Repotrectinib in NTRK fusion–positive advanced solid tumors: a phase 1/2 trial

作者：Benjamin Besse, Jessica J. Lin, Lyudmila Bazhenova, Koichi Goto, A. de Langen, Dong-Wan Kim, Jürgen Wolf, Christoph Springfeld, Sanjay Popat, Wan‐Teck Lim, Misako Nagasaka, Jung Yong Hong, Christina S. Baik, Alice Hervieu, Victor Moreno, Nong Yang, Kanthi Athreya Kollengode, Haisu Yang, Yuanfang Xu, C. Calvet, Yong Yuan, A. Hammell, Alexander D. Drilon, Benjamin J. Solomon · 发表于：Nature Medicine · 年份：2026 · DOI：10.1038/s41591-025-04079-7 · 被引用次数：16 · 研究领域：Lung Cancer Treatments and Mutations、Melanoma and MAPK Pathways、Chronic Myeloid Leukemia Treatments

Abstract Early-generation TRK tyrosine kinase inhibitors (TKIs) approved for treating NTRK fusion–positive ( NTRK + ) solid tumors provide clinical benefit; however, resistance emerges. Repotrectinib is a next-generation ROS1/TRK TKI with a compact macrocyclic structure designed to improve durability of response. TRIDENT-1 is a registrational phase 1/2 trial assessing repotrectinib, a next-generation ROS1/TRK TKI, in adults with advanced solid tumors, including NTRK + disease. The primary endpoint was confirmed objective response; secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival and safety. Median follow-up ranged between 21.3 months and 25.7 months. In the TKI-naive cohort ( n = 51; 95% confidence interval (CI)), the response rate was 59% (44–72); the median DOR was not estimable (NE); and the median PFS was 30.3 months (9.0–NE). In the TKI-pretreated cohort ( n = 69; 95% CI), the response rate was 48% (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). Of 30 TKI-pretreated patients with NTRK solvent front mutations, 16 had a response (53%; 95% CI: 34–72). Intracranial responses were observed in two of three TKI-naive patients and in four of six TKI-pretreated patients with measurable intracranial disease at baseline. Among all treated patients ( n = 565), the most common any-grade treatment-related adverse event (TRAE) was dizziness (57%); most TRAEs were low grade; and 4% ...