University of Pittsburgh, School of Medicine, Division of Hematology/Oncology, Department of Medicine, Pittsburgh, PA 15232, USA.
Expert Opin Investig Drugs. 2012 Jun;21(6):861-9. doi: 10.1517/13543784.2012.679341. Epub 2012 Apr 16.
The advent of effective immunotherapy and targeted therapy, such as ipilimumab (anti-CTLA-4 monoclonal antibody) and vemurafenib (BRAF inhibitor), are changing the treatment paradigm for metastatic melanoma. One of the most readily recognized targets in metastatic melanoma is the oncogenic 'driver' mutations KIT, which is thought to be an important driver mutation in up to 3% of melanomas.
We review the current state of development of KIT-targeted agents in melanoma with KIT mutations. The pharmacokinetic and pharmacodynamic profiles of nilotinib are presented, as well its safety clinical activity data. Finally, we present the knowledge learned from the experience of nilotinib in chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST) to guide its development for melanoma.
Given its favorable safety and efficacy profile in CML and imatinib-resistant GISTs, nilotinib, a second-generation tyrosine kinase inhibitor with greater potency than imatinib, emerges as a promising agent in the treatment of metastatic melanoma harboring the KIT mutation and warrants clinical investigation in this setting.
有效的免疫疗法和靶向疗法的出现，如伊匹单抗（抗 CTLA-4 单克隆抗体）和威罗菲尼（BRAF 抑制剂），正在改变转移性黑色素瘤的治疗模式。转移性黑色素瘤中最容易识别的靶点之一是致癌“驱动”突变 KIT，据认为 KIT 突变在高达 3%的黑色素瘤中是一个重要的驱动突变。
我们回顾了具有 KIT 突变的黑色素瘤中 KIT 靶向药物的最新发展情况。介绍了 nilotinib 的药代动力学和药效学特征及其安全性和临床活性数据。最后，我们介绍了从 nilotinib 在慢性髓性白血病（CML）和胃肠道间质瘤（GIST）的经验中获得的知识，以指导其在黑色素瘤中的开发。
鉴于 nilotinib 在 CML 和伊马替尼耐药 GIST 中的良好安全性和疗效，作为一种比伊马替尼更有效的第二代酪氨酸激酶抑制剂，它在治疗携带 KIT 突变的转移性黑色素瘤方面具有广阔的应用前景，值得在该领域进行临床研究。
