Development of MK-8353, an Orally Administered ERK1/2 Inhibitor, in Patients with Advanced Solid Tumors

Overview

Journal JCI Insight

Specialties Biomedical Engineering
General Medicine

Date 2018 Feb 23

PMID 29467321

Citations 63

Authors

Stergios J Moschos

Ryan J Sullivan

Wen-Jen Hwu

Ramesh K Ramanathan

Alex A Adjei

Peter C Fong

Ronnie Shapira-Frommer

Hussein A Tawbi

Joseph Rubino

Thomas S Rush 3rd

Da Zhang

Nathan R Miselis

Ahmed A Samatar

Patrick Chun

Eric H Rubin

James Schiller

Brian J Long

Priya Dayananth

Donna Carr

Paul Kirschmeier

W Robert Bishop

Yongqi Deng

Alan Cooper

Gerald W Shipps

Blanca Homet Moreno

Lidia Robert

Antoni Ribas

Keith T Flaherty

Affiliations

Soon will be listed here.

Abstract

Background: 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.

Methods: 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.

Results: 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 diarrhea (44%), fatigue (40%), nausea (32%), and rash (28%). Dose-limiting toxicity was observed in the 400-mg and 800-mg dose cohorts. Sufficient exposure to MK-8353 was noted that correlated with biological activity in preclinical data. Three of fifteen patients evaluable for treatment response in the MK-8353-001 study had partial response, all with BRAFV600-mutant melanomas.

Conclusion: MK-8353 was well tolerated up to 400 mg twice daily and exhibited antitumor activity in patients with BRAFV600-mutant melanoma. However, antitumor activity was not particularly correlated with pharmacodynamic parameters.

Trial Registration: ClinicalTrials.gov NCT01358331.

Funding: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., and NIH (P01 CA168585 and R35 CA197633).

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