LIVER-R study protocol: a global real-world study of durvalumab-based regimens in patients with hepatobiliary cancers

ABSTRACT

Background

Durvalumab-based regimens have improved outcomes compared with standard of care in unresectable hepatocellular carcinoma (uHCC) and advanced biliary tract cancer (aBTC) clinical trials. Here we describe the protocol for the LIVER-R study, which will evaluate long-term outcomes with durvalumab-based regimens in patients with hepatobiliary cancers in real-world settings.

Methods

LIVER-R (NCT06252753) is an observational study aiming to initially enroll ~2500 adults with uHCC or aBTC from ~179 sites in 22 countries. Patients treated with durvalumab-based regimens as part of routine clinical practice or a global early access program will be included. The primary outcome is overall survival. Secondary outcomes include duration of treatment, progression-free survival, treatment patterns and safety. Data will be collected at baseline and every 6 months. The study will include a baseline period of up to 5 years before index date (initiation of first-line durvalumab-based regimen) and a follow-up period from index until death, loss to follow-up, withdrawal, or study end. Study variables will be analyzed descriptively; time-to-event outcomes will be analyzed using the Kaplan–Meier method.

Conclusions

LIVER-R will produce a large, global, real-world standardized dataset of patients with uHCC or aBTC treated with a durvalumab-based regimen, providing insights into real-world clinical practice.

Clinical trial registration

www.clinicaltrials.gov identifier is NCT06252753.

Plain Language Summary

Why are we conducting this research?

Hepatocellular carcinoma (HCC) is a type of liver cancer and a leading cause of cancer-related death. Most people with HCC present with a disease that is not treatable by surgery, called unresectable HCC (uHCC). Biliary tract cancers (BTCs) are a group of tumors in the bile ducts and gallbladder. BTCs that are not treatable by surgery are known as advanced BTC (aBTC). Durvalumab is a type of immunotherapy and durvalumab-based treatments were found to be effective for patients with uHCC and aBTC in previous clinical trials. The LIVER-R study will look at how well durvalumab-based treatments work in patients with uHCC or aBTC in day-to-day clinical practice.

How are we conducting this research?

This real-world study aims to enroll approximately 2500 people with uHCC or aBTC globally. Data from patients will be collected as part of routine clinical practice or gathered from patient medical charts every 6 months. The main objective of this study is to measure the length of time that people live after receiving durvalumab-based treatments. Secondary outcomes include the length of time from the start of treatment to when a patient’s cancer worsened or led to death, treatment patterns, and negative side effects experienced during the study period.

Where can I access more information?

This study is still ongoing. More information about this study can be found at https://clinicaltrials.gov/study/NCT06252753.

1. Introduction

Hepatobiliary cancers (HBCs) affect the liver, bile ducts, and gallbladder and are associated with poor prognosis and survival [1–4].

Hepatocellular carcinoma (HCC) accounts for ~90% of all primary liver cancer cases [5]. HCC is the third leading cause of cancer-related deaths worldwide, and most patients present with unresectable disease that cannot be treated with surgery [6,7]. Estimated 5-year survival rates in patients with HCC are 37% for early-stage disease and <10% in patients with unresectable HCC (uHCC) [3].

Biliary tract cancers (BTCs) are a group of cancers comprised of intrahepatic and extrahepatic cholangiocarcinoma, gallbladder cancer, and ampulla of Vater cancer [8]. Cholangiocarcinomas are the second most common type of primary liver cancer after HCC, accounting for ~15% of all primary liver cancers [9]. BTCs are typically diagnosed in the advanced stages of disease when prognosis is poor [8]. Estimated 5-year survival rates in patients with BTCs are 18–69% in patients with early-stage disease and <5% in patients with advanced BTCs (aBTCs) [1,2].

Recent phase III clinical trials have shown that immune checkpoint inhibitor-based regimens, including a single priming dose of tremelimumab (anti-cytotoxic T lymphocyte-associated antigen 4) added to durvalumab (anti-programmed cell death ligand-1) in the STRIDE regimen (Single Tremelimumab Regular Interval Durvalumab; single-dose tremelimumab 300 mg plus durvalumab 1500 mg every 4 weeks) and durvalumab plus gemcitabine and cisplatin (GemCis), are effective in treating uHCC and aBTC, respectively [10,11].

HIMALAYA (NCT03298451) is a randomized, open-label, multicenter, global, phase III study that showed that STRIDE significantly improved overall survival (OS) versus sorafenib in participants with uHCC who had not previously been treated with systemic therapy (hazard ratio [HR] 0.78 [96.02% confidence interval (CI) 0.65–0.93], p = 0.0035) [11]. Based on results from HIMALAYA, STRIDE was approved globally for the treatment of adult patients with uHCC [12–15]. An updated analysis of the HIMALAYA study showed that STRIDE sustained an OS benefit after 5 years of follow-up, with a 5-year OS rate of 19.6% for STRIDE versus 9.4% with sorafenib (OS HR 0.76 [95% CI 0.65–0.89]) [16].

