Observational Study Protocol: LIVER-R

LIVER-R is a real-world, multi-country, multi-centre study aiming to enroll approximately 4,000 patients across hepatobiliary cohorts (approximately 1,385 patients for aBTC, approximately 1,165 patients for uHCC, approximately 1,000 patients for eeHCC, and approximately 400 patients for EMERALD) across multiple countries from North and South America, Europe, the Middle East and the Asia-Pacific region. The study design will include primary and secondary data collection. Primary data will be collected in real-time during the patient's routine visit. Secondary data will be collected from the patient's medical record at enrollment and at prespecified study time points (6-month intervals). The study population includes adult patients whose physician has previously made the decision to treat them with or without a durvalumab-based regimen for hepatobiliary cancer as part of routine clinical practice or patients receiving treatment through EAP. The study will include a baseline period of up to 5 years before the index date (initiation of a durvalumab-based or non durvalumab-based regimen) and a follow-up period to the earliest of death, loss to follow-up, withdrawal, or end of study for a minimum follow-up of 2 years. This is a descriptive, noncomparative study. No formal hypotheses are to be tested. All descriptive analyses will be conducted separately for each primary hepatobiliary cancer indication. Kaplan Meier estimates will be produced for time-to-event outcomes.

Inclusion criteria

General Inclusion Criteria

All patients must meet all of the following general criteria 1-4 along with all respective cohort specific criteria noted below:

• Age ≥18 years and a lawful adult in the country at the index date
• Confirmed presence of malignancy of primary hepatobiliary cancer by any method (e.g., radiological, histological, etc.)
• Decision to treat was made independently and prior to obtaining informed consent
• Informed consent was obtained as per country level regulations (includes waiver of consent for retrospective data collection if approved)

aBTC Specific Inclusion Criteria

A patient will be eligible to be included in the aBTC cohort if they meet all general inclusion criteria 1-4 in addition to the following criteria:

• Patient has unresectable aBTC
• Has received or is intending to receive a durvalumab-based regimen (may have been treated in an EAP)

uHCC Specific Inclusion Criteria

A patient will be eligible to be included in the uHCC cohort if they meet all general inclusion criteria 1-4 in addition to the following criteria:

• Patient has unresectable uHCC
• Not eligible for LRT, as well as for those who progressed following LRT
• Has received or is intending to receive a durvalumab-based regimen (may have been treated in an EAP)

eeHCC Specific Inclusion Criteria

A patient will be eligible to be included in the eeHCC cohort if they meet all general inclusion criteria 1-4 in addition to the following criteria:

• HCC confirmed by radiological or histological diagnosis
• Child-Pugh A-B7
• Disease not amenable to curative treatment but amenable to LRT at index
• Patients with liver-confined HCC who initiated first non-curative intent LRT on or after 01 January 2024
• Patients eligible for LRT with palliative intent such as TACE/ TARE/transarterial infusion chemotherapy (TAIC)/ hepatic arterial infusion chemotherapy (HAIC)/transarterial embolization (TAE) given by itself or in combination with other systemic therapy (can include durvalumab) within 60 days of the LRT

EMERALD Specific Inclusion Criteria

A patient will be eligible to be included in the EMERALD cohort if they meet all general inclusion criteria 1-4 in addition to the following criteria:

• HCC confirmed by radiological or histological diagnosis
• Child-Pugh score of A-B7
• Liver-confined disease not amenable to curative treatment but amenable to LRT at index
• Receipt of a durvalumab-based regimen in combination with LRT administered within 28 days of each other (index is the first of the two treatments administered)

Exclusion criteria

General Exclusion Criteria

A patient will be excluded from participating in this study if they meet any of the following general criteria 1-2 or any cohort specific exclusion criteria:

• Currently/was participating or plans to participate in any clinical trial for investigational treatment for hepatobiliary cancers on or after the diagnosis date until the index date
• Second primary malignancy prior to HCC or BTC diagnosis

aBTC Specific Exclusion Criteria

A patient will be excluded from participating in the aBTC cohort if they meet any of the general exclusion criteria 1-2 or any of the following criteria:

• Received a liver transplant during the baseline period
• Received more than 1 cycle of Gemcitabine + Cisplatin for biliary tract cancer on or after diagnosis of unresectable, locally advanced or metastatic disease through the index date. Patients who received any systemic therapy while having early stage, resectable disease are eligible

uHCC Specific Exclusion Criteria

A patient will be excluded from participating in the uHCC cohort if they meet any of the general exclusion criteria 1-2 or any of the following criteria:

• Received a liver transplant during the baseline period
• Received other systemic therapies for hepatobiliary cancer indication on or after diagnosis date through the index date

eeHCC Specific Exclusion Criteria

A patient will be excluded from participating in the eeHCC cohort if they meet any of the general exclusion criteria 1-2 or any of the following criteria:

• Eligible for curative therapy at the time of receiving LRT (ablation)
• Extrahepatic spread
• Portal vein tumor thrombosis (PVTT) of VP3/4
• Receipt of systemic therapy prior to index LRT in the baseline period
• Liver transplant any time prior to index

EMERALD Specific Exclusion Criteria

A patient will be excluded from participating in the EMERALD cohort if they meet any of the general exclusion criteria 1-2 or any of the following criteria:

• Eligible for curative therapy at the time of receiving LRT (ablation)
• Extrahepatic spread
• Portal vein tumor thrombosis (PVTT) of VP3/4
• Receipt of systemic therapy prior to index LRT in the baseline period
• Liver transplant any time prior to index