Background
Randomized, double-blind, placebo-controlled phase 3 (114 sites; Asia, Europe, North America). N=438. Stage IIIB/IIIC or IV non-squamous EGFR-mutated NSCLC with progression after 3rd-generation EGFR-TKI; ECOG 0–1. Ivonescimab = PD-1 × VEGF bispecific antibody. Stratified by brain metastases and region. Global counterpart of the China-only HARMONi-A.
Results
Interventions and follow up: Arm A: Ivonescimab 20 mg/kg IV q3w + pemetrexed 500 mg/m² + carboplatin AUC 5 q3w
Arm B: Placebo + pemetrexed/carboplatin q3w
Primary endpoint: PFS by BICR and OS (ITT, dual primary)
mFollow up: 22.3 mo (PFS); 29.7 mo (OS)
Results: PFS (BICR): 6.8 vs 4.4 mo; HR 0.52 (95% CI 0.41–0.66); P<.0001
OS: 16.8 vs 14.0 mo; HR 0.79 (95% CI 0.62–1.01); not statistically significant
ORR: NR in abstract
Arm B: Placebo + pemetrexed/carboplatin q3w
Primary endpoint: PFS by BICR and OS (ITT, dual primary)
mFollow up: 22.3 mo (PFS); 29.7 mo (OS)
Results: PFS (BICR): 6.8 vs 4.4 mo; HR 0.52 (95% CI 0.41–0.66); P<.0001
OS: 16.8 vs 14.0 mo; HR 0.79 (95% CI 0.62–1.01); not statistically significant
ORR: NR in abstract
Adverse events
Grade 3–4 TRAEs (most common): neutropenia 19% vs 17%, leukopenia 13% vs 11%, thrombocytopenia 12% vs 6%, anemia 10% vs 12%
Serious TRAEs: 28% vs 15%
Treatment-related deaths: 4 vs 5
Discontinuation: NR
Serious TRAEs: 28% vs 15%
Treatment-related deaths: 4 vs 5
Discontinuation: NR
Conclusions
Adding ivonescimab to platinum-pemetrexed after 3rd-generation EGFR-TKI failure roughly halved the risk of progression (HR 0.52), with a 2.8-month OS gain that did not reach statistical significance at this analysis. First global, Western-inclusive phase 3 of a PD-1×VEGF bispecific in post-TKI EGFR-mutant NSCLC.
Key Limitations
Dual primary endpoint; OS not significant (upper CI 1.01) and OS was the co-primary endpoint. 70% Asian enrollment; Western subgroup OS HR was ~1.0 at primary analysis and only improved with later data cuts (sponsor updates). Chemotherapy-only control omits amivantamab-chemo (MARIPOSA-2) and no comparison with datopotamab or sacituzumab tirumotecan. Serious TRAEs nearly doubled. No upper age limit in the West but 75-year cap in Asia.
Clinical Context
Post-osimertinib EGFR-mutant NSCLC options: platinum-pemetrexed ± amivantamab (MARIPOSA-2, FDA approved 2024), ± bevacizumab/atezolizumab (IMpower150, off-label), datopotamab deruxtecan (FDA accelerated approval 2025 for EGFR-mutant after TKI and chemo). HARMONi-A (China) already showed PFS benefit for ivonescimab-chemo; HARMONi adds global data. FDA accepted the BLA with a PDUFA date of Nov 14, 2026; not yet FDA/EMA approved as of this draft. Not in NCCN/ESMO guidelines yet.