Taletrectinib Hits 89% ORR and 45.6-Month PFS in TKI-Naïve ROS1-Positive NSCLC

Taletrectinib, a next-generation ROS1/ALK tyrosine-kinase inhibitor designed to cover the G2032R resistance mutation and penetrate the CNS, was evaluated in the pooled Phase II TRUST-I/II program (NCT04395677/NCT04919811). Among 273 response-evaluable patients with advanced ROS1-positive NSCLC (0.9-2.6% of all NSCLC cases), the TKI-naïve cohort (n=160) achieved an IRC-confirmed ORR of 88.8% (5% CR) with a median DOR of 44.2 months and median PFS of 45.6 months. Intracranial ORR was 76.5% in those with measurable brain metastases. In TKI-pretreated patients (n=113; prior crizotinib or entrectinib), ORR was 55.8%, DOR 16.6 months, and PFS 9.7 months, with 65.6% intracranial responses and 61.5% ORR in those harboring the ROS1-G2032R mutation. The most common treatment-related AEs were increased AST (70%), increased ALT (67%), diarrhea (61%), nausea (44%), and vomiting (41%); most of these events were grade 1. Grade ≥3 ALT/AST elevations occurred in 6-8%; QT prolongation ≥G3 was 3%. Dose reductions and discontinuations for AEs were 28% and 2.6%, respectively. Compared with first-line crizotinib (ORR 72%, mPFS 19.3 months) and entrectinib (ORR 68%, mPFS 15.7 months), taletrectinib extends PFS by roughly 10-25 mo and more than doubles DOR. Taletrectinib also rivals the newly approved repotrectinib’s 79% ORR and 35.7 month PFS while showing fewer neurologic grade 3 events.