Abstract
BackgroundImmune-checkpoint inhibitors (ICIs) emerged as a novel class of drugs for the treatment of a broad spectrum of malignancies. ICIs can produce durable antitumor responses but they are also associated with immune-related adverse events (irAEs). Endocrinopathies have reported as one of the most common irAEs of ICIs.MethodsThis study aimed to quantify association of endocrine adverse events (AEs) and ICI therapy and also to characterize the profiles of ICI-related endocrine complications from real-world practice. Data from the first quarter of 2014 to first quarter of 2019 in FDA Adverse Event Reporting System (FAERS) database were gathered to conduct disproportionality analysis. The definition of endocrine AEs relied on the preferred terms (PTs) provided by the Medical Dictionary for Regulatory Activities (MedDRA). Two signal indices based on statistical shrinkage transformation, reporting odds ratios (ROR) and information component (IC), were used to evaluate correlations between ICIs and endocrine events. For ROR, it was defined a signal if the lower limit of the 95% confidence interval (ROR025) more than one, with at least 3 cases. For IC, lower end of the 95% confidence interval of IC (IC025) exceeding zero was deemed statistically significant.ResultsA total of 29,294,336 records were involved, among these 6260 records related to endocrine AEs after ICIs treatment were identified. In general, male had a slightly lower reporting frequencies for ICIs-related endocrinopathies compared with female but not significant (ROR = 0.98 95%CI: 0.93–1.04) and the difference varied in several common endocrine AEs. Notably, in general, ICI drugs were significantly associated with over-reporting frequencies of endocrine complications, corresponding to IC025 = 2.49 and ROR025 = 5.99. For monotherapy, three strategies (anti-PD-1, anti-PD-L1 and anti-CTLA-4) were all associated with significant increasing endocrine events. Different reporting frequencies emerged when anti-CTLA-4 therapy was compared with anti-PD-1/PD-L1 medications for endocrine toxicities, corresponding to ROR = 1.68 (95%CI 1.55–1.83), ROR = 2.54 (95%CI 2.20–2.93), respectively. Combination therapy was associated with higher risk of endocrinopathies compared with monotherapy (ROR = 2.00, 95%CI 1.89–2.11). When further analysis, the spectrum of endocrine AEs differed in immunotherapy regimens. Hypothyroidism (N = 885,14.14%), adrenal insufficiency(N = 730,11.66%), hypophysitis (N = 688,10.99%) and hyperthyroidism (N = 472,7.54%) were top 4 ranked endocrine events after ICI therapy and their reporting frequency also differed in ICI immunotherapies.ConclusionOur pharmacovigilance analysis shows a high reporting frequency of endocrine AEs provoked by ICI monotherapy (especially anti-CTLA-4 therapy) and further reinforced by combination therapy. In addition, treatment with different ICI immunotherapies may result in a unique and distinct profile of endocrinopathies. Early recognition and management of ICI-related endocrine irAEs is of vital importance in clinical practice.
Highlights
Immune checkpoint inhibitors (ICIs) are a novel class of medications in cancer treatment and have rapidly gained popularity for their success in improving clinical outcomes in multiple cancer types [1]
Descriptive analysis A total of 29,294,336 records were involved in the full FDA Adverse Event Reporting System (FAERS) dataset, among these 6260 were reported for endocrine adverse events (AEs) after Immune-checkpoint inhibitors (ICIs) treatment
Men accounted for a larger proportion than women regardless in ICIs (54.76% vs 33.47%) or any other drugs (40.90% vs 13.40%).Whereas, when further analysis, male had a slightly lower reporting frequencies for ICIs-related endocrinopathies compared with female but not significant (ROR = 0.98 95%CI: 0.93–1.04) and the difference varied in several common endocrine AEs (Additional file 1:Table S1;Figure S1)
Summary
Immune checkpoint inhibitors (ICIs) are a novel class of medications in cancer treatment and have rapidly gained popularity for their success in improving clinical outcomes in multiple cancer types [1]. The administration of ICIs, whereas, carry the risk of developing immune-related adverse events (irAEs) and may lead to serious and even fatal events [3, 4]. Endocrinopathies are among the most common irAEs associated with ICIs therapy including hypophysitis, thyroid dysfunction (hypothyroidism/hyperthyroidism), insulin-deficient diabetes mellitus [5]. While pharmacovigilance data may lack detailed clinical information, using this approach may help discovery potential drug-toxicity associations [6]. Immune-checkpoint inhibitors (ICIs) emerged as a novel class of drugs for the treatment of a broad spectrum of malignancies. ICIs can produce durable antitumor responses but they are associated with immune-related adverse events (irAEs). Endocrinopathies have reported as one of the most common irAEs of ICIs
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