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, including non-small cell lung cancer (NSCLC). The frequency of aberrations in Chinese NSCLC patients is therefore of great clinical significance.

METHODS

A total of 10,966 NSCLC patients whose tumor specimen and/or circulating cell-free DNA (cfDNA) underwent hybridization capture-based next-generation sequencing were reviewed. Patients' clinical characteristics and treatment histories were also evaluated.

RESULTS

aberrations, including mutations, fusions, and gene amplifications, were detected in 1.9% (210/10,966) of the population. abnormalities were more frequently observed in lung squamous cell carcinomas (6.8%, 65/954) than lung adenocarcinomas (1.3%, 128/9,596). oncogenic mutations were identified in 19 patients (~0.17%), of which, 68% were male lung squamous cell carcinoma patients. Eleven out of the 19 patients (58%) had concurrent altered PI3K signaling, thus highlighting a potential combination therapeutic strategy of dual-targeting FGFR and PI3K signaling in such patients. Furthermore, fusions retaining the intact kinase domain were identified in 12 patients (0.11%), including 9 , 1 , 1 novel , and 1 novel fusion between the and 5'-untranslated regions, which may have caused overexpressions. Concomitant mutations or amplifications were observed in 6 patients, and 4 patients received anti-EGFR inhibitors, in whom fusions may have mediated resistance to anti-EGFR therapies. amplification was detected in 24 patients, with the majority being amplifications. Importantly, oncogenic mutations, fusions, and gene amplifications were almost always mutually exclusive events.

CONCLUSIONS

We report the prevalence of anomalies in a large NSCLC population, including mutations, gene amplifications, and novel fusions.