Current treatment landscape for patients with non–small cell lung cancer with common EGFR mutations

Abstract

Common EGFR mutations including exon-19 deletions and the L858R point mutation in exon 21 constitute predominant actionable genomic alterations in individuals with non–small cell lung cancer (NSCLC). The introduction of EGFR tyrosine kinase inhibitors (TKIs) has fundamentally changed the treatment landscape for such patients by improving both progression-free survival (PFS) and overall survival (OS). Among EGFR-TKIs, third-generation agents such as osimertinib have shown marked efficacy and favorable safety profiles and have become the standard of care in the first-line setting. The combination of osimertinib with platinum-based chemotherapy has recently been shown to improve PFS compared with osimertinib monotherapy in the FLAURA2 trial. Similarly, the MARIPOSA trial demonstrated clinical benefit of the combination of the EGFR-MET bispecific antibody, amivantamab, with the third-generation EGFR-TKI, lazertinib, further supporting the use of combination therapies as first-line treatment for EGFR-mutated NSCLC. Despite these advances, however, challenges such as brain metastases remain substantial barriers to successful treatment outcomes. Management of patients with such metastases often requires a multidisciplinary approach that integrates systemic treatment with local interventions such as radiation therapy. Finally, circulating tumor DNA has emerged as a promising biomarker for real-time monitoring of treatment response and evolution of drug resistance mechanisms. Analysis of such biomarkers can facilitate dynamic and personalized therapeutic adjustments, potentially improving outcomes. This review provides a comprehensive overview of the latest clinical evidence supporting therapeutic advances in the management of EGFR-mutated NSCLC, emphasizing the importance of tailoring treatment strategies based on tumor biology, patient-specific factors, and evolving therapeutic options.