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    Real-World Evidence

    Introduction

    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

    Select characteristics of randomized clinical trials and real-world observational studies

    Real-world evidence can complement clinical trial findings by conducting evaluations in a heterogeneous population and among patients who would not have met clinical trial inclusion criteria.1,2

    Randomized clinical trials

    • Designed to show causality3
    • Patients randomly assigned to treatment or comparator3,4
    • Data derived from prespecified, 
      protocol- defined, uniformly 
      ​​​​​​​assessed endpoints
      4
    • Highly monitored, controlled ​​​​​​​environment4
    • Measure the efficacy of an
      ​​​​​​​intervention (i.e., treatment 
      ​​​​​​​performance under highly 
      ​​​​​​​controlled conditions)4

    Real-world observational studies

    • Designed to assess associations and therefore unable to determine causality2-4
    • Patients are not randomized; bias related to treatment selection and unobserved variables cannot be fully addressed2,4
    • Real-world endpoints derived from assessments based on clinical judgment, with variability in patient assessment and adherence4
    • Based on routine clinical practice, with broad patient populations that can result in varied outcomes4
    • Measure the effectiveness of an intervention (i.e., treatment performance under real-world conditions)4

    Observational retrospective analyses are not intended  for direct comparison with clinical trials.

    NEXT: Clinical trial summary

    See the data


    References:
    1. Gyawali B, Parsad S, Feinberg BA, Nablan C. Real-world evidence and randomized studies in the precision oncology era: the right balance. JCO Precis Oncol. 2017;1:1-5. 
    2. DeMichele A, Cristofanilli M, Brufsky A, et al. Comparative effectiveness of first-line palbociclib plus letrozole versus letrozole alone for HR+/HER2– metastatic breast cancer in US real-world clinical practice. Breast Cancer Res. Published online March 24, 2021. doi:10.1186/s13058-021-01409-8 
    3. Khozin S, Blumenthal GM, Pazdur R. Real-world data for clinical evidence generation in oncology. J Natl Cancer Inst. 2017;109(11):1-5. 
    4. Singal AG, Higgins PD, Waljee AK. A primer on effectiveness and efficacy trials. Clin Transl Gastroenterol. 2014;5(1):e45.

    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