Dr. Debu Tripathy on the CDK4/6 Inhibitor PD 0332991

Debu Tripathy, MD, Co-Leader, Women's Cancer Program, Norris Comprehensive Cancer Center, University of Southern California, discusses a phase II trial that examined the oral cyclin-dependent kinase (CDK) 4 and 6 inhibitor PD 0332991 (991) as a first-line therapy for women with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer.

In general, CDKs are regulated by cyclins and facilitate the cell cycle. The rationale for the trial was based on the observed overproduction of cyclin D in patients with ER-positive breast cancer, Tripathy explains. In general, cyclin D is encoded by the CCND1 gene and interacts with CDK 4 and 6 to moderate cell cycle progression.

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 CCND1 amplification and/or a loss of p16 expression, both indicators of cyclin D abnormality.

The addition of PD 0332991 to letrozole resulted in improved progression-free survival (PFS) between all subgroups of the trial. The median PFS benefit for the combination was 26.1 months compared to 7.5 months for letrozole alone (HR = 0.37; P < .001).

Tripathy notes that toxicities with PD 0332991 did not appear to be significantly greater. The most common adverse event was uncomplicated neutropenia, which was easily managed in the trial.

A randomized phase III trial examining PD 0332991 is scheduled.