Authors' Affiliations: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; and Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
Clin Cancer Res. 2013 Oct 1;19(19):5283-91. doi: 10.1158/1078-0432.CCR-13-2151.
In three years, four drugs have gained regulatory approval for the treatment of metastatic and unresectable melanoma, with at least seven other drugs having recently completed, currently in, or soon to be in phase III clinical testing. This amazing achievement has been made following a remarkable increase of knowledge in molecular biology and immunology that led to the identification of high-valued therapeutic targets and the clinical development of agents that effectively engage and inhibit these targets. The discovery of either effective molecularly targeted therapies or immunotherapies would have led to dramatic improvements to the standard-of-care treatment of melanoma. However, through parallel efforts that have showcased the efficacy of small-molecule BRAF and MAP-ERK kinase (MEK) inhibitors, as well as the immune checkpoint inhibitors, namely ipilimumab and the anti-PD1/PDL1 antibodies (lambrolizumab, nivolumab, MPDL3280), an opportunity exists to transform the treatment of melanoma specifically and cancer generally by exploring rational combinations of molecularly targeted therapies, immunotherapies, and molecular targeted therapies with immunotherapies. This overview presents the historical context to this therapeutic revolution, reviews the benefits and limitations of current therapies, and provides a look ahead at where the field is headed.
在三年内,有四种药物获得了转移性和不可切除性黑色素瘤治疗的监管批准,至少还有七种其他药物最近已经完成、正在进行或即将进入 III 期临床试验。这一惊人的成就得益于分子生物学和免疫学知识的显著增加,这些知识导致了高价值治疗靶点的确定,以及有效针对这些靶点的药物的临床开发。有效的分子靶向治疗或免疫治疗的发现本应导致黑色素瘤标准治疗的显著改善。然而,通过平行努力,展示了小分子 BRAF 和 MAP-ERK 激酶 (MEK) 抑制剂以及免疫检查点抑制剂(即 ipilimumab 和抗 PD1/PDL1 抗体(lambrolizumab、nivolumab、MPDL3280)的疗效,通过探索分子靶向治疗、免疫治疗以及分子靶向治疗与免疫治疗的合理联合,为黑色素瘤乃至癌症的治疗带来了变革的机会。这篇综述介绍了这一治疗革命的历史背景,回顾了当前治疗方法的益处和局限性,并展望了该领域的发展方向。