EGFR-driven stage IV NSCLC treatment pathways

Authored by Stephen Liu, published on 2026-05-14 21:55:00.0

Treatment algorithm for stage IV metastatic non–small cell lung cancer (NSCLC) when biomarker testing confirms EGFR mutation, then a biomarker specific approach is used. Treatment selection is guided by patient comorbidities, performance status, organ function, adverse-event profiles, and access considerations.

  1. Comprehensive next gen sequencing with DNA and RNA confirms EGFR mutation
    Broad NGS panel + PD-L1 testing. If actionable driver → targeted therapy. If no driver → treat based on PD-L1 + histology. Never-smokers = Higher likelihood of driver mutation → ensure comprehensive NGS.
    • If EGFR deletion 19, L858r
      Consider the side effects here between FLAURA 2 and MARIPOSA. OSI would be more frail or can't come in for more frequent infusions. All off trial.
      • Flaura 2
        Chemo + Osi David Planchard 2026, NEJM
        • MARIPOSA 2
          Antonio Passaro, AO 2023.
          • Datapotamab
            Tropion Lung 05, JTO 2025, Ahn
      • MARIPOSA
        Yang NEJM, 2025
        • Chemotherapy (Carbo + Pem)
          • Datapotamab
            Tropion Lung 05, JTO 2025, Ahn
      • Osimertinib
        Flaura trial; Ramalingam NEJM 2017
        • MARIPOSA 2
          • Datapotamab
            Tropion Lung 05, JTO 2025, Ahn
    • EGFR Exon20 insertion
      • Papillon (ami + chemo)
        • Sunvozertinib
    • Atypical EGFR (G719X, L861Q, S768I)
      Uncommon (G719X, L861Q, S768I) → afatinib or osimertinib (context dependent)
      • Afatinib
tosprivacyMolecular Testing Guideline for the Selection of Patients With Lung Cancer for Treatment With Targeted Tyrosine Kinase Inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Clinical Practice Guideline UpdateFlaura 2 resultsSurvival with Osimertinib plus Chemotherapy in EGFR-Mutated Advanced NSCLCSurvival with Osimertinib plus Chemotherapy in EGFR-Mutated Advanced NSCLC (FLAURA2)Overall Survival with Amivantamab–Lazertinib in EGFR-Mutated Advanced NSCLCOsimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung CancerAmivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study☆A Pooled Analysis of Datopotamab Deruxtecan in Patients With EGFR-Mutated NSCLC