Cardiovascular Eligibility Criteria and Adverse Event Reporting in Cancer Therapy Trials of Combined Immune Checkpoint and VEGF Inhibitors: A Systematic Review

Abstract

BackgroundCombination therapy with immune checkpoint inhibitors (ICI) and vascular endothelial growth factor inhibitors (VEGFI) has improved cancer outcomes and are increasingly common treatment regimens. These drug classes are associated with cardiovascular toxicities when used alone but heterogeneity in trial design and reporting may limit knowledge of toxicities in people receiving these in combination. Our aims were to assess consistency and clarity in definitions and reporting of cardiovascular eligibility criteria, baseline characteristics and cardiovascular adverse events in ICI/VEGFI combination trials.MethodsSystematic review of phase II-IV randomised controlled trials of ICI/VEGFI combination therapy for solid organ cancer. We assessed trial cardiovascular eligibility criteria and baseline cardiovascular characteristic reporting in trial publications. We also examined cardiovascular adverse events definitions and reporting criteria.ResultsSeventeen trials (10,313 participants; published 2018-2022) were included. There were multiple cardiovascular exclusion criteria in 15 trials. No primary trial publication reported baseline cardiovascular characteristics. Thirteen trials excluded people with prior heart failure, myocardial infarction, hypertension or stroke. There was heterogeneity in defining cardiovascular conditions. Grade 1-4 cardiovascular adverse events were reported when incidence was ≥5-25% in 15 trials. Nine trials applied a more sensitive threshold for reporting higher grade AEs (severity grade ≥3 or serious AE). Safety follow up was shorter than efficacy follow up. Incident hypertension was recorded in all trials but other cardiovascular events were not consistently reported. Myocardial infarction was only reported in four trials and heart failure was reported in three trials. No trial specifically noted the absence of events. Therefore, in trials that did not report CVAEs, it was unclear whether this was because CVAEs did not occur. AE reporting and classification were by the investigator without further adjudication in 16 trials and one trial had an independent CVAE adjudication committee.ConclusionsIn ICI/VEGFI combination trials, there is heterogeneity in cardiovascular exclusion criteria, reporting of baseline characteristics and lack of reporting of cardiovascular adverse events. This limits optimal understanding of the incidence and severity of events relating to these combinations. Better standardisation of these elements should be pursued.Clinical PerspectiveWhat is new?Immune checkpoint inhibitors (ICI) and VEGF inhibitors (VEGFI) are vital anti-cancer drugs but are associated with cardiovascular (CV) adverse events when given in isolation.VEGFI and ICI are now frequently used in combination, often in patients with pre-existing cardiovascular disease, but trial data to guide their use in such patients is limited.This systematic review of pivotal ICI/VEGFI trials identified heterogeneity in trial exclusion for pre-existing cardiovascular disease, reporting of CV baseline characteristics as well as in definitions and reporting of CV adverse events.What are the clinical implications?ICI/VEGFI oncology trial design and reporting methodology limits optimum understanding of adverse cardiovascular effects associated with ICI/VEGFI combination therapy, and these concerns may be more, or less, common than currently feared.Standardised cardiovascular eligibility criteria and adverse event recording would allow meta-analysis for more accurate assessments of adverse cardiovascular effects of ICI/VEGFI combination therapy.These observations and conclusions are relevant to the design and reporting of the majority of oncology drug trials and have implications to almost all anti-cancer therapeutic classes.