Volume 83, April 2023, 102334Author links open overlay panelAbstractBackground

Immune checkpoint inhibitors (ICI) have revolutionized the treatment of numerous cancers but are associated with increased risk of myocardial infarction. The prevalence of traditional cardiovascular risk factors (CVRF) in patients treated with ICIs is unknown. This study sought to describe the frequency of reporting of CVRFs among landmark ICI trials.

Methods

A systematic review of all phase 2 or 3 cancer trials employing ICIs that led to United States Food and Drug Administration approval was conducted.

Results

Of the 69 identified trials, only one study reported baseline rates of hypertension, diabetes mellitus, and dyslipidemia. Smoking history was reported in 27 studies (39 %) and three (4 %) reported body mass index. No study reported history of previous cardiovascular disease, although 17 (25 %), six (9 %), and 21 (30 %) studies excluded patients with recent myocardial infarction, revascularization and heart failure respectively. Similarly low rates of cardiovascular risk factor reporting were observed in studies employing concurrent vascular endothelial growth factor inhibitors and recruiting (neo)adjuvant cohorts.

Conclusion

The prevalence of CVRFs is poorly described in ICI trials despite increasingly reported risks of myocardial infarction. A systematic approach to collecting and reporting CVRFs should be considered in future trials and real world populations.

Graphical Abstract

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Reporting of cardiovascular risk factors in immune checkpoint inhibitor trials. Cardiovascular risk factors are poorly defined in landmark immune checkpoint inhibitor trials. Each trial included in the systematic review is represented in the figure by their trial name (CM – CheckMate trial, KN – KEYNOTE trial). Trials with cardiac exclusion factors are listed on right of the dotted line. Trials that reported prevalence of smoking are depicted in the red bubble, BMI in the blue bubble, and hypertension, dyslipidemia and diabetes in the yellow bubble. Only one trial reported all conventional cardiovascular risk factors at baseline (overlap of red, blue and yellow bubbles). Trials that did not report any cardiovascular risk factors are depicted outside the coloured bubbles. Trials which utilized concurrent cardiotoxic vascular endothelial growth factor inhibitors are highlighted in red font. A complete list of the included trials are available in the Supplementary appendix. *Adjuvant trials. **Neoadjuvant trials. BMI – Body mass index, CM – CheckMate, KN – KEYNOTE.

Introduction

Immune checkpoint inhibitors (ICI) have revolutionized the treatment of various cancers, with approximately half of all patients with advanced cancer in high income countries eligible for these therapies [1]. The pro-inflammatory effects of ICIs have been associated with increased long-term risks of cardiotoxicities, such as myocardial infarction [2], [3], [4]. This has significant implications for cancer survivorship, with cardiovascular disease (CVD) already identified as a leading cause of non-cancer related mortality among patients living with or cured from cancer, even prior to ICIs [5]. Shared risk factors such as smoking, diabetes, and obesity are implicated in the heightened risks of CVD among cancer patients [6]. Hence, treatment of modifiable cardiovascular risk factors (CVRF) are recommended in patients treated with ICIs to reduce risk of myocardial in cancer survivorship [7]. Despite this, the cardiovascular risk profile of cancer patients treated with ICIs is unknown. This study sought to identify the frequency of CVRFs reporting in landmark ICI trials, to define the baseline cardiovascular risk of participants and whether pre-existing CVD precluded recruitment.

Section snippetsMaterials and methods

A systematic review of Phase 2 and 3 trials that led to United States Food and Drug Administration (U.S. FDA) approved indications for ICIs as cancer therapy was performed in April 2022 according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [8].

Results

The initial search process resulted in 1125 articles. Following the removal of duplicates, 824 records were screened at title and abstract level. A total of 123 full-text articles were reviewed for eligibility and 69 studies were included in the final analysis, investigating eight ICIs across 20 tumor types. Nine studies reported use of concurrent VEGF inhibitors and 10 recruited (neo)adjuvant cohorts. Results are summarized in the Graphical Abstract and Table 1.

All studies reported age and

Discussion

In this systematic review of seminal ICI trials for cancer therapy, we found that the cardiovascular risk profile of recruited patients was rarely reported despite a number of trials evaluating concurrent VEGF inhibitor use known to amplify the risk of cardiotoxicity. Similar results were obtained from studies that recruited (neo)adjuvant cohorts which have generally favorable long-term prognoses and higher likelihood of deriving benefit from long-term cardiovascular risk reduction during

Conclusion

In conclusion, the cardiovascular risk profile of patients recruited in seminal ICI trials is poorly defined despite increasing reports of long-term risks of myocardial infarction. As cancer survivorship improves with the expanding use of ICIs across multiple tumor types, further efforts should be considered toward CVRF reporting in upcoming ICI trials. This would enable the identification of modifiable targets to reduce cardiovascular risk in cancer survivorship, thus improving cardiovascular

CRediT authorship contribution statement

Sean Tan: Conceptualization, Data curation, Formal analysis, Investigation, Writing – original draft, Visualization, Project administration. Seiyon Sivakumar: Data curation, Investigation. Eva Segelov: Conceptualization, Methodology, Supervision, Writing – review & editing. Stephen J Nicholls: Conceptualization, Methodology, Resources, Supervision, Writing – review & editing. Adam J Nelson: Conceptualization, Methodology, Supervision, Writing – review & editing.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Dr. Tan is supported by a Postgraduate Scholarship from the National Health and Medical Research Council of Australia, a PhD Scholarship from the National Heart Foundation of Australia, and an Australian Government Research Training Program Scholarship. Dr Nelson is supported by a Postdoctoral Fellowship from the National Heart Foundation of Australia.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

None.

Submission Declaration and Verification

This article has not been published previously and is currently not being considered for publication elsewhere.

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