Amaria R N, Lewis K D, Jimeno A
University of Colorado Cancer Center, Aurora, CO, USA.
Drugs Today (Barc). 2012 Feb;48(2):109-18. doi: 10.1358/dot.2012.48.2.1745274.
Advanced melanoma has a poor prognosis due to its resistance to traditional chemotherapeutics, leading to the search for alternative treatment approaches. With the finding that approximately 50% of melanomas harbor an activating mutation in the serine/threonine-protein kinase B-raf gene (BRAF), inhibition of mutated B-raf represented an attractive and innovative focus for the development of novel targeted therapy potentially benefiting a large proportion of melanoma patients. Impressive response rates with an overall survival benefit in addition to minimal treatment-related toxicity in phase I-III clinical studies led to the FDA's approval of vemurafenib for patients with locally advanced/unresectable or metastatic BRAFV600E-mutated malignant melanoma in August 2011. While the majority of patients with BRAF-mutated disease show favorable treatment responses shortly after initiation of vemurafenib therapy, the median progression-free survival is 6 months, making the search for resistance mechanisms a high priority. While vemurafenib represents an excellent model for successful targeted anticancer therapy, long-term safety data are needed and rational combination with other agents will be critical to prevent or circumvent the development of resistance.
晚期黑色素瘤由于对传统化疗药物具有抗性，预后较差，这促使人们寻找其他治疗方法。随着发现约50%的黑色素瘤在丝氨酸/苏氨酸蛋白激酶B-raf基因（BRAF）中存在激活突变，抑制突变的B-raf成为开发新型靶向治疗的一个有吸引力且创新的焦点，这可能使很大一部分黑色素瘤患者受益。在I - III期临床研究中，维莫非尼显示出令人印象深刻的缓解率、总生存获益以及最小的治疗相关毒性，这使得美国食品药品监督管理局（FDA）于2011年8月批准维莫非尼用于治疗局部晚期/不可切除或转移性BRAFV600E突变的恶性黑色素瘤患者。虽然大多数BRAF突变疾病患者在开始维莫非尼治疗后不久显示出良好的治疗反应，但无进展生存期的中位数为6个月，这使得寻找耐药机制成为当务之急。虽然维莫非尼是成功的靶向抗癌治疗的一个优秀范例，但仍需要长期安全性数据，并且与其他药物进行合理联合对于预防或规避耐药性的产生至关重要。
