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 journalArticle

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Abstract

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
Volume21
Issue number5
DOIs
StatePublished - Mar 1 2015

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Retinoblastoma
Biomarkers
Hormones
Breast Neoplasms
Safety
Disease-Free Survival
G1 Phase Cell Cycle Checkpoints
Retinoblastoma Protein
palbociclib
Vulnerable Populations
Neutropenia
Thrombocytopenia
Anemia
Neoplasms
Research Design
Therapeutics
Confidence Intervals

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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CDK 4/6 Inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer : Phase II activity, safety, and predictive biomarker assessment. / DeMichele, Angela; Clark, Amy S.; Tan, Kay See; Heitjan, Daniel F.; Gramlich, Kristi; Gallagher, Maryann; Lal, Priti; Feldman, Michael; Zhang, Paul; Colameco, Christopher; Lewis, David; Langer, Melissa; Goodman, Noah; Domchek, Susan; Gogineni, Keerthi; Rosen, Mark; Fox, Kevin; O'Dwyer, Peter.

In: Clinical Cancer Research, Vol. 21, No. 5, 01.03.2015, p. 995-1001.

Research output: Contribution to journalArticle

DeMichele, A, Clark, AS, Tan, KS, Heitjan, DF, Gramlich, K, Gallagher, M, Lal, P, Feldman, M, Zhang, P, Colameco, C, Lewis, D, Langer, M, Goodman, N, Domchek, S, Gogineni, K, Rosen, M, Fox, K & O'Dwyer, P 2015, 'CDK 4/6 Inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: Phase II activity, safety, and predictive biomarker assessment', Clinical Cancer Research, vol. 21, no. 5, pp. 995-1001. https://doi.org/10.1158/1078-0432.CCR-14-2258
DeMichele, Angela ; Clark, Amy S. ; Tan, Kay See ; Heitjan, Daniel F. ; Gramlich, Kristi ; Gallagher, Maryann ; Lal, Priti ; Feldman, Michael ; Zhang, Paul ; Colameco, Christopher ; Lewis, David ; Langer, Melissa ; Goodman, Noah ; Domchek, Susan ; Gogineni, Keerthi ; Rosen, Mark ; Fox, Kevin ; O'Dwyer, Peter. / CDK 4/6 Inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer : Phase II activity, safety, and predictive biomarker assessment. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 5. pp. 995-1001.
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abstract = "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.",
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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

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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.

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