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.

Efficacy and Safety Profile

IBRANCE + letrozole: Stronger together in first line

Efficacy
Adverse
Reactions
Warnings &
Precautions

PALOMA-1|PALOMA-2

PALOMA-1

In a randomized, open-label, Phase 2 trial of postmenopausal women with ER+/HER2- MBC (N=165)1

Compelling 10-month improvement in median PFS (mPFS)

Primary endpoint: Investigator-assessed PFS1

  • HR=0.488 (95% CI: 0.319-0.748)
  • Number of PFS events: 41 (48.8%) with IBRANCE + letrozole vs 59 (72.8%) with letrozole alone
  • First-line IBRANCE + letrozole reduced the risk of disease progression by 51% vs letrozole alone

Secondary Endpoints

  • At the time of final analysis of PFS, overall survival data were not mature with 37% of events
  • Overall response rate (ORR)*: 55.4% with IBRANCE + letrozole vs 39.4% with letrozole alone in the measurable disease population (IBRANCE + letrozole n=65; letrozole alone n=66)1

CI=confidence interval; ER=estrogen receptor; HR=hazard ratio; MBC=metastatic breast cancer.

*ORR was defined as the number (%) of patients with complete response or partial response.2

First-line palbociclib (IBRANCE) + letrozole is a treatment option recommended by NCCN® for postmenopausal women with HR+/HER2- MBC (category 2A)3

HER2=human epidermal growth factor receptor 2; HR=hormone receptor; NCCN®=National Comprehensive Cancer Network®.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate. This category 2A recommendation is based on data from PALOMA-1, the Phase 2 trial presented in the IBRANCE Prescribing Information.3


PALOMA-2

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 endpoint: Investigator-assessed PFS4

In a randomized, double-blind, Phase 3 trial of postmenopausal women with ER+/HER2- MBC (N=666)4

Greater than 2 years of mPFS in first line

  • Number of PFS events: 194 (43.7%) with IBRANCE + letrozole vs 137 (61.7%) with placebo + letrozole
  • First-line IBRANCE + letrozole reduced the risk of disease progression by 42% vs placebo + letrozole

IBR=IBRANCE; LET=letrozole; NE=not estimable; PLB=placebo.

IBRANCE + letrozole is the only treatment for HR+/HER2- MBC to demonstrate more than 2 years of mPFS in a Phase 3 trial

Based on a MEDLINE® literature review for Phase 3 trials in HR+/HER2- MBC treatment as of October 2016.

Preplanned Subgroup Analyses for PFS

Consistent results were observed across patient subgroups of disease-free interval, disease site, and prior therapy in PALOMA-22,4

The graph below depicts preplanned subgroup analyses from the overall trial population in PALOMA-2. Small patient numbers can be a limitation of subgroup analyses. These analyses are not intended to demonstrate efficacy in particular subgroups.

Adapted from Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375(20):1925-1936.

ECOG=Eastern Cooperative Oncology Group; ITT=intent to treat.

Secondary Endpoints

ORR* in PALOMA-24

At the time of final analysis of PFS, overall survival data were not mature in PALOMA-2.4

*ORR was defined as the number (%) of patients with complete response or partial response.2

Next: Adverse Reactions >
Once-daily oral dosing with IBRANCE
IBRANCE + fulvestrant:
Efficacy and Safety Profile
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. 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.
4. Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375(20):1925-1936.

Lab Abnormalities | Neutropenia

Most common adverse reactions in PALOMA-1

  • Most common adverse reactions (≥10%) of any grade reported in IBRANCE + letrozole vs letrozole alone were 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%) 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%)

Adverse events (≥10%) reported in PALOMA-2

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.

The adverse events reported in PALOMA-2 were generally consistent with the known adverse reaction profile of IBRANCE1,2

IBRANCE + letrozole
(n=444)
placebo + letrozole
(n=222)
Adverse Event All Grades
(%)
All
Grades
(%)
Grade 3 (%) Grade 4 (%) All Grades
(%)
All
Grades
(%)
Grade 3 (%) Grade 4 (%)
Neutropenia* 80 56 10 6 1 1
Leukopenia 39 24 1 2 0 0
Fatigue 37 2 0 28 1 0
Nausea 35 <1 0 26 2 0
Arthralgia 33 1 0 34 1 0
Alopecia 33 0 0 16 0 0
Diarrhea 26 1 0 19 1 0
Cough 25 0 0 19 0 0
Anemia§ 24 5 <1 9 2 0
Back pain 22 1 0 22 0 0
Headache 21 <1 0 26 2 0
Hot flush 21 0 0 31 0 0
Constipation 19 1 0 15 1 0
Rash|| 18 1 0 12 1 0
Asthenia 17 2 0 12 0 0
Thrombocytopenia 16 1 <1 1 0 0
Vomiting 16 1 0 17 1 0
Pain in extremity 15 <1 0 18 1 0
Stomatitis 15 <1 0 6 0 0
Decreased appetite 15 1 0 9 0 0
Dyspnea 15 1 0 14 1 0
Insomnia 15 0 0 12 0 0
Dizziness 14 1 0 15 0 0
Nasopharyngitis 14 0 0 10 0 0
URTI 13 0 0 11 0 0
Dry skin 12 0 0 6 0 0
Pyrexia 12 0 0 9 0 0
Myalgia 12 0 0 9 0 0
UTI 12 1 0 8 0 0
Abdominal pain 11 1 0 5 0 0
Peripheral edema 11 0 0 6 0 0
Dysgeusia 10 0 0 5 0 0
Dyspepsia 9 0 0 12 1 0
Anxiety 8 0 0 11 0 0