TOPAZ-1 (NCT03875235) is a randomized, double-blind, placebo-controlled, global, phase III study of durvalumab plus GemCis for participants with unresectable, locally advanced, or metastatic BTC [10], which showed that durvalumab plus GemCis significantly improved OS in patients with aBTC, versus placebo plus GemCis (HR 0.80 [95% CI 0.66–0.97], p = 0.021) [10]. Based on these results, durvalumab plus GemCis was approved as a first-line treatment for adult patients with unresectable or metastatic BTC [12,13]. Recent findings from the TOPAZ-1 3-year analysis showed sustained OS benefit with durvalumab plus GemCis versus placebo plus GemCis (OS HR 0.74 [95% CI 0.63–0.87]) [17].

As a result of improved clinical outcomes in phase III clinical trials of patients with uHCC or aBTC [10,11], treatment guidelines for uHCC and aBTC have been updated to include STRIDE or durvalumab plus GemCis regimens, respectively [18–21].

Preliminary results from real-world studies have provided valuable insights into the effectiveness of durvalumab-based treatments in routine clinical practice in patients with HBCs [22–24]. A recent observational study assessing the effectiveness of STRIDE in 24 patients with uHCC (first-line setting, n = 6; second-line or higher setting, n = 18) from five centers in Asia, Europe, and the United States demonstrated that after a median follow-up of 3.2 months, median OS was not reached with STRIDE and the 6-month OS rate was 95.8% [22]. In addition, an early exploratory analysis of 145 patients with aBTC treated with durvalumab plus GemCis as part of an early access program at 17 centers across Italy showed that median OS was 12.9 months after a median follow-up of 8.5 months [23]. Furthermore, in a global, multicenter, retrospective analysis of 666 patients with aBTC across 39 sites in Asia, Europe, and the United States, median OS was 15.1 months with durvalumab plus GemCis versus 11.1 months with GemCis after a median follow-up of 8.5 months [24]. Although real-world studies have confirmed the effectiveness of durvalumab-based regimens, as seen in the HIMALAYA and TOPAZ-1 clinical trials, interpretations of their results are limited by the short duration of follow-up and the absence of OS rate data for aBTC [22–24]. Assessment of long-term outcomes in large, global patient populations is needed. In real-world settings, the number of patients who complete all eight recommended cycles of durvalumab plus GemCis is not definitively established. For example, some real-world studies have reported that 36.1% to 45.5% of patients completed eight cycles of GemCis-based combination regimens [24,25], whereas another study reported that most patients were unable to receive all eight cycles of GemCis, with treatment being discontinued after a median of 4.6 months (approximately five cycles) [26].

Here, we outline the study design of LIVER-R, a real-world observational study of patients with HBCs treated with durvalumab-based regimens as part of routine clinical practice or an early access program. To our knowledge, LIVER-R will be the first real-world study to provide evidence on long-term outcomes with first-line durvalumab-based regimens in a large, global population of patients with HBCs, providing insights for reimbursement, health technology assessments, and clinical decision-making. The results of LIVER-R will help to further define the role of first-line durvalumab-based regimens in clinical practice for patients with uHCC and aBTC, as well as for new HBC cohorts, as ongoing clinical trials which include durvalumab demonstrate improved outcomes over prior standard of care and achieve regulatory approvals.

2. Methods

2.1. Study design

LIVER-R (NCT06252753 [registered: 21 December 2023]) is a real-world, multi-country, multi-center, non-interventional, ambispective, observational study of patients with uHCC or aBTC treated with a durvalumab-based regimen for an approved HBC indication, either in routine clinical practice or as part of a global early access program. Data may also be collected in patients who are part of a global early access program before the indication is approved in the respective country. The study design is shown in Figure 1.

Figure 1.

LIVER-R study design.

*Germany is currently the only country that has primary data collection. ^†Data abstracted from patient’s medical charts within 2 weeks of the enrollment date for the index date and the baseline period data, and at 6-month intervals over the follow-up period.

Abbreviations: aBTC: advanced biliary tract cancer; HBC: hepatobiliary cancer; uHCC: unresectable hepatocellular carcinoma.

No interventions will be applied as part of this study, and there will be no protocol-mandated patient assessments or follow-up visits. Treatment will be provided at the physician’s discretion as part of routine clinical practice.

The LIVER-R study will include a baseline period of up to 5 years before the index date (date of initiation of a first-line durvalumab-based regimen that occurs no earlier than February 2022 [global early access program start date]) and a follow-up period from the index date until death, loss to follow-up, withdrawal, or end of the study.

LIVER-R study recruitment for patients with uHCC and aBTC started in December 2023 and is planned to be completed in December 2026 in these cohorts. Patients with uHCC will be followed for up to 3 years (until December 2029); patients with aBTC will be followed for up to 2 years (until December 2028).

LIVER-R will allow new HBC cohorts in earlier stages of disease to be incorporated as results from ongoing clinical trials of durvalumab-based regimens become available and new indications are approved.

