Exposure-Response Relationships of the Efficacy and Safety of Ipilimumab in Patients with Advanced Melanoma
Exposure-Response Relationships of the Efficacy and Safety of Ipilimumab in Patients with Advanced Melanoma
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DOI：
10.1158/1078-0432.ccr-12-3243
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发表时间：
2013-07-15
影响因子：
11.5
通讯作者：
Weber, Jeffrey S.
中科院分区：
文献类型：
--
作者：
Feng, Yan;Roy, Amit;Weber, Jeffrey S.
目的：进行回顾性分析，以表征ipilimumab的疗效和安全性的措施，在晚期melanoma.Experimental Design患者的疗效反应关系：数据汇总从498例接受ipilimumab单药治疗0.3，3，或10 mg/kg的4个完成的II期临床试验之一。通过logistic回归模型描述稳态易普利姆玛谷浓度（Cminss）、完全或部分肿瘤缓解（CR或PR）和安全性[免疫相关不良事件（irAE）]之间的关系。暴露与总生存率之间的关系采用考克斯比例风险model.Results：易普利姆玛的稳态谷浓度被认为是CR或PR的显著预测因子（P < 0.001）。基于模型的估计值表明，0.3、3和10 mg/kg组中位Cminss时CR或PR的概率分别为0.6%、4.9%和11.6%。估计0.3 mg/kg伊匹单抗在中位Cminss时的总生存期分别比3和10 mg/kg中位Cminss时低0.85和0.58倍。基于模型的估计表明，在0.3，3和10 mg/kg剂量的中位Cminss下，3级或以上irAE的概率分别为3%，13%和24%.Conclusions：较高剂量的易普利姆玛产生更大的Cminss，这可能与肿瘤反应增加，生存期延长和irAE发生率升高相关。正在进行的III期试验中评估了3 mg/kg与10 mg/kg伊匹单抗在晚期黑色素瘤患者中的疗效和安全性。(C)2013年AACR。
Purpose: This retrospective analysis was conducted to characterize ipilimumab exposure-response relationships for measures of efficacy and safety in patients with advanced melanoma.Experimental Design: Data were pooled from 498 patients who received ipilimumab monotherapy at 0.3, 3, or 10 mg/kg in 1 of 4 completed phase II clinical trials. The relationships between steady-state ipilimumab trough concentration (Cminss), complete or partial tumor response (CR or PR), and safety [immune-related adverse events (irAEs)] were described by logistic regression models. The relationship between exposure and overall survival was characterized using a Cox proportional-hazards model.Results: The steady-state trough concentration of ipilimumab was found to be a significant predictor of a CR or PR (P < 0.001). Model-based estimates indicate that the probabilities of a CR or PR at median Cminss for the 0.3, 3, and 10 mg/kg groups were 0.6%, 4.9%, and 11.6%, respectively. Overall survival at the median Cminss for ipilimumab at 0.3 mg/kg was estimated to be 0.85- and 0.58-fold lower relative to that at the median Cminss for 3 and 10 mg/kg, respectively. Model-based estimates indicate that the probabilities of a grade 3 or more irAE at the median Cminss for the 0.3, 3, and 10 mg/kg doses were 3%, 13%, and 24%, respectively.Conclusions: Higher doses of ipilimumab produce greater Cminss that may be associated with increased tumor responses, longer survival, and higher rates of irAEs. The efficacy and safety of ipilimumab at 3 versus 10 mg/kg in patients with advanced melanoma is being evaluated in an ongoing phase III trial. (C) 2013 AACR.