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First-line treatment with ivonescimab plus chemotherapy increased overall survival and improved progression-free survival, compared to a regimen of tislelizumab plus chemotherapy, in 532 people with untreated advanced squamous non-small cell lung cancer (NSCLC).

The multicenter, randomized, placebo-controlled phase 3 trial, conducted in China, also showed the survival benefit was consistent regardless of whether people were positive or negative for PD-L1 protein expression.

“A PD-1 plus chemotherapy is the standard of care, but we still need to further improve the survival,” said lead author Shun Lu, MD, PhD, during a press briefing at the American Society of Clinical Oncology (ASCO) 2026. “Ivonescimab with chemotherapy significantly improved overall survival for advanced squamous NSCLC first-line treatment compared with tislelizumab plus chemotherapy.”

Lu, a researcher at Shanghai Chest Hospital at Shanghai Jiao Tong University School of Medicine in Shanghai, China, presented the results of the HARMONi-6 trial during the plenary session at the meeting.

Challenging Standard of Care

Ivonescimab is approved for use in China and is in development in the US. Ivonescimab does double duty as an anti-PD-1/VEGF bispecific antibody that combines two distinct mechanisms in a single agent. One component targets PD-1 to enhance immune-mediated tumor destruction, whereas the other inhibits VEGF to disrupt the tumor’s blood supply. Tislelizumab is a checkpoint inhibitor.

Standard care for squamous NSCLC typically involves combining chemotherapy with a checkpoint inhibitor like tislelizumab. A known limitation of this approach is that checkpoint inhibitors tend to be less effective in tumors with low surface expression of the PD-L1 protein, Lu said.

An interim analysis of HARMONi-6 previously published in The Lancet showed progression-free survival favored ivonescimab plus chemotherapy over tislelizumab plus chemotherapy, approximately 11 vs 9 months. But any effect on overall survival remained unknown until this presentation at ASCO 2026. 

Considering Cancer State and PD-L1 Status

All participants had pathologically confirmed stage IIIb-IV squamous NSCLC and no prior systemic therapy. More than 92% of each group had stage IV disease.

Researchers randomly assigned 266 participants to ivonescimab 20 mg/kg every 3 weeks (Q3W) and another 266 people to tislelizumab 200 mg Q3W, each in combination with 175 mg/m² paclitaxel and carboplatin (area under the curve, 5) for four cycles. This was followed by maintenance ivonescimab or tislelizumab monotherapy for up to 24 months.

Randomization was stratified by disease stage — IIIB/IIIC vs IV — and PD-L1 tumor proportion score < 1% or ≥ 1%.

Key Findings

An interim analysis revealed that overall survival favored the ivonescimab regimen over the tislelizumab regimen. After a median follow-up of 21.4 months, the median overall survival was 27.89 months in the ivonescimab group vs 23.69 months in the tislelizumab group (hazard ratio, 0.66; P = .0017).

Ivonescimab plus chemotherapy showed a comparable safety profile to tislelizumab plus chemotherapy, Lu said.

The rate of grade 3 or higher treatment-related adverse events (TRAEs) was higher in the ivonescimab group than in the tislelizumab group (69% vs 59%). Grade 3 or higher immune-related TRAEs occurred in 14% of each cohort.

Serious TRAEs occurred in 41% and 34% of the cohorts, respectively.

The most notable adverse event possibly related to VEGF was hemorrhage, Lu said. Hemorrhage occurred in 24.8% of the ivonescimab group, including 2.6% that was grade 3 or higher. In the tislelizumab group, hemorrhage occurred in 12.1%, including 0.8% grade 3 or higher.

Ivonescimab treatment reduced the risk for death by 34% during the study.

Tislelizumab showed the anticipated sensitivity to PD-L1 expression. Patients with PD-L1 levels ≥ 1% had a median overall survival of 27 months, whereas those with lower PD-L1 expression saw that figure drop to about 19 months.

Ivonescimab, by contrast, appeared to work independently of PD-L1 status. Survival rates in both the high and low PD-L1 subgroups were high enough that researchers could not yet determine a median overall survival for either cohort.

Implications

“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 said.

“This is one of very few studies in advanced squamous [NSCLC] that has shown median survival beyond 2 years,” Lu said in a news release.

A separate study called HARMONi-3 is looking at the effects of ivonescimab in people with NSCLC in populations worldwide, including the US, Europe, and Asia.

‘Very Encouraging’ Results

The study provides a “strong rationale to consider this combination of antiangiogenic and immunotherapy approaches,” David Spigel, MD, said during the briefing.

He added that there is a largely unmet need in people with squamous NSCLC. “Although we’ve had advanced immunotherapy, this group still often has a very poor prognosis.”

