Abstract P224: Update from the Phase 2 registrational trial of repotrectinib in TKI-pretreated patients with ROS1+ advanced non-small cell lung cancer and with NTRK+ advanced solid tumors (TRIDENT-1)
Authors: Lin Jessica J. , Cho Byoung Chul , Springfeld Christoph , Camidge D. Ross , Solomon Benjamin , Baik Christina , Velcheti Vamsidhar , Kim Young-Chul , Moreno Victor , van der Wekken Anthonie J. , Felip Enriqueta , Uprety Dipesh , Trone Denise , Stopatschinskaja Shanna , Drilon Alexander 
Published: December 2021

Abstract
Background: Repotrectinib is a next-generation ROS1/TRK tyrosine kinase inhibitor (TKI) that is currently in a registrational Phase 2 trial (TRIDENT-1). A previous update from the TRIDENT-1 trial showed a generally well tolerated safety profile in 185 treated patients. Interim efficacy data were previously presented. In ROS1+ NSCLC patients with 1 prior TKI and prior platinum-based chemotherapy (EXP-2), confirmed overall response rate (cORR) was 40% (2 of 5 patients); in ROS1+ NSCLC patients with 1 prior TKI without prior platinum-based chemotherapy (EXP-4), cORR was 67% (4 of 6 patients); in ROS1+ NSCLC patients with 2 prior TKIs without prior platinum-based chemotherapy (EXP-3), cORR was 40% (2 of 5 patients). In NTRK+ TKI-pretreated advanced solid tumor patients (EXP-6), cORR was 50% (3 of 6 patients). In addition, efficacy was demonstrated in patients who developed solvent front mutations (SFM) following prior ROS1/TRK TKI treatment. cORR was 67% (4 of 6 patients) and 50% (2 of 4 patients) in ROS1+ NSCLC and NTRK+ solid tumors patients with SFMs, respectively. One patient who developed a SFM after entrectinib treatment (EXP-2) had a cCR with 5.6+ months duration of response. Methods: TRIDENT-1 (NCT03093116) is an ongoing registrational Phase 2 trial enrolling patients whose cancers harbor a ROS1 or NTRK gene fusion. Patients are enrolled into 6 defined expansion cohorts (EXP 1-6), based on cancer type and prior therapy. The primary endpoint is cORR by Blinded Independent Central Review using RECIST v1.1. Results: An updated safety analysis across Phase 1 and Phase 2 patients (n=243) based on a data cut-off date of 4 May 2021 was conducted. 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%). Grade ≥3 treatment-related AEs (TRAEs) were observed in 17% of patients; no Grade 5 TRAEs were observed. 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 including 24% of patients with a TEAE that led to a dose reduction and 10% of patients with a TEAE that led to drug discontinuation. Updated efficacy information for TKI-pretreated ROS1+ NSCLC and NTRK+ advanced solid tumor patients is being collected and will be available for presentation. Conclusions: Repotrectinib is a next-generation ROS1/TRK inhibitor. In an ongoing registrational Phase 2 trial, repotrectinib was generally well tolerated with low frequency of dose modifications. Updated Phase 2 efficacy data will be available for presentation.
Citation Format: Jessica J. Lin, Byoung Chul Cho, Christoph Springfeld, D. Ross Camidge, Benjamin Solomon, Christina Baik, Vamsidhar Velcheti, Young-Chul Kim, Victor Moreno, Anthonie J. van der Wekken, Enriqueta Felip, Dipesh Uprety, Denise Trone, Shanna Stopatschinskaja, Alexander Drilon. Update from the Phase 2 registrational trial of repotrectinib in TKI-pretreated patients with ROS1+ advanced non-small cell lung cancer and with NTRK+ advanced solid tumors (TRIDENT-1) [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 P224.