In the first-line treatment of patients with advanced squamous non-small cell lung cancer (NSCLC) in China, the combination of ivonescimab plus chemotherapy significantly improves overall survival (OS) compared with tislelizumab plus chemotherapy, according to the phase III HARMONi-6 trial.
Over a median follow-up of 21.4 months, the median OS was 27.9 months (95 percent confidence interval [CI], 27.89–not evaluable [NE]) in the ivonescimab arm vs 23.7 months (95 percent CI, 20.11–NE) in the tislelizumab arm, reported first study author Prof Shun Lu from Shanghai Jiao Tong University, Shanghai, China, at the annual ASCO meeting.
Ivonescimab plus chemotherapy reduced the risk of death by 34 percent (hazard ratio [HR], 0.66, 95 percent CI, 0.50–0.87; p=0.0017) compared with tislelizumab plus chemotherapy. [Lancet 2026;doi:10.1016/S0140-6736(26)00966-9]
Lu noted that the OS benefit with ivonescimab plus chemotherapy was consistent across subgroups, including those defined by PD-L1 tumour proportion score (<1%: HR, 0.64; ≥1%: HR, 0.68; 1–49%: HR, 0.67; ≥50%: HR, 0.64).
The estimated OS rates in the ivonescimab and tislelizumab arms were 64.7 percent and 48.6 percent at 24 months, 70.5 percent and 61.3 percent at 18 months, and 78.9 percent and 72.2 percent at 12 months, respectively.
“These results are particularly noteworthy because they represent the first OS data from a phase III trial demonstrating the superiority of an anti-PD1–VEGF bispecific antibody plus chemotherapy over the established standard of a PD-1 inhibitor plus chemotherapy in squamous NSCLC,” Lu said.
Together with the previously reported clinically meaningful doubling of progression-free survival (PFS), the findings of HARMONi-6 support the adoption of ivonescimab plus chemotherapy as a new standard for the first-line treatment of advanced squamous NSCLC in China, according to Lu. He shared that a global phase III trial (HARMONi-3) is currently ongoing to evaluate the efficacy and safety of ivonescimab plus chemotherapy across more diverse populations.
HARMONI-6 trial
Conducted at 50 hospitals across China, HARMONi-6 included 532 patients aged 18–75 years (median age 64 years, 93 percent male) with previously untreated, pathologically confirmed, unresectable stage IIIB, IIIC, or stage IV squamous NSCLC.
The patients were randomly assigned to receive up to 4 cycles of either ivonescimab (n=266) or tislelizumab (n=266) in combination with paclitaxel and carboplatin, followed by up to 24 months of maintenance ivonescimab or tislelizumab.
In both treatment arms, most patients had an ECOG performance status of 1, were current or former smokers, and had stage IV disease. There were 39 percent of patients overall who had a PD-L1 tumour proportion score of <1%.
The previously reported primary endpoint of PFS was significantly longer in the ivonescimab vs tislelizumab arm (median, 11.1 vs 6.9 months; HR, 0.60, 95 percent CI, 0.46–0.78; p<0.0001). [Lancet 2025;406:2078-2088]
As for safety, “ivonescimab plus chemotherapy showed a manageable safety profile in squamous NSCLC [that was] comparable to tislelizumab plus chemotherapy,” Lu said.
Treatment-related adverse events (TRAEs) of grade ≥3 occurred in 69 percent of patients in the ivonescimab arm and 59 percent of those in the tislelizumab arm. The most common TRAEs were alopecia, anaemia, and reductions in neutrophil or white blood cell count. TRAEs led to discontinuation of ivonescimab or tislelizumab in 5.3 percent and 4.5 percent of patients, respectively.
Possible anti-VEGF-related adverse events (AEs) were more common in the ivonescimab vs tislelizumab arm (60 percent vs 26 percent), although most were grade 1 or 2, Lu noted. Grade ≥3 anti-VEGF-related AEs included hypertension, renal injury or proteinuria, and haemorrhage.
Unclear global applicability
Study discussant Dr Julie Brahmer who directs the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland, US, emphasized that the interim OS data from HARMONi-6 show that ivonescimab plus chemotherapy is only efficacious for Chinese patients with advanced squamous NSCLC.
Brahmer also pointed out that ivonescimab was associated with more frequent anti-VEGF-related AEs and that the trial population excluding patients older than 75 years was not reflective of the global population with lung cancer.
“While the HARMONi-6 results are provocative, the applicability to the global, generally older, squamous lung cancer population is unclear,” she said.
Ivonescimab is a bispecific antibody that targets both PD-1 and VEGF. The drug has been approved in China for two lung indications since 2024.
“We need to wait for the global HARMONi trial results to see if [the survival benefit with ivonescimab plus chemotherapy] is applicable to the global, generally older squamous, lung cancer population,” Brahmer said.