Modeling of Proliferating CD4 and CD8 T-Cell Changes to Tremelimumab Exposure in Patients with Unresectable Hepatocellular Carcinoma

Clin Pharmacol Ther. 2023 Oct;114(4):874-882. doi: 10.1002/cpt.2992. Epub 2023 Jul 28.

Abstract

The STRIDE (Single Tremelimumab Regular Interval Durvalumab) regimen of single-dose tremelimumab 300 mg, plus durvalumab 1,500 mg every 4 weeks demonstrated potential for long-term survival in studies of unresectable hepatocellular carcinoma (uHCC; Study 22 and HIMALAYA). The aim of this analysis was to investigate changes in proliferating CD4+ Ki67+ and CD8+ Ki67+ T cells and their relationship with tremelimumab exposure in patients with uHCC. Median cell count, change from baseline, and percent change from baseline in CD4+ and CD8+ T cells peaked around 14 days after STRIDE. A model of CD4+ and CD8+ T cell response to tremelimumab exposure was developed. Patients with lower baseline T cell counts had a greater percent change from baseline in T cell response to tremelimumab, and baseline T-cell count was included in the final model. With the full covariate model, the half-maximal effective concentration (EC50 ) of tremelimumab was 6.10 μg/mL (standard error = 1.07 μg/mL); > 98.0% of patients were predicted to have a minimum plasma concentration greater than EC50 with tremelimumab 300 or 750 mg. For EC75 (9.82 μg/mL), 69.5% and 98.2% of patients were predicted to exceed the EC75 with tremelimumab 300 and 750 mg, respectively. This analysis supports the clinical hypothesis that combination anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) and anti-programmed cell death ligand-1 (anti-PD-L1) therapy primes an immune response that may then be sustained by anti-PD-L1 monotherapy and supports the clinical utility of the STRIDE regimen in patients with uHCC. These insights may also help inform dose selection of anti-CTLA-4 plus anti-PD-L1 combination strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • CD8-Positive T-Lymphocytes
  • Carcinoma, Hepatocellular* / drug therapy
  • Humans
  • Ki-67 Antigen
  • Liver Neoplasms* / drug therapy

Substances

  • tremelimumab
  • Ki-67 Antigen