is still driven by ALK, none of the available agents have demonstrated activity for these patients. Physicians identified addressing the third-line population as the immediate medical need. However, our goal was to not only expand options for patients in need but to deliver potential best-in-class therapies that could advance earlier in the treatment paradigm. To understand the characteristics needed for a best-in-class ALK inhibitor, it was critical to understand the trade-offs between the leading ALK inhibitors alectinib and lorlatinib. In cross-trial comparisons, it appears that lorlatinib may be the more active drug for TKI-naive patients with ALK-positive non-small cell lung cancer. However, lorlatinib is a brain-penetrant dual-Trk ALK inhibitor. And inhibition of Trk in the brain has been associated with a broad spectrum of CNS toxicities that can be treatment limited. Despite the potential for improved activity in the front line, lorlatinib remains primarily used in the second-line setting. With these learnings, we hypothesized that a compound with a same or better activity as lorlatinib that also avoids Trk-related neurotoxicities could become a best-in-class ALK inhibitor with the potential to displace both lorlatinib and alectinib as a new front-line standard of care. This became our target product profile for a novel ALK-selective inhibitor. In ROS1, the medical needs [ are comparable ]. There are 3 approved therapies for patients with ROS1-positive non-small cell lung cancer, with the standard of care being crizotinib. Crizotinib's limitation is that it's not highly brain penetrant, so patients will often experience progression with CNS disease. Disease will also progress with ROS1 resistance mutations. Both of the other approved therapies, entrectinib and repotrectinib, are brain-penetrant dual-Trk ROS1 inhibitors; and CNS neurotoxicities have been observed. As with experience with lorlatinib for ALK, dual-Trk ROS1 inhibitors have not managed to supplant crizotinib as a front-line standard of care. Our approach for ROS1 was to design a novel ROS1-selective compound that can hit the ROS1 oncogenic driver, address or prevent ROS1 resistance mutations, have excellent brain penetrance and avoid Trk-related neurotoxicities. With this target product profile, our goal is to create a best-in-class compound that could eventually displace crizotinib as the new front-line standard of care. Our approach of targeting an established oncogenic driver while also addressing resistance mutations, brain penetrance and selective inhibition is a well-understood strategy in precision oncology drug development. One of the most notable examples of this strategy is in the EGFR space, as summarized on Slide 5. Osimertinib solved for each one of these criteria as a third-generation EGFR inhibitor. Originally, it was approved in previously treated patients with EGFR non-small cell lung cancer, but because it had a better overall profile than the earlier-generation EGFR inhibitors gefitinib and erlotinib, it was able to supplant those as the new standard of care. Since the approval of osimertinib, the annual sales of EGFR inhibitors have more than doubled. This is encouraging for the Nuvalent portfolio because, as been shown -- as shown on Slide 6, the market for ALK and ROS1 inhibitors are already interesting. ALK non-small cell lung cancer represents a greater than $2 billion market with alectinib, the current standard of care, generating $1.9 billion in sales in 2023 alone. Similarly, crizotinib, the current standard of care in ROS1, generates just under $0.5 billion in sales per year. Our goal with both of these programs is to drive even deeper and more durable responses, keeping patients on therapy for years and enabling the opportunity to grow these already compelling ALK and ROS1 markets. Importantly, it's not just the first-line markets that are interesting to us. For example, in the second-line ALK market, the current standard of care is lorlatinib, which achieved over $500 million in sales in 2023 and continues to grow. Our ALK and ROS1 programs were designed to provide opportunities for patients in all lines of treatment. And as we will discuss today, we believe that the clinical data from both programs continues to support this potential. With that, let's dive into the update for zidesamtinib, our novel ROS1-selective inhibitor which is being studied in the ongoing Phase II portion of our ARROS-1 clinical trial for patients with ROS1-positive non-small cell lung cancer. I would like to invite our CMO, Chris Turner, to summarize [ the updated data from ] the Phase I portion of the trial, which was fully enrolled as of August 2023. Chris?

Thanks, Jim. And thank you all for joining us today. Earlier today, we reported updated data from the fully enrolled Phase I portion of the ARROS-1 trial, which in our view continues to support the opportunity for zidesamtinib as a potential best-in-class treatment for patients with ROS1-positive cancers. The following clinical data were presented during the oral presentation at ESMO by Dr. Benjamin Besse, Director of Clinical Research at Gustave Roussy. Slide 8 summarizes the patient population and the key objectives of the Phase I portion of the ARROS-1 trial. Patients with non-small cell lung cancer enrolled in the Phase I portion of the trial must have received at least one prior ROS1 TKI. There was no limit to the number of prior chemotherapy and/or immunotherapy allowed. In January 2022 to August of 2023, 104 patients were enrolled across 6 dose levels ranging from 25 milligrams to 150 milligrams once daily, with 71 patients with ROS1-positive non-small cell lung cancer evaluable for responses as of the data cutoff of July 1, 2024. We're very pleased with the enrollment of ARROS-1, which reflects the broad clinical site activation across global regions with -- and strong investigator enthusiasm for zidesamtinib. We aligned with the FDA on the recommended Phase II dose of 100 milligrams once daily. No clinically significant exposure-response relationships for safety and efficacy were observed. And Phase I data are subsequently reported for all doses. Slide 9 outlines the baseline characteristics of the 104 patients enrolled. The study population was heavily pretreated, with a median of 3 lines of prior therapy. 69% of the patients had received 2 or more prior ROS1 TKIs, and 66% had received prior chemotherapy. Notably, 55% of the patients had received prior lorlatinib and 21% had received prior repotrectinib, highlighting the differentiated nature of this population from prior trials of investigational ROS1 inhibitors. Additionally, 52% of the patients had a history of CNS metastases, including cases of disease progression following treatment with brain-penetrant TKIs lorlatinib and/or repotrectinib. Slide 10 shows that radiographic tumor regressions have been observed across heavily pretreated patients with ROS1-positive non-small cell lung cancer. Of the 71 response-evaluable patients treated across all dose levels, an objective response rate or ORR of 44% was observed by RECIST 1.1 regardless of the -- of prior ROS1 TKIs, with or without chemotherapy. In the subset of 53 patients that were repotrectinib naive, an ORR of 51% was observed; and in those with G2032R mutation, ORR of 72%. Activity against ROS1 mutations is important to drive more durable responses in all lines of therapy, as they are key reasons for the disease progression. Encouraging activity was observed in patients receiving zidesamtinib as third-line therapy or beyond, which is the population for which zidesamtinib has generated breakthrough designation by the FDA and for which there are no approved therapies. In all response-evaluable patients previously treated with 2 or more ROS1 TKIs, an ORR of 41% was observed. In the subset of patients that had previously received lorlatinib, an ORR of 44% was observed. And in the subset of patients who were repotrectinib naive, an ORR of 47% was observed. We are also encouraged by the preliminary activity observed in a subset of patients receiving zidesamtinib as second-line therapy, following the front-line standard of care crizotinib, with or without prior chemotherapy. Here an ORR of 73% was observed. Slide 11 shows that responses to zidesamtinib were durable in this population of patients with previously treated ROS1-positive non-small cell lung cancer. In all responders among patients treated with up to 4 ROS1 TKIs with or without additional chemotherapy, a median duration of response or DOR was not reached. Estimated probability of continued response or DOR rate was 67% at 12 months. In the subset of responders that were repotrectinib naive, the median DOR was not reached, and the 12-month DOR rate was 71%. For responders receiving zidesamtinib as a third-line therapy or beyond, the median DOR was 12.1 months and the 12-month DOR was 54%. For responders receiving zidesamtinib as a second-line therapy after crizotinib, the median DOR was not even reached, and there was no disease progression among responders. Slide 12 shows that treatment with zidesamtinib also resulted in durable responses for patients with CNS disease. In intracranial response-evaluable patients with measurable CNS lesions, an intracranial ORR of 50% was observed. Of note, 7 of 8 intracranial response-evaluable patients have been previously treated with the brain-penetrant TKIs lorlatinib and/or repotrectinib. No CNS progression was observed among all confirmed CNS responders. Moving now to safety. As shown on Slide 13, the preliminary safety profile of zidesamtinib continues to be favorable and supportive of its highly ROS1-selective Trk-sparing design. Here we are reporting treatment-related adverse events that occurred in 10% or more of the 104 patients treated across all doses. The most frequent treatment-related adverse events were peripheral edema in 19% of patients. And ALT increased, AST increased and weight increased each in 11% of patients. Treatment-related adverse events requiring dose modification were infrequent, with dose reductions occurring in 8%. There were no discontinuations due to treatment-related adverse events. This preliminary overall safety profile is consistent with avoiding Trk-related neurotoxicities. With that, I'll turn the call back over to Jim.

