Exposure-Response Analyses of Tremelimumab Monotherapy or in Combination with Durvalumab in Patients with Unresectable Hepatocellular Carcinoma

PURPOSE: A novel single-dose regimen of 300 mg tremelimumab in combination with durvalumab [Single Tremelimumab Regular Interval Durvalumab (STRIDE)] has demonstrated a favorable benefit-risk profile in the phase I/II Study 22 (NCT02519348) and phase III HIMALAYA study (NCT03298451). This study evaluated the pharmacokinetics, exposure–response, and exposure–pharmacodynamics relationships of tremelimumab in patients with unresectable hepatocellular carcinoma (uHCC). PATIENTS AND METHODS: A previous tremelimumab population pharmacokinetic model was validated using data from parts 2 and 3 of Study 22. Exposure–response analyses explored relationships of tremelimumab exposure with efficacy and safety. Pharmacokinetics and pharmacodynamics relationships were evaluated using linear and nonlinear regression models. RESULTS: The observed pharmacokinetics of tremelimumab in uHCC were consistent with predictions; no significant covariates were identified. Tremelimumab exposure was not significantly associated with adverse events, objective response rate, or progression-free survival. Overall survival (OS) was longer for patients with tremelimumab exposure, minimum serum drug concentration (C(min1)) ≥ median versus C(min1) < median (18.99 months vs. 10.97 months), but this exposure-survival analysis might be confounded with baseline characteristics of albumin level and neutrophil to lymphocyte ratio, which had a significant impact on OS (P = 0.0004 and 0.0001, respectively). The predicted C(min1) of tremelimumab in STRIDE regimen (12.9 μg/mL) was greater than the estimated concentration of tremelimumab eliciting half-maximal increases (EC(50) = 5.24 μg/mL) in CD8(+)Ki67(+) T-cell counts. CONCLUSIONS: Our findings support novel insights into tremelimumab pharmacokinetics and exposure–response relationships in HCC and support the clinical utility of the STRIDE regimen in patients with uHCC.