Good morning, and welcome to Nuvalent's Conference Call. At this time, all participants are in a listen-only mode. There will be a question-and-answer session after the prepared remarks. Please be advised that this call is being recorded at the company's request. I would now like to turn the call over to Alexandra 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 program, zidesamtinib and NVL-655, and outlining updated data from the phase 1 portions of the ongoing ARROS-1 trial of zidesamtinib and ALCOVE-1 trial of NVL-655. These data were presented during two 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 2 portion of our ALCOVE-1 trial with registrational intent, which we announced in February, and initiating the phase 1 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 designations 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 three 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 ALCOVE-1 phase 2 trials, and the announcement of our development strategy for frontline ALK. 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 timelines, 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 four. Beginning with ALK on the left, there are currently five FDA-approved therapies for patients with ALK-positive non-small cell lung cancer. Alectinib is well-established as a frontline 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 a 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-naïve 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-limiting. Despite the potential for improved activity in the frontline, lorlatinib remains primarily used in the second-line setting. With these learnings, we hypothesized that a compound with the 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 frontline standard of care. This became our target product profile for a novel ALK selective inhibitor. In ROS1, the medical needs are comparable. There are three 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 frontline standard of care. Our approach for ROS1 was to design a novel ROS1 selective compound that could 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 was to create a best-in-class compound that could eventually displace crizotinib as the new frontline 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 five. 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 shown on slide six, the markets 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 $500 million 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 updates for zidesamtinib, our novel ROS1 selective inhibitor, which is being studied in the ongoing phase 2 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 one 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 1 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 oral presentation at ESMO by Dr. Benjamin Besse, Director of Clinical Research at Gustave Roussy. Slide eight summarizes the patient population and the key objectives of the phase 1 portion of the ARROS-1 trial. Patients with non-small cell lung cancer enrolled in the phase 1 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. From 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 strong investigator enthusiasm for zidesamtinib. We aligned with the FDA on the recommended phase 2 dose of 100 milligrams once daily. No clinically significant exposure response relationships for safety and efficacy were observed, and phase 1 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 two 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 metastasis, 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 pre-treated 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 prior ROS1 TKIs, with or without chemotherapy. In the subset of 53 patients that were refractory and 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 two 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 refractory 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 frontline 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 four 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 refractory 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, seven of eight intracranial response evaluable patients had been previously treated with the brain-penetrant TKIs, lorlatinib and/or entrectinib. 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, an ALT increase, AST increase, and weight increase, 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 one portion of our trial. As summarized on slide fourteen, even in heavily pre-treated patients, zidesamtinib demonstrates durable activity with the potential to address each key area of its target product profile, including activity against ROS1 resistance mutations, 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 fifteen, 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 has progressed with ROS1-resistant mutations or with CNS metastases. Preliminary activity of zidesamtinib in this population of patients previously treated with two 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 the standard of care. Investigation of zidesamtinib for TKI-naive patients with ROS1-positive non-small cell lung cancer is ongoing in the phase 2 portion of the ARROS-1 trial. The enthusiasm for zidesamtinib is widespread, as evident on slide 16 in 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 1 trial in just over a year and a half. Since we initiated the phase 2 portion of the trial, we've enrolled an additional 227 patients, for a total of 331 patients treated with zidesamtinib as of September first, 2024. The rate of enrollment in this clinical trial has been remarkable and speaks to the enthusiasm from the patient advocacy and patients, physician communities for zidesamtinib. We are grateful for and humbled by this 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 seventeen, we're excited to share with this rate of enrollment, we expect to report pivotal data from the ongoing phase 2 portion of the ARROS-1 trial in twenty twenty-five. 