Evidence of NTRK1 Fusion as Resistance Mechanism to EGFR TKI in EGFR+ NSCLC: Results From a Large-Scale Survey of NTRK1 Fusions in Chinese Patients With Lung Cancer

Background Neurotrophin receptor kinase (NTRK) gene fusions (NTRK+) are rare but actionable oncogenic drivers present in a wide variety of solid tumors. However, the clinicopathologic characteristics of NTRK1 fusion–positive non–small-cell lung cancer are largely unknown. Materials and Methods Lung cancer tissue specimens and/or circulating cell-free DNA from patients with lung cancer who had undergone molecular profiling at a Clinical Laboratory Improvement Amendments (CLIA)–certified genomics laboratory in China were retrospectively reviewed. The laboratory performed NTRK1 fusion detection using hybridization-based targeted next-generation sequencing. The patients’ clinical characteristics and treatment history were retrieved from the database for further evaluation. Results A total of 21,155 Chinese lung cancer cases had undergone molecular profiling from April 2016 to March 2019, including 13,630 adenocarcinoma cases. Of these cases, 12 were positive for NTRK1 fusion, including 10 cases of adenocarcinoma (0.073%), 1 primary sarcomatoid carcinoma, and 1 with an unknown histologic classification. Seven fusion partners (CD74, interferon regulatory factor 2 binding protein 2 [IRF2BP2], lamin A/C [LMNA], PHD finger protein 20 [PHF20], sequestosome 1 [SQSTM1], tropomyosin 3 [TPM3], TPR) were identified. Additionally, 1 unique rearrangement occurred upstream of the transcription start site of BCL9 fused to exon 12 of NTRK1 (intragenic region, BCL9-NTRK1). Of the 12 cases of NTRK1+ lung cancer, 6 had had concurrent activating EGFR mutations and/or had received previous treatment with EGFR tyrosine kinase inhibitors (TKIs), with 2 having concurrent EGFR T790M and 1 additional EGFR C797S. Conclusions NTRK1+ lung cancer cases are extremely rare with multiple fusion partners. Additionally, emergence of NTRK1+ fusion might act as a resistance mechanism to EGFR TKIs. When performing comprehensive analysis of acquired resistance to EGFR TKIs, the ability to detect NTRK1 fusions will be important.