2014年ASCO大会中的肺癌口头报告中， METLung（OAM4971g）全球临床试验的结果公布，该III期多中心随机对照试验比较了Onartuzumab联合
背景：
onartuzumab，一种针对MET受体的人源化单价抗体。一项安慰剂对照的II期试验比较了厄洛替尼+onartuzumab与厄洛替尼治疗MET阳性NSCLC患者的疗效，发现前者可带来PFS的获益（JCO 2013;31;4105）。METLung研究的目的是为了确认厄洛替尼+onartuzumab在MET阳性NSCLC患者中的疗效和安全性。
方法：
这是一项前瞻性、随机、双盲、安慰剂对照的临床试验，入组的病人为以前接受过治疗的MET阳性、IIIb/IV期NSCLC患者。通过一项使用CONFIRM抗总MET SP44单克隆抗体（Ventana）的免疫组化（IHC）检测法确定MET状态。入选标准：化疗前ECOG PS 0-1，1-2，器官功能正常。分层因素：EGFR突变状态（激活突变 vs 阴性；cobas® EGFR检测），MET IHC（2+ vs 3+），前期治疗的次数（1 vs 2），组织学（鳞癌 vs 非鳞癌）。
病人随机（1:1）分配接受厄洛替尼150mg（PO）每天+安慰剂或者+onartuzumab 15mg/kg IV，每21天。每6周评估肿瘤。主要终点是总生存期（OS）。基于假设添加onartuzumab后可增加 OS 41%，统计功效90%（单侧α0.025），样本量估算为490。当达到67%（244个事件）最终事件时进行中期分析。
结果：
2012年1月到2013年8月间入组了499例患者。一个独立的数据审查委员会认为结果不好建议停止试验，因为onartuzumab添加到厄洛替尼中并不能提高OS(HR 1.27, p=0.068; 中位OS：6.8 vs 9.1个月), PFS (HR 0.99, p=0.92; 中位PFS 2.7 vs 2.6 个月), 和总缓解率(8.4% vs 9.6%; p=0.63)。
在联合组中比较高的最常见不良事件是外周性
结论：
III期试验没有验证II期试验中观察到的疗效。基于分子亚组的探索性分析仍在进行中。临床试验信息：NCT01456325。
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会议专题》》》2014年ASCO年会专题报道
阅读摘要原文
Onartuzumab plus erlotinib versus erlotinib in previously treated stage IIIb or IV NSCLC: Results from the pivotal phase III randomized, multicenter, placebo-controlled METLung (OAM4971g) global trial.（Abstract No:8000）
Author(s): David R. Spigel, Martin J. Edelman, Kenneth O'Byrne, et al.
Type: Oral Abstract Session
Background: A placebo-controlled, phase II trial of erlotinib + onartuzumab, a humanized monovalent antibody to the MET receptor, demonstrated a benefit in progression-free survival (PFS) when compared with erlotinib in patients with MET-positive NSCLC (JCO 2013;31;4105). The aim of the METLung trial was to confirm the efficacy and safety of onartuzumab + erlotinib in MET-positive NSCLC.
Methods: This prospective, randomized, double-blind, placebo-controlled trial enrolled patients with previously treated MET-positive stage IIIb/IV NSCLC. MET diagnostic status was determined by an immunohistochemistry (IHC) assay using the CONFIRM anti-total MET SP44 monoclonal antibody (Ventana). Eligibility criteria included: ECOG PS 0–1, 1–2 prior lines of chemotherapy, and normal organ function. Stratification factors: EGFR mutation status (activating mutation vs negative; cobas® EGFR assay), MET IHC (2+ vs 3+), number of prior treatments (1 vs 2), and histology (squamous vs non-squamous). Patients were randomized (1:1) to receive erlotinib 150mg PO daily + placebo or onartuzumab 15mg/kg IV every 21 days. Tumor assessments occurred every 6 weeks. The primary endpoint was overall survival (OS). The sample size (n=490) was based on the assumption that adding onartuzumab to erlotinib would improve OS by 41% with 90% power (one-sided alpha 0.025). An interim analysis was planned when 67% (244 events) of the final events were reached.
Results: 499 patients were enrolled between Jan 2012 and Aug 2013. An independent data review committee recommended to stop the trial for futility, as the addition of onartuzumab to erlotinib did not improve OS (HR 1.27, p=0.068; median OS 6.8 mos vs 9.1 mos), PFS (HR 0.99, p=0.92; median PFS 2.7 mos vs 2.6 mos), or overall response rate (8.4% vs 9.6%; p=0.63). The most frequent adverse events that were higher in the combination arm were peripheral edema, hypoalbuminemia, back pain, dyspnea, nausea, acneiform dermatitis, and rash.
Conclusions: The phase III study did not confirm the efficacy results observed in the phase II study. Exploratory analyses based on molecular subgroups are pending. Clinical trial information: NCT01456325.
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