MET inhibitors in cancer: pitfalls and challenges.

Introduction: The HGF/MET axis is a key therapeutic pathway in cancer; it is aberrantly activated because of mutations, fusions, amplification or aberrant ligand production. Extensive efforts have been made to discover predictive factors of anti-MET therapeutic efficacy, but they have mostly unsuccessful. An understanding of the intrinsic and acquired mechanism of MET resistance will be fundamental for the development of new therapeutic interventions.Areas covered: This article provides a systematic review of phase II randomized and phase III clinical trials investigating the use of MET inhibitors in the treatment of cancer. We discuss preliminary findings on efficacy and methodologic design flaws in these trials.Expert opinion: MET inhibitors showed poor activity in unselected patients or patients selected by MET expression, p-MET or high HGF basal levels. The efficacy in advanced solid tumors is very modest and in phase III clinical trials, survival differences did not fulfill the stringent requirements of ESMO-Magnitude Clinical Benefit Score (MCBS). Prospective novel liquid biomarker-driven studies and novel trial designs such as Umbrella and Basket trials are necessary to progress MET inhibitor development.