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

Stronger together with IBRANCE + fulvestrant

Efficacy
Adverse
Reactions
Warnings &
Precautions

Primary Endpoint | Subgroup Analyses for PFS | Secondary Endpoints

Primary Endpoint

In a randomized, double-blind, Phase 3 trial of women with HR+/HER2- MBC whose disease progressed following endocrine therapy (N=521)1

IBRANCE + fulvestrant doubled median progression-free survival (mPFS)

  • Number of PFS events: 145 (41.8%) with IBRANCE + fulvestrant vs 114 (65.5%) with placebo + fulvestrant
  • IBRANCE + fulvestrant reduced the risk of disease progression by 54% vs placebo + fulvestrant when used first line or later

CI=confidence interval; FUL=fulvestrant; HER2=human epidermal growth factor receptor 2; HR (in figure)=hazard ratio; HR (in heading)=hormone receptor; IBR=IBRANCE; MBC=metastatic breast cancer; PLA=placebo.

ACT NOW WITH IBRANCE

Choose IBRANCE + fulvestrant for HR+/HER2- MBC patients whose disease progressed on or after prior endocrine therapy in the adjuvant or metastatic setting

Subgroup Analyses for PFS

Consistent results were observed across patient subgroups of disease site, sensitivity to prior hormonal therapy, and menopausal status2

The graph below depicts subgroup analyses from the overall trial population in PALOMA-3. Small patient numbers can be a limitation of subgroup analyses. These analyses are not intended to demonstrate efficacy in particular subgroups.

Adapted from Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016;17(4):425-439.

Secondary Endpoints

IBRANCE + fulvestrant overall response rate (ORR)

Median duration of response was 9.3 months with IBRANCE + fulvestrant vs 7.6 months with placebo + fulvestrant.

At the time of final analysis of PFS, overall survival data were not mature with 29% of events.

*ORR was defined as the number (%) of patients with complete response or partial response.3

Next: Adverse Reactions >
Once-daily oral dosing with IBRANCE
IBRANCE + letrozole:
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. Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016;17(4):425-439.

3. Data on file. Pfizer Inc, New York, NY.

Lab Abnormalities | Neutropenia

Adverse reactions (≥10%) reported in PALOMA-3

IBRANCE + fulvestrant
(n=345)
placebo + fulvestrant
(n=172)
Adverse Reaction All Grades
(%)
Grade 3
(%)
Grade 4
(%)
All Grades
(%)
Grade 3
(%)
Grade 4
(%)
Infections and infestations
Infections* 47 3 1 31 3 0
Blood and lymphatic system disorders
Neutropenia 83 55 11 4 1 0
Leukopenia 53 30 1 5 1 1
Anemia 30 3 0 13 2 0
Thrombocytopenia 23 2 1 0 0 0
Metabolism and nutrition disorders
Decreased appetite 16 1 0 8 1 0
Nervous system disorders
Headache 26 1 0 20 0 0
Gastrointestinal disorders
Nausea 34 0 0 28 1 0
Stomatitis 28 1 0 13 0 0
Diarrhea 24 0 0 19 1 0
Constipation 20 0 0 16 0 0
Vomiting 19 1 0 15 1 0
Skin and subcutaneous tissue disorders
Alopecia 18 N/A N/A 6§ N/A N/A
Rash|| 17 1 0 6 0 0
General disorders and administration site conditions
Fatigue 41 2 0 29 1 0
Pyrexia 13 <1 0 5 0 0

Grading according to Common Terminology Criteria for Adverse Events (CTCAE) 4.0.
N/A=not applicable.
*Most common infections (>1%) include: nasopharyngitis, upper respiratory infection, urinary tract infection, influenza, bronchitis, rhinitis, conjunctivitis, pneumonia, sinusitis, cystitis, oral herpes, and respiratory tract infection.
Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal discomfort, oropharyngeal pain, and stomatitis.
Grade 1 events: 17%; Grade 2 events: 1%.
§Grade 1 events: 6%.
||Rash includes: rash, rash maculo-papular, rash pruritic, rash erythematous, rash papular, dermatitis, dermatitis acneiform, and toxic skin eruption.

Lab Abnormalities

Lab abnormalities occurring in PALOMA-3 (all grades, IBRANCE plus fulvestrant vs fulvestrant plus placebo) were decreased white blood cell count (99% vs 26%), decreased neutrophils (96% vs 14%), anemia (78% vs 40%), and decreased platelets (62% vs 10%).

ADVERSE REACTION PROFILE SIMILAR ACROSS TRIALS

The adverse reaction profile of IBRANCE from PALOMA-3 was similar to the known adverse reaction profile from PALOMA-11

Neutropenia

  • Neutropenia was the most frequently reported adverse reaction 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-32
  • 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 trials2
  • 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 guidelines3

*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

  • 94% of patients did not discontinue IBRANCE + fulvestrant due to adverse reactions
  • Permanent discontinuation associated with an adverse reaction occurred in 6% of patients receiving IBRANCE + fulvestrant and 3% of patients receiving placebo + fulvestrant
  • Adverse reactions leading to discontinuation of IBRANCE + fulvestrant included fatigue (0.6%), infections (0.6%), and thrombocytopenia (0.6%)
  • In PALOMA-3, dose reductions due to adverse reactions of any grade occurred in 36% of patients receiving IBRANCE + fulvestrant
  • Dose reductions of fulvestrant were not permitted in PALOMA-3
Previous: Efficacy
Next: Warnings & Precautions >
IBRANCE + letrozole: 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. 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.

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