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

Clin Cancer Res. 2023 Feb 16;29(4):754-763. doi: 10.1158/1078-0432.CCR-22-1983.


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 (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 μg/mL) was greater than the estimated concentration of tremelimumab eliciting half-maximal increases (EC50 = 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.

Publication types

  • Clinical Trial, Phase II
  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Carcinoma, Hepatocellular* / drug therapy
  • Carcinoma, Hepatocellular* / etiology
  • Humans
  • Liver Neoplasms* / drug therapy
  • Liver Neoplasms* / etiology
  • Treatment Outcome


  • durvalumab
  • tremelimumab