HARMONi-2: ivonescimab, a PD-1 x VEGF bispecific, beats pembrolizumab head-to-head in PD-L1-positive lung cancer
In the first randomised trial to beat pembrolizumab directly, a single antibody that blocks both PD-1 and VEGF nearly doubled the time to progression in PD-L1-positive lung cancer, though survival data were still immature.
Double-blind phase 3 trial conducted in China of 398 patients with untreated, PD-L1-positive (TPS 1% or more) advanced NSCLC without EGFR or ALK alterations, randomised to ivonescimab or pembrolizumab monotherapy. Primary endpoint was PFS by blinded review.
Median PFS was 11.1 vs 5.8 months (HR 0.51), with benefit in squamous and non-squamous histology and in PD-L1 1-49% and 50% or more. Overall survival was immature at publication and a later interim analysis did not reach statistical significance. It is the first time any agent has beaten pembrolizumab head-to-head in lung cancer and it revived interest in PD-(L)1 x VEGF bispecifics, with several Western companies licensing similar molecules.
- Median PFS 11.1 vs 5.8 months; HR 0.51 (95% CI 0.38-0.69).
- Objective response 50.0% vs 38.5%.
- Benefit seen in PD-L1 TPS 1-49% (HR 0.54) and 50% or more (HR 0.46), and in squamous (HR 0.48) and non-squamous (HR 0.54) tumours.
- Grade 3 or higher treatment-related adverse events 29.4% vs 15.6%, largely VEGF-related (proteinuria, hypertension) with no excess of severe bleeding in squamous tumours.
- Overall survival immature at primary analysis; a subsequent interim OS analysis showed a hazard ratio below 1 that was not statistically significant.
For the first time a new drug has beaten pembrolizumab, the global first-line standard, in a randomised lung cancer trial, and it did so by combining checkpoint blockade with anti-angiogenesis in one molecule. For patients outside China nothing changes yet: the drug is not approved in the West, the trial was single-country, and survival benefit has not been shown. If confirmed in the global HARMONi-3 and HARMONi-7 trials, PD-1 x VEGF bispecifics could replace PD-1 antibodies as the immunotherapy backbone.
- Single-country (China) trial; generalisability to other populations is untested.
- Progression-free survival only; overall survival has not reached significance, and pembrolizumab's own benefit is defined by OS.
- Comparator was pembrolizumab monotherapy, whereas many PD-L1 1-49% patients would receive chemo-immunotherapy.
- VEGF-class toxicities and the cost of a novel bispecific are additional considerations.