Background: Dysregulated hepatocyte growth factor/mesenchymal-epithelial transition (MET) signaling is associated with poor prognosis and resistance to vascular endothelial growth factor inhibition in metastatic colorectal cancer (mCRC). We report outcomes from a double-blind, multicenter phase II trial of the MET inhibitor onartuzumab in combination with mFOLFOX-6 and bevacizumab for mCRC (GO27827; NCT01418222).
Materials and methods: Patients were randomized 1:1 to receive onartuzumab (10 mg/kg intravenously [IV]) or placebo plus mFOLFOX-6 and bevacizumab (5 mg/kg IV). Oxaliplatin was given for 8-12 cycles; other agents were continued until disease progression, unacceptable toxicity, or death. The primary endpoint was progression-free survival (PFS) in the intent-to-treat (ITT) and MET immunohistochemistry (IHC) expression-positive populations.
Results: Between September 2011 and November 2012, 194 patients were enrolled. In September 2013, an interim analysis recommended stopping onartuzumab treatment due to lack of efficacy. At the time of the final analysis in February 2014, no significant improvement in PFS was seen with onartuzumab versus placebo in either the ITT or MET IHC-positive populations. An improvement in PFS was noted in the MET IHC-negative population. Neither overall survival nor response rate was improved with onartuzumab. The incidence of fatigue, peripheral edema, and deep vein thrombosis was increased with onartuzumab relative to placebo.
Conclusion: Onartuzumab combined with mFOLFOX-6 and bevacizumab did not significantly improve efficacy outcomes in either the ITT or MET IHC-positive populations. MET expression by IHC was not a predictive biomarker in this setting. The Oncologist 2017;22:264-271 IMPLICATIONS FOR PRACTICE: The addition of onartuzumab to mFOLFOX-6 plus bevacizumab did not improve outcomes in patients with previously untreated metastatic colorectal cancer in this randomized, phase II study. Although initial results with onartuzumab were promising, a number of phase II/III clinical trials have reported a lack of improvement in efficacy with onartuzumab combined with standard-of-care therapies in several tumor types. Furthermore, negative study data have been published for rilotumumab and ficlatuzumab, both of which block hepatocyte growth factor binding to the mesenchymal-epithelial transition (MET) receptor. MET immunohistochemistry was not a predictive biomarker. It remains to be seen if other biomarkers or small molecule inhibitors may be more appropriate for inhibiting this oncogenic pathway.
摘要
背景. 肝细胞生长因子调节异常/间质‐上皮转化（MET）信号传导与转移性结直肠癌（mCRC）预后不良和对血管内皮细胞生长因子抑制剂耐药有关。我们报告了一项MET抑制剂Onartuzumab联合mFOLFOX‐6和贝伐珠单抗治疗mCRC的双盲、多中心、II期试验的结果(GO27827; NCT01418222)。
材料和方法. 患者按1:1的比例随机接受Onartuzumab[10mg/kg静脉注射（IV）]或安慰剂与mFOLFOX‐6和贝伐珠单抗（5mg/kg IV）联合治疗。奥沙利铂给药8‐12个周期, 其它药物持续给药至出现疾病进展、不可接受的毒性或死亡。主要终点为意向性治疗（ITT）人群和MET免疫组化（IHC）表达阳性人群的无进展生存期（PFS）。
结果. 2011年9月至2012年11月期间入组了194例患者。2013年9月进行了一项中期分析, 结果显示缺乏疗效, 故建议停止Onartuzumab治疗。2014年2月最终分析时, 在ITT或MET IHC阳性人群中均未观察到Onartuzumab与安慰剂相比显著改善PFS。在MET IHC阴性人群中观察到PFS改善。Onartuzumab治疗时总生存期和缓解率均无改善。Onartuzumab治疗时疲乏、外周水肿和深静脉血栓的发生率与安慰剂相比有所增加。
结论. 在ITT或MET IHC阳性人群中, Onartuzumab与mFOLFOX‐6和贝伐珠单抗联用未显著改善疗效结果。在这种情况下, IHC测得的MET表达并非预测性生物标志物。
对临床实践的提示：在本项随机、II期研究中, 既往未经治疗的转移性结直肠癌患者接受Onartuzumab与mFOLFOX‐6和贝伐珠单抗联合治疗未能改善预后。虽然Onartuzumab的初步结果前景良好, 但随后的多项II/III期临床试验报告称Onartuzumab与标准疗法联合治疗多种肿瘤时疗效未见改善。此外, 已发表了对Rilotumumab和Ficlatuzumab不利的研究数据, 二者均是阻断肝细胞生长因子与MET受体结合的药物。MET免疫组化并非预测性生物标志物。其它生物标志物或小分子抑制剂是否更适合抑制该致癌通路仍需拭目以待。
Keywords: Bevacizumb; FOLFOX; Metastatic colorectal cancer; Onartuzumab; Phase II; Randomized.
© AlphaMed Press 2017.