Background: HCC is an aggressive cancer as a sequela of cirrhosis. For pts with no extrahepatic metastases and well-compensated liver function, Y90 radioembolization is a therapeutic option. However, high-risk patients with macrovascular invasion (MVI) or multifocal disease treated with Y90 alone have a median time to progression 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, MVI, or diffuse disease. Eligible pts had disease amenable to 1-2 embolization procedures, Child Pugh A/B7 cirrhosis, no prior Y90 treatment; previous locoregional therapy and resection were allowed. Pts with extrahepatic mets were excluded. Treatment consisted of pembro 200mg every 3 weeks with standard dose Y90 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). Imaging was performed every 9 weeks. Results: A total of 29 pts were enrolled 10/23/17 to 11/24/20. Median age 66 years, 89% male, 7% Child’s Pugh B, and 47% with MVI. 27 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 9.95 months (95% CI 4.14 – 15.24) and median TTP was 9.95 months (95% 4.14 – 18.56). Median OS was 27.30 months (95% CI 10.15 – 39.52). The ORR was 30.8% (Table). Three patients (11%) have ongoing treatment response with one of these patients off treatment for 16 weeks. Most common treatment related grade 3-4 AEs were decreased lymphocytes (n=5), increased bilirubin (n=3), hypertension (n=3), ascites (n=2), and AST/ALT elevation (n=2). 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 in pts with poor prognosis HCC demonstrated promising clinical activity with median TTP and OS that exceeds historical data with three patients having ongoing response. With a 6-month PFS rate of 57.7%, median OS of 27.30 months and an acceptable toxicity profile, the combination of checkpoint blockade and Y90 deserves further evaluation in larger randomized clinical trials. Clinical trial information: NCT03099564.