Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, United States of America.
Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, United States of America.
Gynecol Oncol. 2020 Oct;159(1):88-94. doi: 10.1016/j.ygyno.2020.07.031. Epub 2020 Aug 1.
To examine whether blocking multiple points of the angiogenesis pathway by addition of sorafenib, a multi-kinase inhibitor against VEGFR2/3, Raf, c-Kit, and PDGFR, to bevacizumab would yield clinical activity in ovarian cancer (OvCa).
This phase II study tested bevacizumab plus sorafenib in two cohorts; bevacizumab-naïve and bevacizumab-exposed patients. Bevacizumab (5 mg/kg IV every 2 weeks) was given with sorafenib 200 mg bid 5 days-on/2 days-off. The primary objective was response rate using a Simon two-stage optimal design. Progression-free survival (PFS) and toxicity were the secondary endpoints. Exploratory correlative studies included plasma cytokine concentrations, tissue proteomics and dynamic contrast-enhanced-magnetic resonance imaging (DCE-MRI).
Between March 2007 and August 2012, 54 women were enrolled, 41 bevacizumab-naive and 13 bevacizumab-prior, with median 5 (2-9) and 6 (5-9) prior systemic therapies, respectively. Nine of 35 (26%) evaluable bevacizumab-naive patients attained partial responses (PR), and 18 had stable disease (SD) ≥ 4 months. No responses were seen in the bevacizumab-prior group and 7 (54%) patients had SD ≥ 4 months, including one exceptional responder with SD of 27 months. The overall median PFS was 5.5 months (95%CI: 4.0-6.8 months). Treatment-related grade 3/4 adverse events (≥5%) included hypertension (17/54 [31%]; grade 3 in 16 patients and grade 4 in one patient) and venous thrombosis or pulmonary embolism (5/54 [9%]; grade 3 in 4 patients and grade 4 in one patient). Pretreatment low IL8 concentration was associated with PFS ≥ 4 months (p = .031).
The bevacizumab and sorafenib combination did not meet the pre-specified primary endpoint although some clinical activity was seen in heavily-pretreated bevacizumab-naive OvCa patients with platinum-resistant disease. Anticipated class toxicities required close monitoring and dose modifications.
研究多激酶抑制剂索拉非尼（针对 VEGFR2/3、Raf、c-Kit 和 PDGFR）与贝伐珠单抗联合应用是否能阻断血管生成途径的多个靶点，从而在卵巢癌（OvCa）中发挥临床作用。
这项 2 期研究在两个队列中测试了贝伐珠单抗联合索拉非尼的效果；分别是贝伐珠单抗初治患者和贝伐珠单抗经治患者。贝伐珠单抗（5mg/kg，每 2 周静脉输注 1 次）与索拉非尼（bid，每日 2 次，口服，5 天/2 天停药）联合应用。主要研究终点是使用 Simon 两阶段最优设计的反应率。无进展生存期（PFS）和毒性是次要终点。探索性的相关性研究包括血浆细胞因子浓度、组织蛋白质组学和动态对比增强磁共振成像（DCE-MRI）。
2007 年 3 月至 2012 年 8 月期间，共纳入 54 名女性患者，其中 41 名为贝伐珠单抗初治患者，13 名为贝伐珠单抗经治患者，中位既往系统治疗数分别为 5（2-9）和 6（5-9）。35 名可评估的贝伐珠单抗初治患者中，9 名（26%）获得部分缓解（PR），18 名患者疾病稳定（SD）≥4 个月。贝伐珠单抗经治组未见缓解，7 名（54%）患者疾病稳定（SD）≥4 个月，其中包括 1 名 SD 持续 27 个月的例外响应者。总的中位 PFS 为 5.5 个月（95%CI：4.0-6.8 个月）。≥5%的治疗相关 3/4 级不良事件（AE）包括高血压（54 例中有 17 例[31%]；16 例为 3 级，1 例为 4 级）和静脉血栓形成或肺栓塞（54 例中有 5 例[9%]；4 例为 3 级，1 例为 4 级）。治疗前低 IL8 浓度与 PFS≥4 个月相关（p=0.031）。
尽管在铂类耐药疾病的贝伐珠单抗初治、经大量预处理的卵巢癌患者中观察到了一些临床活性，但贝伐珠单抗联合索拉非尼的方案并未达到预设的主要终点。预期的药物毒性需要密切监测和剂量调整。