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 2 portion of our ALCOVE-1 clinical trial for patients with ALK-positive non-small cell lung cancer. The phase I portion of the ALCOVE-1 trial was fully enrolled as of February twenty twenty-four, and I'd like to invite Chris back to summarize the updated data. Thanks, Jim. The following updated clinical data from the phase 1 portion of the ALCOVE-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 1 portion of the ALCOVE-1 trial. Patients with non-small cell lung cancer enrolled in the phase 1 portion of the trial must have received at least one prior second or third generation ALK TKI. Up to two prior lines of chemotherapy and/or immunotherapy were allowed. From June 2022 to February 2024, 133 patients were enrolled across six 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 three lines of prior therapy. 46% of the patients had three or more prior ALK TKIs, and 56% had prior chemotherapy. Notably, 84% of the patients received prior lorlatinib, and 51% had secondary ALK-resistant mutations, including 26% with more than one or compound ALK mutations. 56% of the patients had a history of CNS metastasis, 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 the 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 two 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 are 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 mutations, the ORR was 88% across those 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 were previously treated with up to five ALK TKIs, with or without additional chemotherapy, the median DOR was 14.4 months, and the six-month DOR rate was 78%. 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 six-month DOR was 75%. The subset who were lorlatinib naive and received NVL-655 as second-line therapy or beyond, the median DOR was not reached, and the six-month DOR rate was 88%. At the RP2D across each of these subgroups, the median DOR was not reached, and the six-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 two prior TKIs, including lorlatinib. The six-month DOR rates were 85% and 80%, respectively. For each of these subgroups, at the RP2D, the median DOR was not reached, and the six-month DOR rate was 100%. Within the responders who are lorlatinib naive with any ALK-resistant mutation, there has been no disease progressions at either all dose levels or at the recommended phase two 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 patient had been previously treated with three lines of therapy, including platinum-based chemotherapy, alectinib, and lorlatinib, and experienced progression with CNS disease on lorlatinib. ALK G1202R and C1156Y resistant mutations were present upon entry to the ALCOVE-1 study. Following treatment with NVL-655 at the recommended phase 2 dose, complete resolution of multiple CNS lesions was achieved after four and a half months of therapy. This patient remains on treatment 11.4 months, with an ongoing confirmed response, CNS complete response. On the bottom of the slide, follow-up on previously presented cases is provided. For these two 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 incidence 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 2 dose. At this dose, NVL-655 maintained 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 1 portion of our trial. To summarize 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 this 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 three generations of ALK TKIs. As with ARROS-1, the enthusiasm for our ALCOVE-1 trial is clear, as shown by the enrollment rates on slide 28. Following the enrollment of 133 patients in our phase 1 in just over a year and a half, we have subsequently enrolled 229 patients in the phase 2 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 2 trial in 2025. The phase 2 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 two drugs next year, zidesamtinib and NVL-655. Importantly, the progress in our ALCOVE-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 ALCAZAR phase 3 randomized controlled trial of NVL-655 in the frontline setting. The evolution of our ALK franchise is illustrated on slide 30. We chose to name our phase 1/2 trial ALCOVE 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 1 portion of our ALCOVE-1 trial had 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 ALCAZAR reflects our aspiration for the phase 3 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 ALCAZAR is illustrated on slide 31. This will be a phase 3 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 ALCAZAR trial will enroll approximately 450 patients who will be randomized 1 to 1 to receive NVL-655 or alectinib, the current standard of care for frontline ALK patients. Primary endpoint is progression-free survival based on blinded independent central review. We expect to initiate the ALCAZAR study in the first half of 2025. As summarized on slide 32, with the ALCAZAR study, we are well positioned to