A Phase III, Multicenter, Randomized, Open-Label Study of Atezolizumab (Anti-PD-L1 Antibody) Plus Bevacizumab Versus Active Surveillance as Adjuvant Therapy in Patients With Hepatocellular Carcinoma at High Risk of Recurrence After Surgical Resection or Ablation
Phase: PHASE3
Conditions: Carcinoma, Hepatocellular
Sponsor: Hoffmann-La Roche

CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche's local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
Protocol WO41535, Version 6 
PROTOCOL 
PROTOCOL TITLE: 
A PHASE III, MULTICENTER, RANDOMIZED, 
OPEN-LABEL STUDY OF ATEZOLIZUMAB 
(ANTI-PD-L1 ANTIBODY) PLUS BEVACIZUMAB 
VERSUS ACTIVE SURVEILLANCE AS ADJUVANT 
THERAPY IN PATIENTS WITH HEPATOCELLULAR 
CARCINOMA AT HIGH RISK OF RECURRENCE 
AFTER SURGICAL RESECTION OR ABLATION 
PROTOCOL NUMBER: WO41535 
STUDY NAME: 
IMbrave050 
VERSION NUMBER: 
6 
TEST COMPOUNDS: 
Atezolizumab (RO5541267) 
Bevacizumab (RO4876646) 
STUDY PHASE: 
Phase III 
REGULATORY 
AGENCY IDENTIFIER 
NUMBERS: 
IND Number:  135913 
EudraCT Number:  2019-002 491-14 
EU CT Number:  2023-504303-86-00 
NCT Number:  04102098 
SPONSOR’S NAME 
AND LEGAL 
REGISTERED 
ADDRESS: 
F. Hoffmann-La Roche Ltd  
Grenzacherstrasse 124  
4070 Basel, Switzerland 
APPROVAL  
See electronic signature and date stamp on the final 
page of this document.. 

 
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
2/Protocol WO41535, Version 6 
PROTOCOL HISTORY 
Protocol 
Associated Country-Specific Protocol 
Version 
Date Final 
Country 
Version 
Date Final 
6 
See electronic date 
stamp on the final 
page of this document. 
 
 
 
5 
25 October 2022 
 
 
 
4 
30 November 2021 
 
 
 
3 
3 December 2020 
 
 
 
2 
17 December 2019 
 
 
 
1 
17 July 2019 
VHP 
1 
17 October 2019 
 

 
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
3/Protocol WO41535, Version 6 
PROTOCOL AMENDMENT, VERSION 6: 
RATIONALE 
Protocol WO41535 has been amended to update safety language following the 
Atezolizumab Investigator’s Brochure Version 19, Addendum 2 and to comply with 
Clinical Trials Regulation (CTR) guidelines.  Substantive changes to the protocol, along 
with a rationale for each change, are summarized below. 
 
The following changes have been made to align the protocol with Addendum 2 of 
the Atezolizumab Investigator's Brochure, Version 19: 
– 
The medical term “Wegener granulomatosis” has been replaced by the term 
“granulomatosis with polyangiitis” to align with the updated preferred term in 
MedDRA (Section 4.1.2 and Appendix 10). 
– 
The list of identified risks for atezolizumab has been revised to include myelitis 
and facial paresis (Section 5.1.1). 
– 
Hemophagocytic lymphohistiocytosis has been updated from a potential risk to 
an identified risk associated with atezolizumab and language has been revised 
accordingly (Section 5.1.1). 
– 
The list of adverse events of special interest has been revised to include 
myelitis and facial paresis (Section 5.2.3). 
– 
Appendix 10 has been revised to indicate that caution should be used when 
considering atezolizumab for patients who have previously experienced a 
pericardial disorder while receiving another immunostimulatory anti-cancer 
agent. 
– 
Appendix 10 has been revised to include autoimmune myelitis. 
– 
The adverse event management guidelines have been updated to align with the 
Addendum 2 to the Atezolizumab Investigator's Brochure, Version 19 
(Appendix 13). 
 
 
The following changes have been made to align the protocol with CTR 
requirements: 
– 
The synopsis has been simplified to align with CTR and other guidelines. 
– 
A section describing the duration of participation has been added to align with 
CTR requirements (Section 3.3). 
– 
A comprehensive list of investigational medicinal products and auxiliary 
medicinal products has been added to align with CTR requirements 
(Section 4.3 and Appendix 14). 
– 
Personal identifiable information (i.e., name and telephone number) for the 
Medical Monitors has been removed from the protocol (front matter and 
Section 5.4.1).  Medical Monitor contact information in Section 5.4.1 has been 
replaced with a sentence indicating that this information will be provided 
separately to sites. 

 
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
4/Protocol WO41535, Version 6 
– 
A description of the technical and organizational security measures taken to 
protect personal data has been added to align with CTR requirements 
(Section 8.4). 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.

 
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
5/Protocol WO41535, Version 6 
 
TABLE OF CONTENTS 
PROTOCOL SYNOPSIS .................................................................................... 13 
1. 
BACKGROUND ............................................................................ 19 
1.1 
Background on Hepatocellular Carcinoma .............................. 19 
1.1.1 
Epidemiology and Disease Burden .......................................... 19 
1.1.2 
Unmet Need in Patients following Resection or Ablation ......... 19 
1.2 
Adjuvant Treatment for Hepatocellular Carcinoma .................. 20 
1.3 
Background on Atezolizumab .................................................. 21 
1.4 
Background on Bevacizumab .................................................. 21 
1.5 
Clinical Studies of Atezolizumab Plus Bevacizumab in 
Patients with Hepatocellular Carcinoma .................................. 22 
1.5.1 
Study GO30140 ....................................................................... 22 
1.5.2 
Study YO40245 ....................................................................... 23 
1.6 
Study Rationale and BenefitRisk Assessment ....................... 24 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 27 
3. 
STUDY DESIGN ........................................................................... 30 
3.1 
Overview of Study Design........................................................ 30 
3.1.1 
Independent Data Monitoring Committee ................................ 35 
3.1.2 
Independent Review Facility .................................................... 35 
3.2 
End of Study and Length of Study ........................................... 35 
3.3 
Duration of participation......................................................... 36 
3.4 
Rationale for Study Design ...................................................... 36 
3.4.1 
Rationale for Atezolizumab Dose and Schedule ...................... 36 
3.4.2 
Rationale for Bevacizumab Dose and Schedule ...................... 36 
3.4.3 
Rationale for Patient Population .............................................. 36 
3.4.4 
Rationale for the Active Surveillance Control Arm (Arm B) ...... 37 
3.4.5 
Rationale for Crossover from Active Surveillance to 
Treatment with Atezolizumab plus Bevacizumab ..................... 37 
3.4.6 
Rationale for Recurrence-Free Survival as Primary 
Endpoint .................................................................................. 37 
3.4.7 
Rationale for Choice of Randomization Stratification 
Factors ..................................................................................... 38 
3.4.8 
Rationale for Biomarker Assessments ..................................... 39 

 
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3.4.9 
Rationale for Patient-Reported Outcomes ............................... 41 
4. 
MATERIALS AND METHODS ...................................................... 41 
4.1 
Patients .................................................................................... 41 
4.1.1 
Inclusion Criteria ...................................................................... 41 
4.1.1.1 
Additional Inclusion Criteria for Crossover for Patients in 
Arm B ....................................................................................... 45 
4.1.2 
Exclusion Criteria ..................................................................... 46 
4.2 
Method of Treatment Assignment and Blinding ....................... 49 
4.3 
Study Treatment and Other Treatments Relevant to the 
Study Design ........................................................................... 50 
4.3.1 
Study Treatment Formulation, Packaging, and Handling ......... 50 
4.3.1.1 
Atezolizumab ........................................................................... 50 
4.3.1.2 
Bevacizumab ........................................................................... 50 
4.3.2 
Study Treatment Dosage, Administration, and Compliance .... 50 
4.3.2.1 
Atezolizumab ........................................................................... 51 
4.3.2.2 
Bevacizumab ........................................................................... 52 
4.3.3 
Investigational Medicinal Product Accountability ..................... 52 
4.3.4 
Continued Access to Atezolizumab and Bevacizumab ............ 53 
4.4 
Concomitant Therapy .............................................................. 53 
4.4.1 
Permitted Therapy ................................................................... 54 
4.4.2 
Cautionary Therapy for Atezolizumab-Treated Patients .......... 54 
4.4.2.1 
Corticosteroids, Immunosuppressive Medications, and 
Tumor Necrosis Factor- Inhibitors ......................................... 54 
4.4.2.2 
Herbal Therapies ..................................................................... 55 
4.4.3 
Prohibited Therapy .................................................................. 55 
4.5 
Study Assessments ................................................................. 56 
4.5.1 
Informed Consent Forms and Screening Log .......................... 56 
4.5.2 
Medical History, Baseline Conditions, Concomitant 
Medication, and Demographic Data ......................................... 57 
4.5.3 
Physical Examinations ............................................................. 57 
4.5.4 
Vital Signs ................................................................................ 57 
4.5.5 
Imaging Assessments .............................................................. 57 
4.5.6 
Laboratory, Biomarker, and Other Biological Samples ............ 60 
4.5.7 
Electrocardiograms .................................................................. 62 

 
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4.5.8 
Patient-Reported Outcomes .................................................... 63 
4.5.8.1 
Data Collection Methods for Patient-Reported Outcomes ....... 63 
4.5.8.2 
Description of Patient-Reported Outcomes Instruments .......... 64 
4.5.9 
Blood Samples for Whole Genome Sequencing or Whole 
Exome Sequencing (Patients at Participating Sites) ................ 64 
4.5.10 
Optional Samples for Research Biosample Repository ........... 65 
4.5.10.1 
Overview of the Research Biosample Repository .................... 65 
4.5.10.2 
Approval by the Institutional Review Board or Ethics 
Committee ............................................................................... 66 
4.5.10.3 
Sample Collection .................................................................... 66 
4.5.10.4 
Confidentiality .......................................................................... 67 
4.5.10.5 
Consent to Participate in the Research Biosample 
Repository................................................................................ 67 
4.5.10.6 
Withdrawal from the Research Biosample Repository ............. 68 
4.5.10.7 
Monitoring and Oversight ......................................................... 68 
4.6 
Treatment, Patient, Study, and Site Discontinuation ................ 68 
4.6.1 
Study Treatment Discontinuation ............................................. 68 
4.6.2 
Patient Discontinuation from the Study .................................... 69 
4.6.3 
Study Discontinuation .............................................................. 70 
4.6.4 
Site Discontinuation ................................................................. 70 
5. 
ASSESSMENT OF SAFETY ......................................................... 70 
5.1 
Safety Plan .............................................................................. 70 
5.1.1 
Risks Associated with Atezolizumab ........................................ 71 
5.1.2 
Risks Associated with Bevacizumab ........................................ 71 
5.1.3 
Risks Associated with Combination Use of Atezolizumab 
and Bevacizumab .................................................................... 72 
5.2 
Safety Parameters and Definitions .......................................... 72 
5.2.1 
Adverse Events ........................................................................ 72 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) .................................................................................. 73 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ...................................................... 73 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................... 75 
5.3.1 
Adverse Event Reporting Period .............................................. 75 

 
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5.3.2 
Eliciting Adverse Event Information ......................................... 76 
5.3.3 
Assessment of Severity of Adverse Events ............................. 76 
5.3.4 
Assessment of Causality of Adverse Events............................ 77 
5.3.5 
Procedures for Recording Adverse Events .............................. 78 
5.3.5.1 
Infusion-Related Reactions ...................................................... 78 
5.3.5.2 
Diagnosis versus Signs and Symptoms ................................... 78 
5.3.5.3 
Adverse Events That Are Secondary to Other Events ............. 79 
5.3.5.4 
Persistent or Recurrent Adverse Events .................................. 79 
5.3.5.5 
Abnormal Laboratory Values ................................................... 80 
5.3.5.6 
Abnormal Vital Sign Values ..................................................... 80 
5.3.5.7 
Abnormal Liver Function Tests ................................................ 81 
5.3.5.8 
Deaths ..................................................................................... 81 
5.3.5.9 
Preexisting Medical Conditions ................................................ 82 
5.3.5.10 
Lack of Efficacy or Worsening of Hepatocellular Carcinoma ... 82 
5.3.5.11 
Hospitalization or Prolonged Hospitalization ............................ 82 
5.3.5.12 
Cases of Accidental Overdose or Medication Error ................. 83 
5.3.5.13 
Patient-Reported Outcome Data .............................................. 84 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................... 84 
5.4.1 
Emergency Medical Contacts .................................................. 85 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest .......................................... 85 
5.4.2.1 
Events That Occur prior to Study Treatment Initiation ............. 85 
5.4.2.2 
Events That Occur after Study Treatment Initiation ................. 85 
5.4.3 
Reporting Requirements for Pregnancies ................................ 86 
5.4.3.1 
Pregnancies in Female Patients .............................................. 86 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ................... 86 
5.4.3.3 
Abortions.................................................................................. 87 
5.4.3.4 
Congenital Anomalies/Birth Defects ........................................ 87 
5.5 
Follow-Up of Patients after Adverse Events............................. 87 
5.5.1 
Investigator Follow-Up ............................................................. 87 
5.5.2 
Sponsor Follow-Up .................................................................. 88 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period ...................................................................... 88 

 
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5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............... 88 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ......... 89 
6.1 
Determination of Sample Size ................................................. 89 
6.2 
Summaries of Conduct of Study .............................................. 90 
6.3 
Summaries of Treatment Group Comparability ........................ 90 
6.4 
Efficacy Analyses ..................................................................... 90 
6.4.1 
Primary Efficacy Endpoint ........................................................ 90 
6.4.2 
Secondary Efficacy Endpoints ................................................. 92 
6.4.2.1 
Overall Survival ........................................................................ 92 
6.4.2.2 
InvestigatorAssessed Recurrence Free Survival ................... 92 
6.4.2.3 
Time to Recurrence ................................................................. 92 
6.4.2.4 
IRF-Assessed and Investigator-Assessed RFS at 24-
Month and 36-Month Landmark Analysis ................................ 93 
6.4.2.5 
Overall Survival 24-Month and 36-Month Landmark 
Analysis ................................................................................... 93 
6.4.2.6 
Time to Extrahepatic Spread or Macrovascular Invasion ......... 93 
6.4.2.7 
Recurrence-Free Survival among Patients with PD-
L1High Tumors ...................................................................... 93 
6.4.3 
Exploratory Efficacy Endpoints ................................................ 93 
6.5 
Safety Analyses ....................................................................... 94 
6.6 
Pharmacokinetic Analyses ....................................................... 95 
6.7 
Immunogenicity Analyses ........................................................ 96 
6.8 
Biomarker Analyses ................................................................. 96 
6.9 
Health Utility Analyses ............................................................. 96 
6.10 
Interim Analyses ...................................................................... 96 
6.10.1 
Interim Analyses of RFS .......................................................... 96 
6.10.2 
Interim Analyses of OS ............................................................ 97 
6.11 
China Subpopulation Analyses .............................................. 100 
7. 
DATA COLLECTION AND MANAGEMENT ............................... 101 
7.1 
Data Quality Assurance ......................................................... 101 
7.2 
Electronic Case Report Forms ............................................... 101 
7.3 
Source Data Documentation .................................................. 102 
7.4 
Use of Computerized Systems .............................................. 102 

 
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7.5 
Retention of Records ............................................................. 102 
8. 
ETHICAL CONSIDERATIONS .................................................... 103 
8.1 
Compliance with Laws and Regulations ................................ 103 
8.2 
Informed Consent .................................................................. 103 
8.3 
Institutional Review Board or Ethics Committee .................... 104 
8.4 
Confidentiality ........................................................................ 105 
8.5 
Financial Disclosure ............................................................... 106 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................... 106 
9.1 
Study Documentation ............................................................ 106 
9.2 
Protocol Deviations ................................................................ 106 
9.3 
Management of Study Quality ................................................ 106 
9.4 
Site Inspections ..................................................................... 106 
9.5 
Administrative Structure ......................................................... 107 
9.6 
Dissemination of Data and Protection of Trade Secrets ........ 107 
9.7 
Protocol Amendments ........................................................... 108 
10. 
REFERENCES............................................................................ 109 
 
 
LIST OF TABLES 
Table 1 
Study GO30140:  Overall Efficacy Summary .............................. 23 
Table 2 
Study YO40245:  Overall Efficacy Summary............................... 24 
Table 3 
Objectives and Corresponding Endpoints ................................... 28 
Table 4 
High Risk Criteria for This Study ................................................. 31 
Table 5 
Administration of First and Subsequent Atezolizumab 
Infusions...................................................................................... 51 
Table 6 
Administration of First and Subsequent Bevacizumab 
Infusions...................................................................................... 52 
Table 7 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 77 
Table 8 
Causal Attribution Guidance ....................................................... 78 
Table 9 
Analysis Timing and Stopping Boundaries for Recurrence-
Free Survival Analyses ............................................................... 98 
Table 10 
Projected Interim and Final OS Analysis Characteristics 
When Statistical Significance is Reached at the Interim 
Analysis for RFS ......................................................................... 99 

 
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Table 11 
Projected Interim and Final OS Analysis Characteristics 
When Statistical Significance is Reached at the Final 
Analysis for RFS ....................................................................... 100 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 32 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Activities ................................................................ 114 
Appendix 2 
Schedule of Activities for Patients in Arm B Who Cross Over 
to Treatment with Atezolizumab plus Bevacizumab .................. 122 
Appendix 3 
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples ................................................................... 127 
Appendix 4 
Child-Pugh Classification .......................................................... 129 
Appendix 5 
Classification of Hepatocellular Carcinoma with Vascular 
Invasion..................................................................................... 130 
Appendix 6 
EASL Clinical Practice Guidelines:  Diagnostic Algorithm and 
Recall Policy in Cirrhotic Liver ................................................... 132 
Appendix 7 
Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1 ................................................................................ 133 
Appendix 8 
IL42–European Organisation for the Research and 
Treatment of Cancer QLQ-C30 (Reduced) ............................... 143 
Appendix 9 
EQ-5D-5L .................................................................................. 144 
Appendix 10 
Preexisting Autoimmune Diseases and Immune Deficiencies .. 146 
Appendix 11 
Anaphylaxis Precautions ........................................................... 147 
Appendix 12 
Overall Guidelines for Management of Patients Who 
Experience Adverse Events ...................................................... 148 
Appendix 13 
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab ............................................................................ 155 
Appendix 14 Investigational Medicinal Product and Non-Investigational 
Medicinal Product Designations (for Use in European 
Economic Area) ......................................................................... 187 

 
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
12/Protocol WO41535, Version 6 
 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
PROTOCOLTITLE: 
A PHASE III, MULTICENTER, RANDOMIZED, 
OPEN-LABEL STUDY OF ATEZOLIZUMAB 
(ANTI-PD-L1 ANTIBODY) PLUS BEVACIZUMAB 
VERSUS ACTIVE SURVEILLANCE AS ADJUVANT 
THERAPY IN PATIENTS WITH HEPATOCELLULAR 
CARCINOMA AT HIGH RISK OF RECURRENCE 
AFTER SURGICAL RESECTION OR ABLATION 
PROTOCOL NUMBER: WO41535 
VERSION NUMBER: 
6 
TEST COMPOUNDS: 
Atezolizumab (RO5541267) 
Bevacizumab (RO4876646) 
SPONSOR NAME: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator's Name  (print) 
 
 
 
 
 
Principal Investigator's Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your local study monitor.  
 

