In the phase III HARMONi-6 trial, conducted in China, the bispecific antibody ivonescimab, given with chemotherapy, improved progression-free survival by 4.2 months over the PD-1 inhibitor tislelizumab-jsgr plus chemotherapy, a 40% reduction in risk as first-line treatment of advanced squamous non–small cell lung cancer (NSCLC).1
Shun Lu, MD, PhD, presented the interim analysis at a Presidential Symposium during ESMO 2025. Dr. Lu is Professor and Chief of the Shanghai Lung Cancer Center at Shanghai Chest Hospital in China.
Shun Lu, MD, PhD
Median progression-free survival, the primary endpoint, was 11.1 months with ivonescimab plus chemotherapy vs 6.9 months with tislelizumab plus chemotherapy (hazard ratio [HR] = 0.60; P < .0001) at a median follow-up of 10.3 months. Benefit was similar across PD-L1 expression subgroups, Dr. Lu reported.
Study Background
As Dr. Lu noted, tislelizumab has been approved by the European Medicines Agency and China’s National Medical Products Administration as a first-line treatment of advanced squamous NSCLC. Ivonescimab, which targets PD-1 and VEGF, is approved in China for patients who have nonsquamous NSCLC and experience disease progression on EGFR-targeted tyrosine kinase inhibitors and for patients with PD-L1–expressing advanced NSCLC as a first-line treatment. HARMONi-6 evaluated the combination of ivonescimab plus chemotherapy vs tislelizumab plus chemotherapy as a first-line treatment of advanced squamous NSCLC.
The multicenter double-blind phase III trial randomly assigned 532 patients with previously untreated stage IIIB–IV squamous NSCLC to receive either ivonescimab or tislelizumab, both given with carboplatin and paclitaxel every 3 weeks for up to four cycles, followed by ivonescimab or tislelizumab alone for up to 24 months. The primary endpoint was progression-free survival by independent radiology review. The presentation at the ESMO Congress was based on the prespecified interim analysis, with 221 events observed.
Other Key Findings
Ivonescimab was favored across all key subgroups, with activity observed regardless of the level of PD-L1 expression by tumor proportion score (TPS). A consistent progression-free survival benefit was observed by investigator assessment, where a 34% risk reduction was reported (HR = 0.64; 95% confidence interval = 0.50–0.84).
“The tumor response was higher and more durable in the ivonescimab arm,” Dr. Lu said. The objective response rate was 75.9% in the ivonescimab arm vs 66.5% (P = .008). In patients with TPS ≥ 1%, the objective response rate was 80.1% and 70.2%, respectively. The median duration of response was 11.2 months vs 8.4 months with tislelizumab (P = .0219). Overall survival data were not mature.
Grade ≥ 3 treatment-related adverse events occurred in 63.9% of patients given ivonescimab and 54.3% of those given tislelizumab, with a similar proportion of grade ≥ 3 immune-related events per arm (9.0% and 10.2%, respectively).
DISCLOSURE: Dr. Lu reported financial relationships with AstraZeneca, Roche, Hansoh Pharmaceutical, Hengrui Pharmaceuticals, Pfizer, Hutchison MediPharma, Zai Lab, Yuhan, Menarini, InventisBio, Shanghai Fosun Pharmaceutical, Simcere Pharmaceutical, and Innovent Bio.
REFERENCE
1. 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). ESMO Congress 2025. Abstract LBA4. Presented October 19, 2025.
EXPERT POINT OF VIEW
“HARMONi-6 represents an important step forward in the management of squamous non–small cell lung cancer [NSCLC],” said the study’s invited discussant, Myung Ju Ahn, MD, PhD, Professor of Medicine at Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. In the phase III study, first-line ivonescimab plus chemotherapy demonstrated “clinically meaningful” progression-free survival and response rates across PD-L1 subgroups, with a low rate of hemorrhage, “even in a population enriched for high-risk features,” she commented.
‘Reappraisal of Antiangiogenic Agents’
As Dr. Ahn pointed out, squamous NSCLC remains a challenging cancer because of its underlying biological features, including a lack of targetable mutations, tumor location and associated complications, and patient comorbidities. Pemetrexed has been ineffective, and although checkpoint inhibitors may work, long-term survival benefit is less consistent than for nonsquamous tumors. “There remains room for improvement,” she noted.
