EGFR-mutated advanced non-small cell lung cancer: new era of systemic therapy towards new standards of care

This review summarizes current systemic treatment strategies for advanced EGFR-mutated non-small cell lung cancer (NSCLC), with a focus on novel first-line regimens and emerging concepts beyond progression. Evidence from pivotal phase III trials and recent regulatory developments was analyzed, emphasizing efficacy outcomes, safety profiles, and patient selection factors relevant for routine clinical practice. Osimertinib has long been the standard first-line therapy, yet resistance inevitably emerges. The two novel combination strategies, osimertinib plus platinum–pemetrexed chemotherapy (FLAURA2) and amivantamab plus lazertinib (MARIPOSA), have shown superior progression-free and overall survival compared with osimertinib monotherapy. These regimens are associated with higher toxicity, treatment burden, and costs, requiring careful patient selection based on comorbidities, risk features, and preferences. After progression, treatment options remain limited. Current postprogression data are almost exclusively derived from patients previously treated with first-line osimertinib monotherapy, and it remains unclear how outcomes will evolve following upfront combination regimens. Platinum-based chemotherapy remains the historical backbone, while continuation of EGFR inhibition with targeted agents or chemotherapy (e.g., MARIPOSA‑2, COMPEL) and the development of antibody–drug conjugates such as datopotamab deruxtecan represent promising strategies, especially in view of the rapidly changing first-line landscape. Upfront combination regimens have redefined the standard of care in EGFR-mutated advanced NSCLC, but their survival benefit must be weighed against added toxicity, logistical complexity, and financial impact. Expanding therapeutic options make individualized shared decision-making essential to balance efficacy, tolerability, logistics, and patient priorities, aiming to maintain quality of life while extending survival.