Population pharmacokinetics and CD20 binding dynamics for mosunetuzumab in relapsed/refractory B-cell non-Hodgkin lymphoma

Abstract

Mosunetuzumab (Mosun) is a CD20xCD3 T-cell engaging bispecific antibody that redirects T cells to eliminate malignant B cells. The approved step-up dose regimen of 1/2/60/30 mg IV is designed to mitigate cytokine release syndrome (CRS) and maximize efficacy in early cycles. A population pharmacokinetic (popPK) model was developed from 439 patients with relapsed/refractory B-Cell Non-Hodgkin lymphoma receiving Mosun IV monotherapy, including fixed dosing (0.05-2.8 mg IV every 3 weeks (q3w)) and Cycle 1 step-up dosing groups (0.4/1/2.8-1/2/60/30 mg IV q3w). Prior to Mosun treatment, ~50% of patients had residual levels of anti-CD20 drugs (e.g., rituximab or obinutuzumab) from prior treatment. CD20 receptor binding dynamics and rituximab/obinutuzumab PK were incorporated into the model to calculate the Mosun CD20 receptor occupancy percentage (RO%) over time. A two-compartment model with time-dependent clearance (CL) best described the data. The typical patient had an initial CL of 1.08 L/day, transitioning to a steady-state CL of 0.584 L/day. Statistically relevant covariates on PK parameters included body weight, albumin, sex, tumor burden, and baseline anti-CD20 drug concentration; no covariate was found to have a clinically relevant impact on exposure at the approved dose. Mosun CD20 RO% was highly variable, attributed to the large variability in residual baseline anti-CD20 drug concentration (median = 10 μg/mL). The 60 mg loading doses increased Mosun CD20 RO% in Cycle 1, providing efficacious exposures in the presence of the competing anti-CD20 drugs. PopPK model simulations, investigating Mosun dose delays, informed treatment resumption protocols to ensure CRS mitigation.

Trial registration: ClinicalTrials.gov NCT02500407.

FIGURE 1

Schematic of the Mosun population PK model and integration of CD20 receptor occupancy derived in Equation 1.

FIGURE 2

Covariate exposure plots. The black dashed vertical line represents the final model prediction for mosunetuzumab AUC_0–42 exposure at 1/2/30/60 mg, with covariates set equal to medians. The typical patient is a male, weighs 78 kg, and has a baseline albumin level of 39 g/L, a baseline anti‐CD20 (aCD20) drug concentration of 0.5 μg/mL, and a baseline tumor SPD of 2970 mm² (square root of tumor is presented on plot). Labels (left panel) show the covariate of interest, with values for the 5th and 95th percentiles of the covariate distribution. The impact of each covariate on mosunetuzumab AUC_0–42 is shown as the median fold change (blue circles) with 90% confidence interval (CI) (horizontal bars); the median with 90%CI values are reported in the right panel.

FIGURE 3

Visual predictive check for the final Mosun PopPK model (Grouped by Time after Dose). Circles are observations. The solid black line is the median of the observations (by bin). Dashed black lines are upper and lower limits of the 95% intervals for the observations (by bin). The solid blue line is the median of model simulations (by bin). Solid red lines are upper and lower limits of the 95% intervals for the model simulations (by bin). Shaded blue area is the 95% CI for the simulated median (by bin). Shaded red areas are 95% CIs for the upper and lower limits of the 95% prediction interval for the simulations (by bin).

FIGURE 4

Selected individual Mosun model fits, and model predictions for rituximab, obinutuzumab, and Mosun CD20 receptor occupancy (RO)% Time Courses. Banner headers indicate the Mosun (M) dosage patients received and predose concentrations of rituximab (R) and/or obinutuzumab (G) present. Black filled circles are Mosun PK observations. The solid black lines are the individual model predictions (IPRED) of Mosun PK. The black dotted lines are model predictions of the individual Mosun CD20 RO–time course (0%–100% scale). The solid green and blue lines are the model‐predicted R and G concentration–time course, respectively.

FIGURE 5

PopPK model simulations illustrating Mosun restart guidance following treatment‐free intervals from 14 to 42 Days After the 2 mg Dose. Model simulations are based on the final population PK model (N = 1000 simulations) with random covariate sampling; gray lines are the individual patient model simulations; pink‐shaded area represents the 95th percent prediction interval; solid red line is the median of simulated data; numbers represent the 1/2/60/30 Mosun dose regimen (mg) administered at time points. The median Day 8 C_max and Day 14 C_trough concentrations are displayed with green stippled lines.