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

ABSTRACT: BACKGROUND: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 also associated with immune-related adverse events (irAEs). Endocrinopathies have reported as one of the most common irAEs of ICIs. METHODS:This 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. RESULTS:A 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. CONCLUSION:Our 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.

SUBMITTER: Zhai Y

PROVIDER: S-EPMC6836403 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Zhai Yinghong Y Ye Xiaofei X Hu Fangyuan F Xu Jinfang J Guo Xiaojing X Zhuang Yonglong Y He Jia J

Journal for immunotherapy of cancer 20191106 1

<h4>Background</h4>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 also associated with immune-related adverse events (irAEs). Endocrinopathies have reported as one of the most common irAEs of ICIs.<h4>Methods</h4>This study aimed to quantify association of endocrine adverse events (AEs) and ICI therapy and also to characterize the profiles of ICI-related endocri ...[more]

PMID: 31694698

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Project description:BackgroundAlthough arrhythmias have been reported in patients treated with immune checkpoint inhibitors (ICIs), the association between arrhythmias and ICIs has not been thoroughly evaluated in real-world studies. We aimed to describe the major features of ICI-related arrhythmic events and identify the factors that contributed to death.MethodsA disproportionality analysis was performed using data from the Food and Drug Administration Adverse Event Reporting System (FAERS) database from January 2011 to December 2021. Reporting odds ratios (RORs), proportional reporting ratio and information component were used to assess whether adverse arrhythmic events were associated with ICIs. The clinical characteristics of patients with ICI-associated arrhythmias were compared with fatal and non-fatal arrhythmias. The time to onset (TTO), fatality rates of arrhythmic events were also investigated.ResultsWe identified a total of 1945 cases of ICI-related arrhythmic events. Men (64.78%) were identified significantly more frequently than women (28.84%). The median age was 68 years ([interquartile range, IQR] 60-75 years). Anti-programmed cell death-1 (PD-1) and anti-programmed cell death ligand-1 (PD-L1) were associated with adverse arrhythmic events, corresponding to ROR 1.11 (95% confidence interval [CI] 1.05-1.17) and ROR 1.34 (95% CI 1.20-1.49), respectively. However, anti-cytotoxic T-lymphocyte associated protein 4 or combination immunotherapy did not appear to be associated with arrhythmic events. Atrial fibrillation (N = 576, 0.62%), cardiac arrest (N = 284, 0.31%), tachycardia (N = 175, 0.19%) were the most common adverse arrhythmic events. Sudden death and complete atrioventricular block are adverse events that are significantly associated with ICI-related arrhythmic events and have strong signal intensity. The TTO of cases that resulted in death (30 days [IQR] 11-73.75) was significantly earlier than that of cases that did not result in death (33 days [IQR 10.5-88.5], p = 0.003). ICI-related arrhythmic events were severe with death occurring in 507 (26.07%) of 1945 arrhythmias cases.ConclusionsTreatment with PD-1/PD-L1 may cause arrhythmic events, which are severe and tend to occur early on during treatment. It is important to identify ICI-related arrhythmias as early as possible, and to manage them appropriately.

Project description:Unlabelled: In recent years, immune checkpoint inhibitors have emerged as effective therapies for advanced neoplasias. As new checkpoint target blockers become available and additional tumor locations tested, their use is expected to increase within a short time. Immune-related adverse events (irAEs) affecting the endocrine system are among the most frequent and complex toxicities. Some may be life-threatening if not recognized; hence, appropriate guidance for oncologists is needed. Despite their high incidence, endocrine irAEs have not been fully described for all immunotherapy agents available. This article is a narrative review of endocrinopathies associated with cytotoxic T lymphocyte-associated antigen-4, blockade of programmed death receptor 1 and its ligand inhibitors, and their combination. Thyroid dysfunction is the most frequent irAE reported, and hypophysitis is characteristic of ipilimumab. Incidence, timing patterns, and clinical presentation are discussed, and practical recommendations for clinical management are suggested. Heterogeneous terminology and lack of appropriate resolution criteria in clinical trials make adequate evaluation of endocrine AEs difficult. It is necessary to standardize definitions to contrast incidences and characterize toxicity patterns. To provide optimal care, a multidisciplinary team that includes endocrinology specialists is recommended.Implications for practiceImmune checkpoint inhibitors are already part of oncologists' therapeutic arsenal as effective therapies for otherwise untreatable neoplasias, such as metastatic melanoma or lung cancer. Their use is expected to increase exponentially in the near future as additional agents become available and their approval is extended to different tumor types. Adverse events affecting the endocrine system are among the most frequent and complex toxicities oncologists may face, and some may be life-threatening if not recognized. This study reviews endocrinopathies associated to immune checkpoint inhibitors available to date. Incidence, timing patterns, and clinical presentation are discussed, and practical recommendations for management are proposed.

