Cardiovascular Safety Assessment in Cancer Drug Development

Abstract

The development of cardiovascular toxicity attributable to anticancer drugs is a pivotal event that is associated with cardiovascular morbidity as well as with worse cancer-specific and overall outcomes. Although broad consensus exists regarding the importance of cardiovascular safety assessment in cancer drug development, real-world data suggest that cardiovascular events are significantly underestimated in oncology trials. This drug safety discrepancy has profound implications on drug development decisions, risk-benefit evaluation, formulation of surveillance and prevention protocols, and survivorship. In this article, we review the contemporary cardiovascular safety evaluation of new pharmaceuticals in hematology and oncology, spanning from in vitro pharmacodynamic testing to randomized clinical trials. We argue that cardiovascular safety assessment of anticancer drugs should be reformed and propose practical strategies, including development and validation of preclinical assays, expansion of oncology trial eligibility, incorporation of cardiovascular end points in early-phase studies, and design of longitudinal multi-institutional cardiotoxicity registries.

Keywords: antineoplastic agents; cardiotoxicity; cardiovascular safety; consensus; randomized controlled trials.

Figure 1. Preclinical tools in the assessment of cardiotoxicity mediated by anticancer drug candidates.

CM indicates cardiomyocytes; hERG, human ether‐a‐go‐go–related Gene; hiPSC, human induced pluripotent stem cells; and hiPSC‐CM, human induced pluripotent stem cell–derived cardiomyocytes.

Figure 2. Framework for optimizing cardiovascular data analysis in oncology trials.

CV indicates cardiovascular; CVD, cardiovascular disease; ECG, electrocardiography; and TTE, transthoracic echocardiography.

Figure 3. Proposed risk‐adapted protocol for cardiovascular safety monitoring in oncology clinical trials.

C‐MRI indicates cardiac magnetic resonance imaging; CV, cardiovascular; CVD, cardiovascular disease; GLS, global longitudinal strain; and TTE, transthoracic echocardiography. *Drug class cardiovascular toxicity (mean incidence>0.5%): non‐serious: hypertension, low‐grade arrhythmia, pericarditis, dyslipidemia; serious: heart failure, cardiogenic shock, ischemic heart disease, high‐grade arrhythmia, myocarditis, hypotension, valvular heart disease, QTc prolongation.

Figure 4. Components of cardiovascular safety assessment in the study of anticancer drugs and suggested interventions to improve early identification of clinically significant cardiotoxicity.

AE indicates adverse events; CV, cardiovascular; CVD, cardiovascular disease; EF, ejection fraction; EMR, electronic medical record; hERG, human ether‐a‐go‐go–related gene; hiPSC‐CM, human induced pluripotent stem cell–derived cardiomyocytes; and GLS, global longitudinal strain.