Core Viewpoint - Nuvalent, Inc. has initiated a rolling New Drug Application (NDA) submission for zidesamtinib, a novel investigational ROS1-selective inhibitor, targeting TKI pre-treated patients with advanced ROS1-positive non-small cell lung cancer (NSCLC), with completion expected in the third quarter of 2025 [1][2]. Group 1: Zidesamtinib Development - Zidesamtinib is designed to overcome limitations of existing ROS1 inhibitors and is intended to remain effective in tumors with resistance mutations, including G2032R [4]. - The drug is also formulated for central nervous system (CNS) penetration, aiming to improve treatment options for patients with brain metastases [4]. - Zidesamtinib has received breakthrough therapy designation for patients with ROS1-positive metastatic NSCLC previously treated with two or more ROS1 TKIs [4]. Group 2: Clinical Trial Insights - The ARROS-1 Phase 1/2 clinical trial is currently investigating zidesamtinib in patients with advanced ROS1-positive NSCLC and other solid tumors, with the Phase 1 portion focusing on safety and tolerability [5]. - The ongoing Phase 2 portion is designed for TKI-naïve and TKI pre-treated patients, with registrational intent [5]. Group 3: Regulatory Engagement - The FDA has accepted the NDA for zidesamtinib under the Real-Time Oncology Review (RTOR) program, allowing for earlier submission of efficacy and safety results [2]. - The company is actively engaging with the FDA regarding potential opportunities for line-agnostic expansion [2]. Group 4: Market Need - There is a significant need for new treatment options for patients with ROS1-positive NSCLC, especially those who cannot tolerate existing TKIs or have disease progression with brain metastases or resistance mutations [3].

Pipeline Programs and Milestones - Nuvalent is advancing parallel lead programs for ROS1+ and ALK+ NSCLC in global clinical development, with potential for first FDA approval in 2026[4] - The company plans to report pivotal data for TKI pre-treated ROS1+ NSCLC from the ARROS-1 trial in 1H 2025 and complete rolling NDA submission in Q3 2025[14] - Topline pivotal data for TKI pre-treated ALK+ NSCLC from the ALKOVE-1 trial is anticipated by year-end 2025, with ALKAZAR Phase 3 trial for TKI-naïve ALK+ NSCLC planned to initiate in early 2H 2025[14, 205] - NVL-330 for HER2-altered NSCLC is in Phase 1a/1b investigation, with additional discovery research programs ongoing[12, 205] Zidesamtinib (NVL-520) for ROS1+ NSCLC - In TKI pre-treated ROS1+ NSCLC patients, the ORR was 44% (51/117), with 78% (95% CI: 62, 88) DOR ≥ 12 months and 62% (95% CI: 28, 84) DOR ≥ 18 months[73] - In patients with prior crizotinib or entrectinib only ± chemotherapy, the ORR was 51% (28/55), with 93% (95% CI: 74, 98) DOR ≥ 12 months and 93% (95% CI: 74, 98) DOR ≥ 18 months[80] - Zidesamtinib demonstrated CNS activity, with an IC-ORR of 48% (27/56) in any prior ROS1 TKI ± chemotherapy and 85% (11/13) in prior crizotinib only ± chemotherapy[90] - The safety profile of zidesamtinib was generally well-tolerated, with peripheral edema reported in 36% of patients, constipation in 17%, blood CPK increased in 16%, fatigue in 16%, and dyspnea in 15%[96] - In TKI-naïve patients with ROS1+ NSCLC, the ORR was 89% (31/35), with 96% (95% CI: 76, 99) DOR ≥ 6 months and 96% (95% CI: 76, 99) DOR ≥ 12 months[103] Neladalkib (NVL-655) for ALK+ NSCLC - In a heavily pre-treated ALK+ solid tumor population, 51% had any secondary ALK mutation, 26% had a compound ALK mutation, and 56% had a history of CNS metastasis[140, 141] - In all NSCLC response evaluable patients, across all doses, the ORR was 38% (39/103), with a mDOR of 144 months and 78% DOR > 6 months[149] - In patients with any ALK resistance mutation at RP2D, the ORR was 55% (12/22), with a mDOR not reached and 100% DOR > 6 months[158] - The preliminary safety profile of neladalkib was consistent with its ALK-selective design, with ALT increased in 34% of patients, AST increased in 30%, constipation in 16%, dysgeusia in 13%, and nausea in 12%[166] Market Overview - The combined worldwide sales for ALK and ROS1 TKIs in 2024 were approximately $31 billion[27]

Core Insights - Nuvalent, Inc. announced the publication of a manuscript in Molecular Cancer Therapeutics, detailing the design and efficacy of zidesamtinib, a selective ROS1 inhibitor for treating advanced ROS1-positive non-small cell lung cancer (NSCLC) and other solid tumors [1][2][4] Company Overview - Nuvalent, Inc. is a clinical-stage biopharmaceutical company focused on developing targeted therapies for cancer, specifically addressing limitations of existing treatments for kinase targets [6] - The company is advancing a pipeline that includes investigational candidates for ROS1-positive, ALK-positive, and HER2-altered NSCLC, along with multiple discovery-stage research programs [6] Product Development - Zidesamtinib is designed to target tumors resistant to current ROS1 inhibitors, including those with the G2032R mutation, and aims to penetrate the central nervous system (CNS) while avoiding TRK-related adverse events [5] - The ongoing ARROS-1 Phase 1/2 trial is evaluating zidesamtinib in TKI pre-treated and TKI-naïve patients, with pivotal clinical data expected in the first half of 2025 [4][5] Research Findings - The manuscript presents the first crystal structure of ROS1 G2032R in complex with zidesamtinib, providing insights into how this mutation affects TKI binding and supporting the drug's design [3] - Preclinical studies indicate that zidesamtinib effectively suppresses on-target resistance and inhibits ROS1 G2032R brain tumors more effectively than other ROS1 TKIs, suggesting its potential to delay tumor progression [2][3]