P1-17-05: Preliminary Results of a Randomized Phase 2 Study of PD 0332991, a Cyclin-Dependent Kinase (CDK) 4/6 Inhibitor, in Combination with Letrozole for First-Line Treatment of Patients (pts) with Post-Menopausal, ER+, HER2−Negative (HER2–) Advanced Breast Cancer.

Background: PD 0332991 is an orally bioavailable selective inhibitor of CDK 4/6 and prevents cellular DNA synthesis by prohibiting progression of the cell cycle from G1 into the S phase. Preclinical evaluations suggest that reduction in CDKN2A (p16) expression and cyclin D1 (CCND1) overexpression confer susceptibility to PD 0332991 (Finn 2009). In addition, PD 0332991 was synergistic in combination with tamoxifen in vitro in ER+ human breast cancer cell lines. Based on these observations, a phase 1/2 study in combination with letrozole as first-line therapy for advanced ER+ post-menopausal breast cancer was initiated. The phase 1 part of the study (completed) determined the recommended phase 2 dose to be PD 0332991 125 mg QD on Schedule 3/1 (3 weeks on treatment followed by 1-week off treatment) in combination with letrozole 2.5 mg QD. The combination was generally well tolerated and encouraging antitumor activity was observed. We present preliminary data from the randomized Phase 2 portion comparing letrozole alone to letrozole plus PD 0332991. Methods: The Phase 2 portion of the study is designed as a two-part study; we present data from Part 1. In both parts, eligible patients are randomized 1:1 to letrozole 2.5 mg QD alone (control) or PD 0332991 125 mg QD on schedule 3/1 and letrozole 2.5 mg QD (treatment, tx). Part 1enrolled post-menopausal women with ER+, HER2− cancer using only ER+, HER2−as a selection criteria. Part 2 is now enrolling post-menopausal women with ER+, HER2− breast cancer with CCND1 amplification and/or loss of p16 by FISH (target N=150). The primary endpoint is progression-free survival (PFS); secondary endpoints include overall survival, response rate, safety, and correlative studies. Pts are stratified for disease site and length from prior adjuvant therapy. Pts continue assigned study treatment until disease progression, unacceptable toxicity, or consent withdrawal and are followed every 2 months to assess disease status. Tumor tissue was required for participation. Results: 66 patients have been randomized in Part 1. At the time of data cut-off (April 2011) median duration of treatment is 20 (range 4–64) wks for control and 27 (2-59) wks for tx. Dose reductions occurred in 9 pts on the tx arm and none on the control arm. There are no complete responses. The number of partial responses for pts with measurable disease are similar between arms (4/22 control vs 5/24 in tx). The number of pts with stable disease> 24 weeks was higher in the tx arm (5 vs 8). The number of pts with best response of progressive disease is lower in the treatment arm (2 vs 6). PFS data are immature. Twelve pts remain on control vs. 21 on tx. As in the Phase I portion of the study, the most common treatment-related AEs were neutropenia and leucopenia without febrile neutropenia. Biomarker studies for CCND1 amplification, p16 loss, RB status, and Ki67 are ongoing. Conclusion: The combination of PD 0332991 and letrozole is well tolerated as first-line treatment of ER+, HER2− post-menopausal breast cancer. Updated efficacy data and biomarker data will be presented. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-17-05.