title: HGF as a circulating biomarker of onartuzumab treatment in patients with advanced solid tumors.
abstract: The objective of this study was to evaluate circulating hepatocyte growth factor (cHGF) as a pharmacodynamic biomarker of Met inhibition for onartuzumab (MetMAb, OA5D5v2) in a phase I trial in patients with advanced cancers and a phase II trial in non-small cell lung cancer (NSCLC). The phase I study was a dose escalation trial with onartuzumab administered i.v. once every three weeks. The phase II study was a randomized two-arm trial in which onartuzumab or placebo was administered in combination with erlotinib in 137 patients with second and third line (2/3L) NSCLC. cHGF levels were evaluated by ELISA at multiple time points over the treatment period. Onartuzumab administration resulted in an acute and sustained rise in cHGF in both the phase I and phase II studies. Elevation in cHGF was independent of dose or drug exposure and was restricted to onartuzumab treatment. Neither higher baseline nor elevated change in cHGF levels upon treatment could simply be attributed to tumor burden or number of liver metastasis. We have shown that elevated cHGF can consistently and reproducibly be measured as a pharmacodynamic biomarker of onartuzumab activity. The elevation in cHGF is independent of tumor type, dose administered, or dose duration. Although these studies were not powered to directly address the contribution of cHGF as a predictive, on-treatment, circulating biomarker, these data suggest that measurement of cHGF in future expanded studies is warranted.
authors.affiliation: Genentech Inc., South San Francisco, CA, USA. epenuel@gene.com
authors.forename: Elicia
authors.initials: E
authors.lastname: Penuel
authors.forename: Congfen
authors.initials: C
authors.lastname: Li
authors.forename: Vaishali
authors.initials: V
authors.lastname: Parab
authors.forename: Luciana
authors.initials: L
authors.lastname: Burton
authors.forename: Kyra J
authors.initials: KJ
authors.lastname: Cowan
authors.forename: Mark
authors.initials: M
authors.lastname: Merchant
authors.forename: Robert L
authors.initials: RL
authors.lastname: Yauch
authors.forename: Premal
authors.initials: P
authors.lastname: Patel
authors.forename: Amy
authors.initials: A
authors.lastname: Peterson
authors.forename: Garret M
authors.initials: GM
authors.lastname: Hampton
authors.forename: Mark R
authors.initials: MR
authors.lastname: Lackner
authors.forename: Priti S
authors.initials: PS
authors.lastname: Hegde
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000097:blood; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D000069347:Erlotinib Hydrochloride; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis / Q000097:blood*; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D009367:Neoplasm Staging; D009360:Neoplastic Cells, Circulating / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis / Q000235:genetics; D011799:Quinazolines / Q000008:administration & dosage
chemical_list: D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; C066855:HGF protein, human; D011799:Quinazolines; D017228:Hepatocyte Growth Factor; D000069347:Erlotinib Hydrochloride; D019859:Proto-Oncogene Proteins c-met; C584058:onartuzumab