Navigating First-Line Treatment Options for Patients With Epidermal Growth Factor Receptor-Positive Non-Small Cell Lung Cancer

The discovery of epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) and the subsequent development of targeted therapeutics represents a groundbreaking advancement in care, shifting the treatment paradigm to more personalized approaches with significantly improved survival because of our evolving understanding of the pathobiology and molecular underpinnings of the disease. First-line regimens for patients with EGFR-positive NSCLC now include EGFR tyrosine kinase inhibitor monotherapy or combination therapy with osimertinib and chemotherapy or amivantamab and lazertinib. There are several pros and cons to each approach of monotherapy vs combination therapy such that we must carefully weigh the balance between efficacy, toxicity, quality of life, and subsequent treatment options with our patients to determine the best approach at diagnosis of advanced disease. Importantly, there are subpopulations of patients who may benefit more from combination therapy, including those with TP53 comutations, high tumor burden, brain metastases, and/or detectable ctDNA. This review discusses current data and treatment approaches for the management of advanced/metastatic EGFR-mutant NSCLC, with a particular emphasis on the complexity of first-line management.