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Tyrosine Kinase Inhibitors: Their On-Target Toxicities as Potential Indicators of Efficacy

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Abstract

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of certain forms of cancers, raising hopes for many patients with otherwise unresponsive tumours. While these agents are generally well tolerated, clinical experience with them has highlighted their unexpected association with serious toxic effects on various organs such as the heart, lungs, liver, kidneys, thyroid, skin, blood coagulation, gastrointestinal tract and nervous system. Many of these toxic effects result from downstream inhibition of vascular endothelial growth factor or epidermal growth factor signalling in cells of normal organs. Many of these undesirable effects such as hypertension, hypothyroidism, skin reactions and possibly proteinuria are on-target effects. Since tyrosine kinases are widely distributed with specific functional roles in different organs, this association is not too surprising. Various studies suggest that the development of these on-target effects indicates clinically desirable and effective inhibition of the corresponding ligand-mediated receptor linked with oncogenesis. This is reflected as improved efficacy in the subgroup of patients who develop these on-target adverse effects compared with those who do not. Inevitably, issues arise with respect to the regulatory assessment of efficacy and risk/benefit of the TKIs as well as the clinical approach to managing patients who develop these effects. Routine subgroup analysis of efficacy data from clinical trials (patients with and without on-target toxicity) may enable more effective clinical use of TKIs since (i) discontinuing or reducing the dose of the TKI has a negative impact if the tumour is TKI-responsive; and (ii) it is usually possible to manage these undesirable on-target effects with conventional clinical approaches. Prospective studies are needed to investigate this proposition further.

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Acknowledgements

The views expressed in this paper are those of the authors and do not necessarily reflect the views or opinions of their affiliates, any regulatory authorities or any of their advisory bodies.

The authors have not received any financial support for writing this commentary. Devron Shah is a first-year house officer at a district general hospital and has no consultancy relationships. 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. Joel Morganroth is the Chief Cardiac Consultant to eResearchTechnology Inc (eRT), Philadelphia, PA, USA, which provides cardiac safety services to the drug development community. Both Rashmi Shah and Joel Morganroth now provide expert consultancy services on the development of new drugs to a number of pharmaceutical companies.

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

    Devron R. Shah & Rashmi R. Shah

  2. eResearch Technology, Philadelphia, PA, USA

    Joel Morganroth

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  1. Devron R. Shah
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  2. Rashmi R. Shah
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Correspondence to Rashmi R. Shah.

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Shah, D.R., Shah, R.R. & Morganroth, J. Tyrosine Kinase Inhibitors: Their On-Target Toxicities as Potential Indicators of Efficacy. Drug Saf 36, 413–426 (2013). https://doi.org/10.1007/s40264-013-0050-x

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