In the phase 3 HARMONi-2 trial of 398 patients in China, first-line treatment with the PD-1/VEGF bispecific antibody ivonescimab significantly extended median overall survival to 30.8 months compared to 22.6 months for pembrolizumab in PD-L1-positive advanced non-small cell lung cancer. Despite these strong survival benefits, particularly in patients with high PD-L1 expression, experts urge caution. Ivonescimab caused higher rates of grade 3 or higher adverse events (42% vs 22%), and the trial's monotherapy control arm does not reflect global clinical standards where chemotherapy is typically added.
HARMONi-2 trial overall survival results
- ▪The HARMONi-2 trial enrolled 398 treatment-naive patients with locally advanced or metastatic non-small cell lung cancer across clinical centers in China between November 2022 and August 2023
- ▪At the August 20, 2026 data cutoff for the phase 3 HARMONi-2 trial comparing ivonescimab with pembrolizumab in PD-L1-positive advanced non-small cell lung cancer, 234 deaths had occurred, representing 104 deaths in the ivonescimab group and 130 in the pembrolizumab group
- ▪In the phase 3 HARMONi-2 trial, first-line treatment with ivonescimab significantly extended median overall survival to 30.8 months compared to 22.6 months with pembrolizumab in patients with PD-L1-positive advanced non-small cell lung cancer
Ivonescimab bispecific antibody mechanism
- ▪Ivonescimab received regulatory approval in China in April 2025 for PD-L1-positive advanced non-small cell lung cancer based on earlier data demonstrating a progression-free survival benefit
- ▪Ivonescimab is a first-in-class bispecific antibody that simultaneously targets programmed cell death protein 1 (PD-1) and vascular endothelial growth factor (VEGF)
PD-L1 expression subgroup analyses
- ▪In the HARMONi-2 trial, patients with high PD-L1 expression of 50% or greater achieved a median overall survival that was not reached with ivonescimab compared to 23.2 months with pembrolizumab
- ▪In the phase 3 HARMONi-2 trial comparing ivonescimab with pembrolizumab in PD-L1-positive advanced non-small cell lung cancer, in the subgroup with PD-L1 expression of 1% to 49%, median overall survival was 28.5 months with ivonescimab compared to 22.1 months with pembrolizumab
Treatment-related adverse events
- ▪Serious treatment-related adverse events occurred in 29.9% of patients in the ivonescimab group compared to 21.6% of patients in the pembrolizumab group during the HARMONi-2 trial
- ▪In the phase 3 HARMONi-2 trial comparing ivonescimab with pembrolizumab in PD-L1-positive advanced non-small cell lung cancer, grade 3 or higher adverse events occurred in 42% of patients treated with ivonescimab compared to 22% of patients treated with pembrolizumab
- ▪Patients treated with ivonescimab in the HARMONi-2 trial experienced higher rates of vascular endothelial growth factor-related toxicities, specifically proteinuria and hypertension, compared to those treated with pembrolizumab
Clinical practice applicability concerns
- ▪Dr. Mariana Brandão stated she would not change her clinical practice for patients with PD-L1-high non-small cell lung cancer until results are available from the global phase 3 HARMONi-7 trial, which is specifically comparing ivonescimab with pembrolizumab in patients with PD-L1-high metastatic NSCLC
- ▪Dr. Mariana Brandão cautioned that the control arm of pembrolizumab monotherapy in the phase 3 HARMONi-2 trial of ivonescimab versus pembrolizumab in PD-L1-positive advanced non-small cell lung cancer does not reflect global clinical practice, where anti-PD-1 therapy is typically combined with chemotherapy
Debatable claims
- ▪Ivonescimab should replace pembrolizumab as the standard first-line treatment for PD-L1-positive advanced NSCLC
- ▪Chemotherapy-free immunotherapy should be preferred over chemo-immunotherapy for first-line advanced NSCLC
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