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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. [ABSTRACT FROM AUTHOR]

BMS-690514, a selective inhibitor of the ErbB and vascular endothelial growth factor receptors, has shown antitumor activity in early clinical development. The compound is metabolized by multiple enzymes, with CYP3A4 responsible for the largest fraction (34%) of metabolism. It is also a substrate of P-glycoprotein (P-gp) in vitro. To assess the effect of ketoconazole on BMS-690514 pharmacokinetics, 17 healthy volunteers received 200 mg BMS-690514 alone followed by 100 mg BMS-690514 with ketoconazole (400 mg once daily for 4 days). The AUC∞ of 100 mg BMS-690514 concomitantly administered with ketoconazole was similar to that of 200 mg BMS-690514 alone. The dose-normalized Cmax and AUC∞ of BMS-690514 from the 100-mg BMS-690514/400-mg ketoconazole treatment increased by 55% and 127%, respectively, relative to those from 200 mg BMS-690514 alone. Prediction of the drug-drug interaction (DDI) using a population-based simulator (Simcyp) indicated that, in addition to CYP3A4 inhibition, the inhibition of P-gp by ketoconazole in the intestine, liver, and kidneys must be invoked to fully account for the DDI observed. This finding suggests that the inhibition of P-gp by ketoconazole, along with its effect on CYP3A4, needs to be considered when designing a DDI study of ketoconazole with a victim drug that is a dual substrate. [ABSTRACT FROM AUTHOR]