Division of Medical Oncology, Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Cancer Chemother Pharmacol. 2023 Jun;91(6):447-456. doi: 10.1007/s00280-023-04517-8. Epub 2023 Mar 22.
Dabrafenib and trametinib are currently administered at fixed doses, at which interpatient variability in exposure is high. The aim of this study was to investigate whether drug exposure is related to efficacy and toxicity in a real-life cohort of melanoma patients treated with dabrafenib plus trametinib.
An observational study was performed in which pharmacokinetic samples were collected as routine care. Using estimated dabrafenib Area Under the concentration-time Curve and trametinib trough concentrations (C), univariable and multivariable exposure-response analyses were performed.
In total, 140 patients were included. Dabrafenib exposure was not related to either progression-free survival (PFS) or overall survival (OS). Trametinib exposure was related to survival, with C ≥ 15.6 ng/mL being identified as the optimal threshold. Median OS was significantly longer in patients with trametinib C ≥ 15.6 ng/mL (22.8 vs. 12.6 months, P = 0.003), with a multivariable hazard ratio of 0.55 (95% CI 0.36-0.85, P = 0.007). Median PFS in patients with trametinib C levels ≥ 15.6 ng/mL (37%) was 10.9 months, compared with 6.0 months for those with C below this threshold (P = 0.06). Multivariable analysis resulted in a hazard ratio of 0.70 (95% CI 0.47-1.05, P = 0.082). Exposure to dabrafenib and trametinib was not related to clinically relevant toxicities.
Overall survival of metastasized melanoma patients with trametinib C levels ≥ 15.6 ng/mL is ten months longer compared to patients with C below this threshold. This would theoretically provide a rationale for therapeutic drug monitoring of trametinib. Although a high proportion of patients are underexposed, there is very little scope for dose increments due to the risk of serious toxicity.
达布拉非尼和曲美替尼目前的给药剂量是固定的，而患者间的暴露量差异很大。本研究旨在探讨达布拉非尼联合曲美替尼治疗黑色素瘤患者的真实临床队列中，药物暴露量与疗效和毒性的关系。
本研究为观察性研究，采集了常规治疗中的药代动力学样本。采用估计的达布拉非尼 AUC0-τ和曲美替尼谷浓度（C）进行单变量和多变量暴露-反应分析。
共纳入 140 例患者。达布拉非尼的暴露量与无进展生存期（PFS）或总生存期（OS）均无关。曲美替尼的暴露量与生存相关，C≥15.6ng/mL 被确定为最佳阈值。曲美替尼 C≥15.6ng/mL 的患者中位 OS 显著延长（22.8 与 12.6 个月，P=0.003），多变量风险比为 0.55（95%CI 0.36-0.85，P=0.007）。曲美替尼 C 水平≥15.6ng/mL 的患者中位 PFS（37%）为 10.9 个月，而 C 低于该阈值的患者为 6.0 个月（P=0.06）。多变量分析得出的风险比为 0.70（95%CI 0.47-1.05，P=0.082）。达布拉非尼和曲美替尼的暴露与临床相关毒性无关。
与曲美替尼 C 水平<15.6ng/mL 的患者相比，曲美替尼 C 水平≥15.6ng/mL 的转移性黑色素瘤患者的总生存期延长了十个月。这从理论上为曲美替尼的治疗药物监测提供了依据。尽管有相当一部分患者的暴露量不足，但由于严重毒性的风险，增加剂量的空间非常有限。