Thanks, Chris. We are incredibly pleased with these updated data on the Phase I portion of our trial. As summarized on Slide 14, even in heavily pretreated patients, zidesamtinib demonstrates durable activity, with the potential to address each key area of its target product profile, including activity against ROS1 resistance mutation, CNS activity and avoidance of Trk-related CNS adverse events that can be dose limiting. We believe these data continue to support zidesamtinib's potential as a differentiated best-in-class ROS1-selective inhibitor. Turning to Slide 15. The goal for all of our programs is to not only address the limitations of existing therapies for later-line patients but to develop treatments that can move up the treatment paradigm and grow the market with deep, durable responses. Today, there is no clear standard of care for patients who have experienced disease progression on an initial ROS1 TKI. Zidesamtinib has demonstrated the ability to deliver durable responses for patients in later-line treatment, even in those that have exhausted all available options, and in patients whose disease have progressed with ROS1 resistance mutations or with CNS metastases. Preliminary activity of zidesamtinib in this population of patients previously treated with 2 or more ROS1 TKIs, for which it received FDA breakthrough therapy designation, highlights a near-term opportunity to address a clear medical need. In this population, ORR was 41%, with a median duration response of 12.1 months and a 12-month DOR rate of 54%. Comparative benchmarks are limited due to the differentiated, heavily pretreated nature of our Phase I population from prior trials of investigational ROS1 inhibitors. However, we note that, for patients receiving prior crizotinib as their only ROS1 TKI, a 73% ORR was observed; and there has been no disease progression among responders. We are encouraged by the potential for these data to translate to deep, durable responses in the front-line setting, where we believe we have the opportunity to supplant crizotinib as a standard of care. Investigation of zidesamtinib for TKI-naive patients with ROS1-positive non-small cell lung cancer is ongoing in the Phase II portion of the ARROS-1 trial. The enthusiasm for zidesamtinib is widespread, as evident on Slide 16 and the incredible enrollment momentum we've experienced in our ARROS-1 trial. As we just shared, we enrolled a total of 104 patients in our Phase I trial in just over 1.5 years. Since we initiated the Phase II portion of the trial, we have enrolled an additional 227 patients, for a total of 331 patients treated with zidesamtinib as of September 1, 2024. The rate of enrollment in this clinical trial has been remarkable and speaks to the enthusiasm from the patient advocacy and physician communities for zidesamtinib. We are grateful for and humbled by the support. And we are committed to bringing zidesamtinib to patients with ROS1-positive non-small cell lung cancer as quickly as possible. Turning to Slide 17, we're excited to share, with this rate of enrollment, we expect to report pivotal data from the ongoing Phase II portion of the ARROS-1 trial in 2025. The progress made by the team on the zidesamtinib program is remarkable. We would now like to turn to the update from our NVL-655 program. NVL-655 is our novel ALK-selective inhibitor which is being studied in the ongoing Phase II portion of our ALKOVE-1 clinical trial for patients with ALK-positive non-small cell lung cancer. The Phase I portion of the ALKOVE-1 trial was fully enrolled as of February 2024, and I'd like to invite Chris back to summarize the updated data.

