Model-based clinical pharmacology profiling of subcutaneous nivolumab in renal cell carcinoma: Bridging to alternative dosing regimens and indications.

A novel model-informed drug development (MIDD) approach was employed to derive the coprimary endpoints (time-averaged serum concentration over 28 days [Cavgd28] and minimum serum concentration at steady state [Cminss]) of the phase III CheckMate 67T study (NCT04810078). This approach also facilitated bridging to alternative subcutaneous (SC) dosing regimens and existing intravenous (IV) nivolumab monotherapy and combination indications. Individual exposures were derived via a population pharmacokinetic (popPK) analysis to establish pharmacokinetic (PK) noninferiority of nivolumab 1200 mg SC every 4 weeks (Q4W) vs. nivolumab 3 mg/kg IV every 2 weeks (Q2W). Bridging to additional indications leveraged previously established nivolumab IV popPK models with the incorporation of SC components. Nivolumab population SC absorption rate constant and bioavailability were estimated to be 0.295 day-1 and 78.8%, respectively. Geometric means of Cavgd28 and Cminss for 1200 mg SC Q4W exceeded those for 3 mg/kg IV Q2W but remained below those for 10 mg/kg IV Q2W, a regimen used regularly to define the exposure safety margins for nivolumab. Simulation-based PK bridging analyses showed that nivolumab SC regimens produced consistently higher exposures than approved nivolumab IV regimens across solid tumor indications, while maintaining exposures below the established safety margin. The MIDD approach provided an integrated and computationally efficient framework to characterize nivolumab SC/IV PK. Simulation-based analyses confirmed comparable benefit-risk profiles of nivolumab SC in adults across solid tumor indications and led to FDA approval of nivolumab SC in existing adult IV indications (except for nivolumab in combination with ipilimumab).