1348 Final overall survival analysis of HARMONi-A study comparing ivonescimab plus chemotherapy to chemotherapy alone in patients with EGFR + NSCLC progressed on EGFR-TKI treatment

Background Ivonescimab is a first in class bispecific antibody that cooperatively targets both programmed cell death protein-1 (PD-1) and vascular endothelial growth factor (VEGF). In an earlier PFS interim analysis of HARMONi-A, Ivonescimab plus chemotherapy significantly prolonged PFS compared with chemotherapy alone in patients with EGFR + NSCLC progressed with EGFR-TKI treatment. Here, we report the overall survival (OS) results in the final and only formal OS analysis of this study.Methods Patients (pts) were randomized 1:1 to receive ivonescimab (20 mg/kg) or placebo plus pemetrexed (500 mg/m 2) and carboplatin (AUC 5) every 3 weeks for 4 cycles, with presence of brain metastases (BM) and prior exposure to 3rd generation EGFR-TKI as two stratification factors. The primary endpoint was progression-free survival (PFS) by independent radiology review committee (IRRC), and overall survival (OS) is a key secondary endpoint. Closed sequential testing procedure is used. PFS was tested first at two-sided alpha level of 0.05, with OS tested at the same level only after PFS achieved statistical significance.Results A total of 322 pts in China were randomized (161 to each arm) and received at least one cycle of study treatment. As of 12 April 2025, with a median follow up of 32.5 months, median OS was 16.8 months (95% CI: 14.5, 20.0) in the ivonescimab + chemotherapy group vs 14.1 months (95% CI: 12.8, 16.3) in the placebo + chemotherapy group, with a hazard ratio of 0.74 (95% CI : 0.58, 0.95) and P=0.019 (two-sided), achieving statistical significance at the pre-specified alpha level of 0.05. The 12-month, 24-month, and 30-month OS rates were 65.0% vs 60.0%, 35.3% vs 28.8%, and 29.1% vs 18.4%, respectively. The safety of the combination therapy remained favorable, with no new safety signals identified.Conclusions Ivonescimab plus chemotherapy demonstrated a clinically meaningful and statistically significant OS benefit in pts with EGFR + NSCLC post EGFR-TKI therapy in this randomized Phase 3 HARMONi-A study. This study results establish ivonescimab plus chemotherapy as a new standard of care for EGFR+ NSCLC patients who progressed on EGFR-TKI treatments.Trial Registration This study has been registered on ClinicalTrial.gov under the registration number NCT05184712.