Effectiveness and Safety of Atezolizumab + Bevacizumab Plus Locoregional Therapies in Patients With Unresectable Hepatocellular Carcinoma in Real-world Clinical Practice
Conditions: Unresectable Hepatocellular Carcinoma
Sponsor: Zhongda Hospital

STUDY PROTOCOL
EFFECTIVENESS AND SAFETY OF ATEZOLIZUMAB + BEVACIZUMAB
PLUS LRTS AMONG PATIENTS WITH UNRESECTABLE
HEPATOCELLULAR CARCINOMA IN REAL-WORLD CLINICAL PRACTICE
Version number:
1.0
Protocol author:
Name: Professor Gao-Jun Teng
Address: Zhongda Hospital Southeast University, 87
Dingjiaqiao,Nanjing, China
Email: gjteng@seu.edu.cn
Protocol co-author:
Name: Professor Jian Lu
Address: Zhongda Hospital Southeast University, 87 Dingjiaqiao,
Nanjing, China
Email: lujian43307131@126.com
Date final:
2025
Leading site and sponsor
Zhongda Hospital, Southeast University
Country of study population:
China and Asia-Pacific region

Study Synopsis
Study Title
Effectiveness and Safety of Atezolizumab + Bevacizumab Combined
with Locoregional Therapies in Patients with Unresectable
Hepatocellular Carcinoma in Real-world Clinical practice
Background
Unresectable hepatocellular carcinoma (uHCC) constitutes a
significant health burden in the Asia-Pacific (APAC) region, particularly
in China, where it is frequently associated with hepatitis B virus (HBV)
infection and diagnosed at advanced stages. The combination of
atezolizumab and bevacizumab (Atezo+Bev) has emerged as the
established first-line standard of care, as evidenced by the IMbrave150
trial, which demonstrated statistically significant improvements in overall
and progression-free survival. However, clinical trial populations are
often selective, and not all patients achieve optimal responses,
underscoring the need for additional therapeutic strategies.
Locoregional therapies (LRTs), including transarterial
chemoembolization (TACE), transarterial radioembolization (TARE),
hepatic arterial infusion chemotherapy (HAIC), ablation (e.g., RFA,
MWA), and radiotherapy (e.g., external beam radiotherapy, iodine-125
brachytherapy), are integral to the management of uHCC, particularly in
intermediate stages (BCLC B). However, their application is markedly
heterogeneous across the APAC region due to variations in clinical
guidelines and limited standardization. Robust evidence supporting
specific combination strategies with systemic therapies like Atezo+Bev
remains scarce.
This gap underscores the critical need for large-scale real-world
evidence (RWE) to elucidate current practices, outcomes, and optimal
timing of LRT+Atezo+Bev combinations in China and selected APAC
regions.
Leading Site
Zhongda Hospital, Southeast University
Clinical Sites
Patient-level data will be retrospectively abstracted from medical records
of approximately 35 study sites after approval by ethics committees.
Objectives
Primary Objective:
To describe the real-world overall survival (OS) in patients with
unresectable hepatocellular carcinoma (uHCC) receiving first-line
systemic therapy with atezolizumab plus bevacizumab (Atezo+Bev) in
combination with locoregional therapies (LRTs).
Secondary Objectives:
To describe real-world progression-free survival (rwPFS), overall
response rate (ORR), real-world disease control rate (DCR), time to
discontinuation (TTD), time to next treatment (TTNT), and time to
progression (TTP) in the cohort, stratified by locoregional therapy (LRT)
categories.
Definitions:
a)
ORR: Proportion of patients achieving a complete response (CR)
or partial response (PR), as assessed by investigators per
RECIST v1.1 or mRECIST criteria using real-world imaging
evaluations.
b)
DCR:
The
proportion
of
patients
who
achieve
complete
response (CR), partial response (PR), or stable disease (SD)
as
assessed
by
investigators
using
real-world
imaging
evaluations in accordance with RECIST v1.1 or mRECIST
criteria. Among these, stable disease (SD) must persist for at

