Evaluation of Atezolizumab and Bevacizumab, with or without Tiragolumab, in Untreated Locally Advanced or Metastatic Hepatocellular Carcinoma

The primary objective of this study is to evaluate the **efficacy** of the combination of atezolizumab, bevacizumab, and tiragolumab compared to atezolizumab and bevacizumab alone in patients with untreated locally advanced or metastatic **hepatocellular carcinoma** (HCC). This will be assessed based on investigator-assessed progression-free survival (PFS) and overall survival (OS). The clinical relevance of this objective lies in determining whether the addition of tiragolumab can improve survival outcomes in this patient population, potentially offering a more effective treatment option.

Secondary objectives include:

• Evaluating the efficacy of the combination therapy based on investigator-assessed confirmed objective response rate (ORR), duration of response (DOR), PFS rate at 6 and 12 months, OS rate at 1 and 2 years, time to confirmed deterioration (TTCD), and changes in global health status/quality-of-life (QoL), physical functioning, and role functioning using the EORTC QLQ-C30.
• Assessing the safety profile of the combination therapy compared to the dual therapy.
• Characterizing the pharmacokinetic (PK) profile of the combination therapy.
• Evaluating the immune response to tiragolumab and atezolizumab.

The clinical trial involves a total of **477 participants** diagnosed with **Hepatocellular Carcinoma (HCC)**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific criteria, including having locally advanced or metastatic and/or unresectable HCC confirmed by histology/cytology or clinically by the American Association for the Study of Liver Diseases (AASLD) criteria in cirrhotic individuals. The trial includes individuals with no prior systemic treatment for HCC, measurable disease according to RECIST v1.1, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Participants are required to have a Child-Pugh Class A status and adequate hematologic and end-organ function. Additionally, a negative HIV test and documented virology status for hepatitis B and C are necessary. Both male and female participants must agree to use protocol-defined methods of contraception. The trial population includes vulnerable groups, ensuring a comprehensive evaluation of the treatment's efficacy across diverse demographics.

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the efficacy of a combination therapy involving **atezolizumab**, **bevacizumab**, and **tiragolumab** in patients with untreated locally advanced or metastatic **hepatocellular carcinoma** (HCC). The trial aims to compare the progression-free survival (PFS) and overall survival (OS) of patients receiving the combination therapy against those receiving atezolizumab and bevacizumab alone. The study is expected to run from August 2023 to September 2026, with the estimated duration of participant involvement being up to 36 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as confirmed diagnosis of HCC, measurable disease, and adequate organ function. Following randomization, participants will receive intravenous infusions of the study drugs or placebo according to their assigned group. Regular follow-up visits will be conducted to monitor treatment response, assess safety, and collect data on primary and secondary endpoints, including PFS, OS, and incidence of adverse events. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.

Early termination from the study may occur if participants experience unacceptable toxicity, disease progression, or withdrawal of consent. The trial will adhere to rigorous scientific and ethical standards, ensuring that all procedures are conducted in compliance with regulatory requirements. The primary endpoints of the study are investigator-assessed PFS and OS, while secondary endpoints include overall response rate (ORR), duration of response (DOR), and quality of life assessments. The trial will also evaluate the pharmacokinetics of atezolizumab and tiragolumab, as well as the prevalence and incidence of anti-drug antibodies.

The clinical trial involves the administration of **Tiragolumab**, a concentrate for solution for infusion, developed by F. Hoffmann-La Roche Ltd. The active substance, tiragolumab, is a protein of non-specified origin. The pharmaceutical form is a concentrate for solution for infusion, and the medication is administered via **intravenous infusion**. The maximum daily dose is 600 mg, with a total dose of 1 mg per treatment period, which lasts for one day.

A **Placebo** for Tiragolumab is also utilized in this study. It is administered in the same manner as the active drug, via intravenous infusion. The placebo is designed to match the experimental treatment in appearance and administration but contains no active substance. The maximum treatment period for the placebo is 36 days, with no active dose administered.

**Tecentriq** (atezolizumab) is another experimental medication used in this trial. It is a concentrate for solution for infusion, with the active substance being atezolizumab, a protein of non-specified origin. The pharmaceutical form is a solution for infusion, and it is administered via intravenous infusion. The maximum daily dose is 1200 mg, with a total dose of 1 mg per treatment period, which lasts for one day. Tecentriq is developed by Roche Registration GmbH.

**Avastin** (bevacizumab) is also included in the trial as a concentrate for solution for infusion. The active substance, bevacizumab, is a protein of non-specified origin. The pharmaceutical form is a solution for infusion, administered via intravenous infusion. The maximum daily dose is 15 mg/kg, with a total dose of 1 mg/kg per treatment period, which lasts for one day. Avastin is developed by Roche Registration GmbH.

The efficacy of the investigational treatment regimen in this clinical trial will be assessed primarily through **progression-free survival (PFS)** and **overall survival (OS)**, as evaluated by investigators. These primary endpoints will provide critical insights into the treatment's impact on disease progression and patient survival. Secondary endpoints include investigator-assessed confirmed objective response rate (ORR), duration of response (DOR), PFS rate at 6 and 12 months, and OS rate at 1 and 2 years. Additionally, the trial will evaluate time to deterioration (TTCD) in global health status/quality of life (GHS/QoL), physical functioning, and role functioning using the EORTC QLQ-C30 questionnaire.

Further assessments will include the incidence and severity of adverse events, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0) and the American Society for Transplantation and Cellular Therapy (ASTCT) CRS Consensus Grading scale for cytokine release syndrome (CRS). Serum concentrations of atezolizumab and tiragolumab will be measured at specified timepoints, and the prevalence and incidence of anti-drug antibodies (ADAs) to both tiragolumab and atezolizumab will be evaluated at baseline and after treatment. These comprehensive efficacy assessments will be conducted to determine the therapeutic potential and safety profile of the treatment regimen in patients with untreated locally advanced or metastatic hepatocellular carcinoma.