CDK 4/6 Inhibitor Palbociclib (PD0332991) in Rb+ Advanced Breast Cancer: Phase II Activity, Safety, and Predictive Biomarker Assessment

Purpose: The G(1)-S checkpoint of the cell cycle is frequently dysregulated in breast cancer (BC). Palbociclib (PD0332991) is an oral inhibitor of CDK4/6. Based upon preclinical/phase I activity, we performed a phase II, single-arm trial of palbociclib in advanced BC. Experimental Design: Eligible patients had histologically confirmed, metastatic BC positive for retinoblastoma (Rb) protein and measureable disease. Palbociclib was given at 125 mg orally on days 1-21 of a 28-day cycle. Primary objectives were tumor response and tolerability. Secondary objectives included progression-free survival (PFS) and assessment of Rb expression/localization, KI-67, p16 loss and CCND1 amplification. Results: 37 patients were enrolled; 84% hormone-receptor (HR)+/Her2-, 5% HR+/Her2(+) and 11% HR-/Her2(-), with a median of 2 prior cytotoxic regimens. Two patients had partial response (PR) and 5 had stable disease >= 6 months for a clinical benefit rate (CBR=PR+6moSD) of 19% overall, 21% in HR+ and 29% in HR+/Her2(-) who had progressed through >= 2 prior lines of hormonal therapy. Median PFS overall was 3.7 months (95% CI 1.9-5.1), but significantly longer for those with HR+ vs. HR- disease (p=0.03) and those who had previously progressed through endocrine therapy for advanced disease (p=0.02). Grade 3/4 toxicities included neutropenia (51%), anemia (5%), and thrombocytopenia (22%). 24% had treatment interruption and 51% had dose reduction, all for cytopenias. No biomarker identified a sensitive tumor population. Conclusion: Single-agent palbociclib is well tolerated and active in patients with endocrine-resistant, hormone-receptor positive, Rb -positive breast cancer. Cytopenias were uncomplicated and easily managed with dose-reduction.