Cardiovascular Toxicity With PD-1/PD-L1 Inhibitors in Cancer Patients: A Systematic Review and Meta-Analysis

• Published in: Frontiers in immunology Vol. 13; p. 908173
• Main Authors: Liu, Surui, Gao, Wei, Ning, Yan, Zou, Xiaomeng, Zhang, Weike, Zeng, Liangjie, Liu, Jie
• Format: Journal Article
• Language: English
• Published: Frontiers Media S.A 08-07-2022
• Subjects: cardiovascular toxicity; Immunology; immunotherapy; malignancies; PD-1/PD-L1 inhibitors; trials
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2022.908173

Background
PD-1/PD-L1 inhibitors have significantly improved the outcomes of those patients with various malignancies. However, the incidence of adverse events also increased. This meta-analysis aims to systematically evaluate the risk of cardiovascular toxicity in patients treated with PD-1/PD-L1 inhibitors.
Materials and methods
We searched PubMed, Embase, the Cochrane Library databases for all randomized controlled trials (RCTs) comparing all-grade and grade 3-5 cardiovascular toxicity of single-agent PD-1/PD-L1 inhibitors to placebo/chemotherapy, PD-1/PD-L1 inhibitors combined with chemotherapy to chemotherapy, or PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors to single-agent immune checkpoint inhibitors (ICIs) and pooled our data in a meta-analysis stratified by tumor types and PD-1 or PD-L1 inhibitors. The Mantel-Haenszel method calculated the odds ratio (OR) and its corresponding 95% confidence intervals (CIs).
Results
A total of 50 trials were included in the analysis. Single-agent PD-1/PD-L1 inhibitors increased the risk of all-grade cardiotoxicity compared with placebo (OR=2.11, 95%CI 1.02-4.36,
P=
0.04). Compared with chemotherapy, patients receiving PD-1/PD-L1 inhibitors combined with chemotherapy had a significant higher risk of all-grade (OR=1.53, 95%CI 1.18-1.99,
P=
0.001) and grade 3-5 cardiotoxicity (OR=1.63, 95%CI 1.11-2.39,
P=
0.01) cardiotoxicity, especially patients with non-small cell lung cancer (NSCLC) [all-grade cardiotoxicity (OR=1.97, 95%CI 1.14-3.41,
P=
0.02) and grade 3-5 cardiotoxicity (OR=2.15, 95%CI 1.08-4.27,
P=
0.03)]. Subgroup analysis showed that PD-1 inhibitors combined with chemotherapy were associated with a higher risk of grade 3-5 cardiotoxicity (OR=2.08, 95%CI 1.18-3.66,
P=
0.01). Compared with placebo or chemotherapy, single-agent PD-1/PD-L1 inhibitors did not increase the risk of all-grade of myocarditis, arrhythmia and hypertension. However, PD-1/PD-L1 inhibitors combined with chemotherapy increased the risk of all-grade arrhythmia (OR=1.63, 95%CI 1.07-2.46,
P=
0.02) [PD-L1 inhibitor-containing treatment (OR=1.75, 95%CI 1.09-2.80,
P=
0.02)], and the risk of all-grade hypertension (OR=1.34, 95%CI 1.02-1.77,
P=
0.04) and grade 3-5 hypertension (OR=1.54, 95%CI 1.10-2.15,
P=
0.01).
Conclusions
Our results suggest that single-agent PD-1/PD-L1 inhibitors increase the risk of all-grade cardiotoxicity, PD-1/PD-L1 inhibitors combined with chemotherapy increase the risk of all-grade and grade 3-5 cardiotoxicity, especially in those patients treated with PD-1 inhibitor-containing treatment and those with NSCLC. In addition, PD-1/PD-L1 inhibitors combined with chemotherapy increase the risk of arrhythmia and hypertension. Therefore, this evidence should be considered when assessing the benefits and risks of PD-1/PD-L1 inhibitors in treating malignancies.
Systematic Review Registration
https://www.crd.york.ac.uk/prospero/
, identifier CRD42022303115.