Adverse Event Profiles of Anti-CTLA-4 and Anti-PD-1 Monoclonal Antibodies Alone or in Combination: Analysis of Spontaneous Reports Submitted to FAERS

Ji, Huanhuan; Tang, Xuewen; Dong, Zhi Wei; Song, Lin; Jia, Yuntao

doi:10.1007/s40261-018-0735-0

Cited by 92 publications

(79 citation statements)

References 35 publications

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“…Furthermore, the research using the SRS database focuses on myasthenia gravis, 14 and myocarditis. 13 Using the FAERS database, Ji et al 10 comprehensively evaluated AE profiles, including irAEs using Standardized MedDRA Queries 20 that consist of PTs grouped according to the level that relates to a defined medical condition. Based on previous reports, 3,6,[9][10][11]13,14,19,21 we categorized irAEs into the following 14 groups: adrenal insufficiency, colitis, eye disease, hematological disorder, hepatitis, hyperthyroidism, hypopituitarism, hypothyroidism, myasthenia gravis, myocarditis, nephritis/renal dysfunction, pneumonitis, rash, and type 1 diabetes mellitus and selected PTs for each category (Table 1).…”

Section: Target Drugs and Iraesmentioning

confidence: 99%

“…63,64 Severe autoimmune hepatitis occurred in 20% of patients who were co-administered nivolumab and ipilimumab. 9,62 It is reported that the ROR signals of nivolumab, pembrolizumab, and ipilimumab were detected in the FAERS database, 10 whereas the signal of pembrolizumab was not detected in the JADER database. Conflicts between reporters and reported AE terms, discrepancies in reported drugs, reported AEs, reporter type, anomalies between reporting systems across countries as a result of country-specific regulation, etc., are well-known.…”

Section: Thyroid Dysfunction Following Treatment With Anti-pd-1 Anti-mentioning

confidence: 99%

“…67 Several studies based on the FAERS database have reported ROR signals for myocarditis. 10,13 We conducted a time-to-onset analysis of the JADER data set and found that the median onset of myocarditis was 3 to 4 weeks follow- A wide range of renal dysfunction symptoms were often observed with the anti-PD-1 antibody. 3,9,10 Rash was a common dermatological AE induced by anti-PD-1 antibodies and the anti-CTLA-4 antibody, ipilimumab.…”

Section: Thyroid Dysfunction Following Treatment With Anti-pd-1 Anti-mentioning

confidence: 99%

“…10,13 We conducted a time-to-onset analysis of the JADER data set and found that the median onset of myocarditis was 3 to 4 weeks follow- A wide range of renal dysfunction symptoms were often observed with the anti-PD-1 antibody. 3,9,10 Rash was a common dermatological AE induced by anti-PD-1 antibodies and the anti-CTLA-4 antibody, ipilimumab. 5,10,[68][69][70] In our study, the ROR signals of the whole data for rash and nephritis/renal dysfunction were not detected.…”

Section: Thyroid Dysfunction Following Treatment With Anti-pd-1 Anti-mentioning

confidence: 99%

“…6 irAEs may affect any organ or system such as the colon (colitis), eye disease, hematological disorder, liver (hepatitis), nervous system (myasthenia gravis), heart (myocarditis), kidneys (renal dysfunction), lungs (pneumonitis), skin (rash), and endocrine system (adrenal insufficiency, hypopituitarism, thyroiditis, diabetes mellitus). 2,9,10 Such irAEs are mostly transient and mild and can lead to the discontinuation of therapy with ICIs or immunosuppressive agents. 11 Although fatal toxic effects associated with ICIs are uncommon and compare favorably with fatal toxic effects that occur with other oncologic interventions, they do occur, at a rate of 0.3-1.3%.…”

Section: Introductionmentioning

confidence: 99%

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Analysis of immune‐related adverse events caused by immune checkpoint inhibitors using the Japanese Adverse Drug Event Report database

Hasegawa

Ikesue

Nakao

et al. 2020

Pharmacoepidemiology and Drug

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The aim of our study was to characterize the clinical features of immunerelated adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) in a real-world setting using the Japanese Adverse Drug Event Report (JADER) database. Methods: The irAEs were defined using the preferred terms of the Medical Dictionary for Regulatory Activities. irAEs were categorized as follows: adrenal insufficiency, colitis, eye diseases, hematological disorder, hepatitis, hyperthyroidism, hypopituitarism, hypothyroidism, myasthenia gravis, myocarditis, nephritis/renal dysfunction, pneumonitis, rash, and type 1 diabetes mellitus. We used several indices such as reporting odds ratio (ROR) to assess disproportionality in pharmacovigilance data, time-to-onset analysis using Weibull shape parameters, and the association rule mining technique to evaluate possible risk factors between variables in the spontaneous reporting system database.