 
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
13/Protocol WO41535, Version 6 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE III, MULTICENTER, RANDOMIZED, OPEN-LABEL 
STUDY OF ATEZOLIZUMAB (ANTI-PD-L1 ANTIBODY) PLUS 
BEVACIZUMAB VERSUS ACTIVE SURVEILLANCE AS 
ADJUVANT THERAPY IN PATIENTS WITH HEPATOCELLULAR 
CARCINOMA AT HIGH RISK OF RECURRENCE AFTER 
SURGICAL RESECTION OR ABLATION 
REGULATORY 
AGENCY IDENTIFIER 
NUMBERS 
IND Number: 135913 
EudraCT Number:  2019-002 491-14 
EU CT NUMBER:  2023-504303-86-00  
NCT NUMBER:  04102098 
 
STUDY RATIONALE 
The purpose of this study is to assess the efficacy and safety of atezolizumab plus 
bevacizumab, in patients with completely resected or ablated hepatocellular carcinoma (HCC) 
who are at high risk for disease recurrence.  Given the poor prognosis associated with high 
recurrence rates and absence of treatment options for these patients, this population is 
considered appropriate for trials of novel therapeutic candidates in the adjuvant setting.   
 
OBJECTIVES AND ENDPOINTS 
 
Primary Efficacy Objective 
(Primary Objective) 
Corresponding Endpoint 
 
To evaluate the efficacy of 
atezolizumab plus 
bevacizumab compared with 
active surveillance  
 
RFS after randomization, defined as the time from 
randomization to the first documented occurrence of 
intrahepatic or extrahepatic HCC as determined by 
an IRF, or death from any cause (whichever occurs 
first) 
 

 
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
14/Protocol WO41535, Version 6 
Secondary Efficacy Objective 
Corresponding Endpoints 
 
To evaluate the efficacy of 
atezolizumab plus 
bevacizumab compared with 
active surveillance 
 
OS after randomization, defined as the time from 
randomization to death from any cause 
 
RFS after randomization as determined by the 
investigator 
 
TTR after randomization, defined as the time from 
randomization to first documented occurrence of 
intrahepatic or extrahepatic HCC, as determined by 
the investigator and by an IRF 
 
IRF-assessed RFS and investigator-assessed RFS 
rate at 24 and 36 months after randomization 
 
OS rate at 24 months and 36 months, defined as the 
proportion of patients who have not experienced death 
from any cause at 24 and 36 months after 
randomization, respectively 
 
Time to EHS or macrovascular invasion after 
randomization, defined as the time from randomization 
to the first appearance of EHS or macrovascular 
invasion, as determined by the investigator 
 
RFS after randomization as determined by the 
investigator and by an IRF, among patients in the  
PD-L1high subgroup 
 
Safety Objective 
 
Corresponding Endpoints 
 
To evaluate the safety of 
atezolizumab plus 
bevacizumab compared with 
active surveillance 
 
Incidence and severity of adverse events, with severity 
determined according to NCI CTCAE v5.0 
 
Change from baseline in targeted vital signs 
 
Change from baseline in targeted clinical laboratory 
test results 
 
Pharmacokinetic Objective 
 
Corresponding Endpoint 
 
To characterize the PK 
profile of atezolizumab when 
given in combination with 
bevacizumab 
 
Serum concentration of atezolizumab at specified 
timepoints 
 
Immunogenicity Objective 
 
Corresponding Endpoint 
 
To evaluate the immune 
response to atezolizumab 
 
Prevalence of ADAs to atezolizumab at baseline and 
incidence of ADAs to atezolizumab during the study 
ADA  anti-drug antibody; EHS  extrahepatic spread; HCC=hepatocellular carcinoma; 
IRF  Independent Review Facility; NCI CTCAE  National Cancer Institute Common 
Terminology Criteria for Adverse Events; OS  overall survival; PK  pharmacokinetic; 
RFS  recurrence-free survival; TTR  time to recurrence. 
 
OVERALL DESIGN AND STUDY POPULATION 
This is a Phase III, global, multicenter, open-label, two-arm, randomized study designed to 
evaluate the efficacy and safety of adjuvant therapy with atezolizumab plus bevacizumab 
compared with active surveillance in patients with completely resected or ablated HCC who are 
at high risk for disease recurrence. Key aspects of the study design and study population are 
summarized below. 
 
 

 
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Phase: 
Phase III 
Population Type: 
Adult patients  
Control Method: 
Standard of care 
Population Diagnosis 
or Condition: 
HCC with high risk of 
recurrence after 
surgical resection or 
ablation 
Interventional 
Model: 
Parallel 
Population Age: 
Age   18 years 
Test Compounds: 
Atezolizumab 
Bevacizumab 
 
Site Distribution: 
Multi-site and 
multi-region 
Active Comparator: Not Applicable  
Study Intervention 
Assignment Method: 
Randomization and 
stratification 
Number of Arms: 
2 
Number of Participants 
to Be Enrolled: 
Approximately 662 
 
STUDY TREATMENT 
The investigational medicinal products (IMPs) for this study are atezolizumab and bevacizumab.  
Atezolizumab will be administered 1200 mg IV every 21 days and bevacizumab will be 
administered 15mg/kg IV every 21 days.  No dose modification for atezolizumab or 
bevacizumab is allowed. 
DURATION OF PARTICIPATION 
The total duration of study participation for each individual is expected to range from 1 day 
up to approximately 91 months. 
 
COMMITTEES 
Independent Committees: 
Independent Data Monitoring Committee 
Other Committees: 
Not Applicable  
 

 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AASLD 
American Association for the Study of Liver Diseases 
ADA 
anti-drug antibody 
AFP 
-fetoprotein 
ATE 
arterial thromboembolic event 
BP 
blood pressure 
CHF 
congestive heart failure 
COVID-19 
coronavirus disease 2019 
CR 
complete response 
CRS 
cytokine release syndrome 
CT 
computed tomography 
ctDNA 
circulating-tumor DNA 
EASL 
European Association for the Study of the Liver 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EHS 
extrahepatic spread 
EORTC 
European Organisation for the Research and 
Treatment of Cancer 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed, paraffin-embedded 
GHS 
global health status 
GI 
gastrointestinal 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCC  
hepatocellular carcinoma 
HCV 
hepatitis C virus 
HGRAC 
Human Genetic Resources Administration of China 
HIPAA 
Health Insurance Portability and Accountability Act 
HLH 
hemophagocytic lymphohistiocytosis 
HR 
hazard ratio 
HRQoL 
health-related quality of life 
ICH 
International Council for Harmonisation 
iDMC 
independent Data Monitoring Committee 
IFN 
interferon 

 
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Abbreviation 
Definition 
IL 
interleukin 
IL42 
item list 42 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
IRF 
Independent Review Facility 
IRR 
infusion-related reaction 
ITT 
intent-to-treat (population) 
IxRS 
interactive voice or web-based response system 
LMWH 
low-molecular-weight heparin 
MAS 
macrophage activation syndrome 
MDD 
minimum detectable difference 
MRI 
magnetic resonance imaging 
MWA 
microwave ablation 
NAFLD 
non-alcoholic fatty liver disease 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria 
for Adverse Events 
NED 
no evidence of disease 
NSAID 
nonsteroidal anti-inflammatory drug 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PR 
partial response 
PRO 
patient-reported outcome 
Q3W 
every 3 weeks 
QoL 
quality of life 
RBR 
Research Biosample Repository 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RFA 
radiofrequency ablation 
RFS 
recurrence-free survival 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
TACE 
transarterial chemoembolization 
TNF- 
tumor necrosis factor- 
TTR 
time to recurrence 

 
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Abbreviation 
Definition 
ULN 
upper limit of normal 
VAS 
Visual Analog Scale 
VEGF 
vascular endothelial growth factor 
WES 
whole exome sequencing 
WGS 
whole genome sequencing 
 

 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON HEPATOCELLULAR CARCINOMA 
1.1.1 
Epidemiology and Disease Burden 
Liver cancer is the fifth most common cancer, accounting for 7% of all cancers, and the 
second most frequent cause of cancer-related death globally, with 854,000 new cases 
and 810,000 deaths per year.  Hepatocellular carcinoma (HCC) represents 
approximately 90% of primary liver cancers and thus represents a significant global 
public health issue.  On the basis of annual projections, the World Health Organization 
estimates that in excess of 1 million people will die from liver cancer in 2030 
(Villanueva 2019). 
The majority of HCCs occur in patients with underlying liver disease, mostly as a result 
of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection or alcohol abuse.  
HBV infection accounts for the majority of HCC cases worldwide; however, in Western 
countries and Japan, HCV is the main cause of HCC (Villanueva 2019).  Universal HBV 
vaccination and wide implementation of direct-acting antiviral agents against HCV are 
likely to change the etiologic landscape of HCC.  However, the incidence of 
non-alcoholic fatty liver disease (NAFLD), which is a risk factor for HCC, is increasing 
worldwide and NAFLD will soon become a leading cause of liver cancer in Western 
countries (Villanueva 2019). 
1.1.2 
Unmet Need in Patients following Resection or Ablation 
There are several potentially curative approaches to the treatment of HCC, including 
surgical resection and ablation.   
Liver resection provides an opportunity for long-term, cancer-free survival and 
represents the primary curative treatment option for patients with HCC deemed to be 
surgical candidates.  Eligibility for curative resection is typically based on disease stage 
as well as assessment of functional liver reserve; however, the concept of "resectability" 
varies significantly depending on local clinical practice and guidelines.  Notably, eligibility 
criteria for curative resection are more aggressive in many Asian guidelines, including 
patients with minor vascular invasion of the portal vein, compared to Western treatment 
guidelines.  
Local ablative strategies such as radiofrequency ablation (RFA) and microwave 
ablation (MWA) are potentially curative options typically offered to patients with very 
early or early stage HCC who are not candidates for resection (Villanueva 2019).  As 
compared with resection, ablation has fewer complications but provides worse local 
control for larger tumors (Villanueva 2019).  
Tumor recurrence is a major post-procedural complication associated with both 
resection and ablation, with 50% to 70% of patients experiencing recurrence by 5 years 
(Villanueva 2019).  The risk of HCC recurrence after curative intervention is primarily 

 
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related to tumor burden (the number and size of tumors) and pathologic characteristics 
or the tumor such as degree of differentiation and the presence of vascular invasion 
(either microvascular or macrovascular).   
For patients harboring one or more of these high risk features (tumor size, tumor 
number, vascular invasion, and poorly differentiated tumor), the prognosis following 
curative intervention is poor.  In one study, 5-year disease-free survival rates following 
resection were 26% in patients with large/multinodular HCC and 18% in patients with 
macrovascular invasion (Zhong et al. 2015).  Five-year survival rates were 42% in 
patients with large/multinodular HCC and 18% in patients with macrovascular invasion.  
In a retrospective analysis, 5-year recurrence-free survival (RFS) rates following 
resection were 13% versus 34% in patients with and without microvascular invasion, 
respectively (Shen et al. 2018).  In addition, histologic tumor grade has been shown to 
influence survival after resection, with patients harboring poorly differentiated tumors 
having a worse prognosis compared with patients with moderately or well-differentiated 
tumors (Pawlik et al. 2005; Martins-Filho et al. 2017).  For patients with high risk 
disease, effective and well-tolerated adjuvant therapies are needed in order to prevent 
disease recurrence and to increase cure rates. 
1.2 
ADJUVANT TREATMENT FOR HEPATOCELLULAR 
CARCINOMA 
Most treatment guidelines do not recommend adjuvant treatment after resection or 
ablation for HCC because to date no adjuvant treatment has been proven effective in 
randomized studies (EASL 2018; Heimbach et al. 2018).  Strategies tested in the 
adjuvant setting have included interferon (IFN), vitamin K2, retinoids, systemic 
chemotherapy, heparanase inhibitors, multikinase inhibitors, and adoptive 
immunotherapy.   
In a randomized, double-blind, placebo-controlled, Phase III trial of sorafenib versus 
placebo as adjuvant therapy after curative resection or ablation of HCC, there was no 
statistically significant difference between the groups in median RFS (33.3 months in the 
sorafenib group vs. 33.7 months in the placebo group; hazard ratio [HR]   0.94; 
95% CI: 0.78 to 1.13; p  0.26; Bruix et al. 2015).   
Chinese HCC treatment guidelines recommend the use of adjuvant transarterial 
chemoembolization (TACE) for high risk cases following resection (Zhou et al. 2017).  
This recommendation is based on multiple retrospective studies, randomized trials, and 
meta-analyses that have reported that administration of adjuvant TACE following 
curative resection can improve time to recurrence and survival (Wang et al. 2018; 
Wei et al. 2018).  However, most of these studies have been single-center trials 
conducted in China in patients with predominantly HBV etiology.   
A multicenter Phase IV study conducted in China found significant prolongation of RFS 
in patients receiving Huaier granule, a traditional Chinese medicine, as adjuvant therapy 

 
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after surgical resection of HCC (Chen et al. 2018).  Although not formally recommended 
in Chinese guidelines (Zhou et al. 2018), use of such medicines following HCC resection 
is not uncommon in China. 
1.3 
BACKGROUND ON ATEZOLIZUMAB 
Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD-L1 and inhibits 
the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), 
both of which function as inhibitory receptors expressed on T cells.  Therapeutic 
blockade of PD-L1 binding by atezolizumab has been shown to enhance the magnitude 
and quality of tumor-specific T-cell responses, resulting in improved anti-tumor activity 
(Fehrenbacher et al. 2016; Rosenberg et al. 2016).  Atezolizumab has minimal binding 
to Fc receptors, thus eliminating detectable Fc-effector function and associated 
antibody-mediated clearance of activated effector T cells. 
Atezolizumab shows anti-tumor activity in both nonclinical models and patients with 
cancer and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant 
therapy settings, as well as in combination with chemotherapy, targeted therapy, and 
cancer immunotherapy. 
Atezolizumab is approved in approximately 90 countries for one or more of the following 
indications:  urothelial carcinoma, nonsmall cell lung cancer (NSCLC), extensive-stage 
small-cell lung cancer, melanoma and triple-negative breast cancer.  In May 2020, 
atezolizumab in combination with bevacizumab was approved by the U.S. Food and 
Drug Administration (FDA) for the treatment of unresectable or metastatic HCC in 
patients who have not received prior systemic therapy. 
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and clinical 
studies. 
1.4 
BACKGROUND ON BEVACIZUMAB 
Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that binds to and 
inhibits the biologic activity of human vascular endothelial growth factor (VEGF) in 
in vitro and in vivo assay systems.   
Bevacizumab was first granted marketing approval in the United States on 
26 February 2004 in combination with IV 5-fluorouracilbased chemotherapy for the 
first-line treatment of patients with metastatic carcinoma of the colon or rectum.  
Bevacizumab is approved in over 100 countries for one or more of the following 
indications:  breast cancer, NSCLC, renal cell cancer, glioblastoma multiforme, cervical 
cancer, epithelial ovarian cancer, primary peritoneal cancer, and fallopian tube cancer.  
In May 2020, bevacizumab in combination with atezolizumab was approved by the 
US FDA for the treatment of unresectable or metastatic HCC in patients who have not 
received prior systemic therapy. 

 
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Refer to the Bevacizumab Investigator's Brochure for details on nonclinical and clinical 
studies. 
1.5 
CLINICAL STUDIES OF ATEZOLIZUMAB PLUS BEVACIZUMAB 
IN PATIENTS WITH HEPATOCELLULAR CARCINOMA 
The efficacy and safety of atezolizumab plus bevacizumab combination therapy as 
first-line treatment of non-resectable or metastatic HCC is currently being assessed in 
two studies:  GO30140 and YO40245 (IMbrave150).   
1.5.1 
Study GO30140  
Study GO30140 is a Phase Ib, multicenter, open-label study of atezolizumab in 
combination with bevacizumab and/or chemotherapy as first-line therapy in patients with 
various metastatic cancers (Lee et al. 2020).  Arms A and F of Study GO30140 were 
specific to unresectable or advanced HCC.  Arm A was designed to evaluate the 
combination of atezolizumab plus bevacizumab in 104 patients with locally advanced or 
metastatic HCC who have not received prior systemic therapy.  Arm F was later added 
to the study to compare combination treatment with atezolizumab plus bevacizumab to 
atezolizumab alone, in which 119 patients with locally advanced or metastatic HCC were 
randomized 1:1 to atezolizumab plus bevacizumab or atezolizumab monotherapy.  
Results for Arm A and Arm F have been recently presented (Lee et al. 2019).  
Arm A 
As of the clinical cutoff date of 14 June 2019, the efficacy data for Arm A showed 
clinically meaningful and durable objective responses.  The confirmed objective 
response rate (ORR) based on Independent Review Facility (IRF) assessment per 
Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 was 35.6% (37 of 
104 patients; Table 1).  Among the 37 responders, 12 patients (11.5%) achieved a 
complete response (CR) and the remaining 25 patients (24.0%) achieved a partial 
response (PR).  Median duration of response was not reached at the time of this 
analysis.   
Arm F 
At the same clinical cutoff date of 14 June 2019, Arm F met its primary efficacy endpoint 
by demonstrating a statistically significant and clinically meaningful improvement in 
progression-free survival (PFS) with the combination compared to atezolizumab 
monotherapy.  Median PFS for the combination was 5.6 months compared to 
3.4 months for the monotherapy resulting in a HR of 0.55 and a stratified p-value of 
0.0108 (Table 1).  These results demonstrate the need for combination therapy rather 
than checkpoint inhibition alone to effectively increase progression free survival in 
patients with HCC. 

 
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Table 1 
Study GO30140:  Overall Efficacy Summary 
Arm 
Median 
Duration of 
Follow-Up 
Key Efficacy Endpoint 
Arm A 
12.4 m 
ORR (95% CI):  35.6% (26.445.6%) 
Median DOR:  Not reached with 76% ongoing responders 
Arm F 
6.6 m 
Median PFS:  5.6 m (Atezo  Bev) vs. 3.4 m (Atezo) 
Stratified HR (80% CI):  0.55 (0.400.74) 
Stratified p-value:  0.0108 
Atezo  atezolizumab; Bev  bevacizumab; DOR  duration of response; HR  hazard ratio; 
m  month; ORR  objective response rate; PFS  progression-free survival. 
 
