Trametinib: a MEK inhibitor for management of metastatic melanoma.
Trametinib: a MEK inhibitor for management of metastatic melanoma.
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DOI：
10.2147/ott.s72951
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发表时间：
2015
影响因子：
4
通讯作者：
Rutkowski P
中科院分区：
文献类型：
--
作者：
Lugowska I;Koseła-Paterczyk H;Kozak K;Rutkowski P
本文综述了选择性丝裂原活化细胞外信号调节激酶（MEK）抑制剂曲美替尼在转移性BRAF V600阳性黑色素瘤患者中的有效性和安全性。药理学、安全性和疗效数据来自曲美替尼单药治疗以及与BRAF抑制剂达拉非尼联合治疗的I、II和III期研究。曲美替尼治疗最常见的不良反应是皮疹、皮炎、腹泻和疲劳。III期METRIC研究显示，曲美替尼优于标准达卡巴嗪或紫杉醇化疗，总体生存期和无进展生存期显著改善。因此，曲美替尼被美国食品药品监督管理局和欧洲药品管理局批准作为单药治疗V600 E突变转移性黑色素瘤患者。曲美替尼单药治疗的无进展生存率和缓解率低于BRAF抑制剂。开发曲美替尼的第二步是使用曲美替尼与BRAF抑制剂（例如，达拉非尼）的组合，以推迟MEK或BRAF抑制剂的进展。最近发表的数据显示，曲美替尼和达拉非尼联合治疗的总生存期和无进展生存期显著改善，优于维罗非尼治疗或达拉非尼单独治疗，耐受性良好。美国食品药品监督管理局已批准达拉非尼（150 mg，口服，每日两次）和曲美替尼（2 mg，口服，每日一次）联合治疗BRAF V600 E/K突变型转移性黑色素瘤患者，使用这两种药物似乎是目前最好的方法。虽然BRAF-MEK抑制是BRAF突变黑色素瘤的标准分子靶向治疗，但其未来的效用必须在快速变化的免疫治疗领域中建立。
This review presents the current data on the efficacy and safety of the selective mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor trametinib in patients with metastatic BRAF V600-positive melanoma. The pharmacological, safety, and efficacy data come from the Phase I, II, and III studies of trametinib monotherapy, as well as those in combination with the BRAF inhibitor dabrafenib. The most common adverse effects of trametinib therapy are rash, dermatitis, diarrhea, and fatigue. The Phase III METRIC study showed significant improvement in overall survival and progression-free survival in favor of trametinib over standard dacarbazine or paclitaxel chemotherapy. Therefore, trametinib was approved by the US Food and Drug Administration and European Medicines Agency as a single agent for the treatment of patients with V600E-mutated metastatic melanoma. Progression-free survival and response rates for trametinib monotherapy were lower than those noted with BRAF inhibitors. The second step in developing trametinib was to use the combination of trametinib with the BRAF inhibitor, eg, dabrafenib, to postpone the progression on MEK or BRAF inhibitors. The recently published data showed significant improvement in overall survival and progression-free survival in favor of the combination of trametinib and dabrafenib over vemurafenib therapy or dabrafenib alone, with good tolerance. The US Food and Drug Administration has approved the combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily) for the treatment of patients with BRAF V600E/K-mutant metastatic melanoma, and their use seems to be currently the best approach. While BRAF-MEK inhibition is a standard, molecular targeted therapy in BRAF-mutated melanomas, its future utility has to be established in the rapidly changing landscape of immunotherapeutics.