SUMMARY: The American Cancer Society estimates that for 2026, about 229,410 new cases of lung cancer will be diagnosed and 124,990 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States.
Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 25% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large cell carcinomas. Non-Small Cell Lung Cancer patients with Squamous Cell histology have been a traditionally hard- to-treat, patient group, with less than 5% of patients with advanced SCC, surviving for five years or longer.
Background
The advent of Immune Checkpoint Inhibitors (ICIs) has fundamentally transformed the treatment landscape of advanced NSCLC. By targeting immune regulatory pathways such as programmed cell death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), these therapies restore T-cell activity and enhance antitumor immune responses. Biomarkers including PD-L1 expression, Tumor Mutational Burden (TMB), and mismatch repair (MMR) status have become important tools for predicting response; however, many patients, particularly those with low PD-L1 expression, continue to experience suboptimal outcomes.
While PD-1 inhibitors have established immunotherapy as a cornerstone of first-line treatment in advanced NSCLC, therapeutic progress has been slower in patients with squamous histology. Squamous NSCLC accounts for approximately 25% of all NSCLC cases and is associated with poorer clinical outcomes and fewer effective treatment options than nonsquamous disease. In addition, the use of conventional VEGF inhibitors has historically been limited in this population because of concerns regarding severe pulmonary hemorrhage.
Rationale for Dual PD-1 and VEGF Inhibition
Ivonescimab (AK112) is a novel bispecific antibody designed to simultaneously target PD-1 and vascular endothelial growth factor (VEGF). This dual-targeting strategy combines immune checkpoint inhibition with antiangiogenic therapy within a single molecule, with the goal of enhancing antitumor activity while minimizing off-target effects.
Preclinical and early clinical evidence suggests that simultaneous inhibition of PD-1 and VEGF may produce synergistic antitumor effects by improving immune cell infiltration, suppressing tumor angiogenesis, and enhancing T-cell activation. Importantly, previous studies demonstrated encouraging efficacy even among patients with low PD-L1 expression, without the excess bleeding complications traditionally associated with VEGF inhibitors in squamous NSCLC.
TEVIMBRA® (Tislelizumab) is a humanized immunoglobulin G4 (IgG4) anti-Programmed cell Death protein- 1 (PD-1) monoclonal antibody with high affinity and binding specificity against PD-1. It is uniquely designed to minimize binding to Fc-gamma receptors on macrophages, helping to aid the body’s immune cells to detect and fight tumors, while minimizing off-target effects.
The HARMONi-6 Study Design
HARMONi-6 is a multicenter, randomized, double-blind, Phase III trial conducted across 50 hospitals in China. The study enrolled 532 patients aged 18–75 years with previously untreated, unresectable Stage IIIB, IIIC, or Stage IV squamous NSCLC and an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. The median age was 64 yrs and 93% of patients were male.
Patients were randomized equally to receive:
- Ivonescimab plus Paclitaxel and Carboplatin for four induction cycles followed by maintenance Ivonescimab, or
- Tislelizumab plus Paclitaxel and Carboplatin followed by maintenance Tislelizumab.
The Primary endpoint was Progression-Free Survival (PFS), while Overall Survival (OS) served as a key Secondary endpoint.
Improved Disease Control
Earlier analyses from HARMONi-6 demonstrated that Ivonescimab significantly delayed disease progression compared with Tislelizumab. Median PFS improved to approximately 11 months versus 9 months, supporting the potential advantage of combining PD-1 and VEGF inhibition over PD-1 blockade alone.
Overall Survival Benefit
The prespecified interim Overall Survival analysis further strengthened the clinical significance of these findings.
After a median follow-up of 21.4 months, patients receiving Ivonescimab plus chemotherapy achieved a median OS of 27.9 months, compared with 23.7 months for those receiving Tislelizumab plus chemotherapy. This translated into a 34% reduction in the risk of death (Hazard Ratio 0.66; 95% CI 0.50–0.87; P=0.0017).
At the time of data cutoff, 84 deaths had occurred in the Ivonescimab arm compared with 120 deaths in the control arm, demonstrating a durable survival advantage for the investigational regimen.
Consistent Benefit Regardless of PD-L1 Expression
One of the most compelling observations from HARMONi-6 was the consistency of benefit across PD-L1 expression subgroups.
Among patients treated with standard immunochemotherapy, survival remained strongly influenced by PD-L1 status. Individuals with PD-L1 expression ≥1% experienced substantially longer survival than those with PD-L1-negative tumors.
In contrast, patients treated with Ivonescimab demonstrated prolonged survival irrespective of PD-L1 expression. Median OS had not yet been reached in either the PD-L1-high or PD-L1-low subgroups at the time of analysis, suggesting that dual PD-1/VEGF inhibition may overcome one of the major limitations of conventional checkpoint inhibitor therapy.
Safety Profile
The safety profile of Ivonescimab was generally consistent with expectations for combination immunochemotherapy.
Grade 3 or higher treatment-related adverse events occurred in 69% of patients receiving Ivonescimab compared with 59% in the Tislelizumab group. The most common severe adverse events included:
- Neutropenia
- Decreased white blood cell count
- Anemia
Given the historical concern regarding VEGF inhibition in squamous NSCLC, bleeding events were carefully monitored. Grade 3 or higher hemorrhage occurred in 3% of patients receiving Ivonescimab versus 1% of those treated with Tislelizumab, indicating that serious bleeding remained relatively uncommon despite the incorporation of VEGF blockade.
Clinical Significance
Historically, advanced squamous NSCLC has been associated with limited therapeutic advances and inferior outcomes compared with nonsquamous disease. HARMONi-6 is among the few Phase III studies in this setting to demonstrate a median OS approaching 28 months, representing an important milestone for this patient population.
The findings suggest that simultaneous inhibition of PD-1 and VEGF using a bispecific antibody can provide clinically meaningful improvements in both disease control and OS while maintaining a manageable safety profile.
Looking Ahead
Although these results are highly encouraging, confirmation in more geographically diverse populations will be essential. Ongoing global studies, including the Phase III HARMONi-3 trial, will further evaluate the efficacy and safety of Ivonescimab across broader patient populations.
Key Clinical Takeaways
- Ivonescimab is a first-in-class bispecific antibody targeting both PD-1 and VEGF.
- HARMONi-6 demonstrated significant improvements in both Progression-Free and Overall Survival compared with Tislelizumab plus chemotherapy.
- Median Overall Survival improved from 23.7 months to 27.9 months, reducing the risk of death by 34%.
- Clinical benefit was observed regardless of PD-L1 expression, potentially expanding treatment options for patients with PD-L1-low disease.
- Serious hemorrhagic events remained uncommon despite VEGF inhibition.
- Dual PD-1/VEGF blockade represents a promising first-line therapeutic strategy for patients with advanced squamous NSCLC and may redefine future standards of care pending global validation.
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. Zhiwei C, Yang F, Luo Y, et al. J Clin Oncol 44, 2026 (suppl 17; abstr LBA4)