evaluate the potential for NVL-655 to move up the treatment paradigm for patients with ALK-advanced ALK-positive non-small cell lung cancer. Today, there is no clear standard of care in the third line following progression on two ALK TKIs, such as sequential alectinib or lorlatinib. NVL-655 has received FDA breakthrough therapy designation in this population based on its preliminary phase one 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 mutations 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 TKI. At the recommended phase two dose, the ORR was 57%, with median duration of response not reached and no disease progression among responders. In lorlatinib-naïve patients with any ALK resistance mutation, treatment with NVL-655 at the recommended phase 2 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 2 dose, the ORR was 64%, with a six-month DOR rate of 100%. While the median DOR was not yet reached at the recommended phase 2 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 frontline, the standard of care is alectinib. In its phase 3 ALEX trial versus crizotinib, alectinib delivered 25.7 months PFS in the frontline, 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 five 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 penetration 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 drug-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 2 dose achieved a 55% ORR in patients with any ALK mutation and 71% ORR in patients with ALK G1202R mutations. The most common mutation observed in patients with prior disease progression on alectinib, with no progression events in the lorlatinib naive responders with ALK resistance mutations. This suggests that NVL-655 may have the potential to limit the emergence of on-target ALK-acquired 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 frontline setting. We are incredibly excited about this opportunity and anticipate initiating the ALCAZAR 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 six years ago as a dream and a list of targets on a whiteboard has evolved into a company with two parallel lead programs and ongoing global registration-directed trials with pivotal readouts on the horizon, a global phase 3 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 advisors, 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 3 ALCAZAR trial for frontline ALK in the first half of the year, reporting pivotal data from both our ROS1 and ALK programs, and progressing our phase 1 HEROEX-1 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. Thank you. Ladies and gentlemen, we will now begin the question-and-answer session. Should you have a question, please press the star followed by the one on your touchtone phone. Questions will be taken in the order received. Should you wish to cancel your request, please press the star followed by the two. If you are using a speakerphone, please lift the handset before pressing any keys. Once again, that is star one should you wish to ask a question. Your first question is from Bradley Canino from Stifel. Please ask your question. Hi, this is Bradley Canino. Congrats on the data enrollment execution. Quick clarification on the data and then a question, because I wanna 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 in a response at this update? Yeah. So thanks, thanks, Brad. You know, we're pleased with what we're seeing with the durability. What we had said from all the patients, the recommended phase 2 dose, we had shared across all patients, two 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, you know, 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. Patients are continuing on therapy almost uniformly. But at the RP2D, what number have progressed after having a response? Sure, sure. Yeah. So I think if you just go through the curves, you can find that of all the patients that had taken NVL-655 at the recommended phase 2 dose, only a single patient has progressed. So we're pretty encouraged by that. You know, the idea was if we had excellent coverage of the ALK resistance mutation seen beyond other therapies like alectinib and lorlatinib, we have excellent CNS progression and the drug is well-tolerated, that we'd 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, you know, ideally moving up the treatment paradigm, second line and frontline. And we're seeing at the recommended phase 2 dose, that really playing out. We're driving deep, durable responses. Patients are staying on therapy and, you know, it sort of supports pushing this drug earlier in the treatment paradigm. Okay, great. And then for the question, you know, given you enrolled 230 treatment-experienced patients in ALCOVE-1 in six months, should I think of that as a similar run rate of what's possible to recruit the 450 treatment-naïve for ALCAZAR, 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. Thank you. ... Yeah, so the, yeah, first on, on-- thanks, Brad. On the execution on ALCOVE-1, you know, we're, we obviously enjoy the outstanding collaboration from the physicians that are executing on the ALCOVE-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. You know, I haven't been involved in my career in many studies that have this much demand and interest for enrollment, and it's really humbling and rewarding for our team, knowing that we're working on something that there's such broad enthusiasm for enrolling 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, you know, this is, you know, 