153: Population Pharmacokinetics/Pharmacodynamics Modeling of INCAGN02385 in Patients With Select Advanced Malignancies

Statement of Purpose, Innovation or Hypothesis: INCAGN02385 is a humanized Fc-engineered immunoglobulin G_1κ (IgG_1κ) monoclonal antibody that selectively binds to the inhibitory receptor lymphocyte activation gene 3 protein (LAG-3), leading to enhanced T-cell receptor signaling and potentially eliciting antitumor immunity. INCAGN02385 is being studied for the treatment of advanced malignancies in combination with other agents. The objective of this study was to develop a population pharmacokinetics (PK)/pharmacodynamics (PD) model to characterize INCAGN02385 exposures, peripheral LAG-3 receptor occupancy (RO), and inter-subject variability in patients with advanced malignancies, when administered intravenously as monotherapy.

Description of Methods & Materials: A total of 202 serum concentration records from 22 patients from the first-in-human study of INCAGN02385 (NCT03538028) were used for this analysis. Patients received intravenous INCAGN02385 doses ranging from 25 to 750 mg every 2 weeks (q2w). The PD effect of INCAGN02385 on LAG-3 RO in blood was determined by a flow cytometry-based assay. A non-linear mixed effects model was developed using PK and RO observations. PK/PD analyses were performed using Monolix^® (version 2021R2). Patient demographic and baseline characteristics, including weight, age, sex, and baseline albumin and alkaline phosphatase were evaluated for covariate search using a stepwise covariate building approach. The predictive performance of the model was assessed by goodness-of-fit (GOF) plots and visual predictive checks (VPCs).

Data & Results: INCAGN02385 PK and LAG-3 RO profiles were adequately described using a simultaneous PK/PD model, which included a 2-compartment PK model with parallel linear and Michaelis-Menten elimination coupled with a sigmoid maximum effect (E_max) model. All parameters and their variabilities were estimated within an acceptable degree of precision and physiologically plausible for an antibody. The mean (% relative standard error of estimate) estimates of linear clearance (CL) and central volume of distribution (V) were 0.0092 L/h (6.39%) and 3.28 L (7.75%), respectively. Baseline albumin and alkaline phosphatase were identified as significant covariates of V. Additionally, baseline albumin was found to impact the maximal velocity of the non-linear elimination (V_max). The VPCs demonstrated that the observed PK and RO profiles were well within the final model based on simulated 90% prediction intervals.

Interpretation, Conclusion or Significance: A population PK/PD model was successfully developed to describe INCAGN02385 PK and peripheral LAG-3 RO in patients with advanced malignancies. The model could be leveraged as a valuable prediction tool to support future dose selection for clinical development.

Disclosures: Funding by Incyte Corporation. All authors are employees and own stock of Incyte Corporation.

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