least 6 weeks from the first documentation of SD, which helps
exclude the interference of short-term disease fluctuations on
assessment results and more objectively reflects the sustained
control effect of treatment on tumors.
c)
TTD: Time from initiation of Atezo+Bev to discontinuation of
Atezo+Bev therapy for any reason (e.g., toxicity, patient decision).
d)
TTNT: Time from initiation of Atezo+Bev to initiation of any
subsequent systemic therapy.
e)
TTP: Time from initiation of Atezo+Bev treatment to radiological
disease progression, as defined by investigator-assessed RECIST
v1.1 or mRECIST criteria.
Safety Objectives:
To describe the safety profile of the LRT+ Atezo+Bev cohort and its
subgroups, including all treatment emergent adverse event (TEAE) ,
treatment-related AE (TRAE)，and AEs of special interests such as
bleeding, hypertension, liver dysfunction/ liver impairment, and immune-
related AEs(irAEs).
Exploratory Objectives:
a)
To describe associations between baseline patient/disease
characteristics and clinical outcomes within specific LRT+
Atezo+Bev pattern.
b)
To describe associations between specific LRT+ Atezo+Bev
pattern and clinical outcomes.
c)
To describe outcomes in specific subgroups (e.g., BCLC/CNLC
stage, liver function [Child-Pugh, ALBI], AFP level, etiology
(HBV vs. others)).
d)
To describe and analyze factors influencing clinical
effectiveness.
e)
To describe subsequent treatment patterns after progression or
discontinuation of LRT+ Atezo+Bev therapy.
Study Design
This is a retrospective, multicenter, cohort study. Approximately
1136 adult patients with uHCC treated with LRT+ Atezo+Bev between
October 28, 2020, and October 31, 2025, will be included from 35 sites
across China (including Mainland China, Hong Kong, Taiwan) and
potentially the broader APAC region (Japan, Korea, Singapore,
Malaysia).
Key Definitions
a)
Index Date: First administration of atezolizumab or
bevacizumab.
b)
Baseline Period: 30 days prior to the index date.
c)
Observation Period: From index date to death, last follow-up,
new primary cancer diagnosis, or withdrawal of consent.
d)
Sensitivity Analysis: Subgroup analyses will assess the optimal
combination timing (e.g., LRT-first vs. concurrent) by adjusting
for immortal time bias using time-dependent Cox models.
Sample Size
All patients who met the inclusion/exclusion criteria shall be included. To
estimate the median OS in this unresectable HCC population (with an
anticipated mOS of 30 months) with a 95% confidence interval that is
approximately 5 months wide (i.e., a margin of error of ±2.5 months), the
study would need to observe about 554 events (deaths). To achieve this
number of events with a 48-month accrual period followed by 12 months
of additional follow-up, and accounting for a 10% dropout rate. A total of

approximately 1,136 patients would need to be enrolled to achieve this
precision.
Population
Study population will consist of adult patients with uHCC who initiated
the study treatment of interest between 28 October 2020 and 31
October 2025.
Inclusion Criteria
Aged≥18 years at the initiation of Atezo+Bev
Initiated first-line Atezo+Bev between October 28, 2020, and July 31,
2025.
Received ≥1 LRT (TACE, TARE, HAIC, Ablation, Radiotherapy)
within ±2 months of Atezo+Bev initiation (i.e., 2 months pre-
initiation, during therapy, or 2 months post-discontinuation) , this
window captures common clinical practice timing variations as
observed in real-world cohorts.
Clinically or pathologically diagnosed uHCC before or at initiation.
Evidence of unresectability includes:
Direct documentation of 'unresectable' or 'advanced' in medical
records.
History
of
extrahepatic
metastasis
(confirmed
by
radiology,
histology, or cytology).
Staging criteria: CNLC Stage IIIb, BCLC Stage B/C, or AJCC Stage
IV, reflecting regional variations and broader applicability.
At least one visit record after the initiation of Atezo+Bev
Exclusion Criteria
Diagnosed with concomitant cancer except for basal cell carcinoma
before or at the initiation of Atezo+Bev
Enrolled in interventional clinical trials at the initiation of Atezo+Bev.
Received any systemic therapy for HCC before the Atezo+Bev
regimen.
Treatment
Definitions
A.
Atezolizumab + Bevacizumab Regimen Definition:
a)
Index Date: Date of first administration of either atezolizumab or
bevacizumab for uHCC.
b)
Treatment Duration: Length of time from index date to date of
last dose of either drug.
c)
Discontinuation: Record date and reason for discontinuation
(disease progression, toxicity, patient choice, death, completion