The combination of atezolizumab plus bevacizumab was generally well tolerated; no 
new safety signals related to the combination therapy were identified beyond the 
established safety profile for each individual agent.  Furthermore, no unexpected 
adverse events were observed.  The most common adverse events were proteinuria, 
decreased appetite, fatigue, pyrexia, and rash. 
1.5.2 
Study YO40245 
Study YO40245 (IMbrave150) is a Phase III, multicenter, randomized, open-label study 
designed to evaluate the efficacy and safety of atezolizumab plus bevacizumab versus 
sorafenib in patients with advanced or metastatic HCC who have received no prior 
systemic treatment (Cheng et al. 2019; Finn et al. 2020).  The study enrolled 
501 patients randomized in a 2:1 ratio to one of the following treatment arms: 
 
Arm A (experimental arm):  atezolizumab 1200 mg IV every 3 weeks 
(Q3W)  bevacizumab 15 mg/kg IV Q3W (336 patients) 
 
Arm B (control arm):  sorafenib 400 mg by mouth, twice per day, continuously 
(165 patients) 
 
The co-primary efficacy endpoints were overall survival (OS) and IRF-assessed PFS by 
RECIST v1.1.   
The last patient was enrolled in April 2019.  Based on a clinical cutoff date of 
29 August 2019, the primary analysis of Study YO40245 demonstrated statistically 
significant and clinically meaningful improvements with atezolizumab plus bevacizumab 
compared with sorafenib in the co-primary endpoints of OS and IRF-assessed PFS per 
RECIST v1.1 in the intent-to-treat (ITT) population (Table 2). 

 
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 
The co-primary endpoint of OS demonstrated a statistically significant and clinically 
meaningful improvement for atezolizumab plus bevacizumab over sorafenib.  The 
observed OS translated into a reduction in the risk of death by 42% in the 
atezolizumab plus bevacizumab arm compared with sorafenib (HR  0.58 [95% CI: 
0.42 to 0.79], p  0.0006, median OS: NE vs. 13.24 months). 
OS benefits were generally consistent across predefined subgroups. 
 
The co-primary endpoint of IRF-assessed PFS per RECIST v1.1 demonstrated a 
statistically significant and clinically meaningful improvement for atezolizumab plus 
bevacizumab over sorafenib (HR  0.59 [95% CI: 0.47 to 0.76]; p  0.0001; median 
PFS: 6.83 vs. 4.27 months). 
These PFS benefits were generally consistent across predefined subgroups. 
 
Similar to Study GO30140, the safety of the combination was consistent with the known 
safety profile of each agent and no new safety signals were identified. 
Table 2 
Study YO40245:  Overall Efficacy Summary 
Co-Primary  
Efficacy 
Endpoints 
Median 
Duration  
of Follow-Up 
 
Sorafenib 
(n  165) 
Atezo+Bev 
(n  336) 
OS 
8.6 months 
Median (months)  
(95% CI) 
13.2 (10.4, NE) 
NE 
Stratified HR (95% CI) 
0.58 (0.42, 0.79) 
Stratified log rank 
p-value 
0.0006 
IRF-PFS 
8.6 months 
Median (months)  
(95% CI) 
4.3 (4.0, 5.6) 
6.8 (5.7, 8.3) 
Stratified HR (95% CI) 
0.59 (0.47, 076) 
Stratified log rank 
p-value 
<0.0001 
Atezo  atezolizumab; Bev  bevacizumab; HR  hazard ratio; IRF  Independent Review Facility; 
NE  not estimable; OS  overall survival; PFS  progression-free survival. 
 
1.6 
STUDY RATIONALE AND BENEFITRISK ASSESSMENT 
Multiple lines of evidence suggest that immune-based therapies may be beneficial in 
patients with resected or ablated HCC.  The PD-L1/PD-1 inhibitors have demonstrated 
clinical benefit across a wide range of cancer types, including HCC.  Although the 
majority of studies with these agents have been conducted in patients with advanced 
unresectable disease, data from studies in resected Stage III melanoma and 
Stage III NSCLC following definitive chemoradiation have shown that PD-1/PD-L1 
blockade may be effective in the adjuvant setting (Antonia et al. 2017; Weber et al. 2017; 
Eggermont et al. 2018).  

 
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Despite the clinical benefit associated with PD-1/PD-L1 blockade, patients who 
experience durable response and/or survival remain only a subset of those treated.  
One likely reason for this finding is that human cancer can utilize multiple immune 
inhibitory mechanisms, leading to primary or secondary immune escape.  One such 
mechanism relates to VEGF.  In addition to its role in angiogenesis, the VEGF pathway 
is thought to play a crucial role in exerting and maintaining an immunosuppressive tumor 
microenvironment through several mechanisms, including downregulating T-cell 
activation via inhibition of dendritic cell maturation, reducing T-cell tumor infiltration; and 
increasing inhibitory cells in the tumor microenvironment (e.g., regulatory T cells 
and myeloid-derived suppressor cells).  The cellular underpinnings of these immune 
suppressive mechanisms have been recently reviewed in depth 
(Chen and Hurwitz 2018).  
The majority of HCC tumors are non-inflamed tumors with immune cells present solely in 
the periphery or with limited or no infiltration of immune cells (Sia et al. 2017; 
Okrah et al. 2018; Gabrielson et al. 2016; unpublished data from the Sponsor).  
Non-inflamed tumors are not as responsive to single-agent immune checkpoint inhibition 
compared with inflamed tumors (Chen and Mellman 2017).  Therefore, combination 
approaches may be needed to address these inherent immune deficits.  Treatment with 
combined PD-L1 and VEGF antagonism may overcome deficits in immune infiltration 
and myeloid-induced immune suppression and therefore represent a more effective 
treatment approach versus single-agent PD-L1 inhibition (Chen and Hurwitz 2018).  
Atezolizumab has been combined with bevacizumab in patients with a range of different 
tumor types in Phase I-III studies.  Overall, the adverse events observed with 
atezolizumab in combination with bevacizumab are consistent with the known risks of 
each individual study treatment across tumor types including HCC (Socinski et al. 2018; 
Rini et al. 2019). 
This trial will enroll patients with high risk HCC who have been definitively treated with 
resection or local ablation.  Given the poor prognosis and limited treatment options for 
these patients, this population is considered appropriate for trials of novel therapeutic 
candidates in the adjuvant setting.  The benefitrisk profile for atezolizumab in 
combination with bevacizumab in this patient population is expected to be favorable. 
Covid-19 Benefit–Risk Assessment 
In the setting of the coronavirus disease 2019 (COVID-19) pandemic, patients with 
comorbidities, including those with cancer, are considered a more vulnerable population, 
with the potential for more severe clinical outcomes from severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) infection.  However, it is unclear whether or how 
systemic cancer therapies such as chemotherapy, targeted therapy, or immunotherapy, 
impact the incidence or severity of SARS-CoV-2 infection. 

 
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A possible consequence of inhibiting the PD-1/PD-L1 pathway may be the modulation of 
the host immune response to acute infection, which may result in immunopathology or 
dysregulated immune system defenses.  In nonclinical models, PD-1/PD-L1 blockade 
appears to be associated with serious exacerbation of inflammation in the setting of 
acute (as opposed to chronic) viral infection with lymphocytic choriomeningitis virus 
(Clone 13) (Frebel et al. 2012).  However, there are insufficient and inconsistent clinical 
data to assess if outcome from SARS-CoV-2 infection is altered by cancer 
immunotherapy. 
Severe SARS-CoV-2 infection appears to be associated with a cytokine release 
syndrome (CRS) involving the inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and 
IFN- (Merad and Martin 2020).  While it is not known, there may be a potential for an 
increased risk of an enhanced inflammatory response if a patient develops acute 
SARS-CoV-2 infection while receiving atezolizumab.  At this time, there is insufficient 
evidence for causal association between atezolizumab and an increased risk of severe 
outcomes from SARS-CoV-2 infection. 
There may be potential synergy or overlap in clinical and radiologic features for 
immune-mediated pulmonary toxicity with atezolizumab and clinical and radiologic 
features for SARS-CoV-2related interstitial pneumonia.  Thus, investigators should use 
their clinical judgment when evaluating and managing patients with pulmonary 
symptoms. 
There are limited data concerning the possible interactions between cancer 
immunotherapy treatment and COVID-19 vaccination, and it is recognized that human 
immune responses are highly regulated and that immune-modifying therapies may 
positively or negatively impact the efficacy and safety of COVID-19 vaccination (Society 
for Immunotherapy of Cancer [SITC] 2020). 
Per recommendations of the National Comprehensive Cancer Network (NCCN) 
COVID-19 Vaccination Advisory Committee, COVID-19 vaccination is recommended for 
all patients with cancer receiving active therapy (including immune checkpoint inhibitors), 
with the understanding that there are limited safety and efficacy data in such patients 
(NCCN 2021).  Given the lack of clinical data, currently no recommendations can be 
made regarding the optimal sequence of COVID-19 vaccination in patients who are 
receiving cancer immunotherapy (SITC 2020).  For patients enrolling in this study and 
receiving atezolizumab treatment, a decision to administer the vaccine to a patient 
should be made on an individual basis by the investigator in consultation with the 
patient. 
In alignment with clinical practice procedures, factors to consider when making the 
individualized decision for patients receiving atezolizumab treatment to receive 
COVID-19 vaccination include the following:  the risk of SARS-CoV-2 infection and 
potential benefit from the vaccine, the general condition of the patient and potential 

 
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complications associated with SARS-CoV-2 infection, underlying disease, and the 
severity of COVID-19 outbreak in a given area or region. 
The SITC and NCCN recommendations along with institutional guidelines should be 
used by the investigator when deciding on administering COVID-19 vaccines.  When 
administered, COVID-19 vaccines must be given in accordance with the approved or 
authorized vaccine label.  Receipt of the COVID-19 vaccine is considered a concomitant 
medication and should be documented as such (see Section 4.4.1). 
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy and safety of adjuvant therapy with atezolizumab 
plus bevacizumab compared with active surveillance in patients with completely 
resected or ablated HCC who are at high risk for disease recurrence.  Patients 
randomized to the active surveillance arm who recur during the active surveillance 
period or during the follow-up period may cross over to treatment with atezolizumab plus 
bevacizumab (see Section 3.1).  Specific objectives and corresponding endpoints for the 
study are outlined below. 
In this protocol, "study treatment" refers to the combination of treatments assigned to 
patients as part of this study (i.e., atezolizumab and bevacizumab). 

 
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Table 3 
Objectives and Corresponding Endpoints 
Primary Efficacy Objective 
(Primary Objective) 
Corresponding Endpoint 
 
To evaluate the efficacy 
of atezolizumab plus 
bevacizumab compared 
with active surveillance  
 
RFS after randomization, defined as the time from 
randomization to the first documented occurrence of 
intrahepatic or extrahepatic HCC as determined by an 
IRF, or death from any cause (whichever occurs first) 
Secondary Efficacy 
Objective 
Corresponding Endpoints 
 
To evaluate the efficacy 
of atezolizumab plus 
bevacizumab compared 
with active surveillance 
 
OS after randomization, defined as the time from 
randomization to death from any cause 
 
RFS after randomization as determined by the 
investigator 
 
TTR after randomization, defined as the time from 
randomization to first documented occurrence of 
intrahepatic or extrahepatic HCC, as determined by the 
investigator and by an IRF 
 
IRF-assessed RFS and investigator-assessed RFS rate 
at 24 months and 36 months after randomization 
 
OS rate at 24 months and 36 months, defined as the 
proportion of patients who have not experienced death 
from any cause at 24 and 36 months after randomization, 
respectively 
 
Time to EHS or macrovascular invasion after 
randomization, defined as the time from randomization to 
the first appearance of EHS or macrovascular invasion, 
as determined by the investigator  
 
RFS after randomization as determined by the 
investigator and by an IRF, among patients in the 
PD-L1high subgroup 
 

 
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Table 3 
Objectives and Corresponding Endpoints (cont.) 
Exploratory Efficacy Objective 
Corresponding Endpoints 
 
To evaluate the efficacy of 
atezolizumab plus 
bevacizumab compared with 
active surveillance 
 
Change from baseline in physical functioning, 
emotional functioning, role functioning, social 
functioning, and global health status/quality of life 
scores as assessed by the IL42–EORTC QLQ-C30 
(Reduced) at specified timepoints (including 
post-treatment (Arm A) or surveillance (Arm B) and 
post-recurrence) 
 
OS among patients in the PD-L1high subgroup 
 
For patients randomized to active surveillance who 
recur and cross over to treatment with atezolizumab 
plus bevacizumab and have NED at the time of 
crossover: 
– 
RFS after first HCC recurrence, defined as the 
time first exposure to any dose of crossover 
treatment to the second documented HCC 
recurrence as determined by the investigator, or 
death from any cause (whichever occurs first).  
HCC recurrence is defined as occurrence of 
intrahepatic or extrahepatic HCC. 
 
For patients randomized to active surveillance who 
recur and cross over to treatment with atezolizumab 
plus bevacizumab and who have measurable 
disease at the time of crossover:  
– 
PFS after first HCC recurrence, defined as the 
time from first exposure to any dose of crossover 
treatment to the first documented occurrence of 
disease progression beyond the initial 
unresectable disease recurrence as determined 
by the investigator according to RECIST v1.1 or 
death from any cause (whichever occurs first),  
– 
ORR, defined as the proportion of patients with a 
complete or partial response, as determined by 
the investigator according to RECIST v1.1 
Safety Objective 
Corresponding Endpoints 
 
To evaluate the safety of 
atezolizumab plus 
bevacizumab compared with 
active surveillance 
 
Incidence and severity of adverse events, with 
severity determined according to NCI CTCAE v5.0 
 
Change from baseline in targeted vital signs 
 
Change from baseline in targeted clinical laboratory 
test results 
Pharmacokinetic Objective 
Corresponding Endpoint 
 
To characterize the PK profile 
of atezolizumab when given 
in combination with 
bevacizumab 
 
Serum concentration of atezolizumab at specified 
timepoints 
Immunogenicity Objective 
Corresponding Endpoint 
 
To evaluate the immune 
response to atezolizumab 
 
Prevalence of ADAs to atezolizumab at baseline and 
incidence of ADAs to atezolizumab during the study 

 
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Table 3 
Objectives and Corresponding Endpoints (cont.)  
Exploratory Immunogenicity 
Objective 
Corresponding Endpoint 
 
To evaluate potential effects of 
ADAs 
 
Relationship between treatment-emergent ADA 
status and efficacy, safety, or PK endpoints 
Exploratory Biomarker 
Objective 
Corresponding Endpoints 
 
To identify and/or evaluate 
biomarkers that are predictive 
of response to study treatment 
(i.e., predictive biomarkers), 
are early surrogates of 
efficacy, are associated with 
progression to a more severe 
disease state (i.e., prognostic 
biomarkers), are associated 
with acquired resistance to 
study treatment, can provide 
evidence of study treatment 
activity (i.e., 
pharmacodynamic 
biomarkers), or can increase 
the knowledge and 
understanding of disease 
biology and drug safety 
 
Relationship between biomarkers in blood, serum, 
plasma, and tumor tissue (see Section 4.5.6) and 
efficacy, safety, PK, immunogenicity, or other 
biomarker endpoints 
 
Exploratory Health Status Utility 
Objective 
Corresponding Endpoint 
 
To evaluate health status 
utility scores of patients 
treated with atezolizumab plus 
bevacizumab compared with 
active surveillance 
 
Change from baseline in EQ-5D-5L index-based and 
VAS scores at specified timepoints (including 
post-treatment (Arm A) or surveillance (Arm B) and 
post-recurrence) 
ADA  anti-drug antibody; EHS  extrahepatic spread; EQ-5D-5L  EuroQol 5-Dimension, 5-
Level Questionnaire; HCC=hepatocellular carcinoma; IL42–EORTC QLQ-C30 
(Reduced)  IL42European Organisation for Research and Treatment of Cancer QLQ-C30 
(Reduced); IRF  Independent Review Facility; NCI CTCAE  National Cancer Institute 
Common Terminology Criteria for Adverse Events; NED  no evidence of disease; 
ORR  objective response rate; OS  overall survival; PFS  progression-free survival; 
PK  pharmacokinetic; RECIST  Response Evaluation Criteria in Solid Tumors; 
RFS  recurrence-free survival; TTR  time to recurrence; VAS  visual analog scale. 
 
3. 
STUDY DESIGN 
3.1 
OVERVIEW OF STUDY DESIGN 
This is a Phase III, global, multicenter, open-label, two-arm, randomized study designed 
to evaluate the efficacy and safety of adjuvant therapy with atezolizumab plus 
bevacizumab compared with active surveillance in patients with completely resected or 
ablated HCC who are at high risk for disease recurrence.   

 
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Patients who have undergone surgical resection may have received 1 cycle of adjuvant 
TACE prior to study entry (randomization), if deemed appropriate by the investigator and 
if consistent with local standards of care (see Section 4.1.1 for details).  
The definition of high risk is based on composite criteria including size of the largest 
tumor, number of tumors, and presence of either microvascular invasion (defined as the 
presence of microscopic tumor emboli within the central vein, the portal vein, or large 
capsular vessels), minor macrovascular invasion of the portal vein (Vp1 or Vp2, see 
Appendix 5), or poorly differentiated microscopic appearance (histologic Grade 3 or 4).  
The criteria for high risk of HCC recurrence used in this study are presented by type of 
curative treatment in Table 4.  In the event that the pathology and the pre-curative 
procedure radiology report are discordant with regards to tumor size and number, the 
modality demonstrating the largest tumor size and number should be used to determine 
eligibility.  Pathological findings should be used to assess microvascular invasion and/or 
poor tumor differentiation.  If macrovascular invasion of Vp1 or Vp2 is detected on either 
the pre-operative computed tomography (CT)/magnetic resonance imaging (MRI) scan 
or the pathology report, this should be a high risk feature. 
Table 4 
High Risk Criteria for This Study 
Curative Treatment 
Criteria for High Risk of HCC Recurrence 
Resection  
 
Up to three tumors, with largest tumor  5 cm regardless of 
vascular invasion (microvascular invasion or minor macrovascular 
portal vein invasion of the portal vein Vp1/Vp2), or poor tumor 
differentiation (Grade 3 or 4) a  
 
Four or more tumors, with largest tumor  5 cm regardless of 
vascular invasion (microvascular invasion or minor macrovascular 
invasion of the portal veinVp1/Vp2), or poor tumor 
differentiation (Grade 3 or 4) a  
 
Up to three tumors, with largest tumor  5 cm with vascular 
invasion (microvascular invasion or minor macrovascular invasion 
of the portal veinVp1/Vp2), and/or poor tumor differentiation 
(Grade 3 or 4) a 
Ablation b 
 
Single tumor  2 cm but  5 cm  
 
Multiple tumors (up to four tumors), all  5 cm 
HCC   hepatocellular carcinoma; MWA  microwave ablation; RFA  radiofrequency ablation. 
a In cases where a patient has evidence of mixed tumor differentiation, the worst 
differentiation status rather than the predominant differentiation status should be used to 
characterize high risk criteria.  
b Ablation must be RFA or MWA. 
 
