Gefitinib in combination with pemetrexed in patients with advanced non-small cell lung cancer harboring EGFR mutations: is there any difference in acquired resistance mechanism between gefitinib monotherapy and the combination treatment?

Somatic mutations within the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) are the most reliable predictors of efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs) in patients with non-small cell lung cancer (NSCLC). In randomized phase III trials, EGFR-TKIs in patients with advanced EGFR mutant NSCLC were associated with longer progression-free survival (PFS) and higher radiographic response rates than the standard first-line platinum-based chemotherapy (1-7). Based on these results, three types of EGFR-TKIs, gefitinib, erlotinib and afatinib have been approved for treatment of advanced EGFR-mutant NSCLC as a first-line setting. Despite an initially marked response, almost all patients treated with EGFR-TKIs eventually acquire resistance to these drugs, with an average PFS of around 1 year. To improve these results, several combinations of EGFR-TKIs and other drugs, such as targeted drugs and chemotherapy, have been developed.