Pharmacokinetic drug evaluation of ribociclib for the treatment of metastatic, hormone-positive breast cancer

Expert Opin Drug Metab Toxicol. 2017 May;13(5):575-581. doi: 10.1080/17425255.2017.1318848. Epub 2017 Apr 21.

Abstract

Cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitor of CDK4/6-retinoblastoma (Rb) pathway hyperactivation is associated with hormone receptor-positive (HR+) breast cancer (BC). Ribociclib is an orally bioavailable, highly selective small molecule inhibitor of CDK4/6 that induces G1 arrest at sub-micromolar concentrations in a variety of pRb-positive cancer cells in vitro. Ribociclib is a new standard of care for metastatic HR+/HER2 negative metastatic breast cancer. Area covered: In this article, we review the preclinical and clinical development of ribociclib as well as discussing the role for novel applications of these agents outside the arena of HR-positive, HER2-negative advanced breast cancer. Expert opinion: Results of pivotal phase II and III trials investigating ribociclib in patients with advanced-stage (HR)-positive breast cancer have demonstrated a substantial improvement in progression-free survival, with a safe toxicity profile. Mechanisms of acquired resistance to CDK4/6 inhibitors are beginning to emerge and might enable rational post-CDK4/6 inhibitor therapeutic strategies to be identified. Extending the use of CDK4/6 inhibitors beyond ER-positive breast cancer is challenging, and will likely require biomarkers that are predictive of a response. The use of combination therapies to optimize CDK4/6 targeting is under development.

Keywords: CDK 4/6 pathway; hormone receptor positive; metastatic breast cancer; pharmacodynamics; pharmacokinetics; ribociclib.

Publication types

  • Review

MeSH terms

  • Aminopyridines / administration & dosage*
  • Aminopyridines / adverse effects
  • Aminopyridines / pharmacokinetics
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors
  • Disease-Free Survival
  • Drug Resistance, Neoplasm
  • Female
  • Humans
  • Neoplasm Metastasis
  • Purines / administration & dosage*
  • Purines / adverse effects
  • Purines / pharmacokinetics
  • Receptor, ErbB-2 / metabolism

Substances

  • Aminopyridines
  • Antineoplastic Agents
  • Purines
  • Receptor, ErbB-2
  • CDK4 protein, human
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • ribociclib