Luke Jason J, Ott Patrick A
Melanoma Disease Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
Drug Healthc Patient Saf. 2014 Jun 24;6:77-88. doi: 10.2147/DHPS.S39568. eCollection 2014.
Development of selective inhibitors of BRAF has improved the survival of patients with BRAF-mutant melanoma. The progression-free survival after treatment with a BRAF inhibitor is modest, however, and BRAF inhibitors induce cutaneous toxicity, likely due to paradoxical activation of the mitogen-activated protein kinase pathway. Combining selective BRAF and MEK inhibition, such as the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib, has been shown to improve the response rate and progression-free survival in patients with advanced melanoma while significantly alleviating the paradoxical activation of mitogen-activated protein kinase. This combination treatment results in a reduction in skin toxicity relative to that seen with a BRAF inhibitor alone; however, addition of the MEK inhibitor adds other toxicities, such as pyrexia and gastrointestinal or ocular toxicity. While combined BRAF-MEK inhibition appears primed to become a standard molecular approach for BRAF-mutant melanoma, the utility of the combination has to be considered in the rapidly changing landscape of immunotherapeutics, such as immune checkpoint blockade using anti-cytotoxic T lymphocyte antigen-4 and anti-programmed death-1/programmed death-L1 antibodies. Here we review the development of the dabrafenib plus trametinib combination, the characteristics of each drug and the combination, and the role of this combination in the management of patients with BRAF-mutant melanoma.
BRAF选择性抑制剂的研发提高了BRAF突变型黑色素瘤患者的生存率。然而，使用BRAF抑制剂治疗后的无进展生存期并不理想，而且BRAF抑制剂会引发皮肤毒性，这可能是由于丝裂原活化蛋白激酶途径的反常激活所致。联合使用选择性BRAF和MEK抑制剂，如BRAF抑制剂达拉非尼和MEK抑制剂曲美替尼，已被证明可提高晚期黑色素瘤患者的缓解率和无进展生存期，同时显著减轻丝裂原活化蛋白激酶的反常激活。相对于单独使用BRAF抑制剂，这种联合治疗可降低皮肤毒性；然而，添加MEK抑制剂会带来其他毒性，如发热以及胃肠道或眼部毒性。虽然BRAF-MEK联合抑制似乎有望成为BRAF突变型黑色素瘤的标准分子治疗方法，但在免疫治疗迅速发展的背景下，如使用抗细胞毒性T淋巴细胞抗原-4和抗程序性死亡蛋白-1/程序性死亡配体-1抗体进行免疫检查点阻断，必须考虑这种联合治疗的实用性。在此，我们综述了达拉非尼加曲美替尼联合治疗的研发情况、每种药物及联合治疗的特点，以及这种联合治疗在BRAF突变型黑色素瘤患者管理中的作用。
