Julia Rotow, MD and Edgardo Santos, MD, FACP,discuss how, when selecting frontline therapy for EGFR-mutated non–small cell lung cancer (NSCLC), key considerations include central nervous system involvement, metastases, and mutational factors like TP53. Shared decision-making prioritizes progression-free survival, toxicity, and convenience. Future therapy sequencing, evolving MARIPOSA data, and novel agents shape treatment strategies while balancing efficacy and tolerability.