Indiana University School of Medicine, Division of Hematology-Oncology, RT-457, 535 Barnhill Dr, Indianapolis, IN 46202, USA.
J Clin Oncol. 2011 Jan 1;29(1):69-75. doi: 10.1200/JCO.2009.26.7856. Epub 2010 Nov 22.
PURPOSE Sorafenib is a kinase inhibitor targeting Raf and other kinases (ie, vascular endothelial growth factor receptor [VEGFR], platelet-derived growth factor receptor [PDGFR], Flt3, and c-KIT). This study assessed its activity and tolerability in patients with recurrent ovarian cancer (OC) or primary peritoneal carcinomatosis (PPC). METHODS This open-label, multi-institutional, phase II study used a two-stage design. Eligible patients had persistent or recurrent OC/PPC after one to two prior cytotoxic regimens, and they experienced progression within 12 months of platinum-based therapy. Treatment consisted of sorafenib 400 mg orally twice per day. Primary end points were progression-free survival (PFS) at 6 months and toxicity by National Cancer Institute criteria. Secondary end points were tumor response and duration of PFS and overall survival. Biomarker analyses included measurement of ERK and b-Raf expression in tumors and phosphorylation of ERK (pERK) in peripheral-blood lymphocytes (PBLs) before and after 1 month of treatment. Results Seventy-three patients were enrolled, of which 71 were eligible. Fifty-nine eligible patients (83%) had measurable disease, and 12 (17%) had detectable disease. Significant grade 3 or 4 toxicities included the following: rash (n = 7), hand-foot syndrome (n = 9), metabolic (n = 10), GI (n = 3), cardiovascular (n = 2), and pulmonary (n = 2). Only patients with measurable disease were used to assess efficacy. Fourteen survived progression free for at least 6 months (24%; 90% CI, 15% to 35%). Two patients had partial responses (3.4%; 90% CI, 1% to 10%); 20 had stable disease; 30 had progressive disease; and seven could not have their tumor assessed. ERK and b-Raf were expressed in all tumors. Exploratory analyses indicated that pERK in post-treatment PBL specimens was associated with PFS. CONCLUSION Sorafenib has modest antitumor activity in patients with recurrent OC, but the activity was at the expense of substantial toxicity.
索拉非尼是一种针对 Raf 和其他激酶（即血管内皮生长因子受体 [VEGFR]、血小板衍生生长因子受体 [PDGFR]、Flt3 和 c-KIT）的激酶抑制剂。本研究评估了其在复发性卵巢癌（OC）或原发性腹膜癌（PPC）患者中的活性和耐受性。
这是一项开放标签、多机构、二期研究，采用两阶段设计。符合条件的患者在接受一到两个先前的细胞毒性方案后出现持续性或复发性 OC/PPC，并且在铂类治疗后 12 个月内出现进展。治疗包括索拉非尼 400mg 口服，每日两次。主要终点是 6 个月时的无进展生存期（PFS）和按国家癌症研究所标准评估的毒性。次要终点是肿瘤反应和 PFS 及总生存期的持续时间。生物标志物分析包括在治疗前和治疗后 1 个月测量肿瘤中的 ERK 和 b-Raf 表达以及外周血淋巴细胞（PBL）中的 ERK 磷酸化（pERK）。
共纳入 73 例患者，其中 71 例符合条件。59 例符合条件的患者（83%）有可测量的疾病，12 例（17%）有可检测的疾病。显著的 3 级或 4 级毒性包括以下情况：皮疹（n=7）、手足综合征（n=9）、代谢（n=10）、胃肠道（n=3）、心血管（n=2）和肺部（n=2）。只有可测量疾病的患者才用于评估疗效。至少有 6 个月无进展生存的患者有 14 例（24%；90%CI，15%至 35%）。两名患者有部分缓解（3.4%；90%CI，1%至 10%）；20 例病情稳定；30 例病情进展；7 例患者无法评估肿瘤。所有肿瘤均表达 ERK 和 b-Raf。探索性分析表明，治疗后 PBL 标本中的 pERK 与 PFS 相关。
索拉非尼在复发性 OC 患者中具有适度的抗肿瘤活性，但这种活性是以显著的毒性为代价的。
