Anti-MET Targeted Therapy Has Come of Age: The First Durable Complete Response with MetMAb in Metastatic Gastric Cancer

Abstract

The MET/hepatocyte growth factor (HGF) signaling pathway plays important roles in oncogenesis and tumor progression in a variety of human cancers. MET/HGF drives an invasive signaling program that can be dysregulated in human cancers through a number of activating mechanisms, including mutations, overexpression, amplification, alternative splicing, and HGF ligand–induced autocrine/paracrine loop signaling. As a testimony of MET-targeting therapeutics is beginning to come to clinical fruition, Catenacci and colleagues report the first case of durable complete response under an anti-MET receptor monoclonal antibody, MetMAb, in a patient with chemotherapy-refractory, advanced gastric cancer metastatic to the liver, found to have high MET gene polysomy and remarkably high serum HGF level. Serum and tissue studies also revealed predictive biomarkers for therapeutic response to MET inhibition. Cancer Discovery; 1(7); 550–4. ©2011 AACR. Commentary on Catenacci et al., p. 573.

Depletion of FOXM1 via MET Targeting Underlies Establishment of a DNA Damage–Induced Senescence Program in Gastric Cancer

“…In addition, about 20% of human gastric cancer cell lines exhibit MET amplification with a corresponding MET addiction phenotype, rendering these tumor cells extremely sensitive to MET inhibition (10). Accordingly, MET is considered to be a prognostic marker and at the same time an important therapeutic target for locally advanced or metastatic gastric cancers (11,12). Currently, several anti-MET antibodies and small-molecule MET inhibitors are undergoing phase I and phase II clinical trials in different types of solid tumors, including gastric cancer (e.g., NCT02435108, NCT01468922, NCT00725712, NCT02002416), with only a modest benefit in otherwise unselected patient populations (13).…”

Biobetters

“…Conventional antibodies can also induce c-Met dimerization, therefore acting as agonists. One-armed antibody-like molecules, such as onartuzumab, do not cross-link c-Met and can inhibit its HGF-induced signaling (Feng and Ma 2011 ;Merchant et al 2013 ). However, such monovalent antibodies can lose up to 100-fold in bioactivity due to the loss of avidity in their binding, making restoration of bivalent targeting benefi cial (Fig.…”

HGF/MET-directed therapeutics in gastroesophageal cancer: a review of clinical and biomarker development

“…In a Phase I study dose-escalation study of onartuzumab in patients with various locally advanced or metastatic solid tumors, a sustained complete response (>2 years) was noted in a patient with chemorefractory GEC with hepatic metastases [49, 50]. Interestingly, serial correlative blood and tissue studies in this patient showed MET gene polysomy, moderate MET expression by IHC and a remarkably high baseline serum HGF level.…”