Department of Plastic and Reconstructive Surgery, IRCCS Azienda Ospedaliera Universitaria San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, Genova, Italy ; Genetics of Rare Cancers, IRCCS Azienda Ospedaliera Universitaria San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Onco Targets Ther. 2015 Jan 16;8:157-68. doi: 10.2147/OTT.S39096. eCollection 2015.
BRAF inhibitors vemurafenib and dabrafenib achieved improved overall survival over chemotherapy and have been approved for the treatment of BRAF-mutated metastatic melanoma. More recently, the combination of BRAF inhibitor dabrafenib with MEK inhibitor trametinib has shown improved progression-free survival, compared to dabrafenib monotherapy, in a Phase II study and has received approval by the US Food and Drug Administration. However, even when treated with the combination, most patients develop mechanisms of acquired resistance, and some of them do not achieve tumor regression at all, because of intrinsic resistance to therapy. Along with the development of BRAF inhibitors, immunotherapy made an important step forward: ipilimumab, an anti-CTLA-4 monoclonal antibody, was approved for the treatment of metastatic melanoma; anti-PD-1 agents achieved promising results in Phase I/II trials, and data from Phase III studies will be ready soon. The availability of such drugs, which are effective regardless of BRAF status, has made the therapeutic approach more complex, as first-line treatment with BRAF inhibitors may not be the best choice for all BRAF-mutated patients. The aim of this paper is to review the systemic therapeutic options available today for patients affected by BRAF V600-mutated metastatic melanoma, as well as to summarize the mechanisms of resistance to BRAF inhibitors and discuss the possible strategies to overcome them. Moreover, since the molecular analysis of tumor specimens is now a pivotal and decisional factor in the treatment strategy of metastatic melanoma patients, the advances in the molecular detection techniques for the BRAF V600 mutation will be reported.
BRAF 抑制剂维莫非尼和达拉非尼在改善总生存期方面优于化疗，已被批准用于治疗 BRAF 突变型转移性黑色素瘤。最近，BRAF 抑制剂达拉非尼联合 MEK 抑制剂曲美替尼的治疗方案与达拉非尼单药治疗相比，在 II 期研究中显示出无进展生存期的改善，并已获得美国食品和药物管理局的批准。然而，即使接受联合治疗，大多数患者仍会产生获得性耐药机制，其中一些患者由于对治疗存在内在耐药性而根本无法实现肿瘤消退。随着 BRAF 抑制剂的发展，免疫疗法取得了重要进展：抗 CTLA-4 单克隆抗体伊匹单抗被批准用于治疗转移性黑色素瘤；抗 PD-1 药物在 I/II 期试验中取得了令人鼓舞的结果，即将公布 III 期研究的数据。这些药物的出现（无论 BRAF 状态如何都有效）使治疗方法变得更加复杂，因为 BRAF 抑制剂的一线治疗可能不是所有 BRAF 突变患者的最佳选择。本文旨在回顾目前针对 BRAF V600 突变转移性黑色素瘤患者的系统治疗选择，并总结 BRAF 抑制剂耐药的机制，探讨克服耐药的可能策略。此外，由于肿瘤标本的分子分析现在是转移性黑色素瘤患者治疗策略的关键和决策因素，因此将报告 BRAF V600 突变的分子检测技术的进展。