Thanks, Jim. The following updated clinical data from the Phase I portion of the ALKOVE-1 trial were presented during an oral presentation at ESMO by Dr. Alexander Drilon, chief of the early drug development service at Memorial Sloan Kettering Cancer Center. We believe these data continue to support the opportunity for NVL-655 as a potential best-in-class treatment for patients with ALK-positive cancers. Slide 19 summarizes the patient population and key objectives of the Phase I portion of the ALKOVE-1 trial. Patients with non-small cell lung cancer enrolled in the Phase I portion of the trial must have received at least one prior second- or third-generation ALK TKI. Up to 2 prior lines of chemotherapy and/or immunotherapy were allowed. From June 2022 to February of 2024, 133 patients were enrolled across 6 dose levels ranging from 15 milligrams to 200 milligrams once daily, with 52 patients enrolled at our recommended Phase II dose of 150 milligrams once daily. As of the data cutoff of June 15, 2024, there were a total of 103 patients with ALK-positive non-small cell lung cancer evaluable for response, including 39 patients at the recommended Phase II dose. Similar to our experience in ARROS-1, the rapid enrollment reflects broad clinical site activation across global regions and strong investigator enthusiasm for NVL-655. Slide 20 outlines the baseline characteristics from the 133 patients enrolled. The study population was heavily pretreated, with a median of 3 lines of prior therapy. 46% of the patients had 3 or more prior ALK TKIs and 56% had prior chemotherapy. Notably, 84% of the patients received prior lorlatinib. And 51% have secondary ALK resistant (sic) [ resistance ] mutations, including 26% with more than one or compound ALK mutations. 56% of the patients had a history of CNS metastases, including cases of disease progression following treatment with brain-penetrant TKI lorlatinib. These characteristics highlight the differentiated nature of this population from prior trials of investigational ALK inhibitors. Slide 21 shows radiographic tumor regressions that have been observed across heavily pretreated patients with ALK-positive non-small cell lung cancer. Of the 103 response-evaluable patients, the ORR as observed by RECIST 1.1 was 38% across all doses regardless of the number of prior ALK TKIs and with or without chemotherapy. Encouraging activity was observed in the subset of patients receiving NVL-655 as third-line therapy or beyond, where there are no approved therapies. And NVL-655 has received breakthrough therapy designation by the FDA. In all response-evaluable patients previously treated with 2 or more ALK TKIs, including lorlatinib, with or without chemotherapy, ORR of 35% was observed across all dose levels. In the subset of patients with compound ALK mutations such as those observed following treatment with sequential alectinib and lorlatinib, the ORR was 54% across all dose levels. In these later lines of therapy, activity against compound mutations is important to drive more durable responses. We're also encouraged by preliminary activity in the subset of patients who were lorlatinib naive and received NVL-655 as a second-line therapy or beyond. In these lorlatinib-naive patients, ORR was 53% across all dose levels. In the subset of lorlatinib-naive patients with any ALK resistant mutation, the OR was 88% across dose levels. Here again, ALK resistant mutations are known to lead to disease progression. And the activity observed with NVL-655 supports the potential to improve durability of response for patients in earlier lines of therapy. In all cases, response rates in patients who received the RP2D were similar to those seen across all dose levels. Slide 22 shows that, even in this heavily pretreated patient population, preliminary evidence of durable tumor responses has been observed across all doses. For responders among patients who are previously treated with up to 5 ALK TKIs, with or without additional chemotherapy, the median DOR was 14.4 months and the 6-month DOR rate was 78%. In the subset who were lorlatinib pretreated and received NVL-655 as third-line therapy or beyond, the median DOR was 9.2 months and the 6-month DOR was 75%. In the subset who were lorlatinib naive and received NVL-655 as second-line therapy or beyond, the median DOR was not reached, and the 6-month DOR rate was 88%. At the RP2D across each of these subgroups, the median DOR was not reached, and the 6-month DOR rate was 100%. Slide 23 shows that responses were also durable in heavily pretreated patients with ALK resistant mutations. Across all doses, the median DOR was 14.4 months for responders with any ALK resistant mutation; and for the subset of patients with compound ALK resistant mutations, following at least 2 prior TKIs, including lorlatinib. The 6-month DOR rate were 85% and 80%, respectively. For each of these subgroups at the RP2D, the median DOR was not reached and the 6-month DOR rate was 100%. Within the responders who are lorlatinib naive, with any ALK resistance mutation, there has been no disease progressions at either all dose levels or at the recommended Phase II dose. Slide 24 shows that treatment with NVL-655 also resulted in durable responses in patients with CNS disease. Intracranial responses were observed in patients with either measurable or unmeasurable CNS lesions, including complete intracranial responses in patients who previously received the brain-penetrant TKI lorlatinib. Lorlatinib has demonstrated impressive CNS activity, and any signs of clinical activity in CNS beyond lorlatinib is encouraging. As of the data cutoff, no CNS progression was observed among confirmed responders. On Slide 25, we present a new case study of intracranial responses following treatment with NVL-655. This patients had been previously treated with 3 lines of therapy including platinum-based chemotherapy, alectinib and lorlatinib; and experienced progression with CNS disease on lorlatinib. ALK G1202R and C1156Y resistant (sic) [ resistance ] mutations were present upon entry to the ALKOVE-1 study. Following treatment with NVL-655 at the recommended Phase II dose, complete resolution of multiple CNS lesions was achieved after 4.5 months of therapy. This patient remains on treatment, 11.4 months, with an ongoing confirmed CNS complete response. On the bottom of the slide, follow-up of -- on previously presented cases is provided. For these 2 heavily pretreated patients, the previously reported CNS responses continue, with treatment durations now out to 14.4 and 13.9 months. Moving to safety on Slide 26. We continue to be encouraged by preliminary safety profile of NVL-655, which has been observed to be favorable and consistent with its ALK-selective Trk-sparing design. Here we present treatment-related adverse events that have been reported in 10% or more of the 133 patients treated across all doses. Treatment-related adverse events with the highest incidents were ALT increase reported in 34% of patients, AST increase reported in 30% [ of patients ], constipation reported in 16% of patients, dysgeusia reported in 13% of patients and nausea reported in 12% of patients. In general, treatment-related adverse events requiring dose modification were infrequent, with discontinuations occurring in 2% of patients and dose reductions occurring in 15% of patients. Overall, NVL-655 is well tolerated. And the preliminary safety profile was consistent with avoidance of Trk-related neurotoxicity. 150 milligrams was selected as the recommended Phase II dose. At this dose, NVL-655 maintains steady-state plasma levels at or above target efficacy thresholds for ALK fusions and ALK single and compound mutations in both the periphery and in the CNS. And there was no clear dose-toxicity relationship through the 150-milligram once-daily dose level. With that, I'll turn the call back over to Jim.

