The Preston Robert Tisch Brain Tumor Center, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Neuro Oncol. 2010 Dec;12(12):1300-10. doi: 10.1093/neuonc/noq099. Epub 2010 Aug 17.
Vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) signaling are established contributors to malignant glioma (MG) biology. We, therefore, evaluated bevacizumab, a humanized anti-VEGF monoclonal antibody, in combination with the EGFR tyrosine kinase inhibitor erlotinib, in this phase 2 study for recurrent MG patients (www.ClinicalTrials.gov, NCT00671970). Fifty-seven patients (n = 25, glioblastoma [GBM]; n = 32, anaplastic glioma [AG]) were enrolled. The primary endpoint was 6-month progression-free survival (PFS-6). Overall survival (OS), radiographic response, pharmacokinetics, and correlative biomarkers were the secondary endpoints. Patients were stratified based on the concurrent use of enzyme-inducing antiepileptic drugs (EIAEDs). Bevacizumab (10 mg/kg) was given intravenously every 2 weeks. Erlotinib was orally administered daily at 200 mg/day for patients not on EIAEDs and 500 mg/day for patients on EIAEDs. PFS-6 and median OS were 28% and 42 weeks for GBM patients and 44% and 71 weeks for AG patients, respectively. Twelve (48%) GBM patients and 10 (31%) AG patients achieved a radiographic response. Erlotinib pharmacokinetic exposures were comparable between EIAED and non-EIAED groups. Rash, mucositis, diarrhea, and fatigue were common but mostly grades 1 and 2. Among GBM patients, grade 3 rash, observed in 32%, was associated with survival benefit, whereas elevated hypoxia-inducible factor-2 alpha and VEGF receptor-2 levels were associated with poor survival. Bevacizumab plus erlotinib was adequately tolerated in recurrent MG patients. However, this regimen was associated with similar PFS benefit and radiographic response when compared with other historical bevacizumab-containing regimens.
血管内皮生长因子 (VEGF) 和表皮生长因子受体 (EGFR) 信号通路是恶性胶质瘤 (MG) 生物学的重要贡献因素。因此，我们在这项 2 期研究中评估了贝伐单抗（一种人源化抗 VEGF 单克隆抗体）联合 EGFR 酪氨酸激酶抑制剂厄洛替尼在复发性 MG 患者中的应用（www.ClinicalTrials.gov，NCT00671970）。共纳入 57 例患者（25 例为胶质母细胞瘤 [GBM]，32 例为间变性胶质瘤 [AG]）。主要终点为 6 个月无进展生存期（PFS-6）。次要终点为总生存期（OS）、影像学反应、药代动力学和相关生物标志物。患者根据是否同时使用酶诱导抗癫痫药物（EIAEDs）进行分层。贝伐单抗（10 mg/kg）每 2 周静脉给药一次。厄洛替尼每天口服 200mg，不使用 EIAEDs 的患者使用该剂量，使用 EIAEDs 的患者使用 500mg。GBM 患者的 PFS-6 和中位 OS 分别为 28%和 42 周，AG 患者分别为 44%和 71 周。12 例（48%）GBM 患者和 10 例（31%）AG 患者获得影像学反应。EIAED 和非 EIAED 组之间厄洛替尼的药代动力学暴露相当。皮疹、黏膜炎、腹泻和疲劳较为常见，但大多为 1 级和 2 级。在 GBM 患者中，32%观察到的 3 级皮疹与生存获益相关，而缺氧诱导因子-2α和 VEGF 受体-2 水平升高与不良预后相关。贝伐单抗联合厄洛替尼在复发性 MG 患者中可耐受。然而，与其他含贝伐单抗的方案相比，该方案的 PFS 获益和影像学反应相似。
