Division of Hematology, Mayo Clinic, Rochester, Minnesota.
Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota.
JAMA Oncol. 2019 Jul 1;5(7):1008-1019. doi: 10.1001/jamaoncol.2019.0393.
Programmed cell death (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have been increasingly used in cancer therapy. Understanding the treatment-related adverse events of these drugs is critical for clinical practice.
To evaluate the incidences of treatment-related adverse events of PD-1 and PD-L1 inhibitors and the differences between different drugs and cancer types.
PubMed, Web of Science, Embase, and Scopus were searched from October 1, 2017, through December 15, 2018.
Published clinical trials on single-agent PD-1 and PD-L1 inhibitors with tabulated data on treatment-related adverse events were included.
Trial name, phase, cancer type, PD-1 and PD-L1 inhibitor used, dose escalation, dosing schedule, number of patients, number of all adverse events, and criteria for adverse event reporting data were extracted from each included study, and bayesian multilevel regression models were applied for data analysis.
Incidences of treatment-related adverse events and differences between different drugs and cancer types.
This systematic review and meta-analysis included 125 clinical trials involving 20 128 patients; 12 277 (66.0%) of 18 610 patients from 106 studies developed at least 1 adverse event of any grade (severity), and 2627 (14.0%) of 18 715 patients from 110 studies developed at least 1 adverse event of grade 3 or higher severity. The most common all-grade adverse events were fatigue (18.26%; 95% CI, 16.49%-20.11%), pruritus (10.61%; 95% CI, 9.46%-11.83%), and diarrhea (9.47%; 95% CI, 8.43%-10.58%). The most common grade 3 or higher adverse events were fatigue (0.89%; 95% CI, 0.69%-1.14%), anemia (0.78%; 95% CI, 0.59%-1.02%), and aspartate aminotransferase increase (0.75%; 95% CI, 0.56%-0.99%). Hypothyroidism (6.07%; 95% CI, 5.35%-6.85%) and hyperthyroidism (2.82%; 95% CI, 2.40%-3.29%) were the most frequent all-grade endocrine immune-related adverse events. Nivolumab was associated with higher mean incidences of all-grade adverse events compared with pembrolizumab (odds ratio [OR], 1.28; 95% CI, 0.97-1.79) and grade 3 or higher adverse events (OR, 1.30; 95% CI, 0.89-2.00). PD-1 inhibitors were associated with a higher mean incidence of grade 3 or higher adverse events compared with PD-L1 inhibitors (OR, 1.58; 95% CI, 1.00-2.54).
Different PD-1 and PD-L1 inhibitors appear to have varying treatment-related adverse events; a comprehensive summary of the incidences of treatment-related adverse events in clinical trials provides an important guide for clinicians.
程序性细胞死亡（PD-1）和程序性细胞死亡配体 1（PD-L1）抑制剂在癌症治疗中被越来越多地使用。了解这些药物的治疗相关不良事件对于临床实践至关重要。
评估 PD-1 和 PD-L1 抑制剂的治疗相关不良事件发生率以及不同药物和癌症类型之间的差异。
从 2017 年 10 月 1 日至 2018 年 12 月 15 日，检索了 PubMed、Web of Science、Embase 和 Scopus 数据库。
纳入了关于单药 PD-1 和 PD-L1 抑制剂的临床试验，其中列出了治疗相关不良事件的数据。
从每项纳入的研究中提取试验名称、阶段、癌症类型、使用的 PD-1 和 PD-L1 抑制剂、剂量递增、剂量方案、患者人数、所有不良事件的数量以及不良事件报告数据的标准，并应用贝叶斯多层次回归模型进行数据分析。
治疗相关不良事件的发生率以及不同药物和癌症类型之间的差异。
本系统评价和荟萃分析纳入了 125 项临床试验，涉及 20128 名患者；来自 106 项研究的 18610 名患者中，有 12277 名（66.0%）患者至少出现了 1 种任何严重程度的不良事件（严重程度），来自 110 项研究的 18715 名患者中，有 2627 名（14.0%）患者至少出现了 1 种 3 级或更高级别的不良事件。最常见的所有严重程度不良事件是疲劳（18.26%；95%CI，16.49%-20.11%）、瘙痒（10.61%；95%CI，9.46%-11.83%）和腹泻（9.47%；95%CI，8.43%-10.58%）。最常见的 3 级或更高级别的不良事件是疲劳（0.89%；95%CI，0.69%-1.14%）、贫血（0.78%；95%CI，0.59%-1.02%）和天冬氨酸转氨酶升高（0.75%；95%CI，0.56%-0.99%）。甲状腺功能减退症（6.07%；95%CI，5.35%-6.85%）和甲状腺功能亢进症（2.82%；95%CI，2.40%-3.29%）是最常见的所有严重程度内分泌免疫相关不良事件。与 pembrolizumab 相比，nivolumab 与所有严重程度不良事件（比值比[OR]，1.28；95%CI，0.97-1.79）和 3 级或更高级别的不良事件（OR，1.30；95%CI，0.89-2.00）的发生率更高。与 PD-L1 抑制剂相比，PD-1 抑制剂与 3 级或更高级别的不良事件的发生率更高（OR，1.58；95%CI，1.00-2.54）。
不同的 PD-1 和 PD-L1 抑制剂似乎具有不同的治疗相关不良事件；对临床试验中治疗相关不良事件发生率的全面总结为临床医生提供了重要指导。
