On February 19, 2015 Pfizer Inc. (NYSE:PFE) reported that the U.S. Food and Drug Administration (FDA) has approved a new indication expanding the use of IBRANCE (palbociclib) 125mg capsules, Pfizer’s metastatic breast cancer therapy (Press release, Pfizer, FEB 19, 2016, View Source [SID:1234509116]). Now IBRANCE also is approved for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer in combination with fulvestrant in women with disease progression following endocrine therapy.1 Pfizer’s supplemental New Drug Application (sNDA) for IBRANCE was reviewed and approved under the FDA’s Breakthrough Therapy designation and Priority Review programs based on results from the Phase 3 PALOMA-3 trial in pre-, peri- and post-menopausal women with HR+, HER2- metastatic breast cancer whose disease progressed on or after prior endocrine therapy in the adjuvant or metastatic setting.1
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IBRANCE first was approved in February 2015 and also is indicated for the treatment of HR+, HER2- advanced or metastatic breast cancer in combination with letrozole as initial endocrine-based therapy in postmenopausal women.1 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.1 The confirmatory Phase 3 trial, PALOMA-2, is fully enrolled.
IBRANCE is the first and only cyclin-dependent kinase 4/6 (CDK 4/6) inhibitor approved by the FDA.
"Today’s news gives more women with metastatic breast cancer the opportunity to benefit from this first-in-class medicine," said Liz Barrett, global president and general manager, Pfizer Oncology. "Since IBRANCE was approved just over one year ago, physicians across the U.S. have embraced it as a standard of care in the first-line setting. The expanded approval of IBRANCE is supported by a robust body of evidence and underscores Pfizer’s continued commitment to addressing the needs of the metastatic breast cancer community. Pfizer is proud to bring forward innovative therapies like IBRANCE that make a meaningful difference in patients’ lives."
The Phase 3 PALOMA-3 trial enrolled 521 women, regardless of menopausal status, randomized 2:1 to receive IBRANCE plus fulvestrant or placebo plus fulvestrant. This trial demonstrated that IBRANCE in combination with fulvestrant, a standard of care hormonal therapy, prolonged PFS compared with placebo plus fulvestrant in women with HR+, HER2- metastatic breast cancer whose disease progressed on or after prior endocrine therapy.1 Women in the IBRANCE plus fulvestrant arm had a median PFS of 9.5 months (95% CI: 9.2, 11.0), a substantial improvement compared with 4.6 months (95% CI: 3.5, 5.6) in the group treated with placebo plus fulvestrant [HR 0.461 (95% CI: 0.360, 0.591), p <0.0001].1 Confirmed overall response rate in patients with measurable disease as assessed by the investigator was 24.6% for the IBRANCE plus fulvestrant arm compared to 10.9% for the placebo plus fulvestrant arm.1 Duration of response was 9.3 months in the IBRANCE plus fulvestrant arm compared with 7.6 months in the placebo plus fulvestrant arm.1
The warnings and precautions of IBRANCE include neutropenia, pulmonary embolism and embryo-fetal toxicity.1 Themost 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%). For more information, please see Important Safety Information for IBRANCE below.1
"There currently is no cure for metastatic breast cancer, so ongoing treatment is usually needed to control the spread of the disease," said Marisa Weiss, M.D., chief medical officer and founder, Breastcancer.org (link is external). "That’s why the availability of a first-of-its-kind treatment option like IBRANCE for women dealing with HR+, HER2- metastatic disease represents a very important advance."
Both palbociclib (IBRANCE) combination options are recommended by the National Comprehensive Cancer Network.2 Palbociclib plus letrozole is recommended (category 2A) as a first-line treatment for postmenopausal women with HR+, HER2- metastatic breast cancer.2 Palbociclib plus fulvestrant is recommended (category 1) for postmenopausal women with HR+, HER2- metastatic breast cancer who have progressed on endocrine therapy or premenopausal women receiving a luteinizing hormone-releasing hormone (LHRH) agonist.2
Pfizer believes patients should have access to the medications they need, and is committed to ensuring that patients who are prescribed IBRANCE have access to the company’s patient assistance programs. Patients in the U.S. can visit www.PfizerRxPathways.com and www.pfizercopayone.com (link is external) to learn more.
The full prescribing information for IBRANCE can be found at www.pfizer.com.
Important Safety Information
Neutropenia was the most frequently reported adverse reaction in Study 1 (75%) and Study 2 (83%). In Study 1, Grade 3 (57%) or 4 (5%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole. In Study 2, 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 Study 2. 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 Study 1 (5%) and in patients treated with IBRANCE plus fulvestrant in Study 2 (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 Study 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 Study 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 Study 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 Study 2 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 Study 2 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 Study 2 (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).
About IBRANCE (palbociclib) 125mg capsules
IBRANCE is an oral inhibitor of CDKs 4 and 6,1 which are key regulators of the cell cycle that trigger cellular progression.3,4 IBRANCE is indicated for the treatment of HR+, 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.1 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.1