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, you know, be excited to participate in such a treatment paradigm changing study. We expect the trial to enroll well. Hard to say, you know, how fast it will enroll, but we expect, you know, broad enthusiasm, excellent enrollment, and obviously, you know, our team is committed to execute on that as quickly as possible. So, maybe operator, next question? Thank you. Your next question is from Anupam Rama from J.P. Morgan. Please ask your question. Hey, guys, thanks so much for taking the question, and 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 looked relative to the totality of data you presented? Thanks so much. Yeah, thanks, Anupam. Yeah, so maybe that didn't come through in the presentation. You know, what we found with zidesamtinib is that, you know, we saw basically no exposure response relationships for safety or activity across the entire dosing interval, starting from 25 all the way through 150. We ended up picking 100 as the recommended phase 2 dose because it provided excellent coverage of the target FC thresholds, but the lowest dose, 25, was just as active as 100, and it was just as well tolerated at 100 as it was 25. We just reported the data across all doses from the phase 1. Whereas within NVL-655, you know, we are seeing better target coverage at those higher dose levels, particularly at the recommended phase 2 dose of 150 milligrams, and because we're seeing better target coverage, we reported the data for, you know, both at the RP2D as well as all dose levels, and what you, I think you saw is that we're starting to see some, you know, interesting trends emerge at the recommended phase 2 dose, where it pretty uniformly is driving, you know, more durable responses than, you know, the duration response across all dose levels. Thanks so much for the clarification, guys. Thanks, Anupam. Thank you. Your next question is from Marc Frahm from TD Cowen. Please ask your question. Hey, thanks for taking my questions, and 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, you know, now that you have all these patients enrolled? And are you expecting the initial filing to include a request for a second-line label or just third line, you know, people who've seen alectinib and lorlatinib? Yeah, yeah. Thanks, Mark. We're gonna push forward on all them, but I'm gonna turn this over to our Chief Development Officer, Darlene Noci. Thanks, Jim. We are seeing excellent enrollment in both ALCOVE-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 for the TKI pretreated patients, including in our BTD populations. 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 in 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 when once you open up the phase III? Yeah, yeah. I mean, what's interesting here is the phase II just started in February, and we don't even have all the sites open yet in the phase II. You know, we had planned for a seamless transition, but we're still getting sites open, and we still enrolled 230 patients in the last six-plus months. Phase III trials will be a different protocol. It would be, you know, 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's preparing for that right now, but we hope to execute just like we've executed in the ALCOVE-1 study, to get this trial enrolled as fast as possible and push this ALCAZAR program forward. Okay, thank you. Thanks, Mark. Thank you. Your next question is from Chris Raymond from Piper Sandler. Please ask your question. Hey, thanks, and congrats from us on the data. Two questions. I guess on both assets. I know there's been a focus on duration response for approved agents in the ALK and ROS1 settings, but you know, you guys had a lot of patients with stable disease, you know, in both trials. Maybe can you help sort of frame the importance of driving durable, stable disease for patients and how you know we should think about PFS, sort of in that context? And then, another sort of question on NVL-655, specifically. You know, we've gotten some questions from investors this morning around CNS activity. I think you had 15% intracranial ORR, but you know, 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? Thanks. Sure. Thanks. Thanks, Chris. Let me start with the PFS question. So, you know, keep in mind, this is a phase 1 study. These patients have exhausted available options, right? And we're enrolling patients that have really, you know, taken the other therapies like alectinib or lorlatinib, so in many cases, chemotherapy, and the drug is still active. I think in a single-arm study, you know what? The way we're gonna, you know, look at this early data is, can we shrink tumors in these patients? Are the patients responding, and are those responses durable? You know, and an endpoint like progression-free survival is certainly important. You know, I know the way regulators often look at single-arm studies is they're keen on response rates and the duration of response as well as safety. That's what you often find in a single-arm approved label. You know, we'll certainly be looking at progression-free survival, but, you know, that's often an endpoint that's reserved for comparing, you know, two different drugs in a randomized setting versus, you know, in a controlled patient population. So as we think about the phase 2 and obviously the phase 3, that is an appropriate endpoint that we'll, you know, be gathering. But for the phase 1, 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, as zidesamtinib and NVL-655. With respect to CNS activity, I'm going to turn it over to our Chief Medical Officer, Chris Turner, to address that. Right. Thanks. So, Chris, as you know, you know, more than 80% of the patients had 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. You know, the intracranial responses that we have observed in patients have either measurable or unmeasurable lesions that we've seen, you know, 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. Yep, thank you. Okay. Thank you. Your next question is from Andrew Berens, from Leerink Partners. Please ask your question. Hi, thanks. Congrats on all the progress and the accelerated timelines for the ALK program. 