Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors

JCI Insight
Stergios J MoschosKeith T Flaherty

Abstract

Constitutive activation of ERK1/2 occurs in various cancers, and its reactivation is a well-described resistance mechanism to MAPK inhibitors. ERK inhibitors may overcome the limitations of MAPK inhibitor blockade. The dual mechanism inhibitor SCH772984 has shown promising preclinical activity across various BRAFV600/RAS-mutant cancer cell lines and human cancer xenografts. We have developed an orally bioavailable ERK inhibitor, MK-8353; conducted preclinical studies to demonstrate activity, pharmacodynamic endpoints, dosing, and schedule; completed a study in healthy volunteers (P07652); and subsequently performed a phase I clinical trial in patients with advanced solid tumors (MK-8353-001). In the P07652 study, MK-8353 was administered as a single dose in 10- to 400-mg dose cohorts, whereas in the MK-8353-001 study, MK-8353 was administered in 100- to 800-mg dose cohorts orally twice daily. Safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity were analyzed. MK-8353 exhibited comparable potency with SCH772984 across various preclinical cancer models. Forty-eight patients were enrolled in the P07652 study, and twenty-six patients were enrolled in the MK-8353-001 study. Adverse events included diarrhe...Continue Reading

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Methods Mentioned

BETA
xenograft
xenografts
biopsies
nuclear translocation
Assay

Clinical Trials Mentioned

NCT02972034
NCT01358331

Software Mentioned

Excel
Aperio ScanScope XT
AxioVision
Statistical Analysis System ( SAS )
Quantity One
Aperio ImageScope
GraphPad
Prism
GraphPad Prism

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