Important Safety Information and Indications
Neutropenia was the most frequently reported adverse reaction in PALOMA-1 (75%) and PALOMA-3 (83%). In PALOMA-1, Grade 3 (57%) or 4 (5%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole. In PALOMA-3, Grade 3 (56%) or Grade 4 (11%) decreased neutrophil counts were reported in patients receiving IBRANCE plus fulvestrant. Febrile neutropenia has been reported in about 1% of patients exposed to IBRANCE. One death due to neutropenic sepsis was observed in PALOMA-3. Inform patients to promptly report any fever.
Monitor complete blood count prior to starting IBRANCE, at the beginning of each cycle, on Day 14 of first 2 cycles, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.
Pulmonary embolism (PE) has been reported at a higher rate in patients treated with IBRANCE plus letrozole in PALOMA-1 (5%) and in patients treated with IBRANCE plus fulvestrant in PALOMA-3 (1%) compared with no cases in patients treated either with letrozole alone or fulvestrant plus placebo. Monitor for signs and symptoms of PE and treat as medically appropriate.
Based on the mechanism of action, IBRANCE can cause fetal harm. Advise females of reproductive potential to use effective contraception during IBRANCE treatment and for at least 3 weeks after the last dose. IBRANCE may impair fertility in males and has the potential to cause genotoxicity. Advise male patients with female partners of reproductive potential to use effective contraception during IBRANCE treatment and for 3 months after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy. Advise women not to breastfeed during IBRANCE treatment and for 3 weeks after the last dose because of the potential for serious adverse reactions in nursing infants.
The most common adverse reactions (≥10%) of any grade reported in PALOMA-1 of IBRANCE plus letrozole vs letrozole alone included neutropenia (75% vs 5%), leukopenia (43% vs 3%), fatigue (41% vs 23%), anemia (35% vs 7%), upper respiratory infection (31% vs 18%), nausea (25% vs 13%), stomatitis (25% vs 7%), alopecia (22% vs 3%), diarrhea (21% vs 10%), thrombocytopenia (17% vs 1%), decreased appetite (16% vs 7%), vomiting (15% vs 4%), asthenia (13% vs 4%), peripheral neuropathy (13% vs 5%), and epistaxis (11% vs 1%).
Grade 3/4 adverse reactions (≥10%) in PALOMA-1 reported at a higher incidence in the IBRANCE plus letrozole group vs the letrozole alone group included neutropenia (54% vs 1%) and leukopenia (19% vs 0%). The most frequently reported serious adverse events in patients receiving IBRANCE plus letrozole were pulmonary embolism (4%) and diarrhea (2%).
Lab abnormalities occurring in PALOMA-1 (all grades, IBRANCE plus letrozole vs letrozole alone) were decreased WBC (95% vs 26%), decreased neutrophils (94% vs 17%), decreased lymphocytes (81% vs 35%), decreased hemoglobin (83% vs 40%), and decreased platelets (61% vs 16%).
The most common adverse reactions (≥10%) of any grade reported in PALOMA-3 of IBRANCE plus fulvestrant vs fulvestrant plus placebo included neutropenia (83% vs 4%), leukopenia (53% vs 5%), infections (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%), constipation (20% vs 16%), vomiting (19% vs 15%), alopecia (18% vs 6%), rash (17% vs 6%), decreased appetite (16% vs 8%), and pyrexia (13% vs 5%).
Grade 3/4 adverse reactions (≥10%) in PALOMA-3 reported at a higher incidence in the IBRANCE plus fulvestrant group vs the fulvestrant plus placebo group included neutropenia (66% vs 1%) and leukopenia (31% vs 2%). The most frequently reported serious adverse reactions in patients receiving IBRANCE plus fulvestrant were infections (3%), pyrexia (1%), neutropenia (1%), and pulmonary embolism (1%).
Lab abnormalities occurring in PALOMA-3 (all grades, IBRANCE plus fulvestrant vs fulvestrant plus placebo) were decreased WBC (99% vs 26%), decreased neutrophils (96% vs 14%), anemia (78% vs 40%), and decreased platelets (62% vs 10%).
Avoid concurrent use of strong CYP3A inhibitors. If patients must be administered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg/day. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3-5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. Grapefruit or grapefruit juice may increase plasma concentrations of IBRANCE and should be avoided. Avoid concomitant use of strong CYP3A inducers. The dose of sensitive CYP3A substrates with a narrow therapeutic index may need to be reduced as IBRANCE may increase their exposure.
IBRANCE has not been studied in patients with moderate to severe hepatic impairment or in patients with severe renal impairment (CrCl <30 mL/min).
Indications
IBRANCE is indicated for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer in combination with:
  • letrozole as initial endocrine-based therapy in postmenopausal women, or
  • fulvestrant in women with disease progression following endocrine therapy
The indication in combination with letrozole is approved under accelerated approval based on progression-free survival (PFS). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

PALOMA-1 and PALOMA-2 Trial Designs

First-in-class IBRANCE + letrozole in first line
Trial Designs
Patient Characteristics
Based on the data from PALOMA-1, IBRANCE received accelerated approval from the US FDA1
  • PALOMA-1 was a 1:1 randomized, open-label, Phase 2 trial2
  • PALOMA-1 evaluated the efficacy and safety of IBRANCE + letrozole compared with letrozole alone as initial endocrine-based therapy for postmenopausal women with ER+/HER2- MBC (N=165)
  • IBRANCE 125 mg PO was given once daily 3 weeks on, 1 week off + letrozole 2.5 mg once daily vs letrozole alone2

ER=estrogen receptor; HER2=human epidermal growth factor receptor 2; MBC=metastatic breast cancer.

