Cancer Chemotherapy and Pharmacology

, Volume 79, Issue 3, pp 559–568 | Cite as

Effect of alectinib on cardiac electrophysiology: results from intensive electrocardiogram monitoring from the pivotal phase II NP28761 and NP28673 studies

  • Peter N. Morcos
  • Katrijn Bogman
  • Stanislas Hubeaux
  • Carolina Sturm-Pellanda
  • Thorsten Ruf
  • Walter Bordogna
  • Sophie Golding
  • Ali Zeaiter
  • Markus Abt
  • Bogdana Balas
Original Article

Abstract

Purpose

Alectinib, a central nervous system (CNS)-active ALK inhibitor, has demonstrated efficacy and safety in ALK+ non-small-cell lung cancer that has progressed following crizotinib treatment. Other ALK inhibitors have shown concentration-dependent QTc prolongation and treatment-related bradycardia. Therefore, this analysis evaluated alectinib safety in terms of electrophysiologic parameters.

Methods

Intensive triplicate centrally read electrocardiogram (ECG) and matched pharmacokinetic data were collected across two alectinib single-arm trials. Analysis of QTcF included central tendency analysis [mean changes from baseline with one-sided upper 95% confidence intervals (CIs)], categorical analyses, and relationship between change in QTcF and alectinib plasma concentrations. Alectinib effects on other ECG parameters (heart rate, PR interval and QRS duration) were also evaluated.

Results

Alectinib did not cause a clinically relevant change in QTcF. The maximum mean QTcF change from baseline was 5.3 ms observed pre-dose at week 2. The upper one-sided 95% CI was <10 ms at all time points. There was no relevant relationship between change in QTcF and alectinib plasma concentrations. Alectinib treatment resulted in a generally asymptomatic exposure-dependent decrease in mean heart rate of ~11 to 13 beats per minute at week 2. No clinically relevant effects were seen on other ECG parameters. Approximately 5% of patients reported cardiac adverse events of bradycardia or sinus bradycardia; however, these were all grade 1–2.

Conclusions

Alectinib does not prolong the QTc interval or cause changes in cardiac function to a clinically relevant extent, with the exception of a decrease in heart rate which was generally asymptomatic.

Keywords

Alectinib ALK inhibitor NSCLC Cardiac safety ECG data 

Notes

Acknowledgements

Third-party medical writing assistance, under the direction of the authors, was provided by Joanna Musgrove, MRes of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.

Compliance with ethical standards

Conflict of interest

All authors are employees of F. Hoffmann-La Roche Ltd. and have stock in F. Hoffmann-La Roche Ltd.

Supplementary material

280_2017_3253_MOESM1_ESM.docx (17 kb)
Supplementary material 1 (DOCX 16 KB)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Peter N. Morcos
    • 1
  • Katrijn Bogman
    • 2
  • Stanislas Hubeaux
    • 2
  • Carolina Sturm-Pellanda
    • 2
  • Thorsten Ruf
    • 2
  • Walter Bordogna
    • 2
  • Sophie Golding
    • 2
  • Ali Zeaiter
    • 2
  • Markus Abt
    • 2
  • Bogdana Balas
    • 2
  1. 1.F. Hoffmann-La Roche LtdInnovation CenterNew YorkUSA
  2. 2.F. Hoffmann-La Roche LtdBaselSwitzerland

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