HARMONi-6 Shows OS Benefit With Ivonescimab/Chemo Over Tislelizumab/Chemo in First-Line Squamous NSCLC

Ivonescimab plus chemotherapy resulted in a significant improvement in overall survival (OS) compared with tislelizumab-jsgr (Tevimbra) plus chemotherapy when used in the first-line treatment of patients with previously untreated advanced squamous non–small cell lung cancer (NSCLC), according to data from the prespecified interim OS analysis of the phase 3 HARMONi-6 trial (NCT05840016).¹

The results, which were presented in a plenary session at the 2026 ASCO Annual Meeting, and published in The Lancet,² showed that at a median follow-up of 21.36 months, the median OS was 27.89 months (95% CI, 27.89-not evaluable [NE]) in the ivonescimab arm (n = 266) vs 23.69 months (95% CI, 20.11-NE) in the tislelizumab arm (n = 266), translating to a 34% reduction in the risk of death (HR, 0.66; 95% CI, 0.50-0.87; P = .0017); this crossed the prespecified efficacy boundary of one-sided P < .0049. The 12-month OS rates in the respective arms were 78.9% and 72.2%; the 24-month OS rates were 64.7% and 48.6%.

“HARMONi-6 is the first [study] in squamous NSCLC to achieve dual OS and PFS success through a prespecified hypothesis test,” Shun Lu, MD, PhD, said in the presentation. “…HARMONi-6 supports adoption of ivonescimab with chemotherapy as a new standard for patients with advanced squamous NSCLC in first-line treatment in China.”

Lu is the director of the Lung Cancer Center at Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, in Shanghai, China, and served as principal investigator of the trial.

What was the design of the HARMONi-6 trial examining ivonescimab?

The multicenter, randomized, double-blind, placebo-controlled, phase 3 trial was conducted at 50 sites across China. To be eligible, patients were required to be 18 to 75 years of age with previously untreated, pathologically confirmed, unresectable stage IIIB to IV squamous NSCLC; have an ECOG performance status no higher than 1; and have no EGFR mutations or ALK rearrangements.

A total of 532 patients were randomly assigned 1:1 to receive ivonescimab at 20 mg/kg or tislelizumab 200 mg, each given with paclitaxel 175 mg/m² and carboplatin at area under the curve 5 once every 3 weeks for 4 cycles, followed by ivonescimab or tislelizumab monotherapy maintenance for up to 24 months. Randomization was stratified by disease stage (IIIB/IIIC vs IV) and PD-L1 tumor proportion score (≥ 1% vs < 1%). The primary end point was PFS by an independent review committee and RECIST v1.1; OS was the key secondary end point, tested hierarchically after PFS using a one-sided alpha. Additional secondary end points comprised investigator-assessed PFS, objective response rate, disease control rate, duration of response, time to response, and safety.

Of the 532 patients who underwent randomization, 266 were assigned to each arm; 266 patients in the ivonescimab arm and 265 patients in the tislelizumab arm received treatment. In the ivonescimab arm, 60 patients were still receiving treatment at the data cutoff date of February 27, 2026; 24 patients had completed treatment, and 182 discontinued. The most common reason for discontinuation was radiographic progression (n = 112). In the tislelizumab arm, 51 patients were still receiving treatment at the time of data cutoff, 28 had completed treatment, and 186 had discontinued. Again, the most common reason for discontinuation was radiographic progression (n = 186).

Baseline characteristics were balanced between the ivonescimab and tislelizumab arms, according to Lu. About half of the patients were under 65 years of age (50.8% vs 52.3%). Most were male (96.2% vs 89.5%), had an ECOG performance status of 1 (84.2%; 83.5%), and were current or former smokers (92.1% vs 86.1%). Moreover, more than 90% of patients had stage IV disease (92.1%; 92.5%). In terms of tumor characteristics, in the ivonescimab arm, 66.9% had central tumors, 18.4% had major blood vessel encasement, and 32.3% had a history of hemoptysis; in the tislelizumab arm, these respective rates were 59.4%, 16.5%, and 29.7%.

What data have previously been reported with ivonescimab from HARMONi-6?

The PFS benefit underpinning the trial was previously reported at the 2025 ESMO Congress, where ivonescimab plus chemotherapy led to a median PFS of 11.14 months (95% CI, 9.86-NE) vs 6.90 months (95% CI, 5.82-8.57) with tislelizumab plus chemotherapy (HR, 0.60; 95% CI, 0.46-0.78; P < .0001).³ The topline PFS finding was announced even earlier, in April 2025, by the drug developer.⁴ At the time of the report, Lu stated in a news release: “It is a great honor for us to witness ivonescimab once again successfully challenge the optimal standard of care. This breakthrough not only advances the treatment of NSCLC but also marks a significant milestone in global oncology immunotherapy.”

