Bispecific Antibody Ivonescimab Added to Chemotherapy in EGFR-Variant Non-Small Cell Lung Cancer: The HARMONi-A Randomized Clinical Trial.

Abstract

Patients with epidermal growth factor receptor (EGFR) gene variant nonsquamous non-small cell lung cancer (NSCLC) who have disease progression after prior EGFR tyrosine kinase inhibitor (TKI) therapy have limited treatment options, creating a need for more effective subsequent therapies. To provide final overall results of a trial assessing whether adding ivonescimab (a bispecific antibody targeting programmed cell death protein 1 and vascular endothelial growth factor) to chemotherapy improves overall survival in this population. Randomized, double-blind, placebo-controlled phase 3 trial conducted at 55 sites in China. From January 25 to November 2, 2022, a total of 322 adult patients with locally advanced or metastatic EGFR-variant nonsquamous NSCLC who had received prior EGFR-TKI therapy were enrolled. The data cutoff date was April 12, 2025. Patients were randomized 1:1 to receive ivonescimab (20 mg/kg; n = 161) or placebo (n = 161) plus chemotherapy with pemetrexed and carboplatin once every 3 weeks for 4 cycles, followed by maintenance therapy. This final results report focuses on overall survival, the key secondary end point, tested in a hierarchical manner (the primary end point was progression-free survival assessed by an independent radiology review committee). The 322 enrolled patients had a median age of 59.4 years, and 51.6% were female. During a median follow-up of 32.5 months, ivonescimab plus chemotherapy improved overall survival compared with chemotherapy alone (median survival, 16.8 months vs 14.1 months; stratified hazard ratio, 0.74; 95% CI, 0.58-0.95; P = .02). The absolute difference in median overall survival was 2.7 months. Estimated 30-month survival rates were 29.1% (95% CI, 22.1%-36.4%) with ivonescimab and 18.4% (95% CI, 12.8%-24.8%) with placebo. Grade 3 or higher treatment-emergent adverse events occurred in 67.1% and 54.7% of patients receiving ivonescimab and placebo, respectively. Ivonescimab plus chemotherapy provided a statistically significant and clinically meaningful improvement in overall survival with an acceptable safety profile in patients with EGFR-variant NSCLC after EGFR-TKI therapy. ClinicalTrials.gov Identifier: NCT05184712.