Hepatocellular carcinoma (HCC) is one of the commonest solid malignancies in Asia Pacific region, primarily because of high incidence of hepatitis B infection in this locality. Resection or liver transplantation is the standard treatment for operable/resectable disease. However more than 50% of HCC are inoperable, primarily because of poor liver function, limited normal liver reserve and advanced disease beyond resectability. Locoregional treatment including transarterial chemoembolization (TACE), percutaneous ethanol injection (PEI), radiofrequency ablation (RFA) and recently radio-embolization are acceptable options. However the response rate was just between 30-80% treated with these modalities. Also some patients are contraindicated to these local therapies. For instance, those who have poor liver function (Child-Pugh B) or have their tumors showing portal vein invasion/thrombosis are contraindicated to TACE. Those who had their tumors close to adjacent critical organs e.g. liver, stomach, duodenum, small bowel and gallbladder, etc were not candidates for RFA or percutaneous ethanol injection. In addition, those who had tumors \>4cm or close to major vessels have high local recurrence after RFA. Stereotactic body radiation therapy (SBRT), with the use of highly conformal and precision radiation techniques with real-time tracing of patient and tumor position so as to offer a high radiation dose to the tumors while sparing the adjacent critical organs from necessary radiation.

Previous preclinical studies suggested synergism of anti-tumor activity between radiation therapy and immune checkpoint inhibitors. Immune checkpoint inhibitors are now comprehensively and extensively tested in combination with radiotherapy (RT) as well (NCT01935921, NCT01860430). It has been recently known that RT increases the expression of the major histocompatibility complex (MHC). In turn, the MHC class-I restricted tumor antigen-specific cells elicited by RT will upregulate interferons in the tumors. This radiation-induced local inflammation and tumor-specific effector T cells will provide an additional mechanism for tumor control by modification of the tumor vasculature. In addition, RT will increase dendritic cell surface antigen presentation to T cells and production of cytokines leading to recruitment and activation of leucocytes from peripheral blood and extravasation to tumor parenchyma. These are part of the mechanisms of abscopal effect, a phenomenon where the tumors at the sites far away from the irradiated sites also regress after localized radiotherapy. Having learnt from the pivotal PACIFIC trial on the use of consolidation therapy with durvalumab (anti-PD-L1 monoclonal antibody) which confirmed the efficacy and safety of combination of chemoradiation and immunotherapy for stage III non-small-cell lung cancer, it is prime time to consider incorporation of immune checkpoint inhibitors into concurrent chemoradiation for other solid tumors like HCC.

In view of the promising activity of SBRT and immune checkpoint inhibitors for HCC, we propose a phase II single-arm study on using durvalumab in combination with SBRT for inoperable/unresectable HCC. Recruited patients with receive durvalumab 750mg intravenously every 2 weeks, starting 1 week before SBRT, for a total of 26 cycles (1 year).