达布拉非尼和曲美替尼在转移性黑色素瘤患者中的暴露-疗效和耐受性：一项药代动力学-药效学真实世界研究。
Dabrafenib and trametinib exposure-efficacy and tolerance in metastatic melanoma patients: a pharmacokinetic-pharmacodynamic real-life study.
机构信息
Department of Pharmacology and Tumor Genomics , AP-HP, Hôpital Saint-Louis, Inserm, UMRS976 Université Paris Diderot, Sorbonne Paris Cité, Faculté de Médecine, 1 avenue Claude Vellefaux, 75010, Paris, France.
Department of Dermatology, AP-HP, Hôpital Saint-Louis, Inserm, UMRS976, Université Paris Diderot, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
出版信息
Cancer Chemother Pharmacol. 2021 Sep;88(3):427-437. doi: 10.1007/s00280-021-04299-x. Epub 2021 May 31.
PURPOSE
Dabrafenib plus trametinib combination has greatly improved survival in BRAFV600 metastatic melanoma patients. However, data regarding the influence of pharmacokinetic markers in real-life patients are lacking. In this study, we aimed to explore dabrafenib and trametinib pharmacokinetic impact on progression-free survival (PFS), duration of response (DOR) or all grades treatment-related adverse events (ARAE) occurrence in routine care patients.
METHODS
BRAFV600 metastatic melanoma patients initiating standard doses of dabrafenib 150 mg BID plus trametinib 2 mg QD were included. Clinical data were collected via the French biobank MelBase, prospectively enrolling unresectable stage III or IV melanoma. Clinical response evaluation, ARAE reporting and dabrafenib and trametinib plasma quantification were performed. Association of individual Bayesian-estimated pharmacokinetic markers (AUC and C) and baseline clinical variables with DOR, PFS, clinical response, and ARAE was then assessed.
RESULTS
Fifty patients (comprising 4 AJCC stage IIIc and 46 stage IV) were included. Median PFS reached 11.4 months, and overall response rate 70%. Fifty percent of patients experienced ARAE (G3 n = 10, G4 n = 0). In univariate analysis, median dabrafenib C within intermediate range was associated with a significantly higher PFS (HR [95% CI] = 0.41 [0.18; 0.91], p = 0.029) and DOR (HR [95% CI] = 0.39 [0.16; 0.94], p = 0.024), and association with DOR remained significant in multivariate analysis (HR [95% CI] = 0.34 [0.12; 0.95], p = 0.040). Trametinib pharmacokinetic markers were significantly higher in patients experiencing ARAE compared to patients without ARAE.
CONCLUSION
In this study, exposure-efficacy and tolerance analysis highlighted the interest of therapeutic drug monitoring to optimize therapeutic management in BRAFV600 metastatic melanoma patients based on trough concentrations of dabrafenib and trametinib.
目的
达拉非尼联合曲美替尼的联合治疗极大地改善了 BRAFV600 转移性黑色素瘤患者的生存。然而，在真实患者中，关于药代动力学标志物影响的数据仍然缺乏。在这项研究中，我们旨在探讨常规治疗患者中达拉非尼和曲美替尼的药代动力学对无进展生存期（PFS）、缓解持续时间（DOR）或所有级别治疗相关不良反应（TRAE）发生的影响。
方法
纳入起始标准剂量达拉非尼 150mg BID 联合曲美替尼 2mg QD 的 BRAFV600 转移性黑色素瘤患者。通过法国生物银行 MelBase 前瞻性收集不可切除的 III 期或 IV 期黑色素瘤的临床数据。进行临床反应评估、TRAEs 报告以及达拉非尼和曲美替尼的血浆定量。然后评估个体贝叶斯估算药代动力学标志物（AUC 和 C）和基线临床变量与 DOR、PFS、临床反应和 TRAE 的关系。
结果
共纳入 50 例患者（包括 4 例 AJCC IIIc 期和 46 例 IV 期）。中位 PFS 达到 11.4 个月，总缓解率为 70%。50%的患者发生 TRAE（G3 例=10 例，G4 例=0 例）。单因素分析中，中等范围内的达拉非尼 C 中位值与 PFS（HR[95%CI] = 0.41[0.18;0.91]，p=0.029）和 DOR（HR[95%CI] = 0.39[0.16;0.94]，p=0.024）显著相关，且在多因素分析中与 DOR 的相关性仍然显著（HR[95%CI] = 0.34[0.12;0.95]，p=0.040）。与无 TRAE 患者相比，发生 TRAE 的患者的曲美替尼药代动力学标志物显著更高。
结论
在这项研究中，暴露-疗效和耐受性分析强调了治疗药物监测的重要性，以基于达拉非尼和曲美替尼的谷浓度优化 BRAFV600 转移性黑色素瘤患者的治疗管理。
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