Thanks, Chris. At the outset of this program, we set out to create a best-in-class treatment for patients. And we are incredibly pleased with these updated data from the Phase I portion of our trial. As summarized on Slide 27, the durable responses observed in this heavily pretreated population and across patient subgroups, combined with durable intracranial responses, encouraging clinical activity and a preliminary safety profile consistent with its Trk-sparing design, continue to suggest that NVL-655 has the potential to address the medical needs of patients with ALK-positive non-small cell lung cancer and to overcome the limitations of the first 3 generations of ALK TKIs. As with ARROS-1, the enthusiasm for our ALKOVE-1 trial is clear, as shown by the enrollment rates on Slide 28. Following the enrollment of 133 patients in our Phase I in just over 1.5 years, we have subsequently enrolled 229 patients in the Phase II portion of the trial, for a total of 362 patients treated with NVL-655 as of September 1, 2024. Based on these enrollment rates, we're happy to share that we also expect pivotal data from the Phase II trial in 2025. The Phase II cohorts are designed to support global registration for patients with TKI-pretreated ALK-positive non-small cell lung cancer, as described on Slide 29. In this industry, bringing a single drug from discovery to pivotal readout is no small feat. Remarkably, we are on track to do that for 2 drugs next year, zidesamtinib and NVL-655. Importantly, the progress in our ALKOVE-1 trial and enthusiasm from patients and physicians supports the investigation of NVL-655 earlier in the treatment paradigm. Today, we're excited to be unveiling the next component of our ALK development strategy: our ALKAZAR Phase III randomized controlled trial of NVL-655 in the front-line setting. The evolution of our ALK franchise is illustrated on Slide 30. We chose to name our Phase I/II trial ALKOVE to reflect our foundational aspiration providing a place for patients with later-line ALK-positive non-small cell lung cancer to turn to. Many of the patients enrolled in the Phase I portion of our ALKOVE-1 trial have received multiple lines of treatment prior to joining our study. And we're encouraged that NVL-655 has demonstrated activity even in those who had exhausted all other treatment options. As we look to our ultimate goal of becoming the preferred treatment option for all patients with ALK-positive non-small cell lung cancer, we are inspired by the strength and durability of a fortress designed to be the stronghold of defense for an entire population. The name ALKAZAR reflects our aspiration for the Phase III trial to establish NVL-655 as a potential best-in-class molecule for all patients with ALK-positive non-small cell lung cancer. Our study design for ALKAZAR is illustrated on Slide 31. This will be a Phase III randomized controlled trial designed to support the global registration of NVL-655 for the treatment of patients with TKI-naive ALK-positive non-small cell lung cancer, reflecting alignment with the FDA and input from collaborating physician scientists. The ALKAZAR trial will enroll approximately 450 patients, who will be randomized 1:1 to receive NVL-655; or alectinib, the current standard of care for front-line ALK patients. Primary end point is progression-free survival based on blinded independent central review. We expect to initiate the ALKAZAR study in the first half of 2025. As summarized on Slide 32, with the ALKAZAR study, we are well positioned to evaluate the potential for NVL-655 to move up the treatment paradigm for patients with advanced ALK-positive non-small cell lung cancer. Today, there is no clear standard of care in the third line following progression on 2 ALK TKIs such as sequential alectinib and lorlatinib. NVL-655 has received FDA breakthrough therapy designation in this population based on its preliminary Phase I activity, highlighting a near-term opportunity to address a clear medical need for patients who have exhausted all available therapies and whose disease may have progressed with single or compound ALK mutation or CNS metastases. In the second line, the current standard of care is lorlatinib. While still early, preliminary data for NVL-655 is encouraging in the population of lorlatinib-naive patients following treatment with one or more prior second-generation ALK TKIs. At the recommended Phase II dose, the ORR was 57%, with median duration response not reached and no disease progression among responders. In lorlatinib-naive patients with any ALK resistance mutation, treatment with NVL-655 at the recommended Phase II dose achieved an 80% ORR. And there was no disease progression among any responders at all dose levels. Moreover, NVL-655 has also demonstrated the ability to deliver deep and durable responses for patients that have experienced disease progression on lorlatinib with compound resistance mutations. At the recommended Phase II dose, the ORR was 64%, with a 6-month DOR rate of 100%. While the median DOR was not yet reached at the recommended Phase II dose, it was 14.4 months across all doses. These data suggest the potential for more durable responses in patients if treated with NVL-655 in the second-line setting. Moving to the front line. The standard of care is alectinib. In its Phase III ALEX trial versus crizotinib, alectinib delivered 25.7 months PFS in the front line, establishing it as the preferred treatment option for patients with ALK-positive non-small cell lung cancer. However, the literature now suggests that it is possible to deliver even more durable responses with a differentiated profile. Notably, a median PFS was not reached after 5 years of follow-up, in a recent update from Pfizer's CROWN study of lorlatinib versus crizotinib. While lorlatinib was designed to improve upon crizotinib through addressing the limitations of brain penetrance and disease progression due to single ALK resistance mutations, we believe that NVL-655 is the only investigational therapy today with the potential to also avoid Trk-related adverse events, in addition to demonstrated activity against both single and compound ALK resistance mutations. Notably, treatment with NVL-655 at the recommended Phase II dose achieved a 55% ORR in patients with any ALK mutation; and 71% ORR in patients with ALK G1202R mutation, the most common mutation observed in patients with prior disease progression on alectinib, with no progression events in lorlatinib-naive responders with ALK resistance mutations. This suggests that NVL-655 may have the potential to limit the emergence of on-target ALK required resistance mutations that may lead to disease progression if utilized in earlier lines of treatment. Overall, we believe that the encouraging profile demonstrated, so far, in a heavily pretreated population puts NVL-655 in a strong position to demonstrate clinically and statistically meaningful benefit versus alectinib in the front-line setting. We are incredibly excited about this opportunity and anticipate initiating the ALKAZAR trial in the first half of 2025. In closing, on Slide 33. This is a remarkable time in the evolution of our company. Nuvalent was born from a desire to approach drug discovery and development differently. We believe that, through deep expertise in chemistry and structure-based drug design, collaboration with physician scientists and a commitment to best-in-class profiles, we can maximize impact through delivering deep, durable responses for patients with cancer. What started just 6 years ago as a dream and a list of targets on a whiteboard has evolved into a company with 2 parallel lead programs and ongoing global registration-directed trials with pivotal readouts on the horizon, a global Phase III trial poised for initiation, a third program now in clinical development and a robust discovery pipeline. This evolution reflects the passion and dedication of an incredible network of people. To the Nuvalent team, collaborators and advisers, I hope you are as proud as I am of this incredible accomplishment that these updates represent. It's truly an honor to be on this journey with you. Most importantly, we recognize that these milestones are made possible by the patients, caregivers and investigators who are participating in our clinical trials. It is because of you that we are able to do this work, and we offer you our most sincere gratitude. Our work is not yet done. Looking ahead, we have a number of meaningful catalysts anticipated in 2025, including initiation of our Phase III ALKAZAR trial for front-line ALK in the first half of the year, supporting pivotal data from both our ROS1 and ALK programs and progressing our Phase I HEROEX trial for our HER2 program. We look forward to sharing more updates in the months and quarters ahead as we advance towards our first potential approved product in 2026. With that, we'd be happy to take your questions.

[Operator Instructions] Your first question is from [ Brad Branino ] from Stifel.

It's Brad Canino. Congrats on the data and enrollment execution. A quick clarification on the data and then a question because I want to know. For NVL-655, this might have been in the slides, but at the RP2D where you had 15 responders, how many of those remain and responds at this update?

Yes. So thanks, Brad. We're pleased with what we're seeing with the durability. The -- what we had said, from all the patients at the recommended Phase II dose, we had shared, across all patients, 2 prior, including lorlatinib; and then the lorlatinib naive. We did not, I think, share that -- the specific question you asked regarding how many patients continue on treatment. What we did share is that we've seen very few patients discontinue NVL-655 due to treatment-related adverse events. I think the number was 3 of 133, so obviously the drug is well tolerated. And patients are continuing on therapy almost uniformly...

But at the RP2D, what number have progressed after having a response?

Sure, sure, yes. So I think, if you just go through the curve, you can find that, of all the patients that have taken NVL-655 at the recommend Phase II dose, only a single patient has progressed. So we're pretty encouraged by that. The idea was, if we have excellent coverage of the ALK resistance mutations seen beyond other therapies like alectinib and lorlatinib, we have excellent CNS progression and the drug is well tolerated, that we will be able to treat patients in any line of ALK therapy. It could be third-, fourth-, fifth-line ALK non-small cell lung cancer but also, ideally, moving up the treatment paradigm, second line and front line. And we're seeing at the recommended Phase II dose that really playing out. We're driving deep, durable responses. Patients are staying on therapy. And it sort of supports pushing this drug earlier in the treatment paradigm.

Got it, great. And then for the question: Given you enrolled 230 treatment-experienced patients in ALKOVE in 6 months, should I think of that as a similar run rate of what's possible to recruit, the 450 treatment naive, for ALKAZAR? Or are there other things to consider in that extrapolation? Because I say that knowing ALEX and CROWN studies took about 18 months to enroll.

Yes. So first, on -- thanks, Brad. On the execution on ALKOVE-1, we obviously enjoy the outstanding collaboration from the physicians that are executing on the ALKOVE-1 study. We really owe a lot to their partnership on this program, but I'd also like to point out just the Nuvalent team for executing. I haven't been involved, in my career, in many studies that have this much demand and interest and enrollment. And it's really humbling and rewarding for our team, knowing that we're working on something that there is such broad enthusiasm for enrolling in the study. And I really compliment the Nuvalent team for being able to keep up on the execution, making sure we have the appropriate supply. It's just phenomenal execution. How that relates to Phase III enrollment. This is potentially treatment-paradigm-changing study, right? And we want to be the leaders in the ALK space. The current standard of care is alectinib. We want to compare our drug to alectinib and show that NVL-655 is better. I think investigators globally, based on our discussions with them, would be excited to participate in such a treatment-paradigm-changing study. We expect the trial to enroll well. Hard to say how fast it will enroll, but we expect broad enthusiasm, excellent enrollment. And obviously our team is committed to execute on that as quickly as possible.

