Important Safety Information and Indications

Neutropenia was the most frequently reported adverse reaction in PALOMA-2 (80%) and PALOMA-3 (83%). In PALOMA-2, Grade 3 (56%) or 4 (10%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole. In PALOMA-3, Grade 3 (55%) or Grade 4 (11%) decreased neutrophil counts were reported in patients receiving IBRANCE plus fulvestrant. Febrile neutropenia has been reported in 1.8% of patients exposed to IBRANCE across PALOMA-2 and PALOMA-3. 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 15 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.

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-2 for IBRANCE plus letrozole vs placebo plus letrozole were neutropenia (80% vs 6%), infections (60% vs 42%), leukopenia (39% vs 2%), fatigue (37% vs 28%), nausea (35% vs 26%), alopecia (33% vs 16%), stomatitis (30% vs 14%), diarrhea (26% vs 19%), anemia (24% vs 9%), rash (18% vs 12%), asthenia (17% vs 12%), thrombocytopenia (16% vs 1%), vomiting (16% vs 17%), decreased appetite (15% vs 9%), dry skin (12% vs 6%), pyrexia (12% vs 9%), and dysgeusia (10% vs 5%).

The most frequently reported Grade ≥3 adverse reactions (≥5%) in PALOMA-2 for IBRANCE plus letrozole vs placebo plus letrozole were neutropenia (66% vs 2%), leukopenia (25% vs 0%), infections (7% vs 3%), and anemia (5% vs 2%).

Lab abnormalities of any grade occurring in PALOMA-2 for IBRANCE plus letrozole vs placebo plus letrozole were decreased WBC (97% vs 25%), decreased neutrophils (95% vs 20%), anemia (78% vs 42%), decreased platelets (63% vs 14%), increased aspartate aminotransferase (52% vs 34%), and increased alanine aminotransferase (43% vs 30%).

The most common adverse reactions (≥10%) of any grade reported in PALOMA-3 for IBRANCE plus fulvestrant vs placebo plus fulvestrant were 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%), diarrhea (24% vs 19%), thrombocytopenia (23% vs 0%), vomiting (19% vs 15%), alopecia (18% vs 6%), rash (17% vs 6%), decreased appetite (16% vs 8%), and pyrexia (13% vs 5%).

The most frequently reported Grade ≥3 adverse reactions (≥5%) in PALOMA-3 for IBRANCE plus fulvestrant vs placebo plus fulvestrant were neutropenia (66% vs 1%) and leukopenia (31% vs 2%).

Lab abnormalities of any grade occurring in PALOMA-3 for IBRANCE plus fulvestrant vs placebo plus fulvestrant were decreased WBC (99% vs 26%), decreased neutrophils (96% vs 14%), anemia (78% vs 40%), decreased platelets (62% vs 10%), increased aspartate aminotransferase (43% vs 48%), and increased alanine aminotransferase (36% vs 34%).

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:

  • an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women, or
  • fulvestrant in women with disease progression following endocrine therapy

Efficacy and Safety Profile

IBRANCE + fulvestrant: Established efficacy in first line or later
Efficacy
Adverse
Reactions
Warnings &
Precautions

Primary Endpoint | Secondary Endpoints |Forest Plot

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 mPFS vs placebo + fulvestrant*

  • 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

*Based on March 2015 data cut (final prespecified analysis).3

Updated non-prespecified mPFS analysis2
  • Number of PFS events: 200 (57.6%) with IBRANCE + fulvestrant vs 133 (76.4%) with placebo + fulvestrant
  • IBRANCE + fulvestrant reduced the risk of disease progression by 50% vs placebo + fulvestrant when used in first line or later

vs. 4.6 months with placebo + fulvestrant (n=174)
(95% CI: 9.5-12.9 vs 3.5-5.6); HR=0.50 (95% CI: 0.40-0.62)

CI = confidence interval; FUL = fulvestrant; HR = hazard ratio; IBR = IBRANCE; mPFS = median progression-free survival; MBC = metastatic breast cancer; PLB = placebo; PFS = progression-free survival.

Based on October 2015 data cut (non-prespecified analysis).2

Secondary Endpoints1
  • ORR*: 24.6% (95% CI: 19.6-30.2) with IBRANCE + fulvestrant vs 10.9% (95% CI: 6.2-17.3) with placebo + fulvestrant in the measurable disease population (IBRANCE + fulvestrant n=267; placebo + fulvestrant n=138)
  • At the time of final analysis of PFS, OS data were not mature. Patients will continue to be followed for the final analysis

FOR A BROAD RANGE OF WOMEN

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

LHRH=luteinizing hormone-releasing hormone; NCCN®=National Comprehensive Cancer Network®; ORR=overall response rate; OS=overall survival.

