Prevalence and Clinical Implications of Somatic and Germline EGFR Mutations in Patients with Non-Small-Cell Lung Cancer

Abstract

Simple Summary Epidermal Growth Factor Receptor (EGFR) is frequently overexpressed or mutated in epithelial-derived tumors. In non-small-cell lung cancer (NSCLC), activating EGFR mutations in the cytoplasmic tyrosine kinase domain are important therapeutic targets. EGFR-targeted therapy was among the earliest successful precision-medicine approaches in lung cancer and remains a well-established example of precision oncology, particularly for women, never-smokers, and patients with adenocarcinoma. Between 2014 and 2024, treatment strategies evolved from unselected approaches to EGFR mutation subtype-guided therapies, from advanced unresectable disease to early-stage resected disease, and from monotherapy to combination regimens. The therapeutic armamentarium has expanded beyond small-molecule tyrosine kinase inhibitors to include bispecific antibodies and antibody–drug conjugates. While somatic EGFR mutations guide tumor-directed treatment and resistance assessment, germline EGFR mutations are increasingly recognized for their potential contribution to inherited lung cancer susceptibility and family risk assessment. However, their population prevalence, penetrance, and optimal surveillance remain uncertain. This review summarizes recent advances and future directions in the management of EGFR-mutant NSCLC.