Risk Stratification and Strategies Towards Front-Line Therapy of EGFR-Mutant NSCLC: A Narrative Review

Background/Objectives: Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) has undergone rapid therapeutic evolution. However, heterogeneous outcomes persist, driven by mutations, central nervous system (CNS) involvement, and dynamic tumor burden reflected in part by circulating tumor DNA (ctDNA). As such, this review aims to summarize the most recent risk stratification frameworks in treating EGFR-mutant NSCLC, evaluate evidence supporting treatment intensification strategies and managing adverse effects, and explore the evolving role of ctDNA in guiding personalized therapy. Methods: A comprehensive literature search was conducted using major medical databases with a focus on key relevant studies on the workup and management of EGFR-mutant NSCLC. All authors reviewed the literature, assessed study quality, and interpreted the results from each study. Results: Molecular co-alterations, such as TP53 and RB1, as well as central nervous system (CNS) involvement, are consistently associated with inferior outcomes, supporting consideration of upfront treatment intensification. Combination strategies, including osimertinib plus chemotherapy or amivantamab-based regimens, demonstrate improved progression-free survival and delayed CNS progression when compared against osimertinib monotherapy. Intensification, however, is associated with a higher risk of increased toxicity, including dermatologic adverse events and infusion-related reactions. Finally, the utilization of circulating tumor DNA (ctDNA) has emerged as a strong prognostic marker, with ongoing trials investigating its predictive role for both escalation and de-escalation of therapy. Conclusions: The treatment paradigm for EGFR-mutant NSCLC is gradually evolving beyond first-line osimertinib to include a more integrated approach that considers molecular features, CNS involvement, and early ctDNA response. Although intensified regimens offer meaningful efficacy gains for high-risk patients, proactive toxicity management is essential to preserving quality of life. ctDNA-guided strategies represent a new and promising frontier for escalation and de-escalation of therapy, with results from ongoing trials poised to further refine personalized treatment algorithms.