Endocrine toxicity of immune checkpoint inhibitors: a real-world study leveraging US Food and Drug Administration adverse events reporting system

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 clin...

Bone fracture as a novel immune‐related adverse event with immune checkpoint inhibitors: Case series and large‐scale pharmacovigilance analysis

“…Only one preliminary case series has been reported so far, raising the hypothesis of skeletal events related to ICIs. 7 Although bone-related toxicity appears to be rare, accounting for less than 1% of overall reports, similarly to other rare irAEs (eg, hepatitis, myocarditis, endocrinopathies, severe cutaneous adverse reactions and hematological toxicities), 5,6,11,[16][17][18] physicians should be aware that skeletal irAEs do occur with ICIs even in patients without other known risk factors.…”

Adverse events associated with potential drugs for COVID-19: a case study from real-world data

“…Analyses of safety data from clinical trials should be undertaken to further investigate the toxicities of these drugs in the COVID-19 setting. Furthermore, FAERS is a postmarketing safety surveillance program for FDA-approved drugs and therapeutic biologic products [ 25 ] and essentially based on spontaneous reports thus provide limited information about patients’ characteristics, treatment and disease histories [ 26–28 ]. Some confounding factors, such as drug–drug interaction, prior diseases and coexisting illness, are lacking from FAERS.…”

Hyponatremia in the cancer patient

“…r e v i e w BT Workeneh et al: Hyponatremia in the onconephrology patient with both CTLA-4 and PD-1 inhibitors (Box 2), but it more frequently occurs with CTLA-4. 42 In hypophysitis, a loss of adrenocorticotropic hormone-secreting corticotrophs leads to a cortisol deficiency and loss of its inhibitory effects over vasopressin. The incidence of hypophysitis in patients treated with this ipilimumab is close to 17% in clinical trials.…”