Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma
Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma
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DOI：
10.1200/jco.2005.02.2574
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发表时间：
2006-01-01
影响因子：
45.3
通讯作者：
Rini, BI
中科院分区：
文献类型：
--
作者：
Motzer, RJ;Michaelson, MD;Rini, BI
目的肾细胞癌（RCC）以von Hippel Lindau肿瘤抑制基因活性丧失为特征，导致促血管生成生长因子：血管内皮生长因子（VEGF）和血小板衍生生长因子（PDGF）高表达。SU11248（苹果酸舒尼替尼）是一种对VEGF和PDGF受体具有高结合亲和力的小分子抑制剂，用于检测转移性RCC患者的临床活性。患者和方法接受一线细胞因子治疗进展的转移性肾细胞癌患者被纳入一项多中心II期试验。SU11248单药治疗以重复的6周周期进行，每天口服治疗4周，然后休息2周，总缓解率是主要终点，进展时间和安全性是次要终点。结果63例患者中有25例（40%）获得部分缓解；另外17例患者（27%）病情稳定，持续时间为>= 3个月，63例患者的中位进展时间为8.7个月。结论SU11248是一种VEGF和PDGF受体的多靶点酪氨酸激酶抑制剂，在转移性RCC中显示出抗肿瘤活性，作为二线治疗，目前还没有发现有效的全身治疗方法。RCC的遗传学和这些有希望的临床结果支持了VEGF和PDGF受体介导的信号传导是RCC有效治疗靶点的假设。
Purpose Renal cell carcinoma (RCC) is characterized by loss of von Hippel Lindau tumor suppressor gene activity, resulting in high expression of pro-angiogenic growth factors: vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). SU11248 (Sunitinib malate), a small molecule inhibitor with high binding affinity for VEGF and PDGF receptors, was tested for clinical activity in patients with metastatic RCC.Patients and Methods Patients with metastatic RCC and progression on first-line cytokine therapy were enrolled onto a multicenter phase II trial. SU11248 monotherapy was administered in repeated 6-week cycles of daily oral therapy for 4 weeks, followed by 2 weeks off, Overall response rate was the primary end point, and time to progression and safety were secondary end points.Results Twenty-five (40%) of 63 patients treated with SU11248 achieved partial responses; 17 additional patients (27%) demonstrated stable disease lasting >= 3 months, Median time to progression in the 63 patients was 8.7 months. Dosing was generally tolerated with manageable toxicities,Conclusion SU11248, a multitargeted receptor tyrosine kinase inhibitor of VEGF and PDGF receptors, demonstrates antitumor activity in metastatic RCC as second-line therapy, a setting where no effective systemic therapy is presently recognized. The genetics of RCC and these promising clinical results support the hypothesis that VEGF and PDGF receptor-mediated signaling is an effective therapeutic target in RCC.