Your next question is from Anupam Rama from JPMorgan.

Congrats on the update. For NVL-655, I noticed that you did give a breakdown by RP2D for response and DOR. Unless I missed it, I didn't see that for zidesamtinib. How did the RP2D dose of 100 mg QD for zidesamtinib? Any color on how that looks relative to the totality of data you presented?

Yes. Thanks, Anupam, yes. So maybe that didn't come through in the presentation. What we found with zidesamtinib is that we saw comparable -- basically no exposure-response relationships for safety or activity across the entire dosing, starting from 25 mg all the way through 150 mg. We ended up picking 100 mg as a recommended Phase II dose because it provided excellent coverage of the target efficacy thresholds, but the lowest dose, 25 mg, was just as active as 100 mg. And it was just as well tolerated at 100 mg as it was at 25 mg, so we just reported the data across all doses from -- in the Phase I, whereas within NVL-655 we are seeing better target coverage at those higher dose levels, particularly at the recommended Phase II dose of 150 milligrams. And because we're seeing better target coverage, we reported the data for both at the RP2D as well as all dose levels. what you -- I think you saw is that we're starting to see some interesting trends emerge at the recommended Phase II dose, where pretty uniformly it's driving more durable responses than the duration response across all dose levels.

Your next question is from Marc Frahm from TD Cowen.

Congrats on the data today. Maybe, first, on just thinking through filing strategy, I guess. What are the kind of key questions that you still need to discuss with the FDA now that you have all of these patients enrolled? And are you expecting the initial filing to include a request for a second-line label? Or just third line, people who've seen alectinib and lorlatinib.

Yes, thanks, Marc. We're going to push forward on all of them, but I'm going to turn this over to our Chief Development Officer, Darlene Noci.

Thanks, Jim. So we are seeing excellent enrollment in both the ALKOVE-1 and the ARROS-1 studies, and this is regardless of cohort. We are really excited by the data, the clinical data that's been generated to date. So the TKI-pretreated patients, including an [ RP2D ] population. We also have an open dialogue with regulators, and we consider them as partners with us in the global development strategy. We plan to explore all available opportunities to accelerate the development programs to bring these products to patients as quickly as possible.

Okay. And then maybe to follow up on one of Brad's questions, just thinking through kind of the enrollment rate that you're seeing here in the Phase II portion versus what we might see in the Phase III. Just are there kind of pushes and pulls you'd note in terms of trial site number -- the site numbers you're expecting or kind of the start-up activities that might be associated with that, to kind of think of how much faster or slower this might go once you open up the Phase III?

Yes. I mean what's interesting here is the Phase II just started in February. And we don't even have all of the sites open yet in the Phase II. We had planned for a seamless transition, but we're still getting sites opened. We still enrolled 230 patients in the last 6-plus months. So Phase III trials, it will be a different protocol. It would be many of the same sites we would use, but also we would use more. And there's always a process for getting any study up and running. Our team is preparing for that right now, but we hope to execute just like we've executed in the ALKOVE-1 study to get this trial enrolled as fast as possible and push this ALKAZAR program forward.

Your next question is from Chris Raymond from Piper Sandler.

Congrats, from us, on the data. 2 questions, I guess, on both assets. I know there's been a focus on duration of response for approved agents in the ALK and ROS1 settings, but you guys had a lot of patients with stable disease in both trials. Maybe, can you help sort of frame the importance of driving durable stable disease for patients and how we should think about PFS sort of in that context? And then another sort of question on 655 specifically. We've gotten some questions from investors this morning around CNS activity. I think you had 15% intracranial ORR, but I know some of these patients discontinued treatment in the absence of CNS progression. How do we think about the data, I guess, translating to earlier lines of therapy in terms of mutational coverage?

Sure. Thanks, Chris. Let me start with the PFS question. So keep in mind this is a Phase I study. These patients have exhausted available options, right? And we're enrolling patients that have really taken the other therapies like alectinib or lorlatinib; in many cases, chemotherapy. And the drug is still active. I think, in a single-arm study, the way we're going to look at this early data is can we shrink tumors in these patients. Are the patients responding? And are those responses durable? An end point like progression-free survival is certainly important. I know the way regulators often look at single-arm studies is they're keen in on response rates and on the duration of response as well as safety. That's what you often find in a single-arm approved label. We'll certainly be looking at progression-free survival, but that's often an end point that's reserved for comparing 2 different drugs in a randomized setting versus in a controlled patient population, so as we think about the Phase II and obviously the Phase III, that is an appropriate end point that we'll be gathering. But for Phase I, we thought the best way to tell what we're learning are, are we shrinking tumors. Yes. And those responses are durable, which is very encouraging for both of these drugs, zidesamtinib and NVL-655. With respect to CNS activity, I'm going to turn this over to our Chief Medical Officer, Chris Turner, to address that.

Right. So thanks. So Chris, as you know, more than 80% of the patients have seen lorlatinib in this trial. And lorlatinib has demonstrated really good CNS activity, so any signs of activity in the brain beyond lorlatinib, we view as encouraging. The intracranial responses that we have observed in patients have either measurable or unmeasurable lesions that we've seen complete responses in patients who have seen the brain-penetrant lorlatinib, so we're really encouraged by the activity that we're seeing. And we certainly believe that this preliminary data suggests the potential for durable intracranial responses and certainly as we move up the lines of therapy as well.

Your next question is from Andrew Berens from Leerink Partners.

Congrats on all the progress and the accelerated time lines for the ALK program. I've got a few: I noticed in the lorlatinib-naive patients with ALK resistance mutations the ORR was actually higher at the lower doses. And obviously some of that could have been due to the small sample in that cohort, but just wondering. Given the lack of dose response and the high activity across all levels as well as the AL/AST elevations you're seeing, which I assume could be exposure related, I'm just wondering how confident you are in the go-forward dose of 150 mg and whether you think the agency is going to agree that that's the right dose. And then you didn't mention an interim look in ALKAZAR for ORR. Is that off the table now? We hear, the agency from other sponsors, that they are encouraging an interim look for ORR, as long as there's a favorable trend in OS and the pivotal trial is largely enrolled, so just wondering if we could get an interim look at the data.