of planned course).
d)
Dose Modifications/Interruptions: Record frequency and
reason, especially for bevacizumab skipped doses.
B.
Locoregional Therapy (LRT) Definition:
a)
Modalities: Classified by records (TACE [cTACE/DEB-TACE],
TARE, Ablation, HAIC, Radiotherapy).Combination LRT
Definition: Administration of two or more distinct LRT modalities
will be classified as a single "Combination LRT" episode,
attributed to the date of the first LRT.
b)
Timing Relative to Atezo+Bev Initiation: LRT exposure will
be categorized based on its temporal relationship to the
Atezo+Bev index date (first administration):
i.
LRT-First: Completed within 2 months pre-Atezo+Bev
(e.g., TACE 6 weeks before Bev infusion).
ii.
Concurrent: Initiated within ±14 days of first Atezo+Bev
dose (e.g., HAIC start 5 days post-initial Atezo).
iii.
LRT-After: Completed within 2 months post-Atezo+Bev
start (e.g., radiotherapy 1 month post-treatment).
Study Endpoints
A.
Primary Endpoint:
Real-world overall survival (OS): defined as time from index date to
death from any cause.
Note: index date = first Atezo+Bev administration
B.
Secondary Endpoints:
a)
Real-world progression-free survival (rwPFS): defined as
the time from index date to clinician-documented disease
progression (local progression, recurrence, new metastasis, or
clinical progression) or death from any cause. Progression
events are based on clinician judgment as recorded in medical
documentation. Formal radiological reassessment or image
archiving is not required due to the retrospective real-world
nature of the study.
b)
Real-world Overall Response Rate (ORR): defined as the
percentage of patients who achieved complete response (CR)
or partial response (PR) after the index date with at least one
response assessment result. Both RECIST 1.1 and mRECIST
will be used to evaluate tumor response.
c)
Real-world Disease Control Rate (DCR):
defined as the
proportion of patients who achieve complete response (CR),
partial response (PR), or stable disease (SD) as assessed by
investigators using real-world imaging evaluations in
accordance with RECIST v1.1 or mRECIST criteria. Among
these, stable disease (SD) must persist for at least 6 weeks
from the first documentation of SD, which helps exclude the
interference of short-term disease fluctuations on assessment
results and more objectively reflects the sustained control effect
of treatment on tumors.
d)
Time to Discontinuation (TTD): defined as time from the

