一项关于转移性非小细胞肺癌、黑色素瘤和肾细胞癌患者纳武利尤单抗药代动力学的前瞻性队列研究。
A prospective cohort study on the pharmacokinetics of nivolumab in metastatic non-small cell lung cancer, melanoma, and renal cell cancer patients.
机构信息
Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
Department of Pulmonology, Erasmus MC Cancer Institute, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
出版信息
J Immunother Cancer. 2019 Jul 19;7(1):192. doi: 10.1186/s40425-019-0669-y.
BACKGROUND
Nivolumab is administered in a weight-based or fixed-flat dosing regimen. For patients with non-small cell lung cancer (NSCLC), a potential exposure-response relationship has recently been reported and may argue against the current dosing strategies. The primary objectives were to determine nivolumab pharmacokinetics (PK) and to assess the relationship between drug clearance and clinical outcome in NSCLC, melanoma, and renal cell cancer (RCC).
METHODS
In this prospective observational cohort study, individual estimates of nivolumab clearance and the impact of baseline covariates were determined using a population-PK model. Clearance was related to best overall response (RECISTv1.1), and stratified by tumor type.
RESULTS
Two-hundred-twenty-one patients with metastatic cancer receiving nivolumab-monotherapy were included of whom 1,715 plasma samples were analyzed. Three baseline parameters had a significant effect on drug clearance and were internally validated in the population-PK model: gender, BSA, and serum albumin. Women had 22% lower clearance compared to men, while the threshold of BSA and albumin that led to > 20% increase of clearance was > 2.2m and < 37.5 g/L, respectively. For NSCLC, drug clearance was 42% higher in patients with progressive disease (mean: 0.24; 95% CI: 0.22-0.27 L/day) compared to patients with partial/complete response (mean: 0.17; 95% CI: 0.15-0.19 L/day). A similar trend was observed in RCC, however, no clearance-response relationship was observed in melanoma.
CONCLUSIONS
Based on the first real-world population-PK model of nivolumab, covariate analysis revealed a significant effect of gender, BSA, and albumin on nivolumab clearance. A clearance-response relationship was observed in NSCLC, with a non-significant trend in RCC, but not in melanoma. Individual pharmacology of nivolumab in NSCLC appears important and should be prospectively studied.
背景
纳武利尤单抗采用基于体重或固定剂量的给药方案。对于非小细胞肺癌（NSCLC）患者，最近报道了一种潜在的暴露-反应关系，这可能与当前的给药策略相悖。主要目的是确定纳武利尤单抗的药代动力学（PK），并评估 NSCLC、黑色素瘤和肾细胞癌（RCC）中药物清除率与临床结局之间的关系。
方法
在这项前瞻性观察队列研究中，使用群体 PK 模型确定纳武利尤单抗清除率的个体估计值，并评估基线协变量的影响。根据 RECISTv1.1 评估最佳总体反应，按肿瘤类型进行分层。
结果
共纳入 221 例接受纳武利尤单抗单药治疗的转移性癌症患者，其中分析了 1715 个血浆样本。3 个基线参数对药物清除率有显著影响，并在群体 PK 模型中进行了内部验证：性别、BSA 和血清白蛋白。与男性相比，女性的清除率低 22%，而导致清除率增加>20%的 BSA 和白蛋白阈值分别为>2.2m 和<37.5g/L。对于 NSCLC，与部分/完全缓解患者相比，疾病进展患者的药物清除率高 42%（平均值：0.24；95%CI：0.22-0.27 L/天）。在 RCC 中也观察到类似的趋势，但在黑色素瘤中未观察到清除率-反应关系。
结论
基于纳武利尤单抗的首个真实世界群体 PK 模型，协变量分析显示性别、BSA 和白蛋白对纳武利尤单抗清除率有显著影响。在 NSCLC 中观察到清除率-反应关系，在 RCC 中观察到非显著趋势，但在黑色素瘤中未观察到。NSCLC 中纳武利尤单抗的个体药理学似乎很重要，应进行前瞻性研究。
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