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-3 Trial Design

IBRANCE + fulvestrant in women with HR+/HER2- MBC whose disease progressed following endocrine therapy

Trial Design
Patient Characteristics

HER2=human epidermal growth factor receptor 2; HR=hormone receptor; MBC=metastatic breast cancer.

Primary endpoint1: Progression-free survival*
Secondary endpoints1,2: Overall response rate (ORR) and duration of response

PALOMA-3 HR+/HER2- MBC patient population included
Pre/-perimenopausal
Postmenopausal
First line
Later lines
Bone-only disease
Visceral disease
*Evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.
ORR was defined as the number (%) of patients with complete response or partial response.2
Pre-/perimenopausal women enrolled in PALOMA-3 received the luteinizing hormone-releasing hormone (LHRH) agonist goserelin for at least 4 weeks prior to and for the duration of the trial.
IBRANCE + fulvestrant: Efficacy and Safety Profile

REFERENCES
1. Turner NC, Ro J, André F, et al. PALOMA3 Study Group. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med. 2015;373(3):209-219.
2. Data on file. Pfizer Inc, New York, NY.
PALOMA-3 included a broad range of patients
PALOMA-3 included women with varying sites of disease, prior treatment histories, and regardless of menopausal status1,2

IBRANCE + fulvestrant
(n=347)
placebo + fulvestrant
(n=174)
Age, years
Median (min, max) 57 (30, 88) 56 (29, 80)
<65 (%) 75.2 75.3
≥65 (%) 24.8 24.7
Race (%)
White 72.6 76.4
Asian 21.3 17.8
Black or other 5.8 5.2
Menopausal status
Pre-/perimenopausal* 20.7 20.7
Postmenopausal 79.3 79.3
Disease site (%)
Visceral disease 59.4 60.3
Bone only 22.8 20.7
Other 17.8 19.0
Disease-free interval (%)
≤24 months 17.9 18.5
>24 months 79.1 76.6
Prior therapy (%)
Chemotherapy 72.3 79.3
Aromatase inhibitor 85.3 86.8
Tomoxifen 60.8 59.8
Prior lines of MBC therapy (%)
0 24.2 25.9
1 38.0 40.2
2 25.9 24.7
≥3 11.8 9.2

MBC=metastatic breast cancer.
*Pre-/perimenopausal women enrolled in PALOMA-3 received the luteinizing hormone-releasing hormone (LHRH) agonist goserelin for at least 4 weeks prior to and for the duration of the trial.
Other is defined as bone with other nonvisceral disease site or other disease site alone. Bone was the site of disease in 75.8% of patients in the IBRANCE + fulvestrant arm vs 74.1% in the placebo + fulvestrant arm.2
Palbociclib (IBRANCE) + fulvestrant
is the only treatment option to receive a category 1 recommendation from NCCN® for HR+/HER2- MBC3§

HER2=human epidermal growth factor receptor 2; HR=hormone receptor; NCCN®=National Comprehensive Cancer Network®.
§Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.3
IBRANCE + fulvestrant:
Efficacy and Safety Profile
IBRANCE + letrozole:
PALOMA-1 and PALOMA-2 Patient Characteristics

REFERENCES
1. Turner NC, Ro J, André F, et al; PALOMA3 Study Group. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med. 2015;373(3):209-219.
2. Data on file. Pfizer Inc, New York, NY.
3. Referenced with permission from NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.2.2016. © National Comprehensive Cancer Network, Inc. 2016. All rights reserved. Accessed September 13, 2016. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.