Clinical Utility of Tremelimumab/Durvalumab as First-line Treatment for Unresectable Hepatocellular Carcinoma: Serum Cytokine Profile Insights.

[BACKGROUND/AIM] Although immunotherapies such as atezolizumab plus bevacizumab (Ate/Bev) and tremelimumab plus durvalumab (Tre/Dur) are recommended as first-line treatments for unresectable hepatocellular carcinoma (uHCC), the clinical utility of Tre/Dur as first- or second-line therapy for uHCC remains debatable. We studied the clinical utility of first-line Tre/Dur treatment for uHCC using serum cytokine profiles.

[PATIENTS AND METHODS] We analyzed preserved serum of adult Japanese patients with liver cirrhosis and uHCC from a previous prospective study who received Tre/Dur at our hospital. Blood samples were collected before and after four weeks of treatment. Dynamic computed tomography (CT) was performed after 8-12 weeks of treatment to assess the response.

[RESULTS] Among nine non-immunotherapy (non-IO) group patients, three, five, and one patients showed partial response (PR), stable disease (SD), and progressive disease (PD), respectively, whereas none of the 10 IO group patients showed PR; three and seven patients showed SD and PD, respectively. Serum tumor necrosis factor (TNF)-alpha and soluble IL-2 receptor (IL-2R) increased significantly in both groups, with no significant changes in interleukin (IL)-6 levels in both groups. No significant difference was noted in serum MHC class I levels before and after treatment in either group, whereas soluble programmed cell death ligand 1 (sPD-L1) level increased in both groups. However, serum soluble MHC class I and sPD-L1 levels before treatment were higher in the IO group than in the non-IO group.

[CONCLUSION] A history of Ate/Bev therapy increased soluble MHC class I and sPD-L1 serum levels. Tre/Dur therapy may be useful as a first-line treatment for uHCC, and elevated sPD-L1 levels may attenuate Dur efficacy. This increase may impair tumor recognition and potentially reduce Tre/Dur therapy effectiveness despite activated cytotoxic T cells.