Ivonescimab plus chemotherapy versus placebo plus chemotherapy in patients with advanced EGFR-mutated non-small-cell lung cancer after disease progression on EGFR tyrosine kinase inhibitor therapy (HARMONi): a multicentre, randomised, double-blind, phase 3 trial

Patients aged 18 years or older (upper age limit 75 years in Asia) with EGFR-mutated non-squamous non-small-cell lung cancer, stage IIIB/IIIC or IV, with disease progression after treatment with a third-generation EGFR tyrosine kinase inhibitor (TKI) and an ECOG performance status of 0 or 1. The trial was conducted at 114 cancer centres and hospitals in Asia, Europe and North America. Of 660 people screened, 438 were enrolled and randomised. Randomisation was stratified by brain metastasis status at enrolment and geographical region.

Primary endpoints: progression-free survival (PFS) by blinded independent central radiology review, and overall survival (OS) in the intention-to-treat (ITT) population. Safety was assessed in patients who had received at least one dose of study treatment.

The most common grade 3-4 treatment-related adverse events with ivonescimab + chemotherapy versus placebo + chemotherapy (218 patients in each group): decreased neutrophil count (42 patients [19%] versus 36 patients [17%]), decreased white blood cell count (28 [13%] versus 24 [11%]), decreased platelet count (27 [12%] versus 14 [6%]) and anaemia (22 [10%] versus 27 [12%]).

Serious treatment-related adverse events occurred in 61 patients (28%) in the ivonescimab group and 33 patients (15%) in the placebo group.

Treatment-related adverse events leading to death occurred in four patients in the ivonescimab + chemotherapy group (disease progression, multiple organ dysfunction syndrome and hepatic failure, one patient each; and gastrointestinal haemorrhage and pulmonary embolism in one patient) and five patients in the placebo + chemotherapy group (pneumonitis, myocardial infarction, stroke, cognitive disorder and embolic stroke, one patient each).

Based on the abstract, adding ivonescimab to pemetrexed plus carboplatin chemotherapy significantly improved progression-free survival in EGFR-mutated NSCLC after failure of a third-generation EGFR-TKI (HR 0.52), and the authors consider it a potential new treatment option. The improvement in overall survival (HR 0.79; 95% CI 0.62–1.01) was not statistically conclusive, and the confidence interval includes 1. Regulatory approval status and the place of this regimen in clinical guidelines are not given in the abstract and should be checked separately.

Based on the abstract: the improvement in overall survival was not statistically conclusive (the 95% CI for the HR includes 1), and treatment and survival follow-up are ongoing. 70% of patients were Asian and 24% White. The rate of serious treatment-related adverse events was higher in the ivonescimab group (28% versus 15%). The trial was funded by Summit Therapeutics. An erratum has been published for this paper (Lancet Oncol 2026;27(10):e450) and should be checked when citing it.