initiation to discontinuation of Atezo+Bev.
e)
Time to next treatment (TTNT): defined as time from the
initiation of Atezo+Bev to the initiation of next systemic
treatment.
f)
Time to Progression (TTP): defined as the time from the
Atezo+Bev index date to the first documented disease
progression. Patients who died without progression may be
censored in this endpoint analysis.
C.
Safety: Describing the safety profile of the LRT+ Atezo+Bev cohort
and its subgroups, including TEAE , TRAE ，and AE of special
interests focusing on the incidence and severity of key adverse
events (AEs) such as bleeding, hypertension, liver dysfunction/ liver
impairment, and immune-related AEs(irAEs).
Data Sources
De-identified patient data will be retrospectively collected from all
participated sites per institutional review board (IRB) approval:
A.
Electronic Medical Record Systems (EMR):
a)
Hospital Information System (HIS).
b)
Laboratory Information System (LIS).
c)
Picture Archiving and Communication System (PACS).
B.
Source Documentation:
a)
Clinician notes & consultation records.
b)
Admission/discharge summaries.
c)
Laboratory test results.
d)
Medication/prescription records.
e)
Radiology and pathology imaging reports.
f)
Adverse event (AE) monitoring logs.
C.
Institutional follow-up tracking systems/databases
independent of EMR (if available)
D.
Investigator-completed reassessment forms (manual/hand-
written documents) independent of EMR
Note: Each patient will be assigned a unique anonymized code to
maintain data linkage while ensuring confidentiality, consistent with
privacy protocols in real-world HCC studies. Pathology reports will be
used solely for diagnostic verification (summary-level H&E/IHC findings);
no human genetic resource samples or raw genetic data will be
collected.
Data Analysis
Any change to the data analysis methods described in the synopsis and
protocol will not require an amendment unless this change substantially
influences a principal feature of the study protocol. Any other changes to
the data analysis methods described in the study protocol and the
justification for making the change should be addressed in the statistical
analysis plan (SAP) and will be described in the final study report.
Missing data will in general not be imputed unless otherwise specified in
the SAP. Study analyses will be performed using SAS® Version 9.2 or
higher (SAS Inc., Cary, N.C., USA) or the latest stable version of R. All
analyses will follow the intention-to-treat principle.
Continuous variables will be summarized using descriptive statistics,
including mean, standard deviation (SD), median, interquartile range,
minimum and maximum. Categorical variables will be summarized as

frequency and percentage.
Time-to-event variables will be estimated using Kaplan-Meier (KM)
method. The median will be calculated along with two-sided 95%
confidence intervals (CIs) by Brookmeyer-Crowley, and KM curve will be
plotted and compared by log-rank test when subgroups are available.
Event-free rate and/or time-to-event rate at month12, 24 and 36 will also
be estimated using KM method and associated two-sided exact 95% CIs
will be calculated using log (-log) transformation.
Subgroup analyses will be conducted for selected primary and
secondary variables where sample size permits. Sensitivity analyses for
selected primary and secondary variables will be conducted if
appropriate/applicable.
1.
Background
2.1. Epidemiology and Clinical Burden of Unresectable Hepatocellular Carcinoma (uHCC) in
China and the Asia-Pacific Region
Hepatocellular carcinoma (HCC) is a prevalent malignant tumor worldwide, characterized by high
morbidity and mortality rates¹. Notably, in Asia—particularly in China—it accounts for nearly half of
the global incidence and mortality, presenting a significant public health challenge2.
Unlike Western countries where HCC is primarily driven by hepatitis C virus (HCV) infection, alcohol
abuse, and non-alcoholic fatty liver disease (MASLD) — which encompasses metabolic dysfunction-
associated steatohepatitis (MASH) as a more advanced form — the main cause of HCC in China
and most Asia-Pacific regions is chronic hepatitis B virus (HBV) infection. Although the proportion of
MASLD-related HCC (including MASH-related cases) has increased in certain Asian regions
recently, HBV infection remains the predominant etiological factor3. This distinct etiological
background may not only influence the biological behavior of the disease but also result in differing
treatment response patterns compared to Western cohorts. Moreover, HBV-related HCC is often
more aggressive4, with a significant proportion of patients in China being diagnosed at intermediate
or advanced stages (e.g., Barcelona Clinic Liver Cancer(BCLC) stage B/C or China Liver
Cancer(CNLC) stage IIb/IIIa/IIIb), thereby substantially limiting curative treatment options5.
Therefore, conducting regional real-world evidence (RWE) studies that address the specific etiology
and
clinical
characteristics
of
the
region
is
essential
for
accurately
evaluating
treatment
effectiveness within this unique biological context.
2.2. Current Standard of Care: Atezolizumab plus Bevacizumab (Atezo+Bev)
The Phase III IMbrave150 clinical trial showed that atezolizumab (an anti-PD-L1 antibody)
combined with bevacizumab (an anti-VEGF antibody) has become the global first-line standard of
care for patients with uHCC who have not undergone prior systemic therapy. The IMbrave150 trial
demonstrated that the ATEZO+BEV regimen significantly improved overall survival (OS) (median
OS: 19.2 months vs 13.4 months) and progression-free survival (PFS) (median PFS: 6.9 months vs

