Senior Director Gilead Sciences, Inc., United States
Disclosure(s):
Xiaoning Wang, PhD: No relevant disclosure to display
Objectives: Domvanalimab (dom) is a fully human, Fc-silent IgG1 monoclonal antibody targeting the human T cell immunoglobulin and ITIM domain (TIGIT). Dom is being developed in multiple oncology indications administered in combination with other therapeutics. The objectives of this analysis were to develop a population pharmacokinetics (PK) model of dom in patients with solid tumors, and to evaluate the effects of intrinsic and extrinsic factors on dom PK.
Methods: Analysis data were pooled from one Phase 1 study in solid tumors, three Phase 2 studies in NSCLC, and one Phase 2 study in gastric, gastroesophageal junction, or esophageal adenocarcinoma (GC/GEJC/EAC). Patients were treated with dom administered intravenously as monotherapy or in combination with other agents including zimberelimab (zim, an anti-PD-1 immune checkpoint inhibitor) and chemotherapy. The analysis dataset included 3967 PK observations from 433 patients, treated with dom doses from 0.5 mg/kg to 20 mg/kg, and 800 mg to 1600 mg. Preliminary data was used for ongoing Phase 2 studies ARC-10 (NSCLC), EDGE-Lung (NSCLC) and EDGE-Gastric (GC/GEJC/EAC). A previously developed model [1] was used as a starting point. The population PK analysis was conducted in NONMEM v7.5 [2]. Population and individual model parameters were estimated using the stochastic approximation expectation maximization method followed by Monte Carlo importance sampling. A full covariate modeling approach was implemented to evaluate covariate effects. The tested covariates included age, race, sex, tumor type (GC/GEJC/EAC vs NSCLC vs other), baseline tumor size, ECOG, liver function, renal function, albumin and LDH. The effect of treatment (monotherapy vs zim and dom vs other) and administration (zim/dom coadministration vs sequential) were examined using post-hoc estimates.
Results: Dom PK was characterized by a two-compartment model with linear clearance. For a typical 63 kg male participant with GC/GEJC/EAC, baseline albumin of 38 g/L, and sum of lesion diameter of 61 mm, the parameter estimates (relative standard error [RSE]) for clearance and central volume were 0.229 L/day (2.7%) and 3.84 L (1.79%), respectively. The effects of body weight were included using allometric scaling with estimated coefficients (0.376 for clearance, 0.522 for volume). Other tested covariates did not show clinically meaningful effect on dom PK. Treatment regimen (monotherapy vs zim and dom vs other) or administration (zim/dom coadministration vs sequential) did not have a clinically meaningful effect on dom PK.
Conclusions: A population PK model with linear clearance was developed to reasonably describe dom PK in patients with solid tumors. Tumor type or combination with zim (vs monotherapy) did not have an impact on dom PK, supporting the same dosing regimen can be applied across different tumor types and treatments. Coadministration of zim with dom, as opposed to sequential administration, does not impact the PK of dom. This approach can enhance patient convenience and reduce clinic time.
Citations: [1] Chaturvedula A., Liao K., Zhao M., Agoram B. Use of A Population Pharmacokinetic Modeling and Simulation Approach to Identify Flat Doses of Domvanalimab in Phase 3 Studies. ASCPT Annual Meeting 2023. [2] Beal S.L., Sheiner L.B., Boeckmann A.J. & Bauer R.J. (Eds). NONMEM 7.4 users guides (ICON plc, Gaithersburg, MD, 1989. –2018).
Keywords: Domvanalimab, solid tumor, population PK model
