Overexpression of tumor vascular endothelial growth factor A may portend an increased likelihood of progression in a phase II trial of bevacizumab and erlotinib in resistant ovarian cancer.
Overexpression of tumor vascular endothelial growth factor A may portend an increased likelihood of progression in a phase II trial of bevacizumab and erlotinib in resistant ovarian cancer.
复制标题
DOI：
10.1158/1078-0432.ccr-10-0974
复制
发表时间：
2010-11-01
期刊：
影响因子：
--
通讯作者：
Alberts DS
中科院分区：
文献类型：
--
作者：
Chambers SK;Clouser MC;Baker AF;Roe DJ;Cui H;Brewer MA;Hatch KD;Gordon MS;Janicek MF;Isaacs JD;Gordon AN;Nagle RB;Wright HM;Cohen JL;Alberts DS
这项II期试验评估了贝伐单抗联合厄洛替尼治疗铂类耐药卵巢癌的疗效;还进行了探索性生物标志物分析，包括肿瘤血管内皮生长因子（VEGF-A）。40例接受过大量预治疗的患者接受厄洛替尼150 mg/天口服和贝伐珠单抗10 mg/kg静脉注射，每2周一次，直至疾病进展。主要终点为客观缓解率和缓解持续时间;次要终点包括无进展生存期（PFS）、毒性以及血管生成蛋白水平、毒性和疗效之间的相关性。3级毒性包括皮疹（n=6）、腹泻（n=5）、疲乏（n=4）和高血压（n=3）。4级毒性为心肌梗死（n=1）和鼻中隔穿孔（n=1）。仅观察到1例3级瘘和1例2级肠穿孔。9/39例（23.1%）可评价患者出现缓解（中位持续时间36.1+周，1例完全缓解），10例（25.6%）患者达到疾病稳定，疾病控制率为49%。中位PFS为4个月，6个月PFS为30.8%。生物标志物分析确定了肿瘤细胞VEGF-A表达与进展之间的相关性（P=0.03）; VEGF-A评分每增加100个单位，进展几率增加3.7倍（95% CI：1.1-16.6）。贝伐珠单抗联合厄洛替尼治疗重度预治疗的卵巢癌患者具有临床活性且耐受性良好。厄洛替尼似乎对疗效无贡献。我们的研究提出了一种有趣的可能性，即高水平的肿瘤细胞VEGF-A，能够自分泌和旁分泌相互作用，与贝伐单抗耐药相关，强调了肿瘤微环境的复杂性。
This phase II trial evaluated bevacizumab plus erlotinib in platinum-resistant ovarian cancer; exploratory biomarker analyses, including that of tumor vascular endothelial growth factor (VEGF-A), were also performed. Forty heavily pretreated patients received erlotinib 150 mg/day orally and bevacizumab 10 mg/kg intravenously every 2 weeks until disease progression. Primary end points were objective response rate and response duration; secondary end points included progression-free survival (PFS), toxicity, and correlations between angiogenic protein levels, toxicity, and efficacy. Grade 3 toxicities included skin rash (n=6), diarrhea (n=5), fatigue (n=4), and hypertension (n=3). Grade 4 toxicities were myocardial infarction (n=1) and nasal septal perforation (n=1). Only 1 grade 3 fistula and 1 grade 2 bowel perforation were observed. Nine (23.1%) of 39 evaluable patients had a response (median duration 36.1+ weeks, 1 complete response), and 10 (25.6%) patients achieved stable disease, for a disease control rate of 49%. Median PFS was 4 months, and 6-month PFS was 30.8%. Biomarker analyses identified an association between tumor cell VEGF-A expression and progression (P=0.03); for every 100 unit increase in the VEGF-A score, there was a 3.7-fold increase in the odds of progression (95% CI: 1.1–16.6). Bevacizumab plus erlotinib in heavily pretreated ovarian cancer patients was clinically active and well tolerated. Erlotinib did not appear to contribute to efficacy. Our study raises the intriguing possibility that high levels of tumor cell VEGF-A, capable of both autocrine and paracrine interactions, are associated with resistance to bevacizumab, emphasizing the complexity of the tumor microenvironment.