CDK 4/6 Inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: Phase II activity, safety, and predictive biomarker assessment

Angela DeMichele, Amy S. Clark, Kay See Tan, Daniel F. Heitjan, Kristi Gramlich, Maryann Gallagher, Priti Lal, Michael Feldman, Paul Zhang, Christopher Colameco, David Lewis, Melissa Langer, Noah Goodman, Susan Domchek, Keerthi Gogineni, Mark Rosen, Kevin Fox, Peter O'Dwyer

Research output: Contribution to journalArticlepeer-review

270 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)995-1001
Number of pages7
JournalClinical Cancer Research
Issue number5
StatePublished - Mar 1 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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