Akeso’s ivonescimab significantly improved overall survival versus pembrolizumab in the Phase III HARMONi-2 trial of first-line PD-L1-positive NSCLC.
Written By: Anshu Gupta, PharmD
Reviewed By: Pharmacally Editorial Team
Akeso’s ivonescimab met the key secondary endpoint of overall survival (OS) in the Phase III HARMONi-2 trial (NCT05499390), demonstrating a statistically significant and clinically meaningful improvement versus pembrolizumab in patients with previously untreated, locally advanced or metastatic non-small cell lung cancer (NSCLC).
The prespecified interim OS analysis, assessed by the Independent Data Monitoring Committee (IDMC), evaluated patients whose tumors expressed PD-L1 at a tumor proportion score (TPS) of at least 1% and had no actionable EGFR or ALK genomic aberrations. Akeso has not yet disclosed the median OS, hazard ratio, confidence interval, or other detailed survival measures. The complete results are expected at an upcoming international medical conference and in a peer-reviewed publication.
A Dual-Target Approach to NSCLC
Ivonescimab, known as SMT112 in Summit Therapeutics’ licensed territories and AK112 elsewhere, is a bispecific antibody that targets both PD-1 and VEGF. It combines immune checkpoint inhibition with anti-angiogenic activity in a single molecule.
The antibody exhibits cooperative binding to its targets, with higher affinity for PD-1 in the presence of VEGF. The rationale is to exploit the higher levels of both targets within the tumor and tumor microenvironment compared with normal tissue.
The approach could provide an alternative to administering separate PD-1 and VEGF-targeting agents, although the clinical significance of this molecular design will depend on the complete efficacy and safety dataset across different populations.
HARMONi-2 Builds on a Strong PFS Result
HARMONi-2 (AK112-303) is a randomized, double-blind, multicenter Phase III trial conducted in China. It compared ivonescimab monotherapy with pembrolizumab monotherapy as first-line treatment for PD-L1-positive locally advanced or metastatic NSCLC.
At a prespecified interim analysis in May 2024, ivonescimab met the primary endpoint of progression-free survival (PFS). The subsequent primary analysis showed a median PFS of 11.14 months versus 5.82 months with pembrolizumab, corresponding to a hazard ratio of 0.51 (95% CI, 0.38-0.69; p<0.0001).
The PFS benefit was reported across key clinical subgroups, including patients with low and high PD-L1 expression and those with squamous and non-squamous histology.
The newly reported OS result extends that efficacy signal to survival. However, the magnitude and durability of the OS benefit remain unavailable until Akeso presents the detailed dataset.
Safety Profile and Regulatory Milestone
The primary HARMONi-2 publication in The Lancet provides the established safety context. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 29% of patients receiving ivonescimab versus 16% with pembrolizumab. Grade ≥3 immune-related adverse events remained low and comparable between groups, occurring in 7% and 8% of patients, respectively.
These figures come from the primary trial analysis and should be distinguished from any updated safety findings associated with the interim OS analysis.
China’s National Medical Products Administration (NMPA) granted ivonescimab marketing authorization for the HARMONi-2 first-line PD-L1-positive NSCLC indication on April 25, 2025. This followed its earlier NMPA approval in May 2024 for second-line or later treatment of EGFR-mutated NSCLC based on HARMONi-A (NCT05184712).
Global Development Expands Beyond China
HARMONi-2 was conducted exclusively in China, making the applicability of its findings to Western populations an important question for the global development program.
Summit Therapeutics, which holds rights to ivonescimab in territories including the United States and Europe, said the HARMONi-2 data were generated, managed, and analyzed by Akeso. Ivonescimab remains investigational in Summit’s licensed territories.
The ongoing global Phase III HARMONi-7 (AK112-3007, NCT06767514) trial is evaluating ivonescimab against pembrolizumab as first-line therapy for patients with PD-L1-high NSCLC, defined as TPS ≥50%. Broader international development, including HARMONi-3 (NCT05899608), will provide additional evidence on whether the efficacy and safety observed in Chinese patients translate across diverse patient populations.
The next major catalyst is the full HARMONi-2 OS dataset, which should clarify the survival effect, subgroup consistency, durability, and updated safety profile. Those data will be central to assessing ivonescimab’s potential role in the global first-line NSCLC treatment landscape.
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About the Writer
Anshu Gupta (LinkedIn) is a PharmD professional and healthcare writer with interests in clinical research, pharmacovigilance, regulatory affairs, and medical writing. She has presented research at academic conferences and completed certifications in Good Clinical Practice (GCP), ICH-GCP, and drug safety. Passionate about clinical trials and evidence-based medicine, she is committed to translating scientific evidence into accurate, reliable, and accessible healthcare content.