Biomarker analyses from a placebo-controlled phase II study evaluating erlotinib±onartuzumab in advanced non-small cell lung cancer: MET expression levels are predictive of patient benefit.
Biomarker analyses from a placebo-controlled phase II study evaluating erlotinib±onartuzumab in advanced non-small cell lung cancer: MET expression levels are predictive of patient benefit.
复制标题
DOI：
10.1158/1078-0432.ccr-13-1836
复制
发表时间：
2014-09-01
期刊：
影响因子：
--
通讯作者：
Yauch RL
中科院分区：
文献类型：
--
作者：
Koeppen H;Yu W;Zha J;Pandita A;Penuel E;Rangell L;Raja R;Mohan S;Patel R;Desai R;Fu L;Do A;Parab V;Xia X;Januario T;Louie SG;Filvaroff E;Shames DS;Wistuba I;Lipkind M;Huang J;Lazarov M;Ramakrishnan V;Amler L;Phan SC;Patel P;Peterson A;Yauch RL
在最近的一项关于奥纳妥珠单抗（MetMAb）的II期研究中，非小细胞肺癌（NSCLC）组织经免疫组化（IHC）检测MET蛋白阳性的患者，与厄洛替尼相比，奥纳妥珠单抗联合厄洛替尼（O+E）有显著的获益。我们描述了标准化MET免疫组化检测的开发和验证，并回顾性地评估了多种生物标志物作为患者获益的预测因子。通过免疫组化、FISH、定量反转录PCR、突变检测技术和ELISA检测MET和/或EGF受体（EGFR）信号相关的生物标志物。在非小细胞肺癌细胞系/组织中，IHC、Western blotting和MET mRNA表达呈正相关。在II期研究的分析中，采用了考虑比例和强度阈值的IHC MET表达评分系统，并得出了最佳的结果区分。进一步分析显示，高MET拷贝数（FISH平均≥5拷贝/细胞）患者的O+E总生存期（OS）改善不显著；然而，“MET ihc阳性”/MET fish阴性患者的获益保持不变（HR, 0.37; P = 0.01）。MET、EGFR、双调节蛋白、表调节蛋白或HGF mRNA表达不能预测使用奥纳妥珠单抗的显著获益；肿瘤MET mRNA水平高的患者OS改善不显著（HR, 0.59; P = 0.23）。低基线血浆肝细胞生长因子（HGF）患者的OS HR为0.519 (P = 0.09)，有利于奥纳妥珠单抗治疗。相对于所有检查的探索性标志物，MET IHC仍然是OS和O+E无进展生存获益的最可靠预测因子。
In a recent phase II study of onartuzumab (MetMAb), patients whose non–small cell lung cancer (NSCLC) tissue scored as positive for MET protein by immunohistochemistry (IHC) experienced a significant benefit with onartuzumab plus erlotinib (O+E) versus erlotinib. We describe development and validation of a standardized MET IHC assay and, retrospectively, evaluate multiple biomarkers as predictors of patient benefit. Biomarkers related to MET and/or EGF receptor (EGFR) signaling were measured by IHC, FISH, quantitative reverse transcription PCR, mutation detection techniques, and ELISA. A positive correlation between IHC, Western blotting, and MET mRNA expression was observed in NSCLC cell lines/tissues. An IHC scoring system of MET expression taking proportional and intensity-based thresholds into consideration was applied in an analysis of the phase II study and resulted in the best differentiation of outcomes. Further analyses revealed a nonsignificant overall survival (OS) improvement with O+E in patients with high MET copy number (mean ≥5 copies/cell by FISH); however, benefit was maintained in “MET IHC-positive”/MET FISH-negative patients (HR, 0.37; P = 0.01). MET, EGFR, amphiregulin, epiregulin, or HGF mRNA expression did not predict a significant benefit with onartuzumab; a nonsignificant OS improvement was observed in patients with high tumor MET mRNA levels (HR, 0.59; P = 0.23). Patients with low baseline plasma hepatocyte growth factor (HGF) exhibited an HR for OS of 0.519 (P = 0.09) in favor of onartuzumab treatment. MET IHC remains the most robust predictor of OS and progression-free survival benefit from O+E relative to all examined exploratory markers.