Rini Brian I, Michaelson M Dror, Rosenberg Jonathan E, Bukowski Ronald M, Sosman Jeffrey A, Stadler Walter M, Hutson Thomas E, Margolin Kim, Harmon Charles S, DePrimo Samuel E, Kim Sindy T, Chen Isan, George Daniel J
Department of Solid Tumor Oncology and Urology, Cleveland Clinic Taussig Cancer Institute, 9500 Euclid Avenue, Desk R35, Cleveland, OH 44195, USA.
J Clin Oncol. 2008 Aug 1;26(22):3743-8. doi: 10.1200/JCO.2007.15.5416.
To assess the safety and efficacy of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma (mRCC) and explore biomarkers for sunitinib response.
Patients with mRCC and disease progression after bevacizumab-based therapy received oral sunitinib 50 mg once daily in 6-week cycles on a 4/2 schedule (4 weeks with treatment followed by 2 weeks without treatment) in a phase II multicenter study. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), duration of response (DR), overall survival (OS), and safety. Plasma soluble proteins (vascular endothelial growth factor [VEGF]-A, VEGF-C, soluble VEGF receptor [sVEGFR]-3, and placental growth factor [PlGF]) levels were measured.
Sixty-one patients were enrolled. The ORR was 23.0% (95% CI, 13.2% to 35.5%), median PFS was 30.4 weeks (95% CI, 18.3 to 36.7 weeks), median DR was 44.1 weeks (95% CI, 25.0 to 102.7 weeks), and median OS was 47.1 weeks (95% CI, 36.9 to 79.4 weeks). Mean plasma VEGF-A and PlGF levels significantly increased whereas VEGF-C and sVEGFR-3 levels decreased with sunitinib treatment. Lower baseline levels of sVEGFR-3 and VEGF-C were associated with longer PFS and ORR. Most treatment-related adverse events were of mild-to-moderate intensity and included fatigue, hypertension, and hand-foot syndrome.
Sunitinib has substantial antitumor activity in patients with bevacizumab-refractory mRCC and modulates circulating VEGF pathway biomarkers. These data support the hypothesis that sunitinib inhibits signaling pathways involved in bevacizumab resistance. Baseline levels of sVEGFR-3 and VEGF-C may have potential utility as biomarkers of clinical efficacy in this setting.
评估舒尼替尼在贝伐单抗难治性转移性肾细胞癌（mRCC）患者中的安全性和疗效，并探索舒尼替尼反应的生物标志物。
在一项II期多中心研究中，mRCC且接受基于贝伐单抗治疗后疾病进展的患者，按照4/2方案（4周治疗，随后2周无治疗），每6周为一个周期，口服舒尼替尼50mg，每日一次。主要终点为客观缓解率（ORR）。次要终点包括无进展生存期（PFS）、缓解持续时间（DR）、总生存期（OS）和安全性。检测血浆可溶性蛋白（血管内皮生长因子 [VEGF]-A、VEGF-C、可溶性VEGF受体 [sVEGFR]-3和胎盘生长因子 [PlGF]）水平。
入组61例患者。ORR为23.0%（95%CI，13.2%至35.5%），中位PFS为30.4周（95%CI，18.3至36.7周），中位DR为44.1周（95%CI，25.0至102.7周），中位OS为47.1周（95%CI，36.9至79.4周）。舒尼替尼治疗后，血浆VEGF-A和PlGF平均水平显著升高，而VEGF-C和sVEGFR-3水平降低。sVEGFR-3和VEGF-C较低的基线水平与更长的PFS和ORR相关。大多数治疗相关不良事件为轻至中度，包括疲劳、高血压和手足综合征。
舒尼替尼在贝伐单抗难治性mRCC患者中具有显著的抗肿瘤活性，并可调节循环VEGF通路生物标志物。这些数据支持舒尼替尼抑制参与贝伐单抗耐药的信号通路这一假说。在这种情况下，sVEGFR-3和VEGF-C的基线水平可能具有作为临床疗效生物标志物的潜在效用。