4.3 months) compared to sorafenib6. Furthermore, the Overall Response Rate (ORR) was notably
enhanced (approximately 30% vs 11% according to RECIST 1.1 criteria) 7. This regimen has been
approved in China and other Asia-Pacific countries/regions, and Chinese subgroup analysis in
IMbrave150 also revealed substantial efficacy benefits (OS HR: 0.44; PFS HR: 0.60) 8.
However, it should be noted that the patient population included in the IMbrave150 study was
relatively selective, primarily comprising individuals with Child-Pugh A liver function and an ECOG
performance status (PS) of 0-1. In contrast, in clinical practice, physicians may encounter patients
with more compromised liver function, poorer PS, or other conditions that were excluded based on
the IMbrave150 criteria. Moreover, despite the significant efficacy demonstrated by Atezo+Bev
therapy, the Overall Response Rate (ORR) reported in the IMbrave150 study (approximately 30%)
suggests that a considerable proportion of patients achieve only stable disease (SD) or experience
progressive disease (PD).
These findings underscore the clinical imperative to explore strategies, such as the integration of
appropriate Locoregional Therapies (LRTs), to further optimize and amplify the therapeutic efficacy
of Atezo+Bev in a broader cohort of patients with uHCC.
2.3. Role and Types of Locoregional Therapy (LRT) in uHCC Management
LRT is a critical component in the management of HCC, particularly for localized but unresectable
intrahepatic lesions. In the treatment of uHCC, the primary LRTs include commonly utilized LRTs
primarily include:
Transarterial chemoembolization (TACE), including conventional TACE (cTACE) and drug-
eluting bead TACE (DEB-TACE).
Transarterial radioembolization (TARE), typically performed using Y-90 microspheres.
Hepatic arterial infusion chemotherapy (HAIC), particularly in China, where FOLFOX-based
HAIC is widely utilized.
Ablation Therapies including
radiofrequency ablation (RFA) and microwave ablation (MWA).
Radiotherapy, including external beam radiotherapy and iodine-125 brachytherapy.
These LRTs not only play a pivotal role in the management of intermediate-stage HCC but also hold
significant importance in advanced HCC. Their applications include tumor downstaging, bridging
therapy for liver transplantation, local lesion control, palliative treatment, and combination with
systemic therapy treatment.9
2.4. Overview of LRT Guideline Differences and Practice Heterogeneity in China and the
Asia-Pacific Region
The application of LRT for uHCC varies significantly across clinical guidelines and practices in
China and other Asia-Pacific (APAC) regions. This variability is driven by the primary etiology of
HCC, regional staging systems, available medical resources, and local expertise.

