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
  • 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.
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