Pivotal topline data from the phase 1/2 TRIDENT-1 trial of repotrectinib in patients with ROS1+ advanced non-small cell lung cancer (NSCLC)

Background: Repotrectinib is a next-generation ROS1 tyrosine kinase inhibitor (TKI) currently under evaluation in the global phase 1/2 TRIDENT-1 trial (NCT03093116). We report updated results in TKI-naïve and -pretreated patients with advanced, ROS1 fusion-positive (ROS1+) NSCLCs.TRIDENT-1Repotrectinib in ROS1+ advanced NSCLCEXP-1 ROS1 TKI-naiven = 71EXP-4 1 prior ROS1 TKI + no prior CTn = 56EXP-2 1 prior ROS1 TKI + 1 platinum-based CT n = 26EXP-3 2 prior ROS1 TKIs + no prior CTn = 18ORR % (95% CI)79 (68,88)38 (25,52)42 (23,63)28 (10,54)iORR%(95% CI)88 (47,100)n = 842 (15,72)n = 1250 (7,93)n = 40n = 2LandmarkDOR % (95% CI)6-mo91 (83,99)80 (62,98)64 (35,92)60 (17,100)12-mo86 (76,96)60 (36,83)40 (8,72)30 (0,77)Landmark PFS% (95% CI)6-mo91 (84,98)67 (54,81)39 (19,58)22 (3,41)12-mo80 (70,90)44 (29,59)15 (0,33)7 (0,21) Open table in a new tab Materials and methods: Patients were assigned to one of four expansion cohorts (EXP). The primary endpoint was objective response rate (ORR) by Blinded Independent Central Review (BICR) using RECIST v1.1. Secondary endpoints included duration of response (DOR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), intracranial objective response rate (iORR) in patients with measurable brain metastases, ORR in TKI-pretreated cancers with ROS1 G2032R, safety, and patient reported outcomes. Efficacy included pooled data from phase 1 (all dose levels meeting pooling criteria) and phase 2 (RP2D of 160 mg QD x 14 days followed by 160 mg BID) and safety included all patients who received 1 dose of repotrectinib. Results: As of June 20, 2022, the primary efficacy population included 71 TKI-naive patients (EXP-1) and 56 TKI-pretreated patients with no prior chemotherapy (CT; EXP-4). ORR was 79% (95% CI 68,88) in EXP-1 and 38% (95% CI 25,52) in EXP-4. DOR (95% CI) by KM estimate was 86% (76,96) at 12 months in EXP-1 and 80% (62,98) at 6 months in EXP-4. Median duration of treatment in EXP-1 and -4 was 13.3 (0.8,60.6+) and 8.25 (0.5,24.8) months, respectively. ORR in pooled patients (EXP-2 to -4) with ROS1 G2032R (n=17) was 59%; six-month DOR by KM estimate was 70% (95% CI 42,98). Additional efficacy data are shown in the table. In the overall safety population of 444 patients, most treatment-related adverse events (AE) were grade 1-2. All-grade treatment-emergent AEs reported in >20% of patients were dizziness (61%), dysgeusia (49%), constipation (37%), anemia (35%), paresthesia (32%), dyspnea (29%), fatigue (24%), nausea (21%), and ALT increase (21%). Dose reductions and drug discontinuation were required in 34.0% and 9.7% of patients, respectively. Conclusions: Repotrectinib achieves durable activity, including intracranial responses, in TKI-naïve and TKI-pretreated patients with ROS1+ advanced NSCLC, and those with ROS1 G2032R. Repotrectinib safety is well characterized, manageable, and compatible with long-term use. Conflict of interest: Ownership: DT, SS Turning Point Therapeutics Employee and Stock or Stock Options Advisory Board: BCC- (Scientific Advisory Board) KANAPH Therapeutic Inc, Brigebio therapeutics, Cyrus therapeutics, Guardant Health, Joseah BIO Board of Directors: BCC- Gencurix Inc, Interpark Bio Convergence Corp. Corporate-sponsored Research: BCC- (Research funding) Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD, Abbvie, Medpacto, GIInnovation, Eli Lilly, Blueprint medicines, Interpark Bio Convergence Corp. JL (Research funding) Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Bayer, Elevation Oncology, Roche, Linnaeus Therapeutics, Nuvalent, and Novartis SL (Research funding) AstraZeneca, Hutchison, BMS, Heng Rui Beigene and Roche, Hansoh Other Substantive Relationships: BCC -(Founder) DAAN Biotherapeutics, (Consulting role) Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, BMS, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, MSD, Medpacto, Blueprint medicines