Emanuel Raschi1, Alessandra Mazzarella2, Ippazio Cosimo Antonazzo2, Nicolò Bendinelli2, Emanuele Forcesi2, Marco Tuccori3, Ugo Moretti4, Elisabetta Poluzzi2, Fabrizio De Ponti2. 1. Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy. emanuel.raschi@unibo.it. 2. Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy. 3. Unit of Adverse Drug Reactions Monitoring, Tuscan Regional Centre of Pharmacovigilance, University Hospital of Pisa, Via Roma 55, 56126, Pisa, Italy. 4. Department of Public Health and Community Medicine, University of Verona, Verona, Italy.
Abstract
BACKGROUND: Immune checkpoint inhibitors (ICIs), including antibodies targeting cytotoxic T-lymphocyte associated protein 4 (CTLA4) and programmed cell death 1 or its ligand (PD1/PDL1), elicit different immune-related adverse events (irAEs), but their global safety is incompletely characterized. OBJECTIVE: The aim of this study was to characterize the spectrum, frequency, and clinical features of ICI-related adverse events (AEs) reported to the FDA Adverse Event Reporting System (FAERS). PATIENTS AND METHODS: AEs from FAERS (up to June 2018) recording ICIs (ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab) as suspect were extracted. Comprehensive disproportionality analyses were performed through the reporting odds ratio (ROR) with 95% confidence interval (95% CI), using other oncological drugs as comparison. An overview of systematic reviews (OoSRs) was also undertaken to identify irAEs with consistent positive associations. RESULTS: ICIs were recorded in 47,266 reports, submitted mainly by consumers receiving monotherapy with anti-PD1/PDL1 drugs. Three areas of toxicity emerged from both disproportionality analysis and the OoSRs (32 studies): endocrine (N = 2863; ROR = 6.91; 95% CI 6.60-7.23), hepatobiliary (2632; 1.33; 1.28-1.39), and respiratory disorders (7240; 1.04; 1.01-1.06). Different reporting patterns emerged for anti-CTLA4 drugs (e.g., hypophysitis, adrenal insufficiency, hypopituitarism, and prescribed overdose) and anti-PD1/PDL1 agents (e.g., pneumonitis, cholangitis, vanishing bile duct syndrome, tumor pseudoprogression, and inappropriate schedule of drug administration). No increased reporting emerged when comparing combination with monotherapy regimens, but multiple hepatobiliary/endocrine/respiratory irAEs were recorded. CONCLUSIONS: This parallel approach through contemporary post-marketing analysis and OoSRs confirmed that ICIs are associated with a multitude of irAEs, with different reporting patterns between anti-CTLA4 and anti-PD1/PDL1 medications. Close clinical monitoring is warranted to early diagnose and timely manage irAEs, especially respiratory, endocrine, and hepatic toxicities, which warrant further characterization; patient- and drug-related risk factors should be assessed through analytical pharmaco-epidemiological studies and prospective multicenter registries.
BACKGROUND: Immune checkpoint inhibitors (ICIs), including antibodies targeting cytotoxic T-lymphocyte associated protein 4 (CTLA4) and programmed cell death 1 or its ligand (PD1/PDL1), elicit different immune-related adverse events (irAEs), but their global safety is incompletely characterized. OBJECTIVE: The aim of this study was to characterize the spectrum, frequency, and clinical features of ICI-related adverse events (AEs) reported to the FDA Adverse Event Reporting System (FAERS). PATIENTS AND METHODS: AEs from FAERS (up to June 2018) recording ICIs (ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab) as suspect were extracted. Comprehensive disproportionality analyses were performed through the reporting odds ratio (ROR) with 95% confidence interval (95% CI), using other oncological drugs as comparison. An overview of systematic reviews (OoSRs) was also undertaken to identify irAEs with consistent positive associations. RESULTS: ICIs were recorded in 47,266 reports, submitted mainly by consumers receiving monotherapy with anti-PD1/PDL1 drugs. Three areas of toxicity emerged from both disproportionality analysis and the OoSRs (32 studies): endocrine (N = 2863; ROR = 6.91; 95% CI 6.60-7.23), hepatobiliary (2632; 1.33; 1.28-1.39), and respiratory disorders (7240; 1.04; 1.01-1.06). Different reporting patterns emerged for anti-CTLA4 drugs (e.g., hypophysitis, adrenal insufficiency, hypopituitarism, and prescribed overdose) and anti-PD1/PDL1 agents (e.g., pneumonitis, cholangitis, vanishing bile duct syndrome, tumor pseudoprogression, and inappropriate schedule of drug administration). No increased reporting emerged when comparing combination with monotherapy regimens, but multiple hepatobiliary/endocrine/respiratory irAEs were recorded. CONCLUSIONS: This parallel approach through contemporary post-marketing analysis and OoSRs confirmed that ICIs are associated with a multitude of irAEs, with different reporting patterns between anti-CTLA4 and anti-PD1/PDL1 medications. Close clinical monitoring is warranted to early diagnose and timely manage irAEs, especially respiratory, endocrine, and hepatic toxicities, which warrant further characterization; patient- and drug-related risk factors should be assessed through analytical pharmaco-epidemiological studies and prospective multicenter registries.
Authors: E Raschi; E Poluzzi; F Salvo; A Pariente; F De Ponti; G Marchesini; U Moretti Journal: Nutr Metab Cardiovasc Dis Date: 2018-03-01 Impact factor: 4.222
Authors: Annamaria Mascolo; Cristina Scavone; Roberto Alfano; Annalisa Capuano; Carmen Ferrajolo; Concetta Rafaniello; Romano Danesi; Marzia Del Re; Antonio Russo; Enrico Coscioni; Francesco Rossi Journal: Drug Saf Date: 2021-06-18 Impact factor: 5.606