Intracranial and systemic efficacy of repotrectinib in advanced ROS1 fusion-positive ( ROS1 +) non-small cell lung cancer (NSCLC) and central nervous system metastases (CNS mets) in the phase 1/2 TRIDENT-1.

9017Background: Repotrectinib is a next-generation ROS1 and TRK tyrosine kinase inhibitor (TKI) that has demonstrated durable activity with a manageable safety profile in TKI-naïve and TKI-pretreated patients (pts) with advanced ROS1+ NSCLC. We report the first analysis of outcomes on repotrectinib in pts with ROS1+ NSCLC by baseline (BL) CNS met status in the global pivotal phase 1/2 TRIDENT-1 trial (NCT03093116). Methods: Pts with ROS1+ NSCLC were assigned to 4 cohorts by treatment history: ROS1 TKI-naïve, 1 ROS1 TKI and no chemotherapy (chemo), 1 ROS1 TKI and 1 platinum-based chemo, and 2 ROS1 TKIs and no chemo. Treated or untreated asymptomatic CNS mets were permitted. Brain scans were mandated for all pts in phase 2 at screening and at protocol-specified intervals until progression. Endpoints included confirmed objective response rate (cORR) and duration of response (DOR) by blinded independent central review (BICR; RECIST v1.1); intracranial ORR (icORR) in pts with measurable brain mets at BL by BICR per mRECIST v1.1; and safety. Results: In pts with BL measurable CNS mets who were TKI-naïve (n = 8) and in those with 1 TKI and no chemo (n = 12), icORR (95% CI) was 88% (47-100) and 42% (15-72), respectively. At data cutoff (June 20, 2022), 0 of 7 responders in the TKI-naïve cohort and 2 of 5 in the cohort with 1 prior TKI and no chemo had intracranial progression or death; intracranial DOR range was 1.9-14.8+ mo (TKI-naïve) and 3.0-11.1+ mo (1 TKI and no chemo), with 86% and 80% of pts with an intracranial response remaining on treatment, respectively. Median follow-up and systemic response by CNS met status are shown in the Table. In pts with ROS1+ NSCLC with (n = 118) or without (n = 178) CNS mets, most common any-grade neurologic treatment-emergent adverse events were dizziness (57% / 63%), dysgeusia (42% / 53%), paresthesia (32% / 34%), headache (27% / 12%), ataxia (17% / 22%), and memory impairment (14% / 10%). Conclusions: In TRIDENT-1, repotrectinib showed durable clinical activity in ROS1 TKI-naïve and -pretreated pts with or without BL CNS mets, including intracranial responses. Repotrectinib safety profile was similar in pts with ROS1+ NSCLC with or without CNS mets. Clinical trial information: NCT03093116 . [Table: see text]