Multinational phase 1-2 trial of repotrectinib in NTRK fusion-positive advanced solid tumors

Early-generation TRK TKIs approved for treating NTRK fusion-positive (NRTK⁺) solid tumors provide clinical benefit; however, resistance emerges. Repotrectinib is a next-generation ROS1/TRK TKI with a compact macrocyclic structure designed to improved durability of response. The multinational phase 1-2 TRIDENT-1 trial evaluated repotrectinib for adult patients with NTRK⁺ advanced solid tumors. The primary endpoint was confirmed objective response. The median follow-up ranged between 21.3 and 25.7 months. The figure shows the efficacy outcomes. In the TKI-naïve cohort (n=51), the response rate was 59% (95% CI 44-72), the median duration of response was not estimable, and the median progression-free survival was 30.3 months (9.0-NE). In the TKI-pretreated cohort (n=69), the response rate was 48% (95% CI 36-60), the median DOR was 9.8 months (7.4-13.0), and the median PFS was 7.4 months (3.9-9.7). Among 30 TKI-pretreated with NRTK solvent front mutations, 16 had a response. Intracranial responses were observed in two of three TKI-naïve patients and in four of six TKI-pretreated patients with baseline measurable intracranial disease. The most common any-grade treatment-related adverse event was dizziness (57%), most TRAEs were low grade. Discontinuation of repotrectinib due to a TRAE occurred in 4% of patients. The authors conclude that these results support use of repotrectinib in patients with NTRK⁺ solid tumors.