Biomarker Analyses from a Placebo-Controlled Phase II Study Evaluating Erlotinib plus or minus Onartuzumab in Advanced Non-Small Cell Lung Cancer: MET Expression Levels Are Predictive of Patient Benefit

• Published in: Clinical cancer research Vol. 20; no. 17; pp. 4488 - 4498
• Main Authors: Koeppen, Hartmut, Yu, Wei, Zha, Jiping, Pandita, Ajay, Penuel, Elicia, Rangell, Linda, Raja, Rajiv, Mohan, Sankar, Patel, Rajesh, Desai, Rupal, Fu, Ling, Do, An, Parab, Vaishali, Xia, Xiaoling, Januario, Tom, Louie, Sharianne G, Filvaroff, Ellen, Shames, David S, Wistuba, Ignacio, Lipkind, Marina, Huang, Jenny, Lazarov, Mirella, Ramakrishnan, Vanitha, Amler, Lukas, Phan, See-Chun, Patel, Premal, Peterson, Amy, Yauch, Robert L
• Format: Journal Article
• Language: English
• Published: 01.09.2014
• ISSN: 1078-0432
• DOI: 10.1158/1078-0432.CCR-13-1836

Purpose: 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.Experimental Design: Biomarkers related to MET and/or EGF receptor (EGFR) signaling were measured by IHC, FISH, quantitative reverse transcription PCR, mutation detection techniques, and ELISA.Results: 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 greater than or equal to 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.Conclusions: MET IHC remains the most robust predictor of OS and progression-free survival benefit from O+E relative to all examined exploratory markers. Clin Cancer Res; 20(17); 4488-98. copyright 2014 AACR.