Iams Wade T, Sosman Jeffrey A, Chandra Sunandana
From the Division of Hematology/Oncology, Northwestern Feinberg School of Medicine, Chicago, IL.
Cancer J. 2017 Jan-Feb;23(1):54-58. doi: 10.1097/PPO.0000000000000242.
Oncogene-targeted therapy is a major component of precision oncology, and although patients with metastatic melanoma have experienced improved outcomes with this strategy, there are a number of potential therapeutic targets currently under study that may further increase the drug armamentarium for this patient population. In this review, we discuss the landscape of targeted therapies for patients with advanced melanoma, focusing on oncogene mutation-specific targets. In patients with typical BRAF V600-mutant melanoma, combination BRAF and MEK inhibition has surpassed outcomes compared with monotherapy with BRAF or MEK inhibition alone, and current strategies seek to address inevitable resistance mechanisms. For patients with NRAS-mutant melanoma, MEK inhibitor monotherapy and combined MEK and CDK4/6 inhibition are burgeoning strategies; for patients with KIT-mutant melanoma, tyrosine kinase inhibition is being leveraged, and for NF-1-mutant melanoma, mTOR and MEK inhibition is being actively evaluated. In patients with atypical, non-V600 BRAF-mutant melanoma, MEK inhibitor monotherapy is the potential novel targeted approach on the horizon. For advanced uveal melanoma, novel targets such as IMCgp100 and glembatumumab have shown activity in early studies. We review additional strategies that remain in the preclinical and early clinical pipeline, so there is much hope for the future of targeted agents for distinct molecular cohorts of patients with advanced melanoma.
靶向癌基因治疗是精准肿瘤学的一个主要组成部分，尽管转移性黑色素瘤患者通过这一策略取得了更好的治疗效果，但目前仍有许多潜在的治疗靶点正在研究中，这可能会进一步增加针对该患者群体的药物储备。在这篇综述中，我们讨论了晚期黑色素瘤患者的靶向治疗前景，重点关注癌基因突变特异性靶点。在典型的BRAF V600突变型黑色素瘤患者中，与单独使用BRAF或MEK抑制剂的单药治疗相比，联合使用BRAF和MEK抑制剂的治疗效果更佳，目前的策略旨在解决不可避免的耐药机制。对于NRAS突变型黑色素瘤患者，MEK抑制剂单药治疗以及MEK与CDK4/6联合抑制是新兴的治疗策略；对于KIT突变型黑色素瘤患者，正在利用酪氨酸激酶抑制疗法，而对于NF-1突变型黑色素瘤患者，mTOR和MEK抑制疗法正在积极评估中。在非典型、非V600 BRAF突变型黑色素瘤患者中，MEK抑制剂单药治疗是即将出现的潜在新型靶向治疗方法。对于晚期葡萄膜黑色素瘤，IMCgp100和glembatumumab等新型靶点在早期研究中已显示出活性。我们还综述了仍处于临床前和临床早期阶段的其他策略，因此晚期黑色素瘤不同分子亚群的靶向药物的未来充满希望。
