Multinational phase 3 trial of ivonescimab plus chemotherapy for advanced EGFR-mutated NSCLC after progression on EGFR TKI therapy

The phase 3 HARMONi trial, at 114 center across Asia, Europe, and North America, evaluated ivonescimab plus chemotherapy versus placebo plus chemotherapy in adult patients with advanced EGFR-mutated NSCLC whose disease progressed after third-generation EGFR TKI therapy, with an ECOG performance status score of 0 or 1. Patients were randomized 1:1 to receive ivonescimab 20 mg/kg (n=219) or placebo (n=219) plus pemetrexed and carboplatin every 3 weeks. Primary endpoints were progression-free survival by blinded independent radiology review (PFS) and overall survival (OS). At a median follow-up of 22.3 months (95% CI 21.5-23.0), median PFS was 6.8 months in the ivonescimab plus chemotherapy group versus 4.4 months in the placebo plus chemotherapy group (HR 0.52; 95% CI 0.41-0.66). At a median follow-up of 29.7 months, median OS was 16.8 months in the ivonescimab plus chemotherapy group versus 14.0 months in the placebo plus chemotherapy group (HR 0.79; 95% CI 0.62-1.01). The most common grade 3-4 TRAEs in the ivonescimab versus the placebo group were decreased neutrophil count (19% versus 17%)m decreased white blood cell count (13% versus 11%), decreased platelet count (12% versus 6%) and anemia (10% versus 12%). Serious TRAEs occurred in 28% versus 15%, and treatment-related deaths in 4 patients versus 5 patients. The authors conclude that ivonescimab plus chemotherapy showed ar clinically meaningful and statistically significant PFS benefit in patients with EGFR-mutated NSCLC after progression on EGFR-TKI therapy.