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 trial.

Abstract

LBA4 Background: In the prespecified interim analysis of progression-free survival (PFS) from the HARMONi-6 study, ivonescimab combined with chemotherapy significantly improved PFS compared with tislelizumab plus chemotherapy in patients with previously untreated advanced squamous NSCLC(sq-NSCLC). Here we report the results of the prespecified overall survival (OS) analysis. Methods: Patients with previously untreated stage III-IV sq-NSCLC were randomly assigned (1:1) to receive ivonescimab 20 mg/kg every 3 weeks (Q3W) or tislelizumab 200 mg Q3W, each in combination with paclitaxel (175 mg/m²) and carboplatin (AUC 5) for 4 cycles, followed by maintenance ivonescimab or tislelizumab monotherapy. Randomization was stratified by disease stage (IIIB/IIIC versus IV) and PD-L1 tumor proportion score (TPS; ≥1% versus <1%). The primary endpoint was PFS assessed by independent radiographic review committee per RECIST v1.1. OS was a key secondary endpoint and was hierarchically tested using a closed sequential testing procedure. PFS was tested first at one-sided α level of 0.025, OS was tested at the same α only after statistical significance for PFS was established. This analysis represents the first planned OS analysis with an efficacy boundary of one-sided P=0.0049. Results: A total of 532 patients were randomly assigned (n=266 per arm). As of February 27, 2026, at a median follow-up of 21.4 months, ivonescimab plus chemotherapy significantly improved OS compared with tislelizumab plus chemotherapy. Median OS was 27.9 months (95% CI, 27.89 to NE) with ivonescimab plus chemotherapy versus 23.7 months (95% CI, 20.11 to NE) with tislelizumab plus chemotherapy (hazard ratio [HR], 0.66; 95% CI, 0.50 to 0.87; one-sided P =0.0017), meeting the prespecified boundary (P<0.0049) for statistical significance.The OS benefit was consistent across prespecified subgroups. Among patients with PD-L1 TPS <1%, median OS was NE versus 18.6 months (HR, 0.64; 95% CI, 0.43 to 0.96). Among patients with PD-L1 TPS≥1%, median OS was NE versus 27.3 months (HR, 0.68; 95% CI, 0.46 to 0.99). The safety profile of ivonescimab plus chemotherapy was manageable and consistent with prior reports, with no new safety signals observed. Conclusion: Ivonescimab plus chemotherapy demonstrated a statistically significant and clinically meaningful improvement in OS compared with tislelizumab plus chemotherapy in previously untreated patients with advanced sq-NSCLC. Notably, ivonescimab plus chemotherapy is the first regimen to show clinical superiority over an active PD-1 inhibitor control arm in the first-line setting. The dual-targeted approach of ivonescimab delivers improved survival outcomes with a favorable risk-benefit profile, establishing a compelling new standard of care in the management of advanced sq-NSCLC. Clinical trial information: NCT05840016 .