Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity.
Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity.
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DOI：
10.1200/jco.2007.10.8332
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发表时间：
2008-08-01
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索拉非尼抑制Raf激酶和血管内皮生长因子（VEGF）受体。贝伐单抗是一种靶向VEGF的单克隆抗体。我们假设对VEGF信号的互补抑制将具有协同治疗作用。患者为进展期实体瘤，东部肿瘤合作组评分0 ~ 1分，终末器官功能良好。由于可能存在重叠毒性，以低于推荐的单药剂量启动了索拉非尼和贝伐单抗的I期剂量缓解试验：索拉非尼200 mg口服，每日两次，贝伐单抗静脉注射，剂量为5 mg/kg（剂量水平[DL] 1）或10 mg/kg （DL2）每2周。其他患者以最大耐受剂量（MTD）入组。39例患者接受了治疗。DL1为MTD，在队列2 （N = 27）中使用。DL2的剂量限制性毒性是3级蛋白尿和血小板减少症。不良事件包括高血压、手足综合征、腹泻、转氨炎和疲劳。13例卵巢癌患者中有6例（43%）出现部分缓解（pr）（缓解持续时间范围，4至22个月以上），3例肾细胞癌患者中有1例（缓解持续时间，14个月）。37例可评估患者中有22例（59%）出现PR或疾病稳定≥4个月（中位为6个月；范围为4至22个月以上）。大多数（74%）患者需要将索拉非尼剂量减少至200mg /d，中位数为4个周期（范围1至12个周期）。索拉非尼和贝伐单抗联合治疗具有良好的临床活性，特别是在卵巢癌患者中。索拉非尼剂量减少的速度和频率表明，索拉非尼200 mg每日2次，贝伐单抗5 mg/kg每2周可能无法长期耐受，应探索替代索拉非尼给药方案。
Sorafenib inhibits Raf kinase and vascular endothelial growth factor (VEGF) receptor. Bevacizumab is a monoclonal antibody targeted against VEGF. We hypothesized that the complementary inhibition of VEGF signaling would have synergistic therapeutic effects. Patients had advanced solid tumors, Eastern Cooperative Oncology Group performance status of 0 to 1, and good end-organ function. A phase I dose-escaiation trial of sorafenib and bevacizumab was initiated at below-recommended single-agent doses because of possible overlapping toxicity: sorafenib 200 mg orally twice daily and bevacizumab intravenously at 5 mg/kg (dose level [DL] 1) or 10 mg/kg (DL2) every 2 weeks. Additional patients were enrolled at the maximum-tolerated dose (MTD). Thirty-nine patients were treated. DL1 was the MTD and administered in cohort 2 (N = 27). Dose-limiting toxicity in DL2 was grade 3 proteinuria and thrombocytopenia. Adverse events included hypertension, hand-foot syndrome, diarrhea, transaminitis, and fatigue. Partial responses (PRs) were seen in six (43%) of 13 patients with ovarian cancer (response duration range, 4 to 22 + months) and one of three patients with renal cell cancer (response duration, 14 months). PR or disease stabilization ≥ 4 months (median, 6 months; range, 4 to 22+ months) was seen in 22 (59%) of 37 assessable patients. The majority (74%) required sorafenib dose reduction to 200 mg/d at a median of four cycles (range, one to 12 cycles). Combination therapy with sorafenib and bevacizumab has promising clinical activity, especially in patients with ovarian cancer. The rapidity and frequency of sorafenib dose reductions indicates that sorafenib at 200 mg twice daily with bevacizumab 5 mg/kg every 2 weeks may not be tolerable long term, and alternate sorafenib dosing schedules should be explored.