Unit of Medical Oncology, Department of Oncology & Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy.
Future Oncol. 2019 Mar;15(9):967-977. doi: 10.2217/fon-2018-0659. Epub 2019 Jan 14.
Approximately 50% 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) is an orally bioavailable, potent and selective MEKi, which significantly improved response rates when combined with BRAFi vemurafenib (median overall survival: 22.3 months). 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.
约 50%的皮肤黑色素瘤存在 BRAF 癌基因的激活突变，这使得 BRAF 抑制剂（BRAFi）成为该疾病的标准治疗方法。然而，由于获得性耐药，疾病反应的持续时间有限。与单独使用 BRAFi 相比，添加 MEK 抑制剂（MEKi）的双重 MAPK 通路抑制可提高疗效和耐受性。考比替尼（Cotellic）是一种口服生物利用度高、强效且选择性的 MEKi，与 BRAFi 维莫非尼联合使用时可显著提高反应率（中位总生存期：22.3 个月）。考比替尼的毒性谱是可控的，因不良反应而停止治疗并不常见。目前正在努力克服耐药性并改善长期结果：基于 BRAFi 和 MEKi 的免疫调节特性的证据，目前正在进行联合靶向和免疫治疗的临床试验，以研究考比替尼在联合治疗或序贯治疗中的作用。
