[Treatment strategy for activating EGFR-mutated non-small cell lung cancer after failure of first-generation EGFR-TKIs]

Somatic activating mutations such as a deletion in exon 19 or the missense mutation L858R in the tyrosine kinase domain of the epidermal growth factor receptor(EGFR)are important mediators of cancer cell oncogenesis, proliferation, and survival. In the last decade, two EGFR target agents have significantly contributed to the understanding of non-small cell lung cancer (NSCLC). Gefitinib and erlotinib are first-generation EGFR-tyrosine kinase inhibitors(EGFR-TKIs)that play a key role in activating EGFR-mutated NSCLC. Although these reversible, small, molecular target agents provide a significant response and survival benefit, all responders eventually acquire resistance. Although various mechanisms of resistance have been identified, nearly 3 0% of patients who acquire resistance to EGFR-TKIs have an unknown mechanism of resistance. Approximately half the patients with EGFR-mutated NSCLC who develop acquired resistance to these molecular target agents have a secondary mutation T790M in the threonine gatekeeper residue that coexists with a primary EGFR activating mutation. The strategy for overcoming acquired resistance to first-generation EGFR-TKIs is a major clinical concept. Afatinib is a second-generation EGFR-targeting agent and an irreversible pan-HER inhibitor. It may improve survival further and help in potentially overcoming resistance to first-generation EGFR-TKIs in EGFR-mutated NSCLC. In patients harboring activating EGFR mutations, certain treatments could be suggested for subsequent therapy after failure of first-generation EGFR-TKIs. This review discusses novel therapeutic strategies for activating EGFR-mutated, advanced NSCLC after failure of first-generation EGFR-TKIs.