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Evaluation of the potential for QTc prolongation in patients with solid tumors receiving nivolumab

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Abstract

Purpose

The fully human monoclonal antibody nivolumab binds to the programmed death-1 (PD-1) receptor, blocking interactions between PD-1 and its ligands on tumor cells and preventing T cell exhaustion in patients with cancer. The potential for corrected QT interval (QTc) prolongation was assessed in a subset of patients enrolled in a phase 2 dose-ranging study of nivolumab.

Methods

Triplicate 12-lead electrocardiograms (ECGs) obtained predose and post-dose were assessed by an independent ECG core laboratory. QTc derived from Fridericia’s formula (QTcF) was evaluated by central tendency, categorical, and concentration–response analyses.

Results

No patients had QTcF intervals or changes from baseline in QTcF (ΔQTcF) exceeding prespecified thresholds indicating borderline or prolonged QTcF (>480 ms) or ΔQTcF (>60 ms). Among 146 patients randomized to nivolumab 0.3, 2.0, or 10.0 mg/kg every 3 weeks, the maximum increases in mean (±SD) ∆QTcF at any time point were 4.9 (±13.4), 1.2 (±10.1), and 2.0 (±8.9) ms, respectively. There was no relationship between ∆QTcF and nivolumab serum concentration and no association between predicted maximum ∆QTcF and mean maximum nivolumab concentration in any dosage group.

Conclusion

Results of these intensive ECG analyses indicate that nivolumab has no clinically meaningful effect on QTc interval when administered at doses up to 10.0 mg/kg.

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Acknowledgments

Editorial support was provided by Blair Jarvis of inScience Communications, Springer Healthcare (Philadelphia, PA, USA), and funded by Bristol-Myers Squibb (Princeton, NJ, USA).

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Authors and Affiliations

  1. Bristol-Myers Squibb, Route 206 & Province Line Road, Princeton, NJ, 08543, USA

    Shruti Agrawal, Ian Waxman, Amit Roy & Raymond Darbenzio

  2. Bristol-Myers Squibb, Braine-l’Alleud, Belgium

    Alexandre Lambert

Authors
  1. Shruti Agrawal
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  2. Ian Waxman
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  3. Alexandre Lambert
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  4. Amit Roy
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  5. Raymond Darbenzio
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Correspondence to Shruti Agrawal.

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Conflict of interest

All authors are employees of and own stock in Bristol-Myers Squibb.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Agrawal, S., Waxman, I., Lambert, A. et al. Evaluation of the potential for QTc prolongation in patients with solid tumors receiving nivolumab. Cancer Chemother Pharmacol 77, 635–641 (2016). https://doi.org/10.1007/s00280-016-2980-3

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  • DOI: https://doi.org/10.1007/s00280-016-2980-3

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