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Update on Cardiovascular Safety of Tyrosine Kinase Inhibitors: With a Special Focus on QT Interval, Left Ventricular Dysfunction and Overall Risk/Benefit

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Abstract

We previously reviewed the cardiovascular safety of 16 tyrosine kinase inhibitors (TKIs), approved for use in oncology as of 30 September 2012. Since then, the indications for some of them have been widened and an additional nine TKIs have also been approved as of 30 April 2015. Eight of these nine are indicated for use in oncology and one (nintedanib) for idiopathic pulmonary fibrosis. This report is an update on the cardiovascular safety of those 16 TKIs, including the post-marketing data concerning their pro-arrhythmic effects, and reviews the cardiovascular safety of the nine new TKIs approved since (afatinib, cabozantinib, ceritinib, dabrafenib, ibrutinib, lenvatinib, nintedanib, ponatinib, and trametinib). As before, we focus on specific aspects of cardiovascular safety, namely their potential to induce QT interval prolongation, left ventricular (LV) dysfunction and hypertension but now also summarise the risks of arterial thromboembolic events (ATEs) associated with these agents. Of the newer TKIs, cabozantinib and ceritinib have been shown to induce a mild to moderate degree of QTc interval prolongation while cardiac dysfunction has been reported with the use of afatinib, dabrafenib, lenvatinib, ponatinib and trametinib. The label for axitinib was revised to include a new association with cardiac dysfunction. Hypertension is associated with cabozantinib, lenvatinib, nintedanib, ponatinib and trametinib. Ponatinib, within 10 months of its approval in December 2012, required voluntary (temporary) suspension of its marketing until significant safety revisions (restricted indication, additional warnings and precautions about the risk of arterial occlusion and thromboembolic events and amended dose) were made to its label. Compared with the previous 16 TKIs, more of the recently introduced TKIs are associated with the risk of LV dysfunction, and fewer with QT prolongation. Available data on morbidity and mortality associated with TKIs, together with post-marketing experience with lapatinib and ponatinib, emphasise the need for effective pharmacovigilance and ongoing re-assessment of their risk/benefit after approval of these novel agents. If not adequately managed, these cardiovascular effects significantly decrease the quality of life and increase the morbidity and mortality in a population already at high risk. Evidence accumulated over the last decade suggests that their clinical benefit, although worthwhile, is modest and extends only to progression-free survival and complete response without any effect on overall survival. During uncontrolled use in routine clinical practice, their risk/benefit is likely to be inferior to that perceived from highly controlled clinical trials.

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Acknowledgments

The authors are grateful to and thank Dr. Ana Szarfman (US FDA) for sparing her valuable time in retrieving and analysing QT-related reports on TKIs from the FAERS database and shown in Table 1.

Compliance with ethical standards

This is a review of data in the public domain, and the authors declare compliance with all ethical standards.

Funding

No sources of funding were used to assist in the preparation of this review.

Conflict of interest

The authors have no conflicts of interest that are directly relevant to the content of this review and have not received any financial support for writing it. Rashmi Shah was formerly a Senior Clinical Assessor at the Medicines and Healthcare products Regulatory Agency (MHRA), London, UK, and the ICH E14 Topic Leader, representing the EU. He now provides expert consultancy services on QT liability of drugs, including TKIs, and development of new drugs to a number of pharmaceutical companies. Joel Morganroth is the Chief Cardiac Consultant to eResearch Technology Inc (eRT), Philadelphia, PA, USA, which provides cardiac safety services to drug development companies and he now provides expert consultancy services on QT liability of drugs, including TKIs, and development of new drugs to a number of pharmaceutical companies.

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  1. Rashmi Shah Consultancy Ltd, 8 Birchdale, Gerrards Cross, Buckinghamshire, SL9 7JA, UK

    Rashmi R. Shah

  2. eResearch Technology, Philadelphia, PA, USA

    Joel Morganroth

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Shah, R.R., Morganroth, J. Update on Cardiovascular Safety of Tyrosine Kinase Inhibitors: With a Special Focus on QT Interval, Left Ventricular Dysfunction and Overall Risk/Benefit. Drug Saf 38, 693–710 (2015). https://doi.org/10.1007/s40264-015-0300-1

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