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 LFT elevation you're seeing, which I assume could be exposure related, just wondering how confident you are in the go-forward dose of 150 and whether you think the agency is gonna agree that that's the right dose. And then, you didn't mention an interim look in ALCAZAR for ORR. Is that off the table now? We hear the agency from other sponsors that they're 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. Thanks. Yeah. Thanks, Andy. I'll start with the first question about the recommended phase 2 dose for NVL-655. Yes, we're absolutely confident in 150 mg as the recommended phase 2 dose. We've 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, you know, 230 patients at that recommended phase 2 dose, and that is the dose we'll take forward in the randomized phase 3 ALCAZAR study. You know, we are not gonna discuss the statistical assumptions at this point in the phase 3 planned study, the ALCAZAR study. You are right that other... There are, you know, other examples where interim analyses are used. You know, what we understand from that precedent is, you know, when you have progression-free survival as an endpoint, 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 something that, you know, 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 are greatly aided by the fact that there's a lot of precedents in the ALK non-small cell lung cancer space. There's four other randomized studies that have been done in the advanced metastatic setting. So a lot of learning that we can take from our, from those trials, and including several of them that did include interim analyses in their studies. Okay. And then, during the presentation, Dr. Julien 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 of whether 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. Yeah, sure, sure, Andy. So, you know, we work with many of the leading academic KOLs in the world in the ALK non-small cell lung cancer space, and we've just been discussing this program with them since we started the company six 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 up front. But some of them, once the initial CROWN data read out a few years ago, and lorlatinib was 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, you know, they know the broader community is not going to make that switch, because of the accompanying CNS toxicity that happens with the lorlatinib, because it hits TRK in the brain. As you know, Andy, like, the current standard of care is still alectinib. That's where it's, that's primarily used globally. We've talked with global investigators of what is the right study to do, and, you know, the study design for ALCAZAR would be randomizing one to one, NVL-655 versus alectinib, and, we're excited to kick that study off. Great. Well, thanks. Congrats again. You guys definitely made the trip to Barcelona worthwhile. So good meeting. Thanks, Andy. Thank you. Your next question is from Richard Law from Goldman Sachs. Please ask your question. Hey, guys, congrats on the data. So just want to follow up on what you guys said earlier. Any thoughts on why you're not seeing dose response in ARROS-1 for NVL-520, but you are seeing for NVL-655? And was that traceable back to your PK data? And then also, following up on that, I know you guys already align with the FDA, the 100 mg as a 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. Yeah, thanks, Rich. So yeah, this actually has to do completely with the discovery, the design of these molecules. This is true precision oncology here, right? Zidesamtinib was designed to cover, you know, the known resistance mutations occurring beyond the earlier generation ROS1 inhibitors, and with also excellent CNS penetrance. And it turns out that, you know, at least 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 based on what we saw non-clinically. The drug was so well tolerated non-clinically, we were able to start at biologically active doses that were above that target actually threshold. You don't often get that, 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 the, 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 2 in September. Now, the reason it's there was a, you know, 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 NVL-655, 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 2 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 six five five could significantly improve on lorlatinib, lorlatinib duration and survival in CROWN based on the ORR and DOR data that you show here in ALCOVE-1, where 84% of patients already had prior lorlatinib? Yeah. So clearly, six five five is showing that it's active beyond lorlatinib, but the activity of lorlatinib in frontline patients is not really the problem. That drug is a very active drug in frontline patients, and it's good enough at covering ALK mutations in frontline that you're not seeing the emergence of... The challenge with lorlatinib in frontline is that it's not very well tolerated, right? It has these 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 ALCOVE-1 study. So we're seeing patients progress on lorlatinib with single mutations or compound mutations. 