2.2. Patients

Patient eligibility criteria are outlined in Table 1. Adult patients diagnosed with uHCC or aBTC who are treated with an approved durvalumab-based regimen, either as part of routine clinical practice or as part of a global early access program, are eligible. Patients who are currently participating or have previously participated or are planning to participate in a clinical trial for the investigational treatment of HBC are not eligible. Those who have previously received other systemic therapies or a liver transplant for HBC will also be excluded. Eligibility criteria in LIVER-R may be amended to allow for the addition of future indications of durvalumab-based regimens for the treatment of HBCs. The aim is to initially enroll ~2500 patients, comprising 1135 patients with uHCC and 1355 patients with aBTC.

Table 1.

Patient eligibility criteria.

Inclusion criteria	Exclusion criteria
≥18 years of age Confirmed diagnosis of HBC (uHCC or aBTC) Type of HBC is approved to be treated with a durvalumab-based regimen as part of routine clinical practice or as part of a global early access program	Currently participating or previously participated or planning to participate in any clinical trial for investigational treatment of HBCs on or after the diagnosis date until the index date Received other systemic therapies for HBC prior to initiating a durvalumab-based regimen Received a liver transplant during the baseline period

Note: Eligibility criteria may be adapted as additional studies/indications are added to LIVER-R.

Abbreviations: aBTC: advanced biliary tract cancer; HBC: hepatobiliary cancer; uHCC: unresectable HCC.

2.3. Study sites

The planned global distribution of participating sites is shown in Figure 2. Enrollment of patients will initially occur at ~179 sites from ~22 countries in the Americas, Europe, the Middle East, and the Asia-Pacific region. All sites will be screened and evaluated for participation, including information on research experience, size of relevant patient population, and expected use of durvalumab-based regimens. Each approved site will obtain ethics approval and undergo training on the study protocol, electronic data capture (EDC) system, and process for identifying and enrolling patients, before enrolling the first patient. Additional sites may be included over time.

Figure 2.

Planned locations of global study sites.

2.4. Data collection

The study design will be ambispective and include primary or secondary data collection, depending on a country’s needs. Currently, Germany is the only country with primary data collection. This is because the healthcare system in Germany is fragmented, and various aspects of healthcare access, including diagnostics, laboratory assessments, and prescriptions, are not documented in a common database. This lack of centralized documentation may result in sparse information for the LIVER-R study. Secondary data will be collected from most sites in this study. All data will be entered into the CLININFO EDC system using electronic case report forms (eCRFs), designed with edit checks and pop-up queries to reduce manual queries.

2.4.1. Primary data collection

Primary data will be collected in patients who are scheduled to receive or have recently received their first durvalumab-based regimen (newly treated patients). Primary data collection will be implemented with prospective patient enrollment and follow-up, and data will be collected when the patient visits the site for routine treatment and follow-up visits.

2.4.2. Secondary data collection

Secondary data will be collected in patients who are either scheduled to receive their first durvalumab-based regimen (newly treated patients), have already received ≥1 dose of a durvalumab-based regimen and are still receiving treatment or are being followed after treatment has stopped (previously treated active patients), or have died or completed the study follow-up period (previously treated completed patients). Previously treated active and completed patients may include patients enrolled in a closed early access program. Secondary data collection will be implemented with either prospective patient identification and enrollment and follow-up, wherein the patient data will be abstracted from medical records at enrollment and at pre-specified study time points (6-month intervals) over the patient’s routine treatment and follow-up visits (newly treated or previously treated active patients) or with retrospective patient identification, wherein the patient data will be abstracted from medical records at patient enrollment (completed patients).

2.5. Study outcomes

Study outcomes in LIVER-R are for currently approved indications for durvalumab-based treatments and may be updated as new indications are added.

2.5.1. Real-world effectiveness outcomes

The primary effectiveness outcome of this study is real-world OS, defined as the time from the index date to death due to any cause (Table 2). OS is relevant for patients with advanced HBCs, and its selection as the primary outcome aligns with the primary endpoints of the phase III HIMALAYA and TOPAZ-1 clinical trials [10,11].

Table 2.

Key outcomes in LIVER-R.