Yes. Thanks, Andy. I'll start with the first question, about the recommended Phase II dose for NVL-655. Yes, we're absolutely confident in 150 mg as the recommended Phase II dose. We aligned with the FDA earlier this year on that dose based on the totality of all data that we had generated. And we since then have enrolled 230 patients at that recommended Phase II dose, and that is the dose we'll take forward in the randomized Phase III ALKAZAR study. We are not going to discuss the statistical assumptions, at this point, in the Phase III planned study, the ALKAZAR study. You are right that other -- there are other examples where interim analyses are used. What we understand from that precedent is, when you have progression-free survival as an end point, the FDA would want to make sure that you have overwhelming efficacy, evidence of overwhelming efficacy, at that interim analysis to consider stopping at the interim analysis. That's -- certainly that's something that we understand about that precedent, but we're not -- we're just not at the point right now where we want to go through the exact statistical assumptions of our study. We have -- we are greatly aided by the fact that there's a lot of precedents in the ALK non-small cell lung cancer space. There's 4 other randomized studies that have been done in the advanced metastatic setting, so a lot of learnings that we can take from those trials and including several of them that did include interim analyses in their studies.

Okay. And then during the presentation, Dr. Drilon made a couple of comments that the optimum pivotal trial would be against lorlatinib but that the practical considerations would make that trial difficult because of the time to complete it. Just wondering what you guys think about those comments that he made. And are you getting a sense that lorlatinib is actually starting to get traction in the first line? Because that's not what -- that's not the sense we're getting, but it was surprising to hear him make those comments.

Yes, sure, Andy. So we work with many of the leading academic KOLs in the world in the ALK non-small cell lung cancer space. And we've been discussing this program with them since we started the company 6 years ago, so we understand how they view this landscape. Most will tell you that they think lorlatinib is the most active drug. And they want to put the most active drug upfront, but some of them, once the initial CROWN data read out a few years ago and lorlatinib is approved front line, didn't make that switch. They felt they had enough knowledge to manage the CNS toxicities that are associated with lorlatinib, but many of those same physicians will tell you that they know the broader community is not going to make that switch because of the accompanying CNS toxicity that happens with lorlatinib because it hits Trk in the brain. So the -- as you know, Andy, like, the current standard of care is still alectinib. That's where it's primarily used globally. We talked with global investigators of what is the right study to do. And the study design for ALKAZAR would be randomizing 1:1 NVL-655 versus alectinib. And we're excited to kick that study up.

Your next question is from Richard Law from Goldman Sachs.

Congrats on the data. So I just want to follow up on what you guys said earlier. Any thoughts on why you're not seeing dose response in ARROS for 520 but you are seeing for 655? And was that traceable back to your PK data? And then also following up on that, I know you guys already aligned with the FDA the 100 mg as pivotal dose for ROS1, but since there's no dose response here, are you obligated to go back and review the new data with the FDA in the near future? And how do you assess the risk that the agency could require you to run a lower dose in light of Project Optimus? And then I have a couple more questions.

Yes, thanks, Rich. So yes, this actually has to do completely with the design of these molecules. This is true precision oncology here, right? Zidesamtinib was designed to cover the known resistance mutations occurring beyond the earlier-generation ROS1 inhibitors and with also excellent CNS penetrants. And it turns out that -- and these -- both these molecules have outstanding pharmacokinetic properties. And with those outstanding pharmacokinetic properties, we get excellent coverage of ROS1 fusions as well as those ROS1 resistance mutations with zidesamtinib at the lowest dose level. That's actually -- that's based on what we saw nonclinically. The drug was so well tolerated nonclinically. We are able to start at biologically active doses that were above that target efficacy threshold. You don't often get that in precision oncology, but because this one is so selective, we're able to do that, so we weren't surprised at all that there was not a dose response as we increased, that we had sort of maxed out those resistance mutations at the lowest dose level. And no, we don't need to go back to the FDA because we've aligned with the FDA that this was the right strategy. And we did that last year, when we transitioned to the Phase II in September. Now the reason it's -- there was a better target coverage for NVL-655 is we're trying to cover more ALK resistance mutations, single mutations beyond alectinib, compound mutations and single mutations that happen beyond lorlatinib. And doing so just requires us to go to a higher dose level. It's just a little bit more complex of a chemistry problem to solve. Now we solved it with 655. It just required more dose, but excellent pharmacokinetic properties from both molecules, alignment with the FDA on both molecules, we are very comfortable with our recommended Phase II dose for both programs.

I see. Got it. And then you guys didn't study first-line patients here, but is it reasonable to expect that 655 could significantly improve on lorlatinib's duration and survival in CROWN, based on the ORR and DOR data that you show here in ALKOVE, where 84% of patients already had prior lorlatinib.

Yes. So clearly, 655 is showing that it's active beyond lorlatinib, but the activity of lorlatinib in front-line patients is not really the problem. That drug is a very active drug in front-line patients. And it's good enough at covering out mutations in front line that you're not seeing the emergence of. The challenge with lorlatinib in front line is that it's not very well tolerated, right? It has the CNS toxicities. And that's been the main reason why many physicians have not made that switch from replacing alectinib with lorlatinib. Now when those ALK mutations do occur beyond alectinib, lorlatinib is actually not very good at treating those patients with those ALK mutations. And that's evidenced by the data that we've generated in our ALKOVE-1 study, so we're seeing patients progress on lorlatinib with single mutations or compound mutations. And in both instances, we're seeing those patients respond to NVL-655. And we're seeing very impressive durability even beyond lorlatinib, so it does portend well that, if we were actually to put 655 in the front-line setting, we would think it would be at least as active, if not more active, than lorlatinib and, hopefully, not have those same off-target toxicities that have been the reason that lorlatinib has not really seen the uptake in the front-line setting. Does that make sense, Rich?

Yes. No, very helpful. And then last question from me: What's the most common AEs below the 10%? And I think I saw a lot of AEs above 10%. Any remarkable, anything remarkable to call out for the CNS AE?

Yes. I'll let Chris take that one.

Yes. In this larger ESMO data set, we've reverted to the more common and customary use of 10%. This is -- reflects the number of patients with a broader period of time that we've studied here. We, ongoing, look at -- comprehensive at safety. And we still are comfortable with the overall safety profile, that Trk-sparing design of the selective ALK inhibitor.

Your next question is from Charles Zhu from LifeSci Capital.

Congrats on all the data and the progress. My first one is a bit of a follow-up on some of Andy Berens' prior comments and questions, but some of our KOL checks do seem to suggest that front-line lorlatinib tends to be concentrated in patients with high-risk features like higher burden of baseline brain metastases, as an example. Do you see this dynamic possibly impacting the types of patients being enrolled onto your front line study?

Thanks, Charles. Certainly, as I mentioned before, there are some patients that -- some physicians that are in favor of using lorlatinib in the front line, but I think that many of those same physicians will tell you that they don't expect that to broadly impact the overall community because it hasn't thus far. We'll certainly -- we certainly believe that we have the right choice here in alectinib. We think globally that is currently the standard of care. And in general we think it sets us up well to run a good study versus the current standard of care. Are some academics more likely to put a certain patient with heavy CNS burden on lorlatinib? Maybe. Maybe they are. I don't think that's going to necessarily significantly impact the study design and execution of our Phase III 450-patient study.

Got it. Great, that makes sense. And regarding the pivotal ALK Phase II, specifically in the setting where you'd be directly competing with lorlatinib, would you need to hit specific figures on efficacy to demonstrate superiority over some sort of benchmark set by lorlatinib, possibly through a 95% confidence interval exclusion? Or is NVL-655, frankly, just so much better on safety that the FDA will be willing to take a perhaps more holistic view on the overall product profile?

