Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA.
Clin Cancer Res. 2013 Jan 1;19(1):258-67. doi: 10.1158/1078-0432.CCR-12-1800. Epub 2012 Oct 18.
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).
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.
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.
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.
Hedgehog 通路抑制剂维莫德吉（Vismodegib）在结直肠癌（CRC）模型中具有临床前活性。本试验评估了维莫德吉联合一线转移性结直肠癌（mCRC）治疗方案（FOLFOX 或 FOLFIRI 化疗加贝伐单抗）治疗转移性结直肠癌（mCRC）的疗效、安全性和药代动力学。
患者随机接受维莫德吉（150 mg/天口服）或安慰剂，联合 FOLFOX 或 FOLFIRI 化疗加贝伐单抗（5 mg/kg）每 2 周一次，直至疾病进展或无法耐受毒性。主要终点是无进展生存期（PFS）。主要次要目标包括评估预测生物标志物和药代动力学药物相互作用。
199 例 mCRC 患者按方案接受治疗（124 例 FOLFOX，75 例 FOLFIRI）。与安慰剂相比，维莫德吉治疗的中位无进展生存期（PFS）风险比（HR）为 1.25（90%CI：0.89-1.76；P=0.28）。安慰剂组和维莫德吉组的总体缓解率分别为 51%（90%CI：43-60）和 46%（90%CI：37-55）。维莫德吉与 FOLFOX 或 FOLFIRI 联合治疗均未观察到获益。肿瘤组织 Hedgehog 表达增加并未预测临床获益。维莫德吉组报告的发生率超过 5%的 3 级至 5 级不良事件包括疲劳、恶心、乏力、黏膜炎、周围感觉神经病变、体重减轻、食欲下降和脱水。维莫德吉未改变 FOLFOX、FOLFIRI 或贝伐单抗的药代动力学。
维莫德吉不能提高 mCRC 标准治疗的疗效。与安慰剂相比，维莫德吉治疗组所有治疗方案的治疗强度均较低，这表明联合毒性可能导致疗效不佳。
