BACKGROUND: Dysregulated hepatocyte growth factor/mesenchymal-epithelial 
transition (MET) signaling is associated with poor prognosis and resistance to 
vascular endothelial growth factor inhibition in metastatic colorectal cancer 
(mCRC). We report outcomes from a double-blind, multicenter phase II trial of 
the MET inhibitor onartuzumab in combination with mFOLFOX-6 and bevacizumab for 
mCRC (GO27827; NCT01418222).
MATERIALS AND METHODS: Patients were randomized 1:1 to receive onartuzumab (10 
mg/kg intravenously [IV]) or placebo plus mFOLFOX-6 and bevacizumab (5 mg/kg 
IV). Oxaliplatin was given for 8-12 cycles; other agents were continued until 
disease progression, unacceptable toxicity, or death. The primary endpoint was 
progression-free survival (PFS) in the intent-to-treat (ITT) and MET 
immunohistochemistry (IHC) expression-positive populations.
RESULTS: Between September 2011 and November 2012, 194 patients were enrolled. 
In September 2013, an interim analysis recommended stopping onartuzumab 
treatment due to lack of efficacy. At the time of the final analysis in February 
2014, no significant improvement in PFS was seen with onartuzumab versus placebo 
in either the ITT or MET IHC-positive populations. An improvement in PFS was 
noted in the MET IHC-negative population. Neither overall survival nor response 
rate was improved with onartuzumab. The incidence of fatigue, peripheral edema, 
and deep vein thrombosis was increased with onartuzumab relative to placebo.
CONCLUSION: Onartuzumab combined with mFOLFOX-6 and bevacizumab did not 
significantly improve efficacy outcomes in either the ITT or MET IHC-positive 
populations. MET expression by IHC was not a predictive biomarker in this 
setting. The Oncologist 2017;22:264-271 IMPLICATIONS FOR PRACTICE: The addition 
of onartuzumab to mFOLFOX-6 plus bevacizumab did not improve outcomes in 
patients with previously untreated metastatic colorectal cancer in this 
randomized, phase II study. Although initial results with onartuzumab were 
promising, a number of phase II/III clinical trials have reported a lack of 
improvement in efficacy with onartuzumab combined with standard-of-care 
therapies in several tumor types. Furthermore, negative study data have been 
published for rilotumumab and ficlatuzumab, both of which block hepatocyte 
growth factor binding to the mesenchymal-epithelial transition (MET) receptor. 
MET immunohistochemistry was not a predictive biomarker. It remains to be seen 
if other biomarkers or small molecule inhibitors may be more appropriate for 
inhibiting this oncogenic pathway.