The China Liver Cancer (CNLC) Guidelines10 often advocate a more aggressive approach to
locoregional therapy (LRT) in Chinese clinical practice. TACE is widely recommended for CNLC
stages Ib to IIIa and, in certain cases, even for stage IIIb patients. HAIC based on the FOLFOX
regimen is a unique recommendation for locally advanced HCC, particularly in cases involving major
vascular invasion. Ablation is an important treatment option for earlier CNLC stages (Ia, Ib, IIa) and
is sometimes combined with TACE in more complex scenarios. Compared to other LRT modalities,
TARE is less frequently utilized in China.
The Asian Pacific Association for the Study of the Liver (APASL) guidelines11, which hold significant
influence across the Asia-Pacific region, also advocate for the active use of LRTs. While the
importance of LRTs is universally recognized, regional variations exist in terms of emphasis on
specific modalities. For instance, Japanese guidelines12 provide more detailed criteria regarding
tumor size and number as indications for TACE. In contrast, Korean guidelines13 offer more
extensive recommendations on TARE.
Overall, the APAC region demonstrates a more aggressive and diverse utilization of LRT compared
to Western approaches. This study aims to clarify how varied LRT practices, particularly those
emphasized in the CNLC and APASL guidelines (such as TACE, HAIC, TARE, ablation and
radiotherapy), are combined with Atezo+Bev in real-world clinical settings. It also evaluates their
impact on patient outcomes. The findings are expected to inform strategies for optimizing the clinical
value of Atezo+Bev.
2.5. Rationale for Combining LRT with Atezo+Bev
LRTs can kickstart an immune response by releasing tumor antigens. Subsequently, systemic
immunotherapies can amplify this response by unleashing T-cell activity. Additionally, anti-
angiogenic agents can work to normalize the tumor environment, making it more conducive for both
the LRTs to be effective and for the immune system to function optimally.9
Recent randomized controlled trials (RCTs), such as LEAP-012 , EMERALD-1 and Talentace,
have demonstrated the feasibility and potential benefits of combining TACE with targeted therapies
and immune checkpoint inhibitors for intermediate-stage HCC. These studies represent significant
progress. However, these studies focus on one HCC stage—intermediate—and a single LRT
modality, TACE, within defined protocols. This highlights a substantial evidence gap for the broader
population of uHCC. In clinical practice, a wider range of LRTs—including TARE, ablation, and
HAIC—is frequently utilized, alongside diverse patient characteristics that extend beyond those
typically included in RCTs. Moreover, clinicians are actively exploring various combinations and
sequences of these LRTs with targeted therapies plus immune checkpoint inhibitors in real-world
settings.14,15 This approach is driven by a strong biological rationale and aims to optimize outcomes
for patients who may not achieve deep or durable responses to targeted therapy combined with
immunotherapy alone.

2.
Research Question and Objectives
Research Question: In clinical practice in China and selected Asia-Pacific regions, what is the
effectiveness and safety for uHCC patients receiving first-line Atezo+Bev combined with LRT?
Primary Objective:
To describe real-world overall survival (OS) in uHCC patients receiving first-line Atezo+Bev in
combination with any type of LRTs, with censoring defined as: loss to follow-up, withdrawal of
consent, or diagnosis of new primary cancer (critical for minimizing false follow-up bias).
Secondary Objectives:
Describe
■
real-world progression-free survival (rwPFS), Overall Response Rate (ORR [RECIST
v1.1/mRECIST]), disease control rate (DCR), overall and stratified by key LRT
categories.
■
TTD: Time from Atezo+Bev initiation to discontinuation of Atezo+Bev monotherapy (e.g.,
due to toxicity/patient decision).
■
TTNT: Time from Atezo+Bev initiation to subsequent systemic therapy.
■
TTP: Time from treatment start to radiological progression (RECIST v1.1/mRECIST).
Describe the safety profile:

TEAE,TRAE

Grade 3-5 TEAE

Grade 3-5 TRAE

Incidence/severity of key AEs: bleeding, hypertension, hepatotoxicity, immune-related
AEs (irAEs)

In subgroup analyses (e.g., by LRT modality)
Exploratory Objectives:
To describe associations between baseline patient/disease characteristics and clinical
outcomes within specific LRT+ Atezo+Bev pattern.
To describe associations between specific LRT+ Atezo+Bev pattern and clinical outcomes.
To describe outcomes in specific subgroups (e.g., BCLC/CNLC stage, liver function [Child-
Pugh, ALBI], AFP level, etiology (HBV vs. others)).
To describe and analyze factors influencing clinical effectiveness.
To describe subsequent treatment patterns after progression or discontinuation of LRT+
Atezo+Bev therapy.
3.
Study Design

