FDA Accepts NDA for Zidesamtinib in Advanced ROS1+ NSCLC

The FDA has accepted the new drug application (NDA) for zidesamtinib (NVL-520), an investigational ROS1-selective inhibitor.¹ Under the Prescription Drug User Fee Act, the FDA has set a target action date of September 18, 2026.

The NDA seeks zidesamtinib’s approval for treatment of adult patients with locally advanced or metastatic ROS1 fusion-positive (ROS1+) non–small cell lung cancer (NSCLC) who have been previously treated with tyrosine kinase inhibitors (TKIs). If approved, the agent would provide a new central nervous system (CNS)-penetrant targeted treatment option that overcomes the challenge of acquired ROS1 drug resistance mutations, which accounts for progression in 30% to 50% of patients on other TKIs.²

"Continued innovation for patients with [ROS1+] NSCLC is needed. Limitations of currently available ROS1 TKIs can lead to trade-offs between efficacy and tolerability in the front-line, and there is no clear targeted therapy care standard for TKI-pretreated patients," said Alexander Drilon, MD, chief, Early Drug Development Service at Memorial Sloan Kettering Cancer Center, in a news release.³

Submission was based on positive data from the ongoing phase 1/2 ARROS-1 trial (NCT05118789) presented in September 2025 at the IASLC World Conference on Lung Cancer (WCLC), which showed promising, durable responses and tolerable safety.⁴ Among 117 TKI-pretreated, ROS1+ patients with NSCLC, the objective response rate (ORR) by blinded independent central review (BICR) was 44% (95% CI, 34%–53%).³

Intracranial activity was also observed, with an intracranial ORR of 48% among the 56 patients that had measurable CNS lesions at baseline.

Zidesamtinib was well-tolerated and consistent with the agent’s design. Of the 432 patients with ROS1+ NSCLC treated at the recommended phase 2 dose (RP2D) as of the data cut-off, the most frequently occurring treatment-emergent adverse events included peripheral edema (36%), constipation (17%), blood creatine phosphokinase increase (16%), fatigue (16%), and dyspnea (15%).

“These data demonstrate the potential for zidesamtinib to deliver meaningful clinical outcomes for TKI-pretreated patients, including those progressing with brain metastases or treatment-emergent resistance mutations, and to offer a favorable tolerability profile consistent with its goal of avoiding off-target side effects through ROS1-selectivity,” Drilon, ARROS-1 trial investigator, added.³

About ARROS-1 and Early Findings

The nonrandomized, open-label, multicenter ARROS-1 trial is a dose escalation and dose expansion study that aims to evaluate the safety, tolerability, and efficacy of zidesamtinib in heavily pretreated patients with advanced ROS1+ solid tumors.⁵ Among prior TKIs received by patients included lorlatinib (Lorbrena), repotrectinib (Augtyro), crizotinib (Xalkori), entrectinib (Rozlytrek), and taletrectinib (Ibtrozi).

In the completed phase 1 portion of the study, which evaluated zidesamtinib’s safety and tolerability and determined the RP2D, doses during escalation ranged from 25 mg to 150 mg daily; the maximum tolerated dose was not reached. The RP2D was ultimately determined to be 100 mg daily, administered orally.

The ongoing phase 2 portion is recruiting both TKI-pretreated and TKI-naive patients to evaluate the primary end point of ORR per BICR at the RP2D, as well as secondary end points of duration of response, time to response, progression-free survival, overall survival, and clinical benefit rate. It aims to assign patients to 1 of 5 expansion cohorts, depending on prior treatment received:

1. Cohort 2a: TKI-naive and up to 1 prior chemotherapy and/or immunotherapy.
2. Cohort 2b: 1 prior ROS1 TKI and no prior chemotherapy or immunotherapy.
3. Cohort 2c: 1 prior ROS1 TKI and 1 prior platinum-based chemotherapy with or without immunotherapy.
4. Cohort 2d: 2 or more prior ROS1 TKIs and up to 1 prior chemotherapy and/or immunotherapy.
5. Cohort 2e: Any prior therapy on which the patient has progressed.

Early clinical activity and safety with zidesamtinib were evident in preliminary data presented at the 2024 European Society for Medical Oncology (ESMO) Congress. Here, the ORR among response-evaluable patients (n = 71) was 44%, including 2 complete responses.⁶ The safety profile at the time was favorable, with no dose-limiting toxicities or discontinuations due to treatment-related adverse events in the population pooled across doses (n = 104).

REFERENCES

1. Nuvalent announces FDA acceptance of new drug application for zidesamtinib for the treatment of TKI pre-treated patients with advanced ROS1-positive NSCLC. News release. Nuvalent. November 19, 2025. Accessed November 20, 2025. https://tinyurl.com/yre6w4tr

2. Tangpeerachaikul A, Mente S, Magrino J, Gu F, Horan JC, Pelish HE. Zidesamtinib selective targeting of diverse ROS1 drug-resistant mutations. Mol Cancer Ther. 2025;24(7):1005-1019. doi:10.1158/1535-7163.MCT-25-0025

3. Nuvalent announces positive pivotal data from ARROS-1 clinical trial of zidesamtinib for TKI pre-treated patients with advanced ROS1-positive NSCLC. News release. Nuvalent. June 24, 2025. Accessed November 20, 2025. https://tinyurl.com/mpb8mfcm

4. Nuvalent presents pivotal data from ARROS-1 clinical trial of zidesamtinib for TKI pre-treated patients with advanced ROS1-positive NSCLC at WCLC 2025. News release. Nuvalent. September 7, 2025. Accessed November 20, 2025. https://tinyurl.com/3h8y3939

5. A study of zidesamtinib (NVL-520) in patients with advanced NSCLC and other solid tumors harboring ROS1 rearrangement (ARROS-1). ClinicalTrials.gov. Updated October 24, 2025. Accessed November 20, 2025. https://clinicaltrials.gov/study/NCT05118789

6. Besse B, Drilon AE, Cho BC, et al. Phase I/II ARROS-1 study of zidesamtinib (NVL-520) in ROS1 fusion-positive solid tumours. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Presentation 1256MO.