An overview of the study design is shown in Figure 1.  A schedule of activities is 
provided in Appendix 1, and a schedule of activities specifically for patients in the active 
surveillance arm that cross over to atezolizumab plus bevacizumab following recurrence 
is provided in Appendix 2.  A schedule for collection of pharmacokinetic (PK), anti-drug 
antibody (ADA), and biomarker samples is provided in Appendix 3.  Samples for PK, 
ADA, and biomarker analyses will not be collected from patients in the active 

 
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surveillance arm who cross over to treatment with atezolizumab plus bevacizumab 
following recurrence. 
Figure 1 Study Schema 
 
APAC  Asia Pacific; HCC  hepatocellular carcinoma; IRF  Independent Review Facility; 
Q3W  every 3 weeks; ROW  rest of world; TACE  transarterial chemoembolization. 
a Patients who are enrolled in Arm B who have documented recurrence during the active 
surveillance period or during follow-up and meet the criteria outlined in Section 4.1.1.1 will 
have the option to cross over to treatment with atezolizumab 1200 mg Q3W plus bevacizumab 
15 mg/kg Q3W.  
b Risk features for resection include tumor size >5 cm, tumor number >3, vascular invasion 
(microvascular invasion or macrovascular invasionVp1/Vp2of the portal vein, see 
Appendix 5), and poor tumor differentiation (defined as Grade 3 or 4). 
 
This study will enroll approximately 662 patients across approximately 175 sites in the 
United States, Europe, and Asia Pacific (including China) in a global enrollment phase.  
After completion of the global enrollment phase, additional patients may be enrolled in 
China in an extended China enrollment phase to ensure a minimum of approximately 
250 patients in a China subpopulation.  The global population will include all patients 
enrolled during the global enrollment phase (including patients enrolled at sites in China 
during that phase), and the China subpopulation will include all patients enrolled at sites 
in China (i.e., during both the global enrollment phase and the extended China 
enrollment phase). 
Patients who withdraw from the study will not be replaced.  If necessary, the Sponsor 
may choose to limit the number of patients with specific curative treatment procedures 
(resection or ablation).  In the event that this cap is implemented, sites will be notified 
with a letter. 

 
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Patients who fail their first screening for study eligibility may qualify for one re-screening 
opportunity (for a maximum of two screenings per patient) at the investigator's discretion.  
The investigator will maintain a record of reasons for screen failure (see Section 4.5.1). 
Eligible patients will be randomized within 412 weeks of surgical resection or ablation 
(only RFA or MWA) in a 1:1 ratio to one of the following two arms: 
 
Arm A (experimental arm):  atezolizumab 1200 mg and bevacizumab 15 mg/kg, 
both administered by IV infusion on Day 1 of each 21-day cycle  
 
Arm B (control arm):  active surveillance 
 
Randomization will be stratified according to the following stratification factors: 
 
Geographic region  
– 
Asia Pacific excluding Japan  
– 
Rest of World 
 
High risk features/curative procedure  
– 
Ablation 
– 
Resection with 1 high risk feature (no adjuvant TACE)  
– 
Resection with 1 high risk feature (with adjuvant TACE) 
– 
Resection with 2 or more high risk features (no adjuvant TACE) 
– 
Resection with 2 or more high risk features (with adjuvant TACE) 
Risk features for resection include tumor size  5 cm, tumor number  3, vascular 
invasion (microvascular invasion or macrovascular invasionVp1/Vp2of the 
portal vein, see Appendix 5), and poor tumor differentiation (defined as 
Grade 3 or 4) 
 
Treatment with atezolizumab plus bevacizumab or active surveillance will continue for up 
to 12 months (or 17 cycles, whichever occurs first) or until IRF-confirmed disease 
recurrence or unacceptable toxicity (for patients receiving atezolizumab  bevacizumab), 
whichever occurs first.  Patients may continue treatment beyond 12 months due to 
delayed or missed visits if deemed in the best interest of the patient by the investigator.  
After 12 months (or 17 cycles, whichever occurs first), information on recurrence, 
survival, and subsequent anti-cancer therapies will be collected every 12 weeks until 
death (unless the patient withdraws consent or the Sponsor terminates the study). 
Patients randomized to Arm A who transiently withhold or permanently discontinue 
bevacizumab for adverse events may continue on single-agent atezolizumab as long as 
they have not met the criteria for HCC recurrence.  If atezolizumab is discontinued, 
bevacizumab should also be discontinued.  If atezolizumab is transiently withheld for 
adverse events, bevacizumab should also be held. 

 
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Patients will undergo imaging assessments at scheduled intervals during the study 
(see Section 4.5.5 and Appendix 1 for details). 
Patients are required to undergo tumor biopsy sample collection at the time of 
radiographic confirmation of disease recurrence unless not clinically feasible as 
assessed and documented by the investigator to evaluate tumor tissue biomarkers 
related to mechanisms of acquired resistance and disease recurrence and clinical 
benefit of atezolizumab plus bevacizumab.  Examples of when tumor biopsy sample 
collection may be considered not clinically feasible include, but are not limited to, cases 
where the location of the tumor renders tumor biopsy unsafe or not clinically feasible per 
the investigator due to patient concerns or is prohibited by the institution or country.   
Treatment with Atezolizumab plus Bevacizumab following Recurrence for 
Patients in Arm B 
Patients randomized to Arm B who experience documented IRF-assessed HCC 
recurrence per protocol-defined criteria (see Section 4.5.5) either during the 12-month 
active surveillance period or during long-term follow-up and meet all eligibility criteria 
(see Section 4.1.1.1) will be offered the option of crossing over to treatment with 
atezolizumab 1200 mg IV and bevacizumab 15 mg/kg IV on Day 1 of each 21-day cycle.  
Patients can cross over directly after the first recurrence or after resection or ablation for 
the first recurrence (resulting in no evidence of disease [NED]).  Patients undergoing 
resection are allowed to have 1 cycle of adjuvant TACE prior to crossover, if deemed 
appropriate by the investigator and if consistent with local standards of care (see 
Section 4.1.1 for details).  Day 1 of Cycle 1 of crossover treatment must be no later than 
12 weeks after documentation of recurrence.  Results of tests or examinations 
performed for crossover and per the relevant protocol-defined window may be used for 
screening assessments rather than repeating such tests. 
Patients who cross over to treatment with atezolizumab plus bevacizumab may continue 
study treatment until unacceptable toxicity or second disease recurrence (for patients 
with NED at the time of crossover), or until unacceptable toxicity or loss of clinical benefit 
as determined by the investigator after an integrated assessment of radiographic and 
biochemical data, local biopsy results (if available) and clinical status (e.g., symptomatic 
deterioration such as pain secondary to disease) (for patients with measurable disease 
at crossover).  In the absence of unacceptable toxicity, patients with measurable disease 
at crossover who meet criteria for disease progression per RECIST v1.1 while receiving 
atezolizumab and bevacizumab or atezolizumab alone will be permitted to continue 
study treatment if they meet all of the following criteria:  
 
Evidence of clinical benefit, as determined by the investigator following a review of 
all available data 
 
Absence of symptoms and signs (including laboratory values, such as new or 
worsening hypercalcemia) indicating unequivocal progression of disease 

 
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 
Absence of decline in Eastern Cooperative Oncology Group (ECOG) Performance 
Status that can be attributed to disease progression 
 
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions 
 
Patients who transiently withhold or permanently discontinue bevacizumab for adverse 
events may continue on single-agent atezolizumab as long as they have not met the 
criteria for HCC recurrence (for patients with NED at crossover) or are experiencing 
clinical benefit in the opinion of the investigator (for patients with measurable disease at 
crossover).  If atezolizumab is discontinued, bevacizumab should also be discontinued.  
If atezolizumab is transiently withheld for adverse events, bevacizumab should also be 
held. 
Patients who cross over will undergo imaging assessments at scheduled intervals during 
the study (see Section 4.5.5 and Appendix 2 for details). 
3.1.1 
Independent Data Monitoring Committee  
An independent Data Monitoring Committee (iDMC) will evaluate safety and efficacy 
data during the study.  Sponsor affiliates will be excluded from iDMC membership.  The 
iDMC will follow a charter that outlines the iDMC roles and responsibilities.   
Unblinded safety data will be reviewed on a periodic basis, approximately every 
6 months from the time of enrollment of the first patient.  Unblinded efficacy data will be 
reviewed as part of the interim analysis of IRF-assessed RFS, scheduled to occur when 
approximately 236 RFS events have occurred (see Section 6.10).  All summaries and 
analyses for the iDMC review will be prepared by an independent Data Coordinating 
Center.   
After reviewing the data, the iDMC will provide a recommendation to the Sponsor as 
described in the iDMC Charter.  Final decisions will rest with the Sponsor.   
Any outcomes of these data reviews that affect study conduct will be communicated in a 
timely manner to the investigators for notification of their respective Institutional Review 
Boards or Ethics Committees (IRBs/ECs). 
3.1.2 
Independent Review Facility 
An IRF will be used to enable centralized, independent reviews of images and other 
clinical data (e.g., histopathology, tumor markers etc.) used for assessment of HCC 
recurrence.  The IRF reviews will be performed prior to the pre-specified efficacy 
analyses.  The IRF membership and procedures will be detailed in an IRF Charter. 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date when approximately 319 OS events have 
been observed for the final analysis of OS in the ITT population.   

 
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In addition, the Sponsor may decide to terminate the study at any time. The total length 
of the study, from randomization of the first patient to the end of the study, is projected to 
be approximately 91 months.  
3.3 
DURATION OF PARTICIPATION 
The total duration of study participation for each individual is expected to range from 
1 day up to approximately 91 months. 
3.4 
RATIONALE FOR STUDY DESIGN 
3.4.1 
Rationale for Atezolizumab Dose and Schedule 
Atezolizumab will be administered at a fixed dose of 1200 mg Q3W (1200 mg on Day 1 
of each 21-day cycle), which is an approved dosage for atezolizumab, as outlined in the 
prescribing information).  Anti-tumor activity has been observed across doses ranging 
from 1 mg/kg to 20 mg/kg Q3W.  In Study PCD4989g, the maximum tolerated dose of 
atezolizumab was not reached and no dose-limiting toxicities were observed at any 
dose.  The fixed dose of 1200 mg Q3W (equivalent to an average body weightbased 
dose of 15 mg/kg Q3W) was selected on the basis of both nonclinical studies 
(Deng et al. 2016) and available clinical PK, efficacy, and safety data (refer to the 
Atezolizumab Investigator's Brochure for details).  
3.4.2 
Rationale for Bevacizumab Dose and Schedule 
Bevacizumab will be administered at a dose of 15 mg/kg Q3W (15 mg/kg on Day 1 of 
each 21-day cycle), which is the approved dosage for bevacizumab (Avastin® U.S. 
Package Insert).  This dose schedule aligns with the atezolizumab dose schedule 
highlighted above and is the dose used in combination with atezolizumab in 
Study GO30140.  In that study, the combination of atezolizumab plus bevacizumab was 
generally safe and well tolerated and no new safety signals related to the combination 
therapy were identified beyond the established safety profile for each individual agent. 
3.4.3 
Rationale for Patient Population 
The target population has been chosen to address patients with HCC who have a high 
risk of disease recurrence following curative resection or ablation. 
The risk of HCC recurrence after curative intervention is primarily related to tumor 
characteristics at the time of surgery or ablation, such as size, number, degree of 
differentiation, and the presence of vascular invasion.  The prevalence of these high risk 
factors is highly interrelated.  In general, larger tumors ( 5 cm) or multiple tumors are 
more likely to exhibit vascular invasion than single small lesions (Pawlik et al. 2005).  
For patients harboring one or more of these high risk features, the prognosis following 
curative intervention with surgery or ablation is particularly poor (see Section 1.1.2).  
For these high risk patients, effective and well-tolerated adjuvant therapies are needed 
in order to prevent disease recurrence and to increase cure rates. 

 
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There are no preexisting criteria to define high risk patients for adjuvant trials because 
available HCC staging criteria (i.e., Barcelona Clinic Liver Cancer and Hong Kong Liver 
Cancer) do not include all key risk factors for HCC recurrence and there are no validated 
tools for risk stratification in HCC that can be incorporated into clinical trials.  Multiple 
and co-existing risk factors are involved in determining prognosis following curative 
treatment and because no single factor is powerful enough to independently predict 
outcomes, composite criteria integrating key variables are required in order to identify 
patients at high risk of recurrence.  
3.4.4 
Rationale for the Active Surveillance Control Arm (Arm B) 
There is no standard adjuvant treatment after resection or ablation for HCC.  For the 
most part, treatment guidelines do not recommend adjuvant therapy for HCC because to 
date no treatment has been proven effective in randomized studies after potentially 
curative treatment (EASL 2018; Heimbach et al. 2018). 
Active surveillance with imaging (with or without -fetoprotein [AFP]) following resection 
or ablation is currently the standard of care represented in treatment guidelines 
(European Association for the Study of the Liver [EASL] 2018; Heimbach et al, 2018).  
The EASL and American Association for the Study of Liver Diseases (AASLD) 
guidelines recommend screening with imaging with or without AFP every 36 months 
following surgery. 
This study will employ an open-label, rather than double-blind placebo-controlled, study 
design because of ethical concerns and the burden of giving mock IV infusions Q3W for 
up to 1 year to patients in Arm B. 
3.4.5 
Rationale for Crossover from Active Surveillance to Treatment 
with Atezolizumab plus Bevacizumab 
Patients randomized to Arm B will be offered the chance to cross over to treatment with 
atezolizumab plus bevacizumab upon documented IRF-confirmed recurrence if deemed 
clinically appropriate by the investigator, to both allow access to atezolizumab and 
bevacizumab and to derive additional data on the combination in the recurrent HCC 
setting. 
3.4.6 
Rationale for Recurrence-Free Survival as Primary Endpoint  
Treatment benefit will be measured in this trial using RFS as the primary efficacy 
endpoint.  The RFS is an endpoint that quantifies clinically meaningful benefit to patients 
with HCC and is recommended by HCC experts as a primary endpoint for adjuvant 
studies (EASL 2018).  Further, RFS, unlike OS, would not be confounded by potential 
use of subsequent treatments in the recurrence and metastatic settings. 

 
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3.4.7 
Rationale for Choice of Randomization Stratification Factors  
To balance the clinical risk factors between the two study arms, randomization will be 
stratified using a permuted-block randomization scheme.  The stratification factors are 
as follows: 
 
Geographic region  
– 
Asia Pacific excluding Japan   
– 
Rest of World 
 
High risk features/curative procedure  
– 
Ablation 
– 
Resection with 1 high risk feature (no adjuvant TACE)  
– 
Resection with 1 high risk feature (with adjuvant TACE) 
– 
Resection with 2 or more high risk features (no adjuvant TACE) 
– 
Resection with 2 or more high risk features (with adjuvant TACE) 
 
Risk features for resection include tumor size  5 cm, tumor number  3, vascular 
invasion (microvascular invasion or macrovascular invasionVp1/Vp2of the 
portal vein, see Appendix 5), and poor tumor differentiation (defined as 
Grade 3 or 4) 
 
The reasons for using these factors are provided below. 
Geographic Region 
Although HCC is a global disease, there is significant geographic heterogeneity in terms 
of treatment outcomes.  Differences in outcome may be attributed to several potential 
causes that include regional differences in disease etiology and clinical practice patterns.  
The geographic distribution of HCC reflects the distribution of HBV and HCV, which 
currently are the two major etiologic risk factors worldwide.  The majority of cases of 
HCC worldwide are caused by HBV, which is endemic in Africa and East Asia except 
Japan.  HCV is the most common cause of HCC in Japan, most of Europe, and the 
United States.  Other non-viral causes of cirrhosis are more prevalent in Japan and the 
West compared with Asia.  Based on the close association between geography and 
HCC etiology, geographic region represents a reasonable surrogate for disease etiology.  
Several studies have reported that patients with HCC arising in the context of HBV or 
HCV infections have different characteristics and outcomes (Omata et al. 2017).  
With respect to long-term surgical outcomes, several studies have reported that HCV 
infection was associated with worse oncological outcomes compared with HBV infection.  
For example, Sasaki et al. (2017) reported that HCV-related HCC had a higher 
cumulative recurrence rate compared with HBV-related HCC, with HCV infection 
representing an independent predictor of recurrence even after accounting for potential 

 
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confounders.  A similar association between outcomes and viral etiology has been noted 
for patients treated with ablation (Huang et al. 2011). 
High Risk Features/Curative Procedure 
Three different components contribute to this stratification factor including curative 
procedure, number of risk factors, and adjuvant TACE. 
Ablation is considered a high risk factor because available data indicate that liver 
resection is typically associated with better outcomes compared with ablation in patients 
with HCC (Gravante et al. 2011).  Although no randomized trials are available comparing 
outcomes using the high risk criteria in this study, a large retrospective analysis 
(n  1061) reported that resection was superior to ablation with respect to both RFS and 
OS in patients with HCC who have either single tumors  3 cm but  5 cm or 23 tumors 
each  5 cm (Huang et al. 2011).  
Resected patients, can have multiple risk factors that are outlined in Section 3.1.  The 
impact of harboring high risk clinicopathologic features on risk of recurrence is 
summarized in Section 3.4.3.  While the presence of a single high risk feature confers a 
negative impact on prognosis, the presence of multiple risk factors imposes significant 
additional risk (Pawlik et al. 2005; Noh et al. 2016).  
The study will allow resected patients to have undergone 1 cycle of post-operative TACE 
prior to study entry (randomization; see Section 4.1.1).  Given the potential positive 
impact of adjuvant TACE on RFS following resection (Wang et al. 2018; Wei et al. 2018), 
use of adjuvant TACE will contribute to the stratification factor High Risk 
Features/Curative Procedure for randomization. 
3.4.8 
Rationale for Biomarker Assessments 
The PD-L1 expression in tumor tissues has been shown to be correlated with the clinical 
benefits from antiPD-1 and antiPD-L1 therapy across many tumor indications 
(Topalian et al. 2012; Herbst et al. 2014, 2016; Borghaei et al. 2015; 
Fehrenbacher et al. 2016; Rosenberg et al. 2016).  Emerging data from published HCC 
studies (El-Khoueiry 2017; Zhu et al. 2018) and preliminary findings from the Sponsor’s 
study of first-line treatment in patients with HCC (Study GO30140; unpublished 
observations) also suggest that PD-L1 expression may be correlated with the clinical 
benefits from antiPD-L1/PD-1 agents.  A more comprehensive analysis of the 
association between PD-L1 expression and clinical outcomes will be conducted in the 
upcoming clinical readouts for both Studies GO30140 and YO40245 (IMbrave150) 
studies of first-line therapy in patients with HCC.  These results will further inform the 
role of PD-L1 in the study design of this adjuvant HCC trial. 

