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

Ana M Novakovic, Justin J Wilkins, Haiqing Dai, Janet R Wade, Berend Neuteboom, Satjit Brar, Carlo L Bello, Pascal Girard, Akash Khandelwal, Ana M Novakovic, Justin J Wilkins, Haiqing Dai, Janet R Wade, Berend Neuteboom, Satjit Brar, Carlo L Bello, Pascal Girard, Akash Khandelwal

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.

Conflict of interest statement

A.M.N. and A.K. are employees of Merck KGaA. J.J.W. and J.R.W. were employed as consultants by Merck KGaA when analyses were performed. H.D. and B.N. are employees of EMD Serono, a business of Merck KGaA. S.B. and C.L.B. are employees of Pfizer Inc. P.G. is an employee of Merck Serono SA, Lausanne, Switzerland, an affiliate of Merck KGaA.

© 2019 MERCK KGAA. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Simulated AUC0–336 h values for weight‐based (10 mg/kg q2w) and flat (800 mg q2w) dosing of avelumab using the first‐cycle population pharmacokinetic model. Box and whisker plots for (a) the entire population and (b) the population split by quartiles of weight; observed data with avelumab 20 mg/kg dosing are included for comparison purposes (n = 27). AUC0–336 h, area under the curve during the first dosing interval.
Figure 2
Figure 2
Mean probability of experiencing an irAE (upper panels) or IRR (lower panels) for weight‐based (10 mg/kg q2w) and flat (800 mg q2w) dosing with avelumab based on the first‐cycle population pharmacokinetic model. Box and whisker plots for (a) probability of irAEs based on AUC0–336 h in all patients; (b) probability of irAEs based on AUC0–336 h stratified by quartiles of weight; (c) probability of IRRs based on Cmax in all patients; and (d) probability of IRRs based on Cmax stratified by quartiles of weight. AUC0–336 h, area under the concentration curve during the first dosing interval; Cmax, maximum concentration; irAE, immune‐related adverse event; IRR, infusion‐related reaction.
Figure 3
Figure 3
Mean probability of objective response in patients with mMCC (upper panels) or advanced/metastatic UC (lower panels) for weight‐based (10 mg/kg q2w) and flat (800 mg q2w) dosing with avelumab based on AUC0–336 h (first‐cycle population pharmacokinetic model). Box and whisker plots in (a) all patients with mMCC, (b) patients with mMCC stratified by quartiles of weight, (c) all patients with advanced/metastatic UC, and (d) patients with advanced/metastatic UC stratified by quartiles of weight. AUC0–336 h, area under the curve during the first dosing interval; Ctrough, minimum serum concentrations; mMCC, metastatic Merkel cell carcinoma; UC, urothelial carcinoma.

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