Outcome	Definition
Real-world effectiveness
Overall survival	Time from the index date to date of death, by any cause. Patient's vital status at the end of their follow-up period or end of the study may be obtained by site personnel through phone call or from publicly available resources (when available)
Duration of treatment	Time from the initiation of treatment to date of discontinuation
Progression-free survival	Time from the index date to date of documented disease progression, as determined by the physician’s assessment or patient's death, whichever is earlier
Time to progression	Time from the index date to date of documented disease progression, as determined by the physician’s assessment
Time to next treatment	Time from the index date to date of initiation of the next treatment
Patient demographics and clinical characteristics
Demographics	Age, gender, race (if allowed for data collection), country, region, weight, height
Type of HBC	aBTC or uHCC
Disease status	Initially unresectable/refractory or recurrent
Disease classification	Locally advanced or metastatic
ECOG PS	ECOG PS as ordinal from PS 0 to PS 4
Diagnosis date	Date of confirmed diagnosis for advanced/unresectable HBC, as confirmed by the Principal Investigator
Time since diagnosis	Time from diagnosis date to index date
Etiologies/risk factors and other comorbidities	Etiologies/risk factors will be classified as either viral or non-viral etiologies Viral etiologies will include the following: HBV infection, HCV infection, and HIV infection Non-viral etiologies/risk factors will include the following: alcohol use, autoimmune liver disease, bile duct stones, cirrhosis, choledochal cyst, chronic biliary tract infection, drug-induced liver injury, gallstones, liver fluke, metabolic storage disease, metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction-associated steatohepatitis, portal hypertension/signs of portal hypertension, primary sclerosing cholangitis, obesity, splenomegaly (or increased spleen size) and all size of varices (small to large), thrombocytopenia, tobacco use, Type 1 diabetes, Type 2 diabetes, and ulcerative colitis Other comorbidities documented will include the following: anemia, ascites, cardiovascular disease (e.g., bleeding risk, cirrhosis, stroke, hypertension), chronic kidney disease, chronic obstructive pulmonary disease, electrolyte imbalance, end-stage renal disease, esophageal varices, evidence of prior or concurrent non-HBC, gastrointestinal hemorrhage, hepatic encephalopathy, hyperlipidemia, hypersplenism, and hypoproteinemia
Liver function test results and ALBI score	Liver function test results will include albumin, bilirubin (total), creatinine (calculated creatinine clearance), international normalized ratio, and prothrombin time The ALBI score will be calculated using the albumin and bilirubin test results
Biomarker test	Biomarker test results will include alpha-fetoprotein, carbohydrate antigen (CA19-9), and carcinoembryonic antigen
Genetic mutations detected after BTC diagnosis (patients with BTC only)	Presence of genetic mutations will include the following: epithelial growth factor receptor, fibroblast growth factor receptor 2, isocitrate dehydrogenase 1 (NADP+), receptor tyrosine-protein kinase erbB-2, serine/threonine-protein kinase B-Raf, and vascular endothelial growth factor
Primary tumor type (patients with BTC only)	Intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma (i.e., perihilar or distal), gallbladder, or ampulla of Vater
Portal vein tumor thrombosis (patients with HCC only)	Portal vein tumor thrombosis as one of the five following grades: Vp0, Vp1, Vp2, Vp3, Vp4
Child-Pugh score (patients with HCC only)	Child-Pugh score categories as A, B, or C at index date and date of disease progression (missing documented Child-Pugh score may be calculated from component data when available [i.e., total bilirubin, albumin, prothrombin time (or international normalized ratio), ascites, and hepatic encephalopathy])
Barcelona Clinic Liver Cancer staging (patients with HCC only)	Barcelona Clinic Liver Cancer stages as ordinal at index date and date of disease progression: Stage 0 (very early stage); Stage A (early stage); Stage B (intermediate stage); Stage C (advanced stage); Stage D (terminal stage)
Esophagogastroduodenoscopy (patients with HCC only)	Occurrence of esophagogastroduodenoscopy and whether varices were detected
Treatment patterns
Treatment regimens	Each treatment regimen administration, either alone or in combination therapy, will be documented with start date and dose. If the treatment regimen is a combination, the other therapy start date also will be documented
Treatment discontinuations, dose modifications, and treatment interruptions	Treatment discontinuations, dose modifications, and treatment interruptions will be documented. Time to discontinuation will be evaluated from first administration to the last documented administration
Reason for treatment discontinuations, dose modifications, and treatment interruptions	Reason for discontinuations, dose modifications, and treatment interruptions will be recorded. Reason for discontinuations may include, but is not limited to, the following: completed course of treatment as planned, disease progression, death, lack of efficacy, lost to follow-up, toxicity or AE, patient decision, or other
Other treatments and procedures
Concomitant medications	The use of antibiotics, antivirals, and steroids along with the date of administration or prescription
Treatments and procedures	The use of the following treatments and procedures for the treatment of HBC along with the date of occurrence: ablation (e.g., radiofrequency ablation, microwave ablation), liver transplant, locoregional treatment (e.g., transarterial chemoembolization, selective internal radiation therapy, stereotactic body radiotherapy, transarterial radioembolization), surgery, systemic treatment (e.g., immuno-oncology agent, tyrosine kinase inhibitors), clinical trial treatment
AEs (primary data collection only)	The following variables will be collected: AE term, the date when the AE started and stopped, whether the AE is serious or not, Principal Investigator causality rating against the medicinal product, action taken with regard to medicinal product, outcome, and administration of treatment for the AE
Clinically significant events of interest
Clinically significant events of interest leading to a medical intervention	Clinically significant events of interest leading to a medical intervention, including durvalumab-based treatment interruption, discontinuation, hospitalization, or which require interventions of concomitant use of corticosteroids, immunosuppressants and/or endocrine therapies, including: adrenal insufficiency, anemia, colitis, deep vein thrombosis, diarrhea, electrolyte imbalance, fatigue/asthenia, hand-foot skin reaction, hemorrhage (gastrointestinal, esophageal varices, upper gastrointestinal), hepatitis, hypertension, hyperthyroidism, hypothyroidism, increased ALT, increased ALP, increased AST, increased bilirubin, increased lipase, myocarditis, nephritis, pancreatitis, pneumonitis, pruritus, thrombocytopenia. Clinically significant events of interest will be defined and graded according to the Common Terminology Criteria for Adverse Events version 4.024

Abbreviations: aBTC: advanced biliary tract cancer; AE: adverse event; ALBI: albumin-bilirubin; ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BTC: biliary tract cancer; ECOG: Eastern Cooperative Oncology Group; HBC: hepatobiliary cancer; HBV: hepatitis B virus; HCV: hepatitis C virus; PS: performance status; uHCC: unresectable HCC.

