Richard Finn, MD, Division of Hematology/Oncology at the Jonsson Comprehensive Cancer Center, University of California, Los Angeles, discusses the rationale for targeting cyclin-dependent kinases (CDK) 4 and 6 with the novel agent PD 0332991 in breast cancer.

The CDK4/6 proteins play an important role in regulating cell cycle progression, Finn notes. Preclinical models showed preferential activity in ER-positive breast cancer, including those with HER2-amplification. In both the preclinical and clinical models, the tumor's sensitivity to PD 0332991 was indicated by the presence of an intact retinoblastoma (RB) pathway, which is common in ER-positive tumors. Mechanistically, the inhibition of CDK4/6 prevents the deactivation of the RB tumor suppressor protein.

Following the preclinical work, a phase II study examined PD 0332991 plus letrozole as a treatment for postmenopausal women with ER-positive metastatic breast cancer. The addition of letrozole, a nonsteroidal aromatase inhibitor, was based on preclinical evidence of synergy between PD 0332991 and antiestrogen agents. Overall, the combination of these agents in the phase II trial resulted in an 18.6-month improvement in progression-free survival.

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Richard Finn, MD, from Jonsson Comprehensive Cancer Center, discusses the rationale for targeting cyclin-dependent kinases 4 and 6 with the novel agent PD 0332991 in breast cancer.

Dr. Richard Finn on the Rationale for Targeting CDK4/6

Richard Finn, MD, Division of Hematology/Oncology at the Jonsson Comprehensive Cancer Center, University of California, Los Angeles, describes results from a phase II study that examined PD 0332991, an oral selective inhibitor of cyclin-dependent kinase 4/6, in combination with letrozole as a treatment for postmenopausal women with metastatic ER-positive breast cancer.

In the trial, 165 patients were randomized 1:1 to receive letrozole alone or in combination with PD 0332991. Patients were further stratified into two parts based on molecular characteristics. Part 2 of the study contained patients with CCND1 amplification and/or a loss of p16 expression.

Finn explains that the addition of PD 0332991 to letrozole resulted in a dramatic improvement between all subgroups of the trial. The median progression-free survival (PFS) benefit for the combination was 26.1 months compared to 7.5 months for letrozole alone (HR = 0.37; 

A phase III trial is planned to begin in 2013 to further examine the efficacy of PD 0332991 in breast cancer.

Richard Finn, MD, from the Jonsson Comprehensive Cancer Center, describes results from a phase II study that examined PD 0332991 in combination with letrozole for women with metastatic ER-positive breast cancer.

Richard S. Finn, MD

Articles

Dr. Richard Finn on the Rationale for Targeting CDK4/6

Dr. Finn on PD 0332991 Plus Letrozole in Breast Cancer