 
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In this study, submission of surgical tumor tissues at baseline will be mandated and the 
expression of PD-L1 will be examined by the central laboratory using a PD-L1 (SP263) 
immunohistochemistry assay.  In addition to assessing the status of PD-L1, other 
exploratory biomarkers (such as potential predictors and prognostic biomarkers 
associated with clinical benefits of atezolizumab  bevacizumab), tumor immunobiology, 
drug resistance mechanisms, or tumor types may also be analyzed.   
Tissue samples will be collected for DNA extraction to enable whole genome sequencing 
(WGS) or whole exome sequencing (WES) to identify variants that are predictive of 
response to study drug, are associated with progression to a more severe disease state, 
are associated with acquired resistance to study drug, are associated with susceptibility 
to developing adverse events, can lead to improved adverse event monitoring or 
investigation, or can increase the knowledge and understanding of disease biology and 
drug safety.  Genomics is increasingly informing researchers’ understanding of disease 
pathobiology.  The WGS and the WES provide a comprehensive characterization of the 
genome and exome, respectively, and, along with clinical data collected in this study, 
may increase the opportunity for developing new therapeutic approaches or new 
methods for monitoring efficacy and safety or predicting which patients are more likely to 
respond to a drug or develop adverse events.  Data will be analyzed in the context of 
this study but may also be explored in aggregate with data from other studies.  The 
availability of a larger dataset will assist in identification and characterization of important 
biomarkers and pathways to support future drug development. 
Blood samples will be collected at baseline and during the study to evaluate changes in 
surrogate biomarkers, which may include circulating-tumor DNA (ctDNA).  The ctDNA is 
extracellular DNA that is present in a number of bodily fluids, including blood, synovial 
fluid and cerebrospinal fluid.  Compared with performing a tissue biopsy, ctDNA 
examination has the advantages of minimal invasion and greater convenience.  
Detection of minimal residual disease through ctDNA analysis in plasma has been 
shown to identify patients at high risk of recurrence in early stage breast cancer and 
colorectal cancer (Wang et al. 2017; Gabriel and Bagaria 2018) among other indications.  
Detection of ctDNA-positive patients following primary liver cancer surgery may help to 
identify patients at high risk for disease recurrence in the adjuvant setting.  Due to 
detection of ctDNA preceding the established clinical parameters (i.e., imaging), 
assessment of ctDNA positivity at benchmark timepoints post-treatment may be used as 
a potential surrogate endpoint for RFS and OS.   
Changes in biomarkers may provide evidence of biologic activity of atezolizumab in 
humans.  Correlations between these biomarkers and safety and efficacy endpoints will 
be explored to identify blood-based biomarkers that might predict which patients are 
more likely to benefit from atezolizumab in combination with bevacizumab. 

 
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3.4.9 
Rationale for Patient-Reported Outcomes  
Early stage HCC is largely asymptomatic, with the majority of patients exhibiting no 
disease-specific, discernable symptoms.  Instead, it is the impact of treatment and the 
associated burden, rather than disease burden, that defines the patient experience.  
Therefore, in this setting it is most important to document the burden associated with 
adjuvant HCC treatment and understand the impact of therapy as reported by patients to 
inform benefitrisk assessment and treatment decision making.  This is especially critical 
in the adjuvant HCC setting, as there is limited information about the impact of 
treatments on patients’ lives in this setting. 
A fit-for-purpose assessment of function and Health Related Quality of Life (HRQoL) will 
be collected in the study.  The validated physical function, role function, emotional 
function, social functioning, and global health status (GHS)/HRQoL scales of the 
European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 
will be administered throughout the study (Aaronson et al. 1993; 
Fitzsimmons et al. 1999).  The original EORTC QLQ-C30 has been modified to reduce 
patient burden of additional questions while capturing the most likely impacts of the 
combination treatment under study.  This reduced version will be hereafter referred to as 
the item list 42 (IL42)–EORTC QLQ-C30 (Reduced).  In addition, the EQ-5D-5L will be 
completed to inform pharmacoeconomic models.  See Section 4.5.8 for details. 
Both the IL42–EORTC QLQ-C30 (Reduced) and the EQ-5D-5L measures will be 
administered at specified timepoints as indicated in Appendix 1. 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Approximately 662 patients with completely resected or ablated HCC who are at 
high risk for disease recurrence will be enrolled during the global enrollment phase of 
this study (see Table 4).  After completion of the global enrollment phase, additional 
patients may be enrolled in China in an extended China enrollment phase to ensure a 
total of a minimum of 250 patients from mainland China in a China subpopulation. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
Signed Informed Consent Form  
 
Age  18 years at time of signing Informed Consent Form  
 
Ability to comply with the study protocol 
 
Participants with a first diagnosis of HCC who have undergone either a curative 
resection or ablation (RFA or MWA only) within 412 weeks prior to randomization 
– 
Multimodality treatment is not permitted, for example resection and ablation. 

 
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– 
Combination treatments (with the exception of one TACE after resection) is not 
allowed. 
– 
Patients may receive a second ablation procedure if this is part of the initial 
curative treatment plan and not due to disease recurrence following the first 
procedure.  In cases where there is more than one ablation procedure, the time 
between the first and the second ablation procedures should not exceed 
1 week.  The time between the second ablation procedure and randomization 
should not exceed 12 weeks. 
 
Documented diagnosis of HCC that has been completely resected or ablated 
(RFA or MWA only) as described below: 
– 
Patients with resected HCC must have documented histological confirmation of 
negative surgical margins (R0) which is documented in a pathology report 
(patients with microscopically positive [R1] or grossly positive [R2] resection 
margins or unknown margins will be excluded from the study).  
– 
Patients with ablated HCC must have documented evidence of complete 
radiological response, including disappearance of any intratumoral arterial 
enhancement in all ablated lesions. 
– 
All patients must have disease-free status documented within 4 weeks prior to 
randomization by a complete physical examination, radiographic images, and 
pathology (resection only), with no subsequent evidence of residual or recurrent 
disease prior to randomization. 
A complete set of baseline (post-curative procedure) radiographic images 
and accompanying report must be available prior to randomization. 
 
Absence of major macrovascular (gross vascular) invasion of the portal vein (Vp3 or 
Vp4) or any grade of macrovascular invasion in the hepatic vein or inferior 
vena cava. 
Note: Patients undergoing resection with minor vascular invasion of the portal vein 
(Vp1 or Vp2) as detected by either imaging or pathological examination are allowed 
(see Appendix 5). 
 
Absence of extrahepatic spread as confirmed by CT or MRI scan of the chest 
abdomen, pelvis, and head prior to and following curative procedure 
 
Full recovery from surgical resection or ablation within 4 weeks prior to 
randomization  
 
High risk for HCC recurrence after resection or ablation as defined in Table 4   
In the event that the pathology and the precurative procedure radiology report 
are discordant with regards to tumor size and number, the modality 
demonstrating the largest tumor size and number should be used to determine 
high risk features.  Pathological findings should be used to assess for 
microvascular invasion and/or poor tumor differentiation.  If macrovascular 
invasion of Vp1 or Vp2 is detected on either the pre-operative CT/MRI scan or 
the pathology report, this should be a high risk feature. 

 
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 
For patients who received post-operative TACE:  full recovery from the procedure 
within 4 weeks prior to randomization, including:  
– 
AST and ALT  5  upper limit of normal (ULN) and total bilirubin  3 mg/dL 
– 
Manifestations of post-embolization syndrome (e.g., fever, nausea, vomiting, 
and abdominal pain) have resolved to National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0 Grade 1  
– 
No significant medical events (e.g., gastrointestinal [GI] bleeding, cardiac 
events, hepatorenal syndrome) during or after the TACE procedure 
 
For patients with resected HCC, availability of a representative baseline tumor tissue 
sample that meets the following criteria: 
– 
A formalin-fixed, paraffin-embedded (FFPE) resected tumor specimen in a paraffin 
block (preferred) or at least 15 slides containing unstained, freshly cut, serial 
sections should be submitted along with an associated pathology report within 
4 weeks after randomization.  For patients in China, tissue samples may be 
submitted retrospectively upon Human Genetic Resources Administration of China 
(HGRAC) approval of sample submission. 
Note:  For patients with ablated HCC, submission of a tumor specimen is 
encouraged but not mandated (see Section 4.5.6).  
 
Negative HIV test at screening 
 
Documented virology status of hepatitis, as confirmed by screening HBV and 
HCV tests 
– 
For patients with active HBV:  HBV DNA  500 IU/mL during screening, initiation 
of anti-HBV treatment at least 14 days prior to randomization and willingness to 
continue anti-HBV treatment during the study (per local standard of care; 
e.g., entecavir) 
– 
Patients with HCV, either with resolved infection (as evidenced by detectable 
antibody) or chronic infection (as evidenced by detectable HCV RNA), are 
eligible 
– 
For patients with detectable HCV RNA and for whom HCV treatment is deemed 
appropriate by the investigator, treatment should begin no sooner than 
6 months following curative procedure consistent with AASLD guidelines  
 
For patients enrolled in the extended China enrollment phase:  current resident of 
mainland China and of Chinese ancestry 
 
Performance of an esophagogastroduodenoscopy either before resection or 
ablation as part of pre-procedure work-up or during screening (i.e., following 
resection or ablation), and assessment and treatment of varices of all sizes per local 
standard of care prior to randomization 
 
ECOG Performance Status of 0 or 1  
 
ChildPugh Class A status (see Appendix 4) 

 
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 
Adequate hematologic and end-organ function, defined by the following laboratory 
test results, obtained within 7 days prior to randomization unless otherwise 
specified: 
– 
AST, ALT, and ALP  5  ULN 
– 
Serum bilirubin  3  ULN  
– 
Albumin  28 g/L (2.8 g/dL) 
– 
Serum creatinine  1.5 × ULN or creatinine clearance  30 mL/min (calculated 
using the Cockcroft-Gault formula) 
– 
Hemoglobin   90 g/L (9 g/dL) 
Patients may be transfused to meet this criterion. 
– 
Platelet count  75  109/L (75,000/L) without transfusion 
– 
Lymphocyte count  0.5  109/L (500/L) 
– 
ANC  1.5  109/L (1500/L) without granulocyte colony-stimulating factor 
support 
– 
For patients not receiving therapeutic anticoagulation:  INR or aPTT  2  ULN  
– 
Urine dipstick for proteinuria  2  (within 7 days prior to Day 1 of Cycle 1) 
Patients discovered to have  2  proteinuria on dipstick urinalysis at 
baseline should undergo a 24-hour urine collection (or an alternative 
method such as protein:creatinine ratio, per local guidance) and must 
demonstrate  1 g of protein in 24 hours. 
 
 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods, and agreement to refrain 
from donating eggs, as defined below:   
Women must remain abstinent or use contraceptive methods with a failure rate 
of  1% per year while they are receiving atezolizumab and bevacizumab and 
for 5 months after the final dose of atezolizumab and for 6 months after the final 
dose of bevacizumab. Women must refrain from donating eggs during the same 
period. 
A woman is considered to be of childbearing potential if she is postmenarchal, 
has not reached a postmenopausal state ( 12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations. 

 
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Examples of contraceptive methods with a failure rate of  1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not adequate methods of contraception.  
If required per local guidelines or regulations, locally recognized adequate 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form. 
 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use a condom, and agreement to refrain from donating sperm, as defined below: 
With a female partner of childbearing potential or pregnant female partner, men 
must remain abstinent or use a condom during the treatment period and for 
6 months after the final dose of bevacizumab to avoid exposing the embryo.  
Men must refrain from donating sperm during this same period. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not adequate methods of preventing drug 
exposure.  If required per local guidelines or regulations, locally recognized 
adequate methods of contraception and information about the reliability of 
abstinence will be described in the local Informed Consent Form. 
 
4.1.1.1 
Additional Inclusion Criteria for Crossover for Patients in 
Arm B 
Patients randomized to Arm B must meet the following criteria to qualify for crossover to 
treatment with atezolizumab plus bevacizumab: 
 
Patient meets all other eligibility criteria in Sections 4.1.1 and 4.1.2.  However the 
following criteria are not applicable for crossover: 
– 
Inclusion criteria: signed informed consent, a first diagnosis of HCC, 
documented diagnosis of HCC that has been completely resected or ablated, 
absence of major macrovascular invasion and extrahepatic spread, high risk for 
HCC recurrence after resection or ablation 
– 
Exclusion criteria: evidence of residual, recurrent, or metastatic disease; any 
treatment for HCC prior to resection or ablation is still excluded except for 
patients who received TACE for initial curative procedure 
 
Documentation of unequivocal recurrence as defined by EASL Clinical Practice 
Guidelines (Appendix 6 and the radiology interpretation guide from Calyx) or 
RECIST v1.1 (Appendix 7) criteria that is confirmed by the IRF 

 
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 
For Arm B patients who undergo surgical resection or ablation for first recurrence:  
full recovery from surgical resection or ablation within 4 weeks prior to Day 1 of 
Cycle 1 
 
Availability of a representative tumor specimen obtained at the time of recurrence 
for exploratory biomarker research (see Section 4.5.6 for information on tumor 
specimens)  
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from the study: 
 
Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and 
HCC 
 
Evidence of residual, recurrent, or metastatic disease at randomization 
 
Clinically significant ascites 
 
History of hepatic encephalopathy 
 
Prior bleeding event due to untreated or incompletely treated esophageal and/or 
gastric varices within 6 months prior to randomization 
 
Have received more than 1 cycle of adjuvant TACE following surgical resection 
 
Active or history of autoimmune disease or immune deficiency, including, but not 
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid 
antibody syndrome, granulomatosis with Polyangiitis, Sjögren syndrome, Guillain-
Barré syndrome, or multiple sclerosis, with the following exceptions: 
Patients with a history of autoimmune-related hypothyroidism who are on 
thyroid-replacement hormone are eligible for the study. 
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen 
are eligible for the study. 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are 
excluded) are eligible for the study provided all of following conditions are met: 
– Rash must cover  10% of body surface area. 
– Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids. 
– There is no occurrence of acute exacerbations of the underlying condition 
requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, 
biologic agents, oral calcineurin inhibitors, or high-potency or oral 
corticosteroids within the 12 months prior to Day 1 of Cycle 1. 
 
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of 
active pneumonitis on screening chest CT scan 

 
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 
Significant cardiovascular disease (such as New York Heart Association Class II or 
greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 
3 months prior to Day 1 of Cycle 1, unstable arrhythmia, or unstable angina 
 
History of malignancy other than HCC within 5 years prior to screening, with the 
exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year 
OS rate  90%), such as adequately treated carcinoma in situ of the cervix, 
non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, 
or Stage I uterine cancer 
 
Active tuberculosis 
 
Severe infection within 4 weeks prior to Day 1 of Cycle 1, including, but not limited 
to, hospitalization for complications of infection, bacteremia, or severe pneumonia, 
or any active infection that in the opinion of the investigator, could impact patient 
safety 
 
Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to Day 1 of 
Cycle 1 
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract 
infection or chronic obstructive pulmonary disease exacerbation) are eligible for 
the study. 
 
Prior allogeneic stem cell or solid organ transplantation 
 
On the waiting list for liver transplantation 
 
Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that contraindicates the use of an investigational drug, may affect 
the interpretation of the results, or may render the patient at high risk from treatment 
complications 
 
Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 5 months after the final dose of atezolizumab or within 6 months after the final 
dose of bevacizumab 
Women of childbearing potential must have a negative serum pregnancy test 
result within 14 days prior to Day 1 of Cycle 1. 
 
Co-infection with HBV and HCV 
Patients with a history of HCV infection but who are negative for HCV RNA by 
polymerase chain reaction will be considered to be negative for HCV infection. 
 
Co-infection with HBV and hepatitis D viral infection 
 
Clinically significant uncontrolled or symptomatic hypercalcemia (ionized 
calcium  1.5 mmol/L, calcium  12 mg/dL, or corrected serum calcium  ULN) 
 
History of severe allergic anaphylactic reactions to chimeric or humanized 
antibodies or fusion proteins 
 
Known hypersensitivity to Chinese hamster ovary cell products or to any component 
of the atezolizumab or bevacizumab formulations 

 
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 
Any treatment for HCC prior to resection or ablation, including systemic therapy 
(including investigational agents) and locoregional therapy such as TACE  
Prior use of herbal therapies or traditional Chinese medicines with anti-cancer 
activity included in the label is allowed, but such therapies must be discontinued 
at least 7 days prior to randomization and are prohibited during the study.   
Portal vein embolization used to increase the functional liver remnant prior to 
surgery is permitted.  
 
Treatment with a live, attenuated vaccine within 4 weeks prior to Day 1 of Cycle 1, 
or anticipation of need for such a vaccine during atezolizumab treatment or within 
5 months after the final dose of atezolizumab 
 
Treatment with investigational therapy within 4 weeks prior to Day 1 of Cycle 1 
 
Prior treatment with CD137 agonists or immune checkpoint blockade therapies, 
including anti-cytotoxic T lymphocyteassociated protein 4, antiPD-1, and 
antiPD-L1 therapeutic antibodies 
 
Treatment with systemic immunostimulatory agents (including, but not limited to, 
IFN and IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) 
prior to Day 1 of Cycle 1 
 
Treatment with systemic immunosuppressive medication (including, but not limited 
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
antitumor necrosis factor- [TNF-agents) within 2 weeks prior to Day 1 of 
Cycle 1, or anticipation of need for systemic immunosuppressive medication during 
study treatment, with the following exceptions: 
– 
Patients who received acute, low-dose systemic immunosuppressant 
medication or a one-time pulse dose of systemic immunosuppressant 
medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible.  
– 
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids 
for chronic obstructive pulmonary disease or asthma, or low-dose 
corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible 
for the study. 
 
Inadequately controlled arterial hypertension (defined as systolic blood pressure 
[BP]  150 mmHg and/or diastolic BP  100 mmHg), based on an average of at least 
three BP readings at two or more sessions 
Anti-hypertensive therapy to achieve these parameters is allowed. 
 
