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Population Pharmacokinetic, Exposure-Response Efficacy and Safety Analyses of Favezelimab in Patients With Solid
Mitali Gaurav1, Heather Barcomb1, Kelly F Maxwell1
1Clinical Pharmacology and Pharmacometric Solutions, Simulations Plus, Inc, Research Triangle Park, North Carolina, USA.
Abstract:
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.
Insights
Favezelimab (MK-4280), a LAG-3 antibody, shows increased exposure in patients with lower body weight, female sex, or Asian race. Higher favezelimab exposure correlated with better objective response rates in gastric cancer patients.
Area of Science:
- Pharmacology
- Immunotherapy
- Oncology
Background:
- Favezelimab (MK-4280) is a novel humanized monoclonal antibody targeting lymphocyte activation gene-3 (LAG-3).
- Understanding favezelimab pharmacokinetics (PK) and exposure-response (E-R) relationships is crucial for optimizing its use in cancer therapy.
Purpose of the Study:
- To characterize the population pharmacokinetics (popPK) of favezelimab across different doses and patient populations.
- To evaluate the exposure-response relationships for efficacy (objective response rate) and safety (adverse events).
- To identify covariates influencing favezelimab exposure and inform Phase 3 dose selection.
Main Methods:
- Population PK analysis using data from Phase 1 and Phase 3 clinical trials.
- A 2-compartment target-mediated drug disposition (TMDD) model was developed.
- Covariate analysis evaluated factors like body weight, sex, race, and albumin levels.
- Exposure-response modeling assessed relationships with objective response rate and adverse events.
Main Results:
- Lower body weight, female sex, and Asian race were associated with higher favezelimab exposure.
- Lower albumin levels were linked to lower exposure.
- Increased favezelimab exposure was associated with a higher objective response rate.
- No significant impact of exposure on safety was observed.
Conclusions:
- The popPK model successfully characterized favezelimab variability, including the impact of antidrug antibodies.
- Favezelimab exposure is influenced by demographic factors and clinical characteristics.
- Higher exposure is linked to improved efficacy without compromising safety, supporting the chosen Phase 3 dose.
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