HARMONi-2 Interim Analysis: Ivonescimab Shows PFS Improvements Over Pembrolizumab in NSCLC

Ivonescimab showed significant improvements in progression-free survival (PFS) compared with pembrolizumab in patients with previously untreated, advanced programmed cell death ligand 1 (PD-L1)–positive non–small cell lung cancer (NSCLC), according to results from the HARMONi-2 trial.

A team led by Anwen Xiong, PhD, and Lei Wang, PhD, conducted the randomized, double-blind phase 3 trial and reported results from the preplanned interim analysis in The Lancet, with a final analysis to be reported later.

The study, which was conducted across 55 hospitals in China, included adults who had locally advanced or metastatic PD-L1–positive NSCLC without sensitizing EGFR mutations or ALK translocations and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

The study investigators screened 879 patients and randomized 398 patients (45%) 1:1 to receive ivonescimab 20 mg/kg (n=198) or pembrolizumab 200 mg (n=200) IV every 3 weeks. They stratified the randomization by histology, clinical stage, and PD-L1 expression. The primary end point of the HARMONi-2 trial was PFS, as assessed by a masked independent radiographic review committee per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in the intention-to-treat population.

The analysis shows that the median PFS was 11.1 months in patients receiving ivonescimab, significantly longer than the median PFS of 5.8 months in those receiving pembrolizumab (stratified hazard ratio [HR], 0.51; 95% CI, 0.38-0.69; one-sided P<0.0001). The study showed that “the PFS benefit of ivonescimab over pembrolizumab was broadly consistent within prespecified subgroups,” according to the investigators. This included patients with a PD-L1 tumor proportion score (TPS) of 1% to 49% (HR, 0.54; 95% CI, 0.37-0.78) and a PD-L1 TPS of 50% or higher (HR, 0.48; 95% CI, 0.29-0.79).

The study authors also reported that grade 3 or higher treatment-related adverse events occurred in 29% of patients receiving ivonescimab, compared with 16% of patients receiving pembrolizumab. When specifically evaluating immune-related adverse events of grade 3 or higher, the authors reported a rate of 7% in patients receiving ivonescimab, compared with 8% in those receiving pembrolizumab.

The researchers reported that ivonescimab “demonstrated a manageable safety profile” in patients with both squamous and nonsquamous NSCLC, and among patients with squamous cell carcinoma, grade 3 or higher treatment-related adverse events “were comparable between the two groups.”

Based on the safety and efficacy findings in the interim analysis of the HARMONi-2 study, the investigators concluded that ivonescimab “might represent another treatment option in the first-line setting” for patients with advanced PD-L1–positive NSCLC.

Reference

Xiong A, Wang L, Chen J, et al. Ivonescimab versus pembrolizumab for PD-L1-positive non-small cell lung cancer (HARMONi-2): a randomised, double-blind, phase 3 study in China. The Lancet. 2025;405(10481):839-849. doi:https://doi.org/10.1016/s0140-6736(24)02722-3