MedDRA=Medical Dictionary for Regulatory Activities; PTs=preferred terms; URTI=upper respiratory tract infection; UTI=urinary tract infection.
*Neutropenia was categorized according to the MedDRA PTs neutropenia and neutrophil count decreased. Febrile neutropenia was reported in 1.8% of patients in the IBRANCE + letrozole arm and in no patients in the placebo + letrozole arm.
Leukopenia was categorized according to the MedDRA PTs leukopenia and white blood cell count decreased.
In the IBRANCE + letrozole arm, 30% of patients had Grade 1 alopecia, and 3% had Grade 2. In the placebo + letrozole arm, 15% of patients had Grade 1 alopecia, and 1% had Grade 2.
§Anemia was categorized according to the MedDRA PTs anemia, hematocrit decreased, and hemoglobin decreased.
||Rash was categorized according to the MedDRA PTs dermatitis, dermatitis acneiform, rash, rash erythematous, rash maculopapular, rash papular, rash pruritic, and toxic skin eruption.
Thrombocytopenia was categorized according to the MedDRA PTs platelet count decreased and thrombocytopenia.

Lab Abnormalities

  • Lab abnormalities occurring in PALOMA-1 (all grades, IBRANCE plus letrozole vs letrozole alone) were decreased white blood cell count (95% vs 26%), decreased neutrophils (94% vs 17%), decreased lymphocytes (81% vs 35%), decreased hemoglobin (83% vs 40%), and decreased platelets (61% vs 16%)
  • Lab abnormalities occurring in PALOMA-2 (all grades, IBRANCE plus letrozole vs placebo + letrozole) were decreased neutrophils (20% vs 3%) and decreased white blood cell count (16% vs 2%)2

Neutropenia

  • Neutropenia was the most frequently reported adverse event in PALOMA-1 (75%) , PALOMA-2 (80%), and PALOMA-3 (83%). Grade ≥3 neutropenia was reported in 62% and 66% of patients receiving IBRANCE + letrozole in PALOMA-1 and PALOMA-2, respectively, and in 66% of patients receiving IBRANCE + fulvestrant in PALOMA-31
  • Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia

  • Febrile neutropenia has been reported in about 1% of patients exposed to IBRANCE in the PALOMA clinical trial program. In PALOMA-2, febrile neutropenia was reported in 1.8% of patients receiving IBRANCE + letrozole. One death due to neutropenic sepsis was observed in the PALOMA clinical trials1
  • Advise patients to immediately report any signs or symptoms of myelosuppression or infection, such as fever, chills, dizziness, shortness of breath, weakness, or any increased tendency to bleed and/or to bruise
  • Primary prophylactic use of granulocyte-colony stimulating factors (GCSFs) was not permitted in PALOMA-1, PALOMA-2, or PALOMA-3, but they could be used to treat treatment-emergent neutropenia, as indicated by the current American Society of Clinical Oncology guidelines2

*Based on PALOMA-1 and PALOMA-3 data presented in the current US Prescribing Information (PI).

Data from PALOMA-2 have not been submitted to or reviewed by the FDA and are not included in the IBRANCE PI. Potential inclusion of these data in the IBRANCE PI has yet to be determined.

Discontinuations and dose reductions due to adverse reactions in PALOMA-1

  • 92% of patients did not discontinue IBRANCE + letrozole due to adverse reactions

–   Permanent discontinuation associated with an adverse reaction occurred in 8% of patients receiving IBRANCE + letrozole vs 3% of patients receiving letrozole alone

  • Adverse reactions leading to discontinuation of IBRANCE + letrozole included neutropenia (6%), asthenia (1%), and fatigue (1%)
  • In PALOMA-1, dose reductions due to adverse reactions of any grade occurred in 36% of patients receiving IBRANCE + letrozole
  • Dose reductions of letrozole were not permitted in PALOMA-1

Discontinuations and dose reductions due to adverse events in PALOMA-21,2

  • 90.3% of patients did not discontinue IBRANCE + letrozole due to adverse events

–   Permanent discontinuation associated with an adverse event occurred in 9.7% of patients receiving IBRANCE + letrozole vs 5.9% of patients receiving placebo + letrozole

  • Adverse events leading to treatment discontinuation included neutropenia (1.1%) and alanine aminotransferase increase (0.7%) in the IBRANCE + letrozole arm and fatigue (0.9%) in the placebo + letrozole arm
  • In PALOMA-2, dose reductions due to adverse events of any grade occurred in 36% of patients receiving IBRANCE + letrozole vs 1.4% of patients receiving placebo + letrozole
  • Dose reductions of letrozole were not permitted in PALOMA-2
Previous: Efficacy
Next: Warnings & Precautions >
IBRANCE + fulvestrant: Safety Profile
REFERENCES
1. Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375(20):1925-1936.
2. Data on file. Pfizer Inc, New York, NY.

Warnings and Precautions

Neutropenia
  • 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 (CBC) prior to starting IBRANCE, at the beginning of each cycle, on Day 14 of the 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
  • 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
Embryo-fetal toxicity
  • 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
Previous: Adverse Reactions
Once-daily oral dosing with IBRANCE