A Randomized Phase II Trial of Vismodegib versus Placebo with FOLFOX or FOLFIRI and Bevacizumab in Patients with Previously Untreated Metastatic Colorectal Cancer
A Randomized Phase II Trial of Vismodegib versus Placebo with FOLFOX or FOLFIRI and Bevacizumab in Patients with Previously Untreated Metastatic Colorectal Cancer
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DOI：
10.1158/1078-0432.ccr-12-1800
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发表时间：
2013-01-01
影响因子：
11.5
通讯作者：
Low, Jennifer A.
中科院分区：
文献类型：
--
作者：
Berlin, Jordan;Bendell, Johanna C.;Low, Jennifer A.
目的：Vismodegib是一种刺猬通路抑制剂，在结直肠癌（CRC）模型中具有临床前活性。该试验评估了转移性结直肠癌（mCRC）一线治疗中加入维莫替吉的疗效、安全性和药代动力学。实验设计：患者随机接受vismodegib （150mg /天口服）或安慰剂，每2周联合FOLFOX或FOLFIRI化疗加贝伐单抗（5mg /kg），直到疾病进展或无法忍受的毒性。主要终点为无进展生存期（PFS）。关键的次要目标包括评估预测性生物标志物和药代动力学药物相互作用。结果：共有199例mCRC患者接受了方案治疗（124例FOLFOX， 75例FOLFIRI）。与安慰剂相比，维莫替吉治疗的中位PFS风险比（HR）为1.25 （90% CI: 0.89-1.76; P = 0.28）。安慰剂组和vismodegib组患者的总有效率分别为51% （90% CI: 43-60）和46% （90% CI: 37-55）。与FOLFOX或FOLFIRI联合使用没有观察到vismodegib相关的益处。肿瘤组织中Hedgehog基因表达的增加并不能预测临床获益。超过5%的患者报告的3 - 5级不良事件是疲劳、恶心、虚弱、黏膜炎、周围感觉神经病变、体重减轻、食欲下降和脱水。Vismodegib没有改变FOLFOX、FOLFIRI或贝伐单抗的药代动力学。结论：维莫德吉不会增加mCRC标准治疗的疗效。与安慰剂相比，接受维莫替吉治疗的患者的所有方案成分的治疗强度都较低，这表明联合毒性可能导致缺乏疗效。临床癌症研究；19 (1);258 - 67。(c) 2012年AACR。
Purpose: Vismodegib, a Hedgehog pathway inhibitor, has preclinical activity in colorectal cancer (CRC) models. This trial assessed the efficacy, safety, and pharmacokinetics of adding vismodegib to first-line treatment for metastatic CRC (mCRC).Experimental design: Patients were randomized to receive vismodegib (150 mg/day orally) or placebo, in combination with FOLFOX or FOLFIRI chemotherapy plus bevacizumab (5 mg/kg) every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Key secondary objectives included evaluation of predictive biomarkers and pharmacokinetic drug interactions.Results: A total of 199 patients with mCRC were treated on protocol (124 FOLFOX, 75 FOLFIRI). The median PFS hazard ratio (HR) for vismodegib treatment compared with placebo was 1.25 (90% CI: 0.89-1.76; P = 0.28). The overall response rates for placebo-treated and vismodegib-treated patients were 51% (90% CI: 43-60) and 46% (90% CI: 37-55), respectively. No vismodegib-associated benefit was observed in combination with either FOLFOX or FOLFIRI. Increased tumor tissue Hedgehog expression did not predict clinical benefit. Grade 3 to 5 adverse events reported for more than 5% of patients that occurred more frequently in the vismodegib-treated group were fatigue, nausea, asthenia, mucositis, peripheral sensory neuropathy, weight loss, decreased appetite, and dehydration. Vismodegib did not alter the pharmacokinetics of FOLFOX, FOLFIRI, or bevacizumab.Conclusions: Vismodegib does not add to the efficacy of standard therapy for mCRC. Compared with placebo, treatment intensity was lower for all regimen components in vismodegib-treated patients, suggesting that combined toxicity may have contributed to lack of efficacy. Clin Cancer Res; 19(1); 258-67. (c) 2012 AACR.