This is a retrospective, multicenter, cohort study. Approximately 1136 adult patients with uHCC
treated with Atezo+Bev plus LRT will be included from 35 sites across China and potentially broader
APAC regions. The study period is strictly defined from October 28, 2020, to October 31, 2025. The
study design schematic is presented in Figure 1.
Key Definitions：
Index Date: First administration of atezolizumab or bevacizumab.
Baseline Period: 30 days prior to the index date.
Observation Period: From index date to death, last follow-up, new primary cancer diagnosis, or
withdrawal of consent.
Sensitivity Analysis:
■
Subgroup analyses for LRT combination timing (LRT-first vs. concurrent).
■
Adjustment for immortal time bias using time-dependent Cox models.
Note: This study will utilize existing retrospective clinical data, and an exemption or waiver of informed
consent will be sought, given the minimal risk and anonymized nature of the data analysis. Additionally,
patients will be censored at the time of loss to follow-up, or upon diagnosis of a new primary malignancy,
minimizing potential bias in follow-up data.
Figure 1. Study design schematic
Note: End of patient observation is defined as 31 Oct 2025 or the day before the ethical approval
from the leading site, whichever later.
4.
Selection Of Study Population
The effectiveness observation period varies among different effectiveness endpoints and is
specified in section 6. The safety observation period is defined as from the date of initiating

Atezo+Bev to the earliest of 90 days post the later last dose of atezolizumab or bevacizumab,
initiation of next systemic treatment, or end of observation. The study population will consist of adult
patients with uHCC who initiated the study treatment of interest. These patients come from
approximately 35 sites across China and potentially the broader APAC region. The eligibility criteria
are shown below:
Inclusion criteria:
Aged≥18 years at the initiation of Atezo+Bev
Initiated first-line Atezo+Bev between October 28, 2020, and July 31, 2025.
Received ≥1 LRT (TACE, TARE, HAIC, Ablation, Radiotherapy) within ±2 months of Atezo+Bev
initiation (i.e., 2 months pre-initiation, during therapy, or 2 months post-discontinuation) , this
window captures common clinical practice timing variations as observed in real-world cohorts.
Clinically or pathologically diagnosed uHCC before or at initiation. Evidence of unresectability
includes:
■
Direct documentation of 'unresectable' or 'advanced' in medical records.
■
History of extrahepatic metastasis (confirmed by radiology, histology, or cytology).
■
Staging criteria: CNLC Stage IIIb, BCLC Stage B/C, or AJCC Stage IV, reflecting regional
variations and broader applicability.
At least one visit record after the initiation of Atezo+Bev
Exclusion criteria:
Diagnosed with concomitant cancer except for basal cell carcinoma before or at the initiation of
Atezo+Bev
Enrolled in interventional clinical trials at the initiation of Atezo+Bev.
Received any systemic therapy for HCC before the Atezo+Bev regimen.
5.
Treatment Definitions
Atezo+Bev Regimen Definition:
Index Date: Date of first administration of either atezolizumab or bevacizumab for uHCC.
Treatment Duration: Length of Time from index date to date of last dose of either drug.
Discontinuation: Record date and reason for discontinuation (disease progression, toxicity,
patient choice, death, completion of planned course).
Dose Modifications/Interruptions: Record frequency and reason, especially for bevacizumab
skipped doses.
LRT Definition:

Modalities:
Classified
by
records
(TACE
[cTACE/DEB-TACE],
TARE,
Ablation,
HAIC,
Radiotherapy).
Combination LRT Definition:
Administration of two or more distinct LRT modalities will be classified as a single "Combination
LRT" episode, attributed to the date of the first LRT.
Timing Relative to Atezo+Bev Initiation: LRT exposure will be categorized based on its
temporal relationship to the Atezo+Bev index date (first administration)
■
LRT-First: Completed within ≤2 months pre-Atezo+Bev (e.g., TACE 6 weeks before Bev
infusion).
■
Concurrent: Initiated within ±14 days of first Atezo+Bev dose (e.g., HAIC start 5 days post-
initial Atezo).
■
LRT-After: Completed within ≤2 months post-Atezo+Bev start (e.g., radiotherapy 1 month
post-treatment).
Examples based on evidence: In clinical practice, concurrent LRT may enhance efficacy but requires
careful AE monitoring (e.g., concurrent HAIC in GO30140).
6.
Data Source(s)
Patient treated with Atezo+Bev will be selected from hospitals across various provinces in China.
After ethics committee (EC) approval, de-identified patient-level data will be retrospectively
abstracted from medical records at approximately 35 sites. Data sources primarily include hospital
information
system
(HIS),
laboratory
information
system
(LIS),
and
picture
archiving
and
communication system (PACS). Each patient is assigned a unique, non-identifiable code to enable
linkage. Source documents include clinician notes, admission/discharge summaries, laboratory
results (including pathology reports for HCC diagnosis, as required without detailed genetic data),
prescription records, imaging results, and communication documents. This approach ensures
compliance with privacy regulations while capturing comprehensive real-world data.
7.
Sample Size
To estimate the median OS in this unresectable HCC population (with an anticipated mOS of 30
months) with a 95% confidence interval that is approximately 5 months wide (i.e., a margin of error
of ±2.5 months), the study would need to observe about 554 events (deaths). To achieve this
number of events, the study will have a 48-month accrual period followed by 12 months of additional
follow-up, accounting for a 10% dropout rate. A total of approximately 1136 patients would need to
be enrolled in a prospective design.

