Regorafenib Plus Pembrolizumab in Patients With Advanced or Spreading Liver Cancer Who Have Been Previously Treated With PD-1/PD-L1 Immune Checkpoint Inhibitors

Inclusion Criteria: * ≥ 18 years of age on the day of signing informed consent. * Histological or cytological confirmation of HCC or non-invasive diagnosis of HCC as per American Association for the Study of Liver Diseases (AASLD) criteria in cirrhotic participants. * Unresectable advanced HCC eligible for systemic therapy. * Participants must have progressed after only one prior line of systemic immunotherapy treatment with an anti-PD-1/PD-L1 mAb administered either as monotherapy or in combination with other checkpoint inhibitors or other therapies. A wash out period of at least 28 days or 5 half-lives, whichever is shorter, must be completed for eligibility in this trial. PD-1/PD-L1 treatment progression is defined by meeting all of the following criteria: 1. Has received at least 2 doses of an approved anti PD-1/PD-L1 mAb or received PD-1/PD-L1 treatment for 8 weeks, whichever is longer. 2. Has demonstrated disease progression after PD-1/PD-L1 treatment as defined by RECIST 1.1. In the absence of rapid clinical progression, the initial evidence of RECIST 1.1 disease progression is to be confirmed using iRECIST by a second assessment no less than four weeks from the date of the first documented progressive disease. i. This determination is made by the investigator. Once progressive disease is confirmed, the initial date of RECIST 1.1 progressive disease documentation will be considered that date of disease progression. ii. In cases of unequivocal clinical or radiological progression, disease progression confirmation may not be required after documented discussion and approval by the sponsor. c. Progressive disease has been documented within 12 weeks from the last dose of anti-PD-1/PD-L1 mAb. \- Participants who receive anti-PD-1 therapy as adjuvant treatment following complete resection of liver cancer and have disease recurrence (unresectable locoregional disease or distant metastases) are eligible if they progressed while on active treatment or within 6 months of stopping anti-PD-1 therapy. This will be considered the first line of systemic therapy. For these participants, the following applies: 1. a second assessment to confirm disease progression beyond recurrence is not required; and 2. they must have received at least 2 prior doses of anti-PD-1/PD-L1 mAb. * Barcelona Clinic Liver Cancer (BCLC) stage B or C. * Liver function status should be Child-Pugh (CP) Class A within 7 days prior to the first dose of study intervention. CP status should be calculated based on clinical findings and laboratory results during the screening period. * Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1 within 7 days prior to the first dose of study intervention. * At least one measurable lesion by CT scan or MRI according to RECIST 1.1. Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, may be considered measurable if there has been demonstrated progression in the lesion. * Participants with controlled (treated) hepatitis B virus (HBV) infection will be allowed if they meet the following criteria: * Antiviral therapy for HBV must be given for at least 4 weeks and HBV viral load must be less than 500 IU/mL prior to first dose of study intervention. * Participants on active HBV therapy with viral loads under 500 IU/ml should stay on the same therapy throughout study treatment. * Participants who are anti-HBc (+), negative for HBsAg, negative for anti-HBs, and have an HBV viral load under 500 IU/mL that do not require HBV antiviral prophylaxis. * Provision of recent tumor tissue (as defined below) is mandatory at screening. Exceptions will be accepted for participants with no recent baseline tumor tissues after documented discussion and approval by the sponsor. * Tumor tissue obtained within 180 days of enrollment and after the last dose of most recent anti-cancer therapy. * Or a new biopsy. Exclusion Criteria: * Fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes. * Patients with disease that is suitable for local therapy administered with curative intent. * Patients who experienced any Common Terminology Criteria for Adverse Events (CTCAE) ≥ 3 or any other immune- related toxicities that led to permanent discontinuation of treatment with immune checkpoint inhibitors in 1 L. * Persistent proteinuria of CTCAE Grade 3 or higher. * Diagnosis of immunodeficiency or patient is receiving chronic systemic steroid therapy (in doses exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study interventions. * Active autoimmune disease. * History of (non-infectious) pneumonitis that required steroids or current pneumonitis. * Any hemorrhage or bleeding event CTCAE Grade ≥ 3 within 28 days prior to the start of study medication. * Patients with large esophageal varices at risk of bleeding that are not being treated with conventional medical intervention. * Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 months before the start of study medication. * Ongoing infection CTCAE Grade \> 2 requiring systemic therapy. * Dual active HBV infection (HBsAg (+) and / or detectable HBV DNA) and HCV infection (anti-HCV Ab (+) and detectable HCV RNA) at study entry. * Uncontrolled hypertension (systolic blood pressure ≥ 140 mmHg or diastolic pressure ≥ 90 mmHg) on more than 2 separate measurements despite optimal medical management. * Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months). * Myocardial infarction less than 6 months before start of study intervention. * Pleural effusion or ascites that causes respiratory compromise (CTCAE Grade ≥ 2 dyspnea). * Patients with previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission was achieved at least 3 years prior to study entry. * Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable. * Significant acute gastrointestinal disorders with diarrhea as a major symptom. * Prior monotherapy treatment with any tyrosine kinase inhibitor in 1L. * Prior treatment with regorafenib, in combination regimens with immune checkpoint inhibitors. * Transfusion of blood products within 7 days prior to signing informed consent, or administration of colony stimulating factors within 4 weeks prior to signing informed consent. * Previous assignment to treatment during this study. * Previous (at least a minimum of 28 days, or 5 half-lives of an investigational drug before the start of study treatment, whichever is shorter) or concomitant participation in another clinical study with investigational medicinal product(s).