Abstract
Background
Chemotherapy (CTx) may cause adverse events such as neutropenia, febrile neutropenia (FN), and cardiotoxicity. Lipegfilgrastim is a once-per-cycle, fixed-dose, glycoPEGylated granulocyte colony-stimulating factor (G-CSF) being developed to reduce the duration of neutropenia and the incidence of FN in cancer patients receiving CTx. Pegfilgrastim is a long-acting covalent conjugate of recombinant methionyl human G-CSF and monomethoxypolyethylene glycol currently available to decrease infection, as manifested by FN, in cancer patients receiving myelosuppressive anti-cancer drugs. Cardiovascular events have seldom been reported in patients receiving colony-stimulating factors.
Objective
To evaluate any possible contributions to the electrocardiogram (ECG) effects of CTx after administration of lipegfilgrastim in lung cancer (vs placebo) and breast cancer (vs pegfilgrastim) patients.
Methods
This analysis is based on 2 phase III studies. Lung cancer patients were given lipegfilgrastim 6 mg (n=248) or placebo (n=125) subcutaneously (SC) once per cycle ∼24 h after CTx (cisplatin, 80 mg/m2/etoposide, 120 mg/m2) for a maximum of 4 cycles. Breast cancer patients were given lipegfilgrastim 6 mg (n=101) or pegfilgrastim 6 mg (n=101) SC once per cycle ∼24 h after CTx (doxorubicin, 60 mg/m2/docetaxel, 75 mg/m2) for a maximum of 4 cycles. ECG analysis was performed on all enrolled patients with ≥1 baseline and 1 on-treatment ECG. Monitoring was performed at baseline (∼24 h before CTx, cycle 1), 24 h after study drug administration in cycles 1 and 4, and at the end-of-study visit. ECG measurements included RR, PR, QRS, and QT intervals; derived variables included QTcF (Fridericia’s formula), QTcB (Bazett’s formula), and heart rate (HR). Central tendency analysis compared baseline ECG values with those during cycle 1, 4, and at end of study. Outlier analysis determined if there were any patients with exaggerated effects on ECG intervals not revealed by central tendency analysis. Morphologic analyses were performed with regard to ECG waveform.
Results
Changes from baseline placebo-corrected values (lung cancer patients) or baseline (breast cancer patients) for HR, PR and QRS interval duration were not clinically relevant, with no difference between lipegfilgrastim and pegfilgrastim in breast cancer patients. Mean changes from baseline placebo-corrected QTcF interval duration showed no signal effect for lipegfilgrastim on cardiac repolarization in lung cancer patients. Changes in QTcF interval duration between lipegfilgrastim and pegfilgrastim in breast cancer patients were comparable. There were no bradycardic outliers in lung cancer patients treated with lipegfilgrastim and 1 at the end of study in breast cancer patients. In the lung cancer study, there were 4%, 2%, and 4% tachycardic outliers in cycle 1, 4, and end of study, respectively, for patients treated with lipegfilgrastim versus 4%, 0%, and 2% in patients receiving placebo. In the breast cancer study, there were 0%, 4%, and 2% tachycardic outliers in cycle 1, 4, and end of study, respectively, for patients treated with lipegfilgrastim versus 1%, 2%, and 1% in patients treated with pegfilgrastim. There were no outliers for PR interval duration in either study. In the lung cancer study, there were 2%, 1%, and 2% QRS outliers in cycle 1, 4, and end of study, respectively, for lipegfilgrastim-treated patients versus 1%, 0%, and 0% in patients receiving placebo. There was only 1 QRS outlier in the breast cancer study (lipegfilgrastim-treated patient, cycle 1). New morphologic changes from baseline were in ST segment and negative T wave inversions and considered nonspecific.
Conclusions
There was no clear effect of lipegfilgrastim on HR, AV nodal conduction measured by PR interval duration, cardiac depolarization measured by QRS duration, or morphology, and no clear signal of effect on cardiac repolarization in the lung cancer study. In the breast cancer study, treatment with lipegfilgrastim and pegfilgrastim had no effect on ECG parameters except for nonspecific ST-T changes and a comparable increase in QTcF (cardiac repolarization) in the 10-15 ms range. The lack of ECG effect versus placebo in the lung cancer study along with the presence of potential QTcF changes in the breast cancer study suggest that the changes observed in the breast cancer study may be due to causes other than the G-CSF treatment.
Disclosures:
Lammerich: Merckle/ratiopharm/Teva Pharm Industries: Employment. Müller:Teva Pharmaceuticals, Inc: Employment.
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