Time‐Varying Clearance and Impact of Disease State on the Pharmacokinetics of Avelumab in Merkel Cell Carcinoma and Urothelial Carcinoma

Abstract

Avelumab, a human anti–programmed death ligand 1 immunoglobulin G1 antibody, has shown efficacy and manageable safety in multiple tumors. A two‐compartment population pharmacokinetic model for avelumab incorporating intrinsic and extrinsic covariates and time‐varying clearance ( CL ) was identified based on data from 1,827 patients across three clinical studies. Of 14 tumor types, a decrease in CL over time was more notable in metastatic Merkel cell carcinoma and squamous cell carcinoma of the head and neck, which had maximum decreases of 32.1% and 24.7%, respectively. The magnitude of reduction in CL was higher in responders than in nonresponders. Significant covariate effects of baseline weight, baseline albumin, and sex were identified on both CL and central distribution volume. Significant covariate effects of black/African American race, C‐reactive protein, and immunogenicity were found on CL . None of the covariate or time‐dependent effects were clinically important or warranted dose adjustment.

Changing Body Weight–Based Dosing to a Flat Dose for Avelumab in Metastatic Merkel Cell and Advanced Urothelial Carcinoma

“…The estimated power exponent for the effect of weight on CL in the avelumab first-cycle population PK model was 0.324. 17 Thus, our data are consistent with published data showing that flat dosing produces less variability in exposure when the estimated exponent defining the relationship is < 0.5. 6 Although overall exposure was slightly increased with flat dosing, this was expected because the median weight of sampled patients (70.6 kg) was lower than the "standard" weight of 80 kg seen in other populations of patients with solid tumors, on which the flat dose was based.…”

“…Compared with weight‐based dosing, flat dosing provides similar predicted exposure with slightly less variability, providing the primary evidence that supports this change. The estimated power exponent for the effect of weight on CL in the avelumab first‐cycle population PK model was 0.324 . Thus, our data are consistent with published data showing that flat dosing produces less variability in exposure when the estimated exponent defining the relationship is < 0.5 .…”

“…The preferred PK exposure metrics used to compare weight‐based and flat‐dosing regimens were simulated based on the population PK model developed using first‐cycle data. Avelumab displays a time‐dependent decrease in CL, which has also been reported for agents within the same class (nivolumab and pembrolizumab) . Thus, the results obtained with simulated PK exposures based on the first‐cycle model minimize the potential impact of time‐dependent changes in CL (also for subsequent exposure‐efficacy and exposure‐safety simulations) .…”

“…16 Single-dose PK for avelumab was reported from the dose-escalation parts of JAVELIN Solid Tumor 12 and JAVELIN Solid Tumor JPN. 13 Population PK models have been developed that show a modest effect of body weight on CL 17 and a potential shallow exposure-response relationship in some tumor types. 18,19 Avelumab was initially approved with weight-based dosing of 10 mg/kg given intravenously q2w, which has been administered in several clinical trials.…”

“…Single‐dose PK for avelumab was reported from the dose‐escalation parts of JAVELIN Solid Tumor and JAVELIN Solid Tumor JPN . Population PK models have been developed that show a modest effect of body weight on CL and a potential shallow exposure‐response relationship in some tumor types …”