Targeting the Epidermal Growth Factor Receptor in EGFR-Mutated Lung Cancer: Current and Emerging Therapies

Simple Summary Epidermal growth factor receptor (EGFR) mutations occur in a significant number of lung cancer patients. Treatment outcomes in this subset of patients has greatly improved over the last decade after the introduction of EGFR tyrosine kinase inhibitors (TKIs), which demonstrated high efficacy and improved survival in randomized clinical trials. Although EGFR TKIs became the standard of care in patients with EGFR-mutated lung cancer, resistance almost inevitably develops. This constitutes a major challenge and creates an unmet need for novel therapies and new approaches to ameliorate or overcome this resistance. In this review we discuss currently approved TKIs for the targeted management of EGFR-mutated lung cancer. We also review common mechanisms of resistance to EGFR-targeted therapies and describe promising approaches that may mitigate resistance. Epidermal growth factor receptor-targeting tyrosine kinase inhibitors (EGFR TKIs) are the standard of care for patients with EGFR-mutated metastatic lung cancer. While EGFR TKIs have initially high response rates, inherent and acquired resistance constitute a major challenge to the longitudinal treatment. Ongoing work is aimed at understanding the molecular basis of these resistance mechanisms, with exciting new studies evaluating novel agents and combination therapies to improve control of tumors with all forms of EGFR mutation. In this review, we first provide a discussion of EGFR-mutated lung cancer and the efficacy of available EGFR TKIs in the clinical setting against both common and rare EGFR mutations. Second, we discuss common resistance mechanisms that lead to therapy failure during treatment with EGFR TKIs. Third, we review novel approaches aimed at improving outcomes and overcoming resistance to EGFR TKIs. Finally, we highlight recent breakthroughs in the use of EGFR TKIs in non-metastatic EGFR-mutated lung cancer.