Project description:Esketamine was approved for the treatment of treatment-resistant depression in 2019. After the approval of esketamine, numerous concerns have been raised regarding its long-term safety and tolerability. A previous systematic pharmacovigilance study on esketamine-related adverse events (AEs) was published in 2020; however, it has not been updated 2 years later. The primary aim of this study was to detect and characterize neurological safety signals of esketamine to partially update the knowledge in this field using the FDA pharmacovigilance database. Reporting odds ratio (ROR) was calculated for esketamine-related neurological AEs from 2019 to 2021 with a signal considered when the lower limit of the 95% confidence interval (CI) of ROR (ROR025) exceeded one. Severe and non-severe cases were compared using an independent samples t-test or chi-squared (χ2) test, and a rating scale was used to prioritize the signals. The database contained 720 cases of esketamine-associated neurological AEs, with 21 signals detected, ranging from a ROR025 of 1.05 (disturbance in attention) to 204.00 (sedation). 16 latest neurological AEs emerged in the second year of marketing approval of esketamine, with eight signals detected. The associations between esketamine and nervous system disorders persisted when stratifying by sex, age, and reporter type, whereas the spectrum of neurological AEs differed in stratification regimens. Esketamine dosage, antidepressant polypharmacy, or co-prescription with benzodiazepines affected AEs severity (t = 2.41, p = 0.017; χ2 = 6.75, p = 0.009; and χ2 = 4.10, p = 0.043; respectively), while age and sex did not (p = 0.053 and p = 0.397, respectively). Three signals were categorized as moderate clinical priority [i.e., sedation, dizziness, and dysgeusia (priority points 7, 5, and 5, respectively)], showing the same early failure type profiles. Notably, seven detected disproportionality signals were not previously detected in clinical trials. Although the majority of results were in line with those obtained in the previous study, there were discrepancies in the spectrum of neurological AEs and the effects of several risk factors on AEs severity among the two studies that should be recognized and managed early in clinical treatments.

Project description:BackgroundRisankizumab, a humanized IgG1 monoclonal antibody that selectively inhibits IL-23, is currently approved for the treatment of moderate-to-severe plaque psoriasis and Crohn's disease. The real-world safety study of risankizumab in a large- sample population is currently lacking. The aim of this study was to evaluate risankizumab-associated adverse events (AEs) and characterize the clinical priority through the data mining of the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS).MethodsDisproportionality analyses were performed by calculating the reporting odds ratios (RORs), deemed significant when the lower limit of the 95% confidence interval was greater than 1, to quantify the signals of risankizumab-related AEs from the second quarter (Q2) of 2019 to 2022 Q3. Serious and non-serious cases were compared, and signals were prioritized using a rating scale.ResultsRisankizumab was recorded in 10,235 reports, with 161 AEs associated with significant disproportionality. Of note, 37 PTs in at least 30 cases were classified as unexpected AEs, which were uncovered in the drug label, such as myocardial infarction, cataract, pancreatitis, diabetes mellitus, stress, and nephrolithiasis. 74.68%, 25.32%, and 0% PTs were graded as weak, moderate, and strong clinical priorities, respectively. A total of 48 risankizumab-related AEs such as pneumonia, cerebrovascular accident, cataract, loss of consciousness, cardiac disorder, hepatic cirrhosis, and thrombosis, were more likely to be reported as serious AEs. The median TTO of moderate and weak signals related to risankizumab was 115 (IQR 16.75-305) and 124 (IQR 29-301) days, respectively. All of the disproportionality signals had early failure type features, indicating that risankizumab-associated AEs gradually decreased over time.ConclusionOur study found potential new AE signals and provided valuable evidence for clinicians to mitigate the risk of risankizumab-associated AEs based on an extensive analysis of a large-scale postmarketing international safety database.

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

Publications

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

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