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

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

  • JCI Insight. 2018 Feb 22;3(4):e92352. doi: 10.1172/jci.insight.92352.
Stergios J Moschos 1,  Ryan J Sullivan 2,  Wen-Jen Hwu 3,  Ramesh K Ramanathan 4,  Alex A Adjei 5,  Peter C Fong 6,  Ronnie Shapira-Frommer 7,  Hussein A Tawbi 8,  Joseph Rubino 9,  Thomas S Rush 3rd 9,  Da Zhang 9,  Nathan R Miselis 9,  Ahmed A Samatar 9,  Patrick Chun 9,  Eric H Rubin 9,  James Schiller 9,  Brian J Long 9,  Priya Dayananth 9,  Donna Carr 9,  Paul Kirschmeier 9,  W Robert Bishop 9,  Yongqi Deng 9,  Alan Cooper 9,  Gerald W Shipps 9,  Blanca Homet Moreno 10,  Lidia Robert 10,  Antoni Ribas 10,  Keith T Flaherty 2
Affiliations

Affiliations

  • 1 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
  • 2 Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
  • 3 Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
  • 4 Translational Genomics Research Institute, Phoenix, Arizona, USA; Virginia G. Piper Cancer Center, Scottsdale, Arizona, USA.
  • 5 Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA.
  • 6 The University of Auckland and Auckland City Hospital, Auckland, New Zealand.
  • 7 Department of International Medicine, Chaim Sheba Medical Center, Tel-HaShomer, Israel.
  • 8 University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.
  • 9 Merck & Co. Inc., Kenilworth, New Jersey, USA.
  • 10 Jonsson Comprehensive Cancer Center at UCLA, University of California Los Angeles, Los Angeles, California, USA.
PMID: 29467321 DOI: 10.1172/jci.insight.92352
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).

Keywords

Cancer; Clinical Trials; Melanoma; Oncology; Signal transduction.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-111407
    99.30%, ERK1/2 抑制剂
    ERK
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