Ivonescimab plus chemotherapy provides survival benefit for difficult-to-treat NSCLC patients

Adding ivonescimab, a first-in-class bispecific antibody targeting both PD-1 and VEGF, to chemotherapy significantly prolonged progression-free survival (PFS) compared to chemotherapy alone in patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations whose disease progressed on third-generation EGFR tyrosine kinase inhibitors (TKIs).

Results from the global Phase 3 HARMONi trial were presented today by Jonathan Goldman, UCLA Health, Los Angeles at the International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer (WCLC).

The randomized, double-blind, placebo-controlled study enrolled 438 patients worldwide, including 38% from North America and Europe, with a median age of 62 years. Nearly one-quarter (24.7%) had brain metastases at study entry. Patients received ivonescimab (20 mg/kg) or placebo in combination with pemetrexed and carboplatin for four cycles, followed by maintenance therapy.

At the primary analysis (N=345; median follow-up 22.3 months), ivonescimab plus chemotherapy reduced the risk of disease progression or death by 48% compared to chemotherapy alone (HR 0.52; 95% CI: 0.41–0.66; P<0.001). Median PFS was 6.8 months (95% CI: 5.7–7.1) versus 4.4 months (95% CI: 4.1–5.5). The PFS benefit was consistent across all predefined subgroups, including patients with brain metastases (HR 0.34; 95% CI: 0.20–0.57) and Western patients.

At final overall survival (OS) analysis (median follow-up 29.7 months), median OS was 16.8 months with ivonescimab versus 14.0 months with chemotherapy alone (HR 0.79; 95% CI: 0.62–1.01; P=0.0570). The overall response rate was higher in the ivonescimab group (44.7% vs. 34.2%), and intracranial PFS was also improved.

Grade ≥3 treatment-related adverse events occurred in 50.0% of patients receiving ivonescimab and 42.2% in the control arm, most commonly laboratory abnormalities. VEGF-related events, including reversible hypertension and proteinuria, were more frequent with ivonescimab but generally manageable. Treatment-related deaths were rare (1.8% vs. 2.3%).

Ivonescimab plus chemotherapy provided a clinically meaningful and statistically significant improvement in progression-free survival while maintaining a favorable safety profile in this difficult-to-treat patient population. The benefits were seen regardless of brain metastases status or geographic region and were supported by a positive overall survival trend."

Dr. Jonathan Goldman, UCLA Health, Los Angeles