Targeted Therapy and Drug Resistance of EGFR Mutations in Non-Small Cell Lung Cancer

Lung cancer remains one of the most lethal malignancies, with non-small cell lung cancer (NSCLS) being the predominant subtype. Activating mutations in the epidermal growth factor receptor (EGFR) increase the receptor's affinity for ATP, leading to sustained downstream signaling and uninhibited tumor proliferation. Small-molecule EGFR inhibitors have transformed treatment, with Osimertinib significantly prolonging progression-free and overall survival while improving control of brain metastases. Long-term treatment inevitably leads to drug resistance, often through targeted secondary or tertiary EGFR mutations (e.g., T790M and C797S), activation of bypass pathways involving MET, HER2, and FGFR, and histologic or phenotypic transformation. These challenges highlight the need for personalized treatment strategies guided by molecular profiling and active monitoring. In recent years, treatment strategies have expanded to include fourth-generation EGFR allosteric inhibitors, antibody-drug conjugates, rational combinations targeting alternative signaling pathways, and immunotherapy. This review will summarize the current evidence for EGFR-targeted therapies, highlight established and emerging mechanisms of resistance, and discuss emerging approaches that may help optimize clinical outcomes.