TY - JOUR
T1 - CDK 4/6 Inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer
T2 - Phase II activity, safety, and predictive biomarker assessment
AU - DeMichele, Angela
AU - Clark, Amy S.
AU - Tan, Kay See
AU - Heitjan, Daniel F.
AU - Gramlich, Kristi
AU - Gallagher, Maryann
AU - Lal, Priti
AU - Feldman, Michael
AU - Zhang, Paul
AU - Colameco, Christopher
AU - Lewis, David
AU - Langer, Melissa
AU - Goodman, Noah
AU - Domchek, Susan
AU - Gogineni, Keerthi
AU - Rosen, Mark
AU - Fox, Kevin
AU - O'Dwyer, Peter
N1 - Publisher Copyright:
© 2014 American Association for Cancer Research.
PY - 2015/3/1
Y1 - 2015/3/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84928318557&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84928318557&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-14-2258
DO - 10.1158/1078-0432.CCR-14-2258
M3 - Article
C2 - 25501126
AN - SCOPUS:84928318557
SN - 1078-0432
VL - 21
SP - 995
EP - 1001
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 5
ER -