A Phase II Feasibility Study of Palbociclib in Combination With Adjuvant Endocrine Therapy for Hormone Receptor-Positive Invasive Breast Carcinoma

E. L. Mayer; A. DeMichele; H. S. Rugo; K. Miller; A. G. Waks; S. E. Come; T. Mulvey; R. Jeselsohn; B. Overmoyer; H. Guo; W. T. Barry; C. Huang Bartlett; M. Koehler; E. P. Winer; H. J. Burstein


Ann Oncol. 2019;30(9):1514-1520. 

In This Article

Abstract and Introduction


Background: The CDK4/6 inhibitor palbociclib prolongs progression-free survival in hormone receptor-positive/HER2-negative (HR+/HER2−) metastatic breast cancer when combined with endocrine therapy. This phase II trial was designed to determine the feasibility of adjuvant palbociclib and endocrine therapy for early breast cancer.

Patients and methods: Eligible patients with HR+/HER2− stage II–III breast cancer received 2 years of palbociclib at 125 mg daily, 3 weeks on/1 week off, with endocrine therapy. The primary end point was discontinuation from palbociclib due to toxicity, non-adherence, or events related to tolerability. A discontinuation rate of 48% or higher would indicate the treatment duration of 2 years was not feasible, and was evaluated under a binomial test using a one-sided α = 0.025.

Results: Overall, 162 patients initiated palbociclib; over half had stage III disease (52%) and most received prior chemotherapy (80%). A total of 102 patients (63%) completed 2 years of palbociclib; 50 patients discontinued early for protocol-related reasons (31%, 95% CI 24% to 39%, P = 0.001), and 10 discontinued due to protocol-unrelated reasons. The cumulative incidence of protocol-related discontinuation was 21% (95% CI 14% to 27%) at 12 months from start of treatment. Rates of palbociclib-related toxicity were congruent with the metastatic experience, and there were no cases of febrile neutropenia. Ninety-one patients (56%) required at least one dose reduction.

Conclusion: Adjuvant palbociclib is feasible in early breast cancer, with a high proportion of patients able to complete 2 years of therapy. The safety profile in the adjuvant setting mirrors that observed in metastatic disease, with approximately half of the patients requiring dose-modification. As extended duration adjuvant palbociclib appears feasible and tolerable for most patients, randomized phase III trials are evaluating clinical benefit in this population.


Inhibitors of the CDK4/6 complex have a growing role in oncology care.[1] Preclinical analysis has suggested preferential activity of CDK4/6 inhibitors for luminal hormone receptor-positive (HR+) human breast cancer cell lines.[2] In the preclinical setting, CDK4/6 inhibition decreases retinoblastoma protein (Rb) phosphorylation, leading to an arrest in cellular growth. Additionally, the antiproliferative effects of prolonged CDK4/6 inhibition may trigger irreversible cellular senescence.[2–4]

Palbociclib is an orally available, highly selective inhibitor of CDK4/6 with important clinical activity in HR+ breast cancer. The addition of palbociclib to endocrine therapy significantly improved progression-free survival compared with endocrine therapy alone in either the first-line setting when added to an aromatase inhibitor (AI), or second-line setting when added to fulvestrant.[5–8] Based on those data, palbociclib is FDA-approved and recommended as treatment of metastatic HR+/HER2– breast cancer in combination with endocrine therapy as either first- or second-line therapy.[9] Uncomplicated neutropenia is the most common treatment-related adverse event with palbociclib, with rates of CTCAE Grade 3/4 neutropenia of ~50%. However, febrile neutropenia is exceedingly rare, reflecting the transient and reversible nature of palbociclib-induced cell cycle arrest of bone marrow progenitor cells.[5,10]

Given the significant efficacy and favorable safety profile of palbociclib with endocrine therapy in HR+/HER2– metastatic breast cancer, there is interest in determining whether the observed benefits translate into the adjuvant breast cancer setting. This phase II study was designed to evaluate the feasibility and tolerability of combination treatment with palbociclib plus endocrine therapy in the adjuvant setting for HR+/HER2– early breast cancer.