Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma
Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma
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DOI：
10.1200/jco.2007.15.5416
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发表时间：
2008-08-01
影响因子：
45.3
通讯作者：
George, Daniel J.
中科院分区：
文献类型：
--
作者：
Rini, Brian I.;Michaelson, M. Dror;George, Daniel J.
目的评价舒尼替尼治疗贝伐单抗难治的转移性肾细胞癌(MRCC)的安全性和有效性，并探索转移性肾细胞癌(MRCC)对舒尼替尼疗效的生物标志物。患者与方法在一项II期多中心研究中，对贝伐单抗治疗后出现疾病进展的转移性肾细胞癌患者口服舒尼替尼50 mg，每日1次，6周为一个周期(先治疗4周，再治疗2周)。主要终点为客观有效率(ORR)。次要终点包括无进展生存期(PFS)、反应持续时间(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A、C、可溶性血管内皮生长因子受体3、胎盘生长因子)水平。ORR为23.0%(95%CI，13.2%~35.5%)，中位PFS为30.4周(95%CI，18.3~36.7周)，中位DR为44.1周(95%CI，25.0~102.7周)，中位OS为47.1周(95%CI，36.9~79.4周)。经舒尼替尼治疗后，血浆平均VEGF-A和PlGF水平显著升高，而VEGF-C和sVEGFR-3水平显著下降。基线水平较低的sVEGFR-3和VEGF-C与较长的PFS和ORR相关。结论舒尼替尼对贝伐单抗耐药的肾细胞癌患者具有显著的抗肿瘤活性，并调节循环中的血管内皮生长因子途径生物标志物。这些数据支持这样的假设，即舒尼替尼抑制与贝伐单抗耐药有关的信号通路。在这种情况下，sVEGFR-3和VEGF-C的基线水平作为临床疗效的生物标志物可能具有潜在的实用价值。
Purpose 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 and Methods 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.Results 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.Conclusion 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.