Efficacy and Safety of Taletrectinib in Chinese Patients With ROS1+ Non-Small Cell Lung Cancer: The Phase II TRUST-I Study

Abstract

Purpose: Taletrectinib, a highly potent, CNS-active, ROS1 tyrosine kinase inhibitor (TKI), has demonstrated high and durable response rates, high intracranial objective response rate (ORR), prolonged progression-free survival (PFS), and activity against G2032R with a favorable safety profile. We report outcomes from the pivotal TRUST-I study (ClinicalTrials.gov identifier: NCT04395677) of taletrectinib for ROS1+ non-small cell lung cancer in China.

Methods: TRUST-I evaluated TKI-naїve and crizotinib-pretreated patients. The primary end point was confirmed ORR (cORR) by independent review committee; key secondary end points included duration of response (DOR), PFS, and safety.

Results: As of November 2023, 173 patients were enrolled (median age, 55 years; 58% female; 73% never smoked; TKI naїve: n = 106; crizotinib pretreated: n = 67). In TKI-naїve patients, cORR and intracranial cORR were 91% and 88%, respectively, and 52% and 73% in crizotinib-pretreated patients. In TKI-naїve patients, median DOR and median PFS were not reached (NR) with 22.1-month and 23.5-month follow-up, respectively. In crizotinib-pretreated patients, the median DOR was 10.6 months (95% CI, 6.3 months to NR; 8.4-month follow-up), and the median PFS was 7.6 months (95% CI, 5.5 to 12.0 months; 9.7-month follow-up). Eight of 12 patients (67%) with G2032R mutations responded. The most frequent treatment-emergent adverse events (TEAEs) were increased AST (76%), diarrhea (70%), and increased ALT (68%), most of which were grade 1-2. Incidences of neurologic TEAEs were low (dizziness: 23%; dysgeusia: 10%) and mostly grade 1. Discontinuations (5%) and dose reductions (19%) due to TEAEs were low.

Conclusion: Taletrectinib continues to show high and durable overall responses, prolonged PFS, robust activity against intracranial lesions and acquired resistance mutations including G2032R, and a favorable safety profile with a low incidence of neurologic TEAEs.

FIG 1.

Treatment disposition flow diagram. TKI, tyrosine kinase inhibitor.

FIG 2.

Responses by IRC assessment of taletrectinib in TKI-naїve and crizotinib-pretreated patients with ROS1+ NSCLC. Best percent change in the sum of diameters from baseline in (A) TKI-naїve (n = 104) and (B) crizotinib-pretreated (n = 60) patients, (C and D) percent change in response over time, DOR and PFS in (E and F) TKI-naїve and (G and H) crizotinib-pretreated patients, and (I) best percent change in the sum of diameters from baseline in patients with baseline metastases. CR, complete response; DOR, duration of response; IRC, independent review committee; NSCLC, non–small cell lung cancer; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; TKI, tyrosine kinase inhibitor.

FIG A1.

Forest plots of IRC-assessed overall response rates by subgroup in (A) TKI-naїve patients and (B) crizotinib-treated patients. Dotted vertical lines represent benchmarks used to declare positive results for each patient cohort. IRC, independent review committee; ORR, objective response rate; RANO-BM, response assessment in neuro-oncology brain metastases; TKI, tyrosine kinase inhibitor.

FIG A2.

Forest plots of investigator-assessed overall response rate by subgroup in (A) TKI-naїve patients and (B) crizotinib-treated patients. Dotted vertical lines represent benchmarks used to declare positive results for each patient cohort. IRC, independent review committee; ORR, objective response rate; RANO-BM, response assessment in neuro-oncology brain metastases; TKI, tyrosine kinase inhibitor.