Yes, thanks, Charles. Let's -- let me share how we think about it. Obviously, alectinib being the front-line standard of care, we're going to do a randomized study versus alectinib. Second line is lorlatinib. This is standard of care. Third line, nothing works. And that's where we received breakthrough designation. And we're seeing very interesting activity, durability and safety in that third-line setting, so we think we have the right strategy with a single-arm Phase II cohort. That's ongoing in ALKOVE-1 and enrolling quite well. The obvious question is why not the randomized study versus lorlatinib in second line. I think that's what you're getting at, and let's walk you through our strategy. We think lorlatinib is a limited drug in that patient population. It is not very good at inhibiting ALK single resistance mutations after they've emerged, as evidenced by the 31% to 39% response rate, roughly 7- to 9-month duration response seen in that setting, right? And we're seeing patients come on our study that have progressed on lorlatinib. They have ALK single resistance mutations due to inefficient coverage of ALK single resistance mutations. Or they have compound resistance mutations that developed on treatment with lorlatinib. And they're responding to 655 and we're driving durable responses in those patients, so you can presume, if you caught those patients earlier, it's unlikely their disease is going to progress with either those single or compound resistance mutations. In addition, we have enrolled a smaller number of second -- truly second-line patients, so patients that have yet to receive lorlatinib. And the activity and durability we're seeing there is definitely trending favorably. In fact, we haven't seen a single patient progress, at the recommended Phase II dose. And we've only had one lorlatinib-naive patient in total that's progressed, and that was at a dose below the recommended Phase II dose. So the Phase II is the right experiment, we believe, to -- in a more homogenous patient population that's truly second line. You have to take lorlatinib. What does the activity, the durability and safety look like? We do not think safety alone is a good-enough argument to make, but we believe that 655 can drive much more durable responses than lorlatinib. We think all of our data that we've generated thus far is supporting that hypothesis. And we think the ALKOVE-1 Phase II cohort, which is designed to support registration in second-line patients, is the right experiment to run. And we would envision that we would take that second-line data in conjunction with our third-line data and use that to have an informed discussion with regulators around a broader previously treated ALK label, as opposed to a third-line-only label. And I think the fact that we have a randomized Phase III study ongoing would help support and augment that case as well, but that's generally how we think about it. Does that make sense?

That does.

Your next question is from Roger Song from Jefferies.

Congrats for the impressive data and strong execution in the first line strategy. So maybe 1 data question, 2 strategy development questions. For the data question: Very clear, for 655 lorlatinib-naive patients -- basically, all the resistance mutations, you have been seeing the response or at least some activity, but for those [indiscernible] lorlatinib, you do see some progression with some mutations. Just curious. Have you done any detailed analysis for those mutations you are not addressing? And then the underlying question is how should we think about this activity on those resistance mutations going to translate into first-line treatment. And then given this lorlatinib first-line activity, PFS and duration of response, what's your expectation for your first-line treatment compared to -- and I know you're not running a head-to-head trial against lorlatinib. Just numerically how you will expect performance against lorlatinib.

Yes, thanks, Roger. So a couple of questions in there. I think let's start, maybe, I think -- make sure I got the question right. I think you're asking, what have we learned about the activity of 655 against mutations beyond lorlatinib? So lorlatinib will -- patients will progress with either single mutations or compound mutations. 655 was designed to address those patients with those mutations, and we're seeing the clinical data play out exactly that way. The drug is active beyond lorlatinib. In particular, [ if the drug ] patients have ALK mutations, whether it's single or compound, the drug is active and it's driving durable responses. And that portends well, if you think about what the drug might do in second line, right, before those mutations emerge, right? They're going to potentially keep the patient on therapy and drive more durable responses than what lorlatinib can do. And then in front line. As I mentioned before, lorlatinib, we know, drives deep, durable responses in front-line patients. The challenge with lorlatinib in front line is really around the safety, all right? And so we try to solve for that by making an ALK-selective drug that spares Trk which is known to drive these neurotoxicities seen with brain-penetrant Trk inhibitors like lorlatinib, right? And although lorlatinib can drive deep, durable responses from patients, it's not for all patients. There are patients that cannot tolerate lorlatinib. If you look at the available 5-year CROWN data, you will see that over 1/3 of the patients are off therapy within the first 2 years on lorlatinib, right? That's not serving the needs of all ALK patients, for sure. And that's -- may support why many physicians globally are not turning to that as the front-line agent of choice and they're sticking with alectinib, so the right experiment to do is, if the standard of care is alectinib, show that your drug is better. We believe our drug is better. That's what you do in clinical development. You put your drugs head-to-head and you show that your drug is better. And that's the ALKAZAR study and we're excited to kick it off.

Yes. Okay, that makes sense. Maybe 2 quick ones regarding the clinical development: The first one is for the second line, yes, second line, for ALK and ROS. Those are the pivotal registrational, registration intent. I mean we noticed the cohort N. They are slightly different from 20 patient to 140-ish. I understand you can file independently for each cohort but curious. What will be the reasonable first approval cohort data [indiscernible] on that end? And then in terms of the first line, understanding that lorlatinib is not the standard of care globally but just curious how -- the distribution in the U.S. versus ex U.S. Should we expect to see more ex U.S. enrollment given maybe a little bit more lorlatinib used at the first line in the U.S.?

Yes, let me take that second one, first. And then I'll go to Darlene on the regulatory strategy here. So the Phase I, the Phase II and, hopefully, the Phase III, we expect to enroll very well, right? And we have enrolled each one of those components of the study, the Phase I and II, globally. So we went to 20-plus sites across U.S., Europe, Asia, Australia in the Phase I. The Phase II, we have, I think it's like, 50-plus sites at this point open in the same geographies. It's enrolling very well across all of those geographies. And we envision the Phase III will as well. I think there's -- this is a potential treatment-paradigm-changing study, and we expect that trial to enroll well. We know there's a lot of interest in such a study from global investigators because we've been talking to them about it, so we will be opening that study up across multiple geographies and we expect it to enroll well. Now your second question was how does the evolving data -- the pivotal readouts next year influence our regulatory strategy. Maybe, Darlene, you want to speak to that.

Sure. So again, we're seeing really encouraging, excellent enrollment in the studies. And this is regardless of the cohort, so we're really excited about that. We also have breakthrough therapy designation for both programs, so we -- with that, we'll have frequent opportunities with regulators. And again we're really proud of our collaboration with those regulators and the speed by which we're executing on the trials. And our goal is to get these programs to patients as quickly as possible.

Your next question is from Colleen Kusy from Baird.

Congrats on all the progress. So in the ALKOVE-1 study, ORR for the RP2D looks really consistent with all the doses, but you're seeing some nice separation on DOR. Is there a hypothesis what's driving the increased DOR at the 150 mg dose? And then what's your confidence that it will translate into PFS in the front line?

