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 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 progres-sion-free survival. Overall survival (OS) was longer for patients with tremelimumab exposure, minimum serum drug concentration (Cmin1) >= median versus Cmin1 < 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 Cmin1 of tremelimumab in STRIDE regimen (12.9 mu g/mL) was greater than the estimated concentration of tremelimumab eliciting half-maximal increases (EC50 = 5.24 mu g/mL) in CD8 thorn Ki67 thorn T-cell counts. Conclusions: Our findings support novel insights into tremelimumab pharmacokinetics and exposure-response relation-ships in HCC and support the clinical utility of the STRIDE regimen in patients with uHCC.

Automated summary

This study evaluated the use of a novel single-dose regimen of tremelimumab in patients with unresectable hepatocellular carcinoma. The analysis found that there was no significant correlation between tremelimumab exposure and efficacy or safety, but the minimum serum drug concentration had an impact on patient survival. The findings suggest that the use of tremelimumab in unresectable hepatocellular carcinoma may have clinical utility.