As reported in The New England Journal of Medicine by Alexander Drilon, MD, and colleagues, the phase I/II TRIDENT-1 trial showed the activity of the next-generation ROS1 tyrosine kinase inhibitor repotrectinib in patients with ROS1 fusion–positive non–small cell lung cancer (NSCLC) with no previous ROS1 tyrosine kinase inhibitor exposure, as well as in those who had previously received one ROS1 tyrosine kinase inhibitor but had not received chemotherapy.
The trial supported the November 2023 approval of repotrectinib in this setting.
Alexander Drilon, MD
Study Details
The international multicenter trial investigated repotrectinib in patients with advanced solid tumors enrolled between February 2017 through December 2022, including 127 patients with ROS1 fusion–positive NSCLC. In the phase I portion, the recommended phase II dose of repotrectinib was determined to be 160 mg daily for 14 days followed by 160 mg twice daily.
The primary outcome measure in the phase II portion was confirmed objective response.
Responses
The ROS1 fusion–positive population included 71 patients (58% from Asia) with no prior ROS1 tyrosine kinase inhibitor treatment and 56 (41% from Asia) with prior treatment with one ROS1 tyrosine kinase inhibitor and no prior chemotherapy.
Among the 71 patients with no prior ROS1 tyrosine kinase inhibitor therapy, objective response was observed in 56 (79%, 95% confidence interval [CI] = 68%–88%), with complete response in 7 (10%). Median duration of response was 34.1 months (95% CI = 25.6 months to not estimable). Median progression-free survival was 35.7 months (95% CI = 27.4 months to not estimable). Median overall survival was not estimable (95% CI = 44.4 months to not estimable).
Among the 56 patients who had received one prior ROS1 tyrosine kinase inhibitor and no chemotherapy, objective response was observed in 21 (38%, 95% CI = 25%–52%), with complete response in 3 (5%). Median duration of response was 14.8 months (95% CI = 7.6 months to not estimable). Median progression-free survival was 9.0 months (95% CI = 6.8–19.6 months). Median overall survival was 25.1 months (95% CI = 17.8 months to not estimable).
Among 17 patients with the ROS1 G2032R resistance mutation who had received at least one prior ROS1 tyrosine kinase inhibitor, objective response was observed in 10 (59%, 95% CI = 33%–82%).
KEY POINTS
- Repotrectinib was associated with activity in groups with no prior receipt of ROS1 tyrosine kinase inhibitors and with prior exposure to one tyrosine kinase inhibitor and no chemotherapy.
- The agent was active in patients with ROS1 tyrosine kinase inhibitor resistance mutations.
Adverse Events
Among 426 patients with advanced solid tumors receiving the phase II dose of repotrectinib, the most common treatment-related adverse events of any grade were dizziness (58%), dysgeusia (50%), and paresthesia (30%). Treatment-related grade ≥ 3 adverse events occurred in 29% of patients, most commonly anemia and increased creatine kinase (4% each). Treatment was discontinued because of treatment-related adverse events in 3% of patients. No treatment-related deaths were reported.
The investigators concluded: “Repotrectinib had durable clinical activity in patients with ROS1 fusion–positive NSCLC, regardless of whether they had previously received an ROS1 [tyrosine kinase inhibitor]. Adverse events were mainly of low grade and compatible with long-term administration.”
Dr. Drilon, of Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, and Byoung Chul Cho, MD, PhD, of Yonsei University College of Medicine, Seoul, are the corresponding authors of The New England Journal of Medicine article.
Disclosure: The study was funded by Turning Point Therapeutics, a wholly owned subsidiary of Bristol Myers Squibb. For full disclosures of the study authors, visit nejm.org.
