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. 2019 Feb 15:15:293-302.
doi: 10.2147/TCRM.S191022. eCollection 2019.

Risk and incidence of fatal adverse events associated with immune checkpoint inhibitors: a systematic review and meta-analysis

Yi Jiang  1 , Ning Zhang  1 , Hailin Pang  1 , Xiaobo Gao  2 , Helong Zhang  1   3
Affiliations

Risk and incidence of fatal adverse events associated with immune checkpoint inhibitors: a systematic review and meta-analysis

Yi Jiang et al. Ther Clin Risk Manag. .

Abstract

Background: Given the increasing use of immune checkpoint inhibitors (ICIs), a concomitant rise in adverse events is inevitable. In a recent Phase III trial of ICIs versus placebo, we found the staggering difference of incidence of fatal adverse events (FAEs). Hence, we should determine the risk of FAEs in ICIs.

Objective: To address the risks of FAEs associated with each ICI regimen, we performed a systematic review and meta-analysis of clinical trials with the Food and Drug Administration-approved ICI regimens in patients with advanced solid tumors.

Methods: Literature searching was based on PubMed before April 15, 2018. The numbers of FAEs in both study group and placebo group were collected. We assessed the risk of fatal adverse reactions associated with ICIs on Pooled Peto OR and associated 95% CI.

Results: Twelve trials were identified. OR value of FADs in all ICIs was 2.32 (95% CI: 1.33, 4.05; P=0.003). The incidence of FAE in ICI in all included studies were up to 3.2%. OR value of clinical trials of prostate cancer was 3.71 (95% CI: 1.12, 12.26; P=0.03). Among the ICI cohorts, the common FAEs were gastrointestinal toxicity (n=12, 25%), pulmonary toxicity (n=10, 20%), cardiac toxicity (n=5, 10%), and hepatic toxicity (n=5, 10%).

Conclusion: The cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) inhibitors have a significantly higher risk of FAE (P=0.01), whereas programmed cell death protein 1 (PD-1) inhibitors were not. The most common CTLA-4-related FAE was gastrointestinal toxicity, and the most common PD-1-related FAE was pulmonary toxicity. Moreover, we have shown that ipilimumab has significant dose-dependent lethal toxicity.

Keywords: immune mediated death; immune mediated mortality; treatment-related mortality.

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Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Flow diagram of study selection. Note: *Two trials were excluded because FAEs did not occur in either study group or control group. Abbreviation: FAE, fatal adverse event.
Figure 2
Figure 2
Forest plots of odds ratios of FAEs with ICIs compared with controls (subgrouped by the types of ICIs). Notes: *In the annotated study, Arm B was compared with the control group; $In the annotated study, Arm B was compared with the control group. Abbreviations: FAE, fatal adverse event; ICI, immune checkpoint inhibitor; CTLA-4, cytotoxic T-lymphocyte-associated protein-4; PD-1, programmed cell death protein 1.
Figure 3
Figure 3
Forest plots of odds ratios of FAEs with ICIs compared with controls (subgrouped by the types of tumors). Notes: *In the annotated study, Arm B was compared with the control group; $In the annotated study, Arm B was compared with the control group. Abbreviations: FAE, fatal adverse event; ICI, immune checkpoint inhibitor; G/GJC, gastric or gastroesophageal junction cancer; NSCLC, non-small-cell lung cancer; SCLC, small-cell lung cancer.
Figure 4
Figure 4
Forest plots of odds ratios of FAEs with ipilimumab compared with controls (subgrouped by the dose of ipilimumab). Note: *In the annotated study, Arm B was compared with the control group. Abbreviation: FAE, fatal adverse event.
Figure 5
Figure 5
Risk of bias graph: review authors’ judgments about each risk of bias item presented as percentages across all included studies. Notes: *In the annotated study, Arm B was compared with the control group; $In the annotated study, Arm B was compared with the control group.
Figure 6
Figure 6
Funnel plot of publication bias.
Figure 7
Figure 7
Begg’s funnel plot for publication bias testing.
Figure 8
Figure 8
Egger’s funnel plot for publication bias testing.
See this image and copyright information in PMC

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