Falchook Gerald S, Wheler Jennifer J, Naing Aung, Piha-Paul Sarina A, Fu Siqing, Tsimberidou Apostolia M, Hong David S, Janku Filip, Zinner Ralph, Jiang Yunfang, Huang Mei, Lin Quan, Parkhurst Kristin, Kurzrock Razelle
Sarah Cannon Research Institute at HealthONE, Presbyterian/St. Luke's Medical Center, 1800 Williams Street, Suite 300, Denver, CO, 80218, USA,
Invest New Drugs. 2015 Feb;33(1):215-24. doi: 10.1007/s10637-014-0176-4. Epub 2014 Nov 4.
Angiogenesis plays a pivotal role in tumor growth and metastasis. Sorafenib, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR), combined with bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF-A), would vertically inhibit VEGF/VEGFR signaling. A phase I trial was performed to assess safety, maximum tolerated dose (MTD), and clinical correlates.
Patients with advanced solid tumors refractory to standard therapy were eligible. In cohorts of escalating doses, patients received sorafenib daily for 28 days and bevacizumab every two weeks. Clinical correlates included VEGF polymorphisms. Expansion cohorts of responding tumor types were enrolled.
One hundred fifteen patients were treated, and the MTD was identified as 200 mg twice daily sorafenib and 5 mg/kg bevacizumab every two weeks. Median number of prior therapies was four. Twenty-nine patients (25 %) achieved stable disease ≥6 months; six patients (5 %) achieved a partial response (total SD ≥ 6 months/PR=35 (30 %)). 76 patients (66 %) experienced adverse events of grade 2 or higher, most commonly hand and foot syndrome (n = 27, 24 %) and hypertension (n = 24, 21 %). Dose-limiting toxicity occurred in eight patients (7 %), and 45 patients (39 %) required dose reduction for toxicity. Grade 3 and 4 hypertension was associated with longer time to treatment failure, overall survival, and higher response rate.
Combination sorafenib and bevacizumab was well-tolerated and demonstrated antitumor activity in heavily pretreated patients with advanced solid tumors.
血管生成在肿瘤生长和转移中起关键作用。索拉非尼是一种血管内皮生长因子受体（VEGFR）的酪氨酸激酶抑制剂，与血管内皮生长因子（VEGF-A）单克隆抗体贝伐单抗联合使用，将垂直抑制VEGF/VEGFR信号传导。进行了一项I期试验以评估安全性、最大耐受剂量（MTD）和临床相关性。
符合条件的患者为对标准治疗难治的晚期实体瘤患者。在剂量递增的队列中，患者每天接受索拉非尼治疗28天，每两周接受贝伐单抗治疗。临床相关性包括VEGF多态性。纳入了有反应的肿瘤类型的扩展队列。
115名患者接受了治疗，MTD确定为索拉非尼每日两次200mg和每两周5mg/kg贝伐单抗。既往治疗的中位数为4次。29名患者（25%）达到疾病稳定≥6个月；6名患者（5%）达到部分缓解（总疾病稳定≥6个月/部分缓解=35（30%））。76名患者（66%）经历了2级或更高等级的不良事件，最常见的是手足综合征（n = 27，24%）和高血压（n = 24，21%）。8名患者（7%）发生剂量限制性毒性，45名患者（39%）因毒性需要降低剂量。3级和4级高血压与更长的治疗失败时间、总生存期和更高的缓解率相关。
索拉非尼和贝伐单抗联合使用耐受性良好，并在晚期实体瘤的大量预处理患者中显示出抗肿瘤活性。
