<i>NTRK1-3</i> point mutations in non-small cell lung cancer: Molecular profiling.

Abstract

e20541 Background: Neurotrophic receptor tyrosine kinase (NTRK) fusions occur in less than 1% in non-small cell lung cancer (NSCLC) cases and have been the focus of recent therapeutic advances. However, the role of NTRK1-3 point mutations in NSCLC remains unexplored. Molecular analyses were performed in a cohort of NSCLC patients with NTRK1-3 point mutations to elucidate their clinical relevance. Methods: Molecular data were collected and analyzed from NSCLC patients with NTRK1-3 point mutations in the Network Genomic Medicine (NGM) database in Germany between 2022 and 2024. Mutations were identified by next-generation sequencing (NGS) and the programmed-cell-death ligand-1 (PD-L1) status was assessed by immunohistochemistry (IHC). Results: Among 215 patients with NTRK1-3 point mutations, 63 patients (29.3%) had NTRK1 mutations, 31 patients (14.4%) harbored NTRK2 mutations, and 123 patients (57.2%) exhibited NTRK3 mutations. These mutations were scattered within the protein tyrosine kinase domain, with several recurrent alterations. In NTRK1 , three patients each harbored R686X and V790I (outside the kinase domain) mutations. In NTRK3 , four patients had a G608X mutation, and another four had R645X mutations. Two NTRK2 cases had V758M mutations. Co-mutations were present in most patients with NTRK1-3 point mutations. Frequently co-occurring mutations (≥10%) included TP53 (75.8%), KRAS (38.1%), KEAP1 (24.2%), and STK11 (20.5%). PD-L1 expression, categorized by Tumor Proportion Score (TPS) — TPS &lt; 1, TPS 1-49, and TPS ≥ 50 — varied among the NTRK mutational subgroups: in NTRK1 , TPS &lt; 1 was predominant (36.5%); in NTRK2 , TPS ≥ 50 was most common (45.2%); and in NTRK3 , TPS 1-49 was predominant (40.7%). Conclusions: NTRK1-3 point mutations have been identified in NSCLC patients of various demographics and histologies. The mutations were embedded throughout the kinase region of the tropomyosin gene with some notable recurrent mutations. Co-mutations were prevalent, and distinct PD-L1 expression profiles were observed among NTRK mutational subgroups. Further investigations are needed to evaluate the prognostic and therapeutic implications of NTRK1-3 point mutations.