Iacovelli Roberto, Albiges Laurence, Escudier Bernard
a 1 Institut Gustave Roussy, Department of Medical Oncology , 114 Rue Edouard Vaillant, 94805 Villejuif, France +331 4211 5410 ; +331 4211 5211 ;
Expert Opin Emerg Drugs. 2015 Sep;20(3):379-92. doi: 10.1517/14728214.2015.1047761. Epub 2015 May 19.
Since both cytotoxic and cytokine therapy were not able to improve the prognosis of advanced renal cell carcinoma (RCC), this tumor has been a good model for the development of new biological agents in the past decade. Five VEGF receptor (VEGFR) and two mammalian target of rapamycin (mTOR) inhibitors are currently available for treatment of this disease but several issues need to be resolved such as a better definition of prognosis, the overcome of resistance and the best therapy for less frequent histologies.
This review focuses on new tyrosine kinase inhibitors (TKIs) under investigation in these patients. Study design, phase of investigation, result and emerging toxicities were reported for each molecule. Combination trials involving TKIs with other strategies such as immunotherapy were also covered.
Despite the development of more potent and more specific VEGFR TKIs, all tumors ultimately develop resistance to therapy and a plateau has been reached in terms of overall survival. Current research effort to develop new agents aims at overcoming both the primary and the acquired resistance to anti-VEGFR TKIs focusing on new molecular pathways. The ultimate goal is not only to improve patient outcome but to achieve durable complete remission. Several pitfalls that have been responsible for failure of other compounds remain, especially the lack of strong predictive biomarkers and the use of inappropriate tumor assessment criteria that may not accurately capture response to these new therapies.
由于细胞毒性疗法和细胞因子疗法均无法改善晚期肾细胞癌（RCC）的预后，在过去十年中，这种肿瘤一直是新型生物制剂研发的良好模型。目前有五种血管内皮生长因子受体（VEGFR）抑制剂和两种雷帕霉素靶蛋白（mTOR）抑制剂可用于治疗该疾病，但仍有几个问题需要解决，例如对预后的更好定义、耐药性的克服以及针对少见组织学类型的最佳治疗方法。
本综述重点关注正在这些患者中进行研究的新型酪氨酸激酶抑制剂（TKIs）。报告了每种分子（抑制剂）的研究设计、研究阶段、结果和新出现的毒性。还涵盖了涉及TKIs与其他策略（如免疫疗法）的联合试验。
尽管已经研发出更有效、更具特异性的VEGFR TKIs，但所有肿瘤最终都会对治疗产生耐药性，总体生存率已达到平台期。目前研发新药物的研究工作旨在克服对抗VEGFR TKIs的原发性和获得性耐药性，重点关注新的分子途径。最终目标不仅是改善患者预后，而且要实现持久的完全缓解。导致其他化合物研发失败的几个陷阱仍然存在，特别是缺乏强有力的预测性生物标志物以及使用可能无法准确捕捉对这些新疗法反应的不适当的肿瘤评估标准。
