Challenges of characterizing proarrhythmic risk due to QTc prolongation induced by nonadjuvant anticancer agents

Abstract

Background: Drug-induced QTc prolongation is becoming increasingly important in oncology since novel therapies result in prolonged survival of cancer patients already predisposed to cardiotoxicity. Methods: We review the challenges of implementing the ICH E14 guidance in oncology and propose an integrated approach to QTc risk assessment of nonadjuvant anticancer agents (NAAs), with quantitative outcome criteria. Results: We recommend informed use of non-clinical cardiac safety pharmacology results, some degree of robust ECG assessments in early phase studies, a dedicated QTc study in cancer patients conducted at the appropriate time pre-, peri-, or post-approval (with the design and timing agreed upon with regulatory agencies), and ECG monitoring in late-phase studies commensurate with the outcome of previous QTc studies. Conclusion: The proposed approach would facilitate risk–benefit assessment for NAAs during clinical development and regulatory review, and enable adequate labeling for safe and effective postmarketing use in cancer patients.