Targeting Acquired and Intrinsic Resistance Mechanisms in Epidermal Growth Factor Receptor Mutant Non-Small-Cell Lung Cancer

Over the past 2 decades, rapid advances in molecular profiling and the development of targeted therapies have dramatically improved the clinical course of advanced non-small-cell lung cancer (NSCLC). Mutations in the epidermal growth factor receptor (EGFR) gene are found in about a third of patients with advanced NSCLC, and the approval of first-generation EGFR targeted kinase inhibitors significantly improved survival when compared with platinum-based doublet chemotherapy (PBC), the previous standard of care. Inevitably, selective pressure from first-generation EGFR inhibitors led to acquired resistance mechanisms, such as the T790M mutation. The advent of third-generation EGFR inhibitors (e.g., osimertinib) successfully overcame the T790M resistance mechanism, and osimertinib subsequently became the first-line therapy for EGFR mutant NSCLC. Currently, research in EGFR mutant NSCLC is primarily focused on targeting resistance mechanisms to osimertinib. Over the past several years, many important acquired and intrinsic mechanisms of resistance to osimertinib have been identified. Acquired resistance mechanisms include C797X, mesenchymal epithelial transition factor (MET) amplification, HER2/HER3 amplification, phosphoinositide 3-kinase (PI3K) pathway mutations, RAS/mitogen-activated protein kinase (MAPK) pathway mutations, cell-cycle gene alterations, oncogenic fusions, and histologic transformations. An important intrinsic resistance mechanism to osimertinib is the EGFR exon 20 insertion mutation, which is sensitive to the newly Food and Drug Administration (FDA)-approved tyrosine kinase inhibitor mobocertinib and the EGFR/MET bispecific antibody amivantamab. This review article aims to (1) summarize the advances in the treatment of EGFR mutant NSCLC, (2) delineate known resistance mechanisms to the current first-line therapy, osimertinib, and (3) describe the development of targeted drugs that aim to overcome these resistance mechanisms.

Automated summary

In the past two decades, advancements in molecular profiling and targeted therapies have significantly improved the treatment outcomes for patients with advanced non-small-cell lung cancer (NSCLC). EGFR gene mutations are commonly found in NSCLC, and first-generation targeted kinase inhibitors have improved survival rates. However, the emergence of resistance mechanisms has posed challenges to treatment. Current research focuses on developing drugs to overcome these resistance mechanisms.