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

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.

• Authors: Hartmut Koeppen, Wei Yu, Jiping Zha, Ajay Pandita, Elicia Penuel, Linda Rangell, Rajiv Raja, Sankar Mohan, Rajesh Patel, Rupal Desai, Ling Fu, An Do, Vaishali Parab, Xiaoling Xia, Tom Januario, Sharianne G Louie, Ellen Filvaroff, David S Shames, Ignacio Wistuba, Marina Lipkind, Jenny Huang, Mirella Lazarov, Vanitha Ramakrishnan, Lukas Amler, See-Chun Phan, Premal Patel, Amy Peterson, Robert L Yauch
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 17 Pg. 4488-98 (Sep 01 2014) ISSN: 1557-3265 [Electronic] United States
• PMID: 24687921 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal
• Biomarkers, Tumor
• Quinazolines
• RNA, Messenger
• Erlotinib Hydrochloride
• EGFR protein, human
• ErbB Receptors
• MET protein, human
• Proto-Oncogene Proteins c-met
• onartuzumab

Topics

• Adolescent
• Adult
• Aged
• Antibodies, Monoclonal (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage)
• Biomarkers, Tumor (genetics)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, pathology)
• Disease-Free Survival
• ErbB Receptors (biosynthesis)
• Erlotinib Hydrochloride
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• In Situ Hybridization, Fluorescence
• Male
• Middle Aged
• Neoplasm Staging
• Proto-Oncogene Proteins c-met (biosynthesis)
• Quinazolines (administration & dosage)
• RNA, Messenger (biosynthesis)