Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase II Study of Onartuzumab Plus Bevacizumab Versus Placebo Plus Bevacizumab in Patients With Recurrent Glioblastoma: Efficacy, Safety, and Hepatocyte Growth Factor and O6-Methylguanine-DNA Methyltransferase Biomarker Analyses.

Purpose Bevacizumab regimens are approved for the treatment of recurrent glioblastoma in many countries. Aberrant mesenchymal-epithelial transition factor (MET) expression has been reported in glioblastoma and may contribute to bevacizumab resistance. The phase II study GO27819 investigated the monovalent MET inhibitor onartuzumab plus bevacizumab (Ona + Bev) versus placebo plus bevacizumab (Pla + Bev) in recurrent glioblastoma. Methods At first recurrence after chemoradiation, bevacizumab-naïve patients with glioblastoma were randomly assigned 1:1 to receive Ona (15 mg/kg, once every 3 weeks) + Bev (15 mg/kg, once every 3 weeks) or Pla + Bev until disease progression. The primary end point was progression-free survival by response assessment in neuro-oncology criteria. Secondary end points were overall survival, objective response rate, duration of response, and safety. Exploratory biomarker analyses correlated efficacy with expression levels of MET ligand hepatocyte growth factor, O6-methylguanine-DNA methyltransferase promoter methylation, and glioblastoma subtype. Results Among 129 patients enrolled (Ona + Bev, n = 64; Pla + Bev, n = 65), baseline characteristics were balanced. The median progression-free survival was 3.9 months for Ona + Bev versus 2.9 months for Pla + Bev (hazard ratio, 1.06; 95% CI, 0.72 to 1.56; P = .7444). The median overall survival was 8.8 months for Ona + Bev and 12.6 months for Pla + Bev (hazard ratio, 1.45; 95% CI, 0.88 to 2.37; P = .1389). Grade ≥ 3 adverse events were reported in 38.5% of patients who received Ona + Bev and 35.9% of patients who received Pla + Bev. Exploratory biomarker analyses suggested that patients with high expression of hepatocyte growth factor or unmethylated O6-methylguanine-DNA methyltransferase may benefit from Ona + Bev. Conclusion There was no evidence of further clinical benefit with the addition of onartuzumab to bevacizumab compared with bevacizumab plus placebo in unselected patients with recurrent glioblastoma in this phase II study; however, further investigation into biomarker subgroups is warranted.

[1]  R. Bourgon,et al.  Patients With Proneural Glioblastoma May Derive Overall Survival Benefit From the Addition of Bevacizumab to First-Line Radiotherapy and Temozolomide: Retrospective Analysis of the AVAglio Trial. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  G. Reifenberger,et al.  EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma. , 2014, The Lancet. Oncology.

[3]  R. Vernhout,et al.  Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. , 2014, The Lancet. Oncology.

[4]  H. Koeppen,et al.  HGF/MET-directed therapeutics in gastroesophageal cancer: a review of clinical and biomarker development , 2014, Oncotarget.

[5]  I. Wistuba,et al.  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 , 2014, Clinical Cancer Research.

[6]  K. Aldape,et al.  A randomized trial of bevacizumab for newly diagnosed glioblastoma. , 2014, The New England journal of medicine.

[7]  K. Hoang-Xuan,et al.  Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. , 2014, The New England journal of medicine.

[8]  M. Fabrini,et al.  Bevacizumab and fotemustine for recurrent glioblastoma: a phase II study of AINO (Italian Association of Neuro-Oncology) , 2013, Journal of Neuro-Oncology.

[9]  J. Simes,et al.  A randomized phase II study of carboplatin and bevacizumab in recurrent glioblastoma multiforme (CABARET). , 2013 .

[10]  A. Zhu,et al.  Targeting the HGF/c-MET Pathway in Hepatocellular Carcinoma , 2013, Clinical Cancer Research.

[11]  J. Barnholtz-Sloan,et al.  CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011. , 2012, Neuro-oncology.

[12]  G. Mills,et al.  Targeting the hepatocyte growth factor-cMET axis in cancer therapy. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  A. Abernethy,et al.  MET and ALK in glioblastoma multiforme (GBM): Comparison of IHC and FISH. , 2012 .

[14]  H. Friedman,et al.  Bevacizumab and daily temozolomide for recurrent glioblastoma , 2012, Cancer.

[15]  F. Marincola,et al.  Hepatocyte growth factor (HGF) autocrine activation predicts sensitivity to MET inhibition in glioblastoma , 2011, Proceedings of the National Academy of Sciences.

[16]  D. Crooks,et al.  Biology, genetics and imaging of glial cell tumours. , 2011, The British journal of radiology.

[17]  Susan M. Chang,et al.  Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  S. Gabriel,et al.  Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. , 2010, Cancer cell.

[19]  T. Mikkelsen,et al.  Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  John A Butman,et al.  Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  John Sampson,et al.  Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  T. Mikkelsen,et al.  A simplified laboratory validated assay for MGMT promoter hypermethylation analysis of glioma specimens from formalin-fixed paraffin-embedded tissue , 2007, Laboratory Investigation.

[23]  M. Westphal,et al.  A Novel One-Armed Anti-c-Met Antibody Inhibits Glioblastoma Growth In vivo , 2006, Clinical Cancer Research.

[24]  Martin J. van den Bent,et al.  Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. , 2005, The New England journal of medicine.

[25]  P. Brenchley,et al.  Vascular endothelial growth factor expression correlates with tumour grade and vascularity in gliomas , 2001, Histopathology.

[26]  E. Hudson,et al.  Met and hepatocyte growth factor/scatter factor expression in human gliomas. , 1997, Cancer research.

[27]  G. Bergers,et al.  Mechanisms of evasive resistance to anti-VEGF therapy in glioblastoma. , 2013, CNS oncology.

[28]  Michael Weller,et al.  Standards of care for treatment of recurrent glioblastoma--are we there yet? , 2013, Neuro-oncology.

[29]  Anupama E. Gururaj,et al.  Regulation of HGF expression by ΔEGFR-mediated c-Met activation in glioblastoma cells. , 2013, Neoplasia.

[30]  G. Reifenberger,et al.  MGMT promoter methylation in malignant gliomas: ready for personalized medicine? , 2010, Nature Reviews Neurology.