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 frontline setting, we would think it'd 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 frontline setting. Does that make sense, Rich? Yeah, no, very helpful. And then, last question from me. What’s the most common AEs below the 10%? I think I saw a lot of AEs above 10%. Any remarkable, anything remarkable to call out for the CNS AE? Yeah. I'll let Chris take that one. Yeah. In this larger ESMO data set, you know, we've reverted to the more common and customary use of 10%. You know, this reflects the number of patients with broader period of time that we've studied here. You know, we ongoing look at comprehensive safety, and we still are comfortable with the overall safety profile, you know, TRK-sparing design of the selective ALK inhibitor. Okay. Thank you so much, and congrats again. Thanks, Rich. Thank you. Your next question is from Charles Zhu from LifeSci Capital. Please ask your question. Hello. Congrats on all the data and the progress, and thanks for taking my questions. My first one is a bit of a follow-up on some of Andrew Berens' prior comments and questions, but, you know, some of our KOL checks do seem to suggest that frontline 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 frontline study? Thank you. Thanks, Charles. You know, certainly, you know, as I mentioned before, there are some patients that-- some physicians that, you know, are in favor of using lorlatinib in the frontline. But I think that many of those same physicians will tell you that they don't expect that to broadly impact the overall community 'cause it hasn't thus far. You know, we'll certainly believe that we have the right choice here in alectinib. We think globally that is currently the standard of care, and, you know, 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, you know, our phase 3, 450 patient study. Got it. Great, that makes sense. And regarding the pivotal ALK phase 2, 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, you know, possibly through a 95% confidence interval exclusion? Or is NVL-655 frankly just so much better on safety, that the FDA would be willing to take a perhaps more holistic view on the overall product profile? Thank you. Yeah. Thanks, Charles. Let me share how we think about it. You know, obviously, alectinib being the frontline standard of care, we're gonna do a randomized study versus alectinib. Second line is lorlatinib. This is standard of care. Third line, nothing works, and that's where we've received breakthrough designation, and we're seeing, you know, very interesting activity, durability, and safety in that third-line setting. So we think we have the right strategy with a single-arm phase two cohort that's ongoing in ALCOVE-1 and enrolling quite well. You know, 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. You know, 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%-39% response rate, roughly seven- to nine-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 develop on treatment with lorlatinib, and they're responding to NVL-655, and we're driving durable responses in those patients. So you could presume if you caught those patients earlier, it's unlikely their disease is gonna progress with either those single or compound resistance mutations. In addition, we have, you know, enrolled, you know, a smaller number of second-, truly second-line patients, so patients that have yet to receive lorlatinib. You know, 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 two dose, and we've only had one lorlatinib naive patient in total that's progressed, and that was a dose below the recommended phase two dose. So, you know, the phase two is the right experiment, we believe, to in a more homogeneous patient population that's truly second line, and 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 six five five 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 ALCOVE-1 phase two cohort, which is designed to support registration of second-line patients, is the right experiment to run. We would envision that we would take that second-line data in conjunction with our third-line data and you know, 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, phase three study ongoing, you know, would help support and augment that case as well. That's generally how we think about it. Does that make sense? That does, and thank you for all that detail and color. Congrats again on all, on all the data and progress. Thanks, Charles. Thank you. Your next question is from Roger Song from Jefferies. Please ask your question. Thank you. Congrats for the impressive data and strong execution in the first-line strategy. So maybe one data question to strategy development question. For the data question, very clear for six five five lorlatinib-naive patient, basically all the resistance mutations you have been seeing the response or at least some activity before those prior 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 resistant mutations gonna translate into first-line treatments? And