Background
Randomised, double-blind, placebo-controlled phase 3 at 55 sites in China. N=322 (161 ivonescimab / 161 placebo) with locally advanced or metastatic EGFR-mutant nonsquamous NSCLC progressing after a prior EGFR-TKI. Ivonescimab is a first-in-class bispecific antibody targeting PD-1 and VEGF. This report provides the final overall survival analysis (OS was a key secondary endpoint; PFS was the primary).
Results
Interventions and follow up: Arm A: Ivonescimab 20 mg/kg IV + pemetrexed + carboplatin q3w ×4, then maintenance
Arm B: Placebo + pemetrexed + carboplatin q3w ×4, then maintenance
Primary endpoint: PFS (independent radiology review); key secondary OS
mFollow up: 32.5 months
Results: PFS (primary, prior analysis): 7.1 vs 4.8 mo, HR 0.46
OS: 16.8 vs 14.1 mo, HR 0.74 (95% CI 0.58–0.95), P=.02; absolute difference 2.7 mo
30-mo OS: 29.1% vs 18.4%
Arm B: Placebo + pemetrexed + carboplatin q3w ×4, then maintenance
Primary endpoint: PFS (independent radiology review); key secondary OS
mFollow up: 32.5 months
Results: PFS (primary, prior analysis): 7.1 vs 4.8 mo, HR 0.46
OS: 16.8 vs 14.1 mo, HR 0.74 (95% CI 0.58–0.95), P=.02; absolute difference 2.7 mo
30-mo OS: 29.1% vs 18.4%
Adverse events
Grade ≥3 TEAE: 67.1% vs 54.7%
VEGF-related: hypertension and proteinuria more frequent with ivonescimab, generally reversible/manageable
VEGF-related: hypertension and proteinuria more frequent with ivonescimab, generally reversible/manageable
Conclusions
With mature follow-up, adding the PD-1/VEGF bispecific ivonescimab to platinum–pemetrexed significantly improved OS (16.8 vs 14.1 mo; HR 0.74) after EGFR-TKI failure, complementing the earlier PFS benefit (7.1 vs 4.8 mo; HR 0.46). This is the first phase 3 OS win for a PD-1/VEGF bispecific in this setting, with an acceptable, VEGF-class safety profile.
Key Limitations
China-only enrollment limits global generalisability — a central regulatory question for the class. The absolute OS gain is modest (2.7 mo). The chemotherapy-alone control reflects regional practice and does not address comparison with anti-angiogenic or immunotherapy-containing regimens. VEGF-related toxicities (hypertension, proteinuria, bleeding) require monitoring.
Clinical Context
Ivonescimab is approved in China (NMPA, 2024) for EGFR-mutant NSCLC progressing after EGFR-TKI, combined with chemotherapy, on the basis of HARMONi-A. It is not FDA/EMA approved; the global HARMONi phase 3 reported a consistent PFS benefit in 2025. These mature OS data strengthen the PD-1/VEGF bispecific class but are not yet reflected in NCCN/ESMO guidance for this setting.