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

Abstract

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.