Background: HCC is the fifth most prevalent cancer globally and the second-leading cause of cancer-related deaths. The high mortality rate is typically due to the late stage of disease at diagnosis and a lack of effective treatment options. Sorafenib, the only systemic agent approved to treat advanced HCC, has shown only a modest survival benefit. More effective treatment options are needed. Nivolumab, a fully human IgG4 monoclonal antibody programmed death receptor-1 (PD-1) inhibitor, has demonstrated overall survival (OS) benefit in pts with metastatic melanoma, non–small-cell lung cancer, and advanced renal cell carcinoma. Preliminary data from the CheckMate-040 trial suggest that nivolumab has clinical activity and is tolerable in pts with HCC, including those with hepatitis B or hepatitis C virus (HCV) infection.¹ CheckMate-459 is a phase 3, randomized, open-label study (NCT02576509) designed to compare the efficacy of nivolumab and sorafenib in pts with advanced HCC. Methods: Eligibility criteria include age ≥ 18 years, histologically confirmed advanced HCC, ≥ 1 measurable untreated lesion, ECOG performance status of 0 or 1, and no prior systemic therapy. Additional criteria include completion of locoregional therapy for HCC ≥ 4 weeks prior to baseline scan and Child-Pugh class A. Pts with fibrolamellar, sarcomatoid HCC; mixed cholangiocarcinoma and HCC; or prior liver transplant will be excluded. An estimated 726 pts will be randomized 1:1 to receive nivolumab or sorafenib until disease progression or unacceptable toxicity. Pts will be stratified by etiology, vascular invasion and/or extrahepatic spread, and geography. CheckMate-459 began in Nov 2015; estimated primary completion date is May 2017. Primary objectives are OS and time to progression. Secondary objectives include overall response rate, progression-free survival, and evaluation of the relationship between PD-L1 expression and efficacy. Exploratory patient-reported measures, including effects of treatment on health status and quality of life, will also be evaluated. Reference:¹El-Khoueiry, et al. J Clin Oncol. 2015;33(suppl):LBA 101. Clinical trial information: NCT02576509