Zai Lab Limited announced The New England Journal of Medicine (NEJM) has published data from the registrational Phase 1/2 TRIDENT-1 study evaluating repotrectinib (TPX-0005) in patients with ROS1 fusion-positive (ROS1+) non-small cell lung cancers (NSCLCs). Repotrectinib is a tyrosine kinase inhibitor (TKI) that has shown robust anti-tumor activity against ROS1+ cancers in preclinical models. In the TRIDENT-1 study, repotrectinib demonstrated high response rates and durable activity in patients with ROS1+ NSCLC, including patients with TKI-naïve and TKI-pretreated tumors, ROS1 G2032R resistance mutations and brain metastases.

Treatment with repotrectinib was generally well tolerated with a manageable safety profile compatible with long-term administration. Turning Point Therapeutics, sponsored and designed the global, registrational TRIDENT-1 study. In August 2022, Bristol Myers Squibb acquired the company, including its asset repotrectinib.

As part of its exclusive license agreement with Turning Point Therapeutics to develop and commercialize repotrectinib in Greater China (mainland China, Hong Kong, Taiwan, and Macau), Zai Lab participated and enrolled 81 patients for this trial. Every year in China, more than 800,000 people are newly diagnosed with lung cancer, and NSCLC accounts for approximately 85% of the cases. ROS1 rearrangements occur in =2% of patients with NSCLC.

Brain metastases are common among patients with ROS1+ NSCLC and intracranial activity of approved ROS1 TKIs can be suboptimal. TRIDENT-1 is a registrational, first-in-human Phase 1/2 study assessing the efficacy and safety of repotrectinib in patients with advanced solid tumors, including ROS1+ NSCLC. In the study, 519 patients received one or more doses of repotrectinib, with 103 treated in Phase 1 and 416 treated in Phase 2. Primary endpoints were maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) and confirmed objective response rate (ORR), as assessed by blinded independent central review (BICR) using RECIST v1.1 (Phase 2).

Secondary endpoints included duration of response (DOR), progression-free survival (PFS) and safety. Based on the results of this trial, the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) accepted the New Drug Application (NDA) for repotrectinib submitted by Zai Lab for the treatment of adult patients with locally advanced or metastatic ROS1-positive NSCLC, after granting priority review in May 2023. In November 2023, the U.S. Food and Drug Administration approved repotrectinib for use in adult patients with locally advanced or metastatic ROS1+ NSCLC in the United States.