Ivonescimab Combo Shows Superior Overall Survival in Advanced Squamous NSCLC

Ivonescimab plus chemotherapy has significantly improved overall survival (OS) compared with tislelizumab plus chemotherapy in patients with previously untreated advanced squamous non-small cell lung cancer (NSCLC), according to results from the phase 3 HARMONi-6 trial presented at the 2026 ASCO Annual Meeting.^1,2,3

At a prespecified interim OS analysis with a data cutoff of February 27, 2026, and a median follow-up of 21.36 months, ivonescimab plus chemotherapy produced a median OS (mOS) of 27.89 months compared with 23.69 months for tislelizumab plus chemotherapy (HR, 0.66; 95% CI, 0.50-0.87; P = .0017), crossing the prespecified significance boundary of 0.0049.¹ The investigators noted that the median OS in the ivonescimab group would not have been reached without the last single event.¹

At 12 months, 78.9% of patients in the ivonescimab arm were alive compared with 72.2% of those in the tislelizumab arm. At 24 months, OS rates were 64.7% and 48.6%, respectively, underscoring the durability of benefit with the bispecific approach.

These OS results follow previously reported progression-free survival (PFS) data, in which ivonescimab plus chemotherapy significantly improved PFS versus tislelizumab plus chemotherapy (median PFS, 11.1 vs 6.9 months; HR, 0.60; 95% CI, 0.46-0.78; P < .0001), which met its prespecified significance boundary of 0.0094 and enabled formal OS testing per the hierarchical testing strategy.

"Squamous NSCLC is associated with worse clinical outcomes than non-squamous non-small cell lung cancer. This is one of very few studies in advanced squamous non-small cell lung cancer that has shown median survival beyond 2 years," said lead study author Shun Lu, MD, PhD, Shanghai Chest Hospital, Jiao Tong University School of Medicine, Shanghai, China.³

Safety Profile in HARMONi-6 Trial

Overall, ivonescimab plus chemotherapy demonstrated a comparable safety profile to tislelizumab plus chemotherapy. Treatment-related adverse events (TRAEs) occurred in 99.2% of patients in both arms.¹ Grade ≥ 3 TRAEs were reported in 69.2% of patients receiving ivonescimab plus chemotherapy versus 58.9% of those receiving tislelizumab plus chemotherapy. Serious TRAEs occurred in 41.4% and 34.3% of patients, respectively.

Discontinuation of ivonescimab or tislelizumab due to TRAEs was low and similar across arms (5.3% vs 4.5%), as were TRAEs leading to death (3.8% vs 4.2%). Grade ≥ 3 immune-related adverse events (irAEs) were comparable between the two groups (14% in each arm).

As anticipated given ivonescimab's anti-VEGF activity, possibly VEGF-related adverse events occurred more frequently in the ivonescimab arm, though most were grade 1-2. Proteinuria was the most common, occurring in 42.5% of patients in the ivonescimab arm vs 12.8% in the tislelizumab arm; grade ≥ 3 proteinuria occurred in 6.8% vs 0%, respectively. Hemorrhage occurred in 24.8% vs 12.1% (grade ≥ 3: 2.6% vs 0.8%), and hypertension in 14.7% vs 5.7% (grade ≥ 3: 3.8% vs 1.9%). Arterial thromboembolism was rare, occurring in 1.5% of ivonescimab-treated patients (grade ≥ 3: 1.1%) compared with none in the tislelizumab arm.

HARMONi-6 Design and Patient Characteristics

HARMONi-6 (NCT05840016) is a multicenter, randomized, double-blind, parallel-controlled phase 3 trial enrolling patients with pathologically confirmed squamous NSCLC, stage IIIB-IV disease, no prior systemic therapy, no EGFR mutations or ALK rearrangements, and an Eastern Cooperative Oncology Group performance status of 0 or 1.¹ A total of 532 patients were randomized 1:1 to receive either ivonescimab (20 mg/kg every 3 weeks [Q3W]) or tislelizumab (200 mg Q3W), each combined with carboplatin (AUC 5 Q3W) and paclitaxel (175 mg/m² Q3W) for up to 4 cycles, followed by ivonescimab or tislelizumab monotherapy for up to 24 months.¹ Stratification factors included disease stage (IIIB/IIIC vs IV) and PD-L1 tumor proportion score (TPS; ≥ 1% vs < 1%).

The primary end point was PFS by independent radiology review committee per RECIST v1.1, with OS as the key secondary endpoint. Additional secondary endpoints included investigator-assessed PFS, overall response rate, disease control rate, duration of response, time to response, and safety.

Baseline characteristics were well balanced between arms. The median age was below 65 years in approximately half of patients in each group. The population was predominantly male (96.2% in the ivonescimab arm; 89.5% in the tislelizumab arm) and the majority had a history of smoking (92.1% vs 86.1%). Most patients had stage IV disease (92.1% vs 92.5%). PD-L1 TPS was ≥ 1% in 60.5% of patients in each arm. Tumor characteristics including central-type tumors, major blood vessel encasement, and hemoptysis history were similarly distributed. Liver metastases were present in 10.5% of the ivonescimab group and 16.9% of the tislelizumab group; brain metastases were present in 3.4% and 6.4%, respectively.

The investigators concluded that HARMONi-6 supports the adoption of ivonescimab plus chemotherapy as a new standard of care for patients with advanced squamous NSCLC in the first-line setting in China, and noted that the global phase 3 HARMONi-3 study (NCT05899608) is currently underway.

ASCO Expert Perspective

"This is the first large prospective trial to prove that an anti-PD-1/VEGF bispecific therapy plus chemotherapy is superior to the established standard of PD-1 inhibitor plus chemotherapy in patients with advanced squamous lung cancer. While this study included participants from China and efficacy data from global populations are pending, it provides a vital new path forward for patients with these difficult-to-treat cancers who have limited treatment options," said David R. Spigel, MD, FASCO, President and Chief Medical Officer at Sarah Cannon Research Institute and an ASCO Expert in lung cancer.³

REFERENCES

1. Zhiwei C, Yang F, 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 trial. J Clin Oncol. 2026;44(suppl 17):LBA4. doi:10.1200/JCO.2026.44.17_suppl.LBA4

2. Lu S, Liu B, Luo Y, et al. Ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy in advanced squamous non-small cell lung cancer (HARMONi-6): interim overall survival analysis of a randomised, double-blind, phase 3 trial in China. The Lancet. 2026. doi:10.1016/S0140-6736(26)00966-9

3. American Society of Clinical Oncology. Ivonescimab may improve overall survival in patients with advanced squamous non-small cell lung cancer. ASCO website. Published May 31, 2026. Accessed June 1, 2026. https://tinyurl.com/3fntxhzx