Background: NTRK gene fusions are oncogenic drivers in lung cancer and other cancers. Larotrectinib is the highly selective and central nervous system (CNS)-active TRK inhibitor approved for use in patients with TRK fusion cancer based on a robust and durable overall response rate (ORR) in patients with various tumor types. Here, we report long-term efficacy and safety in a cohort of patients with TRK fusion lung cancer treated with larotrectinib. Methods: Patients with TRK fusion lung cancer treated with larotrectinib in two clinical trials (NCT02122913, NCT02576431) were included. Larotrectinib was administered at 100 mg twice daily. Response was assessed by an independent review committee (IRC) per RECIST v1.1. Results: As of July 20, 2023, 32 patients with a median age of 55.5 years (range 25-81) with TRK fusion lung cancer were enrolled, including 12 patients with CNS metastases at baseline. NTRK gene fusions were identified by next-generation sequencing in all 32 patients. The gene fusions involved NTRK1 (n=24; 75%) and NTRK3 (n=8; 25%). Patients had received a median of two prior lines of systemic therapies; one patient was treatment-naïve. The ORR per IRC was 66% (95% confidence interval [CI] 47-81): four complete responses, 17 partial responses, seven stable disease, two progressive disease, and two not evaluable. Median time to first response was 1.8 months (range 1.5-7.3). Median duration of response (DoR) was 33.9 months (95% CI 9.5-not estimable [NE]); median follow-up was 25.8 months. Median progression-free survival (PFS) was 22.0 months (95% CI 9.9-NE); median follow-up was 27.7 months. Median overall survival (OS) was 39.3 months (95% CI 17.2-NE); median follow-up was 32.9 months. The 48-month rates for DoR, PFS, and OS were 47% (95% CI 19-76), 34% (95% CI 11-56), and 38% (95% CI 13-64), respectively. Duration of treatment ranged from 2 to 75+ months. At the data cutoff, 11 patients had progressed; six patients continued treatment post-progression for ≥4 weeks due to continued clinical benefit. Treatment-related adverse events (TRAEs) were predominantly Grade 1/2. Grade 3/4 TRAEs were reported in nine patients. One patient discontinued treatment due to TRAEs (increased alanine aminotransferase, aspartate aminotransferase and gamma-glutamyltransferase). Conclusions: Larotrectinib continued to demonstrate rapid and durable responses, extended survival benefit, and a favorable safety profile in patients with advanced TRK fusion lung cancer. These results support the wider adoption of next-generation sequencing panels that include NTRK gene fusions in patients with lung cancer to identify those who may benefit from targeted treatment. Clinical trial information: NCT02122913, NCT02576431.