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    Real-World Evidence

    Clinical trial summary

    Real-world evidence complements data from randomized clinical trials. It is important to understand both the randomized clinical trial results and the limitations of this observational retrospective real-world study.

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    • Review results from PALOMA-2, the randomized clinical trial that evaluated IBRANCE + letrozole in postmenopausal women with estrogen receptor-positive (ER+)/HER2- mBC and no prior treatment in the metastatic setting
    • Understand the limitations of this observational retrospective real-world study: 
      • Observational retrospective database analyses cannot conclude causality, are not intended for direct comparison with randomized controlled trials or other real-world studies, may have missing data or erroneous data entry, and incomplete capture of comorbid conditions and performance status
      • Bias related to treatment selection and unobserved variables may confound these findings 
      • Disease progression was based on the individual treating physician’s clinical assessment or interpretation of radiographic or pathologic results and not on standard criteria, such as Response Evaluation Criteria in Solid Tumors (RECIST)
      • Significant censoring in the OS analysis highlights the need for subsequent evaluation with longer follow-up
      • Subsequent treatment may have impacted OS outcomes, and further research is warranted
      • Subgroup analyses are exploratory and are not sufficiently powered to detect significant differences
      • Findings from the Flatiron Health Analytic Database  should not be generalized to other patient populations 
      • Safety data were not collected as part of the study

    PALOMA-2 randomized clinical trial

    In combination with letrozole, IBRANCE delivered more than 2 years of median progression-free survival (mPFS) in first-line mBC*

    Study design1

    2:1 randomized, double-blind, Phase 3 trial studying IBRANCE + letrozole vs placebo + letrozole in postmenopausal women receiving first-line treatment for estrogen receptor-positive (ER+)/HER2- mBC (N=666)

    Primary endpoint1​​​​​​​

    Investigator-assessed progression-free survival (PFS)

    • 24.8 months of mPFS with IBRANCE + letrozole (n=444; 95% CI: 22.1-not estimable [NE]) vs 14.5 months with placebo + letrozole (n=222; 95% CI: 12.9-17.1); HR=0.58 (95% CI: 0.46-0.72); P<0.0001
    • Number of PFS events: 194 (43.7%) in the IBRANCE + letrozole arm and 137 (61.7%) in the placebo + letrozole arm
    • IBRANCE + letrozole reduced the risk of disease progression or death by 42% vs placebo + letrozole 

    Select secondary endpoints1

    • Objective response rate (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)
    • Overall survival (OS): At the time of final analysis of PFS, OS data were not mature. Patients will continue to be followed for the final analysis

    *   Unless otherwise stated, PALOMA-2 data are based on the February 2016 data cut (final prespecified analysis).1

       PALOMA-2 studied IBRANCE 125 mg PO once daily taken 3 weeks on, 1 week off + letrozole 2.5 mg PO once daily vs placebo + letrozole in postmenopausal women.1

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

    Adverse reactions (ARs) reported in ≥10% of patients in PALOMA-2

         Grading according to Common Terminology Criteria for Adverse Events (CTCAE) version 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.

    ​​​​​​​||   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.​​​​

       Stomatitis includes aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oral discomfort, oropharyngeal pain, and stomatitis.

    #   Rash includes the following PTs: rash, rash maculo-papular, rash pruritic, rash erythematous, rash papular, dermatitis, dermatitis acneiform, and toxic skin eruption.

    Updated non-prespecified analysis of PFS**

    27.6 months of mPFS with IBRANCE + letrozole (n=444; 95% CI: 22.4-30.3) vs 14.5 months with placebo + letrozole (n=222; 95% CI: 12.3-17.1); HR=0.56 (95% CI: 0.46-0.69)2

    • Number of PFS events: 245 (55.2%) in the IBRANCE + letrozole arm and 160 (72.1%) in the placebo + letrozole arm3

    Updated non-prespecified subgroup analyses2

    The graph below depicts subgroup analyses from the overall trial population in an updated non-prespecified PFS analysis of PALOMA-2.** These analyses are considered exploratory. No adjustments were made for multiple comparisons in the subgroup analyses. Small patient numbers can be a limitation of subgroup analyses. These analyses are not intended to demonstrate efficacy in a particular subgroup. 

    IBR=IBRANCE; LET=letrozole; PLB=placebo.

    Selected adverse events (AEs) reported in an updated non-prespecified analysis of PALOMA-22

    ​​​​​​​With an additional 15 months of follow-up, no new safety signals were observed for patients treated with IBRANCE + letrozole.**

    ​​​​​​​The most common selected AEs (≥10%, all causality)†† of any grade reported in an updated non-prespecified analysis of PALOMA-2 for IBRANCE + letrozole vs placebo + letrozole were neutropenia (82% vs 6%), infections (63% vs 45%), leukopenia (40% vs 2%), fatigue (40% vs 28%), nausea (37% vs 27%), alopecia (34% vs 16%), stomatitis (32% vs 15%), diarrhea (28% vs 21%), anemia (26% vs 10%), rash (20% vs 13%), thrombocytopenia (20% vs 1%), asthenia (18% vs 12%), decreased appetite (17% vs 9%), vomiting (17% vs 17%), dry skin (13% vs 7%), pyrexia (13% vs 9%), alanine aminotransferase (ALT) increased (13% vs 6%), aspartate aminotransferase (AST) increased (12% vs 6%), and dysgeusia (10% vs 5%).

    **  Based on May 2017 data cut (non-prespecified analysis), with a median follow-up of 38 months.2

    †† Incidences of AEs reported in this updated non-prespecified analysis are all causality, and the AEs were selected based on their designation as ARs (treatment-related) in PALOMA-2 in the IBRANCE Prescribing Information.2

    Differences between clinical trials and real-world observational studies

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    NEXT: Real-world study design and study limitations 

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    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. Rugo HS, Finn RS, Diéras V, et al. Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up. Breast Cancer Res Treat. 2019;174(3):719-729. 
    3. Data on file. Pfizer Inc., New York, NY.

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    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.

    Severe, life-threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis can occur in patients treated with CDK4/6 inhibitors, including IBRANCE when taken in combination with endocrine therapy. Across clinical trials (PALOMA-1, PALOMA-2, PALOMA-3), 1.0% of IBRANCE-treated patients had ILD/pneumonitis of any grade, 0.1% had Grade 3 or 4, and no fatal cases were reported. Additional cases of ILD/pneumonitis have been observed in the post-marketing setting, with fatalities reported.

    Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis (e.g., hypoxia, cough, dyspnea). In patients who have new or worsening respiratory symptoms and are suspected to have developed pneumonitis, interrupt IBRANCE immediately and evaluate the patient. Permanently discontinue IBRANCE in patients with severe ILD or pneumonitis.

    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 to consider sperm preservation before taking IBRANCE. 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. 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.

    For patients with severe hepatic impairment (Child-Pugh class C), the recommended dose of IBRANCE is 75 mg. The pharmacokinetics of IBRANCE have not been studied in patients requiring hemodialysis

    Please see full Prescribing Information for IBRANCE capsules and tablets.

    IBRANCE (palbociclib) 125 mg capsules and tablets are indicated for the treatment of adult patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (mBC) in combination with:

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

    INDICATIONS

    IBRANCE (palbociclib) 125 mg capsules and tablets are indicated for the treatment of adult patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (mBC) in combination with:

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