Population Pharmacokinetics and Exposure-Response Analysis of Tremelimumab 300 Mg Single Dose Combined With Durvalumab 1,500 Mg Q4w (Stride) in Patients With Unresectable Hepatocellular Carcinoma.

A novel single-dose regimen of 300 mg tremelimumab in combination with durvalumab (STRIDE) has demonstrated a favorable benefit-risk profile in the phase 1/2 Study 22 (patients with unresectable hepatocellular carcinoma [uHCC]) and in the phase 3 HIMALAYA study. The current analysis evaluated the population pharmacokinetics (PopPK) of tremelimumab and durvalumab, and exposure-response relationship for efficacy and safety of STRIDE in patients with uHCC. Previous PopPK models for tremelimumab and durvalumab were updated using data from previous studies in various cancers combined with data from Study 22 and HIMALAYA. Typical population mean parameters and associated inter- and intraindividual variability were assessed, as was the influence of covariates. Individual exposure metrics were derived from the individual empirical Bayes estimates as drivers for exposure-response analysis related to efficacy and safety from HIMALAYA. The observed pharmacokinetics of tremelimumab in uHCC were well described by a two-compartment model with both linear and time-dependent clearance. All identified covariates changed tremelimumab PK parameters by <25% and thus had minimal clinical relevance; similar results were obtained from durvalumab PopPK analysis. None of tremelimumab or durvalumab exposure metrics were significantly associated with overall survival, progression-free survival (PFS), or adverse events. Baseline aspartate aminotransferase and neutrophil-to-lymphocyte ratio were associated with overall survival (p < 0.001) by Cox proportional hazards model. No covariate was identified as significant factor for the PFS hazard. No dose adjustment for tremelimumab or durvalumab is needed based on PopPK covariate analyses or exposure-response analyses. Our findings support the novel STRIDE dosing regimen in patients with uHCC. This article is protected by copyright. All rights reserved.