Mechanism of afatinib resistance in non-small cell lung cancer patients with nonclassical EGFR mutations: A multicenter, retrospective study.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard treatments for non-small cell lung cancer (NSCLC) patients with EGFR mutations, but resistance inevitably develops. While resistance mechanisms in classical mutations are well studied, those in nonclassical mutations remain unclear. As a widely used EGFR-TKI, afatinib's resistance mechanisms in nonclassical mutations warrant further investigation to improve clinical outcomes. This study included NSCLC patients from multiple hospitals with nonclassical mutations who were finally resistant to afatinib. Baseline information and samples, including peripheral blood, tissue, and pleural fluid, were obtained for panel gene testing to identify potential gene mutations of resistance. A total of 21 eligible patients were included in this study. EGFR-related gene mutations accounted for 29.7% of all mutations, with TP53 accounting for 16.6%, other genes accounting for 41.5%, and MET amplification 2.7%. What we found different from classical mutations was that T790M mutation was the highest proportion in this study, followed by A767V, L858R, R776G. Concretely, T790M accounted for 7.8%, while A767V, L858R, R776G for 4.8% each, then NF1, CDK4 amplification and ALK accounted for 3.3%, 3.2% and 2.4%, respectively. This study represents the latest investigation of resistance mechanisms to afatinib in NSCLC patients with nonclassical mutations. The mechanism of resistance to EGFR-TKI in this study was discovered different from that of patients with classical mutations.