Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Department of Soft Tissue/Bone Sarcoma and Melanoma , Roentgena 5, 02-781 Warsaw , Poland +48 22 6439375 ; +48 22 6439791 ;
Expert Opin Drug Saf. 2014 Sep;13(9):1249-58. doi: 10.1517/14740338.2014.939954. Epub 2014 Jul 11.
V-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors are emerging as the standard of care for treating advanced melanomas harboring the BRAF V600 oncogenic mutation. Dabrafenib is the second approved selective BRAF inhibitor (after vemurafenib) for the treatment of unresectable or metastatic BRAF V600-positive melanoma.
This review covers the current data on the efficacy and safety of the selective BRAF inhibitor dabrafenib in patients with metastatic BRAF V600 positive melanoma. The pharmacological, safety and efficacy data are discussed from Phase I, II, and III studies of dabrafenib monotherapy as well as in combination with the MEK inhibitor trametinib.
Dabrafenib has demonstrated comparable efficacy to vemurafenib in BRAF V600E mutant melanoma patients. Dabrafenib is well tolerated in patients with metastatic melanoma, including patients with brain metastases. Nevertheless side effects are common, but usually manageable. In the Phase III study testing dabrafenib, 53% of patients reported grade 2 or higher adverse events (AEs). Toxicities were similar to those seen in the early-phase trials, with the most common being cutaneous manifestations (hyperkeratosis, papillomas, palmar-plantar erythrodysesthesia), pyrexia, fatigue, headache, and arthralgia. Combining a BRAF inhibitor with a MEK inhibitor, which may block paradoxical MAPK activation in BRAF wild type (skin) cells, may lower the incidence of squamoproliferative eruptions.
V-raf 鼠肉瘤病毒癌基因同源物 B1（BRAF）抑制剂作为治疗携带 BRAF V600 致癌突变的晚期黑色素瘤的标准治疗方法正在出现。达拉非尼是第二种批准用于治疗不可切除或转移性 BRAF V600 阳性黑色素瘤的选择性 BRAF 抑制剂（继vemurafenib 之后）。
本文综述了选择性 BRAF 抑制剂达拉非尼在转移性 BRAF V600 阳性黑色素瘤患者中的疗效和安全性的现有数据。讨论了达拉非尼单药治疗以及与 MEK 抑制剂 trametinib 联合治疗的 I 期、II 期和 III 期研究中的药理学、安全性和疗效数据。
达拉非尼在 BRAF V600E 突变黑色素瘤患者中的疗效与 vemurafenib 相当。达拉非尼在转移性黑色素瘤患者中耐受性良好，包括脑转移患者。然而，副作用很常见，但通常可以控制。在 III 期研究中，53%的患者报告了 2 级或更高的不良反应（AE）。毒性与早期试验中观察到的相似，最常见的是皮肤表现（角化过度、乳头瘤、手掌-足底红斑感觉异常）、发热、疲劳、头痛和关节痛。将 BRAF 抑制剂与 MEK 抑制剂联合使用，可能会降低 BRAF 野生型（皮肤）细胞中 MAPK 激活的反常性，从而降低鳞片状增生性皮疹的发生率。
