Background: Recently, checkpoint inhibitors have shown modest activity in patients (pts) with advanced, unresectable hepatocellular carcinoma (HCC). In multicenter trials with nivolumab and pembrolizumab, the response rates have been reported to be 14% and 16%, respectively. We report a prospective single-institution investigator-initiated clinical/translational study of pembrolizumab in advanced HCC. Methods: A phase II trial is ongoing, with pembrolizumab administered at a fixed dose of 200 mg iv every 3 weeks for advanced HCC patients who may have progressed on, were intolerant of, or refused sorafenib. CT or MRI scans were performed after every 3 doses. RECIST 1.1 was used to assess response. Time to tumor progression (TTP) and overall survival (OS) were estimated by Kaplan-Meier method. Median TTP and median OS were estimated along with the corresponding 95% confidence interval. Results: Twenty six patients have been treated and 21 were evaluable for response at this time. Ten of the 21 patients had prior sorafenib. Seven had hepatitis C and 1 had hepatitis B. Sixteen had extrahepatic metastases. The median TTP was 3 months(95%CI:2-7) and median OS was 14 months(95%CI: 3- not estimable). In terms of response, one had complete response and 6 had partial response (PR) for overall response rate of 33%. Two others had stable disease. TTP for responding pts were 6+, 7, 8, 8,9, 9+, and 14 + months with 3 having ongoing responses. Five of these 7 had extrahepatic metastases which responded to treatment. Four of 7 had prior sorafenib. Drug-related toxicity included: hypothyroidism (4 patients) grade 4 neutropenia (1 ) and reversible, temporary elevation of liver function tests (grade 3 in 3 pts). Other grade 1-2 toxicities included: diarrhea (4 ), skin rash (5) and fatigue (2). Correlative studies including hepatitis B and C titers, IL1B, IL12, IL18, IL6, TGF beta, gamma interferon, and PD-L1/PD-1 staining are ongoing and will be presented. Conclusions: Pembrolizumab has activity in advanced HCC patients, including those with extrahepatic metastases. Toxicity was generally well tolerated and reversible. A set of immunological markers as well as PD-L1/PD-1 staining is being investigated as possible indicator for response. Clinical trial information: NCT02658019