Efficacy and safety of larotrectinib in patients with TRK fusion lung cancer: An updated analysis.

8618 Background: NTRK gene fusions are oncogenic drivers in various tumor types, including lung cancer. Larotrectinib is the first-in-class, highly selective, central nervous system (CNS)-active TRK inhibitor approved for tumor-agnostic use in patients with TRK fusion cancer based on a robust and durable objective response rate in patients with various cancers. Here, we report updated long-term efficacy and safety data in the subset of patients with TRK fusion lung cancer treated with larotrectinib after 1 additional year of follow-up. Methods: Patients with TRK fusion lung cancer enrolled in 2 larotrectinib clinical trials (NCT02122913, NCT02576431 [NAVIGATE]) were included. Larotrectinib was administered at 100 mg twice daily. In NCT02122913, primary endpoints were safety and the minimum tolerated and recommended dose; secondary endpoints included pharmacokinetics, overall response rate (ORR), and duration of response (DoR). In NCT02576431, the primary endpoint was best overall response; secondary endpoints included DoR, survival, and safety. Responses were independent review committee-assessed per Response Evaluation Criteria in Solid Tumors version 1.1. The data cutoff was July 20, 2025. Results: A total of 32 patients with measurable disease were treated, including 12 with known CNS metastases at baseline. Median age was 56 years (range 25–81). One patient (3%) was systemic treatment-naïve in the metastatic/unresectable setting; 19 (59%) had received ≥2 prior therapies. All NTRK gene fusions were identified by next-generation sequencing (NGS). The ORR was 69% (95% confidence interval [CI] 50–84): 4 (13%) complete responses, 18 (56%) partial responses, 6 (19%) stable disease, 2 (6%) progressive disease, and 2 (6%) not evaluable or undefined. Median duration of treatment was 20 months (range 2–81); at data cutoff, no patients remained on treatment. Median time to response was 1.8 months (range 1.5–7.3). Median DoR, progression-free survival (PFS), and overall survival (OS) were 20 months (95% CI 13–67), 19 months (95% CI 10–36), and 41 months (95% CI 17−not estimable), respectively, with median follow-ups of 53, 49, and 58 months. The 4-year rates for DoR, PFS, and OS were 34% (95% CI 12–57), 26% (95% CI 8–44), and 49% (95% CI 30–69), respectively. Treatment-related adverse events (TRAEs) were predominantly Grade 1/2. Grade 3/4 TRAEs were reported in 10 (31%) patients. One patient (3%) discontinued treatment due to TRAEs (alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyltransferase increased). Conclusions: Larotrectinib continues to demonstrate rapid and durable responses, extended clinical benefit, and a favorable safety profile in patients with advanced TRK fusion lung cancer. These results support the wider adoption of NGS panels that include NTRK gene fusions in patients with lung cancer to identify those who may benefit from TRK inhibitor therapy. Clinical trial information: NCT02122913 , NCT02576431 .