Population Pharmacokinetic, Exposure‐Response Efficacy and Safety Analyses of Favezelimab in Patients With Solid Tumors

Favezelimab (MK-4280) is a humanized monoclonal antibody (mAb) targeting lymphocyte activation gene-3 (LAG-3). Favezelimab population pharmacokinetics (popPK) was evaluated using data from 2 trials; a Phase 1 study evaluating favezelimab across a range of doses (7 to 800 mg administered intravenously [IV] every 3 weeks [Q3W]) in patients with advanced solid tumors, and a Phase 3 study evaluating 800 mg IV Q3W favezelimab combined with pembrolizumab (200 mg Q3W) in patients with programmed death ligand 1 (PD-L1) positive colorectal cancer (CRC). Prespecified covariates of clinical interest were evaluated using a full model. Favezelimab exposure measures from the final popPK model were used to evaluate the exposure-response (E-R) relationships with objective response rate (ORR), Grade ≥ 3 drug-related adverse events (AE), and drug-related AE of special interest (AEOSI) occurrence in gastric cancer patients evaluated across 2 randomized doses. The final popPK model was a 2-compartment target-mediated drug disposition (TMDD) model and included the effect of antidrug antibody status on linear clearance (CL). Population volume and clearance parameters, and corresponding random effects were estimated with < 15% relative standard error. Lower body weight, as well as female sex and Asian race (covariates correlated with lower body weight), were associated with higher exposure. Lower albumin levels were also associated with lower exposure. Increasing favezelimab exposures were associated with increased ORR and had no significant effect on safety. No covariates were associated with ORR. This analysis was used to characterize variability in favezelimab pharmacokinetics and support the choice of Phase 3 dose.