Secondary real-world effectiveness outcomes include duration of treatment, progression-free survival (PFS; investigator-assessed), time to progression (TTP; investigator-assessed), and time to next treatment (TTNT; Table 2).

2.5.2. Patient demographics and clinical characteristics

Patient demographics and clinical characteristics (Table 2) will be assessed as a secondary outcome of LIVER-R, providing a comprehensive description of the global patient populations receiving durvalumab-based regimens. Patient demographics and clinical characteristics will be documented on the index date. If data are unavailable on the index date, the date closest to the index date from the baseline period will be used.

2.5.3. Treatment patterns

Treatment patterns will be documented over the follow-up period or abstracted from medical records. They will include the initial durvalumab-based regimen administered and any subsequent treatments received (Table 2). The treatment type, start date, and dose will be recorded. Treatment discontinuation, dose modifications, interruptions, and reasons for these events will also be assessed (Table 2). Concomitant medications, including date of administration or prescription, and treatments and procedures for HBCs will be assessed during the baseline and follow-up period (Table 2).

2.5.4. Safety variables

2.5.4.1. Adverse events

Adverse events (AEs) will be evaluated in patients with primary data collection only. AEs will encompass any unfavorable or unintended sign (e.g., abnormal laboratory findings), symptom, or disease temporally associated with the treatment, regardless of whether it is treatment-related (Table 2). Both serious and non-serious AEs will be assessed. AEs will be documented on the index date and throughout the follow-up period through 90 days after the final durvalumab or tremelimumab administration or death, whichever occurs first. All AEs, including those with a fatal outcome, will be recorded in the eCRF.

2.5.4.2. Clinically significant events of interest

Clinically significant events of interest (evaluated in patients with primary and secondary data collection) include any event that leads to treatment interruption, discontinuation, or hospitalization, or requires concomitant corticosteroids, immunosuppressant, or endocrine therapy use (Table 2). Clinically significant events of interest will be documented during the follow-up period through 90 days after the final durvalumab or tremelimumab administration or death, whichever occurs first.

2.6. Sample size estimations

In LIVER-R, real-world median OS times of 16 and 13 months were used to estimate precision for uHCC and aBTC, respectively. Precision estimates were based on findings from the HIMALAYA and TOPAZ-1 clinical trials, which reported a median OS of 16.4 months for STRIDE (uHCC), 16.6 months with durvalumab monotherapy (uHCC), and 12.8 months with durvalumab plus GemCis (aBTC) [10,11].

Precision estimates for median OS were calculated in sample sizes ranging from 50 to 400 patients. With a sample size of 100 patients, the upper and lower 95% CI limits for median OS were within approximately ±5 months of the point estimate for patients with uHCC and aBTC. Similarly, the upper and lower 95% CI limits of the 24-month survival rate were within approximately ±10%. Based on these results, a sample size ranging from 50 to 200 patients was determined to be sufficient for each indication in each country, considering the size of the country’s population. Sample sizes for new cohorts included in LIVER-R will be determined when new indications are approved.

2.7. Statistical analysis

LIVER-R is a descriptive, non-comparative study; no formal hypothesis will be tested. All outcomes will be analyzed separately for each HBC indication (uHCC and aBTC) and data collection method (primary and secondary).

Descriptive summary statistics will be provided for continuous and categorical variables, including frequency counts and percentages. Survival and other time-to-event endpoints will be analyzed using the Kaplan–Meier method, with the median time-to-event and related 95% CIs reported. CIs will be calculated using the Brookmeyer–Crowley method. Patients will be censored for survival outcomes if they are lost to follow-up or if the study ends before the event of interest is observed. For other time-to-event outcomes, patients will be censored if they die, are lost to follow-up, or if the study ends before the event of interest is observed. The proportion of patients alive at landmark time points will be evaluated.

Data will be analyzed for observed data without imputation of missing values, except in cases where dates are missing or incomplete, for which mid-month or mid-year dates will be imputed. Deaths between the date of diagnosis and the index date will not be included in the study.

Interim analyses will be conducted on patients with aBTC at ~6 months following enrollment of the first patient, with further analyses conducted on patients with aBTC at 1 year and on patients with uHCC at 1 and 2 years. Additional interim analysis may be planned as needed, for example, for regulatory or health technology assessments or further insights. Final analyses will be conducted on patients with aBTC and uHCC at the end of the respective follow-up periods.

Subgroup analyses may be performed for certain groups of interest, e.g., country (if the sample size is ≥50 patients) or region, demographic characteristics (e.g., gender, age, and race), or stage of disease at index. Other subgroups of interest may include patients treated in a global early access program.

