QTc prolongation induced by targeted biotherapies used in clinical practice and under investigation: a comprehensive review

Abstract

In anticancer drug development, there has been increasing consideration for the potential of a compound to cause adverse electrocardiographic changes, especially QT interval prolongation, which can be associated with risk of torsades de pointes and sudden death. Irrespective of overt clinical toxicities, QTc assessment can influence decision making during the conduct of clinical studies, including eligibility for protocol therapy, dose delivery or discontinuation, and analyses of optimal dose for subsequent development. Efforts are needed to refine strategies for risk management, avoiding unintended consequences that negatively affect patient access and clinical development of promising new cancer treatments. In this comprehensive review, we will analyze potential effects on QTc prolongations of targeted agents approved by regulatory agencies and under investigation. A thoughtful risk management plan was generated by an organized collaboration between oncologists, cardiologists, and regulatory agencies to support a development program essential for oncology agents with cardiac safety concerns.

Evaluation of Cardiac Repolarization in the Randomized Phase 2 Study of Intermediate- or High-Risk Smoldering Multiple Myeloma Patients Treated with Daratumumab Monotherapy

“…Even if the observed small increase in QTcF does represent a true, drug-induced effect on cardiac repolarization, the small increase in QTcF observed in this substudy is similar to that observed for moxifloxacin, a fluoroquinolone antibacterial agent [28,29], and is well within the range of QTc increases observed for many oncologic agents [30][31][32]. For oncologic agents in general, a QTcF increase with an upper CI below 20 ms is generally not considered to be clinically significant [22].…”

China National Medical Products Administration approval summary: anlotinib for the treatment of advanced non‐small cell lung cancer after two lines of chemotherapy

“…QT interval prolongation was a common ADR of anti-angiogenesis TKIs such as sorafenib, sunitinib, and vandetanib [21]. In the ALTER0303 trial, QT interval prolongation occurred in 77 (26.2%) patients in the anlotinib arm and 27 (18.9%) patients in the placebo arm.…”

Drug–drug interactions in patients receiving tyrosine kinase inhibitors

“…With the notable exceptions of vandetinib, sunitinib, and nilotinib, the majority of TKIs are associated with minor but significant QT prolongation from a drug development standpoint. 14,15 In a comprehensive analysis of regulatory data on the QT liability of TKIs, Shah et al. 14 report larger QT interval aberration with vandetinib, sunitinib, and nilotinib when compared to other TKIs.…”

“…QT prolongation greater than 500 ms is generally accepted as a significant risk factor for ventricular arrhythmias. 16 TKIs are unlikely to cause this degree of QT prolongation alone, 14,15 making drug interactions particularly important in oncology; as many agents coprescribed with TKIs may increase the risk for larger magnitude QT prolongation and by extension, arrhythmic events. 1 Two frequently occurring interactions identified in our analysis (ondansetron and TKI, SSRI and TKI) which may result in additive QT prolongation demonstrate the need for careful assessment of torsadogenic risk in oncology patients being initiated on TKIs.…”