Psychiatric disorders associated with immune checkpoint inhibitors: a pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) database

Zhou, Chaozheng; Shu, Peng; Lin, Anqi; Jiang, Aimin; Peng, Yuanxi; Gu, Tianqi; Han, Xinwei; Cheng, Quan; Zhang, Jian; Luo, Peng

doi:10.1016/j.eclinm.2023.101967

Cited by 65 publications

(14 citation statements)

References 58 publications

(62 reference statements)

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“…Conversely, analyzing ADEs in isolation without understanding the underlying molecular etiology of the observed signals can lead to “fragmentation” in the relationship between ADEs and genomic alterations. By integrating genomic-level evidence and participant target data from clinical trials, this fragmentation can be partially mitigated, aiding in the identification of high-risk individuals and populations for ADEs, thus enhancing drug safety, efficacy, and overall public health ( Zhou et al, 2023 ). Recently, studies have emerged linking genomics and pharmacovigilance.…”

Section: Discussionmentioning

confidence: 99%

From genomic spectrum of NTRK genes to adverse effects of its inhibitors, a comprehensive genome-based and real-world pharmacovigilance analysis

Cui,

Zhai,

Xie

et al. 2024

Front. Pharmacol.

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Introduction: The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions has facilitated the development of precision oncology. Two first-generation NTRK inhibitors (larotrectinib and entrectinib) are currently approved for the treatment of patients with solid tumors harboring NTRK gene fusions. Nevertheless, comprehensive NTRK profiling at the pan-cancer genomic level and real-world studies pertaining to the adverse events of NTRK inhibitors are lacking.Methods: We characterize the genome of NTRK at the pan-cancer level through multi-omics databases such as The Cancer Genome Atlas (TCGA). Through the FDA Adverse Event Reporting System (FAERS) database, we collect reports of entrectinib and larotrectinib-induced adverse events and perform a pharmacovigilance analysis using various disproportionality methods.Results:NTRK1/2/3 expression is lower in most tumor tissues, while they have higher methylation levels. NTRK gene expression has prognostic value in some cancer types, such as breast invasive carcinoma (BRCA). The cancer type with highest NTRK alteration frequency is skin cutaneous melanoma (SKCM) (31.98%). Thyroid carcinoma (THCA) has the largest number of NTRK fusion cases, and the most common fusion pair is ETV6-NTRK3. Adverse drug events (ADEs) obtained from the FAERS database for larotrectinib and entrectinib are 524 and 563, respectively. At the System Organ Class (SOC) level, both drugs have positive signal value for “nervous system disorder”. Other positive signals for entrectinib include “cardiac disorders”, “metabolism and nutrition disorders”, while for larotrectinib, it is “hepatobiliary disorders”. The unexpected signals are also listed in detail. ADEs of the two NTRK inhibitors mainly occur in the first month. The median onset time of ADEs for entrectinib and larotrectinib was 16 days (interquartile range [IQR] 6–86.5) and 44 days ([IQR] 7–136), respectively.Conclusion: Our analysis provides a broad molecular view of the NTRK family. The real-world adverse drug event analysis of entrectinib and larotrectinib contributes to more refined medication management.

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Section: Discussionmentioning

confidence: 99%

From genomic spectrum of NTRK genes to adverse effects of its inhibitors, a comprehensive genome-based and real-world pharmacovigilance analysis

Cui,

Zhai,

Xie

et al. 2024

Front. Pharmacol.

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“…It is commonly used in pharmacovigilance studies as a method for evaluating potential associations between different types of AE and a particular drug, which can then be evaluated clinically through the assessment of individual case reports ( 23 ). Reporting odds ratio (ROR) reflects the likelihood of a particular drug being reported for a specific event of interest in comparison to the likelihood of reporting events for other drugs in the FAERS database ( 24 ), and ROR was calculated in this study to evaluate AE signals in ICI reports among NSCLC patients ( 10 ). Using full AE reports of NSCLC patients from the FAERS database as comparators, we conducted disproportionality analysis to evaluated possible relationship between AEs and ICIs in NSCLC patients by the ROR ( 25 ).…”

Section: Methodsmentioning

confidence: 99%

“…Due to their ability to block the pathways that are involved in regulating the immune system, ICIs may associate with high risk of immune-related adverse events (irAEs) by inducing inflammation in the organs ( 6 ). ICI-associated irAEs can potentially involve multiple system organ classes (SOC), including the skin (eg, rash and pruritus) ( 7 ), gastrointestinal tract (eg, diarrhea and colitis) ( 8 ), endocrine (eg, hypothyroidism and hypophysitis) ( 9 ), lung (eg, pneumonitis) ( 7 ), and psychiatric disorders (eg, delirium) ( 10 ). Without proper management, irAEs can be severe and life-threatening and may result in treatment discontinuation or failure.…”

Section: Introductionmentioning

confidence: 99%

Adverse events associated with immune checkpoint inhibitors in non-small cell lung cancer: a safety analysis of clinical trials and FDA pharmacovigilance system

Liang,

Xiao,

et al. 2024

Front. Immunol.

