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Review |

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

Amy S. Clark, MD, MSCE1,2; Thomas B. Karasic, MD2; Angela DeMichele, MD, MSCE1,2,3,4; David J. Vaughn, MD1,2; Mark O’Hara, MD1,2; Rodolfo Perini, MD1,4; Paul Zhang, MD5; Priti Lal, MD5; Michael Feldman, MD, PhD5; Maryann Gallagher, RN1; Peter J. O’Dwyer, MD1,2
[+] 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
JAMA Oncol. 2016;2(2):253-260. doi:10.1001/jamaoncol.2015.4701.
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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.

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Figure 1.
Biological Roles of CDK4/6

In the cell cycle, cyclin-dependent kinase (CDK) 4/6 complexes with cyclin D and phosphorylates retinoblastoma (Rb), causing transcription of E2F and progression through the cell cycle. Non–cell-cycle effects include direct activation of vascular endothelial growth factor (VEGF) transcription, thus promoting angiogenesis and nuclear factor (NF)-κB activation via the p65 transcription factor. P indicates phosphorus.

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Figure 2.
Fluorothymidine (FLT) Positron Emission Tomography (PET)/PET–Computed Tomography Images From a Patient With Metastatic Colorectal Cancer

Baseline pretreatment images show radiotracer uptake in the right upper lobe lung nodule (arrowheads). Posttreatment images reveal interval decrease in tracer uptake (arrowheads). The activity in vertebral body, sternum, ribs, and proximal humeri represents the physiologic distribution of FLT and denotes the proliferation of hematopoietic cells.

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