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

Drug-induced QTc prolongation is becoming increasingly important in oncology since novel therapies result in prolonged survival of cancer patients already predisposed to cardiotoxicity.

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.

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.

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.