Cobimetinib in malignant melanoma: how to MEK an impact on long-term survival
Cobimetinib in malignant melanoma: how to MEK an impact on long-term survival
复制标题
DOI：
10.2217/fon-2018-0659
复制
发表时间：
2019-03-01
期刊：
影响因子：
3.3
通讯作者：
Mandala, Mario
中科院分区：
文献类型：
--
作者：
Indini, Alice;Tondini, Carlo Alberto;Mandala, Mario
大约50%的皮肤黑色素瘤携带BRAF癌基因的激活突变，使得BRAF抑制剂（BRAFi）成为该疾病的标准治疗。然而，主要由于获得性抗性，疾病反应的持续时间有限。与单独的BRAFi相比，在BRAFi中添加MEK抑制剂（MEKi）的双重MAPK途径抑制改善了功效和耐受性。Cobimetinib（Cotellic（（R）是一种口服生物可利用的、强效的和选择性的MEKi，当与BRAFi vemurafenib联合使用时，它显著提高了应答率（中位总生存期：22.3个月）。cobimetinib的毒性特征是可控的，并且由于不良事件而停止治疗是罕见的。目前的努力是为了克服耐药性和改善长期结果：基于BRAFi和MEKi的免疫调节特性的证据，目前联合靶向和免疫治疗的临床试验正在研究cobimetinib在联合治疗或序贯治疗中的作用。
Approximately50% of cutaneous melanomas harbor activating mutations of the BRAF-oncogene, making BRAF inhibitors (BRAFi) the standard treatment for this disease. However, disease responses are limited in duration mainly due to acquired resistance. Dual MAPK pathway inhibition with addition of a MEK inhibitor (MEKi) to a BRAFi improved the efficacy and tolerability compared with BRAFi alone. Cobimetinib (Cotellic((R))) is an orally bioavailable, potent and selective MEKi, which significantly improved response rates when combined with BRAFi vemurafenib (median overall survival: 22.3months). The toxicity profile of cobimetinib is manageable and treatment discontinuation due to adverse events is uncommon. Present efforts are addressed to overcome resistance and improve long-term outcomes: based on the evidence of the immunomodulatory properties of BRAFi and MEKi, current clinical trials of combined targeted and immunotherapy are investigating the role of cobimetinib in the context of combination or as sequential treatments.