Acquired resistance to first-line osimertinib is heterogeneous in EGFR-mutant advanced non-small cell lung cancer

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI), has shown remarkable efficacy in EGFR-mutant non-small cell lung cancer (NSCLC). However, acquired resistance remains inevitable. This study aimed to explore the underlying resistance mechanisms and evaluate second-line treatment strategies to improve survival outcomes. Data from 67 patients with advanced or metastatic EGFR-mutant NSCLC treated with first-line osimertinib were retrieved from the CAPTRA-LUNG (NCT003334864) database. Among them, 42 patients underwent next-generation sequencing (NGS) to identify resistance mechanisms. Subsequent second-line treatment strategies and progression-free survival (PFS) were analysed. NGS revealed EGFR-dependent resistance in 10% of patients, bypass signaling activation in 38%, histologic transformation in 5%, and unknown mechanisms in 47%. Reported PFS values were: replacement EGFR-TKI (1.9–4.4 months), platinum-pemetrexed chemotherapy (1.6–20.7 months), osimertinib plus platinum-pemetrexed (3.9–6.9 months), chemotherapy plus anti-angiogenic agents (1.8–16.8 months), and chemotherapy plus immune checkpoint inhibitors (3.8 months). Resistance to first-line osimertinib in EGFR-mutant NSCLC arose through heterogeneous mechanisms, including EGFR-dependent alterations, bypass pathway activation, histologic transformation, and unknown mechanisms. Post-progression molecular testing and, where feasible, tissue re-biopsy are important to guide subsequent treatment decisions. Second-line outcomes were variable, with chemotherapy combined with anti-angiogenic agents showing numerically longer progression-free survival in a small subgroup; however, these findings are descriptive due to the small sample size and treatment heterogeneity.