Repotrectinib in ROS1 Fusion-Positive Non-Small-Cell Lung Cancer

Background: Early-generation ROS1 tyrosine kinase inhibitors (TKIs) approved for treating ROS1 fusion-positive non-small-cell lung cancer (NSCLC) show antitumor activity, but resistance often develops, and intracranial efficacy remains suboptimal. Repotrectinib is a next-generation ROS1 TKI with demonstrated preclinical activity against ROS1 fusion-positive cancers, including those with resistance mutations like ROS1 G2032R.

Methods: In this registrational phase 1-2 trial, we evaluated the efficacy and safety of repotrectinib in patients with advanced solid tumors, including ROS1 fusion-positive NSCLC. The primary efficacy endpoint for the phase 2 trial was confirmed objective response, with efficacy analyses combining data from phase 1 and phase 2. Secondary endpoints included duration of response, progression-free survival, and safety in phase 2.

Results: Based on phase 1 trial results, the recommended phase 2 dose of repotrectinib was 160 mg daily for 14 days, followed by 160 mg twice daily. Among 71 patients with ROS1 fusion-positive NSCLC who had not previously received a ROS1 TKI, 56 (79%; 95% CI, 68 to 88) showed a response. The median duration of response was 34.1 months (95% CI, 25.6 to not estimable), and median progression-free survival was 35.7 months (95% CI, 27.4 to not estimable). In 56 patients with ROS1 fusion-positive NSCLC who had received one prior ROS1 TKI but no chemotherapy, 21 (38%; 95% CI, 25 to 52) responded, with a median duration of response of 14.8 months (95% CI, 7.6 to not estimable), and median progression-free survival of 9.0 months (95% CI, 6.8 to 19.6). Of 17 patients with the ROS1 G2032R mutation, 10 (59%; 95% CI, 33 to 82) responded. A total of 426 patients received the phase 2 dose, with the most common treatment-related adverse events being dizziness (58%), dysgeusia (50%), and paresthesia (30%). Three percent of patients discontinued repotrectinib due to treatment-related adverse events.

Conclusions: Repotrectinib demonstrated durable clinical activity in patients with ROS1 fusion-positive NSCLC, regardless of prior ROS1 TKI treatment. Adverse events were predominantly low-grade and manageable, supporting long-term use. (Funded by Turning Point Therapeutics, a wholly owned subsidiary of Bristol Myers Squibb; TRIDENT-1 ClinicalTrials.gov number, NCT03093116).