Zidesamtinib Shows Promise in TKI-Pretreated ROS1+ NSCLC: ARROS-1 Data at WCLC 2025

Nuvalent Initiates Rolling NDA Submission for Zidesamtinib in Advanced ROS1-Positive NSCLC, Completion Expected Q3 2025

CAMBRIDGE, Mass., Sept. 7, 2025 – Nuvalent, Inc. (Nasdaq: NUVL), a biopharmaceutical firm specializing in precision-targeted cancer therapies, has announced the initiation of a rolling New Drug Application (NDA) submission to the U.S. Food and Drug Administration (FDA) for zidesamtinib. This investigational ROS1-selective inhibitor is targeted for patients with advanced ROS1-positive non-small cell lung cancer (NSCLC) who have been previously treated with tyrosine kinase inhibitors (TKIs). The pivotal data supporting this submission were presented at the IASLC 2025 World Conference on Lung Cancer (WCLC 2025) in Barcelona, Spain. The data, derived from the global ARROS-1 Phase 1/2 clinical trial, have put Nuvalent on track to complete the rolling submission in Q3 2025.

The FDA has granted zidesamtinib participation in the Real-Time Oncology Review (RTOR) program. This initiative accelerates the review process by allowing for the early submission of topline efficacy and safety data before the complete application is finalized. This decision significantly accelerates the potential timeline for zidesamtinib to reach patients. The company confirmed ongoing dialogues with the FDA about possible expansions into indications beyond pre-treated patients lines.

“New treatment options are crucial for individuals with ROS1-positive NSCLC, particularly those who experience intolerance to existing TKIs, disease progression with brain metastases, or the development of resistance mutations,” stated Christopher Turner, M.D., Chief Medical Officer at Nuvalent. “The efficacy and tolerability profile of zidesamtinib, as demonstrated in the ARROS-1 trial, presents a significant opportunity to improve outcomes for this patient population. We are committed to making zidesamtinib a new standard of care.”

Zidesamtinib: A Novel ROS1 Inhibitor

Zidesamtinib is a novel, brain-penetrant ROS1-selective inhibitor engineered to overcome limitations of currently available ROS1 inhibitors. Its design aims to maintain activity against tumors that have developed resistance mutations, such as G2032R. The drug’s ability to penetrate the central nervous system (CNS) is intended to improve treatment outcomes in patients with brain metastases, a common and devastating complication of NSCLC. Furthermore, zidesamtinib’s selectivity is engineered to avoid inhibiting the tropomyosin receptor kinase (TRK) family, potentially mitigating TRK-related CNS adverse events associated with dual TRK/ROS1 inhibitors. This novel approach represents a paradigm shift in ROS1 inhibition, with the potential for deep and durable responses across various lines of therapy. Zidesamtinib has been granted breakthrough therapy designation by the FDA for ROS1-positive metastatic NSCLC patients previously treated with two or more ROS1 TKIs, as well as orphan drug designation for ROS1-positive NSCLC.

ARROS-1 Clinical Trial Details

The ARROS-1 trial (NCT05118789) is a Phase 1/2 clinical study evaluating zidesamtinib in patients with advanced ROS1-positive NSCLC and other solid tumors. The Phase 1 portion of the trial focused on safety, tolerability, pharmacokinetic profiling, and preliminary anti-tumor activity in patients who had previously received at least one ROS1 TKI or had other previously treated ROS1-positive solid tumors. The ongoing Phase 2 portion is a registrational intent, single arm, open label study designed to assess zidesamtinib in both TKI-naïve and TKI pre-treated patients with advanced ROS1-positive NSCLC. This Phase 2 design could potentially set the stage for a broader market access depending on the study’s results and subsequent regulatory evaluations.

Nuvalent’s Strategic Focus

Nuvalent, Inc. (Nasdaq: NUVL) is dedicated to developing precisely targeted therapies for cancer patients. The company utilizes extensive expertise in chemistry and structure-based drug design to create innovative small molecules that can overcome resistance, minimize adverse events, address brain metastases, and drive more durable responses. Nuvalent’s pipeline includes investigational candidates for ROS1-positive, ALK-positive, and HER2-altered non-small cell lung cancer, as well as multiple discovery-stage research programs. Nuvalent’s commitment extends beyond NSCLC, suggesting a broad strategic approach to addressing clinically proven kinase targets in the oncology landscape. The company’s approach is resonating with investors, attracting funding for its promising clinical programs.

Forward-Looking Statements

This press release includes forward-looking statements regarding Nuvalent’s strategy, business plans, data announcements, NDA submissions, clinical development programs, potential benefits of product candidates, clinical trial designs, pipeline programs, research and development efforts, and associated risks and uncertainties. These statements are based on current expectations and are subject to risks including, but not limited to, enrollment delays, unexpected clinical trial results, regulatory approval timelines, unexpected costs, and intellectual property risks. Actual events may differ materially from those projected. Nuvalent undertakes no obligation to update these forward-looking statements.