Organ-specific Responses to Atezolizumab Plus Bevacizumab in Patients With Advanced Hepatocellular Carcinoma
Conditions: Advanced Hepatocellular Carcinoma
Sponsor: CHA University

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Study Protocol 
 
Organ-specific responses to 
atezolizumab plus bevacizumab in 
patients with advanced 
hepatocellular carcinoma: A 
multinational multicenter study 
 
NCT Number: 
NCT04862949 
Version: 
Version 1.3 
Document Date: 
April 27, 2023 
 
 

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1. Clinical Study Protocol 
Study Title: Organ-specific responses to atezolizumab plus bevacizumab in patients 
with advanced hepatocellular carcinoma: A multinational multicenter study 
Target Disease: Advanced hepatocellular carcinoma 
Investigational Products: 
Atezolizumab and Bevacizumab 
Laboratory/Diagnostic Tests: Not applicable 
Principal Investigator: 
Hong Jae Chon, Division of Hematology and Oncology, CHA Bundang Medical 
Center, Korea 
E-mail: minidoctor@cha.ac.kr Tel: +82-31-780-7590 
 
 
 
 
 
 
 
 
 
 

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2. Summary 
Study Title: 
Organ-specific responses to atezolizumab plus 
bevacizumab in patients with advanced 
hepatocellular carcinoma: A multinational 
multicenter study 
Study Objective 
The purpose of this study is to analyze organ-
specific responses to the combination of 
atezolizumab and bevacizumab in patients with 
advanced hepatocellular carcinoma (HCC) and to 
evaluate their impact on survival outcomes. 
 
Primary Objective: Organ-specific 
response rate 
Principal Investigator 
Hong Jae Chon, Division of Hematology and 
Oncology, CHA Bundang Medical Center 
Participating Institutions 
Ulsan University Hospital, Korea.  
The Chinese University of Hong Kong 
Study Population 
Patients with advanced hepatocellular carcinoma 
who received atezolizumab plus bevacizumab 
between May 2020 and June 2021 
Study Design 
Retrospective analysis using medical records 
Evaluation Method 
Organ-specific responses and survival outcomes 
of patients treated with atezolizumab plus 
bevacizumab were analyzed. 
Statistical Analysis 
For categorical variables, chi-square test or 
Fisher’s exact test was used. 
Survival outcomes for each variable were 
estimated using the Kaplan–Meier method, and 
survival curves were compared with the log-rank 
test. 
 
 

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3. Objectives 
The purpose of this study is to identify the organ-specific responses of atezolizumab 
plus bevacizumab combination therapy in patients with advanced hepatocellular 
carcinoma (HCC), and to analyze the impact of these responses on survival outcomes. 
Primary Objective: Organ-specific response rate 
Secondary Objectives: 
- Objective response rate (ORR) according to RECIST v1.1 
- Progression-free survival (PFS) 
- Overall survival (OS) 
 
4. Background 
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death 
worldwide and in Korea. Many patients are diagnosed at an advanced stage, where 
systemic therapy is the mainstay of treatment.{3,4} 
Immune checkpoint inhibitors (ICIs) as monotherapy have shown responses in early-
phase trials, but failed to significantly improve survival in phase 3 trials. Retrospective 
analyses suggest organ-specific response variability: intrahepatic lesions respond less 
favorably than extrahepatic metastases. VEGF overexpression plays a role in HCC 
progression. Anti-VEGF therapy can reduce immunosuppression, enhance T-cell 
infiltration, and improve ICI responses. Thus, the combination of atezolizumab (anti-
PD-L1) and bevacizumab (anti-VEGF) has strong biological rationale and 
demonstrated clinical benefit in phase 3 studies. 

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Kim HS, Cheon J, Chon HJ et al. Different organ-specific response to nivolumab to 
determine the survival 
outcome of patients with advanced hepatocellular carcinoma (aHCC), ASCO 2020 
Annual Meeting 
 
Overexpression of vascular endothelial growth factor (VEGF) and activation of its 
downstream pathways have been associated with the development and progression 
of hepatocellular carcinoma (HCC) [10]. 
 

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Chon HJ, Kim C et al. Combination of anti-angiogenic therapy and immune 
checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer 
immunity, Experimental & Molecular Medicine 2020 
 
Anti-VEGF therapy can reduce VEGF-mediated immunosuppression within the tumor 
and its microenvironment, and by reversing VEGF-mediated immunosuppression, it 
can promote T-cell infiltration into tumors and thereby enhance responses to 
immune checkpoint inhibitor (ICI) therapy [11,12]. 
 

