Comparison of SBRT and SIRT With Combination IO for Locally-advanced, Unresectable HCCs (BIIRTH)

Inclusion Criteria: * Patients diagnosed with HCC either by histology or by the American Association for the Study of Liver Diseases Criteria (AASLD) 2018 * Patients age 18-80 years of age with HCCs deemed unresectable at the Multidisciplinary Team Meetings (MDTs) because of the following: * R0 resection not feasible e.g. unfavourable tumour location * Remnant liver volume \<30% in non-cirrhotic patients or 40% in cirrhotic patients * Indocyanine green test \>15% * Patients with Barcelona Clinic Liver Cancer (BCLC) stage B2-4 (unresectable group) or C * Tumour sizes of ≥5cm, of which ≥1 is a measurable lesion as defined by the mRECIST criteria * Subjects aged 18-80 years of age * ECOG performance status of 0-1 * Predicted life expectancy should be of ≥ 3 months * Child Pugh (CP) score of A5-B7 * Adequate organ and marrow functions, as listed below: * Haemoglobin ≥9 g/dL * Absolute neutrophil count ≥1,500/uL * Platelet count ≥100,000/L * Total bilirubin ≤2.0 x upper limit of normal (ULN) * Albumin ≥2.8 g/dL * ALT ≤3 x ULN * INR ≤1.6 * Calculated creatinine clearance (eGFR) ≥45 mL/minute as determined by Cockcroft-Gault (using actual body weight) or 24-hour urine creatinine clearance * Liver volume minus intrahepatic gross tumour volume (GTV) with \>700cc * Patients with concomitant HBV infection (defined as having HBsAg positive and/or detectable HBV DNA level) must be treated with antiviral therapy (per local institutional practice) to ensure adequate viral suppression (defined as HBV DNA \<2,000 IU/mL) prior to enrolment, throughout study duration and continue for at least 6 months following the last dose of local-systemic therapy * Informed consent provided * Females of childbearing potential or non-sterilized male who are sexually active must use a highly effective method of contraception * Females of childbearing potential must have negative serum or urine pregnancy test Exclusion Criteria: * Prior invasive malignancy within 2 years except for noninvasive malignancies such as cervical carcinoma in situ, in situ prostate cancer, non-melanomatous carcinoma of the skin, lobular or ductal carcinoma in situ of the breast that has been surgically cured * Presence of any extra-hepatic metastases * Presence of main portal vein (PV) or inferior vena cava (IVC) involvement * Presence of active, uncontrolled varices * Presence of active, severe comorbidities including uncontrolled cardiovascular or cerebrovascular diseases or recent events within 6months prior to treatment * Received prior non-curative locoregional (including TACE, RT to liver, SIRT) or systemic therapy received for HCC\\ * Prior treatment with any anti-programmed cell death protein-1 (anti-PD-1), PD Ligand-1 (PD-L1) or PD Ligand-2 (PD-L2) agent, or an antibody targeting other immune-regulatory receptor(s) or mechanism(s) * Use of chronic systemic steroid or any other immunosuppressive medication within 14days prior to treatment initiation, except: * Intranasal, inhaled, topical steroids, or local steroid injection; * Systemic corticosteroids at physiologic doses ≤10mg/day of prednisone or equivalent; * Steroids as premedication for hypersensitivity reactions * Active or documented autoimmune or inflammatory disorders within 2years, except diabetes type I, vitiligo, psoriasis, or hypo-/hyperthyroid diseases not requiring immunosuppressant(s) * Known history of a positive HIV test, primary/acquired immunodeficiency syndrome, or solid organ transplantation * Receipt of live, attenuated vaccine within 28 days prior to study treatment * Severe hypersensitivity reaction to another monoclonal antibody * Presence of any contraindication to TACE not otherwise listed: cisplatin allergy * Presence of any contraindication to SBRT not otherwise listed: * Maximal size of any one HCC \>25 cm * Direct tumour extension into gastrointestinal structures (stomach, duodenum, remaining small or large bowel) * Presence of any contraindication to SIRT not otherwise listed: * Pre-treatment 99mTc-MAA scan \>20% lung shunting of hepatic artery blood flow, or a demonstration of radiation exposure to the lungs potentially \>25Gy * Pre-treatment hepatic angiogram showing potential Y90 microspheres deposition in the gastrointestinal tract or any other organ(s) which is not correctable by catheter embolization techniques. * Pregnant or lactating females