History of hypertensive crisis or hypertensive encephalopathy 
 
Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent 
peripheral arterial thrombosis) within 6 months prior to Day 1 of Cycle 1 
 
History of hemoptysis ( 2.5 mL of bright red blood per episode) within 1 month prior 
to Day 1 of Cycle 1 
 
Evidence of bleeding diathesis or significant coagulopathy (in the absence of 
therapeutic anticoagulation) 

 
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 
Current or recent (within 10 days of Day 1 of Cycle 1) use of aspirin ( 325 mg/day) 
or current or recent treatment with dipyramidole, ticlopidine, clopidogrel, and 
cilostazol 
 
Current or recent (within 10 days prior to Day 1 of Cycle 1) use of full-dose oral or 
parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to 
prophylactic) purpose 
Prophylactic anticoagulation for the patency of venous access devices is 
allowed provided the activity of the agent results in an INR  1.5  ULN and 
aPTT is within normal limits (according to institutional standards) within 14 days 
prior to Day 1 of Cycle 1. 
Prophylactic use of low-molecular-weight heparin (LMWH; i.e., enoxaparin 
40 mg/day) is allowed.  However, the use of direct oral anticoagulant therapies 
such as dabigatran (Pradaxa®) and rivaroxaban (Xarelto®) is not recommended 
due to bleeding risk.  Benefits and risks should be assessed and caution 
exercised for use of direct oral anticoagulants.  The investigator should 
consider switching to other approved anticoagulants due to the risk of upper 
GI bleeding in patients with HCC. 
 
Core biopsy or other minor surgical procedure, excluding placement of a vascular 
access device, within 3 days prior to Day 1 of Cycle 1  
 
History of GI fistula, GI perforation, or intra-abdominal abscess within 6 months prior 
to Day 1 of Cycle 1 
 
Evidence of abdominal free air that is not explained by paracentesis or recent 
surgical procedure 
 
Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture 
 
Major surgical procedure within 4 weeks prior to Day 1 of Cycle 1 or anticipation of 
need for a major surgical procedure during the study 
 
History of clinically significant intra-abdominal inflammatory process within 6 months 
prior to Day 1 of Cycle 1, including, but not limited to, peptic ulcer disease, 
diverticulitis, or colitis 
 
Chronic daily treatment with a non-steroidal anti-inflammatory drug (NSAID) 
Occasional use of NSAIDs for the symptomatic relief of medical conditions such 
as headache or fever is allowed. 
Chronic use of low dose aspirin ( 325 mg/day) is allowed. 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
This is a randomized, open-label study.  After written informed consent has been 
obtained, all screening procedures and assessments have been completed, and 
eligibility has been established for a patient, the study site will obtain the patient's 
identification number and treatment assignment from the interactive voice or web-based 
response system (IxRS). 

 
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Patients will be randomly assigned to one of two study arms:  Arm A 
(atezolizumab  bevacizumab) or Arm B (active surveillance).  Randomization will occur 
in a 1:1 ratio through use of a permuted-block randomization method to ensure a 
balanced assignment to each study arm.  Randomization will be stratified according to 
the criteria outlined in Section 3.1.   
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
The investigational medicinal products (IMPs) for this study are atezolizumab and 
bevacizumab.  Appendix 14 identifies all IMPs.  
4.3.1 
Study Treatment Formulation, Packaging, and Handling 
4.3.1.1 
Atezolizumab 
The atezolizumab drug product will be supplied by the Sponsor as a sterile liquid in a 
single-use, 20-mL glass vial.  The vial contains approximately 20 mL (1200 mg) of 
atezolizumab solution. 
For information on the formulation and handling of atezolizumab, see the pharmacy 
manual and the Atezolizumab Investigator's Brochure. 
4.3.1.2 
Bevacizumab 
The bevacizumab drug product will be supplied by the Sponsor as a sterile liquid in 
single-use, 16-mL, preservative-free glass vials that contain 400 mg of bevacizumab 
(25 mg/mL). 
For information on the formulation and handling of bevacizumab, see the pharmacy 
manual and the Bevacizumab Investigator's Brochure. 
4.3.2 
Study Treatment Dosage, Administration, and Compliance 
The treatment regimens are summarized in Section 3.1.  Atezolizumab will be 
administered first followed by bevacizumab, with a minimum of 5 minutes between 
dosing.  Patients will receive treatment as described in Sections 4.3.2.1 and 4.3.2.2.  
Treatment must be initiated no later than 3 business days after randomization, with the 
exception of the emergence of an adverse event for which dosing may be postponed.  
If scheduled dosing and study assessments are precluded because of a holiday, 
weekend, or other event, then dosing may be postponed to the soonest following date, 
with subsequent dosing continuing on a 21-day schedule, with one exception:  
If treatment was postponed for fewer than 3 days, the patient can resume the original 
schedule. 
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 

 
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Any dose modification should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).  Cases of accidental overdose or medication error, along 
with any associated adverse events, should be reported as described in 
Section 5.3.5.12. 
Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Appendix 12 and Appendix 13. 
4.3.2.1 
Atezolizumab 
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of 
each 21-day cycle.  Treatment duration is described in Section 3.1. 
Administration of atezolizumab will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to 
manage potentially serious reactions.  For anaphylaxis precautions, see Appendix 11.  
Atezolizumab infusions will be administered per the instructions outlined in Table 5. 
Table 5 
Administration of First and Subsequent Atezolizumab Infusions 
First Infusion 
Subsequent Infusions 
 
No premedication is permitted prior to the 
atezolizumab infusion. 
 
Vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) should 
be measured within 60 minutes prior to 
the infusion. 
 
Atezolizumab should be infused over 
60 ( 15) minutes. 
 
If clinically indicated, vital signs should be 
measured every 15 ( 5) minutes during 
the infusion and at 30 ( 10) minutes after 
the infusion. 
 
Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms. 
 
If the patient experienced an infusion-
related reaction with any previous 
infusion, premedication with 
antihistamines, antipyretics, and/or 
analgesics may be administered for 
subsequent doses at the discretion of 
the investigator. 
 
Vital signs should be measured within 
60 minutes prior to the infusion. 
 
Atezolizumab should be infused over 
30 ( 10) minutes if the previous infusion 
was tolerated without an infusion-related 
reaction, or 60 ( 15) minutes if the 
patient experienced an infusion-related 
reaction with the previous infusion. 
 
If the patient experienced an infusion-
related reaction with the previous 
infusion or if clinically indicated, vital 
signs should be measured during the 
infusion and at 30 ( 10) minutes after 
the infusion. 
 
Guidelines for medical management of infusion-related reactions (IRRs) are provided in 
Appendix 12. 
No dose modification for atezolizumab is allowed. 

 
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4.3.2.2 
Bevacizumab 
Bevacizumab will be administered by IV infusion at a dose of 15 mg/kg on Day 1 of each 
21-day cycle.  Treatment duration is described in Section 3.1. 
Administration of bevacizumab will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to 
manage potentially serious reactions.  For anaphylaxis precautions, see Appendix 11.  
Bevacizumab infusions will be administered per the instructions outlined in Table 6. 
Table 6 
Administration of First and Subsequent Bevacizumab Infusions 
First Infusion 
Subsequent Infusions 
 
No premedication is permitted prior to the 
bevacizumab infusion. 
 
Vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) should 
be measured within 60 minutes prior to 
the infusion. a 
 
Bevacizumab should be infused over 
90 ( 15) minutes. 
 
Vital signs should be measured at the end 
of the infusion and 2 ( 1) hours after the 
infusion. 
 
Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms. 
 
If the patient experienced an infusion-
related reaction with any previous 
infusion, premedication with 
antihistamines, antipyretics, and/or 
analgesics may be administered for 
subsequent doses at the discretion of the 
investigator. 
 
Vital signs should be measured within 
60 minutes prior to the infusion. 
 
Bevacizumab should be infused over 
60 ( 10) minutes if the previous infusion 
was tolerated without an infusion-related 
reaction, or 90 ( 15) minutes if the 
patient experienced an infusion-related 
reaction with the previous infusion.  If the 
60-minute infusion was well tolerated, 
bevacizumab may be infused over 
30 ( 15) minutes thereafter. 
 
Vital signs should be measured at the 
end of the infusion and 2 ( 1) hours after 
the infusion. 
a For patients with borderline blood pressure, repeated measurements can be used to obtain 
an average blood pressure. 
 
Guidelines for medical management of IRRs are provided in Appendix 12. 
No dose modification for bevacizumab is allowed. 
4.3.3 
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study (atezolizumab and bevacizumab) will be 
provided by the Sponsor.  The study site will acknowledge receipt of IMPs supplied by 
the Sponsor using the IxRS to confirm the shipment condition and content.  Any 
damaged shipments will be replaced. 
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor with the appropriate 

 
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documentation.  The site's method of destroying Sponsor-supplied IMPs must be agreed 
to by the Sponsor.  The site must obtain written authorization from the Sponsor before 
any Sponsor-supplied IMP is destroyed, and IMP destruction must be documented on 
the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 
4.3.4 
Continued Access to Atezolizumab and Bevacizumab 
The Sponsor will offer continued access to Roche IMPs (atezolizumab and 
bevacizumab) free of charge to eligible patients in accordance with the Roche Global 
Policy on Continued Access to Investigational Medicinal Product, as outlined below. 
A patient will be eligible to receive Roche IMPs (atezolizumab and bevacizumab) after 
completing the study if all of the following conditions are met: 
 
The patient has a life-threatening or severe medical condition and requires 
continued Roche IMP treatment for his or her well-being 
 
There are no appropriate alternative treatments available to the patient 
 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
 
A patient will not be eligible to receive Roche IMPs (atezolizumab and bevacizumab) 
after completing the study if any of the following conditions are met: 
 
The Roche IMP is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient) 
 
The Sponsor has discontinued development of the IMP or data suggest that the IMP 
is not effective for HCC 
 
The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
HCC 
 
Provision of the Roche IMP is not permitted under the laws and regulations of the 
patient's country 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
4.4 
CONCOMITANT THERAPY 
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 7 days 
prior to Day 1 of Cycle 1 to the treatment/surveillance discontinuation visit.  All such 

 
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medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF. 
4.4.1 
Permitted Therapy  
Patients are permitted to use the following therapies during the study: 
 
Oral contraceptives with a failure rate of  1% per year (see Section 4.1.1) 
 
Hormone-replacement therapy 
 
Vaccinations (such as influenza, COVID-19) 
Live, attenuated vaccines are not permitted (see Section 4.4.3) 
 
Megestrol acetate administered as an appetite stimulant  
 
Mineralocorticoids (e.g., fludrocortisone) 
 
Corticosteroids administered for chronic obstructive pulmonary disease or asthma 
 
Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency 
 
Low-dose aspirin ( 325 mg/day).  
Co-administration of proton-pump inhibitors is strongly recommended to reduce 
potential GI damage. 
 
Premedication with antihistamines, antipyretics, and/or analgesics may be administered 
for the second and subsequent atezolizumab infusions only, at the discretion of the 
investigator.  
In general, investigators should manage a patient's care (including preexisting 
conditions) with supportive therapies other than those defined as cautionary or 
prohibited therapies (see Sections 4.4.2 and 4.4.3) as clinically indicated, per local 
standard practice.  Patients who experience infusion-associated symptoms may be 
treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or 
H2-receptor antagonists (e.g., famotidine, cimetidine), or equivalent medications per local 
standard practice.  Serious infusion-associated events manifested by dyspnea, 
hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or 
respiratory distress should be managed with supportive therapies as clinically indicated 
(e.g., supplemental oxygen and 2-adrenergic agonists; see Appendix 12). 
4.4.2 
Cautionary Therapy for Atezolizumab-Treated Patients  
4.4.2.1 
Corticosteroids, Immunosuppressive Medications, and Tumor 
Necrosis Factor- Inhibitors 
Systemic corticosteroids, immunosuppressive medications, and TNF- inhibitors may 
attenuate potential beneficial immunologic effects of treatment with atezolizumab.  
Therefore, in situations in which systemic corticosteroids, immunosuppressive 
medications, or TNF- inhibitors would be routinely administered, alternatives, including 
antihistamines, should be considered.  If the alternatives are not feasible, systemic 

 
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corticosteroids, immunosuppressive medications, and TNF- inhibitors may be 
administered at the discretion of the investigator. 
Systemic corticosteroids or immunosuppressive medications are recommended, at the 
discretion of the investigator, for the treatment of specific adverse events when 
associated with atezolizumab therapy (refer to Appendix 12 and Appendix 13 for details). 
4.4.2.2 
Herbal Therapies 
Concomitant use of herbal therapies, including traditional Chinese medicine, is not 
recommended because their pharmacokinetics, safety profiles, and potential drugdrug 
interactions are generally unknown.  However, herbal therapies not intended for the 
treatment of cancer (see Section 4.4.3) may be used during the study at the discretion of 
the investigator.  Prior use of herbal therapies or traditional Chinese medicines with 
anti-cancer activity included in the label is allowed, but such therapies must be 
discontinued at least 7 days prior to randomization. 
4.4.3 
Prohibited Therapy 
Any concomitant therapy intended for the treatment of cancer, whether 
health authorityapproved or experimental, is prohibited for various time periods prior to 
Day 1 of Cycle 1 (depending on the anticancer agent; see Section 4.1.2), during study 
treatment/active surveillance, and during long-term follow-up until IRF-confirmed disease 
recurrence.  This includes but is not limited to the following: 
 
Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy [e.g., Xiao Chai Hu Tang, Kanglaite]), whether health authorityapproved or 
experimental, is prohibited for various time periods prior to Day 1 of Cycle 1, 
depending on the agent (see Section 4.1.2), during study treatment/active 
surveillance, and during long-term follow-up until IRF-confirmed disease recurrence 
is documented. 
 
Investigational therapy is prohibited within 4 weeks prior to Day 1 of Cycle 1, during 
study treatment/active surveillance, and during long-term follow-up until 
IRF-confirmed disease recurrence. 
The following medications are prohibited for patients receiving atezolizumab plus 
bevacizumab, unless otherwise noted: 
 
Live, attenuated vaccines (e.g., FluMist®) are prohibited within 4 weeks prior to 
initiation of study treatment, during atezolizumab treatment, and for 5 months after 
the final dose of atezolizumab. 
 
Systemic immunostimulatory agents (including, but not limited to, IFNs and IL-2) are 
prohibited within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior 
to initiation of study treatment and during study treatment because these agents 
could potentially increase the risk for autoimmune conditions when given in 
combination with atezolizumab. 

 
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 
Current use of full dose oral or parenteral anticoagulants or thrombolytic agents for 
therapeutic (as opposed to prophylactic) purposes or anti-platelet therapy are 
prohibited within 10 days prior to Day 1 of Cycle 1 and during study treatment.   
– 
Local label recommended doses for prophylactic use of anticoagulants or 
thrombolytic therapies are allowed.  Benefits and risks should be assessed and 
caution exercised for use of direct oral anticoagulants.  Other approved 
anticoagulants should be considered due the risk of upper GI bleeding in 
patients with HCC.  
– 
Low-dose aspirin (  325 mg/day) is permitted.  Co-administration of 
proton-pump inhibitors is strongly recommended to reduce potential 
GI damage.  
– 
However, if a patient experiences a venous thromboembolism event while still 
receiving study treatment, it may still be possible for the patient to remain on 
study medication despite anticoagulation treatment (see Section 4.1.2). 
 
Use of warfarin or warfarin-like products is not permitted at all (includes for 
prophylactic use) 
Prophylactic use of low-dose anticoagulation, unfractionated heparin or LMWH is 
permitted.  The preferred choice for anticoagulation treatment should be LMWH as 
per American Society of Clinical Oncology guidelines (Lyman et al. 2015). 
 
Concomitant chronic use of NSAIDs while receiving study treatment is prohibited, 
with the exception of chronic low-dose aspirin ( 325 mg/day).  However, for the 
symptomatic relief of medical conditions (e.g., headache, fever), sporadic or 
short-term intake of oral NSAIDs is allowed, when co-administered with 
proton-pump inhibitors to reduce potential GI damage. 
 
4.5 
STUDY ASSESSMENTS  
The schedule of activities to be performed in the study is provided in Appendix 1.  
A schedule of activities for patients randomized to Arm B who cross over to treatment 
with atezolizumab plus bevacizumab is provided in Appendix 2.  All activities should be 
performed and documented for each patient.   
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site. 

 
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All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a detailed record of 
all patients screened and to document eligibility or record reasons for screening failure, 
as applicable. 
4.5.2 
Medical History, Baseline Conditions, Concomitant Medication, 
and Demographic Data 
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history, 
and use of alcohol and drugs of abuse, will be recorded at baseline.  In addition, all 
medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or 
homeopathic remedies, nutritional supplements) used by the patient within 7 days prior 
to Day 1 of Cycle 1 will be recorded.  At the time of each follow-up physical examination, 
or patient contact by means of telephone or telemedicine, an interval medical history 
should be obtained and any changes in medications and allergies should be recorded. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.3 
Physical Examinations 
A complete physical examination, performed at screening, should include an evaluation 
of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, GI, genitourinary, and neurologic systems.  
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF. 
Limited, symptom-directed physical examinations should be performed at specified 
postbaseline visits and as clinically indicated.  Changes from baseline abnormalities 
should be recorded in patient notes.  New or worsened clinically significant abnormalities 
should be recorded as adverse events on the Adverse Event eCRF. 
Physical examinations should include the evaluation of the presence and degree of 
enlarged lymph nodes, hepatomegaly, and splenomegaly. 
4.5.4 
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, systolic and 
diastolic BP, and temperature.  Abnormalities observed at baseline should be recorded 
on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, 
any new or worsened clinically significant abnormalities should be recorded on the 
Adverse Event eCRF. 
4.5.5 
Imaging Assessments 
Patients will undergo imaging assessments at screening, every 12 weeks for the first 
3 years following randomization and every 24 weeks thereafter, regardless of treatment 
delays, until IRF-confirmed disease recurrence or until the end of Year 7 after 

 
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randomization, whichever occurs first even if the patient starts a new anti-cancer 
therapy.  Thus, imaging assessments are to continue according to schedule in patients 
who discontinue treatment for reasons other than disease recurrence, even if they start 
new anti-cancer therapy.  At the investigator's discretion, imaging assessments may be 
repeated at any time if clinically indicated. 
Screening assessments must include CT scans with IV contrast (and oral contrast per 
site standard of care) or MRI scans of the chest, abdomen, and pelvis.  A spiral CT scan 
of the chest may be obtained but is not a requirement.  If a CT scan with contrast is 
contraindicated (e.g., in patients with impaired renal clearance), a non-contrast CT scan 
of the chest may be performed and MRI scans of the abdomen and pelvis should be 
performed.  If a CT scan with contrast is not contraindicated, it is mandatory to obtain a 
dual-phase imaging scan of the liver, and every effort should be made to time the 
contrast administration so that high-quality arterial-phase imaging is obtained throughout 
the liver on the first run, and high-quality portal venous-phase imaging is obtained 
throughout the liver on the second run.  A CT scan with contrast or MRI scan of the head 
must be done at screening to evaluate CNS metastasis in all patients (MRI scan must be 
performed if CT scan is contraindicated).  An MRI scan of the head is required to confirm 
or refute the diagnosis of CNS metastases at baseline in the event of an equivocal CT 
scan.  Bone scans and CT scans of the neck should also be performed if clinically 
indicated.   
If a CT scan is performed in a positron emission tomography/CT scanner, the CT 
acquisition must be consistent with the standards for a full-contrast diagnostic CT scan. 
All postbaseline imaging assessments will include CT scans with IV contrast (and oral 
contrast per site standard of care) or MRI scans of the chest, abdomen, and pelvis; 
scans of the head will be included per local practice or as clinically indicated.   
The same radiographic procedures used at screening should be used for subsequent 
imaging assessments (e.g., the same contrast protocol for CT scans).  Assessments 
should be performed by the same evaluator, if possible, to ensure internal consistency 
across visits.   
Diagnosis of intrahepatic recurrence will be based on non-invasive criteria and/or 
biopsy-proven pathologic confirmation of recurrence as defined by the EASL Clinical 
Practice Guidelines 2018 (see Appendix 6 as well as the radiology interpretation guide 
from Calyx).  Intrahepatic recurrence is defined by the appearance of one or more 
intrahepatic lesions with a longest diameter of  1 cm and a typical vascular pattern of 
HCC on dynamic imaging (i.e., hypervascularization in the arterial phase with washout in 
the portal venous or late venous phase).  Lesions that do not show a typical vascular 
pattern can be diagnosed as HCC recurrence by evidence of a growth interval of at least 
1 cm in subsequent scans.  Extrahepatic recurrence will be defined as per RECIST v1.1 
(see Appendix 7).  

