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≥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.