Repotrectinib in tyrosine kinase inhibitor (TKI)-naïve patients (pts) with advanced ROS1 fusion-positive (ROS1+) NSCLC in the phase 1/2 TRIDENT-1 trial: Clinical update, treatment beyond progression and subsequent therapies.

Abstract

8522 Background: Repotrectinib, a next-generation ROS1 TKI, has demonstrated durable clinical activity in the pivotal phase 1/2 TRIDENT-1 trial (NCT03093116). We report updated efficacy with a median follow-up of 33.9 months (mo) [~10 mo of additional follow-up], the first analyses of progression patterns, treatment beyond progression, and an update on subsequent anticancer therapies. Methods: Recommended phase 2 dose was 160 mg QD for 14 days, then 160 mg BID. Phase 2 primary endpoint was confirmed objective response rate (cORR) by blinded independent central review (BICR) per RECIST v1.1. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), intracranial ORR (icORR), and safety. Treatment beyond BICR-assessed progression and sites of progression (per investigator) were also assessed. Safety assessments included all treated pts. Results: As of 15 Oct 2023, median follow-up in the TKI-naïve cohort (n = 71) was 33.9 (range, 24.0–76.5) months (mo). cORR was 79% (95% CI, 68–88); median DOR was 34.1 (95% CI, 27.4–not estimable [NE]) mo and 70% (95% CI, 57–83) of responders maintained a response of ≥ 24 mo. Median PFS was 35.7 (95% CI, 24.6–NE) mo and 63% (95% CI, 51–75) of pts were progression-free at 24 mo. Of 9 pts with measurable baseline brain metastases, icORR was 89% (95% CI, 52–100). Results for pts who received repotrectinib beyond progression are shown in the table. Of pts with disease progression per investigator (n = 37), the most common sites were lung (49%) and lymph nodes (35%). Of 42 (59%) pts who discontinued repotrectinib for any reason, 11 (26%) received single-agent TKI as the first subsequent anticancer therapy, 10 (24%) received chemo with/without immunotherapy (IO), and 2 (5%) received IO alone. Among all pts who received ≥ 1 dose of repotrectinib (n = 565), grade ≥ 3 treatment-emergent adverse events occurred in 323 (57%) pts and treatment-related adverse events in 162 (29%) pts. Treatment-emergent dizziness occurred in 63% of pts and was mostly grade 1-2. Conclusions: With a median follow-up of ~3 years in TRIDENT-1, repotrectinib continued to demonstrate durable clinical activity in ROS1 TKI-naïve pts. Progression patterns and treatment beyond progression were described for the first time. Clinical trial information: NCT03093116 . [Table: see text]