 
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Sites will provide any CT, MRI, or PET/CT scans used for assessments of HCC 
recurrence to an IRF for central review.  Contrast-enhanced ultrasound and AFP 
changes cannot be reviewed by the IRF to evaluate recurrence.  Any biopsy results that 
have been done to diagnose HCC recurrence or to investigate suspicious lesions, 
should be entered in RAVE so that the IRF can review.  Baseline screening scans 
performed after curative procedure will be submitted to the IRF only after the patient has 
been randomized. 
Imaging for Patients in Arm B Who Cross Over to Treatment with 
Atezolizumab plus Bevacizumab 
Patients randomized to Arm B who cross over to treatment with atezolizumab plus 
bevacizumab after documented IRF-assessed recurrence will undergo imaging 
assessments every 12 weeks from the Crossover Cycle 1 Day 1 visit, regardless of 
treatment delays, until a second disease recurrence (for patients with NED at the time of 
crossover) or loss of clinical benefit as determined by the investigator (for patients with 
measurable disease at the time of crossover).  Thus, imaging assessments are to 
continue according to schedule in patients who discontinue treatment for reasons other 
than disease recurrence or loss of clinical benefit (as appropriate), even if they start new 
anti-cancer therapy.  At the investigator's discretion, imaging assessments may be done 
more frequently or repeated at any time if clinically indicated.  Images collected following 
confirmation of disease recurrence by the IRF do not need to be submitted to the IRF for 
central review. 
An imaging assessment is not required during screening for crossover.  For crossover 
patients not undergoing a second resection or ablation, the scan confirming recurrence 
can serve as the baseline imaging assessment assuming chest, abdomen, and pelvis 
imaging has been obtained.  For patients undergoing a second resection or ablation 
procedure, imaging of chest, abdomen, and pelvis following resection or ablation is 
needed and should represent baseline. 
The same radiographic procedures used to assess disease sites prior to crossover 
should be used during crossover (e.g., the same contrast protocol for CT scans).  
Assessments should be performed by the same evaluator, if possible, to ensure internal 
consistency across visits. 
For patients with measurable disease at crossover, all measurable and evaluable lesions 
identified at the time of documented recurrence should be re-assessed at each 
subsequent tumor evaluation.  Objective response at a single timepoint will be 
determined by the investigator according to RECIST v1.1 (see Appendix 7).   
For patients with NED at the time of crossover, diagnosis of intrahepatic and 
extrahepatic recurrence will be made as described above.  

 
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4.5.6 
Laboratory, Biomarker, and Other Biological Samples 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
 
Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, and 
other cells) 
 
Chemistry panel (serum or plasma):  bicarbonate or total carbon dioxide (if 
considered standard of care for the region), sodium, potassium, chloride, glucose, 
BUN or urea, creatinine, total protein, albumin, phosphate, calcium, total bilirubin, 
ALP, ALT, AST, and lactate dehydrogenase 
 
Coagulation:  INR and aPTT 
 
Thyroid function testing:  TSH, free T3 (or total T3 for sites where free T3 is not 
performed), and free thyroxine (also known as T4) 
 
AFP 
 
HIV serology 
 
HBV serology:  hepatitis B surface antigen (HBsAg), hepatitis B surface antibody, 
total hepatitis B core antibody (HBcAb), HBV DNA 
If a patient has a positive HBsAg test and/or a positive total HBcAb test at 
screening, an HBV DNA test and quantitative HBsAg test must also be 
performed during screening to determine if the patient has an HBV infection, as 
well as at Cycles 5, and 9, and at the discontinuation visit.  If local quantitative 
HBsAg test is not available, a qualitative HBsAg followed by quantitative HBV 
DNA can be performed as an alternative. 
 
HCV serology:  HCV antibody and (if HCV antibody test is positive) HCV RNA 
If a patient has a positive HCV antibody test at screening, an HCV RNA test 
must also be performed to determine if the patient has an HCV infection at 
screening, Cycles 5, and 9, and at the discontinuation visit. 
 
C-reactive protein  
 
Pregnancy test 
All women of childbearing potential will have a serum pregnancy test within 
14 days before Day 1 of Cycle 1.  Urine pregnancy tests will be performed at 
specified subsequent visits (see Appendix 1 and Appendix 2).  If a urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
A woman is considered to be of childbearing potential if she is postmenarchal, 
has not reached a postmenopausal state ( 12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis). 

 
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 
Urinalysis (pH, specific gravity, glucose, protein, ketones, and blood); dipstick 
permitted  
 
The following samples will be sent to one or several central laboratories or to the 
Sponsor or a designee for analysis: 
 
Serum samples for atezolizumab PK analysis through use of a validated 
immunoassay 
 
Serum samples for assessment of ADAs to atezolizumab through use of a validated 
immunoassay 
 
Blood, serum, and plasma samples for exploratory research on biomarkers 
 
For patients with resected HCC and only if available for patients with ablated HCC, 
an archival tumor tissue sample obtained at baseline for exploratory research on 
biomarkers and biomarker assay development 
For patients with resected HCC (mandatory), an FFPE resected tumor 
specimen in a paraffin block (preferred) or at least 15 slides containing 
unstained, freshly cut, serial sections should be submitted along with an 
associated pathology report within 4 weeks after randomization.  For patients in 
China, tissue samples may be submitted retrospectively upon HGRAC approval 
of sample submission. 
For patients with ablated HCC (if available), biopsy is not mandated.  Although 
any available tumor tissue sample can be submitted, sites are strongly 
encouraged, if available, to submit a representative FFPE tumor specimen in a 
paraffin block (preferred) or approximately 1015 slides containing unstained, 
freshly cut, serial sections along with an associated pathology report.  Samples 
collected via resection, core-needle biopsy, or excisional, incisional, punch, or 
forceps biopsy are preferred.  However, all specimen types (e.g., fine-needle 
aspiration, brushing, cell pellets from pleural effusion, and lavage samples) are 
acceptable. 
 
Tumor tissue sample obtained at the time of radiographic confirmation of disease 
recurrence unless not clinically feasible as assessed and documented by the 
investigator for exploratory research on biomarkers and biomarker assay 
development  
Biopsies at the time of recurrence should be performed within 12 weeks after 
recurrence or prior to the next anti-cancer therapy, whichever is sooner.  
Samples collected via resection, core-needle biopsy (at least three cores 
preferred), or excisional, incisional, punch, or forceps biopsy are preferred. 
 
Exploratory biomarker research may include, but will not be limited to, PD-L1, ctDNA, 
tumor-immune phenotypes, molecular subtypes of HCC, mutations, tumor mutation 
burden, copy number variations, T-effector signature, immune subsets, and pathway 
signatures.  Research may involve extraction of DNA, cell-free DNA, or RNA; analysis of 
mutations, single nucleotide polymorphisms, and other genomic variants; and genomic 
profiling through use of next-generation sequencing of a comprehensive panel of genes.  

 
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DNA extracted from blood may be compared with DNA extracted from tissue to identify 
somatic variants by distinguishing germline variants from somatic variants.   
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.10), biological samples will be destroyed 
no later than the time of completion of the final Clinical Study Report, with the following 
exceptions: 
 
Serum samples collected for PK or immunogenicity analysis may be needed for 
additional immunogenicity characterization and for PK or immunogenicity assay 
development and validation; therefore, these samples will be destroyed no later than 
5 years after the final Clinical Study Report has been completed. 
 
Blood, serum, plasma, and tumor tissue samples collected for biomarker research 
will be destroyed no later than 5 years after the final Clinical Study Report has been 
completed. 
 
For enrolled patients, remaining archival tissue blocks will be returned to the site 
upon request or no later than the time of final closure of the study database, 
whichever occurs first.  For patients who are not enrolled, remaining archival tissue 
blocks will be returned to the site no later than 6 weeks after eligibility determination. 
 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis, including data on genomic variants, will be subject to 
the confidentiality standards described in Section 8.4. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication. 
4.5.7 
Electrocardiograms 
An ECG is required at screening and when clinically indicated.  ECGs for each patient 
should be obtained from the same machine wherever possible.  Lead placement should 
be as consistent as possible.  ECG recordings must be performed after the patient has 
been resting in a supine position for at least 10 minutes. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 

 
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study file at the site.  Any morphologic waveform changes or other ECG abnormalities 
must be documented on the eCRF. 
4.5.8 
Patient-Reported Outcomes 
To more fully characterize the clinical profile of atezolizumab in combination with 
bevacizumab, patient-reported outcome (PRO) data will be obtained through use of the 
following instruments:  the IL42–EORTC QLQ-C30 (Reduced) and the EQ-5D-5L.  
Refer to Appendix 1 for the frequency and timing of PRO assessments. 
4.5.8.1 
Data Collection Methods for Patient-Reported Outcomes 
The PRO instruments will be completed at the clinic or by means of a telephone call at 
specified timepoints during the study (see Appendix 1).  To ensure instrument validity 
and that data standards meet health authority requirements, questionnaires must be 
completed by the patient at the start of the clinic visit before any discussion with the 
investigator of the patient’s health state, laboratory results, or health record; before 
administration of study treatment; and prior to the completion of all other study 
assessments.  If the patient is unable to complete the measure on her or his own, 
interviewer assessment is allowed but may only be conducted by a member of the clinic 
staff.  With interviewer assessment, questionnaire items must be read to the patient 
verbatim; no interpretation, rephrasing, or rewording of the questions is allowed during 
interview-assisted completion. 
 
During clinic visits, PRO instruments should be administered as outlined below: 
 
Patients' health status should not be discussed prior to administration of the 
instruments. 
 
Sites must administer the official version of each instrument, as provided by the 
Sponsor.  Instruments must not be copied from the protocol. 
 
Sites should allow sufficient time for patients to complete the instruments. 
 
Sites should administer the instruments in a quiet area with minimal distractions and 
disruptions. 
 
Patients should be instructed to answer questions to the best of their ability; there 
are no right or wrong answers. 
 
Site staff should not interpret or explain questions, but may read questions verbatim 
upon request. 
 
Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments. 
 
Site staff should review all completed instruments and should ask the patient to 
rectify any response that is not clearly marked in the appropriate location.  If a 
response is missing, site staff should ask the patient to complete the item or confirm 
that the item was intentionally left blank. 
 

 
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After treatment (Arm A) or surveillance (Arm B) discontinuation, the IL42–EORTC 
QLQ-C30 (Reduced) and EQ-5D-5L instruments will be administered at the first four 
long-term follow-up assessments for approximately 1 year at clinic visits or by means of 
a telephone call.  Patients who experience disease recurrence should complete the PRO 
questionnaires at the visit when disease recurrence is determined by the investigator if 
operationally feasible, at the treatment/surveillance discontinuation visit, and then at the 
first four long-term follow-up assessments at clinic visits or by means of a telephone call.  
For patients who experience disease recurrence after the collection of the first four long-
term follow-up PRO assessments, PROs do not need to be collected again. 
Patients in Arm B who cross over to treatment with atezolizumab plus bevacizumab will 
not complete PRO instruments after they cross over.  
4.5.8.2 
Description of Patient-Reported Outcomes Instruments 
IL42–EORTC QLQ-C30 (Reduced)  
The IL42–EORTC QLQ-C30 (Reduced) is a reduced version of the validated, reliable 
EORTC QLQ-C30, self-report measure (Aaronson et al. 1993; Fitzsimmons et al. 1999).  
This reduced version contains the validated patient functioning (physical, emotional, role, 
and social) and GHS/quality of life (QoL) scales and was created for this study from the 
EORTC Quality of Life Group Item Library (https://www.eortc.be/itemlibrary/).  The 
measure consists of 15 questions in total and will employ the same recall period of the 
EORTC-QLQ-C30 of the previous week (see Appendix 8).  The IL42–EORTC QLQ-C30 
(Reduced) will follow the original scoring for each scale as is specified in the EORTC 
Scoring manual (Fayers et al. 2001).  The functioning items are scored on a 4-point 
scale that ranges from "not at all" to "very much," and the GHS/QoL scale is scored on a 
7-point scale that ranges from "very poor" to "excellent."  It takes less than 10 minutes to 
complete the measure.   
EQ-5D-5L 
The EQ-5D-5L is a validated self-report health status questionnaire that is used to 
calculate a health status utility score for use in health economic analyses 
(EuroQol Group 1990; Brooks 1996; Herdman et al. 2011; Janssen et al. 2013; 
(see Appendix 9).  There are two components to the EQ-5D-5L:  a five-item health state 
profile that assesses mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression, as well as a Visual Analog Scale (VAS) that measures health state.  
The EQ-5D-5L is designed to capture the patient's current health status.  Published 
weighting systems allow for creation of a single composite score of the patient's health 
status.  The EQ-5D-5L takes approximately 3 minutes to complete.  It will be used in this 
study for informing pharmacoeconomic evaluations. 
4.5.9 
Blood Samples for Whole Genome Sequencing or Whole 
Exome Sequencing (Patients at Participating Sites)  
At participating sites, blood samples will be collected for DNA extraction to enable WGS 
or WES to identify variants that are predictive of response to study drug, are associated 

 
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with progression to a more severe disease state, are associated with acquired 
resistance to study drug, are associated with susceptibility to developing adverse events, 
can lead to improved adverse event monitoring or investigation, or can increase the 
knowledge and understanding of disease biology and drug safety.  The DNA extracted 
from blood may be compared with DNA extracted from tissue to identify somatic variants 
by distinguishing germline variants from somatic variants.  The samples may be sent to 
one or more laboratories for analysis. 
Collection and submission of blood samples for WGS or WES is contingent upon the 
review and approval of the exploratory research by each IRB/EC and, if applicable, an 
appropriate regulatory body.  If a site has not been granted approval for WGS or WES, 
this section of the protocol (Section 4.5.9) will not be applicable at that site. If collection 
of the WES sample is missed at Cycle1 Day 1, this sample may be collected at any 
other time during the study (See Appendix 3). 
Genomics is increasingly informing researchers' understanding of disease pathobiology.  
The WGS and the WES provide a comprehensive characterization of the genome and 
exome, respectively, and, along with clinical data collected in this study, may increase 
the opportunity for developing new therapeutic approaches or new methods for 
monitoring efficacy and safety or predicting which patients are more likely to respond to 
a drug or develop adverse events.  Data will be analyzed in the context of this study but 
may also be explored in aggregate with data from other studies.  The availability of a 
larger dataset will assist in identification and characterization of important biomarkers 
and pathways to support future drug development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.   
Blood samples collected for WGS or WES are to be stored until they are no longer 
needed or until they are exhausted.  However, the storage period will be in accordance 
with the IRB/EC-approved Informed Consent Form and applicable laws (e.g., health 
authority requirements). 
Refer to Section 4.5.6 for details on use of samples after patient withdrawal, 
confidentiality standards for data, and availability of data from biomarker analyses. 
4.5.10 
Optional Samples for Research Biosample Repository 
4.5.10.1 
Overview of the Research Biosample Repository 
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biological specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The 
collection, storage, and analysis of RBR samples will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future. 

 
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Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  The RBR samples will be analyzed to achieve one 
or more of the following objectives: 
 
To study the association of biomarkers with efficacy or disease progression 
 
To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation 
 
To increase knowledge and understanding of disease biology and drug safety 
 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.10.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not 
been granted approval for RBR sampling, this section of the protocol (Section 4.5.10) 
will not be applicable at that site. 
4.5.10.3 
Sample Collection 
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to atezolizumab and 
bevacizumab, HCC, diseases, or drug safety: 
 
Leftover blood, serum, plasma, and tumor tissue samples (with the exception of 
remaining archival tissue blocks, which will be returned to sites) and any derivatives 
thereof (e.g., DNA, RNA, proteins, peptides). 
 
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic variants via WGS, WES, or other genomic analysis methods.  Genomics is 
increasingly informing researchers' understanding of disease pathobiology.  The WGS 
and the WES provide a comprehensive characterization of the genome and exome, 
respectively, and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches or new methods for monitoring 
efficacy and safety or predicting which patients are more likely to respond to a drug or 
develop adverse events.  
Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 

 
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For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.   
The RBR samples are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
4.5.10.4 
Confidentiality 
The RBR samples and associated data will be labeled with a unique patient identification 
number. 
Patient medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication. 
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
4.5.10.5 
Consent to Participate in the Research Biosample Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR samples.  Patients 
who decline to participate will not provide a separate signature. 
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF. 
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research. 

 
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4.5.10.6 
Withdrawal from the Research Biosample Repository 
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed or will no longer be linked to the patient.  However, if RBR samples 
have been tested prior to withdrawal of consent, results from those tests will remain as 
part of the overall research data.  If a patient wishes to withdraw consent to the testing of 
his or her RBR samples during the study, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and must enter the date of withdrawal on the RBR Research Sample 
Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent to the 
testing of his or her RBR samples after closure of the site, the investigator must inform 
the Sponsor by emailing the study number and patient number to the following email 
address: 
global.rcr-withdrawal@roche.com 
A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from Study WO41535. 
4.5.10.7 
Monitoring and Oversight 
The RBR samples will be tracked in a manner consistent with Good Clinical Practice by 
a quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RBR for the purposes of verifying 
the data provided to the Sponsor.  The site will permit monitoring, audits, IRB/EC review, 
and health authority inspections by providing direct access to source data and 
documents related to the RBR samples. 
 
