TY - JOUR
T1 - Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors
AU - Moschos, Stergios J.
AU - Sullivan, Ryan J.
AU - Hwu, Wen Jen
AU - Ramanathan, Ramesh K.
AU - Adjei, Alex A.
AU - Fong, Peter C.
AU - Shapira-Frommer, Ronnie
AU - Tawbi, Hussein A.
AU - Rubino, Joseph
AU - Rush, Thomas S.
AU - Zhang, Da
AU - Miselis, Nathan R.
AU - Samatar, Ahmed A.
AU - Chun, Patrick
AU - Rubin, Eric H.
AU - Schiller, James
AU - Long, Brian J.
AU - Dayananth, Priya
AU - Carr, Donna
AU - Kirschmeier, Paul
AU - Bishop, W. Robert
AU - Deng, Yongqi
AU - Cooper, Alan
AU - Shipps, Gerald W.
AU - Moreno, Blanca Homet
AU - Robert, Lidia
AU - Ribas, Antoni
AU - Flaherty, Keith T.
PY - 2018/2/22
Y1 - 2018/2/22
N2 - 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).
AB - 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).
KW - Cancer
KW - Clinical Trials
KW - Melanoma
KW - Oncology
KW - Signal transduction
UR - http://www.scopus.com/inward/record.url?scp=85048570173&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85048570173&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.92352
DO - 10.1172/jci.insight.92352
M3 - Article
C2 - 29467321
AN - SCOPUS:85048570173
SN - 2379-3708
VL - 3
JO - JCI Insight
JF - JCI Insight
IS - 4
ER -