Background: Neurotrophic tyrosine receptor kinase (NTRK) gene fusions have been identified as oncogenic drivers in a variety of tumor types, including lung cancer. Larotrectinib is a highly selective, central nervous system (CNS)-active TRK inhibitor that demonstrated an objective response rate (ORR) of 73% across 15 investigator-assessed patients (pts) with lung cancer (Drilon et al, JCO Precis Oncol 2022). We report data on an expanded cohort of pts with TRK fusion lung cancer treated with larotrectinib. Methods: Pts with TRK fusion lung cancer enrolled in two larotrectinib clinical trials (NCT02576431 and NCT02122913) were included for this analysis. Larotrectinib was administered at 100 mg twice daily. Response was assessed by independent review committee (IRC) per RECIST v1.1. Results: As of July 20, 2021, a total of 26 pts with TRK fusion lung cancer (24 non-small cell lung cancer, 1 atypical carcinoid, 1 neuroendocrine) were enrolled, including 10 pts with CNS metastases at baseline. Median age was 51.5 years (range 25.0–76.0). The gene fusions involved NTRK1 (n =21; 81%) or NTRK3 (n =5; 19%). Pts received a median of 2 prior lines of systemic therapies with 19 (73%) receiving ≥2. Among 23 pts evaluable per IRC, the ORR was 83% (95% confidence interval [CI] 61–95): two complete responses, 17 partial responses (PR), and four stable disease (SD). The median time to response was 1.8 months. Among 10 evaluable pts with baseline CNS metastases, the ORR was 80% (95% CI 44–97): eight PR and two SD. Median duration of response (DoR) and progression-free survival (PFS) were not reached; median follow-up was 12.9 and 14.6 months, respectively. The 24-month rates for DoR and PFS were 72% and 67%, respectively. Median follow-up for overall survival (OS) was 12.9 months. The 24-month and 36-month rates for OS were both 72%. For the 10 evaluable pts with CNS metastases, the 12-month DoR, PFS, and OS rates were 26%, 22%, and 78%, respectively. Duration of treatment for all pts evaluable per IRC ranged from 2.1 to 52.7+ months. At data cut-off, six pts had progressed, with all six continuing treatment post-progression for ≥4 weeks. Treatment-related adverse events (TRAEs) were predominantly Grade 1–2. Grade 3–4 TRAEs were reported in five pts (increased alanine aminotransferase, increased aspartate aminotransferase, hypersensitivity, myalgia, and increased weight). There were no treatment discontinuations due to TRAEs. Conclusions: In this larger dataset, larotrectinib demonstrated rapid and durable responses, extended survival, and a favorable long-term safety profile in pts with advanced lung cancer harboring NTRK gene fusions, including in pts with CNS metastases. These results support testing for NTRK gene fusions in pts with lung cancer. Clinical trial information: NCT02576431, NCT02122913.