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