EGFR-Mutant Stage IV NSCLC: Systemic Therapy

EGFR-Mutant Stage IV NSCLC: overview

This algorithm covers systemic therapy for EGFR-mutant stage IV non-small cell lung cancer, with the first branch point being the type of EGFR mutation. For common mutations (exon 19 deletion or L858R), osimertinib is preferred (FLAURA), with chemotherapy plus osimertinib as an intensified option (FLAURA2) and amivantamab plus lazertinib as a chemotherapy-free alternative (MARIPOSA). FLAURA2 showed that adding platinum-pemetrexed to osimertinib improved both progression-free and overall survival, at the cost of substantially more grade 3 or higher toxicity.

For exon 20 insertions, first-line options are amivantamab plus chemotherapy (PAPILLON) or the exon 20-selective TKI sunvozertinib. Atypical EGFR mutations are treated with afatinib or osimertinib depending on context. After progression on osimertinib, the chart lists amivantamab plus chemotherapy (MARIPOSA-2), the antibody-drug conjugate datopotamab deruxtecan (TROPION LUNG 01), and docetaxel with or without ramucirumab (REVEL) as the cytotoxic option. Osimertinib and amivantamab plus lazertinib are flagged for CNS activity.

Trials behind this algorithm

• FLAURA trial Soria J-C et al, NEJM, 2018, PMID: 29151359
• FLAURA2 Jänne PA et al, NEJM, 2025; PMID: 41104938
• MARIPOSA-2 Trial Passaro A et al., Ann Oncol, 2024, PMID: 37879444
• PAPILLON trial Zhou C et al, N Engl J Med, 2023, PMID: 37870976
• TROPION LUNG 01 Dato-DXd in 2L NSCLC Ahn MJ et al, JCO, 2025; PMID: 39250535

Background reading: NSCLC (Part 2): Stage IV, Targeted and Systemic Therapy board review notes.