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 + letrozole: Established efficacy in first line

Efficacy
Adverse
Reactions
Warnings &
Precautions

PALOMA-2 Primary Endpoint| Secondary Endpoints| Forest Plot | PALOMA-1

PALOMA-2 Primary Endpoint

In a randomized, double-blind, Phase 3 trial of postmenopausal women with ER+/HER2- MBC (N=666)1

IBRANCE + letrozole demonstrated a compelling 10-month mPFS improvement vs placebo + letrozole

CI=confidence interval; ER=estrogen receptor; HR=hazard ratio; IBR=IBRANCE; ITT=intent to treat; LET=letrozole; mPFS=median progression-free survival; MBC=metastatic breast cancer; NE=not estimable; PLB=placebo; PFS=progression-free survival.

  • 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

The treatment effect of IBRANCE + letrozole on PFS was also supported by an independent review of radiographs1

In a blinded, independent central review of PFS (a secondary analysis) in the ITT population

vs. 19.3 months with placebo + letrozole (n=222)
(95% CI: 24.7-NE vs 16.4-30.6); HR=0.65 (95% CI: 0.51-0.84)

Secondary Endpoints

  • ORR*: 55.3% (95% CI: 49.9-60.7) of patients with measurable disease achieved an objective response with IBRANCE + letrozole vs 44.4% (95% CI: 36.9-52.2) with placebo + letrozole (IBRANCE + letrozole n=338; placebo + letrozole n=171)
  • At the time of final analysis of PFS, overall survival data were not mature in PALOMA-2. Patients will continue to be followed for the final analysis

ORR=overall response rate.

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

IBRANCE + letrozole as initial MBC therapy delays the need for later lines of treatment, including hormonal agents and chemotherapies

PALOMA-2 Forest Plot

Preplanned subgroup analyses for PFS

Consistent results were observed across patient subgroups of disease-free interval, disease site, and prior therapy1,2

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.

Broad approval: First-line IBRANCE + aromatase inhibitor

The FDA has approved IBRANCE for first-line use with any aromatase inhibitor for postmenopausal women with HR+/HER2- MBC

First-line palbociclib (IBRANCE) + letrozole is a category 1 treatment recommendation from NCCN® for postmenopausal women with HR+/HER2- MBC3*

NCCN®=National Comprehensive Cancer Network®.

*Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.3

If there is disease progression while on a CDK4/6 inhibitor + letrozole, there are no data to support an additional line of therapy with another palbociclib regimen.3

PALOMA-1

In a randomized, open-label, Phase 2 trial of postmenopausal women with ER+/HER2- MBC (N=165)4

Compelling 10-month improvement in median progression-free survival

Primary endpoint

  • mPFS was 20.2 months (95% CI: 13.8-27.5) with IBRANCE + letrozole vs 10.2 months (95% CI: 5.7-12.6) with letrozole alone
  • HR=0.49 (95% CI: 0.32-0.75)
  • 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 endpoints2,4

  • ORR*: 55.4% (95% CI: 42.5-67.7) with IBRANCE + letrozole vs 39.4% (95% CI: 27.6-52.2) with letrozole alone in the measurable disease population (IBRANCE + letrozole n=65; letrozole alone n=66)
  • Overall survival (OS): A final OS analysis was conducted with 116 events having occurred. These data show a numerical improvement in favor of IBRANCE + letrozole vs letrozole alone that did not reach statistical significance

–   Median OS was 37.5 months (95% CI: 31.4 - 47.8) with IBRANCE + letrozole vs 34.5 months (95% CI: 27.4 - 42.6) for letrozole alone (HR=0.897 [95% CI: 0.623 - 1.294]; P=0.281)

*ORR was defined as the number (%) of patients with confirmed complete response or partial response.4

Next: Adverse Reactions >
Once-daily oral dosing with IBRANCE
IBRANCE + fulvestrant:
Efficacy and 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.
3. Referenced with permission from NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.2.2017. © National Comprehensive Cancer Network, Inc. 2017. All rights reserved. Accessed April 11, 2017. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
4. 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.

PALOMA-2| PALOMA-1| Neutropenia| Lab Abnormalities

Adverse Reactions (≥10%) Reported in PALOMA-2

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

 
IBRANCE + letrozole (n=444)
placebo + letrozole (n=222)
ADVERSE REACTION
All
Grades
(%)
Grade 3
(%)
Grade 4
(%)
All
Grades
(%)
Grade 3
(%)
Grade 4
(%)
INFECTIONS AND INFESTATIONS
Infections*
60
6
1
42
3
0
BLOOD AND LYMPHATIC SYSTEM DISORDERS
Neutropenia
80
56
10
6
1
1
Leukopenia
39
24
1
2
0
0
Anemia
24
5
<1
9
2
0
Thrombocytopenia
16
1
<1
1
0
0
METABOLISM AND NUTRITION DISORDERS
Decreased appetite
15
1
0
9
0
0
NERVOUS SYSTEM DISORDERS
Dysgeusia
10
0
0
5
0
0
GASTROINTESTINAL DISORDERS
Stomatitis
30
1
0
14
0
0
Nausea
35
<1
0
26
2
0
Diarrhea
26
1
0
19
1
0
Vomiting
16
1
0
17
1
0
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Alopecia
33§
N/A
N/A
16||
N/A
N/A
Rash
18
1
0
12
1
0
Dry skin
12
0
0
6
0
0
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
Fatigue
37
2
0
28
1
0
Asthenia
17
2
0
12
0
0
Pyrexia
12
0
0
9
0
0

N/A=not applicable.
Grading according to Common Terminology Criteria for Adverse Events (CTCAE) 4.0.
*Infections includes all reported preferred terms (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, oral herpes, sinusitis, rhinitis, bronchitis, influenza, pneumonia, gastroenteritis, conjunctivitis, herpes zoster, pharyngitis, cellulitis, cystitis, lower respiratory tract infection, tooth infection, gingivitis, skin infection, gastroenteritis viral, respiratory tract infection, respiratory tract infection viral, and folliculitis.
Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oral discomfort, oropharyngeal pain, and stomatitis.
§Grade 1 events – 30%; Grade 2 events – 3%.
||Grade 1 events – 15%; Grade 2 events – 1%.
Rash includes the following PTs: rash, rash maculo-papular, rash pruritic, rash erythematous, rash papular, dermatitis, dermatitis acneiform, and toxic skin eruption.

Discontinuations and dose reductions due to adverse reactions in PALOMA-21

 
IBRANCE + letrozole
(n=444)
placebo + letrozole
(n=222)
ARs leading to permanent discontinuation of the IBRANCE regimen included:
Neutropenia (1.1%)
ALT increase (0.7%)
N/A
Dose reductions due to an AR of any grade#
36%
1.4%

AR=adverse reaction; ALT=alanine aminotransferase; N/A=not applicable.
#Dose reductions of letrozole were not permitted in PALOMA-2. The dose reductions listed were of IBRANCE or placebo.

Most Common Adverse Reactions in PALOMA-12

  • 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%)

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

  • 8% of patients discontinued IBRANCE + letrozole due to adverse reactions (vs 3% with 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

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