Ivy S Percy, Wick Jeannette Y, Kaufman Bennett M
Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA.
Nat Rev Clin Oncol. 2009 Oct;6(10):569-79. doi: 10.1038/nrclinonc.2009.130. Epub 2009 Sep 8.
VEGFR inhibitors are in broad use for the treatment of metastatic renal-cell carcinoma, gastrointestinal stromal tumors and hepatocellular carcinoma and in development in a number of other oncology indications, including colorectal cancer, non-small-cell lung cancer, pancreatic cancer, thyroid malignancies, ovarian cancer, breast cancer and sarcomas. This Review outlines the structure-activity relationships of the 44 VEGFR inhibitors currently in development. An overview of the pharmacokinetic profile of each molecule and its stage in development is provided. Phase III clinical trials being conducted for licensing of these agents for specific indications and phase III developmental efficacy trials are described in detailed tables that include the disease studied, trial design including combination therapy, study end points, and projected or final accrual. The relative frequency of on-target and off-target adverse events observed in 3,060 patients is described for a subset of agents in development in clinical trials sponsored by the National Cancer Institute. No interagent comparisons were undertaken and no data from pharmaceutical pharmacovigilance databases were used. The on-target effects seem to be mechanistically based and predicted by VEGFR inhibition. Small-molecule inhibitors of angiogenesis are active in a wide variety of malignancies and fill a unique niche for cancer therapeutics.
血管内皮生长因子受体（VEGFR）抑制剂广泛用于治疗转移性肾细胞癌、胃肠道间质瘤和肝细胞癌，并且正在针对包括结直肠癌、非小细胞肺癌、胰腺癌、甲状腺恶性肿瘤、卵巢癌、乳腺癌和肉瘤在内的许多其他肿瘤学适应症进行研发。本综述概述了目前正在研发的44种VEGFR抑制剂的构效关系。提供了每种分子的药代动力学概况及其研发阶段的概述。针对这些药物用于特定适应症的许可进行的III期临床试验以及III期开发疗效试验在详细表格中进行了描述，表格包括所研究的疾病、试验设计（包括联合治疗）、研究终点以及预计或最终入组人数。对于美国国立癌症研究所赞助的临床试验中正在研发的一部分药物，描述了在3060名患者中观察到的靶向和非靶向不良事件的相对频率。未进行药物间比较，也未使用来自药物警戒数据库的数据。靶向效应似乎基于机制并由VEGFR抑制所预测。小分子血管生成抑制剂在多种恶性肿瘤中具有活性，为癌症治疗填补了独特的空白。
