Evaluation of the potential for QTc prolongation in patients with solid tumors receiving nivolumab.
The fully human monoclonal antibody nivolumab binds to the programmed death-1 (PD-1) receptor, blocking interactions between PD-1 and its ligands on tumor cells and preventing T cell exhaustion in patients with cancer. The potential for corrected QT interval (QTc) prolongation was assessed in a subset of patients enrolled in a phase 2 dose-ranging study of nivolumab. Triplicate 12-lead electrocardiograms (ECGs) obtained predose and post-dose were assessed by an independent ECG core laboratory. QTc derived from Fridericia's formula (QTcF) was evaluated by central tendency, categorical, and concentration-response analyses. No patients had QTcF intervals or changes from baseline in QTcF (ΔQTcF) exceeding prespecified thresholds indicating borderline or prolonged QTcF (>480 ms) or ΔQTcF (>60 ms). Among 146 patients randomized to nivolumab 0.3, 2.0, or 10.0 mg/kg every 3 weeks, the maximum increases in mean (± SD) ∆QTcF at any time point were 4.9 (± 13.4), 1.2 (± 10.1), and 2.0 (± 8.9) ms, respectively. There was no relationship between ∆QTcF and nivolumab serum concentration and no association between predicted maximum ∆QTcF and mean maximum nivolumab concentration in any dosage group. Results of these intensive ECG analyses indicate that nivolumab has no clinically meaningful effect on QTc interval when administered at doses up to 10.0 mg/kg.