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

Background Combination 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. Methods Systematic 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. Results Seventeen 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. Conclusions In 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. What is new? What are the clinical implications? ### Competing Interest Statement Disclosures Each author has completed the ICJME conflicts of interest form. N.N.L. reports research grants from Roche Diagnostics, Astra Zeneca and Boehringer Ingelheim as well as consultancy/speaker?s fees from Roche Diagnostics, Myokardia, Pharmacosmos, Akero Therapeutics, CV6 Therapeutics, Jazz Pharma and Novartis all outside the submitted work. Outside the submitted work, J.S.L. has received personal lectureship honoraria from Astra Zeneca, Pfizer and Bristol Myers Squibb. P.B.M. reports grants and personal fees from Boehringer Ingelheim; honoraria from Astrazeneca, GSK, Pharmacosmos, and Astellas, outside the submitted work. B.E has no conflicts of interest to declare. S.R. receives support through an unrestricted grant from Roche Diagnostics. Outside of the submitted work, BV receives: Consultancy or advisory role: Bristol Myers Squibb, EUSA Pharma, Merck Sharp & Dohme; travel/accommodation/expenses: Bristol Myers Squibb, EUSA Pharma, Ipsen; Research funding (institution): Bristol Myers Squibb, Exelixis, Ipsen, Merck Sharp & Dohme, Pfizer; Honoraria (self): Bristol Myers Squibb, Ipsen, Pfizer; Speaker bureau/expert testimony: Bristol Myers Squibb, Eisai, EUSA Pharma, Merck Serono, Merck Sharp & Dohme, Pfizer. R.J.J. reports grants from Astellas, Clovis, Exelixis, Bayer and Roche; honoraria from Astellas, Janssen, Bayer, Pfizer, Merck Serono, MSD, Novartis, Roche, Ipsen, Bristol Myers Squib. M.C.P reports grants from Boehringer Ingelheim, Roche, SQ Innovations, Astra Zeneca, Novarttis, Novo Nordisk, Medtronic, Boston Scientific, Horizon and Phramacosmos, all outside the submitted work; honoraria from Boehringer Ingelheim, Novartis, Astra Zeneca, Novo Nordisk, Abbvie Bayer, Takeda, Corvia, Cardiorentis, Pharmacosmos, Siemens and Vifor. ### Clinical Protocols ### Funding Statement Funding SR receives support through an unrestricted grant from Roche Diagnostics. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: source data was openly available before initiation of the study and was identified using web platforms outlined in methods, such as pubmed and clinicaltrials.gov I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes original data can be made available on request.