Heterogeneous Response to First-Generation Tyrosine Kinase Inhibitors in Non-Small-Cell Lung Cancers with Different EGFR Exon 19 Mutations

Background Epidermal growth factor receptor (EGFR) exon 19 deletions (19dels) appear in a large number of variants, which has not been distinguished in previously published trials despite differences in deletion and insertion locations. Objective The aim of this study was to investigate the therapeutic response of patients with different EGFR exon 19dels to first-generation tyrosine kinase inhibitors (TKIs) and the mechanisms by which their tumors acquire resistance to these TKIs. Patients and Methods The clinical outcomes of 195 patients harboring EGFR exon 19dels and receiving first-generation EGFR TKIs between July 2011 and June 2019 were retrospectively analyzed. Results A total of twenty EGFR exon 19dels variants were identified. The patients were divided into three groups according to the first residue of the deletion, including E746, L747, and other residues (T751 or S752). The median progression-free survival (PFS) of patients treated with EGFR TKIs was significantly different between groups (p < 0.001). Patients harboring EGFR exon 19dels starting at T751 or S752 had the shortest median PFS (2.9 months), followed by those with E746 (11.4 months) and those with L747 (17.2 months). Analyzing 140 patients who had progressed on therapy, EGFR exon 19dels beginning at T751 or S752 were associated with a low incidence of the T790M mutation (16.7%). Conclusions Deletion location and type variants (with or without an insertion and/or a substitution) might affect first-generation TKI efficacy, and different EGFR exon 19dels should be considered when making decisions on which EGFR TKI should be used.