Institut de Cancérologie Gustave Roussy, Villejuif, Paris-Sud, France.
Eur J Cancer. 2011 Sep;47(14):2150-7. doi: 10.1016/j.ejca.2011.06.052. Epub 2011 Jul 27.
Current developments in systemic therapies for melanoma are spectacular. Over the last 40 years no one drug or combination of drugs demonstrated any impact on survival in metastatic melanoma. In contrast, in 2011 a number of new drugs will be approved. In 2011 immunomodulation with ipilimumab, a monoclonal antibody targeting the ligand CTLA-4, has been approved for patients with advanced melanoma in first- and second-line treatment by the Food and Drug Administration (FDA) and in second-line treatment by the European Medicines Agency (EMA). Also in 2011, a significant survival benefit of the combination of ipilimumab with dacarbazine compared with dacarbazine alone for first-line treatment was reported. Other monoclonal antibodies targeting T-cell ligands, such as programmed death-1 (PD-1), also show promise. Various inhibitors of v-Raf murine sarcoma viral oncogene homologue B1 (BRAF) yield high response rates in patients harbouring the BRAF-V600E mutation. A significant impact on both progression-free and overall survival was demonstrated for vemurafenib compared with dacarbazine in a phase-III trial. Approval is expected in 2011. Both drugs had only modest effects of 2-3 months on median survival, so combination therapies must be explored. BRAF inhibitors in combination with mitogen-activated protein kinase (MEK) inhibitors show great potential. Moreover, combinations of immunomodulators and pathway inhibitors are expected to be very active, and phase-III trials are planned. Pegylated interferon-α2b was approved in 2011 on the basis of the results of the European Organisation for Research and Treatment of Cancer (EORTC) 18991 phase-III trial demonstrating a sustained impact on relapse-free survival in patients with lymph-node-positive melanoma. The efficacy of adjuvant therapy with ipilimumab is assessed in the now fully accrued EORTC18071 trial. Adjuvant trials with BRAF and MEK inhibitors are in the planning phase. Never was there a more exciting period in the world of melanoma treatment.
目前黑色素瘤的系统治疗进展显著。在过去的 40 年中，没有一种药物或药物组合对转移性黑色素瘤的生存有任何影响。相比之下，2011 年将有许多新药获得批准。2011 年，免疫调节剂 ipilimumab（一种针对配体 CTLA-4 的单克隆抗体）已获得美国食品和药物管理局（FDA）批准，用于一线和二线治疗晚期黑色素瘤患者，以及欧洲药品管理局（EMA）批准，用于二线治疗。同样在 2011 年，报道了 ipilimumab 联合达卡巴嗪与单独使用达卡巴嗪相比，一线治疗的总生存期有显著获益。针对 T 细胞配体的其他单克隆抗体，如程序性死亡受体-1（PD-1），也显示出良好的前景。各种抑制 v-Raf 鼠肉瘤病毒致癌基因同源物 B1（BRAF）的抑制剂在携带 BRAF-V600E 突变的患者中产生了很高的反应率。与达卡巴嗪相比，vemurafenib 在 III 期试验中显示出对无进展生存期和总生存期的显著影响。预计在 2011 年获得批准。这两种药物对中位生存期的影响仅为 2-3 个月，因此必须探索联合治疗。BRAF 抑制剂联合丝裂原活化蛋白激酶（MEK）抑制剂显示出巨大的潜力。此外，预计免疫调节剂和通路抑制剂的联合将非常有效，正在计划进行 III 期试验。聚乙二醇化干扰素-α2b 基于欧洲癌症研究与治疗组织（EORTC）18991 期 III 期试验的结果获得批准，该试验显示在淋巴结阳性黑色素瘤患者中持续影响无复发生存率。EORTC18071 试验现在已完全入组，正在评估辅助治疗用 ipilimumab 的疗效。BRAF 和 MEK 抑制剂的辅助试验正在计划阶段。黑色素瘤治疗领域从未有过如此激动人心的时期。
