Almutairi Abdulaali R, McBride Ali, Slack Marion, Erstad Brian L, Abraham Ivo
Center for Health Outcomes and PharmacoEconomic Research, College of Pharmacy, University of Arizona, Tucson, AZ, United States.
Department of Pharmacy Practice and Science, College of Pharmacy, University of Arizona, Tucson, AZ, United States.
Front Oncol. 2020 Feb 11;10:91. doi: 10.3389/fonc.2020.00091. eCollection 2020.
The use of ipilimumab, nivolumab, and pembrolizumab as monotherapies or in combination has transformed the management of advanced melanoma even though these drugs are associated with a new profile of immune-related adverse events (irAEs). The incidence of irAEs from clinical trials of these agents is an important factor for clinicians when treating patients with advanced melanoma. In the current study, we aimed to profile the incidence of potential irAEs of these agents when used as monotherapy and as combination therapy. We searched the Medline, Embase, and Cochrane databases; clinicaltrials.gov; and websites of regulatory agencies in the USA, Europe, Australia, and Japan for phase 1-3 trials of ipilimumab, nivolumab, and pembrolizumab for advanced melanoma. Random effect meta-analysis was utilized to profile the incidence of potential irAEs. A total of 58 reports of 35 trials including 6,331 patients with advanced melanoma and reporting irAE data were included in the meta-analyses. We found higher incidences of potential irAEs in combination therapies vs. monotherapies for most of the types of irAEs. Among the monotherapies, ipilimumab users had the most frequent incidence of potential irAEs related to the gastrointestinal system (diarrhea, 29%; and colitis, 8%) and skin (rash, 31%; pruritus, 27%; and dermatitis, 10%), with hypophysitis in 4% of the patients. The most frequent potential irAEs among nivolumab users were maculopapular rash (13%), erythema (4%), hepatitis (3%), and infusion-related reactions (3%), while they were arthralgia (12%), hypothyroidism (8%), and hyperglycemia (6%), among pembrolizumab users. Especially the combination therapies tend to elevate the incidence of potential irAEs. Clinicians should be vigilant about irAEs following combination therapy as well as gastrointestinal and skin irAEs following ipilimumab therapy, in addition to being aware of potential irAEs leading to hyperglycemia, thyroid, hepatic, and musculoskeletal disorders following nivolumab and pembrolizumab therapy.
尽管伊匹单抗、纳武单抗和帕博利珠单抗单药治疗或联合使用会引发一系列新的免疫相关不良事件（irAE），但其改变了晚期黑色素瘤的治疗方式。这些药物临床试验中irAE的发生率是临床医生治疗晚期黑色素瘤患者时的重要参考因素。在本研究中，我们旨在分析这些药物单药治疗和联合治疗时潜在irAE的发生率。我们检索了Medline、Embase和Cochrane数据库、clinicaltrials.gov以及美国、欧洲、澳大利亚和日本监管机构的网站，查找伊匹单抗、纳武单抗和帕博利珠单抗治疗晚期黑色素瘤的1-3期试验。采用随机效应荟萃分析来分析潜在irAE的发生率。荟萃分析共纳入了35项试验的58份报告，涉及6331例晚期黑色素瘤患者并报告了irAE数据。我们发现，大多数类型的irAE联合治疗的潜在发生率高于单药治疗。在单药治疗中，使用伊匹单抗的患者出现与胃肠道系统相关潜在irAE（腹泻，29%；结肠炎，8%）和皮肤相关潜在irAE（皮疹，31%；瘙痒，27%；皮炎，10%）的发生率最高，4%的患者出现垂体炎。纳武单抗使用者中最常见的潜在irAE是斑丘疹（13%）、红斑（4%）、肝炎（3%）和输液相关反应（3%），而帕博利珠单抗使用者中则是关节痛（12%）、甲状腺功能减退（8%）和高血糖（6%）。特别是联合治疗往往会提高潜在irAE的发生率。临床医生除了要注意纳武单抗和帕博利珠单抗治疗后导致高血糖、甲状腺、肝脏和肌肉骨骼疾病的潜在irAE外，还应警惕联合治疗后的irAE以及伊匹单抗治疗后的胃肠道和皮肤irAE。
