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Meta-Analysis
. 2021 May:148:76-91.
doi: 10.1016/j.ejca.2021.01.043. Epub 2021 Mar 16.

Cardiotoxicity of immune checkpoint inhibitors: A systematic review and meta-analysis of randomised clinical trials

Elisa Agostinetto  1 , Daniel Eiger  2 , Matteo Lambertini  3 , Marcello Ceppi  4 , Marco Bruzzone  4 , Noam Pondé  5 , Chris Plummer  6 , Ahmad H Awada  7 , Armando Santoro  8 , Martine Piccart-Gebhart  7 , Evandro de Azambuja  2
Affiliations
Meta-Analysis

Cardiotoxicity of immune checkpoint inhibitors: A systematic review and meta-analysis of randomised clinical trials

Elisa Agostinetto et al. Eur J Cancer. 2021 May.

Abstract

Background: Immune checkpoint inhibitors (ICIs) may cause potentially life-threatening adverse events (AEs), but the risk of cardiotoxicity has not been fully investigated. It is also unknown whether ICI combinations increase cardiotoxicity compared with single ICI. We aimed to assess the cardiotoxicity of ICI in a range of tumour types.

Methods: This systematic review and meta-analysis was conducted according to PRISMA guidelines (PROSPERO registration number: CRD42020183524). A systematic search of PubMed, MEDLINE, Embase databases, and conference proceedings was performed up to 30 June 2020. All randomised clinical trials comparing ICI with other treatments (primary objective) or dual-agent ICI versus single-agent ICI (secondary objective) in any solid tumour were included. Pooled risk ratios (RRs) with 95% confidence intervals (95% CIs) for cardiotoxicity events were calculated using random effect models.

Results: Eighty studies including 35,337 patients were included in the analysis (66 studies with 34,664 patients for the primary endpoint and 14 studies with 673 patients for the secondary endpoint). No significant differences in terms of cardiac AEs were observed between ICI and non-ICI groups (RR 1.14, 95% CI 0.88-1.48, p = 0.326) nor between dual ICI and single ICI groups (RR 1.91, 95% CI 0.52-7.01, p = 0.329). Myocarditis incidence did not significantly differ between ICI and non-ICI groups (RR 1.11, 95% CI 0.64-1.92, p = 0.701) nor between dual ICI and single ICI groups (RR 1.10, 95% CI 0.31-3.87, p = 0.881). No differences were observed in subgroup analyses according to tumour type, setting of disease, treatment line, and type of treatment.

Conclusion: The use of ICI as single or combination regimens is not associated with increased risk of cardiotoxicity.

Keywords: Cardiotoxicity; Drug-related adverse events; Immune checkpoint inhibitors; Immunotherapy; Myocarditis.

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Conflict of interest statement

Conflict of interest statement This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article. EA, MC, and MB have no conflicts of interest to declare. DEF funding for his ESMO fellowship (2018–2019) from Novartis and received honoraria from Janssen for speaking (outside the submitted work). ML acted as a consultant for Roche and Novartis and received honoraria from Theramex, Takeda, Roche, Lilly, Pfizer, and Novartis (outside the submitted work). NP acted as a consultant for Lilly and has received honoraria from Roche, Lilly, Novartis, and AstraZeneca (outside the submitted work). CP has received honoraria for speaking at educational meetings from Amgen, Ferring, Incyte, Ipsen, Novartis, Pfizer, and Roche (outside the submitted work). AHA received advisory role, speaker fees, and research funding for his institute from Roche, Lilly, Amgen, EISAI, BMS, Pfizer, Novartis, MSD, Genomic Health, Ipsen, AstraZeneca, Bayer, and Leo Pharma (outside the submitted work). AS is a member of the advisory boards at BMS, Servier, Gilead, Pfizer, Eisai, Bayer, and MSD; participated in conference at Takeda, Roche, AbbVie and Amgen, Celgene, AstraZeneca, Lilly, Sandoz, Novartis, BMS, Servier, Gilead, Pfizer, ArQule, and Eisai; and was a consultant at ArQule (outside the submitted work). MP was a board member (Scientific Board) at Oncolytics, Radius; was a consultant (honoraria) at AstraZeneca, Camel-IDS, Crescendo Biologics, Debiopharm, G1 Therapeutics, Genentech, Huya, Immunomedics, Lilly, Menarini, MSD, Novartis, Odonate, Oncolytics, Periphagen, Pfizer, Roche, and Seattle Genetics; and received grants to her institute from AstraZeneca, Lilly, MSD, Novartis, Pfizer, Radius, Roche-Genentech, Servier, and Synthon (outside the submitted work). EdA received honoraria from and was a member of advisory board at Roche/GNE, Novartis, Seattle Genetics, Zodiacs, Libbs, and Pierre Fabre; received travel grants from Roche/GNE and GSK/Novartis; received grant for his institute from Roche/GNE, Astra-Zeneca, Novartis, and Servier (outside the submitted work).

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