Thanks, Colleen. Yes. So we do believe, at the recommended Phase II dose, we're getting better coverage of the broad spectrum of ALK mutations that occur beyond all of the other therapies. Keep in mind, and especially in these third-, fourth-, fifth-line patients, there's a number of ALK mutations that could have emerged, either single mutation, compound mutations. 655 was optimized for all of them, but it really does the best job of doing so at those higher dose levels like 150 mg. And that's why we picked it as the recommended Phase II dose. And we're seeing pretty consistent response rates across all dose levels, where we're seeing what's looking like trending to be better durability at the higher dose, so that's encouraging. How will that play out as we push to earlier lines of treatment? That's an experiment we're running, right, so we're -- the Phase II is going very well across second-line cohort, third-line cohorts; and we're excited to see how that data plays out. As we mentioned earlier today, we're expecting pivotal readouts from that program next year. And then the Phase III obviously is going to start next year as well. And we would anticipate that -- with excellent coverage of ALK mutations and excellent brain penetration with a well-tolerated drug, that we can drive much more durable responses than alectinib. And that's why we designed the ALKAZAR study as such. So hopefully, that makes sense, Colleen.

Yes, that's helpful. And one quick follow-up, if I can, on the enrollment of the pivotal Phase II portions. Can you just comment? I know you previously laid out the different subgroups you plan to enroll. Is that enrollment going aligned with what you guys had previously expected in terms of the type of patients you're enrolling?

Yes, sure, I can take -- Colleen, thanks for the question. So enrollment has gone well across all of the studies. And as we mentioned in our update, we now anticipate reporting pivotal data [ first half of ] next year.

Your next question is from Etzer Darout from BMO Capital Markets.

Congrats on the update. I guess, the first one, you've sort of touched on prior but just wondered what impact, if any, does the alectinib approval in the adjuvant setting have on your enrollment assumptions for ALKAZAR and whether or not there were any kind of thought perhaps of sort of doing a physician's choice front-line study with alectinib or lorlatinib. And then I have a second question.

Thanks, Etzer, yes. The -- with the adjuvant approval of alectinib, no, it didn't really impact our strategy or plans. Let me explain why. Most patients, unfortunately, are diagnosed in the advanced metastatic setting, that have ALK non-small cell lung cancer and where alectinib already was the standard of care. The approval in the adjuvant setting, yes, I think it's a great option for ALK patients because for those -- the small percentage that are caught in the earlier setting, they could potentially get surgery and then adjuvant alectinib treatment, hopefully, driving more disease-free survival in those patients, but unfortunately, many of them do get diagnosed in the advanced metastatic setting, where alectinib is the standard of care. And we wanted to compare to the standard of care. In the -- I think, the second part -- maybe you can repeat the second part of your question. I'm just blanking on what it was.

[indiscernible].

Physician's choice...

Yes. Just whether you've considered sort of a physician's choice for front line.

Yes. We wanted to keep it simple here, right? There's plenty of precedent in this space of randomized ALK non-small cell lung cancer trials, 4 that we're aware of in the advanced metastatic setting. They've all been randomized 1:1. They've all been progression-free survival end points, showing one drug is better than the other. No reason to make it more complex here. If alectinib is the standard of care, let's go show we're better.

Got it. Great. And then just one for NVL-655. I realize only about 10% or so of patients sort of enrolled had one prior TKI but just curious if these patients were evaluated at all separately given that it kind of represents sort of a "true" second-line population.

Was that in ROS1, or ALK, Etzer, of -- your question?

ALK, NVL-655.

Yes, yes, yes. So we actually -- in the Phase I, we were surprised to see lorlatinib-naive patients get enrolled. Like most Phase I studies, investigators are going to exhaust the available options for the patients before they would put them on a Phase I clinical study, so we expected that third-plus-line patient population, but we were pleasantly surprised to see some lorlatinib-naive patients get enrolled into the Phase I. And the responses are there. They're durable. The drug is performing as we had hoped. The best way to assess the evolving data there is really going to be that Phase II cohort which is dedicated to that second-line patient population. And that's enrolling well and we're going to have data from that program soon. Those, the activity and monitoring those patients, it's performed in the exact same manner across the entire study, so no differences to how we, the team, is monitoring the performance of 655 in those second-line patients versus third-plus line.

Your next question is from Kelsey Goodwin from Guggenheim Securities.

Congrats on the impressive clinical updates today. For 655's safety, I guess, could you just comment? Was the profile consistent across doses, or was there any dose response there like we saw with the efficacy? And then specifically on ALT and AST, I guess, can you just confirm, was there any increase in bilirubin? Or were these mainly just seen [ on the labs ]?

Do you want to take that, Chris?

Sure. So overall, NVL-655 was well tolerated. There was no clear dose-related trend in adverse events, including ALT and AST, across the various doses, so the preliminary safety activity was really consistent with avoidance of Trk neurotoxicity. And that's really the important concern for physicians in using it for newly diagnosed patients that we hope to eventually get to. In terms of the bilirubin in -- it didn't fall in the greater than 10%. And in terms if you're asking about Hy's law and the combination with them, no, we haven't seen any cases that lead to drug-induced liver toxicity.

[Operator Instructions] Your next question is from Peter Lawson from Barclays.

First question is just on the ALKOVE-1 study, that 15% dose reduction you saw in ALKOVE. Is that something that needs to improve or you think improves in the real-world setting or improves as you move into earlier lines? And then another question, just around physicians and sites that are kind of wavering around front-line 655 study. What else would they be looking to see?

Let me start with -- thanks, Peter. Let me start with the second one. So I think your question is what would physicians and regulators need to see to do the front-line study. I think we're there. What we're telling you today is that we've aligned with global investigators and with the FDA on that study design. And we're just in the process of getting it started, so I think we have what we need, as far as what we think is compelling data in heavily pretreated patients. We have a dose. We have a plan. Your first question was around the safety. Chris, do you want to take that?

Yes. For the heavily pretreated population we -- 15% dose reduction in what we're seeing is very impressive across what you're looking at with the other ALK drugs, so we're very comfortable with that, particularly in this heavily pretreated population. It's hard to say exactly what happens as we move up on line, but certainly those patients are less heavily pretreated. And we'll continue to follow that, but we're very comfortable where that is right now.

And then on zidesamtinib, are you seeing resistance mutations? And when do they occur?

Yes. So it's something, a question, Peter, that we're obviously very interested in, right? We started these programs because we followed what happened with resistance on the other drugs, the earlier-generation TKIs. So our teams, especially our discovery scientists, are always interested in things like that. And we're working closely with the development team to understand the evolving data. Where we stand today, though, overall is, quite frankly, we don't have enough progressors on either drug, zidesamtinib or 655, to really draw any broad conclusions about liabilities of zidesamtinib and 655. If we do identify them, we certainly will -- the chemistry team will go to the drawing board and say like, "What can we come up with to try to solve for that?" but right -- today, we don't have a clear need that's emerging beyond zidesamtinib and 655 to go solve for with a next-generation TKI. Does that make sense?

All right, that's perfect.

Thank you. There are no further questions at this time. I will now hand the call back to Jim Porter for the closing remarks. Please proceed.

Great. Thank you all for joining us today. We are 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. Ladies and gentlemen, the conference has now ended. Thank you all for joining. You may all disconnect your lines.

[ Thank you ].