Evaluation of the potential for QTc prolongation in patients with solid tumors receiving nivolumab

Purpose: 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. Methods: 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. Results: 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) ΔQTcF 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 ΔQTcF and nivolumab serum concentration and no association between predicted maximum ΔQTcF and mean maximum nivolumab concentration in any dosage group. Conclusion: 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.