Flat dosing regimens of NIVO 240 mg every 2 weeks (Q2W) and 480 mg every 4 weeks (Q4W) were approved in the US across indications (not including 480 Q4W in MSI-H or dMMR CRC) and the EU across indications (240 mg Q2W) and in melanoma and renal cell carcinoma (480 mg Q4W) to provide flexible and convenient treatment options than the initially approved 3 mg/kg Q2W weight-based regimen. These changes were supported by model-based bridging of available efficacy and safety data.
NIVO exposures with flat dosing regimens were predicted and compared with 3 mg/kg Q2W dosing for 3817 patients with melanoma, non-small cell lung cancer, renal cell carcinoma, squamous cell carcinoma of the head and neck, urothelial carcinoma, classical Hodgkin’s lymphoma, small cell lung cancer, hepatocellular carcinoma, colorectal carcinoma, and gastric carcinoma. The impact on differences in time-varying exposure on safety were assessed by time-to-event models of Grade (Gr)2+ immune-mediated adverse events (IMAEs) and treatment-related AEs (TRAEs). The impact of differences in early (month 1) exposure on efficacy was assessed by models of tumor growth dynamics and overall survival (OS). Additionally, the potential impact of time-varying exposure on efficacy was assessed by predicting intratumoral programmed cell death 1 (PD-1) receptor occupancy (RO).
The predicted time-averaged concentration at steady-state for 240 mg Q2W and 480 mg Q4W was similar to 3 mg/kg Q2W (<6% difference), whereas the peak and time-averaged concentration after the first dose were higher with 480 mg Q4W. The predicted cumulative probability of experiencing Gr2+ IMAEs or TRAEs with NIVO 240 mg Q2W and 480 mg Q4W were similar to 3 mg/kg Q2W (<1% difference at 2 years). The exposure–response relationship of tumor shrinkage and growth rates were flat. Hazard ratios of OS with NIVO 240 mg Q2W and 480 mg Q4W relative to standard-of-care were predicted to be similar to 3 mg/kg Q2W. The median trough intratumoral RO at steady state was predicted to be maintained above 90% for all 3 dosing regimens.
The benefit-risk of NIVO 240 mg Q2W and 480 mg Q4W regimens are expected to be similar to 3 mg/kg Q2W, with the added convenience and flexibility for patients and providers.
Clinical trial identification
Legal entity responsible for the study
Medical writing assistance was provided by Eric Rabinovsky, PhD, of Spark Medica Inc. (US), funded by Bristol-Myers Squibb.
X. Zhao J. Shen, B.J. Schmidt, P. Statkevich, T. Kelleher: Employee: BMS. Y. Feng: Owned BMS stock. M. Rashford, S. Agrawal, A. Roy, A. Bello: Employee, Stockholder: BMS. All other authors have declared no conflicts of interest.