rst-line treatment with ivonescimab significantly improves overall survival (OS) in patients with PD-L1-positive (PD-L1+) locally advanced or metastatic nonsmall cell lung cancer (NSCLC) compared with pembrolizumab, according to a prespecified interim analysis of the phase III HARMONi-2 trial presented at WCLC 2026.
The HARMONi-2 trial enrolled 398 treatment-naïve patients with locally advanced or metastatic NSCLC whose tumours expressed PD-L1 (TPS* ≥1 percent), recruited from 55 centres in China between November 2022 and August 2023. Participants were randomized in a 1:1 ratio to receive either ivonescimab 20 mg/kg Q3W (n=198) or pembrolizumab 200 mg Q3W (n=200).
At a median follow-up of 36 months, patients treated with ivonescimab achieved a significantly prolonged median OS than those treated with pembrolizumab (30.8 vs 22.6 months; hazard ratio [HR], 0.73; p=0.009), translating to a 27-percent reduction in the risk of death. [WCLC 2026, abstract OA14.01]
Furthermore, 24- and 36-month OS rates were higher in the ivonescimab group than in the pembrolizumab group (57.9 percent vs 48 percent and 45 percent vs 33.1 percent, respectively).
The OS benefit of ivonescimab over pembrolizumab was consistent across prespecified subgroups, particularly by PD-L1 expression level, tumour histology, or age.
OS by PD-L1 expression level
Among patients with high-PD-L1 expression (TPS ≥50 percent), the median OS was not reached in the ivonescimab group vs 23.2 months in the pembrolizumab group (HR, 0.58).
Likewise, in patients with low-PD-L1 expression (TPS 1–49 percent), ivonescimab was associated with a longer median OS than pembrolizumab (28.5 vs 22.1 months; HR, 0.85).
At 36 months, both the high- and low-PD-L1 subgroups had higher OS rates with ivonescimab than with pembrolizumab (53.4 percent vs 31.3 percent and 38.6 percent vs 34.1 percent, respectively).
OS by tumour histology
Patients receiving ivonescimab demonstrated longer median OS than those receiving pembrolizumab, regardless of whether they had squamous (30.5 vs 19.3 months; HR, 0.65) or nonsquamous (33.6 vs 25.6 months; HR, 0.79) histology.
Higher 36-month OS rates were also observed in the ivonescimab group than in the pembrolizumab group (41 percent vs 26.9 percent in the squamous subgroup and 48.2 percent vs 38.3 percent in the nonsquamous subgroup).
OS by age subgroup
A longer median OS was observed with ivonescimab compared with pembrolizumab irrespective of age, both in the younger cohort aged <65 years (32.8 vs 25 months; HR, 0.74) and the older cohort aged ≥65 years (30.2 vs 22.1 months; HR, 0.72).
Correspondingly, 3-year OS rates favoured ivonescimab over pembrolizumab in both cohorts (46.5 percent vs 33.7 percent [younger] and 43.7 percent vs 32.5 percent [older]).
Standard of care
In the previous study of HARMONi-2, a significantly longer median progression-free survival, the primary endpoint, was observed with ivonescimab compared with pembrolizumab (11.1 vs 5.8 months; HR, 0.51; p<0.0001) in this patient population.
Subsequently, the current study demonstrated that “ivonescimab significantly improved clinical outcomes, [particularly OS], in PD-L1+ advanced NSCLC,” according to lead author Dr Caicun Zhou from Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
With longer follow-up, ivonescimab continued to show a favourable and manageable safety profile, with no new safety signals, he added.
Overall, the HARMONi-2 findings support ivonescimab as a chemotherapy-free first-line treatment with the potential to redefine the standard of care and serve as a cornerstone of treatment in this patient population, the researchers noted.
Additionally, a global phase III trial (HARMONi-7) comparing ivonescimab with pembrolizumab in PD-L1-high metastatic NSCLC is underway, with the aim of providing a potential chemotherapy-free regimen to patients worldwide.