All analyses will be performed using SAS Software, version 9.4 or higher (SAS Institute, Cary, NC).

3. Ethics and dissemination

Patients will be approached for consent to enroll in the study on or after the date they receive their first durvalumab-based regimen, but not before. Newly treated patients (primary or secondary data collection), previously treated active patients (secondary data collection), and previously treated completed patients who are alive (secondary data collection) will be approached for consent to enroll in the study, consecutively, as they visit the site for their routine treatment and follow-up visits.

Previously treated completed patients (secondary data collection) who have died may be enrolled if patient consent is waived or if an exemption is obtained as per ethics committee requirements for that site or country. Sites are allowed to enroll patients who have died at the time of enrollment, given they had started treatment with a durvalumab-based regimen on or after February 2022 (i.e., the start of the global early access program) and met all other eligibility criteria. Consent will be documented on a paper-based informed consent form that the patient must sign before enrollment in the study.

The treating physician must have decided to treat a patient with a durvalumab-based regimen before, and independent of the decision, to enroll them into the LIVER-R study. The final protocol (including any amendments) is reviewed and approved by each participating country/study site according to their respective ethics review board setup. Informed consent form must be approved by an ethics committee, institutional review board, or independent ethics committee. Patients can voluntarily withdraw from the study at any time and discontinue their durvalumab-based regimen as per routine clinical practice and based on their physician’s clinical judgment without prejudice to further treatment, procedure, or care. LIVER-R is funded by AstraZeneca and will be conducted in accordance with the Declarations of Helsinki and Istanbul and will be consistent with the International Council for Harmonisation, Good Clinical Practice guidelines, and applicable legislation on non-interventional studies and/or observational studies. The findings will be disseminated through publications in peer-reviewed scientific journals and presentations at congresses.

4. Conclusion

Preliminary real-world studies have confirmed findings from clinical trials of durvalumab-based regimens in patients with uHCC or aBTC [22–24]. However, they do present limitations, such as short duration of follow-up, impact interpretation, and applicability to clinical practice [22–24]. To our knowledge, LIVER-R will be the first real-world study to provide evidence on long-term outcomes with first-line durvalumab-based regimens in a large, global population of patients with HBCs.

Durvalumab-based regimens are currently being assessed for earlier stages of HBC, including in patients with uHCC who are eligible for embolization and in patients with HCC that are at high risk of recurrence after curative resection or ablation [27–29]. Given the growing number of anticipated approvals of durvalumab-based regimens in the first-line setting for HBC, there is a need for real-world data. LIVER-R will allow new HBC cohorts in earlier stages of disease to be incorporated as results from ongoing clinical trials of durvalumab-based regimens become available and new indications are approved. This will enable real-world data to be collected across indications and provide insights into outcomes with first-line durvalumab-based regimens in additional patient cohorts.

Clinical trials are usually designed with strict eligibility criteria, which may result in the underrepresentation of patient subgroups that reflect routine clinical practice [30]. For example, in the HIMALAYA trial, only a few patients with an Eastern Cooperative Oncology Group performance status of 2 and Child-Pugh class B were included, and those with main portal vein thrombosis were excluded [11]. In the TOPAZ-1 trial, patients with active or previously documented autoimmune or inflammatory disorders, such as inflammatory bowel disease, were excluded [10]. Exclusion criteria for enrollment into LIVER-R will be minimal. Therefore, patients enrolled in LIVER-R are more likely to be representative of routine clinical practice, offering potential insights into underrepresented subgroups of patients with uHCC and aBTC who may have been excluded from clinical trials.

Pan-Asian adapted ESMO Clinical Practice Guidelines for BTC were recently updated, and durvalumab plus GemCis is now recommended for patients with aBTC following molecular testing for certain genetic mutations [19]. LIVER-R aims to assess the presence of certain genetic mutations detected after diagnosis in patients with BTCs and has the potential to provide insight into the prevalence of certain genetic mutations within a real-world setting.

Strengths of LIVER-R include that all data will be documented using standardized eCRFs in an EDC system to synthesize data across countries, which may minimize the extent of missing data for both primary and secondary data collection. Data checks will also be performed to assess the internal consistency of the data entered and limit missing data, further supporting data collection and improving quality. In addition, ad hoc exploratory sensitivity analyses may be performed to explore the robustness of results. An additional strength of LIVER-R is that primary and secondary data collection methods will increase the range and patient sample size to provide a deeper understanding of patients and their experience with durvalumab-based regimens in real-world clinical practice. The analysis of subgroups can also offer valuable insights into real-world outcomes for specific groups, which may be informative for the treatment of HBCs in clinical practice. Another strength of LIVER-R is that the large number of patients, sites, and countries may allow better global generalizability of results, providing insights for health technology assessments and clinical decision-making.

