CDK 4/6 Inhibitor Palbociclib (PD0332991) in Rb+ Advanced Breast Cancer: Phase II Activity, Safety and Predictive Biomarker Assessment
Mené sur 37 patientes atteintes d'un cancer du sein métastatique surexprimant la protéine du rétinoblastome, cet essai de phase II évalue la réponse tumorale et la toxicité du palbociclib
Purpose: The G1/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.