Background: HCC is an aggressive cancer that is challenging to treat due to the concomitant diagnosis of cirrhosis. For HCC pts with no extrahepatic metastases and well-compensated liver function, Y90 radioembolization is a standard therapy. In observational studies, pts with multifocal disease or portal vein thrombosis (PVT) had worse outcomes with short disease control intervals of less than 6 months. Pembro is an anti-PD-1 monoclonal antibody that is FDA-approved for advanced HCC pts who have progressed on sorafenib. Given pre-clinical evidence that radiotherapy can increase PD-L1 expression and enhance tumoral T-cell recruitment, this study explored the safety and efficacy of pembro with Y90 radioembolization in pts with poor prognosis HCC. Methods: GI15-225 was a multi-center, single-arm study in poor prognosis HCC pts, defined as having multifocal disease, branch PVT and/or diffuse disease (NCT03099564). Pts with extrahepatic metastatic disease were excluded; eligible pts had disease amenable to 1-2 embolization procedures. Pts had Child Pugh A/B7 cirrhosis with no prior Y90 treatment; previous TAE, TACE, SBRT, liver resection or ablation were allowed. Treatment consisted of pembro 200mg every 3 weeks with Y90 radioembolization performed 7-10 days after first dose of pembro. The primary objective was to estimate the progression free survival (PFS) rate at 6 months per RECIST 1.1; secondary endpoints included safety, time to progression (TTP), overall response rate (ORR) and overall survival (OS). Results: A total of 29 pts were enrolled 10/23/17 to 11/24/20. Median age 66 years, 89% male, and 47% with PVT. 26 pts were evaluable for primary endpoint having received Y90 and at least one dose of pembro. The 6 month PFS rate was 57.7% (95% CI 36.9 – 76.6). Median PFS was 8.6 months (95% CI 4.1 – 13.4) and median TTP was 9.9 months (95% 4.2 – NR). Median OS was 22 months (95% CI 8.4 – 32.0). The ORR was 27% (Table). Most common treatment related grade 3-4 AEs were decreased lymphocytes (18%), increased bilirubin (11%), hypertension (11%), ascites (7%), and AST/ALT elevation (7%). One pt experienced grade 5 toxicity of hepatic failure after receiving one dose of pembro and Y90 that was attributed to Y90 and disease progression. Conclusions: Concurrent administration of pembro with Y90 radioembolization in pts with poor prognosis HCC demonstrated promising clinical activity with median TTP and OS that exceeds historical data reported in similar patients treated with Y90 alone. With a 6 month PFS rate of 57.7% and a favorable toxicity profile, the combination of immune checkpoint blockade and Y90 deserves further evaluation in larger randomized clinical trials. Clinical trial information: NCT03099564.