Given the observational nature of this study, different biases may be introduced, including selection, consent, information, survival selection, and survival bias. Selection bias may occur if the study population is not representative of the target population, limiting the applicability of the results. For example, in certain countries/regions, physicians may select atezolizumab plus bevacizumab to treat patients with uHCC, reserving STRIDE for specific patient subgroups, such as those at risk of bleeding or thrombosis [18,21]. This may result in the study population not accurately representing the target population, leading to selection bias. Selection bias in LIVER-R will be minimized by including multiple sites representative of the healthcare service providers for the target population in each respective country and through the consecutive enrollment of patients. Consent bias may occur if there are differences between study patients and patients who decline to participate or could not consent. This bias applies in cases of death where waiver of consent could not be obtained and in cases where patients were lost to follow-up before consent was obtained. Information on consent requirements will be summarized and considered when interpreting the results. Information bias may occur due to variability in data abstraction (secondary data) and missing data (primary and secondary data). For example, in countries where secondary data collection is implemented, study outcomes will be reported based on patients’ medical records. This may lead to differential criteria for defining the study variables. To minimize bias, the study will implement a standard measurement instrument, including carefully designed eCRFs in the EDC system, data entry training materials, and required training for staff entering the data. Survival selection bias may also occur and could undermine the primary outcome of LIVER-R in countries where patients died before study enrollment (e.g., patients from an early access program). There is also potential for survival bias due to the varying time from primary HBC diagnosis to treatment initiation of the durvalumab-based regimen. For example, patients in countries with earlier approval and reimbursement of durvalumab-based regimens may have a shorter time to treatment initiation and, therefore, less risk of progression, recurrence, or mortality versus countries with later approval and reimbursement of durvalumab-based regimens. Survival bias may limit within-country estimates of recurrence, progression, or survival among the study population. Different countries may be impacted by changes in health or healthcare services that may occur over time (e.g., changes in reimbursement policy or approval of other treatment regimens for the indication of interest), potentially inhibiting the comparability and generalizability of results between different countries. The use of investigator-assessed PFS and TTP, and the absence of standardized approaches to tumor assessment and standardized intervals for response assessment, may affect patient outcome evaluation and may be a source of potential bias. However, the inclusion of TTNT, a surrogate for PFS in real-world settings, may help to contextualize and complement these findings. Here, we have described the study design of LIVER-R, which, to our knowledge, is the largest study to date to assess real-world effectiveness, patient demographics, clinical characteristics, treatment patterns, and safety for patients who initiate treatment with a durvalumab-based regimen for an approved HBC indication in real-world clinical practice. The results of LIVER-R will help to further define the role of first-line durvalumab-based regimens in clinical practice for patients with uHCC and aBTC, as well as for new HBC cohorts, as ongoing clinical trials with durvalumab demonstrate improvements over prior standards of care and achieve regulatory approvals. The results from LIVER-R will enhance our understanding of durvalumab-based therapies, particularly in subgroups of patients with HBCs that may have otherwise been underrepresented in previous clinical trials.

Funding Statement

This study is funded by AstraZeneca. The funder of the study has a role in study design, data analysis, data interpretation, and reporting of this study.

Article highlights

Background & rationale

• Durvalumab-based regimens have shown improved outcomes in several types of hepatobiliary cancers (HBCs), including unresectable hepatocellular carcinoma (uHCC) and advanced biliary tract cancer (aBTC).

• Results from phase III clinical trials investigating the STRIDE regimen (Single Tremelimumab Regular Interval Durvalumab) in participants with uHCC and the durvalumab plus gemcitabine and cisplatin regimen in participants with aBTC have reported significantly improved overall survival (OS) versus the previous standard of care that was sustained at long-term follow-up. Both regimens are approved for the treatment of adult patients.

• Preliminary results from real-world studies have reported the effectiveness of durvalumab-based treatments in routine clinical practice but have been limited by a short duration of follow-up and an absence of OS rate data for aBTC. Assessment of long-term outcomes in a large, global patient population is needed.

The present study

• This real-world observational study was designed to evaluate long-term outcomes in patients with HBCs receiving first-line durvalumab-based regimens as part of routine clinical practice or an early access program.

• The primary outcome is OS. Secondary outcomes include patient demographics, clinical characteristics, duration of treatment, progression-free survival, and safety.

• Approximately 2500 adult patients with uHCC or aBTC are planned to be enrolled across ~179 sites globally.

• This study will expand understanding of first-line durvalumab-based regimens in real-world practice for patients with uHCC and aBTC, including those underrepresented in previous clinical trials, and provide insights for reimbursement, health technology assessments, and clinical decision-making.

Strengths and limitations of this study

• This study will have minimal exclusion criteria and will likely be more representative of routine clinical practice.

• This is an observational study, which may introduce biases including selection, consent, information, survival selection, and survival bias. Methods to minimize bias are in place.

