Palbociclib as Initial Endocrine-Based Therapy in Postmenopausal Women With Metastatic Breast Cancer

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Combination Treatment With Palbociclib for Metastatic Breast Cancer

In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.


On February 3, 2015, palbociclib (Ibrance) was granted accelerated approval for use in combination with letrozole in treatment of postmenopausal women with estrogen receptor–positive, HER2-negative advanced breast cancer as initial endocrine-based therapy for metastatic disease.1,2 Continued approval for this indication may be contingent upon verification of benefit in a confirmatory trial.

Supporting Trial

Approval was based on the finding of prolonged progression-free survival with the addition of palbociclib to letrozole in an open-label phase II trial.2,3 In the trial, 165 patients with no prior systemic treatment for metastatic disease were randomized to receive oral palbociclib 125 mg/d for 21 days followed by 7 days off treatment plus letrozole 2.5 mg/d continuously throughout the 28-day cycle (n = 84) or letrozole alone (n = 81). Overall, 43% of patients had received chemotherapy, 33% had received antihormonal therapy as neoadjuvant or adjuvant treatment, and 49% had no prior systemic neoadjuvant or adjuvant treatment; 98% of patients had metastatic disease, 48% had visceral disease, 75% had bone disease, and 19% had bone-only disease.

Median investigator-assessed progression-free survival was 20.2 months (95% confidence interval [CI] = 13.8–27.5 months) in the palbociclib plus letrozole group vs 10.2 months (95% CI = 5.7–12.6 months) in the letrozole group (hazard ratio [HR] = 0.488, 95% CI = 0.319–0.748). A positive effect of palbociclib-letrozole vs letrozole was supported by a retrospective independent radiographic review (HR = 0.621, 95% CI = 0.378–1.019). Among patients with measurable disease, investigator-assessed objective response rate was 55.4% vs 39.4%.

How It Works

Palbociclib is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6. Cyclin D1 and CDK4/6 are downstream of signaling pathways that induce cellular proliferation. In studies in vitro, palbociclib reduced cellular proliferation of estrogen receptor–positive breast cancer cell lines by blocking progression from the G1 into the S phase of the cell cycle.

Treatment of breast cancer cell lines with the combination of palbociclib and an antiestrogen led to decreased retinoblastoma protein (Rb) phosphorylation, reduced expression and signaling of transcription factor E2F, and increased growth arrest compared with treatment with each drug alone. In patient-derived estrogen receptor–positive breast cancer xenograft models, the combination of palbociclib and letrozole increased inhibition of Rb phosphorylation, downstream signaling, and tumor growth vs each drug alone.

How It Is Given

The recommended dose of palbociclib is 125 mg/d for 21 consecutive days followed by 7 days off treatment in each 28-day cycle in combination with letrozole 2.5 mg/d given continuously. Dose modifications are permitted for management of adverse events, with a first reduction to 100 mg/d and a second to 75 mg/d.

For hematologic adverse events, no dose adjustment is necessary for grade 3 events. Repeating complete blood cell count at 1 week can be considered, and the next cycle should be withheld until recovery to grade ≤ 2. For grade 3 neutropenia with fever/infection and for grade 4 events, palbociclib should be withheld until recovery to grade ≤ 2 and restarted at the next lower dose.

For grade ≥ 3 nonhematologic toxicity, palbociclib should be withheld until recovery to grade 1 (or grade 2 if no safety risk to patient) and restarted at the next lower dose.

Concomitant use of strong CYP3A inhibitors (eg, clarithromycin, indinavir, ketoconazole), should be avoided with palbociclib. If one must be used, the palbociclib dose should be reduced to 75 mg/d. If the strong inhibitor is discontinued, the palbociclib dose should be increased to the prior dose after three to five half-lives of the inhibitor.

Due to the risk of hematologic toxicity with palbociclib, complete blood cell count should be monitored prior to the start of treatment, at the beginning of each cycle, on day 14 of the first two cycles, and as clinically indicated. Patients should be monitored for infection, with dosing withheld as appropriate.

Safety Profile

In the phase II trial, the median duration of treatment was 13.8 months for palbociclib and 7.8 months for letrozole in the letrozole-alone group. The most common nonhematologic adverse events of any grade with palbociclib-letrozole were fatigue (41% vs 23% in the letrozole-alone group), upper respiratory infection (31% vs 18%), stomatitis (25% vs 7%), and nausea (25% vs 13%); the most common grade 3 or 4 event was diarrhea (4% grade 3 vs 0%). Any grade 3 or 4 hematologic adverse event rates in the combination group were 75% and 54% for neutropenia (vs 5% and 1% in the letrozole-alone group), 43% and 19% for leukopenia (vs 3% and 0%), 35% and 6% for anemia (vs 7% and 1%), and 17% and 2% for thrombocytopenia (vs 1% and 0%).

The most frequently reported serious adverse events in the palbociclib-letrozole group were pulmonary embolism (4%) and diarrhea (2%). Adverse events led to dose reduction in 36% of patients receiving the combination and treatment discontinuation in 8% (neutropenia in 6%, asthenia in 1%, fatigue in 1%) vs 3%. Infection was observed in 55% vs 34% of patients. Febrile neutropenia has been observed in patients in the palbociclib clinical program, but no cases were observed in the current trial.

Palbociclib carries warnings/precautions for hematologic adverse events, infections, and embryo-fetal toxicity. ■


1. U.S. Food and Drug Administration: Drug approvals: Palbociclib. Available at Accessed February 19, 2015.

2. Ibrance (palbociclib capsule) prescribing information, Pfizer, Inc, February 2015. Available at Accessed February 19, 2015.

3. Finn RS, Crown JP, Lang I, et al: The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): A randomised phase 2 study. Lancet Oncol 16:25-35, 2015.


Report Adverse Events

Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).