Clinical Pharmacology, EMD Serono Research and Development Institute, Inc, 45 Middlesex Turnpike, Billerica, MA, 01821, USA.
Global Clinical Development Immuno-Oncology, Merck KGaA, Darmstadt, Germany.
Cancer Chemother Pharmacol. 2019 Nov;84(5):1017-1026. doi: 10.1007/s00280-019-03925-z. Epub 2019 Sep 3.
To report integrated electrocardiogram (ECG) summary and exposure-QTc analyses for avelumab, a human immunoglobulin G1 monoclonal antibody that binds programmed cell death 1 ligand 1, to assess potential effects on cardiac repolarization.
Data were pooled from three-phase 1/2 studies of patients with advanced solid tumors who received avelumab monotherapy (22,000 ECGs from 1818 patients). All analyses used 12-lead singlet ECGs taken using local ECG machines before and approximately 2 h after avelumab infusion on prespecified days. The exposure-QTc and outlier analyses used locally read ECGs; since larger variability is known to be associated with local reading, outlier ECGs were subsequently reevaluated by central read. QTc derived from Fridericia's formula (QTcF) and a project-specific formula (QTcP) were analyzed. Multivariable linear mixed-effects models were used to describe the relationship between serum concentration of avelumab and QTc absolute value or change from baseline (ΔQTc).
Exposure-QTc models showed that the effect of avelumab on QTc or ΔQTc was minimal and not statistically significant for both QTcP and QTcF. In addition, models including avelumab concentration and diphenhydramine premedication use did not show a clinically meaningful effect on the QT interval. The frequency of QTc outliers in both short and long ranges was overestimated by local reads. Six patients (0.3%) were QTc outliers; all had either received concomitant medication known to cause QT prolongation or had a preexisting cardiac condition.
Avelumab does not have any clinically relevant effect on cardiac repolarization.
报告avelumab 的整合心电图 (ECG) 总结和暴露-QTc 分析结果，avelumab 是一种与人程序性死亡配体 1 结合的免疫球蛋白 G1 单克隆抗体，用于评估其对心脏复极的潜在影响。
对接受avelumab 单药治疗的晚期实体瘤患者进行的三项 1/2 期研究的数据进行了汇总（来自 1818 名患者的 22000 份心电图）。所有分析均使用在预设日期于avelumab 输注前后使用当地心电图机获取的 12 导联单导联 ECG。暴露-QTc 和异常值分析使用当地读取的心电图；由于已知当地读取会出现更大的变异性，因此随后对异常心电图进行了中心读取重新评估。分析了 Fridericia 公式 (QTcF) 和特定项目公式 (QTcP) 得出的 QTc。使用多变量线性混合效应模型描述 avelumab 血清浓度与 QTc 绝对值或与基线相比的变化 (ΔQTc) 之间的关系。
暴露-QTc 模型表明，avelumab 对 QTc 或 ΔQTc 的影响极小，对于 QTcP 和 QTcF 均无统计学意义。此外，包括 avelumab 浓度和苯海拉明预用药的模型也没有显示出对 QT 间期有临床意义的影响。短范围和长范围的 QTc 异常值的频率被当地读数高估。6 名患者（0.3%）为 QTc 异常值；所有患者均接受了已知会导致 QT 延长的合并用药，或存在先前存在的心脏疾病。
avelumab 对心脏复极没有任何临床相关影响。
