Molecularly Targeted Oncology Therapeutics and Prolongation of the QT Interval

Abstract

Investigation and utilization of molecularly targeted agents has induced a number of drug adverse effects that are not typically associated with conventional chemotherapy. QT interval prolongation, a cardiac toxicity that increases the risk of fatal arrhythmia, is associated with several novel oncology therapies. Classes of molecularly targeted agents with described QT effects include histone deacetylase inhibitors, multitargeted tyrosine kinase inhibitors, vascular disruption agents, farnesyl protein transferase inhibitors, Src/Abl kinase inhibitors, and protein kinase C inhibitors. Concurrently, guidelines for monitoring the QT-prolonging effects of drugs under development have become increasingly rigorous. Although these guidelines apply to anticancer agents, they were not specifically designed for the oncology patient population. This article will review the pathophysiology of QT prolongation, methods of preclinical QT assessment, and current guidelines for QT evaluation in early phase trials. Additionally, molecularly targeted agents with QT effects will be summarized, and mechanisms of addressing this toxicity in the context of oncology drug development will be explored.

A phase II multiple dose clinical trial of histone deacetylase inhibitor ITF2357 in patients with relapsed or progressive multiple myeloma

“…Quite likely, they were related to ITF2357 because they developed after a few weeks of treatment and resolved after drug discontinuation. Similar cardiac abnormalities have also been reported for other HADACIs [20,21]. Only one patient needed anti-arrhythmic therapy for atrial fibrillation, which developed 2 months after the end of ITF2357 treatment.…”

Overview and Management of Cardiac Adverse Events Associated With Tyrosine Kinase Inhibitors

“…Clinical utility of the QT interval to evaluate the risk of cardiac events is imprecise and is limited by the lack of a standardized approach to measurement as well as by intrapatient and interpatient variability, along with numerous other factors that reduce its reliability and predictive value in clinical practice [42]. Specifically, measured values of the QT interval are known to vary according to heart rate, preexisting cardiac disease, sex, diurnal effects, autonomic tone, activity levels, food ingestion, and operator-generated factors (e.g., variability in placement of ECG leads, body position, observer readings) and between automated readings and physician readings [5,[42][43][44]. Several correction formulae have been developed to improve the accuracy of QT measurement with corrected QT (QTc) values (Table 3) [5,[45][46][47][48][49].…”

“…The QT interval recorded on an electrocardiogram (ECG) reflects the total duration of ventricular activation and recovery [5]. Clinical utility of the QT interval to evaluate the risk of cardiac events is imprecise and is limited by the lack of a standardized approach to measurement as well as by intrapatient and interpatient variability, along with numerous other factors that reduce its reliability and predictive value in clinical practice [42].…”

“…Specifically, measured values of the QT interval are known to vary according to heart rate, preexisting cardiac disease, sex, diurnal effects, autonomic tone, activity levels, food ingestion, and operator-generated factors (e.g., variability in placement of ECG leads, body position, observer readings) and between automated readings and physician readings [5,[42][43][44]. Several correction formulae have been developed to improve the accuracy of QT measurement with corrected QT (QTc) values (Table 3) [5,[45][46][47][48][49]. Although these formulae and management strategies have helped reduce the confounding factors in the measurement of the QT interval, these approaches have not been validated with respect to clinical outcomes.…”

“…Some of these agents have improved patient outcomes and transformed the way many types of cancers are treated [2]. Cardiovascular (CV) events, including hypertension, heart failure, left ventricular (LV) systolic dysfunction, and QT prolongation, have emerged as potential adverse events (AEs) with small-molecule TKI therapy [3][4][5][6][7][8]. With a broad population of patients being treated with TKIs as well as increased patient survival and delayed tumor progres-sion from improvements in cancer therapy, prevention and management of TKI-associated CV AEs will become increasingly important [6].…”