title: Pharmacokinetic drug evaluation of ribociclib for the treatment of metastatic, hormone-positive breast cancer.
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.
authors.affiliation: a Early Drugs Development for Innovative Therapies Division , European Institute of Oncology , Milan , Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Curigliano
authors.affiliation: a Early Drugs Development for Innovative Therapies Division , European Institute of Oncology , Milan , Italy.
authors.forename: Carmen
authors.initials: C
authors.lastname: Criscitiello
authors.affiliation: a Early Drugs Development for Innovative Therapies Division , European Institute of Oncology , Milan , Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Esposito
authors.affiliation: b Division of Senology , European Institute of Oncology , Milan , Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Intra
authors.affiliation: a Early Drugs Development for Innovative Therapies Division , European Institute of Oncology , Milan , Italy.|c School of Medicine , University of Milano , Milan , Italy.
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
mesh_terms: D000631:Aminopyridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D009362:Neoplasm Metastasis; D011687:Purines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D011687:Purines; D018719:Erb-b2 Receptor Tyrosine Kinases; C495900:CDK4 protein, human; C495911:CDK6 protein, human; C000589651:ribociclib
keywords: CDK 4/6 pathway; hormone receptor positive; metastatic breast cancer; pharmacodynamics; pharmacokinetics; ribociclib