Ruggiero Rosanna, Fraenza Federica, Scavone Cristina, di Mauro Gabriella, Piscitelli Raffaele, Mascolo Annamaria, Ferrajolo Carmen, Rafaniello Concetta, Sportiello Liberata, Rossi Francesco, Capuano Annalisa
Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Department of Experimental Medicine, Section of Pharmacology "L. Donatelli", University of Campania "Luigi Vanvitelli", Naples, Italy.
Front Pharmacol. 2020 Jun 9;11:830. doi: 10.3389/fphar.2020.00830. eCollection 2020.
The introduction of immune checkpoint inhibitors (ICIs) in clinical practice has brought significant benefits for patients. Seven ICIs are available in Europe: nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, cemiplimab, and ipilimumab. Despite their proven clinical efficacy, these innovative drugs may cause serious immune-related adverse drugs reactions (irADRs). Given the significance of these ADRs for patients' health, we analyzed individual case safety reports (ICSRs) related to ICIs, focusing on those reporting irADRs, collected in the Italian spontaneous reporting database.
We analyzed ICI-induced irADRs collected in the Italian Pharmacovigilance database (Rete Nazionale di Farmacovigilanza [RNF]) from January 1, 2002, to February 28, 2019, focusing on those reported in the Campania Region. We retrieved from an open-access Italian pharmacovigilance system, the RAM system (for national safety data), and from the RNF (for Campania safety data) all ICSRs reporting ADRs related to ICIs authorized until the analysis date. Focusing on irADRs, we performed descriptive and disproportionality analyses through the reporting odds ratio (ROR) with 95% confidence interval.
. Among 2,088 ICI-related ICSRs, 801 reported irADRs. The majority of such ADRs occurred in male patients reporting gastrointestinal and skin toxicities. Nivolumab and pembrolizumab were drugs most commonly reported as suspect drugs. Compared to other ICIs, ROR was statistically significant for pembrolizumab and ipilimumab.. Out of 253 ICI-related ICSRs sent to Regional Pharmacovigilance Center of Campania Region, 121 reported at least one ICI-induced irADR. These were serious in 37.2% of cases and had an unfavorable outcome in 32.2% of cases. Overall, out of 8 ICSRs reported ADR with a fatal outcome, four reported irADRs. From disproportionality analyses on Campania Region ICSRs, statistically significant ROR emerged only for ipilimumab.
Our results showed that during the study period several serious irADRs were reported, some of which had fatal outcome. Given the clinical relevance of irADRs, further investigations in real-life context are necessary for a better characterization of ICIs safety profiles. Oncologists should be trained to early recognize and adequately manage irADRs. Patients should also be educated to immediately report any new symptom or worsening of pre-existed ones during the ICI treatment.
免疫检查点抑制剂（ICI）引入临床实践给患者带来了显著益处。欧洲有七种ICI：纳武单抗、帕博利珠单抗、阿特珠单抗、阿维鲁单抗、度伐鲁单抗、西米普利单抗和伊匹木单抗。尽管这些创新药物已被证实具有临床疗效，但它们可能会引起严重的免疫相关药物不良反应（irADR）。鉴于这些不良反应对患者健康的重要性，我们分析了意大利自发报告数据库中与ICI相关的个体病例安全报告（ICSR），重点关注报告irADR的报告。
我们分析了2002年1月1日至2019年2月28日在意大利药物警戒数据库（国家药物警戒网络[RNF]）中收集的ICI诱导的irADR，重点关注坎帕尼亚地区报告的病例。我们从一个开放获取的意大利药物警戒系统、RAM系统（用于国家安全数据）以及RNF（用于坎帕尼亚安全数据）中检索了截至分析日期所有报告与已批准ICI相关不良反应的ICSR。针对irADR，我们通过报告比值比（ROR）及其95%置信区间进行描述性和不成比例性分析。
在2088份与ICI相关的ICSR中，801份报告了irADR。此类不良反应大多发生在报告有胃肠道和皮肤毒性的男性患者中。纳武单抗和帕博利珠单抗是最常被报告为可疑药物的药物。与其他ICI相比，帕博利珠单抗和伊匹木单抗的ROR具有统计学意义。在发送至坎帕尼亚地区药物警戒中心的253份与ICI相关的ICSR中，121份报告了至少一种ICI诱导的irADR。其中37.2%的病例为严重不良反应，32.2%的病例预后不良。总体而言，在报告有致命结局不良反应的8份ICSR中，4份报告了irADR。通过对坎帕尼亚地区ICSR的不成比例性分析，仅伊匹木单抗出现了具有统计学意义的ROR。
我们的结果表明，在研究期间报告了数起严重的irADR，其中一些有致命结局。鉴于irADR的临床相关性，有必要在实际环境中进行进一步调查，以更好地描述ICI的安全性概况。肿瘤学家应接受培训，以便早期识别并妥善处理irADR。患者也应接受教育，以便在ICI治疗期间立即报告任何新症状或原有症状的恶化情况。
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