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, ontreatment, circulating biomarker, these data suggest that measurement of cHGF in future expanded studies is warranted.

cMET as a potential therapeutic target in gastric cancer (Review)

“…This observation suggests that circulating HGF is a biomarker for therapeutic response (17). Similar results have been reported in non-small cell lung cancer (NSCLC); circulating HGF levels were measured as a pharmacodynamic biomarker of onartuzumab activity (58). Other studies using PET with (89)Zr-df-onartuzumab and (76)Br-onartuzumab in gastric carcinoma xenografts showed that the uptake of both tracers significantly correlated with tumor mass and cMET expression and was not affected by the presence of plasma shed cMET (59).…”

A Randomized Phase II Study of FOLFOX With or Without the MET Inhibitor Onartuzumab in Advanced Adenocarcinoma of the Stomach and Gastroesophageal Junction

“…The RILOMET-1 phase III study of HGF inhibitor rilotumumab for gastric cancer also reported negative results and closed prematurely because of lackof activity [14]. Circulating HGF levels have been explored in other tumor types as a potential biomarker for MET inhibitor efficacy [15], and high levels of circulating HGF were found in the patient who had a complete response in the phase I study [10]; however, HGF levels determined by PCR had no relationship with efficacy in this study. This suggests that alternative biomarkers are needed to define the optimal patient population for onartuzumab.…”

MET in Lung Cancer: Biomarker Selection Based on Scientific Rationale

“…For example, elevated cHGF, as measured by ELISA, has been used as a pharmacodynamic biomarker of activity with onartuzumab (74). However, in cases of ligand-independent activation of MET, it is feasible that monoclonal antibody therapy, without drug internalization, may be a less effective therapeutic strategy than TKIs that target the receptor protein kinase directly.…”