Factors Associated With Immune Checkpoint Inhibitor–Related Myocarditis

Abstract

This analysis investigates risk factors for immune checkpoint inhibitor–related myocarditis using a large pool of data gathered from the US Food and Drug Administration Adverse Event Reporting System database.

Immune-related adverse events (irAE) can develop in patients treated with immune checkpoint inhibitors (ICIs). For example, ICI treatment can increase the risk of myocarditis as a lethal irAE,¹ with a mortality rate up to 50%.² However, the frequency of ICI-related myocarditis is low, and thus the detailed pathogenic mechanisms and risk factors remain unknown. General myocarditis and ICI-related myocarditis have distinct manifestations, suggesting different risk factors; however, the differences of risk factors in these 2 types are unclear.

Risk factors for adverse drug events can be determined in a real-world setting through risk assessment using a large-scale spontaneous reporting system covering patients of various backgrounds and observation areas. Here, we investigated the risk factors for ICI-related myocarditis using the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database, an adverse event spontaneous report database from the United States.

Material and Methods

As an observational study using an open access database (FAERS) with anonymized patient information, institutional review board review and approval were waived. Because it is impossible to identify individual patients, informed consent was not required.

Adverse event reports were downloaded from the FDA website, and FAERS data collected between July 2014 and June 2018 were analyzed. Dates of analysis were October 7, 2013, to June 30, 2018. Because FAERS includes duplicate reports, only the most recent report of a patient was used, as recommended by the FDA. Patients aged 0 to 100 years were included in this study. Myocarditis was defined according to the 7 preferred terms listed in the National Center for Biomedical Ontology Medical Dictionary for Regulatory Activities Terminology (ie, autoimmune myocarditis, eosinophilic myocarditis, hypersensitivity myocarditis, lupus myocarditis, myocarditis, myocarditis postinjection, and radiation myocarditis; http://bioportal.bioontology.org/ontologies/MEDDRA?p=classes&conceptid=10029548). Multiple logistic regression analysis, including age, sex, ICI use, and interactions as covariates for the risk of ICI-related myocarditis, was performed using R statistical software version 3.3.2 (R Foundation for Statistical Computing).

Results

We identified 1 979 157 reports including 13 096 cases that received 5 different ICIs. Nivolumab was the most common ICI (n = 6029 of 13 096 [46.04%]). Reporting rates of myocarditis were significantly high in each ICI group (atezolizumab: odds ratio [OR] 6.38, [95% CI, 1.59-25.59]; P = .04; durvalumab: OR, 16.81 [95% CI, 4.18-67.69]; P = .007; ipilimumab alone: OR, 14.26 [7.85-25.88]; P < .001; nivolumab alone: OR, 19.09 [95% CI, 14.34-25.42]; P < .001; and pembrolizumab: OR, 15.70 [95% CI, 10.17-24.23]; P < .001; concomitant ipilimumab and nivolumab: OR, 30.26 [95% CI, 19.58-46.78]; P < .001) (Table 1).

Table 1. Complete Analysis of Patients With Myocarditis Based on Specific Immune Checkpoint Inhibitors^a,b.

Drug A	Without Drug A		With Drug A		Odds Ratio (95% CI)	P Valuec
	Myocarditis/Total Cases	Proportion of Myocarditis (95% CI)	Myocarditis/Total Cases	Proportion of Myocarditis (95% CI)
Atezolizumab	912/1 978 475	0.046 (0.043-0.049)	2/682	0.293 (0.036-1.055)	6.38 (1.59-25.59)	.04
Durvalumab	912/1 978 897	0.046 (0.043-0.049)	2/260	0.769 (0.093-2.751)	16.81 (4.18-67.69)	.007
Ipilimumabd	903/1 977 457	0.046 (0.043-0.049)	11/1700	0.647 (0.323-1.155)	14.26 (7.85-25.88)	<.001
Nivolumabe	864/1 973 128	0.044 (0.041-0.047)	50/6029	0.829 (0.616-1.092)	19.09 (14.34-25.42)	<.001
Pembrolizumab	893/1 976 177	0.045 (0.042-0.048)	21/2980	0.705 (0.437-1.075)	15.70 (10.17-24.23)	<.001
Concomitant (Ipilimumab and Nivolumab)	893/1 977 600	0.045 (0.042-0.048)	21/1557	1.349 (0.837-2.054)	30.26 (19.58-46.78)	<.001

^aAll data analyzed were obtained from the US Food and Drug Administration Adverse Event Reporting System database.