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Based on preclinical data and results from a phase Ib clinical trial, a global, 
multicenter, open-label phase III clinical trial, IMbrave150, was conducted [13]. In the 
IMbrave150 trial, the combination of atezolizumab and bevacizumab demonstrated 
superiority over sorafenib in the first-line treatment of patients with advanced 
hepatocellular carcinoma (HCC) in terms of overall survival (OS) and progression-free 
survival (PFS) according to RECIST v1.1 criteria. Furthermore, the objective response 
rate (ORR) improved to 27.3% [14]. Considering that ICI monotherapy has shown 
ORRs of approximately 17–20%, the combination of atezolizumab and bevacizumab 
provided an enhanced response [5,6,7,15]. 
It is expected that combining atezolizumab and bevacizumab may overcome the 
immunosuppressive microenvironment of the liver and improve intrahepatic 
responses to immune checkpoint inhibitors (ICIs). 

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The mechanism of action of ICIs is explained by reactivation of inactivated T cells 
within the tumor microenvironment. Since the tumor microenvironment differs by 
organ, the therapeutic efficacy of ICIs may vary depending on the site of the tumor 
[16]. 
In retrospective analyses of patients treated with pembrolizumab for advanced 
melanoma and non–small cell lung cancer (NSCLC), those with liver metastases 
showed shorter PFS and lower ORRs compared to those without liver metastases 
(melanoma: 33.3% vs. 71.4%; NSCLC: 28.6% vs. 56.7%) [17]. Similar findings were 
reported in patients with metastatic triple-negative breast cancer, where 
pembrolizumab showed no response in patients with liver metastases [18]. 
Collectively, these results suggest that liver metastases, regardless of cancer type, 
exhibit lower responses to ICIs compared with metastases in other organs. 
In addition, ICI therapy in advanced HCC has demonstrated heterogeneous organ-
specific responses [8,9]. The low intrahepatic response rate to ICIs may be explained 
by the liver-specific immunosuppressive microenvironment [19]. Previous studies have 
shown that myeloid-derived suppressor cells (MDSCs) and regulatory T cells 
accumulate in the liver and suppress antitumor cytotoxic T cells and NK cells [20,21]. 
Moreover, liver-resident cells—including hepatic stellate cells, liver sinusoidal 
endothelial cells, and macrophages—induce resistance and dysfunction in cytotoxic T 
cells [22–25]. To overcome this immunosuppressive hepatic microenvironment, 
strategies such as combining ICIs with other agents to induce stronger antitumor 
immune responses or to modulate the immunosuppressive microenvironment are 
required. 
Since the major cause of death in most patients with HCC is intrahepatic disease 
progression or hepatic failure due to underlying cirrhosis, the intrahepatic response 
rate to ICIs is a critical determinant of overall prognosis in advanced HCC [26]. 

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Therefore, we hypothesize that combination therapy with atezolizumab and 
bevacizumab can increase organ-specific responses in patients with advanced 
hepatocellular carcinoma and thereby improve survival outcomes. 
 
5. Subjects and Methods 
Patients with advanced hepatocellular carcinoma who received combination therapy 
with atezolizumab and bevacizumab between May 2020 and June 2021 at CHA 
Bundang Medical Center, Ulsan University Hospital, and The Chinese University of 
Hong Kong will be analyzed for organ-specific response rates and survival outcomes. 
[Measurement of Organ-Specific Response Rate] 
In previous studies, the concept of “organ-specific response rate” was proposed to 
evaluate heterogeneous responses to immune checkpoint inhibitor therapy by organ 
[8]. 
The largest lesion representing each involved organ will be selected (up to 2 lesions 
per organ, with a maximum of 5 lesions per patient). Each lesion will be measured 
unidimensionally and evaluated according to RECIST v1.1 criteria: 
 
Complete Response (CR): Complete disappearance of the lesion or lymph 
node short axis < 1.0 cm 
 
Partial Response (PR): At least 30% decrease in size 
 
Progressive Disease (PD): At least 20% increase in size 
 
Stable Disease (SD): Neither CR, PR, nor PD 
New lesions were not always indicative of disease progression but were added to the 
original target lesions to determine the total tumor burden. 

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Response evaluation will be performed by blinded, independent radiologists who will 
review and measure the images. 
 
