Update from the ongoing phase 1/2 registrational trial of repotrectinib: results in TKI-naïve and TKI-pretreated patients with NTRK fusion-positive advanced solid tumors (TRIDENT-1)

Abstract

Background: Repotrectinib is a selective, highly potent, next-generation ROS1 and TRK inhibitor that is currently under evaluation in the global registrational phase 1/2 TRIDENT-1 trial. Early clinical data from the TRIDENT-1 trial was presented in a plenary session at the 2021 AACR-NCI-EORTC conference. Repotrectinib was generally well tolerated. In NTRK fusion-positive tyrosine kinase inhibitor (TKI)-naïve (expansion cohort [EXP]-5) and TRK TKI-pretreated (EXP-6) patients with advanced solid tumors, confirmed overall response rates (cORR) per investigator assessment were 41% (95% CI: 18–67) and 48% (95% CI: 27–69), respectively. Efficacy was also observed in patients whose cancers developed solvent front mutations following prior TRK TKI treatment, with investigator-assessed cORR of 62% (95% CI: 32–86). Materials and methods: TRIDENT-1 (NCT03093116) is an ongoing trial enrolling patients whose cancers harbor a ROS1 or NTRK gene fusion. Patients enter 1 of 6 defined EXPs based on cancer type and prior therapy. The primary efficacy endpoint is cORR by Blinded Independent Central Review using RECIST v1.1. Safety and tolerability are also assessed. Results: The data cutoff for the present safety analysis was 11 February 2022. All treated patients were evaluable for safety (n = 380). The most common (>35% of patients) treatment-emergent adverse events (TEAE) were dizziness (60%), dysgeusia (48%), and constipation (35%). The majority (76%) of reported dizziness cases were grade 1 and no events of dizziness led to treatment discontinuation. Most treatment-related AEs (TRAE) were grade 1 or 2. Grade ≥3 TRAEs were observed in 21% of patients; no grade 5 TRAEs were observed. Dose reductions and discontinuations due to TEAEs were reported in 32% and 10% of patients, respectively. Safety results in patients with NTRK fusion-positive advanced solid tumors were similar to those in the overall population. Updated safety and efficacy data for NTRK fusion-positive TKI-naïve (EXP-5) and TKI-pretreated (EXP-6) patients will be available for presentation. Conclusions: In the ongoing registrational phase 1/2 TRIDENT-1 trial, repotrectinib generally was well tolerated in 380 patients. The most common TEAE was low-grade dizziness. Updated efficacy and safety data from this ongoing trial will be presented.