Dual-axis cardiotoxicity associated with the first-in-class anti-PD-1/VEGF-A bispecific antibody ivonescimab: a narrative review

Ivonescimab is a first-in-class tetravalent, fragment crystallizable (Fc)-silenced bispecific antibody that binds programmed cell death protein 1 (PD-1) and vascular endothelial growth factor-A (VEGF-A) with mutually cooperative avidity. It is the lead molecule of a rapidly expanding PD-(L)1/VEGF bispecific class, has demonstrated superiority over both pembrolizumab and tislelizumab-based regimens in randomized phase III trials, and is under regulatory review in the United States. Its design combines two distinct cardiovascular liabilities in a single agent: the vascular toxicity of VEGF signaling pathway inhibition and the immune-mediated toxicity of PD-1 blockade. Cardio-oncology currently has no framework that addresses both at once. This narrative review aims to characterize the VEGF-A-axis and PD-1-axis cardiovascular toxicities of ivonescimab at the level of mechanism and clinical evidence, to appraise whether the molecular architecture of the antibody attenuates either of them, and to translate that appraisal into a bedside surveillance framework and a research agenda. Throughout, findings observed in ivonescimab-treated patients are distinguished from extrapolations drawn from the VEGF signaling pathway inhibitor and immune checkpoint inhibitor classes, and from hypotheses generated by this review. The VEGF-A arm appears to reproduce the class toxicity of VEGF signaling pathway inhibitors: hypertension and proteinuria as on-target endothelial and glomerular effects, thromboembolism and left-ventricular strain as downstream consequences, and hemorrhage as a renewed concern now that a survival benefit has been shown in squamous non-small cell lung cancer. The PD-1 arm carries a low-probability, high-lethality myocarditis hazard together with pericardial disease, vasculitis, and accelerated atherosclerosis. Cooperative binding chiefly supports tumor-enriched efficacy and offers limited protection to the systemic vasculature, since circulating VEGF-A is measurably suppressed and proteinuria occurs in roughly one in five patients. Fc silencing is a coherent but weakly supported rationale for reduced immune toxicity, and intermittent VEGF-A suppression remains an untested basis for vascular sparing. Ivonescimab’s cardiovascular profile appears favorable within the populations studied, but its mechanisms make it unlikely to be free of cardiovascular risk, and the trials conducted to date were not designed to measure the endpoints most relevant to cardio-oncology. We propose a risk-stratified surveillance framework, a set of falsifiable predictions, and a cardiovascular core outcome set for the PD-(L)1/VEGF bispecific class while registrational datasets are still open. Cardiovascular implications of ivonescimab, a first-in-class tetravalent, Fc-silenced PD-1/VEGF bispecific antibody. Ivonescimab combines two pharmacologic mechanisms with distinct cardiovascular liabilities: VEGF inhibition may cause hypertension, proteinuria, thromboembolism, left ventricular strain, and hemorrhage, whereas PD-1 blockade carries a low probability but potentially severe risk of immune-mediated myocarditis, pericardial disease, vasculitis, and accelerated atherosclerosis. Its mutually cooperative binding and Fc silencing provide plausible biological explanations for selective tumor activity and reduced immune toxicity, although cardiovascular sparing remains incompletely demonstrated. The available clinical evidence suggests a favorable cardiovascular profile within studied populations but is limited by the absence of systematic cardiovascular phenotyping, adjudicated cardiovascular endpoints, and longitudinal cardiac surveillance. A risk-stratified cardio-oncology framework incorporating baseline assessment, early myocarditis surveillance, ongoing blood pressure and renal monitoring, thrombotic risk assessment, and long-term cardiovascular follow-up is therefore proposed, alongside a cardiovascular core outcome set for future PD-(L)1/VEGF bispecific antibody trials.