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ObjectivesImmune checkpoint inhibitors (ICIs) have revolutionized the treatment of non-small cell lung cancer (NSCLC). However, the application of ICIs can also cause treatment-related adverse events (trAEs) and immune-related adverse events (irAEs). This study was to evaluate both the irAEs and trAEs of different ICI strategies for NSCLC based on randomized clinical trials (RCTs). The study also examined real-world pharmacovigilance data from the Food and Drug Administration Adverse Event Reporting System (FAERS) regarding claimed ICI-associated AEs in clinical practice.MethodsBased on Pubmed, Embase, Medline, and the Cochrane CENTRAL, we retrieved RCTs comparing ICIs with chemotherapy drugs or with different ICI regimens for the treatment of NSCLC up to October 20, 2023. Bayesian network meta-analysis (NMA) was performed using odds ratios (ORs) with 95% credible intervals (95%CrI). Separately, a retrospective pharmacovigilance study was performed based on FAERS database, extracting ICI-associated AEs in NSCLC patients between the first quarter (Q1) of 2004 and Q4 of 2023. The proportional reports reporting odds ratio was calculated to analyze the disproportionality.ResultsThe NMA included 51 RCTs that involved a total of 26,958 patients with NSCLC. Based on the lowest risk of any trAEs, cemiplimab, tislelizumab, and durvalumab were ranked as the best. Among the agents associated with the lowest risk of grades 3-5 trAEs, tislelizumab, avelumab, and nivolumab were most likely to rank highest. As far as any or grades 3-5 irAEs are concerned, atezolizumab plus bevacizumab plus chemotherapy is considered the most safety option. However, it is associated with a high risk of grades 3-5 trAEs. As a result of FAERS pharmacovigilance data analysis, 9,420 AEs cases have been identified in 7,339 NSCLC patients treated with ICIs, and ICIs were related to statistically significant positive signal with 311 preferred terms (PTs), and comprehensively investigated and identified those AEs highly associated with ICIs. In total, 152 significant signals were associated with Nivolumab, with malignant neoplasm progression, death, and hypothyroidism being the most frequent PTs.ConclusionThese findings revealed that ICIs differed in their safety profile. ICI treatment strategies can be improved and preventive methods can be developed for NSCLC patients based on our results.

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“…The FDA Adverse Event Reporting System (FAERS) is one of the world's largest pharmacovigilance databases, comprising voluntary reports on FDA-approved therapies 11 . In this study, the clinical safety of capmatinib was investigated based on the FAERS database.…”

Section: Introductionmentioning

confidence: 99%

A real-world pharmacovigilance study of FDA adverse event reporting system events for Capmatinib

Qi,

Li,

Lin

et al. 2024

Sci Rep

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Capmatinib is a potent selective mesenchymal-epithelial transition inhibitor approved in 2020 for the treatment of metastatic non-small cell lung cancer. As real-world evidence is very limited, this study evaluated capmatinib-induced adverse events through data mining of the FDA Adverse Event Reporting System database. Four disproportionality analysis methods were employed to quantify the signals of capmatinib-related adverse events. The difference in capmatinib-associated adverse event signals was further investigated with respect to sex, age, weight, dose, onset time, continent, and concomitant drug. A total of 1518 reports and 4278 adverse events induced by capmatinib were identified. New significant adverse event signals emerged, such as dysphagia, dehydration, deafness, vocal cord paralysis, muscle disorder, and oesophageal stenosis. Notably, higher risk of alanine aminotransferase and aspartate aminotransferase increases were observed in females, especially when capmatinib was combined with immune checkpoint inhibitors. Compared with Europeans and Asians, Americans were more likely to experience peripheral swelling, especially in people > 65 years of age. Renal impairment and increased blood creatinine were more likely to occur with single doses above 400 mg and in Asians. This study improves the understanding of safety profile of capmatinib.

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Psychiatric disorders associated with immune checkpoint inhibitors: a pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) database

Cited by 65 publications

References 58 publications

From genomic spectrum of NTRK genes to adverse effects of its inhibitors, a comprehensive genome-based and real-world pharmacovigilance analysis

From genomic spectrum of NTRK genes to adverse effects of its inhibitors, a comprehensive genome-based and real-world pharmacovigilance analysis

Adverse events associated with immune checkpoint inhibitors in non-small cell lung cancer: a safety analysis of clinical trials and FDA pharmacovigilance system

A real-world pharmacovigilance study of FDA adverse event reporting system events for Capmatinib

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