Sicilian Regional Pharmacovigilance Center, University Hospital of Messina, Messina, Italy.
Dept. of Biomedical and Dental Sciences and Morpho-functional Imaging, University of Messina, Messina, Italy.
Br J Clin Pharmacol. 2021 Feb;87(2):527-541. doi: 10.1111/bcp.14413. Epub 2020 Jul 9.
To provide an overview of immune checkpoint inhibitors (ICIs) safety profile using the Italian spontaneous adverse drug reaction (ADR) reporting system.
We selected all ADR reports attributed to ipilimumab (CTLA-4 inhibitor), nivolumab, pembrolizumab, atezolizumab (PD-1/PD-L1 inhibitors) from the Italian spontaneous reporting system (2011-2018). Descriptive analyses of reports for ICIs have been conducted. Time to onset of adverse effects was stratified by system organ class. Reporting odds ratio was used as measure of ADR reporting disproportionality. ICI-related ADR reports were compared with 2 reference groups, i.e. all other suspected drugs or all other antineoplastic agents.
Overall, 2217 (0.7%) reports were related to ICIs (nivolumab: 72.2% of those reports; ipilimumab: 14.3%; pembrolizumab: 10.3%; and atezolizumab: 3.5%). ICI-related ADR reports mostly involved males (65%) and median age was 67 (interquartile range 59-73) years. Serious reports accounted for 48.8%. Frequencies of endocrine, general, hepatobiliary, metabolism, musculoskeletal, respiratory disorders, infections and neoplasms were significantly higher for ICIs than for all other drugs (P < .001). Except for infections, similar results emerged through comparison with other anticancer drugs. Colitis, hypophysitis and skin disorders were more frequently reported for anti-CTLA-4 drugs than PD-1/PD-L1 ICIs, and the opposite for musculoskeletal effects, pneumonia, and thyroid dysfunctions. ICIs were disproportionally associated also with less known risks, e.g. ischaemic heart disease, cardiac failure and optic nerve disorders.
The most frequently reported safety issues were probably immune-related adverse events including general, gastrointestinal and respiratory disorders. Potentially emerging safety signals, such as ischaemic heart disease and cardiac failure, requiring further investigation were detected.
利用意大利自发药物不良反应（ADR）报告系统，提供免疫检查点抑制剂（ICI）安全性概况概述。
我们从意大利自发报告系统（2011-2018 年）中选择了所有归因于 ipilimumab（CTLA-4 抑制剂）、nivolumab、pembrolizumab、atezolizumab（PD-1/PD-L1 抑制剂）的 ADR 报告。对 ICI 的报告进行了描述性分析。按系统器官分类分层不良事件的发病时间。报告比值比（ROR）用于衡量 ADR 报告的不均衡性。将 ICI 相关 ADR 报告与 2 个参考组（即所有其他可疑药物或所有其他抗肿瘤药物）进行比较。
总体而言，2217 份（0.7%）报告与 ICI 相关（nivolumab：占这些报告的 72.2%；ipilimumab：14.3%；pembrolizumab：10.3%；atezolizumab：3.5%）。ICI 相关 ADR 报告主要涉及男性（65%），中位年龄为 67 岁（四分位间距 59-73）。严重报告占 48.8%。与所有其他药物相比，内分泌、一般、肝胆、代谢、肌肉骨骼、呼吸紊乱、感染和肿瘤的频率明显更高（P <.001）。除了感染，与其他抗癌药物相比也出现了类似的结果。与抗 CTLA-4 药物相比，ICI 更常报告结肠炎、垂体炎和皮肤疾病，而肌肉骨骼效应、肺炎和甲状腺功能障碍则相反。ICI 还与不太常见的风险相关，例如缺血性心脏病、心力衰竭和视神经疾病。
报告的最常见安全问题可能是免疫相关的不良反应，包括一般、胃肠道和呼吸系统疾病。还发现了一些潜在的新的安全信号，例如缺血性心脏病和心力衰竭，需要进一步研究。
