title: 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.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Genentech Inc., South San Francisco;
authors.forename: Hartmut
authors.initials: H
authors.lastname: Koeppen
authors.affiliation: Genentech Inc., South San Francisco;
authors.forename: Wei
authors.initials: W
authors.lastname: Yu
authors.affiliation: Crown Bioscience Inc., Jiangsu Province, China.
authors.forename: Jiping
authors.initials: J
authors.lastname: Zha
authors.affiliation: OncoMDx, Inc., Palo Alto;
authors.forename: Ajay
authors.initials: A
authors.lastname: Pandita
authors.affiliation: Genentech Inc., South San Francisco;
authors.forename: Elicia
authors.initials: E
authors.lastname: Penuel
authors.affiliation: Genentech Inc., South San Francisco;
authors.forename: Linda
authors.initials: L
authors.lastname: Rangell
authors.affiliation: Genentech Inc., South San Francisco;
authors.forename: Rajiv
authors.initials: R
authors.lastname: Raja
authors.affiliation: OncoMDx, Inc., Palo Alto;
authors.forename: Sankar
authors.initials: S
authors.lastname: Mohan
authors.affiliation: Genentech Inc., South San Francisco;
authors.forename: Rajesh
authors.initials: R
authors.lastname: Patel
authors.affiliation: Genentech Inc., South San Francisco;
authors.forename: Rupal
authors.initials: R
authors.lastname: Desai
authors.affiliation: Genentech Inc., South San Francisco;
authors.forename: Ling
authors.initials: L
authors.lastname: Fu
authors.affiliation: Genentech Inc., South San Francisco;
authors.forename: An
authors.initials: A
authors.lastname: Do
authors.affiliation: Genentech Inc., South San Francisco;
authors.forename: Vaishali
authors.initials: V
authors.lastname: Parab
authors.affiliation: Genentech Inc., South San Francisco;
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Xia
authors.affiliation: Genentech Inc., South San Francisco;
authors.forename: Tom
authors.initials: T
authors.lastname: Januario
authors.affiliation: Genentech Inc., South San Francisco;
authors.forename: Sharianne G
authors.initials: SG
authors.lastname: Louie
authors.affiliation: Genentech Inc., South San Francisco;
authors.forename: Ellen
authors.initials: E
authors.lastname: Filvaroff
authors.affiliation: Genentech Inc., South San Francisco;
authors.forename: David S
authors.initials: DS
authors.lastname: Shames
authors.affiliation: Department of Translational Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; and.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Wistuba
authors.affiliation: Genentech Inc., South San Francisco;
authors.forename: Marina
authors.initials: M
authors.lastname: Lipkind
authors.affiliation: Genentech Inc., South San Francisco;
authors.forename: Jenny
authors.initials: J
authors.lastname: Huang
authors.affiliation: Gilead Sciences, Inc., Foster City, California;
authors.forename: Mirella
authors.initials: M
authors.lastname: Lazarov
authors.affiliation: Genentech Inc., South San Francisco;
authors.forename: Vanitha
authors.initials: V
authors.lastname: Ramakrishnan
authors.affiliation: Genentech Inc., South San Francisco;
authors.forename: Lukas
authors.initials: L
authors.lastname: Amler
authors.affiliation: Genentech Inc., South San Francisco;
authors.forename: See-Chun
authors.initials: SC
authors.lastname: Phan
authors.affiliation: Genentech Inc., South San Francisco;
authors.forename: Premal
authors.initials: P
authors.lastname: Patel
authors.affiliation: Medivation, Inc., San Francisco;
authors.forename: Amy
authors.initials: A
authors.lastname: Peterson
authors.affiliation: Genentech Inc., South San Francisco; bobyauch@gene.com.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Yauch
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D014408:Biomarkers, Tumor / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000096:biosynthesis; D000069347:Erlotinib Hydrochloride; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis*; D011799:Quinazolines / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000096:biosynthesis
chemical_list: D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D011799:Quinazolines; D012333:RNA, Messenger; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C584058:onartuzumab