5.1 Inclusion Criteria 
Patients will be eligible for inclusion if they meet all of the following criteria: 
 
Histologically or non-invasively confirmed hepatocellular carcinoma (HCC) 
according to the American Association for the Study of Liver Diseases 
(AASLD) criteria 
 
ECOG performance status of 0 or 1 
 
Patients who received combination therapy with atezolizumab and 
bevacizumab as first-line systemic treatment for unresectable HCC 
 
Barcelona Clinic Liver Cancer (BCLC) stage B or C 
 
Child-Pugh class A liver function 
 
At least one measurable lesion 
 
Adequate hematologic and organ function 
5.2 Exclusion Criteria 
Patients will be excluded from the study if they meet any of the following criteria: 
 
History of autoimmune disease 
 
Use of therapeutic-dose anticoagulants 
o 
Exception: Low-dose aspirin for cardiovascular protection is permitted 
 
6. Rationale for Sample Size 

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As this is a multicenter retrospective study, there is no precise statistical basis for 
sample size calculation. It is estimated that approximately 124 patients per year are 
diagnosed with advanced hepatocellular carcinoma and treated with Tecentriq 
(atezolizumab) plus Avastin (bevacizumab) at the Chinese University of Hong Kong, 
Ulsan University Hospital, and CHA Bundang Medical Center. Among these, about 90 
patients from CHA Bundang Medical Center are expected to be included in this 
study. 
This study will include patients with measurable disease. Organ-specific response 
criteria using RECIST v1.1 will be applied to evaluate objective responses of tumors 
located in the liver, lungs, lymph nodes, and other intra-abdominal sites to 
atezolizumab plus bevacizumab combination therapy. 
 
7. Data Collection Methods 
Data will be retrospectively collected through the electronic medical record (EMR) 
system. Extracted data will be transmitted electronically to the principal investigator 
following standard procedures. After extraction, all data will be stored in anonymized 
form. 
Access to the data will be restricted to the principal investigator and sub-
investigators participating in the study. Imaging data from each hospital will be 
anonymized, extracted, and sent to independent radiologists for review and 
evaluation. 
 
8. Statistical Analysis Methods 
Comparisons of categorical variables will be performed using the chi-square test. 
Survival curves will be estimated using the Kaplan–Meier method. Statistical 

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comparisons between survival curves will be conducted using the log-rank test, with 
a significance level of 5%. 
Multivariate analysis will be performed using the Cox proportional hazards regression 
model. All available data will be included in the analysis. In general, missing data will 
not be imputed and will be treated as “missing” in the statistical analysis. 
 
9. Expected Study Period 
The study is expected to take approximately two years from the date of IRB approval 
until April 30, 2023. 
Planned Timeline 
 
First data extraction: April 30, 2021 
 
Final data extraction: December 31, 2022 
 
Final study report: February 28, 2023 
 
Manuscript submission: April 30, 2023 
 
10. Study Design 
This study is a retrospective study. After identifying patients who meet the inclusion 
and exclusion criteria, organ-specific responses and patient status will be evaluated 
through chart review, without any additional testing or administration of drugs. 
 
11. Ethical Considerations 

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This is a retrospective study involving patients who have already received treatment 
at the study site, and the research will be conducted using anonymized data. As this 
is a retrospective study, obtaining informed consent is waived. The study will not 
involve any additional treatment or testing for the patients. Patient information will 
be minimized to avoid direct disclosure of personal data. Future research will be 
conducted in accordance with the Declaration of Helsinki and reviewed by the 
Institutional Review Board (IRB). 
 
12. Data Quality Assurance and Data Management Plan 
As this is a retrospective study, the use of direct patient identifiers will be minimized, 
and there will be no disclosure of personal information. Patient names, resident 
registration numbers, and hospital registration numbers will not be recorded. 
Measures will be taken to protect patient confidentiality. 
Access to patient information will be restricted to the principal investigator and co-
investigators. Patient information files will be encrypted and stored on computers 
accessible only to the principal investigator and co-investigators. 
Collected data will be retained for five years. After the retention period, printed 
personal information will be destroyed using a shredder or incineration, and digital 
files will be permanently deleted using technical methods that prevent record 
recovery. 
 
13. Data Items Collected in the Case Report Form (CRF) 
The following information will be recorded in the case report form: 
 
Patient initials 

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 
Study registration number 
 
Sex 
 
Age 
 
Date of birth 
 
Survival status 
 
Date of diagnosis 
 
Histological diagnosis (if available) 
 
Disease extent at the time of diagnosis 
 
Surgical history (yes/no) and date of surgery 
 
Clinical stage 
 
Pathological findings 
 
Recurrence status and date of recurrence 
 
Presence of recurrence or metastasis 
 
Response evaluation according to RECIST v1.1 
 
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