Onartuzumab (DB11746): A Comprehensive Review of a Novel Monovalent MET Inhibitor from Rational Design to Clinical Discontinuation

Introduction

The signaling axis defined by the hepatocyte growth factor (HGF) and its cognate receptor, the mesenchymal-epithelial transition factor (MET) tyrosine kinase, has long been recognized as a compelling therapeutic target in oncology.[1] Aberrant activation of the HGF/MET pathway—driven by ligand overexpression, receptor overexpression, gene amplification, or activating mutations—is implicated in the proliferation, survival, invasion, and metastasis of a diverse array of human malignancies.[4] Despite this strong biological rationale, the pathway has proven to be a remarkably challenging target for therapeutic intervention. Within this challenging landscape, the investigational agent Onartuzumab (DrugBank ID: DB11746) stands as a seminal case study in the narrative of modern drug development.

This report will provide an exhaustive analysis of Onartuzumab, framing its trajectory not as a simple drug failure, but as a paradigm of exquisite molecular engineering that was ultimately defeated by the profound complexities of tumor biology, the critical limitations of its companion diagnostic biomarker, and the inherent strategic risks of clinical trial design. The central thesis of this review is that Onartuzumab represents a landmark in the evolution of precision oncology. Its development showcased a brilliant solution to the specific biochemical problem of antibody-induced receptor agonism, yet its definitive clinical failure marked a crucial turning point for the field. The experience with Onartuzumab forced a fundamental re-evaluation of biomarker strategy, accelerating the shift away from targeting broadly "overexpressed" proteins toward the more precise targeting of validated, functional "driver" alterations. The story of Onartuzumab, therefore, is a microcosm of this evolution. Its development initially followed