PALOMA-2: Phase 3 trial for first-line IBRANCE + letrozole

Approval of IBRANCE + letrozole is subject to the requirement to conduct an additional, adequate, well-controlled trial to verify the clinical benefit seen in PALOMA-1. Data from PALOMA-2 have not been reviewed by the FDA as of October 2016 and are not included in the IBRANCE Prescribing Information (PI). Potential inclusion of these data in the IBRANCE PI has yet to be determined.


Primary endpoint3: Investigator-assessed PFS
Secondary endpoints3: Overall survival, overall response rate, safety, and tolerability

PALOMA-1 and PALOMA-2 ER+/HER2- MBC patient populations included3
Postmenopausal
First line
Bone-only disease
Visceral disease

PALOMA-2 was designed to assess first-line IBRANCE + letrozole in a Phase 3 setting3
IBRANCE + letrozole: Efficacy and Safety Profile

REFERENCES
1. Pfizer receives U.S. FDA accelerated approval of IBRANCE® (palbociclib) [news release]. New York, NY: Pfizer Inc; February 3, 2015. http://www.pfizer.com/news/press-release/press-release-detail/pfizer_receives_u_s_fda_accelerated_approval_of_ibrance_palbociclib. Accessed September 13, 2016.
2. 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. 2015;16(1):25-35.
3. Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375(20):1925-1936.

Patient populations were generally well balanced in both PALOMA-1 and PALOMA-2.1,2

PALOMA-1: Selected baseline patient characteristics3

IBRANCE + letrozole
(n=84)
letrozole alone
(n=81)
Age, years
Median (min, max) 62.5 (41, 89) 64.0 (38, 84)
<65 (%) 56.0 51.8
≥65 (%) 44.0 48.1
ECOG performance status (%)
0 54.8 55.6
1 45.2 44.4
Disease site (%)
Visceral disease 46.4 49.4
Bone only 20.2 17.3
Other* 33.3 33.3
Disease-free interval (%)
>12 months from the end of adjuvant treatment to disease recurrence 44.1 44.4
≤12 months from the end of adjuvant treatment to disease recurrence or de novo advanced disease 56.0 55.6
Current disease stage (%)
Stage IIIB (locally advanced) 2.4 1.2
Stage IV (metastatic) 97.6 98.8
Systemic therapy prior to MBC diagnosis (%)
No 52.4 45.7
Yes 47.6 54.3
Chemotherapy 40.5 45.7
Antihormonal therapy 32.1 34.6
Other 2.4 0

ECOG=Eastern Cooperative Oncology Group; MBC=metastatic breast cancer.

*Other is defined as bone with other nonvisceral disease site or other disease site alone. Bone was the site of disease in 72.6% of patients in the IBRANCE + letrozole arm vs 76.5% in the letrozole alone arm.3

PALOMA-2: Selected baseline patient characteristics2*

Approval of IBRANCE + letrozole is subject to the requirement to conduct an additional, adequate, well-controlled trial to verify the clinical benefit seen in PALOMA-1. Data from PALOMA-2 have not been reviewed by the FDA as of October 2016 and are not included in the IBRANCE Prescribing Information (PI). Potential inclusion of these data in the IBRANCE PI has yet to be determined.

IBRANCE + letrozole
(n=444)
placebo + letrozole
(n=222)
Age, years
Median (min, max) 62 (30, 89) 61 (28, 88)
<65 (%) 59.2 63.5
≥65 (%) 40.8 36.5
ECOG performance status (%)
0 57.9 45.9
1 40.1 52.7
2 2.0 1.4
Disease site (%)
Visceral 48.2 49.5
Nonvisceral 51.8 50.5
   Bone only 23.2 21.6
Disease-free interval (%)
De novo disease 37.6 36.5
≤12 months 22.3 21.6
>12 months 40.1 41.9
Prior hormonal therapy use in the adjuvant setting (%)
No 43.9 43.2
Yes 56.1 56.8

*Some percentages do not sum to 100 because of rounding.

Disease-free interval was defined as the time from neoadjuvant or adjuvant therapy to recurrence.

Patients who received anastrozole or letrozole as a component of their adjuvant or neoadjuvant therapy were excluded from the study if they had disease progression while receiving the therapy or within 12 months after completing the therapy.2

IBRANCE + letrozole:
Efficacy and Safety Profile
IBRANCE + fulvestrant:
PALOMA-3 Patient Characteristics

REFERENCES
1. 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. 2015;16(1):25-35.
2. Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375(20):1925-1936.
3. Data on file. Pfizer Inc, New York, NY.