then, given this lorlatinib first-line activity, PFS and duration response, what's your expectations for your first-line treatment compared to lorlatinib? I know you're not running a head-to-head trial against the lorlatinib, just numerically how you will expect performance against the lorlatinib. Thank you. Yeah. Thanks, Roger. So a couple questions in there. I think let's start, make sure I got the question right. I think you're asking, you know, what have we learned about the activity of NVL-655 against mutations that beyond lorlatinib? So lorlatinib will patients will progress with either single mutations or compound mutations. NVL-655 was designed to address those patients, those mutations, and we're seeing the clinical data play out exactly that way. The drug is active beyond lorlatinib. In particular, if the patients have ALK mutations, whether 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 gonna potentially keep the patient on therapy and drive more durable responses than what lorlatinib could do. And then in frontline, as I mentioned before, lorlatinib, you know, we know drives deep, durable responses in frontline patients. The challenge of lorlatinib in frontline is really around the safety, 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, you know, although lorlatinib can drive deep, durable responses for patients, it's not for all patients. There are patients that cannot tolerate lorlatinib. If you look at the available five-year CROWN data, you'll see that, you know, over a third of the patients are off therapy within the first two years on lorlatinib, right? That's not serving the needs of all ALK patients for sure. That's, you know, may support why many physicians globally are not turning to that as the frontline agent of choice, and they're sticking with alectinib. 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 ALCAZAR study, and we're excited to kick it off. Yep. Okay, that makes sense. Maybe two quick ones regarding the clinical development. The first one is for the second line or second, yeah, second line, for ALK and ROS. Those are the pivotal registrational registration intent. We noticed the cohort N, they are slightly different from 20 patients to 14 to 140-ish. Understand you can file independently for each cohort, but just curious, what will be the reasonable first approval cohort data 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-US enrollment, given maybe a little bit more lorlatinib use as the first line in the US? Thank you. ... Yeah. Let me take that second one first, and then I'll go to Darlene on the regulatory strategy here. So, you know, the phase one, the phase two, and hopefully the phase three, we expect to enroll very well, right? And we have enrolled each one of those components of the study, the phase one and two, global. So we went to twenty-plus sites across U.S., Europe, Asia, Australia, in the phase one. The phase two, we have, you know, I think it's like fifty-plus sites at this point open in the same geographies. It's enrolling very well across all those geographies, and we envision the phase three will as well. They think 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 'cause 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, you know, how does the evolving data, the pivotal readouts next year, influence our regulatory strategy, and maybe, Darlene, you want to speak to that. Sure. 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, you know, the speed by which we're executing on the trials, and you know, our goal is to get these programs to patients as quickly as possible. Got it. Thank you. Thanks, Andrew. Thank you. Thank you. Your next question is from Colleen Kusy, from Baird. Please ask your question. Great. Thanks for taking our questions, and congrats on all the progress. So in the ALCOVE-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'll translate into PFS in the frontline? Thanks, Colleen. Yeah, so you know, we do believe at the recommended phase 2 dose, we're getting better coverage of the broad spectrum of ALK mutations that occur beyond all the other therapies. So keep in mind, you know, especially in these third, fourth, fifth-line patients, you know, there's a number of ALK mutations that could have emerged, either single mutation, compound mutations. NVL-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 2 dose. And we're seeing, you know, 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 the experiment we're running, right? So the phase two 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 three, 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 ALCAZAR study as such. So hopefully that makes sense, Colleen. Yep, that's helpful. Thank you, and one quick follow-up, if I can, on the enrollment of the pivotal phase 2 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? Yeah, sure, I can. Hi, Colleen. Thanks for the question, so enrollment has gone well across all of the studies, and, you know, as we mentioned in our update, we now anticipate reporting pivotal data for the program next year. Great. Thanks for taking our questions. Thank you. Your next question is from Etzer Darout, from BMO Capital Markets. Please ask your question. Great. Thanks for taking the question. Congrats on the update. I guess the first one you 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 ALCAZAR? And whether or not there were any kind of thought, perhaps, of sort of doing a physician's choice