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Section: Target Drugs and Iraesmentioning

confidence: 99%

Section: Thyroid Dysfunction Following Treatment With Anti-pd-1 Anti-mentioning

confidence: 99%

Section: Thyroid Dysfunction Following Treatment With Anti-pd-1 Anti-mentioning

confidence: 99%

Section: Thyroid Dysfunction Following Treatment With Anti-pd-1 Anti-mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Analysis of immune‐related adverse events caused by immune checkpoint inhibitors using the Japanese Adverse Drug Event Report database

Hasegawa

Ikesue

Nakao

et al. 2020

Pharmacoepidemiology and Drug

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Hematological toxicities in immune checkpoint inhibitors: A pharmacovigilance study from 2014 to 2019

Zhai

et al. 2020

Hematological Oncology

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Immune checkpoint inhibitors (ICIs) have shown remarkable clinical effects in many cancer types. However, ICIs could also induce severe organ system toxicities, including those of the hematological system. The present study aimed to extensively characterize the hematological toxicities of ICIs immunotherapy. Data were extracted from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database from January 1, 2014, to March 31, 2019. Disproportionality analysis, including information component (IC) and reporting odds ratio (ROR), was used to detect potential disproportionality signal. The lower boundary of the 95% confidence interval of IC (IC 025) exceeding zero or that of ROR (ROR 025) exceeding one was considered statistically significant for detecting disproportionality signal. A total of 29 294 335 records were extracted from the database, with 132 573 related to ICIs. Overall, hematological adverse events (AEs) were more frequently reported in ICIs (IC 025 : 0.81; ROR 025 : 1.80). On further analysis, hematological AEs were overreported in female patients (female vs male, ROR 025 : 1.04) and anti-CTLA-4 monotherapy groups (anti-CTLA-4 vs anti-PD-1, ROR 025 : 1.33) and polytherapy groups (polytherapy vs monotherapy, ROR: 1.20, ROR 025 : 1.11). Moreover, class-specific hematological AEs were also detected and differed in unique ICI regimens. Notably, disseminated intravascular coagulation had the highest proportion of death outcomes among the top 10 most frequently reported ICI-associated hematological AEs. Our study shows a high reporting frequency of hematological AEs induced by ICI monotherapy (especially by anti-CTLA-4 therapy) and reinforced by polytherapy. A spectrum of class-specific disproportionality signal was also detected; some were fatal and reported for the first time. The heterogeneous clinical spectrum of hematological toxicities, including the non-negligible proportion of death as reported outcome, are warranted to be reminded by clinicians. Early recognition and management of ICIrelated hematological AEs are highly important and further studies are needed to confirm the results of our study.

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

Filippini

Gatti

Martino

et al. 2021

Intl Journal of Cancer

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Although immune checkpoint inhibitors (ICIs) are associated with different immune-related adverse events (irAEs), the potential effect on the skeleton is poorly defined albeit biologically plausible and assessable through pharmacovigilance. We described a case series of patients experiencing skeletal fractures while on ICIs at the National Cancer Institute of Milan. To better characterize the clinical features of skeletal irAEs reported with ICIs, we queried the FDA Adverse Event Reporting System (FAERS) and performed disproportionality analysis by means of reporting odds ratios (RORs), deemed significant by a lower limit of the 95% confidence interval (LL95% CI) > 1. Bone AEs emerging as significant were scrutinized in terms of demographic and clinical data, including concomitant irAEs or drugs affecting bone resorption or causing bone damage. Four patients with skeletal events while on ICIs were included in our case series, of which three exhibited vertebral fractures. In FAERS, 650 patients with bone and joint injuries and treated with ICIs were retrieved, accounting for 822 drug-event pairs. Statistically significant ROR was found for eight, two and one bone AEs respectively with PD-1, PD-L1 and CTLA-4 inhibitors, being pathological fracture (N = 46; ROR = 3.17; LL95%CI = 2.37), spinal compression fracture (42; 2.51; 1.91), and femoral neck fracture (26; 2.38; 1.62) the most common. Concomitant irAEs or drugs affecting bone metabolism were poorly reported.The increased reporting of serious vertebral fractures in patients without concomitant irAEs and no apparent preexisting risk factors could suggest a possible cause-effect relationship and calls for close clinical monitoring and implementation of dedicated guidelines.

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Adverse Event Profiles of Anti-CTLA-4 and Anti-PD-1 Monoclonal Antibodies Alone or in Combination: Analysis of Spontaneous Reports Submitted to FAERS

Cited by 92 publications

References 35 publications

Analysis of immune‐related adverse events caused by immune checkpoint inhibitors using the Japanese Adverse Drug Event Report database

Analysis of immune‐related adverse events caused by immune checkpoint inhibitors using the Japanese Adverse Drug Event Report database

Hematological toxicities in immune checkpoint inhibitors: A pharmacovigilance study from 2014 to 2019

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

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