Biological impact of chemotherapy during treatment with EGFR tyrosine kinase inhibitors for non-small cell lung cancer positive for EGFR activating mutations.

BACKGROUND: The aim of this study was to explore the biological impact of chemotherapy during epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment in individuals with non-small cell lung cancer (NSCLC). METHODS: Plasma and tumor tissue specimens were prospectively collected from NSCLC patients with EGFR activating mutations who participated in a randomized phase III study comparing EGFR-TKI therapy with or without inserted chemotherapy (JCOG1404/WJOG8214L). The specimens were analyzed for genetic mutations by droplet digital polymerase chain reaction analysis and next-generation sequencing. RESULTS: Two hundred patients were enrolled in this biomarker study, with 113 and 87 individuals receiving EGFR-TKI monotherapy and EGFR-TKI treatment plus inserted chemotherapy, respectively. Although progression-free survival (PFS) for EGFR-TKI monotherapy was shorter in patients with than in those without detectable EGFR activating mutations in cell-free DNA at baseline, inserted chemotherapy improved PFS compared with EGFR-TKI monotherapy for the former patients (median, 17.5 vs. 11.8 months). Inserted chemotherapy suppressed the number of alleles positive for activating and T790M mutations of EGFR in cell-free DNA at disease progression. The benefit of inserted chemotherapy relative to EGFR-TKI monotherapy was more apparent in patients with (median PFS, 18.8 vs. 13.5 months) than in those without detectable concurrent mutations of TP53. CONCLUSIONS: Chemotherapy has the potential to suppress the development of EGFR-TKI resistance as well as to inhibit tumor growth for NSCLC positive for EGFR activating mutations. Our results provide biological insight into combination treatment with EGFR-TKIs and chemotherapy for such patients.