Study of Pembrolizumab (MK-3475) vs. Best Supportive Care in Participants With Previously Systemically Treated Advanced Hepatocellular Carcinoma (MK-3475-240/KEYNOTE-240)

Inclusion Criteria:

* Has a HCC diagnosis confirmed by radiology, histology or cytology (fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes are not eligible).
* Has Barcelona Clinic Liver Cancer (BCLC) Stage C disease, or BCLC Stage B disease not amenable to locoregional therapy or refractory to locoregional therapy, and not amenable to a curative treatment approach.
* Has a Child-Pugh Class A liver score within 7 days of first dose of study drug.
* Has a predicted life expectancy \>3 months.
* Has at least one measurable lesion based on RECIST 1.1 as confirmed by the blinded central imaging vendor.
* Has a performance status of 0 or 1 using the Eastern Cooperative Oncology Group (ECOG) Performance Scale within 7 days of first dose of study drug.
* Has documented objective radiographic progression during or after treatment with sorafenib or intolerance to sorafenib.
* Participants with chronic infection by Hepatitis C Virus (HCV) who are treated (successfully or treatment failure) or untreated are allowed on study. In addition, participants with successful HCV treatment are allowed as long as there are ≥4 weeks between achieving sustained viral response (SVR12) and start of study drug.
* Has controlled Hepatitis B Virus (HBV) infection.
* Is willing to use an adequate method of contraception for the course of the study through at least 120 days or longer based on local regulation after the last dose of study drug (male and female participants of childbearing potential).
* Demonstrates adequate organ function.

Exclusion Criteria:

* Is currently participating, or has participated in a study of an investigational agent and received study drug, herbal/complementary oral or IV medicine, or used an investigational device within 4 weeks of the first dose of study drug. Participants must also have recovered from associated therapy (i.e., to Grade ≤1 or baseline) and from adverse events (AEs) due to any prior therapy.
* Has received sorafenib within 14 days of first dose of study drug.
* Has had esophageal or gastric variceal bleeding within the last 6 months.
* Has clinically apparent ascites on physical examination. Note: ascites detectable on imaging studies only ARE allowed.
* Portal vein invasion at the main portal (Vp4), inferior vena cava, or cardiac involvement of HCC based on imaging.
* Has had clinically diagnosed hepatic encephalopathy in the last 6 months.
* Has had a solid organ or hematologic transplant.
* Has had prior systemic therapy for HCC in the advanced (incurable) setting other than sorafenib, prior to the start of study drug.
* Has a known severe hypersensitivity (≥Grade 3) to pembrolizumab, its active substance and/or any of its excipients.
* Has active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs).
* Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
* Has received locoregional therapy to liver (transcatheter chemoembolization \[TACE\], transcatheter embolization \[TAE\], hepatic arterial infusion \[HAI\], radiation, radioembolization, or ablation) within 4 weeks prior to the first dose of study drug.
* Has had major surgery to liver or other site within 4 weeks prior to the first dose of study drug.
* Has had minor surgery (i.e., simple excision, tooth extraction) ≤7 days prior to the first dose of study drug (Cycle 1, Day 1).
* Has not recovered adequately (i.e., Grade ≤1 or baseline) from the toxicity and/or complications from any intervention prior to starting study drug.
* Has a diagnosed additional malignancy within 3 years prior to first dose of study drug with the exception of curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin and/or curatively resected in situ cancers.
* Has known history of, or any evidence of, central nervous system (CNS) metastases and/or carcinomatous meningitis.
* Has a history of non-infectious pneumonitis that required steroids or current pneumonitis.
* Has an active infection requiring systemic therapy.
* Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
* Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the first dose of study drug through 120 days or longer based on local regulation after the last dose of study drug.
* Has received prior immunotherapy including anti-programmed cell death-1 (anti-PD-1), anti-PD-ligand-1 (anti-PD-L1), or anti-PD-L2 agents, or if the participant has previously participated in Merck pembrolizumab (MK-3475) studies.
* Has a known history of human immunodeficiency virus (HIV).
* Has dual active HBV infection and HCV infection at study entry.
* Has received a live vaccine within 30 days of planned start of study drug (Cycle 1, Day 1).