PMID- 30927173 OWN - NLM STAT- MEDLINE DCOM- 20200109 LR - 20200922 IS - 1776-260X (Electronic) IS - 1776-2596 (Linking) VI - 14 IP - 2 DP - 2019 Apr TI - Toxicities with Immune Checkpoint Inhibitors: Emerging Priorities From Disproportionality Analysis of the FDA Adverse Event Reporting System. PG - 205-221 LID - 10.1007/s11523-019-00632-w [doi] AB - 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. FAU - Raschi, Emanuel AU - Raschi E AUID- ORCID: 0000-0003-0487-7996 AD - Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy. emanuel.raschi@unibo.it. FAU - Mazzarella, Alessandra AU - Mazzarella A AD - Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy. FAU - Antonazzo, Ippazio Cosimo AU - Antonazzo IC AD - Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy. FAU - Bendinelli, Nicolo AU - Bendinelli N AD - Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy. FAU - Forcesi, Emanuele AU - Forcesi E AD - Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy. FAU - Tuccori, Marco AU - Tuccori M AD - Unit of Adverse Drug Reactions Monitoring, Tuscan Regional Centre of Pharmacovigilance, University Hospital of Pisa, Via Roma 55, 56126, Pisa, Italy. FAU - Moretti, Ugo AU - Moretti U AD - Department of Public Health and Community Medicine, University of Verona, Verona, Italy. FAU - Poluzzi, Elisabetta AU - Poluzzi E AD - Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy. FAU - De Ponti, Fabrizio AU - De Ponti F AD - Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy. LA - eng PT - Journal Article PT - Observational Study PT - Research Support, Non-U.S. Gov't PL - France TA - Target Oncol JT - Targeted oncology JID - 101270595 RN - 0 (Antineoplastic Agents, Immunological) SB - IM MH - Adolescent MH - Adult MH - Adverse Drug Reaction Reporting Systems/*statistics & numerical data MH - Aged MH - Antineoplastic Agents, Immunological/*adverse effects MH - Cell Cycle Checkpoints/*drug effects MH - Child MH - Child, Preschool MH - Drug-Related Side Effects and Adverse Reactions/*etiology MH - Female MH - Follow-Up Studies MH - Humans MH - Immunotherapy/adverse effects MH - Infant MH - Infant, Newborn MH - Male MH - Middle Aged MH - Neoplasms/*drug therapy/pathology MH - *Pharmacovigilance MH - Prognosis MH - Retrospective Studies MH - United States MH - United States Food and Drug Administration MH - Young Adult EDAT- 2019/03/31 06:00 MHDA- 2020/01/10 06:00 CRDT- 2019/03/31 06:00 PHST- 2019/03/31 06:00 [pubmed] PHST- 2020/01/10 06:00 [medline] PHST- 2019/03/31 06:00 [entrez] AID - 10.1007/s11523-019-00632-w [pii] AID - 10.1007/s11523-019-00632-w [doi] PST - ppublish SO - Target Oncol. 2019 Apr;14(2):205-221. doi: 10.1007/s11523-019-00632-w.