ESMO 2025 and the Future of EGFRm NSCLC Sequencing: First-line Choices that Preserve Subsequent Therapy Eligibility

The therapeutic landscape for EGFR-mutated non-small-cell lung cancer (NSCLC) has rapidly evolved with the advent of thirdgeneration tyrosine kinase inhibitors (TKIs), bispecific antibodies, and antibody–drug conjugates (ADCs). Despite substantial improvements in first-line efficacy, a significant proportion of patients fail to reach targeted second-line therapies because of rapid clinical decline at progression. This concise review synthesizes evidence from phase II-III clinical trials and recent real-world data to evaluate how current first-line strategies influence the feasibility of subsequent therapies, with particular attention to central nervous system (CNS) risk, co-mutational biology, and treatment tolerability. Osimertinib monotherapy remains the global standard owing to its robust systemic and intracranial efficacy. The addition of chemotherapy, as shown in FLAURA2, further enhances firstline tumor control but may compromise salvage opportunities by reducing the likelihood of preserving actionable resistance. The amivantamab-lazertinib combination provides clear benefit in biomarker-defined high-risk disease but often limits the potential to reuse TKI-based approaches later in the course of treatment. Across studies, approximately 35%-40% of patients are unable to receive a targeted second-line regimen, and real-world survival after osimertinib failure is frequently restricted to 8-12 months. These data collectively suggest that the optimal first-line approach in EGFR-mutated NSCLC is not simply the regimen with the longest progression-free survival but rather the one that preserves access to subsequent effective therapies. Clinical decisions at diagnosis must therefore be made with downstream eligibility in mind, ensuring that patients remain candidates for HER3- and TROP2-directed ADCs and other emerging agents that are likely to shape survival beyond the first-line setting.