Myung Ju Ahn, MD, PhD
VEGF is the critical driver of tumor progression in this tumor. Bevacizumab and other anti-VEGF drugs neutralize VEGF-A, block VEGF-VEGF receptor signaling, inhibit new vessel formation, normalize tumor vasculature, enhance drug delivery, and suppress the tumor microenvironment. “Unfortunately, the historical experience with bevacizumab has been challenging,” she reminded listeners, as the drug was found to cause life-threatening bleeding that led to its contraindication in squamous NSCLC, where it had been shown to be effective. “In the era of immunotherapy, there has been a reappraisal of antiangiogenic agents,” as the combination of anti-VEGF and checkpoint inhibitors has demonstrated activity.
HARMONi Trials of Ivonescimab
Ivonescimab is a first-in-class bispecific antibody that blocks both VEGF and PD-1, creating “mutual cooperativity” through a tetravalent structure, stronger binding, enhanced VEGF-signaling blockade, and improved safety, explained Dr. Ahn. In the previous HARMONi-2 trial in advanced NSCLC (in both squamous and nonsquamous histologies),1 ivonescimab reduced the risk of disease progression by 49% vs pembrolizumab (P < .0001) and by 50% (95% confidence interval = 0.33–0.76) in patients with squamous histology, whose median progression-free survival was 9.7 vs 5.8 months, respectively. In the interim analysis of overall survival, a 33% relative risk reduction was seen as well. “More importantly, the proteinuria, hypertension, and hemorrhage rates were very low,” she emphasized.
HARMONi-6 has now reported data for ivonescimab that are more favorable than were reported for pembrolizumab in KEYNOTE-407 in squamous histology,2 where median progression-free survival with pembrolizumab plus chemotherapy was 8.0 months, and the response rate was 57.9%. Of note, the control arm in HARMONi-6, tislelizumab, produced a median progression-free survival of 6.9 months, which was comparable to that of pembrolizumab in KEYNOTE-407.
Regarding safety, although these findings were overall “reassuring” in HARMONi-6, Dr. Ahn commented, five patients treated with ivonescimab did develop grade ≥ 3 hemorrhage. All but one had a history of hemoptysis, major vessel encasement, and a central lesion location, but she acknowledged, “we cannot completely ignore the risk of hemorrhage.”
Questions Remain
“The duration of response and treatment exposure will be key in interpreting whether the observed progression-free survival gain translates into a durable survival benefit,” Dr. Ahn stated. Only one trial—IMpower150 in nonsquamous NSCLC3—has shown a survival benefit for an antiangiogenic agent plus a checkpoint inhibitor, so the precedent is unsubstantiated, she added.
Dr. Ahn continued: “HARMONi-6 is raising the bar for progression-free survival. Is it safe enough for broad use in squamous NSCLC? Quite likely. But is it raising the bar for overall survival? That’s not certain yet. Real-world application will require multidisciplinary vigilance, particularly in patients with central tumors or cavitation. And, as this study was conducted exclusively in China, global external validation across diverse populations is needed. The global phase III HARMONi-3 trial is enrolling patients with both squamous and nonsquamous NSCLC and will be critical to confirm these findings.”
DISCLOSURE: Dr. Ahn reported financial relationships with AstraZeneca, BMS, MSD, Lilly, Merck, Ono Pharmaceutical, Roche, Takeda, Yuhan, Amgen, Novartis, Arcus Biosciences, Pfizer, Daiichi Sankyo, Alpha Pharma, Voronoi, and Eutilex.
REFERENCES
1. Xiong A, Wang L, Chen J, et al: Ivonescimab versus pembrolizumab for PD-L1-positive non-small cell lung cancer (HARMONi-2): A randomised, double-blind, phase 3 study in China. Lancet 405:839-849, 2025.
2. Paz-Ares L, Luft A, Vicente D, et al: Pembrolizumab plus chemotherapy for squamous non–small-cell lung cancer. N Engl J Med 379:2040-2051, 2018.
3. Socinski MA, Nishio M, Jotte RM, et al: IMpower150 final overall survival analyses for atezolizumab plus bevacizumab and chemotherapy in first-line metastatic nonsquamous NSCLC. J Thorac Oncol 16:1909-1924, 2021.
