On February 19, 2016, palbociclib (Ibrance) was approved for use in combination with fulvestrant (Faslodex) for treatment of hormone receptor–positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy.^1,2 In February 2015, palbociclib in combination with letrozole was granted accelerated approval for treatment of hormone receptor–positive, HER2-negative advanced breast cancer as initial endocrine-based therapy in postmenopausal women.

Supporting Efficacy Data

The current approval is based on results of a double-blind phase III trial (PALOMA3) in which 521 pre- and postmenopausal women with advanced or metastatic disease who had disease progression on or after adjuvant or metastatic endocrine therapy were randomized 2:1 to receive oral palbociclib plus fulvestrant (n = 347) or fulvestrant plus placebo (n = 174) until disease progression or unacceptable toxicity.^2,3 Palbociclib was given at 125 mg/d for 21 days followed by 7 days off treatment; fulvestrant was given intramuscularly at 500 mg on days 1, 15, 29, and once monthly thereafter. Pre- or perimenopausal women received goserelin. The primary endpoint was progression-free survival.

Overall, patients had a median age of 57 years (range = 29–88 years), 74% were white, 80% were postmenopausal, all had received previous systemic therapy, 75% had received previous chemotherapy, 25% had not received previous therapy for metastatic disease, 60% had visceral metastases, and 23% had bone-only disease.

Median progression-free survival was 9.5 months (95% confidence interval [CI] = 9.2–11.0 months) in the palbociclib/fulvestrant group vs 4.6 months (95% CI = 3.5–5.6 months) in the fulvestrant group (hazard ratio = 0.46, P < .0001).

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 to 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 vs treatment with each drug alone. Treatment of estrogen receptor–positive breast cancer cell lines with palbociclib and antiestrogens led to increased cell senescence, which was sustained following drug removal. 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. The recommended dose of fulvestrant in the combination is 500 mg intramuscularly on days 1, 15, 29, and once monthly thereafter. Pre- and perimenopausal women receiving palbociclib/fulvestrant should receive luteinizing hormone–releasing hormone agonists, according to current practice standards.

Palbociclib dose modifications for management of adverse events consist of a first reduction to 100 mg/d and a second to 75 mg/d, with treatment discontinuation thereafter. Complete blood cell counts should be performed prior to treatment, at the start of each cycle, on day 14 of the first 2 cycles, and as clinically indicated. For grade 3 hematologic toxicity on cycle day 1, the drug should be withheld and complete blood cell counts obtained within 1 week; the next cycle can be started at the same dose after recovery to grade ≤ 2. For grade 3 hematologic toxicity on day 14 of the first two cycles, the drug should be continued at the current dose until cycle completion and complete blood cell counts repeated on day 21.

Dose reduction should be considered for prolonged recovery (> 1 week) from or recurrent grade 3 neutropenia. For grade 3 neutropenia with fever or grade 4 hematologic adverse events, the drug should be withheld until recovery to grade ≤ 2, with treatment resumed 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 resumed at the next lower dose.

Concomitant use of strong CYP3A inhibitors (eg, clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole, grapefruit, grapefruit juice) should be avoided. If one of these agents 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 give half-lives of the inhibitor.

Safety Profile

In the phase III trial, the most common adverse events of any grade in the palbociclib/fulvestrant group were neutropenia (83% vs 4%), leukopenia (53% vs 5%), infection (47% vs 31%), fatigue (41% vs 29%), nausea (34% vs 28%), anemia (30% vs 13%), stomatitis (28% vs 13%), headache (26% vs 20%), diarrhea (24% vs 19%), thrombocytopenia (23% vs 0%), and constipation (20% vs 16%). The most common grade 3 or 4 adverse events were neutropenia (66% vs 1%), leukopenia (31% vs 1%), and infection (4% vs 3%).

Grade 3 or 4 laboratory abnormalities in the palbociclib group included leukopenia in 46% (45% grade 3), neutropenia in 67% (56% grade 3), anemia in 3% (all grade 3), and thrombocytopenia in 3% (2% grade 3). The most common serious adverse events in the palbociclib/fulvestrant group were infection (3%), pyrexia (1%), neutropenia (1%), and pulmonary embolism (1%). Adverse events led to dose reduction in 36% of patients in the palbociclib group and discontinuation of treatment in 6%. No fulvestrant dose reductions were permitted in the study.

Palbociclib carries warnings/precautions for neutropenia, pulmonary embolism, and embryofetal toxicity. Complete blood cell counts must be monitored prior to the start of treatment, at the start of each cycle, on day 14 of the first two cycles, and as clinically indicated. Pulmonary embolism was observed in 5% of patients receiving palbociclib/letrozole vs 0% of those receiving letrozole in the trial supporting the 2015 approval and was observed in 1% of palbociclib/fulvestrant patients vs 0% of fulvestrant patients in the trial supporting the current approval. ■

References

1. U.S. Food and Drug Administration: Palbociclib (Ibrance capsules). Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm487080.htm. Accessed March 1, 2016.

2. Ibrance (palbociclib) capsules, for oral use, prescribing information, Pfizer, Inc, February 2016. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/207103s002lbl.pdf. Accessed March 1, 2016.

3. Turner NC, Ro J, André F, et al: Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med 373:209-219, 2015.