Targeting FGFR in non-small cell lung cancer: implications from the landscape of clinically actionable aberrations of FGFR kinases.

Objective: Dysfunction in fibroblast growth factor receptor (FGFR) signaling has been reported in diverse cancer types, includingnon-small cell lung cancer (NSCLC). The frequency of FGFR aberrations in Chinese NSCLC patients is therefore of great clinicalsignificance. Methods: A total of 10,966 NSCLC patients whose tumor specimen and/or circulating cell-free DNA (cfDNA) underwenthybridization capture-based next-generation sequencing were reviewed. Patients’ clinical characteristics and treatment histories werealso evaluated. Results: FGFR aberrations, including mutations, fusions, and gene amplifications, were detected in 1.9% (210/10,966) of thepopulation. FGFR abnormalities were more frequently observed in lung squamous cell carcinomas (6.8%, 65/954) than lungadenocarcinomas (1.3%, 128/9,596). FGFR oncogenic mutations were identified in 19 patients (~0.17%), of which, 68% were malelung squamous cell carcinoma patients. Eleven out of the 19 patients (58%) had concurrent altered PI3K signaling, thus highlightinga potential combination therapeutic strategy of dual-targeting FGFR and PI3K signaling in such patients. Furthermore, FGFRfusions retaining the intact kinase domain were identified in 12 patients (0.11%), including 9 FGFR3-TACC3, 1 FGFR2-INA, 1 novelFGFR4-RAPGEFL1, and 1 novel fusion between the FGFR1 and SLC20A2 5′-untranslated regions, which may have caused FGFR1overexpressions. Concomitant EGFR mutations or amplifications were observed in 6 patients, and 4 patients received anti-EGFRinhibitors, in whom FGFR fusions may have mediated resistance to anti-EGFR therapies. FGFR amplification was detected in 24patients, with the majority being FGFR1 amplifications. Importantly, FGFR oncogenic mutations, fusions, and gene amplificationswere almost always mutually exclusive events. Conclusions: We report the prevalence of FGFR anomalies in a large NSCLC population, including mutations, gene amplifications,and novel FGFR fusions.