Ivonescimab Plus Chemotherapy Extends PFS After Tyrosine Kinase Inhibitor Progression in EGFR-Mutant Non-Small Cell Lung Cancer

Clinical Summary: 

• Design/Population: HARMONi was a randomized, double-blind, placebo-controlled phase 3 trial evaluating ivonescimab plus pemetrexed and carboplatin vs placebo plus chemotherapy in patients with advanced nonsquamous EGFR-mutated non-small cell lung cancer (NSCLC) who experienced disease progression after third-generation EGFR tyrosine kinase inhibitor (TKI) therapy.
• Key Outcomes: Ivonescimab plus chemotherapy improved median progression-free survival to 6.8 months vs 4.4 months with chemotherapy alone, reducing the risk of progression or death by 48%. Median overall survival was 16.8 vs 14 months, respectively. Serious treatment-related adverse events occurred more frequently with ivonescimab plus chemotherapy.
• Clinical Relevance: Ivonescimab plus chemotherapy produced a clinically meaningful and statistically significant progression-free survival benefit after third-generation EGFR TKI progression, supporting the combination as a potential treatment option in this setting. 

Results from the phase 3 HARMONi trial showed that ivonescimab plus pemetrexed and carboplatin significantly improved progression-free survival (PFS) compared with chemotherapy alone in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC) who experienced disease progression following third-generation EGFR tyrosine kinase inhibitor (TKI) therapy.

In this double-blind, placebo-controlled trial, researchers enrolled 438 patients with stage IIIB, IIIC, or IV nonsquamous EGFR-mutant NSCLC with an ECOG performance status of 0 or 1 who experienced disease progression after a third-generation EGFR TKI. Patients were randomized 1:1 to receive either 20 mg/kg of intravenous ivonescimab plus 500 mg/m² of pemetrexed and carboplatin at a target area under the curve of 5 mg/mL per minute every 3 weeks (n = 219) or placebo plus the same chemotherapy regimen (n = 219). Randomization was stratified by brain metastasis status and geographic region. Primary end points included PFS, by blinded independent radiology review, and overall survival (OS). A key secondary end point was safety. 

At a median follow-up of 22.3 months for the PFS analysis, median PFS was 6.8 months in the ivonescimab plus chemotherapy arm and 4.4 months in the placebo plus chemotherapy arm. The combination reduced the risk of progression or death by 48% (hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.41 to 0.66; P < .0001). 

At a median follow-up of 29.7 months for OS, 262 deaths had occurred. Median OS was 16.8 months in the ivonescimab plus chemotherapy arm and 14 months in the placebo plus chemotherapy arm. 

The most common grade 3/4 treatment-related adverse events were primarily hematologic and included decreased neutrophil count (19% vs 17%), decreased white blood cell count (13% vs 11%), decreased platelet count (12% vs 6%), and anemia (10% vs 12%). 

Serious treatment-related adverse events occurred in 28% of patients in the ivonescimab plus chemotherapy arm and 15% of patients in the placebo plus chemotherapy arm. Treatment-related adverse events led to 4 deaths in the ivonescimab plus chemotherapy arm and 5 deaths in the placebo arm. 

As study authors concluded, "the clinical benefit and lack of new safety signals of ivonescimab with chemotherapy support the potential for the combination as a new treatment option in this patient population." 

Source: 

Le X, Passaro A, Zhao Y, et al. Ivonescimab plus chemotherapy versus placebo plus chemotherapy in patients with advanced EGFR-mutated non-small-cell lung cancer after disease progression on EGFR tyrosine kinase inhibitor therapy (HARMONi): A multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. Published online: September 1, 2026. doi: 10.1016/S1470-2045(26)00282-2