Study Comparing BGB-B2033 With Sorafenib or Lenvatinib in Relapsed Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. It can develop when abnormal cells in the liver grow uncontrollably and may spread to other parts of the body. For people whose cancer has returned or continued to grow after treatment, additional treatment options are needed.

BGB-B2033 is a new investigational drug designed to bind to a protein called glypican-3 (GPC3), a protein found on certain cancer cells and cells of the immune system, helping the immune system to recognize and attack the cancer cells. Lenvatinib and sorafenib are approved medicines that work by blocking signals that help cancer cells grow and form new blood vessels.

The purpose of this study is to test whether BGB-B2033 is safe and can help treat HCC in adults whose cancer has been treated with up to 2 previous treatments that included programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) medicines. The main goal of the study is to see how well BGB-B2033 controls cancer compared to the treatments selected by the study doctor (either lenvatinib or sorafenib).

This study has 2 treatment groups. Participants will be randomly assigned, like flipping a coin, to receive either:

• BGB-B2033, given by intravenous infusion.
• Sorafenib, taken by mouth or lenvatinib, taken by mouth per their doctor's choice The study will enroll approximately 492 adults with HCC at multiple centers worldwide. Participants will make regular visits to the clinic for treatment, health checks, blood tests, and tumor and imaging tests.

The overall study will last about 3.5 years, not including the screening period.

Key Inclusion Criteria:

• Participants must have histologically confirmed Hepatocellular Carcinoma (HCC) that is not amenable to curative surgical or locoregional therapies.
• Participants must have documented disease progression or intolerance after at least 1 but not exceeding 2 prior lines of systemic therapy containing Programmed Cell Death Protein 1 / Programmed Death-Ligand 1 (PD-1/PD-L1). Prior cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) targeting therapy or v ascular endothelial growth factor (VEGF) is permitted but not required.
• Glypican-3 (GPC3) expression level must be known for stratification.
• Participants must have at least 1 measurable lesion as assessed by RECIST v1.1
• Participants must have a stable Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1.

Key Exclusion Criteria:

• Prior therapy targeting GPC3 or 4-1BB
• Participants not feasible to be treated with lenvatinib or sorafenib

• prior exposure to both medications
• siginificant precautions of administering lenvatinib or sorafenib such as clinically significant active bleeding within 3 months prior to first dose, tumor thombus involving main portal vein trunk, inferior vena cava, or cardiac involvement,
• any history of gastrointestinal perforation or larger than grade 3 fistula within 6 months prior to the first dose,
• or any history of heart failure meeting NYHA classification III or IV ≤ 6 months before the first dose of study drug.
• Active leptomeningeal disease or uncontrolled and untreated brain metastasis
• History of previous or present encephalopathy
• Presence of clinically significant ascites ((≥ Grade 2).
• History of liver transplantation

NOTE: Other eligbility criteria may apply.