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Predictive Immune Modeling of Solid Tumors
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Predictive Immune Modeling of Solid Tumors

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

Stergios J Moschos1, Ryan J Sullivan2, Wen-Jen Hwu3

  • 1Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

JCI Insight
|February 23, 2018
PubMed
Abstract

Insights

MK-8353, an orally available ERK inhibitor, demonstrated antitumor activity in BRAFV600-mutant melanoma patients. Further studies are needed to correlate activity with pharmacodynamic parameters.

Area of Science:

  • Oncology
  • Pharmacology

Background:

  • Constitutive activation of ERK1/2 is implicated in various cancers and MAPK inhibitor resistance.
  • ERK inhibitors offer a potential strategy to overcome resistance to MAPK inhibitors.
  • SCH772984, a dual-mechanism ERK inhibitor, shows preclinical promise in BRAFV600/RAS-mutant cancers.

Purpose of the Study:

  • To develop and evaluate an orally bioavailable ERK inhibitor, MK-8353.
  • To assess the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of MK-8353 in preclinical models and human trials.

Main Methods:

  • MK-8353 was evaluated in preclinical cancer models.
  • Phase I clinical trial (MK-8353-001) in advanced solid tumors and a study in healthy volunteers (P07652) were conducted.
  • Safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity were assessed.

Main Results:

  • MK-8353 showed comparable potency to SCH772984 in preclinical models.
  • Adverse events included diarrhea, fatigue, nausea, and rash. Dose-limiting toxicity was observed at higher doses.
  • Three of fifteen evaluable patients with BRAFV600-mutant melanoma achieved partial response.

Conclusions:

  • MK-8353 is well-tolerated up to 400 mg twice daily.
  • MK-8353 demonstrated antitumor activity in patients with BRAFV600-mutant melanoma.
  • Antitumor activity did not strongly correlate with pharmacodynamic parameters in this study.
Keywords:
CancerClinical TrialsMelanomaOncologySignal transduction

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