Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors
Stergios J. Moschos, … , Antoni Ribas, Keith T. Flaherty
Stergios J. Moschos, … , Antoni Ribas, Keith T. Flaherty
Published February 22, 2018
Citation Information: JCI Insight. 2018;3(4):e92352. https://doi.org/10.1172/jci.insight.92352.
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Clinical Research and Public Health Clinical trials Oncology

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

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).

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 III, 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

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Figure 2

MK-8353 induces tumor growth inhibition or regression across various human cancer xenograft models.

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MK-8353 induces tumor growth inhibition or regression across various hum...
Female athymic nude mice (Colo-205) or SCID mice (SK-MEL-28) were injected with human Colo-205 colon cancer cells (B) and SK-MEL-28 melanoma cells (A) (both BRAFV600E-mutant), as described in the Methods section. (A and B). Tumor growth curves show mean tumor volumes ± SEM (10 mice per group for each xenograft experiment). There was a statistically significant dose-dependent effect on tumor growth compared with the vehicle-treated group in both xenograft models that ranged from tumor growth inhibition (TGI) to regression (REG) and was present as early as day 3 from treatment initiation (P < 0.01, across all time points except for the day 3 time point in the Colo-205 xenograft model, in which the 30-mpk group was significantly different, P < 0.05; Student’s t test). (C and D) Expression of pERK by tissue immunohistochemistry in Colo-205 tumor xenografts (C) and same-animal normal skin tissues (D) following a single dose of MK-8353 administered by oral gavage at various doses. Representative tissue sections from corresponding tissues that were harvested at various time points (0–12 hours) following a single dose of MK-8353 were stained with antibodies against pERK. See the Methods section for details and Supplemental Figure 1 for representative images of 3 animals, with tumors and normal skin imaged at each time point. Results are shown as percentage change of pERK from vehicle using the formula described in the Methods section. mpk, milligrams per kilogram; TGI, tumor growth inhibition; REG; regression; Veh, drug vehicle.