Ivonescimab outperforms Keytruda with OS improvement…in first-line lung cancer

Signficant effectiveness observed in patients with high expression…no new safety signals

The limitation of the study is that it was conducted exclusively in Chinese patients…attention to global phase 3 clinical results that are currently underway

The bispecific antibody 'ivonescimab' significantly improved overall survival compared to 'Keytruda' in the first-line treatment of PD-L1-positive advanced non-small cell lung cancer (NSCLC).

On the 15th, at the World Conference on Lung Cancer (WCLC 2026), the results of the phase 3 HARMONi-2 study, which directly compared ivonescimab and Keytruda (pembrolizumab) in patients with PD-L1-positive advanced NSCLC, were unveiled.

Ivonescimab is a PD-1/VEGF bispecific antibody developed by China's Akeso. Akeso is currently leading its development in China. In major regions outside of China, US-based Summit Therapeutics has secured development and commercialization rights and is conducting global clinical trials.

The HARMONi-2 trial is a randomized, double-blind, phase 3 study conducted in China. It enrolled 398 patients with locally advanced or metastatic NSCLC who had no prior systemic treatment and a PD-L1 tumor proportion score (TPS) of 1% or higher.

Patients received either ivonescimab 20 mg/kg or Keytruda 200 mg every 3 weeks. Patients with EGFR or ALK mutations were excluded. The primary endpoint was progression-free survival (PFS), assessed by an independent radiologic review committee, and the secondary endpoint was overall survival (OS).

Professor Caicun Zhou of Shanghai Pulmonary Hospital in China presented clinical results of the bispecific antibody ivonescimab. 

Median OS of 30.8 months...Difference in 3-year survival rate

With a median follow-up of 36 months, ivonescimab significantly improved OS compared to Keytruda.

The median OS was 30.8 months in the ivonescimab group and 22.6 months in the Keytruda group. Ivonescimab reduced the risk of death by 27% compared to Keytruda.

The survival difference persisted over time. At 2 years, OS was 57.9% in the ivonescimab group and 48.0% in the Keytruda group. At 3 years, it was 45.0% and 33.1%, respectively.

At the time of this analysis, there were 104 deaths in the ivonescimab group and 130 deaths in the Keytruda group.

In the previously announced PFS analysis, ivonescimab also outperformed Keytruda. The median PFS was 11.1 months and 5.8 months, respectively, reducing the risk of disease progression or death by 49%.

The objective response rate (ORR) was also higher in the Ivonescimab group (50.0%) than in the Keytruda group (38.5%).

Significant OS difference in PD-L1 50% or higher

In the subgroup analysis by PD-L1 expression level, the survival extension benefit of ivonescimab was prominent in patients with high expression.

In patients with a PD-L1 TPS of 50% or higher, the ivonescimab group had not reached the median OS by the time of analysis, whereas the Keytruda group's median OS was 23.2 months. The risk of death was 42% lower in the Ivonescimab group.

At 2 years, OS was 63.2% in the ivonescimab group and 49.7% in the Keytruda group. At 3 years, OS was 53.4% and 31.3%, respectively.

In contrast, in patients with a PD-L1 TPS of 1-49%, the median OS was 28.5 months and 22.1 months, respectively.

The researchers explained that a favorable trend for ivonescimab was generally observed not only across PD-L1 expression levels but also in multiple prespecified subgroups, such as histology and age.

In squamous NSCLC, the median OS was 30.5 months for the ivonescimab group and 19.3 months for the Keytruda group, with a hazard ratio (HR) of 0.65. In non-squamous histology, they were 33.6 months and 25.6 months, respectively, with an HR of 0.79.

However, these subgroup analyses were descriptive and were not designed to secure statistical power.

The proportion of patients receiving subsequent anti-cancer treatment after disease progression was relatively higher in the Keytruda group.

Patients received chemotherapy in 36.4% of the ivonescimab group and 46.0% of the Keytruda group, and subsequent immunotherapy rates were 27.8% and 38.0%, respectively. Targeted therapy was reported in 19.2% and 27.5% of patients. Patients received ADC treatments in 15.7% of the ivonescimab group and 17.5% of the Keytruda group.

This analysis also showed an OS advantage in the ivonescimab group, despite the generally higher rate of subsequent systemic treatments in the Keytruda group.

Increase in VEGF-related proteinuria and hypertension... no new safety signals

In terms of safety, adverse events related to ivonescimab's VEGF inhibition mechanism were relatively more frequent.

Any-grade treatment-related adverse events (TRAEs) occurred in 93.4% of the ivonescimab group and 84.9% of the Keytruda group. Grade 3 or higher TRAEs occurred in 41.6% and 21.6% of the ivonescimab and Keytruda groups, respectively.

Serious TRAEs were reported in 29.9% of the ivonescimab group and 21.6% of the Keytruda group, and treatment discontinuations due to adverse events were 4.1% and 5.0%, respectively. Treatment-related deaths were 0.5% and 1.5%, respectively.

In the ivonescimab group, proteinuria and hypertension were reported in 48.2% and 20.3% of patients, higher than 13.1% and 3.0% in the Keytruda group. Grade 3 or higher proteinuria and hypertension were 8.1% and 7.1%, respectively.

Professor Caicun Zhou of Shanghai Pulmonary Hospital in China

The researchers said they identified no new safety signals during long-term follow-up and observed no distinct increase in bleeding risk.

Professor Caicun Zhou of Shanghai Pulmonary Hospital in China, who presented the findings, evaluated, 'ivonescimab improved OS, PFS, and response rates in PD-L1-positive advanced NSCLC.'

Professor Zhou explained, 'A manageable safety profile was maintained even in long-term follow-up. These results confirm ivonescimab as a standard first-line treatment option for PD-L1-positive non-small cell lung cancer in China.'

However, the HARMONi-2 trial was conducted exclusively in Chinese patients.

Currently, the global phase 3 study HARMONi-7, which directly compares ivonescimab and Keytruda in patients with PD-L1 high-expressing metastatic NSCLC, is underway. Whether the survival benefit shown in HARMONi-2 trial will be reproduced in the global patient population is expected to be a key factor in determining the future therapeutic scope of ivonescimab.