Pembrolizumab has been the default first-line treatment for PD-L1-positive advanced NSCLC since its FDA approval in 2016, and until now no randomized Phase III trial had beaten it on both progression-free and overall survival. Akeso’s HARMONi-2 data, presented as a late-breaking abstract at WCLC 2026, changes that: ivonescimab cut the risk of death by 27% versus pembrolizumab in the intention-to-treat population, with median overall survival of 30.8 months against 22.6 months (HR 0.73; 95% CI 0.57–0.95; P=0.009). That 8.2-month gap in median OS, read out at 36 months of follow-up and 234 events, meets a prespecified O’Brien-Fleming threshold and is not a borderline result.
The PD-L1-high subgroup is where the data gets sharper. Among patients with TPS of 50% or above, the hazard ratio drops to 0.58, a 42% reduction in death risk. That population is exactly where pembrolizumab monotherapy is considered most competitive, with real-world data placing its median OS in the low-to-mid 20s of months. A sub-0.60 HR at high PD-L1 expression is a harder number to dismiss than a trial-level benefit driven by one histology or one subgroup.
The squamous finding deserves its own read. Nearly half the HARMONi-2 population (45.5%) had squamous histology, and within that group a large proportion carried features that have historically excluded patients from anti-VEGF therapy: central tumor location (72.2%), cavitation or necrosis (10%), and major vessel encasement (6.7%). Ivonescimab showed no apparent increase in bleeding risk in these patients, and the squamous OS hazard ratio was 0.65. Because conventional anti-VEGF agents carry bleeding warnings that put squamous patients off-limits, a PD-1/VEGF bispecific that appears safe in this group would open a meaningful portion of the NSCLC population to a treatment class that previously excluded them.
Ivonescimab is already approved in China for this indication, based on the 2024 PFS readout. The global Phase III study, HARMONi-7, is enrolling PD-L1-high patients internationally and will be the dataset regulators outside China will require. Whether the OS benefit observed in a China-only cohort replicates across a broader, more diverse enrollment is the number worth watching when HARMONi-7 reports.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
