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February 2016

Palbociclib (PD0332991)—a Selective and Potent Cyclin-Dependent Kinase InhibitorA Review of Pharmacodynamics and Clinical Development

Author Affiliations
  • 1Abramson Cancer Center, Philadelphia, Pennsylvania
  • 2Division of Hematology/Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia
  • 3Center for Clinical Epidemiology and Biostatistics, Philadelphia, Pennsylvania
  • 4Division of Nuclear Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia
  • 5Department of Pathology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia

Copyright 2016 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.

JAMA Oncol. 2016;2(2):253-260. doi:10.1001/jamaoncol.2015.4701

Importance  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.

Evidence Review  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.

Findings  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 and Relevance  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.