Phase II Study to Evaluate the Efficacy and Safety of Rilotumumab and Bevacizumab in Subjects with Recurrent Malignant Glioma

Lessons Learned Due to evolving imaging criteria in brain tumors and variation in magnetic resonance imaging evaluation, it is not ideal to use response rate as a primary objective. Future studies involving antiangiogenic agents should use overall survival. Disease‐expected toxicities should be considered when defining the clinical significance of an adverse event. For example, vascular thromboembolic events are common in brain tumor patients and should not be attributed to the study drug in the safety analysis. Background Recurrent malignant glioma (rMG) prognosis is poor, with a median patient survival of 3–11 months with bevacizumab (BEV)‐containing regimens. BEV in rMG has 6‐month progression free survival (PFS‐6) of ∼40% and an objective response rate of 21.2%. BEV‐containing regimens improve PFS‐6 to 42.6%–50.3%, indicating that BEV combination therapies may be superior to single agent. Rilotumumab, a hepatocyte growth factor (HGF) antibody, inhibits angiogenesis and expression of angiogenic autocrine factors (e.g., vascular endothelial growth factor [VEGF]) by c‐Met inhibition. Combination of rilotumumab with BEV to block vascular invasion and tumor proliferation may synergistically inhibit tumor growth. Methods Thirty‐six BEV‐naïve rMG subjects received rilotumumab (20 mg/kg and BEV (10 mg/kg) every 2 weeks. Endpoints included objective response rate (using Response Assessment in Neuro‐Oncology [RANO] criteria), PFS‐6, overall survival (OS), and toxicity. Results Median patient follow‐up was 65.0 months. Objective response rate was 27.8% (95% confidence interval [CI]: 15.7%–44.1%). Median OS was 11.2 months (95% CI: 7–17.5). PFS‐6 was 41.7% (95% CI: 25.6%–57.0%). Most frequent treatment‐related grade ≤2 events included weight gain, fatigue, allergic rhinitis, and voice alteration; grade ≥3 events included venous thromboembolism (four patients), including one death from pulmonary embolism. Conclusion Rilotumumab with BEV did not significantly improve objective response compared with BEV alone, and toxicity may preclude the use of rilotumumab in combination BEV regimens. 经验获取 • 由于脑肿瘤影像标准的不断发展以及磁共振影像评估的变化,以缓解率作为主要指标不够理想。未来有关抗血管生成药物的研究应使用总生存期。 • 在界定不良事件的临床意义时,应考虑疾病的预期毒性。例如,血管血栓栓塞事件在脑肿瘤患者中常见,做安全性分析时不应归因于研究药物。 摘要 背景. 复发性恶性胶质瘤(rMG)预后较差,采用含贝伐单抗(BEV)的治疗方案时,患者生存期中位数为3~11个月。BEV在治疗rMG患者中,6个月无进展生存期(PFS‐6)的比例约40%,客观缓解率为21.2%。含BEV的治疗方案将PFS‐6提高至42.6%~50.3%,提示BEV联合治疗可能优于单药治疗。Rilotumumab是一种肝细胞生长因子(HGF)抗体,通过c‐Met抑制剂抑制血管生成及血管生成自分泌因子[如血管内皮生长因子(VEGF)]的表达。Rilotumumab联合BE