Ivonescimab Plus Chemotherapy Improves Progression-Free Survival in EGFR-Mutated Non-Small Cell Lung Cancer
Clinical Summary:
- Design/Population: This double-blind, placebo-controlled trial evaluated ivonescimab plus pemetrexed and carboplatin vs placebo plus chemotherapy in patients with advanced non-squamous EGFR-mutated non-small cell lung cancer (NSCLC) whose disease progressed after third-generation EGFR tyrosine kinase inhibitor (TKI) therapy.
- Key Outcomes: Ivonescimab plus chemotherapy significantly improved progression-free survival, reducing the risk of progression or death by 48% compared with chemotherapy alone. Overall survival numerically favored ivonescimab, although the confidence interval included the null. Serious treatment-related adverse events were more frequent with ivonescimab plus chemotherapy.
- Clinical Relevance: The significant progression-free survival benefit supports ivonescimab plus chemotherapy as a potential treatment option for advanced EGFR-mutated NSCLC following progression on third-generation EGFR TKI therapy, although the overall survival benefit remains uncertain.
Results from the phase 3 HARMONi trial demonstrated that ivonescimab plus chemotherapy significantly improved progression-free survival (PFS) compared with chemotherapy alone in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC) whose disease progressed after third-generation EGFR tyrosine kinase inhibitor (TKI) therapy.
In this double-blind, placebo-controlled trial, 438 patients with stage IIIB/IIIC or IV non-squamous EGFR-mutated NSCLC, disease progression following a third-generation EGFR TKI, and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomized 1:1 to receive ivonescimab plus chemotherapy or placebo plus chemotherapy.
Patients received either 20 mg/kg of ivonescimab or placebo plus 500 mg/m² of pemetrexed and carboplatin at a target area under the curve of 5 mg/mL per minute intravenously every 3 weeks. Randomization was stratified by brain metastasis status at enrollment and geographic region. The primary end points were PFS by blinded independent radiology review committee and overall survival (OS), with safety also assessed.
At a median follow-up of 22.3 months for the PFS analysis, median PFS was 6.8 months with ivonescimab plus chemotherapy compared with 4.4 months with placebo plus chemotherapy, corresponding to a 48% reduction in the risk of progression or death (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, median OS was 16.8 months with ivonescimab plus chemotherapy compared with 14 months with placebo plus chemotherapy. OS numerically favored ivonescimab, although the confidence interval included the null (HR, 0.79).
The most common grade 3/4 treatment-related adverse events 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% and 15% of patients, respectively. Treatment-related adverse events led to death in 4 patients in the ivonescimab plus chemotherapy arm and 5 patients in the placebo plus chemotherapy 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
