Larotrectinib (TRK inhibitor) delivers 69% ORR and ~19-mo PFS in NTRK fusion lung cancer

Larotrectinib is a first-in-class, highly selective, CNS-active TRK (NTRK1/2/3) tyrosine kinase inhibitor evaluated in an updated pooled subset from two clinical trials (NCT02122913; Phase I/II NAVIGATE, NCT02576431) in TRK fusion lung cancer. In 32 patients with measurable advanced disease (n=12 with baseline CNS metastases; 59% with ≥2 prior therapies), independent review–assessed ORR was 69% (13% CR, 56% PR) with median time to response 1.8 months; median DoR 20 months, median PFS 19 months, and median OS 41 months at a July 20, 2025 cutoff—substantially above typical post–platinum chemotherapy benchmarks (e.g., docetaxel ORR generally ~7–10% with median OS ~7–9 months in unselected NSCLC). Grade 3/4 TRAEs occurred in 31%, and discontinuation for TRAEs was 3% (transaminase/GGT elevations); notably, no patients remained on treatment at cutoff (range on therapy 2–81 months), underscoring eventual progression/intolerance even in long responders. Take Home: If you can find the ~0.1–0.3% of NSCLC patients with NTRK fusions via broad NGS, these long-term outcomes look meaningfully better than “standard” salvage chemo—but the fact that everyone eventually stopped therapy keeps next-line resistance strategies (next-gen TRK inhibitors, sequencing with CNS control) very much on the critical path.