New findings from the phase III HARMONi-6 trial presented at the 2026 ASCO Annual Meeting showed that the investigational bispecific antibody ivonescimab combined with chemotherapy significantly improved overall survival compared with tislelizumab plus chemotherapy in patients with advanced squamous non–small cell lung cancer (NSCLC), including those with low or absent PD-L1 expression (Abstract LBA4).
Background and Study Details
Ivonescimab is a bispecific antibody designed to target both PD-1 and vascular endothelial growth factor (VEGF), combining immune checkpoint blockade with antiangiogenic activity in a single molecule. Unlike conventional VEGF inhibitors, which have historically been associated with bleeding risks in squamous NSCLC, previous analyses of HARMONi-6 suggested that ivonescimab did not substantially increase serious bleeding complications.
The multicenter study enrolled 532 patients in China with stage IIIB, IIIC, or IV squamous NSCLC who had not received prior systemic therapy. Participants were randomly assigned to receive either ivonescimab plus paclitaxel and carboplatin (n = 266) or tislelizumab plus the same chemotherapy regimen (n = 266).
Key Takeaways
After a median follow-up of 21.4 months, patients treated with ivonescimab plus chemotherapy achieved a median overall survival of 27.9 months (95% confidence interval [CI] = 27.89 months to not estimable), compared with 23.7 months (95% CI = 20.11 months to not estimable) for those treated with tislelizumab plus chemotherapy (hazard ratio = 0.66, 95% CI = 0.50–0.87, one-sided P = .0017). Treatment with ivonescimab reduced the risk of death by 34% during the study period. These overall survival findings build on earlier progression-free survival results from the trial, which demonstrated a median progression-free survival of approximately 11 months with ivonescimab vs 9 months with tislelizumab.
A notable finding was the consistency of benefit across PD-L1 expression subgroups. In the control arm, outcomes were strongly influenced by PD-L1 status: median overall survival was approximately 27 months among patients with PD-L1 expression of at least 1%, compared with about 19 months among those with PD-L1 expression below 1%. In contrast, in both the high– and low–PD-L1 groups receiving ivonescimab, median overall survival could not be measured because many patients remained alive at the time of analysis.
“Squamous [NSCLC] is associated with worse clinical outcomes than nonsquamous [NSCLC]. This is one of very few studies in advanced squamous [NSCLC] that has shown median survival beyond 2 years,” said lead author Shun Lu, MD, PhD, of Shanghai Chest Hospital, Jiao Tong University School of Medicine.
The safety profile was generally comparable between treatment groups. Grade 3 or higher adverse events included neutropenia (32% with ivonescimab vs 26% with tislelizumab), decreased white blood cell counts (11% vs 9%), and anemia (7% vs 5%). Bleeding events occurred in approximately 3% of patients receiving ivonescimab and 1% of those receiving tislelizumab.
According to the investigators, the results suggest that dual inhibition of PD-1 and VEGF through a bispecific antibody may offer a new first-line treatment option for advanced squamous NSCLC, a disease with limited therapeutic advances and historically poorer outcomes than nonsquamous NSCLC. Additional evaluation of ivonescimab in broader global populations is ongoing in the phase III HARMONi-3 study.
DISCLOSURE: For full disclosures of the study authors, visit coi.asco.org.
