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http://purl.uniprot.org/citations/29467321http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/29467321http://www.w3.org/2000/01/rdf-schema#comment"

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)."xsd:string
http://purl.uniprot.org/citations/29467321http://purl.org/dc/terms/identifier"doi:10.1172/jci.insight.92352"xsd:string
http://purl.uniprot.org/citations/29467321http://purl.uniprot.org/core/author"Deng Y."xsd:string
http://purl.uniprot.org/citations/29467321http://purl.uniprot.org/core/author"Zhang D."xsd:string
http://purl.uniprot.org/citations/29467321http://purl.uniprot.org/core/author"Carr D."xsd:string
http://purl.uniprot.org/citations/29467321http://purl.uniprot.org/core/author"Schiller J."xsd:string
http://purl.uniprot.org/citations/29467321http://purl.uniprot.org/core/author"Cooper A."xsd:string
http://purl.uniprot.org/citations/29467321http://purl.uniprot.org/core/author"Dayananth P."xsd:string
http://purl.uniprot.org/citations/29467321http://purl.uniprot.org/core/author"Robert L."xsd:string
http://purl.uniprot.org/citations/29467321http://purl.uniprot.org/core/author"Bishop W.R."xsd:string
http://purl.uniprot.org/citations/29467321http://purl.uniprot.org/core/author"Kirschmeier P."xsd:string
http://purl.uniprot.org/citations/29467321http://purl.uniprot.org/core/author"Adjei A.A."xsd:string
http://purl.uniprot.org/citations/29467321http://purl.uniprot.org/core/author"Flaherty K.T."xsd:string
http://purl.uniprot.org/citations/29467321http://purl.uniprot.org/core/author"Samatar A.A."xsd:string
http://purl.uniprot.org/citations/29467321http://purl.uniprot.org/core/author"Ribas A."xsd:string
http://purl.uniprot.org/citations/29467321http://purl.uniprot.org/core/author"Rubin E.H."xsd:string
http://purl.uniprot.org/citations/29467321http://purl.uniprot.org/core/author"Hwu W.J."xsd:string
http://purl.uniprot.org/citations/29467321http://purl.uniprot.org/core/author"Long B.J."xsd:string
http://purl.uniprot.org/citations/29467321http://purl.uniprot.org/core/author"Chun P."xsd:string
http://purl.uniprot.org/citations/29467321http://purl.uniprot.org/core/author"Rush T.S."xsd:string
http://purl.uniprot.org/citations/29467321http://purl.uniprot.org/core/author"Ramanathan R.K."xsd:string
http://purl.uniprot.org/citations/29467321http://purl.uniprot.org/core/author"Moschos S.J."xsd:string
http://purl.uniprot.org/citations/29467321http://purl.uniprot.org/core/author"Fong P.C."xsd:string
http://purl.uniprot.org/citations/29467321http://purl.uniprot.org/core/author"Sullivan R.J."xsd:string
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