Mapping endocrine toxicity spectrum of immune checkpoint inhibitors: a disproportionality analysis using the WHO adverse drug reaction database, VigiBase

Abstract

Purpose: Our study aimed to map endocrine toxicity spectrum of immune checkpoint inhibitors (ICIs).

Methods: We obtained data from VigiBase, between January 1, 2011 and March 6, 2019. All endocrine adverse drug reactions (ADRs) were classified by group queries according to the Medical Dictionary for Regulatory Activities. Disproportionality analysis was performed with information component (IC) and reporting odds ratio (ROR). We used IC to identify meaningful endocrinopathies associated with ICIs and ROR to compare differences between ICI subgroups of ADRs. IC₀₂₅ (lower end of the 95% confidence interval of IC) is considered significant if larger than 0.

Results: In all, 6089 reports for endocrinopathies associated with ICIs were involved, with a male to female ratio of 1.5:1. The disproportionality analysis indicated significance of not only common endocrinopathies: thyroid dysfunction, hypophysitis/hypopituitarism, adrenal insufficiency, T1DM, fulminant T1DM (IC₀₂₅: 4.12-6.62), but also rare endocrinopathies: hypoparathyroidism, diabetes insipidus, hypogonadism (IC₀₂₅: 1.56-2.04). Increased risk of ADR reporting emerged in anti-CTLA-4 (e.g., hypophysitis/hypopituitarism, adrenal insufficiency) or in anti-PD-1/PD-L1 (e.g., thyroid dysfunction, T1DM, fulminant T1DM). In general, combination therapy (anti-CTLA-4 plus anti-PD-1/PD-L1) had a stronger association with endocrinopathies than monotherapy (ROR: 2.8, 95% CI: 2.5-3.1). Onset time of common endocrinopathies differed between different ICI therapies, typically within 12 weeks in anti-CTLA-4 monotherapy but diffusely ranging from 0 to 48 weeks in anti-PD-1 monotherapy.

Conclusions: Our study shows rising reporting frequencies of endocrinopathies caused by ICIs, especially aggravated in combination therapy. Clinicians should be early aware of latent endocrine toxicity and different onset time of endocrinopathies when implementing ICI therapies.

Keywords: Endocrine toxicity; Endocrinopathy; Immune checkpoint inhibitor; Immune-related adverse event; Onset time.

Fig. 1

The comprehensive spectrum of endocrine ADRs associated with ICIs reported from VigiBase. Information component (IC) reflects the strength of the drug-adverse event association. Positive IC value is regarded as a significant signal in VigiBase. All endocrine ADRs (N = 6089) classified by group queries according to the Medical Dictionary for Regulatory Activities (MedDRA, version 20.1). ICI immune checkpoint inhibitor, ADR adverse drug reaction, SIADH inappropriate antidiuretic hormone secretion, LADA latent autoimmune diabetes in adults, Cushing’s disease pituitary-dependent Cushing’s syndrome, secondary ACI secondary adrenocortical insufficiency. adrenal crisis: acute adrenocortical insufficiency. DM decompensation diabetic metabolic decompensation, DM inadequate control diabetes mellitus inadequate control, HHNS hyperglycaemic hyperosmolar nonketotic syndrome, fulminant T1DM fulminant type 1 diabetes mellitus, ectopic ADH secretion ectopic antidiuretic hormone secretion

Fig. 2

Endocrine toxicity spectra in different ICI therapies. IC information component, IC₀₂₅ the lower end of the 95% confidence interval of IC. IC₀₂₅ > 0 is regarded as statistically significant. Combination therapies include ipilimumab + nivolumab, ipilimumab + pembrolizumab, and ipilimumab + nivolumab + pembrolizumab

Fig. 3

Comparison of endocrine ADRs in different ICI therapies. a P1 vs. C4: anti-PD-1/PD-L1 monotherapy vs. anti-CTLA-4 monotherapy. b P1C4 vs. P1/C4: anti-PD-1/PD-L1 combined with anti-CTLA-4 vs. anti-PD-1/PD-L1 monotherapy and anti-CTLA-4 monotherapy. On the analysis of ROR, a minimum count of drug-adverse reaction (N ≥ 3) was imposed. SIADH inappropriate antidiuretic hormone secretion, secondary ACI secondary adrenocortical insufficiency, adrenal crisis acute adrenocortical insufficiency, fulminant T1DM fulminant type 1 diabetes mellitus

Fig. 4

Onset time of major endocrine ADRs associated with a (nivolumab), b (pembrolizumab), c (ipilimumab), d (combination). Combination: anti-PD-1/PD-L1 combined with anti-CTLA-4. ICI-ACI ICI-related adrenocortical insufficiency, ICI-HypoP ICI-related hypophysitis/hypopituitarism, ICI-HyperT ICI-related hyperthyroidism, ICI-HypoT ICI-related hypothyroidism