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.

FIGURE 1

Exposures for avelumab plus axitinib in the aRCC population: (a) AUC_tau,ss, (b) C_max,ss, and (c) C_trough,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; AUC_tau,ss, steady‐state area under the concentration‐time profile of dosing interval; C_max,ss, steady‐state maximum concentration; C_trough,ss, steady‐state trough concentration; PopPK, population pharmacokinetic; Q2W, every 2 weeks

FIGURE 2

Box and whisker plots for the simulated (a) C_trough,ss, (b) C_avg,ss, and (c) C_max,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; C_avg,ss, steady‐state average concentration; C_max,ss, steady‐state maximum concentration; C_trough,ss, steady‐state trough concentration; PopPK, population pharmacokinetics

FIGURE 3

Probability of (a) TEAEs grade ≥3 by avelumab C_trough,sd, (b), any‐grade irAEs by C_max,sd, and (c) any‐grade IRRs by C_trough,sd. Horizontal line and corresponding shaded region represent predicted probability and 95% CI. Solid gray line represents the median C_trough,sd or C_max,sd. Gray dashed lines represent the 25th and 75th percentiles and Dotted gray lines represent the fifth and 95th percentiles. CI, confidence interval; C_max,sd, maximum concentration after single dose_; C_trough,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