Activity of Sorafenib in Recurrent Ovarian Cancer and Primary Peritoneal Carcinomatosis: A Gynecologic Oncology Group Trial
Activity of Sorafenib in Recurrent Ovarian Cancer and Primary Peritoneal Carcinomatosis: A Gynecologic Oncology Group Trial
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DOI：
10.1200/jco.2009.26.7856
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发表时间：
2011-01-01
影响因子：
45.3
通讯作者：
Birrer, Michael J.
中科院分区：
文献类型：
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作者：
Matei, Daniela;Sill, Michael W.;Birrer, Michael J.
orafenib是一种靶向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。方法：这项开放标签、多机构、II期研究采用两阶段设计。符合条件的患者在先前的一到两次细胞毒性治疗方案后出现持续性或复发性OC/PPC，并且在铂类药物治疗的12个月内出现进展。治疗包括索拉非尼400毫克，每天口服两次。主要终点是6个月无进展生存期（PFS）和国家癌症研究所标准的毒性。次要终点是肿瘤反应、PFS持续时间和总生存期。生物标志物分析包括在治疗前后1个月测量肿瘤中ERK和b-Raf的表达以及外周血淋巴细胞（pbl）中ERK （pERK）的磷酸化。结果纳入73例患者，其中71例符合条件。59名符合条件的患者（83%）有可测量的疾病，12名（17%）有可检测的疾病。显著的3级或4级毒性包括：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）。仅使用可测量疾病的患者来评估疗效。14例存活至少6个月无进展（24%;90% CI， 15%至35%）。2例患者部分缓解（3.4%;90% CI， 1%至10%）；病情稳定的20例；30例为进行性疾病；其中7人无法进行肿瘤评估。ERK和b-Raf在所有肿瘤中均有表达。探索性分析表明，治疗后PBL标本中的pERK与PFS相关。结论索拉非尼对复发性OC患者有一定的抗肿瘤活性，但其抗肿瘤活性是以牺牲毒性为代价的。
PurposeSorafenib 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).MethodsThis 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.ResultsSeventy-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.ConclusionSorafenib has modest antitumor activity in patients with recurrent OC, but the activity was at the expense of substantial toxicity.