Author contributions

Conception and design of the study: Masafumi Ikeda, Marcus-Alexander Wörns, Mehmet Akce, Chiun Hsu, Janvi Sah, Heide A. Stirnadel-Farrant, Michael J. Paskow, Jennifer J. Knox. Data acquisition: Masafumi Ikeda, Marcus-Alexander Wörns, Chiun Hsu, James Schmidt, Jennifer J. Knox.Analysis and interpretation of data: Masafumi Ikeda, Marcus-Alexander Wörns, Mehmet Akce, Chiun Hsu, Niall C. Tebbutt, Andrea Casadei-Gardini, Janvi Sah, Mufiza Farid-Kapadia, Heide A. Stirnadel-Farrant, Michael J. Paskow, Boris Baur, Giovanni Melillo, James Schmidt, Anna Daktera, Jennifer J. Knox. Administrative, technical, or material support: Mufiza Farid-Kapadia, Heide A. Stirnadel-Farrant, James Schmidt. Study supervision: Marcus-Alexander Wörns, Mufiza Farid-Kapadia, Heide A. Stirnadel-Farrant, James Schmidt, Anna Daktera. Writing – review and editing: Masafumi Ikeda, Marcus-Alexander Wörns, Mehmet Akce, Chiun Hsu, Niall C. Tebbutt, Andrea Casadei-Gardini, Janvi Sah, Mufiza Farid-Kapadia, Heide A. Stirnadel-Farrant, Michael J. Paskow, Boris Baur, Giovanni Melillo, James Schmidt, Anna Daktera, Jennifer J. Knox.

Disclosure statement

Masafumi Ikeda reports membership on an advisory board for AstraZeneca, Chugai Pharmaceutical, Eisai, Eli Lilly Japan, MSD, Nihon Servier, and Novartis; membership on a steering committee for Chugai Pharmaceutical, Nihon Servier, Novartis, and Takeda; being an invited speaker for Abbott Japan, AbbVie, AstraZeneca, Bayer, Bristol Myers Squibb, Chugai Pharmaceutical, Eisai, Eli Lilly Japan, Fujifilm Toyama Chemical, Guardant Health Japan, Incyte Biosciences Japan, MSD, Nihon Servier, Nippon Kayaku, Novartis, Ono Pharmaceutical, Taiho, Taisho Pharmaceutical, Takeda, Teijin Pharma, and Yakult; and being a coordinating principal investigator for AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Chiome Bioscience, Chugai Pharmaceutical, Delta-Fly Pharma, Eisai, Eli Lilly Japan, Invitae, J-Pharma, Merck, Merus N.V., MSD, Nihon Servier, Novartis, Ono Pharmaceutical, Pfizer, and Syneos Health. Marcus-Alexander Wörns reports membership on an advisory board for AstraZeneca, Bristol Myers Squibb, Eisai, Incyte, Ipsen, MSD, and Roche; and being an invited speaker for AstraZeneca, Boston Scientific, Bristol Myers Squibb, Incyte, Ipsen, MSD, and Roche. Mehmet Akce reports a consulting or advisory role for AstraZeneca, Bristol Myers Squibb, Curio Science, Daiichi Sankyo, Eisai, Exelixis, Genentech, GlaxoSmithKline, Incyte, Ipsen, Isofol, Partner Therapeutics, QED, and Taiho; and research funding (to institution) from AstraZeneca, Bayer, Bristol Myers Squibb/Ono Pharmaceutical, Eisai, Exelixis, GlaxoSmithKline, Merck Sharp & Dohme, ProDa BioTech, Relay, Roche/Genentech, and Xencor. Chiun Hsu reports membership on an advisory board for AstraZeneca; being an invited speaker for AstraZeneca, Bayer, Bristol Myers Squibb/Ono Pharmaceutical, Eisai, Roche, and TTY Biopharm; and being a coordinating principal investigator for Bristol Myers Squibb/Ono Pharmaceutical and Roche. Niall C. Tebbutt reports membership on an advisory board for AstraZeneca, BeiGene, Bristol Myers Squibb, and MSD. Andrea Casadei-Gardini reports consulting fees from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Incyte, Ipsen, IQVIA, MSD, Roche, and Servier; lecture fees from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Incyte, Ipsen, Roche, and Servier; travel expenses from AstraZeneca; and research grants (to institution) from AstraZeneca and Eisai. Janvi Sah, Mufiza Farid-Kapadia, Heide A. Stirnadel-Farrant, Michael J. Paskow, Boris Baur, Giovanni Melillo, and James Schmidt are employees of and hold stock in AstraZeneca. Anna Daktera is an employee of AstraZeneca. Jennifer J. Knox reports consulting fees from AstraZeneca, Incyte, Ipsen, Roche, and Servier. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Medical writing support, under the direction of the authors, was provided by Judy Alper, PhD, CMC Connect, and Eilidh McLachlan, PhD, on behalf of CMC Connect, a division of IPG Health Medical Communications, and was funded by AstraZeneca, in accordance with Good Publication Practice (GPP 2022) guidelines (Ann Intern Med. 2022;175:1298–304). Study design support was provided by Kathryn Anastassopoulos, Reema Patel, and Shoshana Daniel of Labcorp Drug Development, funded by AstraZeneca.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have received honoraria for lectures, consulting activities and travel support from the AbbVie, AstraZeneca, Falk Foundation, Gilead, Ipsen, Novartis, and Roche. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose

Ethical declaration

This study will be conducted according to the principles outlined in the Declarations of Helsinki and Istanbul and will be consistent with the International Council for Harmonisation, Good Clinical Practice guidelines, and applicable legislation on non-interventional studies and/or observational studies.