Translational biomarker in early oncology clinical development: decision case study for MEK inhibitors in healthy volunteer studies

Author(s): Lucy Lee

Biomarkers of drug activity are increasingly important tools in oncology early drug development, particularly in this era of targeted therapies. In early development, their main use is to help select the best drugs and/or dosing regimens to progress in development. The case study demonstrates how a biomarker of molecular target activity was developed in a preclinical setting and translated into the clinic to assess the ‘proof of mechanism’ for two competing MEK inhibitors, CH4987655 and RO5068760. Inhibition of ERK phosphorylation (pERK) was measured using a surrogate tissue, ex vivo phorbol 12-myristate 13-acetate-stimulated peripheral blood mononuclear cells. CH4987655 demonstrated concentration-dependent pERK inhibition with exposures covering pERK inhibition from the no effect level to near maximum effect of 100%. However, RO5068760 demonstrated a rather modest pERK inhibition of only 55%. The biomarker demonstrated CH4987655 was superior in terms of MEK inhibition and the potential for therapeutic effects enabled the choice to progress only CH4987655 into further clinical development.