S. Agrawal, D. Williams, I. Waxman, D. Liu, A. Lambert, A. Roy, R. Darbenzio; Bristol-Myers Squibb, Princeton, NJ
BACKGROUND: NIVO and IPI are fully human monoclonal antibodies that target PD-1 and CTLA-4 receptors, respectively, thereby acting as immune checkpoint inhibitors for cancer immunotherapy. This analysis aimed to assess the potential of NIVO or IPI to cause QTP in subjects with solid tumors.
METHODS: The effect of NIVO on QTP was assessed using data from an intensive ECG substudy of a phase II dose-ranging study at 0.3, 2, and 10 mg/kg every three weeks (n=146). The effect of IPI on QTP was assessed in a dose-ranging phase II study at 3 (n=25) and 10 mg/kg, IV (n=32), and in a phase III study at 10 mg/kg (n=103) every 3 weeks. Triplicate 12-lead ECGs were obtained at pre- and post-dose and assessed by an independent laboratory. Evaluation of the corrected QT interval (QTc) was performed after dose 1 and multiple doses to determine any potential delayed effects on QTc interval. Central tendency and categorical analyses and concentration-response relationships were conducted, as appropriate.
RESULTS: NIVO ≤10 mg/kg did not meaningfully affect the QTc interval (mean QTcF change from baseline [ΔQTcF] range, -7.2 to 4.9 msec). There was no dose response for QTcF, ΔQTcF or change from baseline in heart rate, PR interval, or QRS interval after doses 1 or 7. There was also no relationship between ΔQTcF and NIVO serum concentration. After examination of adverse events (AEs) of seizure/convulsion, syncope/presyncope, QTP and tachycardia, no AE was determined to be related to an abnormal ECG finding potentially related to proarrhythmia. There was also no evidence that IPI 3 or 10 mg/kg (mean ΔQTcF range, -3.7 to 4.7 msec) had any meaningful effect on any ECG interval, including QTP or other ECG findings or cardiac arrhythmic AEs.
CONCLUSION: Neither NIVO or IPI cause QTP or ECG changes related to cardiac arrhythmias at doses ≤10 mg/kg.