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

PURPOSE: The G1-S checkpoint of the cell cycle is frequently dysregulated in breast cancer. 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 breast cancer. EXPERIMENTAL DESIGN: Eligible patients had histologically confirmed, metastatic breast cancer positive for retinoblastoma (Rb) protein and measureable disease. Palbociclib was given at 125 mg orally on days 1 to 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: Thirty-seven 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% confidence interval (CI), 1.9-5.1, but significantly longer for those with HR(+) versus 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%). Twenty-four percent had treatment interruption and 51% had dose reduction, all for cytopenias. No biomarker identified a sensitive tumor population. CONCLUSIONS: Single-agent palbociclib is well tolerated and active in patients with endocrine-resistant, HR(+), Rb-positive breast cancer. Cytopenias were uncomplicated and easily managed with dose reduction.