Clinical strategies for acquired epidermal growth factor receptor tyrosine kinase inhibitor resistance in non-small-cell lung cancer patients

Abstract

Epidermal growth factor receptor (EGFR) mutations (EGFRm⁺) occur in 10–35% of non-small-cell lung cancer (NSCLC) cases and confer sensitivity to EGFR tyrosine kinase inhibitors (TKIs). EGFR TKIs are standard treatments for NSCLC patients harboring EGFR exon 19 deletions or exon 21 L858R point mutations. Despite initial benefit, most patients develop drug resistance, posing a challenge to oncologists. The secondary T790M point mutation in EGFR exon 20 contributes to approximately 60% of resistance cases. Optimum strategies for overcoming acquired EGFR TKI resistance are not clearly defined, although current common practice is to switch to platinum-based chemotherapy following resistance onset. While the second-generation EGFR TKIs, including afatinib, dacomitinib, and neratinib, exhibit promising preclinical activity against T790M mutants, dose-limiting toxicities in patients have limited clinical success. However, third generation EGFR TKIs appear able to overcome this mutation. Other treatment options aimed at EGFR TKI resistance include use of an EGFR TKI beyond progression, and chemotherapy plus an EGFR TKI. This review focuses on improved anticancer agents and therapy options for NSCLC patients with acquired EGFR TKI resistance.