Abstract P02-01: Repotrectinib in patients with NTRK fusion-positive advanced solid tumors: update from the registrational phase 2 TRIDENT-1 trial

Abstract Background: NTRK fusions drive a broad range of solid tumors. Two FDA approved TRK tyrosine kinase inhibitors (TKIs) have demonstrated efficacy in patients (pts) with NTRK fusion+ advanced solid tumors; however, emergent TRK solvent front (SF) and gatekeeper resistance mutations occur. Repotrectinib is a next-generation ROS1/TRK TKI with potency against wildtype and mutant forms of ROS1 and TRK. In preclinical studies, repotrectinib was more potent than larotrectinib, entrectinib, and selitrectinib against wildtype TRK, SF and gatekeeper mutations. Early interim data from the Phase 1/2 TRIDENT-1 trial led to Fast Track designation by the FDA for repotrectinib in TRK TKI-pretreated pts. This abstract is an updated analysis of this population and the first presentation of repotrectinib activity in TRK TKI-naïve pts. Methods: Pts with NTRK fusion+ advanced solid tumors were enrolled into the ongoing registrational Phase 2 TRIDENT-1 trial (NCT03093116). Pts with no prior TRK TKIs were enrolled into Expansion Cohort 5 (EXP-5) and pts who received up to 2 lines of prior TRK TKIs were enrolled into EXP-6. Prior chemotherapy and/or immunotherapy were allowed in both cohorts. The primary endpoint is cORR by Blinded Independent Central Review using RECIST v1.1. Results: As of efficacy data cutoff date of 28 July 2021, 8 pts in EXP-5 and 19 pts in EXP-6 had at least 2 post-baseline scans and were evaluable for efficacy analysis. Median age was 63 y (range 33–80) in EXP-5 and 50 y (range 23–81) in EXP-6; median number of prior lines of chemo/immunotherapy was 1 (range 0–2) in EXP-5 and 1 (range 0–4) in EXP-6. In EXP-6, 79% (15/19) of pts received 1 prior TRK TKI. Confirmed responses were reported by physician assessment. In EXP-5, cORR was 63% (5 of 8 pts; 95% CI: 24–91%) with DOR from 1.9+ to 7.4+ months (mo). In EXP-6, cORR was 47% (9 of 19 pts; 95% CI: 24–71%) with DOR from 1.9+ to 15.1 mo. In 10 pts enrolled in EXP-6 with a SF mutation, the cORR was 60% (6 of 10 pts; 95% CI: 26–88%). Median duration of treatment was 6.3 mo (range 0.9–13.4+) in EXP-5 and 8.1 mo (range 1.1–20.8) in EXP-6. An updated safety analysis for Phase 1 and Phase 2 (n=243) based on a data cut-off date of 4 May 2021 was conducted. Repotrectinib was generally well tolerated. Treatment-emergent adverse events (TEAEs) observed in ≥20% of patients were dizziness (62%), dysgeusia (43%), constipation (33%), dyspnea (30%), paresthesia (28%), anemia (26%), and fatigue (26%). The majority (77%) of dizziness TEAEs were Grade 1 and 4% were Grade 3; none of the dizziness events led to treatment discontinuation. Dose modifications remained infrequent (24% of pts had a dose reduction and 10% of pts discontinued study drug due to a TEAE). Conclusions: Repotrectinib is a next-generation ROS1 and TRK inhibitor. In an ongoing registrational Phase 2 trial, repotrectinib demonstrated efficacy in TRK TKI-naïve and TKI-pretreated pts and was generally well tolerated. Enrollment in the multi-cohort Phase 2 trial is ongoing. Citation Format: Benjamin Besse, Christina Baik, Christoph Springfeld, Alice Hervieu, Victor Moreno, Lyudmila Bazhenova, Jessica J. Lin, D. Ross Camidge, Benjamin Solomon, Vamsidhar Velcheti, Anthonie J. van der Wekken, Enriqueta Felip, Dipesh Uprety, Denise Trone, Shanna Stopatschinskaja, Byoung Chul Cho, Alexander Drilon. Repotrectinib in patients with NTRK fusion-positive advanced solid tumors: update from the registrational phase 2 TRIDENT-1 trial [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P02-01.