Multinational phase 1-2 trial of repotrectinib for advanced ROS1 fusion-positive non-small cell lung cancer

The early-generation ROS1 tyrosine kinase inhibitors that are approved for the treatment of ROS1 fusion-positive non-small cell lung cancer have antitumor activity, but resistance develops in tumors. Repotrectinib is a next-generation ROS1 TKI. The multinational phase 1-2 TRIDENT-1 trial evaluated repotrectinib for advanced ROS1 fusion-positive NSCLC. Based on results of phase 1 the recommended phase 2 dose (RP2D) was repotrectinib 160 mg daily for 14 days, followed by 160 mg twice daily. Among patients who had not previously received a ROS1 TKI, response occurred in 79% (95% CI 68-88), with a median duration of response 34.1 months and median progression-free survival 35.7 months. Among patients who had previously received a ROS1 TKI and had never received chemotherapy, response occurred in 38% (95% CI 25-52), with a median duration of response 14.8 months and median progression-free survival 9.0 months The most common RP2D treatment-related adverse events were dizziness (in 58% of patients), dysgeusia (50%), and paresthesia (30%), while 3% discontinued repotrectinib because of TRAEs. The authors conclude that repotrectinib had durable clinical activity in patients with ROS1 fusion-positive NSCLC, regardless of whether they had previously received a ROS1 TKI. Treatment was well-tolerated (quick take video summary).