Zidesamtinib (Jideytro®): a new selective, brain-penetrant ROS1 inhibitor approved for the treatment of ROS1-positive non-small cell lung cancer

Abstract

ROS1-targeted therapies have improved outcomes in ROS1-positive non-small cell lung cancer (NSCLC), but acquired resistance, CNS progression, and off-target toxicities remain important limitations. Zidesamtinib (Jideytro®, NVL-520) is a next-generation, brain-penetrant, tropomyosin receptor kinase (TRK)-sparing ROS1 inhibitor designed to retain activity against resistance mutations, including G2032R. In preclinical models, it demonstrated potent, selective ROS1 inhibition, broad resistance coverage, and durable intracranial activity. Administered orally at 100 mg once daily, zidesamtinib exhibits a favorable pharmacokinetic profile. Data from the ARROS-1 phase 1/2 trial demonstrated durable clinical efficacy and manageable safety in previously treated ROS1-positive NSCLC, including patients with CNS metastases and G2032R resistance. These results led to its accelerated FDA approval on July 22, 2026, for patients previously treated with a ROS1-targeted tyrosine kinase inhibitor.