Population Pharmacokinetic and Exposure Response Analysis of Belzutifan in Advanced Renal Cell Carcinoma
Anne Chain (1), Stefanie Hennig (2), Gerly van der Vleuten (2), Katrina Hui (2), Huub Jan Kleijn (2), Petra Jauslin (2)
(1) MSD, Rahway, NJ, USA, (2) Certara Strategic Consulting, USA
Objectives:
A previously developed population pharmacokinetic (PopPK) model for belzutifan based on data from patients with VHL disease [1] was extended to patients with advanced RCC (aRCC) adding data from a Phase 3 randomized study. The updated PopPK model based on the pooled data provided exposures for exposure-response (E-R) analyses for selected safety (anemia, hypoxia, time to first dose reduction/ first dose interruption / dose discontinuation) and efficacy endpoints (overall survival [OS], progression-free survival [PFS], overall response rate [ORR], best overall response [BOR], duration of response [DOR]), as well as pharmacodynamic (PD) markers (hemoglobin [Hgb] and erythropoietin [EPO]) in aRCC patients for an indication extension.
Methods: The PopPK analysis was performed in NONMEM, version 7.4.3 [2]. Previously identified covariate effects remained in the model unless not supported by the added data, and additional covariates (disease status, sex, race, hepatic and renal function) were retested. Model selection and evaluation was guided by goodness-of-fit plots, objective function value changes, and prediction-corrected visual predictive checks.
Relationships between exposure and efficacy endpoints, safety endpoints, and PD biomarkers were evaluated using graphical analyses, logistic regression techniques and time-to-event analyses in R version 4.2.2. The influence of baseline Hgb on safety endpoints was explored as a covariate.
Results:
Data from 381 patients with advanced RCC and 14 healthy volunteers were added to the previous data set based on 239 patients. The pooled dataset included 6779 evaluable belzutifan concentrations. Consistent with the previous PopPK model developed in patients with VHL, the PK of belzutifan after oral administration was well-characterized by a 2-compartment model with first order absorption and elimination. Updated PopPK model parameters were similar to previous estimates. Belzutifan’s apparent clearance (CL/F) was 5.79 L/h, central volume of distribution (V2/F) was 87.9 L, peripheral volume of distribution (V3/F) was 33.1 L, and inter-compartmental clearance (Q/F) was 5.17 L/h. Covariates from the previous PopPK model were retained; body weight, age, UGT2B17 and CYP2C19 polymorphism on CL/F, age on V2/F, food status and formulation on the absorption rate constant, and UGT2B17 polymorphism on bioavailability were statistically significant. No new covariates were identified, and no difference in PopPK between patients with aRCC and those with VHL was identified.
The E-R analysis for efficacy and safety was based on 379 patients with aRCC. A general trend towards higher efficacy with higher exposure was observed. For PFS and OS, the exposure-efficacy relationship reached statistical significance, most pronouncedly for PFS. ORR and DOR did not show a significant relationship with belzutifan exposure. Regarding safety, a significant E-R relationship was observed for anemia ≥ grade 3, hypoxia all grades and hypoxia ≥ grade 3. The anemia risk was largely driven by baseline Hgb. However, logistic regression analysis showed that after correction for Hgb, belzutifan exposure was still a significant predictor of anemia ≥ grade 3. Furthermore, a significant E-R relationship was detected for time to first dose reduction, time to first dose interruption and time to dose discontinuation due to a drug-related adverse event. Exposure-dependent reductions in EPO and Hgb were observed.
Conclusions: Based on the cumulative benefit-risk assessment in patients with aRCC, no a priori dose adjustment is recommended for any subpopulation. These analyses supported the benefit-risk profile of belzutifan 120 mg QD in patients with aRCC for labeling and the overall development program.
References:
[1] Marathe DD, Jauslin PM, Kleijn HJ, de Miranda Silva C, Chain A, Bateman T, Shaw PM, Abraham AK, Kauh EA, Liu Y, Perini RF, de Alwis DP, Jain L. Population pharmacokinetic analyses for belzutifan to inform dosing considerations and labeling. CPT Pharmacometrics Syst Pharmacol. 2023 Oct;12(10):1499-1510.
[2] ICON, Hanover, MD, USA