Exposure-Response Analysis and Quantitative Systems Pharmacology Modeling for Optimal RP2D Selection of AZD0486 in Follicular Lymphoma Patients

Introduction: AZD0486, a novel IgG4 fully human CD19xCD3 bispecific T-cell engager (TCE) is uniquely designed to bind CD3 with low affinity to reduce cytokine release upon T cell activation, while preserving effective T cell cytotoxicity against malignant B cells. AZD0486 was active and well-tolerated in patients (pts) with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL), including follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) (NCT04594642). Here, we present our quantitative approaches for determining an optimal dose for AZD0486 in patients with R/R FL with exposure-response (ER) analysis and quantitative systems pharmacology (QSP) modeling.

Methods: Pts with R/R B-NHL received escalating doses of AZD0486 intravenously every 2 weeks in 28-D cycles (C) in either fixed target dose (day [D]1, D15 0.03–2.4 mg), single step-up dose (1SUD) (D1 0.27 or 1 mg, D15 0.8-10 mg), or double SUD (2SUD) (D1 0.27 mg, D8 1 mg, D15 2.4-15 mg) schedules. PK data from serial sampling at the evaluated doses was used to develop a popPK model in NONMEM^® software. The relationships between AZD0486 PK parameters were explored for their correlation with either Grade 1 or Grade 2 CRS or ICANS in pts with all disease histologies. The ER relationships between AZD0486 PK and overall response rate (ORR) or complete response rate (CRR) were also characterized in pts with FL who reached C3D1. Further, QSP modelling was developed to link the AZD0486 PK to the trimeric complex formation, considering T- and B-cell dynamics, CD3 and CD19 expression and target binding. Based on the mechanism of action, trimer concentration was assumed to drive the killing of tumor lesion, leading to clinically observed response. The QSP model was used to predict trimer formation and tumor response in pts with FL of different disease categories. The data cutoff was 15Mar 2024 and 104 Pts with all histology were analyzed for safety and 34 pts with FL were analyzed for efficacy.

Results: AZD0486 PK was best described with a two-compartment PK model with linear clearance and were comparable in pts with FL and DLBCL. The effect of bodyweight on volumes was retained. The mean half-life is approximately 8 to 12 days across the dose cohorts after Cycle 1 Day 1 dose. Dose proportional increases in exposure is observed across the dose ranges tested (≥0.27 mg).

Based on exposure-safety analysis of CRS and ICANS, a trend of higher exposure during the 7 days after the first dose (AUC_0-7d) correlates with ≥Grade 2 CRS incidence. Model prediction shows low CRS risk with an initial priming dose of 0.27 mg. With 0.27 mg as the first priming dose, increasing target dose from 2.4 mg to 7.2 mg is not expected to increase the risk of CRS. The analysis also showed trend of early ≥Grade 2 ICANS risk correlating with the incremental ratio of C_max between first and second priming doses. This suggests that multiple incremental steps to achieve target dose may mitigate ICANS. With 2SUD of 0.27/1.0 mg, the risk of ≥Grade 2 ICANS is predicted to be comparable (< 5%) between target dose of 2.4 mg and 7.2 mg.

Exposure-efficacy analysis in pts with FL showed that higher ORR appears to be related to higher exposure (eg, AUC_ss or C_trough) and a trend of improvement in CRR with increasing exposure (eg, AUC_0-56days). Although the predicted ORR is comparably high, CRR shows a trend of improvement from target dose 2.4mg to 7.2mg.

Based on the QSP model calibrated with preclinical and emerging clinical data, the maximal trimer concentration at the tumor site is predicted to increase from 2.4 mg to 7.2 mg. Model simulations of a virtual cohort of high-risk FL patients, characterized by higher tumor proliferative rate and poor tumor infiltration (ie, bulky disease), predicted a potential improvement in efficacy of target at 7.2 mg vs 2.4 mg.

Conclusion: The ER analysis and QSP modelling confirmed the clinical benefit with increased dose from 2.4 to 7.2 mg in terms of CRR and in particular predicts an improved response in pts with highly proliferative and bulky tumors. The ER analysis of ICANS or CRS also confirmed the comparable safety profile with 2SUD at target doses of 2.4 to 7.2 mg. Overall, the comprehensive analysis package supported the benefit vs risk at the dose of 0.27/1.0/7.2 mg in r/r pts with FL.