frontline study with alectinib or lorlatinib. And then I have a second question. Thanks, Etzer. Yeah. Yeah, the, with the adjuvant approval of alectinib, no, it didn't really impact our strategy, our plans. Let me explain why. You know, 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. You know, the approval in the adjuvant setting, I think, is a great option for outpatients, 'cause for those, the small percentage that are caught in the earlier setting, you know, they could potentially get surgery and then adjuvant alectinib treatment, you know, 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, you know, compare to the standard of care. You know, in the, you know, the, I think the second part, maybe you can repeat the second part of your question? I'm just blanking on what it was. Yeah, just whether- Oh, because- It's considered sort of a physician's choice for frontline. Yeah. You know, 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 before that we're aware of in the advanced metastatic setting. They've all been randomized one to one. They've all been progression-free survival endpoints, showing one drug is better than the other. No reason to make it more complex here. If elective to standard care, let's go show we're better. Got it. Great. Then just one for NVL-655. I realize only about 10% or so of patients sort of enrolled had 1 prior TKI, but just curious if these patients were evaluated at all separately, given that, you know, it kind of represents sort of a quote-unquote "true" second-line population. Is that in ROS1 or ALK, your question? ALK, NVL-655. Yeah, yeah. Yeah, so we actually, in the phase 1, we were surprised to see lorlatinib naive patients get enrolled. Like, you know, most phase 1 studies, investigators are gonna exhaust the available options for the patients before they would put them on a phase 1 clinical study. So we expected that third plus line patient population, but we were, you know, pleasantly surprised to see some lorlatinib naive patients get enrolled into the phase 1. And the responses are there, they're durable. The drug's performing as we had hoped. The best way to assess the evolving data there is really gonna be that phase 2 cohort, which is dedicated to that second-line patient population, and that's enrolling well, and we're gonna have, you know, data from that program soon. You know, the activity and monitoring those patients is performed the exact same manner across the entire study. So no differences to how we, you know, the team's monitoring the performance of NVL-655 in those second-line patients versus third plus line. Got it. Great. Thank you. Congrats again. Thanks, Etzer. Thank you. Your next question is from Kelsey Goodwin from Guggenheim Securities. Please ask your question. Oh, hey, thanks for taking my questions, and congrats on the impressive clinical updates today. For NVL-655 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? Thanks so much. You wanna 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 pulmonary 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, you know, it didn't fall in the greater than 10%. And in terms of if you're asking about, you know, Hy's Law and the combination with them, no, we haven't seen any cases that lead to drug-induced liver toxicity. Great. Thank you. Thank you. Once again, please press star one should you wish to ask a question. Your next question is from Peter Lawson from Barclays. Please ask your question. Great. Thank you so much. First question, just on the ALCOVE-1 study, that 15% dose reduction you saw in ALCOVE, 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' insights, the kind of wavering around frontline 655 study. What else would they be looking to see? 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 frontline study? I think we're there. Yeah. 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, you know, 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, you want to take that? Yeah. You know, for the heavily pretreated population we're treating, you know, 15% dose reduction in what we're seeing is very impressive across, you know, what you're looking at with the other ALK drugs. So we're very comfortable with that, particularly in this heavily pretreated population. You know, it's hard to say exactly what happened as we move up online, but certainly those patients are less heavily pretreated, and you know, we'll continue to follow that, but we're very comfortable where that is right now. On zidesamtinib, are you seeing resistance mutations, and when do they occur? Yeah. So, it's 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 TKI. So our team, 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. You know, where we stand today, though, overall, is quite frankly, we don't have enough progressors on either drug, zidesamtinib or six five five, to really draw any, you know, broad conclusions about liabilities of zidesamtinib and six five five. If we do identify them, we certainly would, will... You know, 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, you know, need that's emerging beyond zidesamtinib and NVL-655 to go solve for, with the next generation TKI. Does that make sense? Great. That's perfect. Thank you so much. 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. You know, we are proud of the progress we have made across our pipeline and appreciate your continued support in 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.