Abstract
Abstract Lonca is an antibody (Ab) drug conjugate comprising a humanized monoclonal Ab directed against B-cell antigen CD19, conjugated with a potent pyrrolobenzodiazepine (PBD) dimer toxin. In a Phase 1 (NCT02669017) study in relapsed or refractory (R/R) B-NHL, a recommended Phase 2 dosing regimen for Lonca of 150 µg/kg once every 3 weeks (Q3W) for two doses, followed by 75 µg/kg Q3W was identified then evaluated in a Phase 2 (NCT03589469) study in R/R diffuse large B-cell lymphoma (DLBCL). A population pharmacokinetic (PPK) model was developed to characterize the pharmacokinetics (PK) of the Lonca dosing regimen and evaluate exposure covariates. The integrated PPK model was used to describe drug concentrations for Lonca PBD-conjugated Ab (5,301 samples), total Ab (5,241 samples), and unconjugated warhead SG3199 (239 samples) in serum from 328 patients. Samples were taken pre-dose, at end of infusion and at pre-determined timepoints post-infusion throughout the trials. Analysis was performed using non-linear mixed-effects modeling (NONMEM, v7.4 [ICON Solutions]). Subgroup analyses were conducted on model-predicted exposure metrics derived from simulation of Lonca PK profiles based on empirical Bayesian estimates of individual PK parameters. Concentration-time data of Lonca PBD-conjugated Ab and total Ab were best characterized by a two-compartment model with parallel linear clearance (0.218 L/day), and a time-dependent clearance component which approached zero by ~15 weeks. The estimated volume of distribution of central compartment was 3.86 L and the estimated typical half-life at steady state of Lonca is ~3 weeks. The effect of body weight, age, sex, race, renal impairment, drug formulation, anti-drug Ab, ECOG, and concomitant P-gp inhibitors did not show clinically important influence on exposure (< ±30% change relative to reference). Based on model-predicted Cycle 1 average concentration (Cavg) patients with low albumin (<35 g/L, n=49) had 52% lower Cavg than patients with normal albumin levels (≥35 g/L, n=279). Patients with non-DLBCL (n=44) had 61% lower Cavg than patients with DLBCL (n=284). Trends of lower exposures with baseline mild/moderate hepatic impairment and ECOG status >1 were noted but did not appear to be of clinical relevance. In conclusion, Lonca exposure was well described by a two-compartment model with linear and time-dependent clearance; the latter is thought to reflect reduction of tumor cells. Lonca exposure was lower in non-DLBCL patients, and lower in patients with hypoalbuminemia secondary to enhanced protein clearance in patients with critical illness. Overall, modeling demonstrates rapid attainment of steady-state exposure for Lonca given 150 µg/kg Q3W for two doses, and a sustaining profile for Lonca given 75 µg/kg Q3W thereafter for patients with DLBCL. Citation Format: Melhem Solh, Juan Pablo Alderuccio, Anastasios Stathis, David Ungar, Sam Liao, Lisa Khouri, Xiaoyan Zhang, Joseph Boni. Integrated population modeling of loncastuximab tesirine (Lonca) exposure in B-cell non-Hodgkin lymphoma (B-NHL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1366.