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

The STRIDE (Single Tremelimumab Regular Interval Durvalumab) regimen of 300 mg single-dose tremelimumab, plus 1500 mg durvalumab 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 EC of tremelimumab was 6.10 μg/mL (standard error = 1.07 μg/mL); > 98.0% of patients were predicted to have a C greater than EC with tremelimumab 300 mg or 750 mg. For EC (9.82 μg/mL), 69.5% and 98.2% of patients were predicted to exceed the EC with tremelimumab 300 mg and 750 mg, respectively. This analysis supports the clinical hypothesis that combination anti-cytotoxic T lymphocyte 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.