Ivonescimab Plus Chemotherapy Improves Overall Survival in Squamous NSCLC

Results from the prespecified overall survival (OS) interim analysis of the phase 3 HARMONi-6 trial (NCT05840016), found ivonescimab plus chemotherapy significantly improved OS vs tislelizumab (Tevimbra) plus chemotherapy in patients with previously untreated advanced squamous non–small cell lung cancer (NSCLC).¹

Results were presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting. Ivonescimab is the world’s first PD-1/VEGF dual-target bispecific antibody and has been approved in China in 2 lung cancer indications since 2024. In the previously reported interim progression-free survival (PFS) analysis of HARMONi-6, published in The Lancet, ivonescimab plus chemotherapy significantly improved PFS vs tislelizumab plus chemotherapy (median PFS, 11.1 vs 6.9 months; HR, 0.60; 95% CI, 0.46–0.78; P <0.0001).²

At a data cutoff of February 27, 2026, and a median follow-up of 21.36 months, the prespecified interim OS analysis was triggered at 204 events (significance boundary, 0.0049). Ivonescimab plus chemotherapy demonstrated a statistically significant improvement in OS vs tislelizumab plus chemotherapy (median OS, 27.89 months [95% CI, 27.89–not estimable (NE)] vs 23.69 months [95% CI, 20.11–NE]; stratified HR, 0.66; 95% CI, 0.50–0.87; P = .0017), crossing the prespecified OS significance boundary. The 12-month OS rate was 78.9% in the ivonescimab arm vs 72.2% in the tislelizumab arm, and the 24-month OS rate was 64.7% vs 48.6%, respectively.¹

The OS benefit was consistent across key prespecified subgroups. Among patients with PD-L1 TPS less than 1%, the HR for OS was 0.64, and among those with PD-L1 TPS of 1% or greater, the HR was 0.68. Across narrower PD-L1 strata, the HRs were 0.67 for TPS 1% to 49% and 0.64 for TPS 50% or greater. Favorable OS trends were observed across subgroups defined by sex, ECOG performance status, disease stage, presence of liver or brain metastases, and number of metastatic sites, supporting the robustness of the primary OS finding.¹

HARMONi-6 is a multicenter, randomized, double-blind, parallel-controlled phase 3 study. Eligible patients had pathologically confirmed squamous NSCLC, stage IIIB to IV disease, no prior systemic therapy, no EGFR mutations or ALK rearrangements, and an ECOG performance status of 0 or 1. A total of 532 patients were randomly assigned 1:1 to receive ivonescimab (20 mg/kg every 3 weeks [Q3W]) plus carboplatin (AUC 5, Q3W) and paclitaxel (175 mg/m² Q3W) for up to 4 cycles followed by ivonescimab maintenance for up to 24 months, or tislelizumab (200 mg Q3W) plus the same chemotherapy backbone for up to 4 cycles followed by tislelizumab maintenance. Randomization was stratified by disease stage (IIIB/IIIC vs IV) and PD-L1 tumor proportion score (TPS; ≥1% vs <1%). The primary end point was progression-free survival (PFS) by independent radiology review committee per RECIST v1.1, with OS as a key secondary endpoint.

The safety profile of ivonescimab plus chemotherapy was manageable and consistent with prior studies. Treatment-related adverse events (TRAEs) occurred in 99.2% of patients in both arms. Grade 3 or higher TRAEs were reported in 69.2% of patients in the ivonescimab arm compared with 58.9% in the tislelizumab arm. Serious TRAEs occurred in 41.4% and 34.3% of patients, respectively. TRAEs leading to discontinuation of ivonescimab or tislelizumab occurred in 5.3% vs 4.5% of patients, and TRAEs leading to death were reported in 3.8% vs 4.2%. Grade 3 or higher immune-related adverse events were observed at an equal rate of 14% in both arms. Possibly VEGF-related adverse events occurred more frequently in the ivonescimab arm, most of which were grade 1 or 2, including proteinuria (42.5% vs 12.8%), hemorrhage (24.8% vs 12.1%), and hypertension (14.7% vs 5.7%). Rates of adverse events leading to treatment discontinuation or death were similar between arms.

Investigators concluded that ivonescimab plus chemotherapy significantly improved OS vs tislelizumab plus chemotherapy and supports adoption as a new standard of care for patients with previously untreated advanced squamous NSCLC in China. A global phase 3 study, HARMONi-3 (NCT05899608), is currently underway to evaluate ivonescimab in an international patient population.

References

1. Lu S, Chen Z, Luo Y, et al. Ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy in previously untreated advanced squamous non–small cell lung cancer: overall survival results of the phase 3 HARMONi-6. Presented at: 2026 American Society of Clinical Oncology Annual Meeting; Chicago, IL. Abstract LBA4.

2. Chen Z, Yang F, Jiang Z, et al. Ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy as first-line treatment for advanced squamous non-small-cell lung cancer (HARMONi-6): a randomised, double-blind, phase 3 trial. Lancet. 2025;406(10515):2078-2088. doi:10.1016/S0140-6736(25)01848-3