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

Abstract

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.

Trial registration: ClinicalTrials.gov NCT02684006 NCT02493751.

Conflict of interest statement

J.C. Masters and A. di Pietro are employees of Pfizer, and own stock and other ownership interests in Pfizer. A. Khandelwal is an employee of the healthcare business of Merck KGaA, Darmstadt, Germany, owns stock and other ownership interests in Merck KGaA, Darmstadt, Germany, and holds patents, royalties, or other intellectual property in the healthcare business of Merck KGaA, Darmstadt, Germany. H. Dai is an employee of EMD Serono, and owns stock and other ownership interests in Merck KGaA, Darmstadt, Germany. S. Brar was an employee of Pfizer.

© 2022 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

FIGURE 1

Exposures for avelumab plus axitinib in the aRCC population: (a) AUCtau,ss, (b) Cmax,ss, and (c) Ctrough,ss. Pink boxplot is exposure (derived from individual parameters) in aRCC population (488 patients) receiving combination treatment avelumab 10 mg/kg Q2W plus axitinib using the current PopPK model (described in this report). The purple and teal boxplots are previously simulated reference exposures following 10 mg/kg Q2W and 800 mg Q2W, respectively, using the previous PopPK model in solid‐tumor monotherapy populations. aRCC, advanced renal cell carcinoma; AUCtau,ss, steady‐state area under the concentration‐time profile of dosing interval; Cmax,ss, steady‐state maximum concentration; Ctrough,ss, steady‐state trough concentration; PopPK, population pharmacokinetic; Q2W, every 2 weeks

FIGURE 2

Box and whisker plots for the simulated (a) Ctrough,ss, (b) Cavg,ss, and (c) Cmax,ss at steady state for the weight‐based (10 mg/kg Q2W) and flat (800 mg Q2W) dosing regimens by extremes of weight in the aRCC population. aRCC, advanced renal cell carcinoma; Cavg,ss, steady‐state average concentration; Cmax,ss, steady‐state maximum concentration; Ctrough,ss, steady‐state trough concentration; PopPK, population pharmacokinetics

FIGURE 3

Probability of (a) TEAEs grade ≥3 by avelumab Ctrough,sd, (b), any‐grade irAEs by Cmax,sd, and (c) any‐grade IRRs by Ctrough,sd. Horizontal line and corresponding shaded region represent predicted probability and 95% CI. Solid gray line represents the median Ctrough,sd or Cmax,sd. Gray dashed lines represent the 25th and 75th percentiles and Dotted gray lines represent the fifth and 95th percentiles. CI, confidence interval; Cmax,sd, maximum concentration after single dose; Ctrough,sd, trough concentration after single dose; irAE, immune‐related adverse event; IRR, infusion‐related reaction; TEAE, treatment‐emergent adverse event

FIGURE 4

Probability of experiencing (a) grade ≥3 TEAEs, (b) any‐grade irAEs, and (c) any‐grade IRRs for the avelumab weight‐based 10 mg/kg Q2W and flat 800 mg Q2W doses in the aRCC population receiving combination therapy with axitinib. irAE, immune‐related adverse reaction; IRR, infusion‐related reaction; TEAE, treatment‐emergent adverse event; Q2W, every 2 weeks