T Cell Receptor and Immune Gene Expression Pharmacodynamics for Durvalumab alone and with Tremelimumab or Bevacizumab in Unresectable Hepatocellular Carcinoma

Purpose: In the phase I/II Study 22 (NCT02519348) trial, objective response rates were 24.0% with STRIDE (Single Tremelimumab Regular Interval Durvalumab), 21.3% with durvalumab plus bevacizumab (D+B), and 11.5% with durvalumab (D) monotherapy in unresectable hepatocellular carcinoma (uHCC). Increased proliferating CD8+ T cells were associated with improved efficacy of STRIDE versus D monotherapy. Here, analyses of changes in T cell clonal expansion and gene expression signatures (GES) in peripheral blood were performed to explore the mechanisms of action associated with the anti-cancer activity of STRIDE and D+B versus D monotherapy. Patients and Methods: Participants with uHCC and no prior immune checkpoint inhibitor therapy were enrolled. DNA and RNA were isolated from peripheral blood collected at baseline and at the end of the first treatment cycle. Baseline values and changes from baseline in T cell clonality and GES were measured across treatment arms, and associations with radiographic response were assessed. Results: There were no significant differences in baseline richness or Simpson clonality of T cells across treatment arms. STRIDE, but not D+B, elicited an increase in the number of expanded T cell clones versus D monotherapy; the increase was associated with clinical response. Both STRIDE and D+B upregulated interferon-gamma response GES compared with D alone, but other immune-related changes differed, with STRIDE showing upregulation of CD4+ and T effector signatures, while D+B upregulated interferon-alpha response and both myeloid cell and endothelial GES. Conclusions: These findings suggest that STRIDE and D+B have distinct, and potentially complementary, mechanisms of action in uHCC.