AI Article Synopsis
- - MK-8353 is an orally administered ERK inhibitor showing promise against BRAFV600/RAS-mutant cancers, with similar effectiveness to an existing drug, SCH772984, in preclinical tests.
- - Phase I clinical trials on MK-8353 involved healthy volunteers and patients with solid tumors, assessing safety, dosing, and antitumor effects, with adverse reactions including diarrhea and fatigue.
- - The drug demonstrated good tolerance at doses up to 400 mg twice daily and achieved partial response in some patients with BRAFV600-mutant melanoma, though its effectiveness wasn't strongly linked to expected pharmacodynamic outcomes.
Article 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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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916243 | PMC |
| http://dx.doi.org/10.1172/jci.insight.92352 | DOI Listing |
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