ASCO updated its living guideline for stage IV non-small cell lung cancer (NSCLC) with driver alterations to reflect new data in EGFR-mutant disease and NRG1 fusions. In EGFR exon 19 deletion or L858R NSCLC, the phase 2 RAMOSE trial showed that adding ramucirumab to first-line osimertinib improved median progression-free survival (PFS) to 24.8 vs 15.6 months (hazard ratio 0.55), with similar response rates but more grade ≥3 toxicities (53% vs 41%). Given US-only enrollment and immature overall survival, the guideline does not change first-line recommendations (osimertinib plus platinum doublet chemotherapy or amivantamab + lazertinib remain options). However, it notes anti-VEGF add-on as a reasonable approach and highlights the ongoing EA5182 study of osimertinib plus bevacizumab. ASCO also issued a concurrent update to the living guideline for NSCLC without driver mutations.
For tumors with NRG1 fusions, the guideline now states clinicians may offer zenocutuzumab based on the phase 2 eNRGy study, which showed in NSCLC an overall response rate of 29%, median duration of response of 12.7 months, and median PFS 6.8 months, with mostly low-grade diarrhea, fatigue, and nausea. Because NRG1 fusions are rare and often require RNA sequencing to detect, the panel emphasizes comprehensive molecular testing. It also recognizes the need for further trials to define optimal sequencing across patient subgroups.
Reference: Levitan D. Studies on EGFR Mutations and NRG1 Fusions Included in ASCO NSCLC Living Guideline Update. The ASCO Post. Published August 25, 2025. Accessed September 16, 2025. https://ascopost.com/issues/august-25-2025/studies-on-egfr-mutations-and-nrg1-fusions-included-in-asco-nsclc-living-guideline-update/
