Phase 3 Randomized Controlled Trial of Cabozantinib and Atezolizumab Versus Sorafenib in Treatment-Naïve Advanced Hepatocellular Carcinoma

The primary objective of this study is to evaluate the **efficacy** of cabozantinib in combination with atezolizumab versus sorafenib in subjects with advanced **hepatocellular carcinoma** (HCC) who have not received previous systemic anticancer therapy. This is clinically relevant as it aims to determine the potential benefits of a novel combination therapy in improving outcomes for patients with advanced HCC, a condition with limited treatment options and poor prognosis.

The secondary objective is to evaluate the activity of single-agent cabozantinib compared with sorafenib in subjects with advanced HCC who have not received previous systemic anticancer therapy. This assessment is crucial for understanding the individual contribution of cabozantinib to the treatment regimen and its potential as a standalone therapy.

The clinical trial involves a total of **575 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 includes adults and older adults. Participants were selected based on specific criteria, including a histological or cytological diagnosis of HCC or a clinical diagnosis in cirrhotic patients, as per the American Association for the Study of Liver Diseases (AASLD) or European Association for the Study of the Liver (EASL 2018) guidelines. The trial excludes vulnerable populations and focuses on individuals with disease stages not amenable to curative treatment approaches. Participants are required to have a measurable disease per RECIST 1.1, a Barcelona Clinic Liver Cancer (BCLC) stage of Category B or C, a Child-Pugh Score of A, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The selection process ensures a representative sample of the target population for evaluating the efficacy of cabozantinib in combination with atezolizumab versus sorafenib in subjects with advanced HCC who have not received previous systemic anticancer therapy.

The clinical trial is a **randomized**, controlled Phase 3 study designed to evaluate the efficacy of **cabozantinib** in combination with **atezolizumab** versus **sorafenib** in subjects with advanced **hepatocellular carcinoma** who have not received previous systemic anticancer therapy. The trial employs a **double-blind** methodology to ensure unbiased results. Participants will be randomly assigned to either the experimental arm receiving cabozantinib and atezolizumab or the control arm receiving sorafenib. The primary endpoints include the duration of progression-free survival (PFS) and overall survival (OS) as assessed by a Blinded Independent Radiology Committee (BIRC) using RECIST 1.1 criteria.

The trial is expected to run until December 31, 2025, with participant recruitment having commenced on April 30, 2019. The study involves several key visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a histological or cytological diagnosis of hepatocellular carcinoma, measurable disease per RECIST 1.1, and a Child-Pugh Score of A. Participants will undergo regular follow-up visits to monitor treatment efficacy and safety, with assessments conducted by the investigator. The end-of-study visit will conclude the participant's involvement, during which final evaluations will be performed.

Participant involvement is anticipated to last until the study's completion, contingent upon individual response to treatment and adherence to protocol requirements. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The trial's design and procedures are structured to ensure rigorous assessment of the investigational treatments' efficacy and safety, contributing valuable data to the field of oncology.

The clinical trial involves the administration of **CABOMETYX** 20 mg film-coated tablets, which contain the active substance **cabozantinib**. This medication is provided in the form of film-coated tablets and is intended for **oral use**. The maximum daily dose is 40 mg, with a total dose limit of 9999.99 mg. The treatment period is set to a maximum of 9999 days. The clinical trial material differs slightly from the marketed product, as detailed in the Investigational Medicinal Product Dossier (IMPD) for cabozantinib. Participant compliance will be monitored through regular assessments.

Another experimental treatment in the study is **CABOMETYX** 60 mg film-coated tablets, also containing **cabozantinib**. Similar to the 20 mg formulation, these tablets are administered orally. The maximum daily dose for this formulation is 60 mg, with the same total dose limit and treatment period as the 20 mg tablets. The clinical trial material for this formulation also differs slightly from the marketed product, as specified in the IMPD.

The trial also includes the administration of **Nexavar** 200 mg film-coated tablets, which contain the active substance **sorafenib**. This medication is administered orally, with a maximum daily dose of 800 mg and a total dose limit of 9999.99 mg. The treatment period is set to a maximum of 9999 days. Nexavar is used as a comparator treatment in this study, and it has been re-labeled for clinical trial use.

Additionally, the study involves the administration of **Tecentriq** 1,200 mg concentrate for solution for infusion, containing the active substance **atezolizumab**. This medication is provided as a solution for infusion and is administered via **intravenous use**. The maximum daily dose is 60 mg/ml, with a total dose limit of 9999.99 mg. The treatment period is set to a maximum of 9999 days. The clinical trial label will be added to the unlabeled single-dose vial, which will be packaged into a carton with an additional clinical trial label.

The efficacy of the clinical trial will be assessed by evaluating the primary endpoints, which include the **Duration of Progression Free Survival (PFS)** and **Duration of Overall Survival (OS)**. These endpoints will be measured for the experimental arm, consisting of cabozantinib in combination with atezolizumab, compared to the control arm, which involves sorafenib. The PFS will be determined per RECIST 1.1 criteria by a Blinded Independent Radiology Committee (BIRC). Additionally, a secondary endpoint will assess PFS for the single-agent cabozantinib arm versus the control arm.