On March 31, 2017, palbociclib (Ibrance) was granted regular approval for treatment of hormone receptor–positive, HER2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women.1,2
Palbociclib received accelerated approval in February 2015 for use in combination with letrozole for the treatment of estrogen receptor–positive, HER2-negative advanced breast cancer as initial endocrine-based therapy in postmenopausal women. Palbociclib received regular approval in February 2016 for use in combination with fulvestrant (Faslodex) for the treatment of hormone receptor–positive, HER2-negative advanced or metastatic breast cancer in women with disease progression following endocrine therapy.
Supporting Efficacy Data
The current approval is based on findings in a double-blind phase III trial (PALOMA-2) in which 666 postmenopausal women were randomized 2:1 to receive oral palbociclib at 125 mg once daily for 21 consecutive days followed by 7 days off in each cycle plus letrozole at 2.5 mg once daily (n = 444) or letrozole plus placebo (n = 222).2,3 Treatment continued until disease progression or unacceptable toxicity.
Patients had a median age of 62 years, 78% were white, 98% had an Eastern Cooperative Oncology Group performance status of 0 or 1, 48% had received chemotherapy and 56% had received antihormonal therapy in the neoadjuvant or adjuvant setting prior to diagnosis of advanced breast cancer, 37% had no prior systemic neoadjuvant or adjuvant therapy, and 97% had metastatic disease (including bone-only disease in 23% and visceral disease in 49%).
Median progression-free survival was 24.8 months (95% confidence interval [CI] = 22.1 months to not estimable) in the palbociclib group vs 14.5 months (95% CI = 12.9–17.1 months) in the placebo group (hazard ratio = 0.576, P < .0001). Objective response rates in 338 and 171 patients with measurable disease were 55.3% vs 44.4%, respectively. Overall survival data are not yet mature.
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 palbociclib removal and was greater if antiestrogen treatment was continued. 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. Human bone marrow mononuclear cells treated with palbociclib in the presence or absence of an antiestrogen did not become senescent and resumed proliferation following palbociclib withdrawal.
How It Is Used
The recommended dose of palbociclib is 125 mg once daily given with food for 21 consecutive days followed by 7 days off in each 28-day cycle, given together with the recommended dose of the concomitant aromatase inhibitor.
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.
Monitoring for hematologic toxicities includes obtaining complete blood cell count (CBC) prior to treatment, at the start of each cycle, on day 15 of the first 2 cycles, and as clinically indicated. In patients experiencing grade 1 or 2 neutropenia in the first 6 cycles, CBC should be monitored in subsequent cycles every 3 months, prior to the start of a cycle, and as clinically indicated. For grade 3 hematologic toxicity on cycle day 1, the drug should be withheld and CBC 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 15 of the first 2 cycles, the drug should be continued at the current dose until cycle completion and CBC repeated on day 22.
Dose reduction should be considered for prolonged recovery (> 1 week) from or recurrent grade 3 neutropenia on day 1 of subsequent cycles. For grade 3 neutropenia with fever or infection or grade 4 toxicity at any time, the drug should be withheld until recovery to grade ≤ 2, with treatment resumed at the next lower dose.
For grade ≥ 3 nonhematologic toxicity (persisting despite optimal treatment), 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 [Crixivan], itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir [Viracept], posaconazole [Noxafil], ritonavir, saquinavir [Fortovase], telaprevir, telithromycin [Ketek], 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 3 to 5 half-lives of the inhibitor. Concomitant use of strong CYP3A inducers (eg, phenytoin, rifampin, carbamazepine, enzalutamide [Xtandi], and St John’s wort) should be avoided.
In the phase III trial, the median duration of treatment was 19.8 months in the palbociclib group and 13.8 months in the placebo group. The most common adverse events of any grade in the palbociclib group were neutropenia (80% vs 6% in placebo group), infections (60% vs 42%), leukopenia (39% vs 2%), fatigue (37% vs 28%), nausea (35% vs 26%), alopecia (33% vs 16%), and stomatitis (30% vs 14%). The most common grade 3 or 4 adverse events were neutropenia (66% vs 2%), leukopenia (25% vs 0%), infections (7% vs 3%), and anemia (6% vs 2%). The most common grade 3 or 4 laboratory abnormalities were decreased neutrophils (68% vs 2%), decreased white blood cell count (36% vs 1%), and anemia (6% vs 2%). In the palbociclib group, adverse events led to dose reduction in 36% of patients and permanent treatment discontinuation in 9.7%, including neutropenia in 1.1% and alanine transaminase increase in 0.7%.
Palbociclib carries warnings/precautions for neutropenia and embryofetal toxicity. CBC must be monitored prior to the start of treatment, at the start of each cycle, on day 15 of the first 2 cycles, and as clinically indicated. Patients should be advised of the potential risk to a fetus and to use effective contraception. Patients should not breastfeed during treatment with palbociclib. ■
1. U.S. Food and Drug Administration: Palbociclib (Ibrance). Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm549978.htm. Accessed April 25, 2017.
2. Ibrance (palbociclib) capsules prescribing information, Pfizer, Inc, March 2017. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207103s004lbl.pdf. Accessed April 25, 2017.
3. Finn RS, Martin M, Rugo HS, et al: Palbociclib and letrozole in advanced breast cancer. N Engl J Med 375:1925-1936, 2016.