Efficacy and safety of taletrectinib in patients with advanced or metastatic ROS1+ non–small cell lung cancer: The phase 2 TRUST-I study.

8520 Background: Taletrectinib, a highly potent, next-generation, central nervous system–active, selective ROS1 tyrosine kinase inhibitor (TKI), was previously reported to provide high overall and intracranial (IC) response rates, prolonged progression-free survival (PFS), and activity against G2032R with favorable tolerability. We report updated data from the TRUST-I study (NCT04395677), the largest clinical trial to date conducted in patients living with ROS1+ NSCLC. Methods: TRUST-I, a multicenter, single-arm, open-label, pivotal phase 2 study of taletrectinib conducted in China, had 2 cohorts: TKI-naïve and TKI-pretreated. The primary endpoint was objective response rate (ORR) by Independent Review Committee (IRC) per RECIST 1.1. Secondary endpoints included duration of response (DoR), PFS, overall survival (OS), and safety. Results: As of November 2023, 173 patients were enrolled (median age: 55 y; 58% female; 73% never smoked; TKI-naïve: n = 106; TKI-pretreated: n = 67). In TKI-naïve patients, 21% had prior chemotherapy, and 17% had brain metastases; in TKI-pretreated patients, 34% had prior chemotherapy, and 42% had brain metastases. In TKI-naïve patients, the ORR was 91% (95% CI: 83, 95) and IC-ORR was 88% (7/8; 95% CI: 47, 100). In TKI-pretreated patients, the ORR was 52% (95% CI: 40, 65) and IC-ORR was 75% (12/16; 95% CI: 48, 93). In patients with G2032R mutation, 8 of 12 patients (67% 95% CI: 35, 90) responded. DoR and PFS remain durable, with median follow-up of 23.5 months in TKI-naïve patients and 9.7 months in TKI-pretreated patients (Table). Among all patients (n = 173), the most frequent treatment-emergent adverse events (TEAEs) were AST increase (76%), diarrhea (70%), and ALT increase (68%). Rates of neurologic TEAEs were low (dizziness: 23%; dysgeusia: 10%) and mostly grade 1. Discontinuation (5%) and dose reductions (19%) due to TEAEs were low. Conclusions: With longer follow-up, taletrectinib continues to show high and durable overall responses, robust intracranial and G2032R activity, and a favorable safety profile with a low incidence of neurologic AEs. An additional ongoing pivotal phase 2 study, TRUST-II (NCT04919811), is further evaluating the efficacy and safety of taletrectinib in patients in the US, Europe, and Asia. Clinical trial information: NCT04395677 . Table: see text