Stanford Cancer Institute, Division of Oncology, Stanford School of Medicine, Stanford, CA, USA.
Clin Genitourin Cancer. 2013 Jun;11(2):100-6. doi: 10.1016/j.clgc.2012.12.002. Epub 2013 Jan 24.
Agents that inhibit the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways in metastatic renal cell carcinoma (mRCC) prolong progression-free survival (PFS), but durable complete responses are rare. Combinations of these cytostatic therapies have great potential to improve efficacy and to escape tumoral resistance mechanisms, but supra-additive toxicity is a valid concern. We investigated whether horizontal blockade with the combination of bevacizumab, a monoclonal antibody to VEGF-A, and of everolimus, an oral mTOR inhibitor, improved PFS in patients with clear cell mRCC who had received prior VEGF blockade.
In this phase II investigator-initiated study, 10 of 30 planned patients were enrolled. Bevacizumab 10 mg/kg was administered intravenously every 14 days. Everolimus was orally dosed at 10 mg daily. The patients were treated until disease progression or unacceptable toxicity. The primary endpoint was PFS.
The median age was 55 years. The majority of patients were white men with an Eastern Cooperative Oncology Group performance status of 1 (80%) and intermediate risk disease by Memorial Sloan-Kettering Cancer Center criteria (70%). All the patients had received 1 prior VEGF inhibitor. The median PFS in the 10 evaluable patients was 5.1 months, which was less than the expected historical control of bevacizumab monotherapy at 6 months. The median overall survival was 21 months. The best response was a partial response in 1 patient and stable disease in 9. Forty percent of the patients were discontinued from the study due to toxicity.
In our experience, the combination of bevacizumab and everolimus was toxic. The efficacy achieved did not support its combined use over sequential administration. Ongoing randomized studies will definitively evaluate the combination's efficacy and tolerability.
在转移性肾细胞癌（mRCC）中，抑制血管内皮生长因子（VEGF）和哺乳动物雷帕霉素靶蛋白（mTOR）通路的药物可延长无进展生存期（PFS），但完全缓解的持久性罕见。这些细胞抑制剂的联合应用具有提高疗效和逃避肿瘤耐药机制的巨大潜力，但超相加毒性是一个合理的关注点。我们研究了贝伐单抗（一种抗 VEGF-A 的单克隆抗体）联合依维莫司（一种口服 mTOR 抑制剂）在接受过 VEGF 阻断治疗的透明细胞 mRCC 患者中的应用，是否能改善 PFS。
在这项由研究者发起的 II 期研究中，计划入组 30 例患者，其中 10 例入组。贝伐单抗 10mg/kg 每 14 天静脉输注一次。依维莫司每日口服 10mg。患者持续治疗直至疾病进展或不可接受的毒性。主要终点是 PFS。
中位年龄为 55 岁。大多数患者为白人男性，ECOG 表现状态为 1 分（80%），根据 Memorial Sloan-Kettering 癌症中心标准为中危疾病（70%）。所有患者均接受过 1 种 VEGF 抑制剂治疗。10 例可评估患者的中位 PFS 为 5.1 个月，短于贝伐单抗单药治疗的预期历史对照值 6 个月。中位总生存期为 21 个月。最佳缓解为 1 例部分缓解，9 例疾病稳定。由于毒性，40%的患者退出研究。
根据我们的经验，贝伐单抗联合依维莫司具有毒性。所获得的疗效不支持其联合应用优于序贯应用。正在进行的随机研究将明确评估该联合治疗的疗效和耐受性。