The study “met its progression-free survival in a remarkable way, and we’ve been waiting for overall survival results, and…there was an improvement in survival by 34% with a hazard ratio of 0.66,” said Spigel, who is president and chief medical officer at the Sarah Cannon Research Institute in Nashville, Tennessee.

Invited commenter, Julie Brahmer, MD, MSc, and Spigel agreed that it will be necessary to wait for the global study results to ascertain if these results apply to populations outside of China.

“While these results are provocative, the applicability to the global, generally older population is unclear,” said Brahmer, director of the Thoracic Oncology Program and professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore and the Marilyn Meyerhoff Professor in Thoracic Oncology. The median age in the HARMONi-6 trial was 64 years, she added, and the median age of people with lung cancer in the US is about 70 years.

Although there was a 4-month survival advantage with ivonescimab, “these results should be taken with some words of caution.” The median follow-up was only 21 months, she added, and less than half of the patients were followed for more than 2 years.

“It is possible with longer follow-up, both the hazard ratio and the results may change,” Brahmer said. “This does limit interpreting these results.”

It was “quite noteworthy” that there were no new safety signals, Spigel added. “We wait on other studies like the HARMONi-3 study, but these results are certainly very encouraging.”

The study was funded by Akeso, Inc. Lu reported having a leadership role in Innovent Biologics, Inc.; Shanghai Fosun; and Simcere Zaiming. He also reported being a consultant or advisor for AstraZeneca; Boehringer Ingelheim; GenomiCare; Hutchison MediPharma; InventisBio Co., Ltd.; Menarini; Pfizer; Roche; Simcere; Yuhan; and Zai Lab. Moreover, he reported being on the speakers bureau for AstraZeneca, Hansoh Pharma, Hengrui Therapeutics, and Roche. In addition, his institution reported receiving funding from AstraZeneca, BeiGene, BMS, Hansoh, Hengrui Therapeutics, Hutchison MediPharma, Lilly Suzhou Pharmaceutical Co. Ltd., and Roche. Spigel disclosed having a consulting or advisory role for AbbVie, Amgen, AstraZeneca, Circle Pharma, Daiichi Sankyo, Genentech/Roche, GlaxoSmithKline, Jazz Pharmaceuticals, Lyell Immunopharma, MedImmune, ModeX Therapeutics, Novartis, and Novocure and a leadership role at ASCO. Spigel also disclosed receiving receipt of research funding from AbbVie; Agios; Amgen; AnHeart Therapeutics; Apollomics; Arcus Biosciences; Arrys Therapeutics; Ascendis Pharma; Asher Bio; Astellas Pharma; AstraZeneca; Bayer; BeiGene; BioNTech; Blueprint Medicines; Boehringer Ingelheim; Bristol Myers Squibb; Celgene; Chugai Pharma; Cyteir; Daiichi Sankyo; Denovo Biopharma; Eisai; Elevation Oncology; Ellipses Pharma; EMD Serono; Endeavor BioMedicines; Erasca, Inc.; Faeth Therapeutics; Foundation Bio; Fujifilm; G1 Therapeutics; Genentech/Roche; Gilead Sciences; GlaxoSmithKline; GRAIL; Hutchison MediPharma; Incyte; Ipsen; Janssen Oncology; Janux Therapeutics; Jazz Pharmaceuticals; Kronos Bio; Lilly; Loxo; Lyell Immunopharma; MacroGenics; MedImmune; Merck; Millennium; Moderna Therapeutics; Molecular Templates; Monte Rosa Therapeutics; Nektar; Novartis; Novocure; Oncologie; Peloton Therapeutics; Phanes Therapeutics; PTC Therapeutics; PureTech; Razor Genomics; Repare Therapeutics; RGenix; Seagen; Shenzhen Chipscreen Biosciences; Stemline Therapeutics; Strata Oncology; Synthekine; Taiho Oncology; Takeda; Tango Therapeutics; Tarveda Therapeutics; Tizona Therapeutics, Inc.; Verastem; and Zai Lab and receipt of travel, accommodations, and expenses from AstraZeneca, Genentech, and Novartis. Brahmer disclosed being a consultant or advisor for Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Foundation Medicine, Genentech/Roche, Genmab, GlaxoSmithKline, Janssen Oncology, Johnson & Johnson/Janssen, Mestag Therapeutics, RAPT Therapeutics, Sanofi, and Summit Therapeutics and having other relationships with Bristol Myers Squibb, Merck, and Regeneron. Her institution reported receiving research funding from AstraZeneca and Bristol Myers Squibb.

Damian McNamara is a freelance contributor to Medscape Medical News. He worked full-time for Medscape and WebMD from 2018 to 2024. Damian has a BA in chemistry and an MA in science, health and environmental reporting/journalism.