*ORR was defined as the number (%) of patients with confirmed complete response or partial response.1

Pre-/perimenopausal women enrolled in PALOMA-3 received the LHRH agonist goserelin for at least 4 weeks prior to and for the duration of the trial.

PALOMA-3 Forest Plot

Preplanned subgroup analyses for PFS
Consistent results were observed across patient subgroups of disease site, sensitivity to prior hormonal therapy, and menopausal status3

The graph below depicts preplanned 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.

ITT=intent to treat.

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. Turner NC, André F. Cristofanilli M, et al. Treatment postprogression in women with endocrine-resistant HR+ HER2- advanced breast cancer who received palbociclib plus fulvestrant in PALOMA-3. Poster presented at: 39th Annual San Antonio Breast Cancer Symposium (SABCS); December 6-10, 2016; San Antonio, TX.

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


Adverse Reactions | Neutropenia |Lab Abnormalities

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
4
0
13
2
0
Thrombocytopenia
23
2
1
0
0
0
METABOLISM AND NUTRITION DISORDERS
Decreased appetite
16
1
0
8
1
0
GASTROINTESTINAL DISORDERS
Nausea
34
0
0
28
1
0
Stomatitis
28
1
0
13
0
0
Diarrhea
24
0
0
19
1
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
N/A=not applicable.
Grading according to Common Terminology Criteria for Adverse Events (CTCAE) 4.0.
*Infections includes all reported PTs that are part of the System Organ Class Infections and infestations.
Most common infections (≥1%) include: nasopharyngitis, upper respiratory tract infection, urinary tract infection, bronchitis, rhinitis, influenza, conjunctivitis, sinusitis, pneumonia, cystitis, oral herpes, respiratory tract infection, gastroenteritis, tooth infection, pharyngitis, eye infection, herpes simplex, and paronychia.
Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal discomfort, oropharyngeal pain, 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, toxic skin eruption.
Discontinuations and dose reductions due to adverse reactions1
 
IBRANCE +fulvestrant
(n=345)
placebo + fulvestrant
(n=172)
ARs leading to permanent
discontinuation of the
IBRANCE regimen included:
Fatigue (0.6%)
Infections (0.6%)
Thrombocytopenia (0.6%)
N/A
Dose reductions due to an AR of any grade#
36%
1.7%
AR=adverse reaction.
#Dose reductions of fulvestrant were not permitted in PALOMA-3. The dose reductions listed were of IBRANCE or placebo.

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-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 1.8% of patients exposed to IBRANCE. One death due to neutropenic sepsis was observed across the PALOMA clinical trials
  • 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

Neutropenia management in PALOMA-2 and PALOMA-32

  • Dose reductions or dose modifications due to neutropenia occurred in 24.3% of patients taking IBRANCE + letrozole in PALOMA-2 and 21.2% of patients taking IBRANCE + fulvestrant in PALOMA-3
  • 1.1% of patients discontinued IBRANCE due to neutropenia in PALOMA-2 and no patients discontinued in PALOMA-3

Lab Abnormalities

Lab abnormalities occurring in PALOMA-3 (all grades, IBRANCE plus fulvestrant vs fulvestrant plus placebo) were decreased white blood cells (99% vs 26%), decreased neutrophils (96% vs 14%), anemia (78% vs 40%), decreased platelets (62% vs 10%), increased aspartate aminotransferase (43% vs 48%), and increased alanine aminotransferase (36% vs 34%).

ADVERSE REACTION PROFILE SIMILAR ACROSS TRIALS

The adverse reaction profile of IBRANCE from PALOMA-3 was similar to the profiles in PALOMA-2 and PALOMA-12

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

Warnings and Precautions

NEUTROPENIA
  • Neutropenia was the most frequently reported adverse reaction in PALOMA-2 (80%) and PALOMA-3 (83%). In PALOMA-2, Grade 3 (56%) or 4 (10%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole. In PALOMA-3, Grade 3 (55%) or Grade 4 (11%) decreased neutrophil counts were reported in patients receiving IBRANCE plus fulvestrant
  • Febrile neutropenia has been reported in about 1.8% of patients exposed to IBRANCE across PALOMA-2 and PALOMA-3
  • 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 15 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
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