title: Palbociclib (PD0332991)-a Selective and Potent Cyclin-Dependent Kinase Inhibitor: A Review of Pharmacodynamics and Clinical Development.
abstract: OBJECTIVE
  Palbociclib (PD0332991) is a newly developed drug that received breakthrough designation and recent US Food and Drug Administration approval in combination with endocrine therapy in the treatment of hormone receptor positive, ERBB2-negative (formerly HER2 or HER2/neu) breast cancer in the first-line metastatic setting.
  
  
  OBJECTIVE
  Herein we describe the preclinical and translational data and early- and late-phase clinical trials in which palbociclib has been investigated in a broad array of tumor types. We discuss the pharmacodynamics, pharmacokinetics, toxic effects, and clinical response rates.
  
  
  METHODS
  On March 1, 2015, we conducted a review of the literature describing the development of palbociclib. We used the PubMed search terms "PD0332991," "palbociclib," and "CDK4/6 inhibitor" to find all published articles of interest, without limitation as to publication date.
  
  
  RESULTS
  Palbociclib is a potent and specific oral cyclin-dependent kinase (CDK) 4/6 inhibitor that has strong preclinical data to support its activity in retinoblastoma protein-expressing tumors. Phase 1 trials have demonstrated safety, and phase 2 trials have shown single-agent activity in mantle-cell lymphoma, breast cancer, liposarcoma, and teratoma with reversible neutropenia as the main toxic effect. Addition of palbociclib to endocrine therapy improves progression-free survival in endocrine therapy-naïve and endocrine therapy-resistant metastatic settings.
  
  
  CONCLUSIONS
  Palbociclib is well tolerated and has therapeutic potential for multiple cancers, including breast cancer, where its efficacy has been demonstrated alone and in combination with endocrine therapy. Additional combinations of palbociclib with endocrine therapy, chemotherapy, and targeted therapy have potential in various tumors, and phase 3 trials are under way.
authors.affiliation: Abramson Cancer Center, Philadelphia, Pennsylvania2Division of Hematology/Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
authors.forename: Amy S
authors.initials: AS
authors.lastname: Clark
authors.affiliation: Division of Hematology/Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Karasic
authors.affiliation: Abramson Cancer Center, Philadelphia, Pennsylvania2Division of Hematology/Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia3Center for Clinical Epidemiology and Biostatistics, Philadelphia, Pennsylvania4Division of Nucl.
authors.forename: Angela
authors.initials: A
authors.lastname: DeMichele
authors.affiliation: Abramson Cancer Center, Philadelphia, Pennsylvania2Division of Hematology/Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Vaughn
authors.affiliation: Abramson Cancer Center, Philadelphia, Pennsylvania2Division of Hematology/Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
authors.forename: Mark
authors.initials: M
authors.lastname: O'Hara
authors.affiliation: Abramson Cancer Center, Philadelphia, Pennsylvania4Division of Nuclear Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Perini
authors.affiliation: Department of Pathology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
authors.forename: Paul
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
authors.forename: Priti
authors.initials: P
authors.lastname: Lal
authors.affiliation: Department of Pathology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
authors.forename: Michael
authors.initials: M
authors.lastname: Feldman
authors.affiliation: Abramson Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Maryann
authors.initials: M
authors.lastname: Gallagher
authors.affiliation: Abramson Cancer Center, Philadelphia, Pennsylvania2Division of Hematology/Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: O'Dwyer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D010879:Piperazines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011725:Pyridines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib