Ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy as first-line treatment for advanced squamous non-small-cell lung cancer (HARMONi-6): a randomised, double-blind, phase 3 trial.

Summary

This double-blind phase 3 RCT showed that ivonescimab plus chemotherapy significantly improved median progression-free survival (11.1 vs 6.9 months; HR 0.60) compared with tislelizumab plus chemotherapy in first-line advanced squamous NSCLC, independent of PD-L1 status. Grade ≥3 treatment-related AEs occurred in 64% vs 54% and immune-related AEs in 9% vs 10%, with grade ≥3 hemorrhage in 2% vs 1%, indicating a manageable safety profile.

Key Findings

• Median PFS: 11.1 months with ivonescimab+chemo vs 6.9 months with tislelizumab+chemo (HR 0.60; one-sided p<0.0001).
• Benefit was consistent regardless of PD-L1 status.
• Grade ≥3 treatment-related AEs: 64% vs 54%; grade ≥3 immune-related AEs: 9% vs 10%.
• Grade ≥3 treatment-related hemorrhage occurred in 2% vs 1% of patients.
• Randomized, double-blind, multicenter design with 532 participants and median follow-up of 10.3 months.

Clinical Implications

Ivonescimab plus chemotherapy may be adopted as a first-line option regardless of PD-L1 status; clinicians should monitor for hemorrhagic events and immune-related AEs and consider comparative positioning versus established PD-1 plus chemotherapy regimens.

Limitations

• Overall survival and quality-of-life outcomes not yet mature at median follow-up of 10.3 months.
• Study conducted in China; external generalizability and comparisons with other global standards (e.g., pembrolizumab-based regimens) require consideration.

Future Directions

Assess overall survival, patient-reported outcomes, biomarker correlatives (e.g., angiogenesis signatures), and global confirmatory trials; clarify optimal management of hemorrhagic and immune-related AEs.