A Phase III, Randomised, Open-Label, Sponsor-Blinded, Multicenter Study of Rilvegostomig in Combination with Bevacizumab with or without Tremelimumab as First-line Treatment in Patients With Advanced Hepatocellular Carcinoma (ARTEMIDE-HCC01)

The primary objective of this study is to demonstrate the efficacy of rilvegostomig in combination with tremelimumab and bevacizumab (Arm A) relative to atezolizumab and bevacizumab (Arm C) by assessment of overall survival (OS) in participants with advanced hepatocellular carcinoma. This comparison is clinically relevant as it evaluates whether the novel combination therapy can improve survival outcomes compared to the current standard treatment regimen in this patient population.

The secondary objectives include:

• To demonstrate the efficacy of Arm B relative to Arm C by assessment of OS in participants with advanced HCC

• To further demonstrate the efficacy of Arm A relative to Arm C and Arm B relative to Arm C in participants with advanced HCC

• To demonstrate the efficacy of Arm A relative to Arm B in participants with advanced HCC

• To demonstrate the efficacy of Arm A relative to Arm C in the population defined by PD-L1 expression subgroups

• To demonstrate the efficacy of Arm B relative to Arm C in the population defined by PD-L1 expression subgroups

• To investigate the immunogenicity of Arm A and Arm B

• Occurrence of adverse events (AEs) and serious adverse events (SAEs)

The clinical trial enrolled a total of **947 participants** diagnosed with **advanced hepatocellular carcinoma**. The study population included both **male** and **female** adults and elderly individuals. Participants were required to have **locally advanced** or **metastatic** and/or **unresectable HCC** classified as **BCLC stage B** (not eligible for locoregional therapy) or **stage C**, with **Child-Pugh Score class A** liver function. Eligible participants demonstrated a **WHO/ECOG performance status** of 0 or 1, indicating good functional capacity, and possessed at least one **measurable target lesion**. The trial population was selected to include individuals with disease not amenable to curative surgical and/or locoregional therapies. Key exclusion criteria included prior systemic therapy for intermediate, advanced, or metastatic HCC, co-infection with both **HBV** and **HCV**, and inadequate organ and bone marrow function. Participants who had received approved adjuvant therapy, including immune checkpoint inhibitor treatment, were required to have a minimum interval of 6 months between therapy completion and documented diagnosis of recurrent or metastatic disease. For those who underwent locoregional therapy, treatment must have been completed at least 28 days prior to baseline imaging. The trial included a vulnerable population subset.

This is a Phase III, randomized, open-label, sponsor-blinded, multicenter clinical trial evaluating **rilvegostomig** in combination with **bevacizumab** with or without **tremelimumab** as first-line treatment in participants with **advanced hepatocellular carcinoma**. The trial will compare the efficacy of rilvegostomig in combination with tremelimumab and bevacizumab (Arm A) relative to **atezolizumab** and bevacizumab (Arm C). The primary objective is to demonstrate the efficacy of the investigational treatment regimen by assessment of **overall survival** in participants with advanced hepatocellular carcinoma. Secondary endpoints include **progression-free survival**, **objective response rate**, and **duration of response** as assessed by blinded independent central review according to RECIST version 1.1 criteria.

Eligible participants must have locally advanced or metastatic and/or unresectable hepatocellular carcinoma classified as **Barcelona Clinic Liver Cancer** stage B (not eligible for locoregional therapy) or stage C. Participants must have a **WHO/ECOG performance status** of 0 or 1, **Child-Pugh Score** class A, and at least one measurable target lesion. Participants must not have received prior systemic therapy for intermediate, advanced, or metastatic hepatocellular carcinoma. Disease must not be amenable to curative surgical and/or locoregional therapies. Participants who have received approved adjuvant therapy, including immune checkpoint inhibitor treatment, must have a minimum interval of 6 months between the completion of such therapy and the documented diagnosis of recurrent or metastatic disease. For participants who received locoregional therapy for hepatocellular carcinoma, such therapy must have been completed at least 28 days prior to the baseline scan. Participants co-infected with **hepatitis B virus** and **hepatitis C virus** are not eligible. Adequate organ and bone marrow function measured during the screening period is required.

The investigational medicinal products include **rilvegostomig** (AZD2936) as a **solution for infusion** administered via **intravenous use**, tremelimumab (IMJUDO 20 mg/ml concentrate for solution for infusion) administered via intravenous use, and bevacizumab as a solution for infusion administered via intravenous use. The comparator product is atezolizumab administered via intravenous use. Auxiliary medicinal products include **mycophenolate mofetil** administered via **oral** route and **infliximab** administered via intravenous use. All investigational and comparator products will be provided with clinical labeling and secondary packing or repacking as applicable.

The estimated recruitment start date is January 1, 2026, and the estimated end date of the trial is March 15, 2030. The maximum treatment period for all investigational and auxiliary products is not specified with a fixed duration, allowing for extended treatment as clinically indicated. Participant involvement will extend from the screening visit through the treatment period and follow-up assessments until the end-of-study visit. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision based on clinical judgment. The trial design incorporates regular study visits to assess safety, efficacy, and disease status throughout the participant's involvement in the study.

The experimental medication rilvegostomig (sponsor product code AZD2936) is administered as a solution for infusion via intravenous use. The active substance is rilvegostomig, a bispecific IgG1 monoclonal antibody against PDCD1 and TIGIT. The concentration is expressed in milligrams per milliliter. This investigational product is supplied with clinical labelling and secondary packing for the purposes of this trial.

Tremelimumab is administered as IMJUDO 20 mg/ml concentrate for solution for infusion via intravenous use. The pharmaceutical form is solution for infusion containing tremelimumab as the active substance, which is a protein of other origin. The product is authorized under EU/1/22/1713/001 and EU/1/22/1713/002 with marketing authorization number EMEA/H/C/006016. The product will be supplied with clinical labelling and secondary packing. The ATC code is L01FX20.

Bevacizumab is administered via intravenous use. The active substance bevacizumab is a protein of other origin with concentration expressed in milligrams per milliliter. The product has ATC code L01FG01. The pharmaceutical form is indicated for intravenous administration. This product will be supplied with clinical labelling and repacking for use in the study.

Atezolizumab serves as a comparator treatment in this trial. The product is administered via intravenous use with concentration expressed in milligrams per milliliter. The ATC code is L01FF05. The product will be supplied with clinical labelling and repacking. The maximum treatment period is specified in months.

Mycophenolate mofetil is included as an auxiliary medication in capsule form for oral administration. The active substance is mycophenolate mofetil, a chemical drug. The dose is expressed in grams. This product will be supplied with clinical labelling and repacking.

Infliximab is included as an auxiliary medication administered as a concentrate for solution for infusion via intravenous use. The dosage is expressed in milligrams per kilogram. This product will be supplied with clinical labelling and repacking for use in the clinical trial.

Efficacy will be assessed using Overall Survival (OS) as the primary endpoint. The main objective is to demonstrate the efficacy of rilvegostomig in combination with tremelimumab and bevacizumab relative to atezolizumab and bevacizumab by assessment of OS in participants with advanced hepatocellular carcinoma. Secondary efficacy endpoints include Progression-Free Survival (PFS), Objective Response Rate (ORR), and Duration of Response (DoR) as assessed by Blinded Independent Central Review (BICR) per RECIST v1.1 criteria.