At the current interim analysis, the OS improvement translated that PFS advantage into a survival benefit, with a hazard ratio of 0.66.¹ The OS benefit was consistent across key subgroups, including those defined by sex, age, ECOG performance status, disease stage, PD-L1 expression, and brain metastases. By PD-L1 status, the OS hazard ratio (HR) was 0.64 (95% CI, 0.43-0.96) in those with a PD-L1 tumor proportion score (TPS) less than 1% and 0.68 (95% CI, 0.46-0.99) in those with a PD-L1 TPS of 1% or higher; within the PD-L1–positive group, the HR was 0.76 (95% CI, 0.42-1.05) in patients with a PD-L1 TPS ranging from 1% to 49% and 0.64 (95% CI, 0.32-1.31) in those with a TPS of 50% or higher.

Subsequent antitumor therapy was similar between arms, according to Lu. Specifically, 35.7% of those in the ivonescimab arm received systemic therapy vs 36.5% of those in the tislelizumab arm, and this was in the form of chemotherapy for 24.1% and 22.6% of patients, respectively. Additionally, 13.9% of those who received ivonescimab vs 19.2% of those given tislelizumab received immunotherapy, 12.4% vs 17.3% had targeted therapy, 4.5% vs 5.3% received traditional Chinese medicine, 4.5% vs 5.6% received an antibody-drug conjugate, 0.8% vs 2.3% received blinded investigational agents, and 1.1% vs 0.8% received other therapy. Moreover, 1.1% vs 0.4% of patients in the respective arms received surgery, and 9.4% vs 9.8% received radiotherapy.

What was the safety profile of ivonescimab paired with chemotherapy in this NSCLC population?

Ivonescimab plus chemotherapy showed a safety profile consistent with prior reports, according to Lu. Treatment-related adverse effects (TRAEs) occurred in 99.2% of patients in both arms; 69.2% of patients in the ivonescimab arm experienced grade 3 or higher TRAEs vs 58.9% of patients in the tislelizumab arm. Serious TRAEs occurred in 41.4% of those given ivonescimab vs 34.3% of those who received tislelizumab. TRAEs leading to discontinuation of ivonescimab or tislelizumab occurred in approximately 5% of patients in both arms (5.3% vs 4.5%). The number of TRAEs that proved fatal was similar between arms (n = 10 vs n = 11).

The most common TRAEs occurring in at least 15% of patients were predominantly hematologic, including anemia (any grade, 57.1% with ivonescimab vs 60.8% with tislelizumab) and neutropenia (47.0% vs 44.5%), and were consistent with the chemotherapy backbone. Possible VEGF-related adverse effects appeared more frequently with ivonescimab but were mostly grade 1 or 2, according to Lu. The most common any-grade, possibly VEGF-related AEs in the ivonescimab and tislelizumab arms were proteinuria (42.5% vs 12.8%), hemorrhage (24.8% vs 12.1%), hypertension (14.7% vs 5.7%), arterial thromboembolism (1.5% vs 0%), venous thromboembolism (0.8% vs 1.1%), and fistula (0.4% vs 0%).

What are the next steps for ivonescimab?

The global phase 3 HARMONi-3 study (NCT05899608) is ongoing and is examining ivonescimab-based therapy in a broader, international NSCLC population.⁵ Specifically, the trial will examine ivonescimab combined with chemotherapy vs pembrolizumab (Keytruda) combined with chemotherapy in those with first-line stage IV squamous or nonsquamous NSCLC.⁶ The trial is currently recruiting.

Disclosures: Lu disclosed serving in a leadership position for Innovent Biologics, Shanghai Fosun, and Simcere Zaiming. He serves in a consulting or advisory role for AstraZeneca, Boehringer Ingelheim, GenomiCare, Hutchison MediPharma, InventisBio, Menarini, Pfizer, Roche, Rimcere, Yuhan, and Zai Lab. He is on the Speakers’ Bureau for AstraZeneca, Hansoh Pharma, Hengrui Therapeutics, and Roche. Research funding was provided by AstraZeneca, BeiGene, Bristol-Myers Squibb, Hansoh, Hengrui Therapeutics, Hutchison MedPharma, Lilly Suzhou Pharmaceutical, and Roche.

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. Lancet. Published online May 31, 2026. doi:10.1016/S0140-6736(26)00966-9
3. Lu S, Yang F, Jiang Z, et al. Phase III study of ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy as first-line treatment for advanced squamous non-small cell lung cancer (HARMONi-6). Ann Oncol. 2025;36(suppl 2):S1613. doi:10.1016/j.annonc.2025.09.084
4. Ivonescimab in combination with chemotherapy demonstrates statistically significant and strongly positive results in first-line treatment of squamous non-small cell lung cancer (sq-NSCLC) vs. tislelizumab in combination with chemotherapy. News Release. Akeso. April 23, 2025. Accessed May 31, 2026. https://www.akesobio.com/en/media/akeso-news/250423/
5. Clinical study of ivonescimab for first-line treatment of metastatic NSCLC patients. ClinicalTrials.gov. Updated April 30, 2026. Accessed May 31, 2026. https://clinicaltrials.gov/study/NCT05899608
6. HARMONi-3 phase 3 clinical trial. Summit Therapeutics website. Accessed May 31, 2026. https://smmttx.com/clinical-trials/harmoni-3-clinical-trial/default.aspx