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

Abstract

Avelumab, an anti–programmed death‐ligand 1 monoclonal antibody approved for the treatment of metastatic Merkel cell carcinoma and platinum‐treated urothelial carcinoma, was initially approved with a 10 mg/kg weight‐based dose. We report pharmacokinetic (PK)/pharmacodynamic analyses for avelumab comparing weight‐based dosing and a flat 800 mg dose, developed using data from 1,827 patients enrolled in 3 clinical trials (NCT01772004, NCT01943461, and NCT02155647). PK metrics were simulated for weight‐based and flat‐dosing regimens and summarized by quartiles of weight. Derived exposure metrics were used in simulations of exposure‐safety (various tumors) and exposure‐efficacy (objective responses; Merkel cell or urothelial carcinoma). Flat dosing was predicted to provide similar exposure to weight‐based dosing, with slightly lower variability. Exposure‐safety and exposure‐efficacy simulations suggested similar benefit:risk profiles for the two dosing regimens. These pharmacometric analyses provided the basis for the US Food and Drug Administration approval of a flat dose of avelumab 800 mg every 2 weeks in approved indications.

Mechanism‐based treatment of cancer with immune checkpoint inhibitor therapies

“…Although some difference in exposure to the drug was seen in the extremes of weight, overall there was considerable overlap seen in exposure for all weight quartiles. Similarly, the probabilities of AEs and responses were comparable across all weight quartiles 73 Durvalumab phase I study used doses ranging from 0.1 to 10 mg/kg every 2 weeks and 15 mg/kg every 3 weeks, and no DLTs were observed even with the highest dose 69 .…”

Opportunities for using in silico‐based extended dosing regimens for monoclonal antibody immune checkpoint inhibitors

“…Subsequent indications of urothelial carcinoma (9 May 2017) and RCC (14 May 2017) followed, each with the recommended dose of 10 mg/kg q2wk. Novakovic et al demonstrated comparable exposure between 10 mg/kg q2wk and flat 800 mg q2wk, 64 which was the basis of the most recent Bavencio label change.…”

Cancer Immunotherapy Dosing: A Pharmacokinetic/Pharmacodynamic Perspective

“…First, they revealed that BW contributes only marginally to inter-individual variability (IIV) of PK parameters, particularly the CL. Secondly, they made it possible to simulate flat dosing and then to compare simulated plasma ICI concentrations to actual concentrations corresponding to a mg/kg dose [ 21 , 39 , 42 , 43 ]. Flat dosing was not associated with a larger IIV in plasma concentrations, and led to statistically similar exposures, regardless of the dosing.…”