Regorafenib Plus Pembrolizumab in First Line Systemic Treatment of HCC

Inclusion Criteria:

- Male or female patients ≥ 18 years of age on day of signing informed consent.

- Histological or cytological confirmation of HCC (hepatocellular carcinoma) or
non-invasive diagnosis of HCC as per American Association for the Study of Liver
Diseases (AASLD) criteria in patients with a confirmed diagnosis of cirrhosis.

- Barcelona Clinic Liver Cancer (BCLC) stage B or C that cannot benefit from treatments
of established efficacy such as resection, local ablation, chemoembolization.

- Liver function status Child-Pugh (CP) Class A. CP status should be calculated based on
clinical findings and laboratory results during the screening period.

- Any local or loco-regional therapy of intrahepatic tumor lesions (e.g. surgery,
radiation therapy, hepatic arterial embolization, chemoembolization, radiofrequency
ablation, percutaneous ethanol injection, or cryoablation) must have been completed ≥
4 weeks before first dose of study medication. Note: patients who received sole
intrahepatic intra-arterial chemotherapy, without lipiodol or embolizing agents are
not eligible.

- Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.

- At least one uni-dimensional measurable lesion by computed tomography (CT) scan or
magnetic resonance imaging (MRI) according to RECIST (RECIST version 1.1) and no older
than 28 days before start of the study treatment. 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.

- Life expectancy of at least 3 months.

- Adequate bone marrow and organ function as assessed by the laboratory tests performed
within 7 days before of treatment initiation.

- For patients recruited in the expansion cohort only, provision of archival (block) or
fresh tumor tissue samples at baseline is mandatory. If archival tumor tissue is not
available, patients should be willing to undergo a biopsy for provision of fresh tumor
samples

Exclusion Criteria:

- Prior systemic therapy for HCC; prior exposure to regorafenib.

- Previous treatment with a programmed death 1 (PD1), programmed death-ligand (PD-L1),
or cytotoxicT-lymphocyte-associated protein 4 (CTLA-4) inhibitors, or any form of
immunotherapy for HCC.

- Previous treatment with live vaccine within 30 days of planned start of study drugs
(seasonal flu vaccines that do not contain a live virus are permitted).

- Active autoimmune disease (active defined as having autoimmune disease related
symptoms and detectable autoantibodies) that has required systemic treatment in the
past 2 years (i.e., with use of diseasemodifying agents, corticosteroids, or
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency,
etc.) is not considered a form of systemic treatment.

- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of study drugs. The
use of physiologic doses of corticosteroids may be approved after consultation with
the Sponsor.

- Known history of human immunodeficiency virus (HIV) infection (HIV 1/2 antibodies).

- Dual active HBV infection (HBsAg (+) and /or detectable HBV DNA) and HCV infection
(anti-HCV Ab(+) and detectable HCV RNA) at study entry.

- Pleural effusion or ascites that causes respiratory compromise (≥ CTCAE Grade 2
dyspnea).

- Known history of metastatic brain or meningeal tumors.

- Significant acute gastrointestinal disorders with diarrhea as a major symptom e.g.,
Crohn's disease,malabsorption, or CTCAE Grade ≥ 2 diarrhea of any etiology.