Clonal MET Amplification as a Determinant of Tyrosine Kinase Inhibitor Resistance in Epidermal Growth Factor Receptor–Mutant Non–Small-Cell Lung Cancer

PurposeMesenchymal epithelial transition factor (MET) activation has been implicated as an oncogenic driver in epidermal growth factor receptor (EGFR)–mutant non–small-cell lung cancer (NSCLC) and can mediate primary and secondary resistance to EGFR tyrosine kinase inhibitors(TKI). High copy number thresholds have been suggested to enrich for response to MET inhibitors. We examined the clinical relevance of MET copy number gain (CNG) in the setting of treatment-naive metastatic EGFR-mutant–positive NSCLC.Patients and MethodsMET fluorescence in situ hybridization was performed in 200 consecutive patients identified as metastatic treatment-naive EGFR-mutant–positive. We defined MET-high as CNG greater than or equal to 5, with an additional criterion of MET/centromeric portion of chromosome 7 ratiο greater than or equal to 2 for amplification. Time-to-treatment failure (TTF) to EGFR TKI in patients identified as MET-high and -low was estimated by Kaplan-Meier method and compared using log-rank test. Multire...