Cardiovascular information

IBRANCE is the first-in-class cyclin-dependent kinase 4/6 (CDK4/6) inhibitor1,2 to have demonstrated >2 years mPFS,3 as seen in the IBRANCE clinical and real-world experience section. In addition, IBRANCE has a well-studied and consistent safety profile.1,3-7 The most frequent (≥20%) AEs of any grade observed across the PALOMA clinical trial programme (based on a pooled dataset from N=872 patients in 3 randomised studies) were:1* neutropenia (716 [82.1%]), infections (516 [59.2%]), leukopenia (424 [48.6%]), fatigue (362 [41.5%]), nausea (314 [36.0%]), stomatitis (264 [30.3%]), anaemia (258 [29.6%]), alopecia (234 [26.8%]) and thrombocytopenia (194 [22.2%]). In all grades, febrile neutropenia and ILD/pneumonitis both occured in 1.4% of patients (n=12).1 While neutropenia was the most frequent AE experienced in the PALOMA clinical trial programme,1 it differs from chemotherapy (CT)-induced neutropenia.4,8 Uncomplicated Neuropenia can be effectively managed without apparent loss of efficacy4 (please refer to the Common adverse events section to see how).

The overall consistent and managaeble1,3,4,7 safety profile of IBRANCE is also true in terms of cardiac safety, having demonstrated no clinically relevant effects on the QT interval corrected for heart rate (QTc) in an analysis of 125 breast cancer patients from the 1st line PALOMA-2 study evaluating the effect of IBRANCE + letrozole on QTc*, where IBRANCE did not prolong the QTc interval to a clinically relevant extent (<8 msec mean change from clock time-matched baseline)†1,9.

Accordingly, IBRANCE does not require electrocardiogram (ECG) monitoring, meaning that full blood counts (FBC) for haematological toxicities are the only regular monitoring requirement in clinical practiceǂ1. Please see the table below for more information on the monitoring requirements for IBRANCE.

IBRANCE monitoring requirements1

 

Additional monitoring may be necessary based on the individual patient and clinical requirements1

*PALOMA-2 was a randomised, double-blind, placebo-controlled, Phase III efficacy study that assessed the safety and efficacy of IBRANCE + letrozole vs letrozole + placebo as 1st line treatment in 666 patients with ER+/HER2- mBC3,9. One of the secondary objectives of the PALOMA-2 study was to characterise the effects of IBRANCE + letrozole at therapeutic doses vs letrozole + placebo on QTc: 76 patients in the IBRANCE+ letrozole arm reported post-baseline ECG data. Routine ECG monitoring for pharmacovigilance and comprehensive QTc evaluation were included: 12-lead (with a 10-second rhythm strip) tracings were performed in triplicate ~2 minutes apart but within 10 minutes for all 3 ECG replicates. On Day 0 (baseline) triplicate ECGs were obtained at time 0, 2, 4, 6, and 8 hours and clock time-matched to Cycle 1 Day 14 (C1D14) time points and on C1D14 (± 2 days), triplicate ECGs clock time-matched to baseline ECG assessments on Day 0 (± 35 min) were obtained9. Patients were excluded from PALOMA-2 if they had myocardial infarction, severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE version 4.0 grade ≥2, atrial fibrillation of any grade, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident including transient ischaemic attack, or symptomatic pulmonary embolism in the previous 6 months, or had taken drugs known to prolong the QT interval within the last 7 days. Patients were also excluded if they had a QTc >480 msec (based on the mean value of the triplicate ECGs), family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or TdP or uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging drug (e.g. hypocalcaemia, hypokalaemia, hypomagnesaemia)10.

Based on a random-effect model to estimate the mean change in ECG parameter data from clock time-matched baseline at each post-baseline nominal time point. Three correction methods for the effect of heart rate on QT interval were included: Bazett’s correction (QTcB), Fridericia’s correction (QTcF), and a study-specific correction factor (QTcS). QTcS provided the best correction, followed by QTcF and QTcB. The QTcS, along with QTcF, were used for QTc analysis data interpretation and conclusion. The results of the QTcB analyses were included for completeness. The upper bounds of the 1-sided 95% CI for the mean change from clock time-matched baseline for QTcF, QTcS, and QTcB were all <8 msec at all post-baseline time points in the QTc assessment period9.

Patients should be monitored for signs and symptoms of infection and treated as medically appropriate1.

References:

  1. IBRANCE® Summary of Product Characteristics.
  2. Kim ES, et al. Target Oncol. 2017;12(3):373-383.
  3. Finn RS, et al. N Engl J Med. 2016;375(20):1925-1936.
  4. Verma S, et al. Oncologist. 2016;21:1165-1175.
  5. Dieras V, et al. SABCS 2016; poster P4-22-07.
  6. Finn RS, et al. Lancet Oncol. 2015;16(1):25-35.
  7. Cristofanilli M, et al. Lancet Oncol. 2016;17(4):425-430.
  8. Hu W, et al. Clin Cancer Res. 2016;22(8):2000-2008.
  9. Ruiz-Garcia A, et al. SABCS 2016; poster P4-22-10.
  10. IBRANCE EPAR Public assessment report. 25 Nov 2016. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003853/WC500217198.pdf. Accessed May 2017

PP-IBR-GBR-2139. December 2019