Study of Pembrolizumab and Radiotherapy in Liver Cancer

Inclusion Criteria: * Willing and able to provide written informed consent/assent for the trial * Be ≥18 years of age on day of signing informed consent. * Have a histologically- or cytologically-confirmed diagnosis of hepatocellular carcinoma (HCC), and at least one measurable lesion. * Have current liver function meeting Child Pugh Class A (5-6 points), with no encephalopathy or ascites. * Have intrahepatic HCC amenable to stereotactic body radiotherapy (SBRT): * maximum 10 lesions to be treated, and * total tumor diameter to be treated \<20 cm * No single liver tumor \>15 cm in diameter * No evidence of common or main branch bile duct invasion * No evidence of direct tumor extension into stomach, duodenum, small bowel, large bowel or diaphragm * Smaller satellites of HCC or non-definite HCC need not be encompassed within SBRT volumes if needed to respect normal tissue limits. * Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. * Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. * Have demonstrated disease progression, after previous treatment with sorafenib for advanced or metastatic disease, lasting a minimum of 8 week period, allowing for appropriate interruptions and dose reductions. * Have recovered (to ≤ grade 1) from prior toxicities related to previous treatments at the time of study enrollment, with the exception of alopecia or skin depigmentation. * Be tested during screening for Hepatitis B-Virus surface antigen (HbsAg) status. Patients may be included in the study if they have adequately controlled hepatitis B * Patients must be tested during study screening for hepatitis C virus (HCV) RNA status. Patients with chronic infection by HCV who are untreated are allowed on study. In addition, patients with successful HCV treatment are allowed as long as 4 weeks have passed between completion of HCV therapy and start of study treatment. * Demonstrate adequate organ function. * Women of child-producing potential must agree to use effective contraceptive methods prior to study entry, during study participation, and for at least 30 days after the last administration of study medication. A serum pregnancy test within 72 hours prior to the initiation of therapy will be required for women of childbearing potential. Men treated or enrolled on this trial must agree to use adequate contraception prior to and for 4 months after completion of pembrolizumab administration. Exclusion Criteria: * Has received any second-line systemic therapy for advanced HCC after disease progression following sorafenib therapy, or has had prior radiotherapy to the proposed treatment field. * Is currently participating and receiving experimental treatment as part of a clinical trial, or has participated in a study of an immune checkpoint inhibitor and received study therapy, or used an investigational device within 4 weeks of the first dose of treatment. * Has had a previous solid organ transplant, 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 trial treatment. * Has liver tumor not amenable to SBRT, or has had prior upper abdominal radiation therapy within planned volumes (exceeding standard tolerances). * Has a histological or cytological diagnosis of fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma-HCC. * Has had prior radioembolization or other selective internal radiotherapy treatment to the liver. * Has dual active HBV infection (HBsAg (+) and/or detectable HBV DNA) and HCV infection (anti-HCV Ab(+) and detectable HCV RNA) at study entry. * Has had esophageal or gastric variceal bleeding within 3 months prior to study enrollment. * Has had encephalopathy in the past 6 months, or has clinically apparent ascites at the time of study enrollment. * Has a known history of active TB (Bacillus Tuberculosis). * Hypersensitivity to pembrolizumab or any of its excipients. * Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 1 week prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. * Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. * Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. * Has a known history of prior invasive malignancy except if the subject has undergone curative-intent therapy with no evidence of disease recurrence for 2 years prior to study entry. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, low-risk prostate cancer or in situ cervical cancer. * Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. * HHas active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy at a dose of ≤ 10 mg/day of prednisone or equivalent) is not considered a form of systemic treatment. * Has known history of, or any evidence of active, non-infectious pneumonitis/interstitial lung disease. * Has an active infection requiring systemic therapy. * Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. * Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. * Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment. * Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. * Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). * Has alcohol related or non-alcoholic steatohepatitis (NASH) related cirrhosis. * Has had a history of significant active or unstable heart disease * Has received a live vaccine or live-attenuated vaccine within 30 days of planned start of study therapy. Administration of killed vaccines is allowed.