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JCI Insight. 2018 Feb 22;3(4). pii: 92352. doi: 10.1172/jci.insight.92352. eCollection 2018 Feb 22.

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

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Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Translational Genomics Research Institute, Phoenix, Arizona, USA; Virginia G. Piper Cancer Center, Scottsdale, Arizona, USA.
Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA.
The University of Auckland and Auckland City Hospital, Auckland, New Zealand.
Department of International Medicine, Chaim Sheba Medical Center, Tel-HaShomer, Israel.
University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.
Merck & Co. Inc., Kenilworth, New Jersey, USA.
Jonsson Comprehensive Cancer Center at UCLA, University of California Los Angeles, Los Angeles, California, USA.



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 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.


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.



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


Cancer; Clinical Trials; Melanoma; Oncology; Signal transduction

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