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

Besse, B; Lin, JJ; Bazhenova, L; Goto, K; de Langen, AJ; Kim, DW; Wolf, J; Springfeld, C; Popat, S; Lim, DWT; Nagasaka, M; Hong, JY; Baik, CS; Hervieu, A; Moreno, V; Yang, N; Kollengode, K; Yang, H; Xu, Y; Calvet, CY; Yuan, Y; Hammell, AB; Drilon, A; Solomon, BJ

Author(s): Besse, B; Lin, JJ; Bazhenova, L; Goto, K; de Langen, AJ; Kim, DW; Wolf, J; Springfeld, C; Popat, S; Lim, DWT; Nagasaka, M; Hong, JY; Baik, CS; Hervieu, A; Moreno, V; Yang, N; Kollengode, K; Yang, H; Xu, Y; Calvet, CY; Yuan, Y; Hammell, AB; Drilon, A; Solomon, BJ;
Details: Publication Year 2026-02,Volume 32,Issue #2,Page 682-689
Journal Title: Nature Medicine
Publication Type: Research article
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% discontinued repotrectinib due to a TRAE. Here repotrectinib demonstrated durable systemic and intracranial responses with generally low-grade adverse events in patients with NTRK(+) solid tumors, including those with previous TRK TKI treatment and solvent front mutations. These results support the use of repotrectinib to treat patients with NTRK(+) solid tumors. ClinicalTrials.gov identifier: NCT03093116 .
Publisher: Springer Nature
Keywords: Humans; Male; Female; Middle Aged; *Neoplasms/drug therapy/genetics/pathology; Adult; Aged; *Protein Kinase Inhibitors/therapeutic use/adverse effects/administration &; dosage; *Oncogene Proteins, Fusion/genetics; *Receptor, trkA/genetics/antagonists & inhibitors; *Pyrazoles/therapeutic use/adverse effects/administration & dosage; Protein-Tyrosine Kinases/genetics; *Pyrimidines/therapeutic use/adverse effects; Proto-Oncogene Proteins/genetics/antagonists & inhibitors; Young Adult; Receptor, trkC/genetics; Progression-Free Survival
Department(s): Medical Oncology
Publisher's Version: https://doi.org/10.1038/s41591-025-04079-7
Open Access at Publisher's Site: https://doi.org/10.1038/s41591-025-04079-7
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-02-19 05:52:45

Last Modified: 2026-03-05 03:10:33