Phase II study of bevacizumab in combination with sorafenib in recurrent glioblastoma (N0776): a north central cancer treatment group trial.
Phase II study of bevacizumab in combination with sorafenib in recurrent glioblastoma (N0776): a north central cancer treatment group trial.
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DOI：
10.1158/1078-0432.ccr-13-0708
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发表时间：
2013-09-01
期刊：
影响因子：
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通讯作者：
Buckner JC
中科院分区：
文献类型：
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作者：
Galanis E;Anderson SK;Lafky JM;Uhm JH;Giannini C;Kumar SK;Kimlinger TK;Northfelt DW;Flynn PJ;Jaeckle KA;Kaufmann TJ;Buckner JC
我们假设，在复发性胶质母细胞瘤（rGBM）患者中，通过联合贝伐单抗和索拉非尼垂直阻断VEGF信号传导将产生协同治疗效果。我们还研究了VEGF、VEGFR 2和HIF-1α单核苷酸多态性（SNP）、血管生成的循环生物标志物和磁共振（MR）成像标志物（如表观扩散系数（ADC））是否与治疗疗效和/或毒性相关。患者接受贝伐珠单抗（5 mg/kg，每2周一次）和索拉非尼B（200 mg bid，每周一次，第1-5天）（A组），但由于毒性，索拉非尼B的起始剂量随后修改为200 mg qd（B组）。入组了54例患者：A组19例，B组35例。客观缓解率为18.5%，中位持续时间为6.7个月（范围0.5-24.1个月）。6个月无进展生存期（PFS 6）为20.4%（11/54），中位OS为5.6个月（95% CI 4.7 - 8.2）;两个剂量组的结局相似。我们鉴定了VEGF和VEGFR 2启动子区的单核苷酸多态性，它们与PFS 6相关（p<0.022）。在血管生成的分子标志物中，基质细胞衍生因子-1的较高log 2基线水平与PFS 6成功相关（p=0.04）。治疗期间循环内皮细胞log 2倍降低，随后在疾病进展时增加（p=0.022）。影像学分析显示ADC-L与不良结局相关的趋势。与既往接受过贝伐单抗治疗的对照组相比，贝伐单抗/索拉非尼联合治疗不能改善复发性GBM患者的结局。胶质瘤中贝伐单抗应答和耐药的生物学标志物值得前瞻性验证。
We hypothesized that vertical blockade of VEGF signaling by combining bevacizumab with sorafenib in recurrent glioblastoma (rGBM) patients would result in a synergistic therapeutic effect. We also investigated whether VEGF, VEGFR2, and HIF-1α single nucleotide polymorphisms (SNPs), circulating biomarkers of angiogenesis and Magnetic Resonance (MR) imaging markers, such as apparent diffusion coefficient (ADC), correlated with treatment efficacy and/or toxicity. Patients received bevacizumab (5 mg/kg every 2 weeks) with sorafenib (200 mg bid, weekly, days 1-5) (Group A), but due to toxicity the starting sorafenib dose was subsequently modified to 200 mg qd (Group B). 54 patients were enrolled: 19 patients in Group A and 35 in Group B. Objective response rate was 18.5% with median duration of 6.7 mo (range 0.5-24.1 mo). Six-month progression free survival (PFS6) was 20.4% (11/54), and median OS was 5.6 months (95% CI 4.7 – 8.2); outcome was similar between the two dose groups. We identified single nucleotide polymorphisms in the VEGF and VEGFR2 promoter regions which were associated with PFS6 (p<0.022). Among molecular markers of angiogenesis, a higher log2 baseline level of stromal cell derived factor-1 was associated with PFS6 success (p=0.04). The circulating endothelial cell log2-fold decreased during treatment with subsequent increase at disease progression (p=0.022). Imaging analysis demonstrated a trend associating ADC-L with poor outcome. The bevacizumab/sorafenib combination did not improve outcome of recurrent GBM patients versus historic bevacizumab treated controls. Biologic markers of response and resistance to bevacizumab in gliomas were identified which merit prospective validation.