^bEffects of factors not included in the US Food and Drug Administration Adverse Event Reporting System database, such as comorbidity, cancer type, and prior therapy, could not be adjusted. Therefore, it is inappropriate to compare the risks of myocarditis among immune checkpoint inhibitors based on these results alone.

^cHypothesis tests were 2-sided, and statistical significance was set at P < .05. P values were calculated by Fisher exact test.

^dThese data are limited to only ipilimumab users and do not include nivolumab users.

^eThese data are limited to only nivolumab users and do not include ipilimumab users.

As shown in Table 2, multiple logistic regression analysis showed that myocarditis risk was significantly associated with ICI use (OR, 9.66; 95% CI, 7.16-13.05; P < .001). Female sex or age of 75 years or older alone was not associated with an increase in the reported frequency of myocarditis; however, in the analysis of interaction with ICI, myocarditis risk was significantly higher in female patients (OR, 1.92; 95% CI, 1.24-2.97; P = .004) and patients 75 years or older (OR, 7.61; 95% CI, 4.29-13.50; P < .001). In addition, the combination of ICIs (ipilimumab and nivolumab) was also associated with an increased risk of myocarditis (OR, 1.93; 95% CI, 1.19-3.12; P = .008).

Table 2. Multivariate Logistic Analysis of Patients With Myocarditis^a.

Characteristic	Total Cases, No.	Cases of Myocarditis	Proportion of Myocarditis (95% CI)	Odds Ratio (95% CI)		P Valueb
				Crude	Adjusted
Sex
Male	748 314	533	0.071 (0.065-0.078)	1 [Reference]	1 [Reference]
Female	1 199 488	370	0.031 (0.028-0.034)	0.43 (0.38-0.49)	0.44 (0.38-0.51)	<.001
Not reported	31 355	11	0.035 (0.018-0.063)	0.49 (0.27-0.89)	0.42 (0.21-0.84)	.01
Age, y
<75	1 652 576	857	0.052 (0.048-0.055)	1 [Reference]	1 [Reference]
≥75	326 581	57	0.017 (0.013-0.023)	0.34 (0.26-0.44)	0.19 (0.14-0.28)	<.001
ICIs
Nonuser	1 966 061	809	0.041 (0.038-0.044)	1 [Reference]	1 [Reference]
User	13 096	105	0.802 (0.656-0.970)	19.63 (16.01-24.08)	9.66 (7.16-13.05)	<.001
ICIsc,d
Female sex	4798	34	0.709 (0.491-0.989)	NA	1.92 (1.24-2.97)	.004
Age ≥75 years	2442	26	1.065 (0.697-1.556)	NA	7.61 (4.29-13.50)	<.001
Concomitant use of other ICIs	1557	21	1.349 (0.837-2.054)	NA	1.93 (1.19-3.12)	.008

Abbreviations: ICIs, immune checkpoint inhibitors; NA, not applicable.

^aAll data analyzed were obtained from the US Food and Drug Administration Adverse Event Reporting System database.

^bHypothesis tests were 2-sided, and statistical significance was set at a P value <.05. P values were calculated by multiple logistic regression analysis

^cInteraction between each factor and myocarditis.

^dThe imbalance between any 2 groups of comorbidity, cancer type, and concurrent drugs may have affected the increased risk of ICI-related myocarditis in female patients and patients 75 years or older.

Discussion

Our findings suggest that careful monitoring of ICI-related myocarditis is warranted for populations regarded as low-risk for general myocarditis,³ such as female patients and patients 75 years or older. A limitation of the present study is that the FAERS database is a self-reporting database that may include reporting bias and inaccurate reports. In addition, FAERS provides limited information regarding prior diseases, cancer type, and treatment history. Therefore, it is inappropriate to compare the risks of myocarditis among different ICIs based on the results of present study. In addition, the imbalance between 2 groups of irAE risk factors, such as autoimmune disease,⁴ may have contributed to the increased risk of ICI-related myocarditis in female patients and patients 75 years or older.

In previous randomized clinical trials, target patients included relatively healthy elderly patients, in contrast to those in the FAERS database, which might explain the increased risk of ICI-related myocarditis in this population. In addition, the sex differences on irAE outcomes remain controversial, and therefore further specific studies of this association are needed.^5,6 Nevertheless, the FAERS database enables rapid risk assessment, and the present results are useful for improved management of ICI-related myocarditis in clinical practice as well as provide helpful information for detailed future investigations.