Model-informed drug development supporting the approval of the avelumab flat-dose regimen in patients with advanced renal cell carcinoma.

Avelumab is an anti-PD-L1 monoclonal antibody approved as monotherapy for Merkel cell carcinoma (MCC) and urothelial carcinoma (UC), and in combination with axitinib for advanced renal cell carcinoma (aRCC). Although initially approved with weight-based dosing (10 mg/kg intravenously [IV] every 2 weeks [Q2W]), avelumab was subsequently approved for flat dosing (800 mg IV Q2W) based on population pharmacokinetic (PopPK), exposure-efficacy, and exposure-safety modeling in MCC and UC. Here, through modeling and simulation, we provide justification for a flat-dose regimen of avelumab plus axitinib in aRCC. Simulated exposure metrics from the previous monotherapy PopPK model (1827 patients) for both weight-based and flat-dose regimens were compared with exposure metrics from treatment-naive patients with aRCC who received avelumab plus axitinib (488 patients). The aRCC population exposures were derived from a fit-for-purpose PopPK model developed using data from monotherapy and combination studies and the existing base structural PopPK model. Exposure-response relationships for safety were analyzed, including grade ≥3 treatment-emergent adverse events (TEAEs), any-grade infusion-related reactions, and TEAE any-grade immune-related adverse events (irAEs). Weight-based dosing of avelumab in the aRCC population yielded similar PK exposures to the flat-dose regimen reference exposures in the monotherapy population. Increased avelumab exposure was not associated with increased probabilities of grade ≥3 TEAEs or any-grade IRRs, although there was a weak association with an increased probability of any-grade irAEs. Overall, models in aRCC suggest that the avelumab 800-mg Q2W flat-dose regimen would provide similar benefits compared with weight-based dosing with no meaningful change in the probability of AEs.