However, in a retrospective design, all patients who met the inclusion/exclusion criteria shall be
included. The exact sample size may be different from 1136. A post hoc power analysis will provide
a retrospective assessment of whether the study had adequate power to estimate the primary
endpoint (mOS) with the desired precision.
8.
Data Analysis
Changes to the data analysis methods described in the synopsis and protocol will not require an
amendment unless they substantially affect a principal feature of the study protocol. Any other
changes and their justification should be documented in the statistical analysis plan (SAP) and
described in the final study report. Analyses will be performed using SAS® Version 9.2 or higher
(SAS Institute, Cary, NC, USA) or the latest stable version of R. All analyses will follow the intention-
to-treat (ITT) principle. Missing data should be minimized and handled using appropriate imputation
methods.
Continuous variables will be summarized using descriptive statistics, including the number of
observations (n), mean, standard deviation (SD), median, first and third quartiles (Q1, Q3), minimum,
and maximum. Categorical variables will be summarized as frequency and percentage.
Time-to-event variables will be estimated using the Kaplan-Meier (KM) method. The median and
two-sided 95% confidence intervals (CIs) will be calculated using the Brookmeyer-Crowley. KM
curves will be plotted and compared using the log-rank test. Event-free rate and/or time-to-event
rate at month 12,24 and 36 will also be estimated using KM method and associated two-sided exact
95% CIs will be calculated using log (-log) transformation. ORR will be calculated at 1, 3, and 6
months.
KM curves for OS and PFS will also be generated for pre-defined key subgroups. Median survival
times and survival rates with 95% CIs will be presented for these subgroups. Exploratory
comparisons between strata within a subgroup category (e.g., different LRT modalities, different
BCLC stages) may be performed using the log-rank test, understanding its limitations due to
confounding in an observational setting. ORR and DCR, along with their 95% CIs, will also be
calculated and presented for pre-defined key subgroups. Exploratory comparisons of response
rates between strata may be performed using Chi-square or Fisher's exact tests, as appropriate.
Missing values will be minimized and imputed with suitable statistical methods, detailed in the SAP.
9.
Data Quality Assurance and Quality Control
The investigators must maintain adequate and accurate records to enable the conduct of the study
to be fully documented, including but not limited to the protocol, protocol amendments, ICFs (if
applicable), and documentation of Institutional Review Board (IRB)/EC and governmental approval
(if necessary).

10. Management and Reporting of Adverse Events
All adverse events extracted from the data source for the study as specified in the protocol will be
summarized as part of any interim safety analyses (if applicable) and in the final study report and
final publication (if any).
11. Plans for Dissemination and Communication of Study Results
The results will be published in peer-reviewed journals and presented as abstracts/posters at medical
congresses. Adherence to established guidelines is essential: Strengthening the Report of Observational
Studies in Epidemiology (STROBE) for observational designs, Good Publication Practice 3 (GPP3), and
International Committee of Medical Journal Editors (ICMJE). Publications will also comply with other top-
tier standards like GRACE and CONSORT adaptations for observational data to ensure transparency
and reproducibility.
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