Cardiotoxicity of ErbB2-targeted therapies and its impact on drug development, a spotlight on trastuzumab

ABSTRACT

Introduction: Trastuzumab, a therapeutic monoclonal antibody directed against ErbB2, is often noted as a successful example of targeted therapy. Trastuzumab improved outcomes for many patients with ErbB2-positive breast and gastric cancers, however, cardiac side effects [e.g., left ventricular dysfunction and congestive heart failure (CHF)] were reported in the early phase clinical studies. This finding, subsequently corroborated by multiple clinical studies, raised concerns that the observed cardiotoxicity induced by trastuzumab might adversely impact the clinical development of other therapeutics targeting ErbB family members.

Areas covered: In this review we summarize both basic research and clinical findings regarding trastuzumab-induced cardiotoxicity and assess if there has been an impact of trastuzumab-induced cardiotoxicity on the development of other agents targeting ErbB family members.

Expert opinion: There are a number of scientific gaps that are critically important to address for the continued success of HER2-targeted agents. These include: 1) elucidating the molecular mechanisms contributing to cardiotoxicity; 2) developing relevant preclinical testing systems for predicting cardiotoxicity; 3) developing clinical strategies to identify patients at risk of cardiotoxicity; and 4) enhancing management of clinical symptoms of cardiotoxicity.

KEYWORDS:

• ErbB2-targeted therapies
• cardiotoxicity
• trastuzumab
• HER2/ErbB2-positive breast cancer
• HER2/ErbB2-targeted therapy
• drug development

Article highlights

• Trastuzumab treatment provides considerable therapeutic benefit in HER2-positive breast cancers, but is also associated with cardiotoxicity

• Other drugs have been developed that also target ErbB family members and exhibit varying degrees of cardiotoxicity

• Cardiotoxicity of ErbB2-targeted therapies raises the question if concerns over cardiotoxicity may adversely impact clinical development of other therapeutics targeting this family

• Based on a literature survey of both basic and clinical research findings, the following areas were identified with critical importance to advance discovery of novel ErbB family receptor targeted agents:

  • Elucidation of the molecular mechanisms contributing to cardiotoxicity

  • Development of relevant preclinical testing systems for predicting cardiotoxicity

  • Development of clinical strategies to identify patients at risk of cardiotoxicity

  • Management of clinical symptoms of cardiotoxicity

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Disclaimer

This article reflects the views of the authors and should not be construed to represent FDA’s views or policies.

Acknowledgement

We thank Drs. Chikako Torigoe and Lorraine Pelosof of U.S. FDA for the critical review of this manuscript.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper is funded by the FDA-Office of Women’s Health Research Science Program Award to Wen Ju Wu (Project ID 750912CDR). This project was supported in part by an appointment to the ORISE Research Participation Program at the Center for Drug Evaluation and Research, U.S. Food and Drug Administration, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and FDA.