4.6 
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Study Treatment Discontinuation 
Patients must permanently discontinue study treatment (atezolizumab and 
bevacizumab) if they experience any of the following: 
 
Intolerable toxicity related to study treatment, including development of an 
immune-mediated adverse event determined by the investigator to be unacceptable 
given the individual patient's potential response to therapy and severity of the event 
 
Any medical condition that may jeopardize the patient's safety if he or she continues 
study treatment 
 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient 
 
Use of another non-protocol anti-cancer therapy 

 
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 
Pregnancy 
 
For patients in Arm A and crossover patients with NED at the time of crossover:  
disease recurrence (confirmed by IRF for patients in Arm A), as determined by 
EASL Clinical Practice Guidelines for intrahepatic recurrence or RECIST v1.1 for 
extrahepatic recurrence 
 
For crossover patients with measurable disease at the time of crossover:  loss of 
clinical benefit as determined by the investigator after an integrated assessment of 
radiographic and biochemical data, local biopsy results (if available), and clinical 
status (e.g., symptomatic deterioration such as pain secondary to disease; see 
Section 3.1 for details) 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 
Patients will return to the clinic for a treatment/surveillance discontinuation 
visit  30 days after the final dose of study treatment (Arm A) or final visit or telephone 
contact (Arm B).   
After treatment/surveillance discontinuation, information on survival follow-up and new 
anti-cancer therapy will be collected by telephone calls, patient medical records, and/or 
clinic visits approximately every 12 weeks until death (unless the patient withdraws 
consent or the Sponsor terminates the study).  The first long-term follow-up should occur 
approximately 12 weeks from the last scheduled imaging assessment (for patients who 
have experienced disease recurrence and discontinued from surveillance/treatment 
period) or at the next scheduled imaging assessment (for patients who have not 
experienced disease recurrence and have discontinued from the surveillance/treatment 
period). 
4.6.2 
Patient Discontinuation from the Study 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time. 
Reasons for patient discontinuation from the study may include, but are not limited to, 
the following: 
 
Patient withdrawal of consent 
 
Study termination or site closure 
 
Adverse event 
 
Loss to follow-up 
 
Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor 
 

 
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Every effort should be made to obtain a reason for patient discontinuation from the 
study.  The primary reason for discontinuation from the study should be documented on 
the appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator.  Patients 
who withdraw from the study will not be replaced. 
If a patient withdraws from the study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status. 
4.6.3 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
 
Patient enrollment is unsatisfactory. 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.   
4.6.4 
Site Discontinuation 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
The safety plan for patients in this study is based on clinical experience with 
atezolizumab and bevacizumab in completed and ongoing studies.  The anticipated 
important safety risks are outlined below (see Sections 5.1.15.1.3).   
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria and close monitoring of 
patients during the study.  Administration of atezolizumab and bevacizumab will be 
performed in a monitored setting in which there is immediate access to trained personnel 
and adequate equipment and medicine to manage potentially serious reactions.  
Guidelines for managing patients who experience anticipated adverse events, including 
criteria for treatment interruption or discontinuation, are provided in Appendix 12 and 

 
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Appendix 13.  Refer to Sections 5.25.6 for details on safety reporting (e.g., adverse 
events, pregnancies) for this study. 
Patients with active infection that in the opinion of the investigator could impact patient 
safety are excluded from study participation.  In the setting of a pandemic or epidemic, 
screening for active infections (including SARS-CoV-2) prior to and during study 
participation should be considered according to local or institutional guidelines or 
guidelines of applicable professional societies (e.g., American Society of Clinical 
Oncology or European Society for Medical Oncology). 
Severe SARS-CoV-2 infection appears to be associated with a CRS involving the 
inflammatory cytokines IL-6, IL-10, IL-2, and IFN- (Merad and Martin 2020).  If a patient 
develops suspected CRS during the study, a differential diagnosis should include 
SARS-CoV-2 infection, which should be confirmed or refuted through assessment of 
exposure history, appropriate laboratory testing, and clinical or radiologic evaluations per 
investigator judgment.  If a diagnosis of SARS-CoV-2 infection is confirmed, the disease 
should be managed as per local or institutional guidelines. 
5.1.1 
Risks Associated with Atezolizumab 
Atezolizumab has been associated with risks such as the following:  IRRs and 
immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré 
syndrome, myasthenic syndrome or myasthenia gravis, meningoencephalitis, facial 
paresis, myelitis, myocarditis, pericardial disorders, nephritis, myositis, and severe 
cutaneous adverse reactions.  In addition, immune-mediated reactions may involve any 
organ system and  lead to hemophagocytic lymphohistiocytosis (HLH).  Refer to 
Appendix 13 of the protocol and Section 6 of the Atezolizumab Investigator's Brochure 
for a detailed description of anticipated safety risks for atezolizumab.   
5.1.2 
Risks Associated with Bevacizumab  
Bevacizumab has been associated with risks such as the following: GI perforations, 
all-bladder perforation, hemorrhage, pulmonary hemorrhage, arterial thromboembolic 
events (ATE), fistulae, wound-healing complications, hypertension, congestive heart 
failure (CHF), cardiac disorders (excluding CHF and ATE), neutropenia, infections, 
necrotizing fasciitis, thrombocytopenia, venous thromboembolism, posterior reversible 
encephalopathy syndrome, pulmonary hypertension, ovarian failure, embryo-fetal 
development disturbance, hypersensitivity reactions/infusion reactions, peripheral 
sensory neuropathy, osteonecrosis of the jaw, non-mandibular osteonecrosis, thrombotic 
microangiopathy, and proteinuria.  
Refer to Section 6 of the Bevacizumab Investigator's Brochure for a detailed description 
of anticipated safety risks for Bevacizumab.   

 
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5.1.3 
Risks Associated with Combination Use of Atezolizumab and 
Bevacizumab  
The risk of overlapping toxicities between atezolizumab and bevacizumab is anticipated 
to be minimal based on the known safety profile of each agent and available data from 
clinical studies.  Nevertheless, the attribution and management of certain adverse events 
that have been associated with each agent separately (e.g., hemorrhage, 
hypothyroidism, and GI toxicity) may be ambiguous when the agents are administered 
together.  It is theoretically possible that allergic or inflammatory adverse events 
associated with bevacizumab could be exacerbated by the immunostimulatory activity of 
atezolizumab.  
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  For patients in the active 
surveillance arm, an adverse event is any untoward medical occurrence. 
An adverse event can therefore be any of the following: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.9 and 
5.3.5.10 for more information) 
 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study treatment 
 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 

 
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5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
 
Is fatal (i.e., the adverse event actually causes or leads to death) 
 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that, had it occurred in a more severe form 
or was allowed to continue, might have caused death. 
 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.11) 
 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions) 
 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study treatment 
 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 
for reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
For patients receiving active treatment with atezolizumab plus bevacizumab, adverse 
events of special interest are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 
for reporting instructions).  Adverse events of special interest for this study are as 
follows: 
 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.7) 

 
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 
Suspected transmission of an infectious agent by the study treatment, as defined 
below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of study treatment is suspected. 
 
Pneumonitis 
 
Colitis 
 
Endocrinopathies:  (e.g., diabetes mellitus, pancreatitis, adrenal insufficiency, 
hyperthyroidism, and hypophysitis) 
 
Hepatitis, including AST or ALT  10  ULN 
 
Systemic lupus erythematosus 
 
Neurological disorders:  e.g., Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis 
 
Events suggestive of hypersensitivity, IRRs, CRS, HLH, and MAS 
 
Nephritis 
 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
 
Myositis 
 
Myopathies, including rhabdomyolysis 
 
Grade  2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
 
Vasculitis 
 
Autoimmune hemolytic anemia 
 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis) 
 
Myelitis 
 
Facial paresis  
 
Grade  3 hypertension  
 
Grade  3 proteinuria 
 
Any grade GI perforation, abscess, or fistula 
 
Grade  2 non-GI fistula or abscess 
 
Grade  3 wound-healing complication 
 
Hemorrhage 
– 
Any grade CNS bleeding 
– 
Grade  2 hemoptysis 

 
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Other Grade  3 hemorrhagic event 
 
Any ATE  
 
Grade  3 venous thromboembolic event 
 
Any grade posterior reversible encephalopathy syndrome 
 
Grade  3 CHF 
 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).   
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact (at clinic 
visits or using telemedicine).  All adverse events, whether reported by the patient or 
noted by study personnel, will be recorded in the patient's medical record and on the 
Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study treatment or 
surveillance on Day 1 of Cycle 1, only serious adverse events caused by a 
protocol-mandated intervention (e.g., invasive procedures such as biopsies, 
discontinuation of medications) should be reported (see Section 5.4.2 for instructions for 
reporting serious adverse events). 
After initiation of study treatment or surveillance on Day 1 of Cycle 1, all adverse events 
will be reported until 30 days after the final cycle (i.e., final cycle of treatment or 
surveillance) or until initiation of new systemic anti-cancer therapy, whichever occurs 
first, and serious adverse events and adverse events of special interest will continue to 
be reported until 90 days after the final cycle or until initiation of new systemic anti-
cancer therapy, whichever occurs first. 
In patients in Arm B crossing over to treatment with atezolizumab and bevacizumab, 
after the end of the reporting period for serious adverse events (i.e., 90 days after the 
final cycle of surveillance) but prior to initiation of study treatment, if applicable, only 
serious adverse events caused by a protocol-mandated intervention (e.g., resection or 
ablation to treat disease recurrence, invasive procedures such as biopsies) should be 
reported.  If an adverse event occurs prior to crossover and the frequency, severity, or 
character of the adverse event worsens after initiation of the crossover treatment , a 
separate adverse event should be reported with an onset date after initiation of the 

 
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crossover treatment.  When recording the separate adverse event, it is important to 
convey the concept that the prior adverse event has changed after initiation of crossover 
treatment by including applicable descriptors (e.g., “more frequent headaches” or 
“worsening of hypertension”).   
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity.  Table 7 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 

 
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Table 7 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to study treatment, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see 
also Table 8): 
 
Temporal relationship of event onset to the initiation of study treatment 
 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study treatment, or reintroduction of study treatment (as 
applicable) 
 
Known association of the event with study treatment or with similar treatments 
 
Known association of the event with the disease under study 
 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 

 
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Table 8 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by study treatment on the basis of facts, 
evidence, science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of study treatment, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to study treatment; and/or the 
adverse event abates or resolves upon discontinuation of study treatment or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.   
Evidence exists that the adverse event has an etiology other than study treatment 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of study treatment (e.g., cancer diagnosed 2 days after 
first dose of study treatment). 
 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Infusion-Related Reactions 
Adverse events that occur during or within 24 hours after study treatment administration 
and are judged to be related to study treatment infusion should be captured as a 
diagnosis (e.g., "infusion-related reaction") on the Adverse Event eCRF.  If possible, 
avoid ambiguous terms such as "systemic reaction".  Associated signs and symptoms 
should be recorded on the dedicated Infusion-Related Reaction eCRF.  If a patient 
experiences both a local and systemic reaction to the same dose of study treatment, 
each reaction should be recorded separately on the Adverse Event eCRF, with signs 
and symptoms also recorded separately on the dedicated Infusion-Related Reaction 
eCRF. 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 

 
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eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
 
If a severe GI hemorrhage leads to renal failure, both events should be reported 
separately on the eCRF. 
 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 

 
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5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment  
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events. 
 
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5  ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention or a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment  
 

 
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It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high BP), only the diagnosis (i.e., hypertension) should be recorded on the 
Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( 3  baseline value) in combination with either 
an elevated total bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
 
Treatment-emergent ALT or AST  3  baseline value in combination with total 
bilirubin  2  ULN (of which   35% is direct bilirubin) 
 
Treatment-emergent ALT or AST  3  baseline value in combination with clinical 
jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2). 
5.3.5.8 
Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.3.1) that are attributed 
by the investigator solely to progression of HCC should be recorded on the Death 
Attributed to Progressive Disease eCRF.  All other deaths that occur during the adverse 
event reporting period, regardless of relationship to study treatment, must be recorded 
on the Adverse Event eCRF and immediately reported to the Sponsor 
(see Section 5.4.2).  The iDMC will monitor the frequency of deaths from all causes. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 

 
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be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
5.3.5.9 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  
When recording such events on the Adverse Event eCRF, it is important to convey the 
concept that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.10 
Lack of Efficacy or Worsening of Hepatocellular Carcinoma 
Events that are clearly consistent with the expected pattern of disease recurrence should 
not be recorded as adverse events.  These data will be captured as efficacy assessment 
data only.  However, in situations in which there is no confirmation of disease 
recurrence, the underlying symptoms should be captured as adverse events and 
assessed accordingly for seriousness, severity, and causality until a diagnosis or cause 
for such events is established or until confirmation of HCC recurrence.  If the symptoms 
are later confirmed to be due to recurrence of disease, symptoms reported as adverse 
events should be retracted.  
For patients with measurable disease at the time of crossover, events that are clearly 
consistent with the expected pattern of progression of the underlying disease should not 
be recorded as adverse events.  These data will be captured as efficacy assessment 
data only.  In most cases, the expected pattern of progression will be based on 
RECIST v1.1.  In rare cases, the determination of clinical progression will be based on 
symptomatic deterioration.  However, every effort should be made to document 
progression through use of objective criteria.  If there is any uncertainty as to whether an 
event is due to disease progression, it should be reported as an adverse event. 
5.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.   

 
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An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
 
Hospitalization for respite care 
 
Planned hospitalization required by the protocol (e.g., for study treatment 
administration or performance of an efficacy measurement for the study) 
 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease. 
The patient has not experienced an adverse event. 
 
Hospitalization due solely to recurrence  or progression of the underlying cancer 
 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead: 
 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.12 
Cases of Accidental Overdose or Medication Error  
Accidental overdose and medication error (hereafter referred to as “special situations”) 
are defined as follows: 
 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
 
Medication error:  accidental deviation in the administration of a drug  
In some cases, a medication error may be intercepted prior to administration of 
the drug. 
 
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria or qualifies as an adverse event of special interest, the event should 
be reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).  For atezolizumab and bevacizumab, adverse events 
associated with special situations should be recorded as described below for each 
situation: 
 
Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes. 
 
Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box. 

 
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 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes. 
In addition, all special situations associated with atezolizumab and bevacizumab, 
regardless of whether they result in an adverse event, should be recorded on the 
Adverse Event eCRF as described below: 
 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 
 
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details. 
 
Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details. 
 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries. 
5.3.5.13 
Patient-Reported Outcome Data  
Adverse event reports will not be derived from PRO data by the Sponsor.  Sites are not 
expected to review the PRO data for adverse events. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study treatment: 
 
Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements) 
 
Adverse events of special interest for patients receiving active treatment (defined in 
Section 5.2.3; see Section 5.4.2 for details on reporting requirements) 
 
Pregnancies (see Section 5.4.3 for details on reporting requirements) 
 

 
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For serious adverse events and adverse events of special interest in patients receiving 
active treatment and serious events in all patients, the investigator must report new 
significant follow-up information to the Sponsor immediately (i.e., no more than 24 hours 
after becoming aware of the information).  New significant information includes the 
following: 
 
New signs or symptoms or a change in the diagnosis 
 
Significant new diagnostic test results 
 
Change in causality based on new information 
 
Change in the event's outcome, including recovery 
 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
 
To ensure the safety of study participants, access to the Medical Monitors is available  
24 hours per day, 7 days per week.  Details will be provided separately. 
The Emergency Medical Call Center will also be available 24 hours per day, 7 days per 
week.  The Emergency Medical Call Center will connect the investigator with an 
Emergency Medical Contact, provide medical translation service if necessary, and track 
all calls. Contact information including toll-free numbers for the Emergency Medical 
Call Center, will be distributed to investigators. 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Treatment Initiation 
After informed consent has been obtained but prior to initiation of study treatment or 
surveillance on Day 1 of Cycle 1, only serious adverse events caused by a 
protocol-mandated intervention should be reported.  The paper Clinical Trial Adverse 
Event/Special Situations Form provided to investigators should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the event), either by faxing or by scanning and emailing the form using the 
fax number or email address provided to investigators. 
5.4.2.2 
Events That Occur after Study Treatment Initiation 
After initiation of study treatment or surveillance on Day 1 of Cycle 1, serious adverse 
events and adverse events of special interest will be reported until 90 days after the final 
cycle (i.e., final cycle of treatment or surveillance) or until initiation of new systemic 
anti-cancer therapy, whichever occurs first.  For adverse events of special interest in 
patients receiving active treatment and for serious adverse events in all patients, 
investigators should record all case details that can be gathered immediately (i.e., within 

 
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24 hours after learning of the event) on the Adverse Event eCRF and submit the report 
via the electronic data capture (EDC) system.  A report will be generated and sent to 
Roche Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Adverse 
Event/Special Situations Form provided to investigators should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the event), either by faxing or by scanning and emailing the form using the 
fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.   
Instructions for reporting serious adverse events that occur after the reporting period are 
provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the study or 
within 5 months after the final dose of atezolizumab or 6 months after the final dose of 
bevacizumab.  A paper Clinical Trial Pregnancy Reporting Form should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the pregnancy), either by faxing or by scanning and emailing the form 
using the fax number or email address provided to investigators.  Pregnancy should not 
be recorded on the Adverse Event eCRF.  The investigator should discontinue study 
treatment and counsel the patient, discussing the risks of the pregnancy and the 
possible effects on the fetus.  Monitoring of the patient should continue until conclusion 
of the pregnancy.  Any serious adverse events associated with the pregnancy (e.g., an 
event in the fetus, an event in the mother during or after the pregnancy, or a congenital 
anomaly/birth defect in the child) should be reported on the Adverse Event eCRF.  In 
addition, the investigator will submit a Clinical Trial Pregnancy Reporting Form when 
updated information on the course and outcome of the pregnancy becomes available. 
5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
6 months after the final dose of bevacizumab.  The investigator should report the 
pregnancy on the paper Clinical Trial Pregnancy Reporting Form and submit the form to 
the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), either by faxing or by scanning and emailing the form using the fax number 
or email address provided to investigators.  Attempts should be made to collect and 
report details of the course and outcome of any pregnancy in the partner of a male 
patient exposed to study treatment.  When permitted by the site, the pregnant partner 
would need to sign an Authorization for Use and Disclosure of Pregnancy Health 
Information to allow for follow-up on her pregnancy.  If the authorization has been 

 
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signed, the investigator should submit a Clinical Trial Pregnancy Reporting Form with 
additional information on the pregnant partner and the course and outcome of the 
pregnancy as it becomes available.  An investigator who is contacted by the male patient 
or his pregnant partner may provide information on the risks of the pregnancy and the 
possible effects on the fetus, to support an informed decision in cooperation with the 
treating physician and/or obstetrician. 
5.4.3.3 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic 
or elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.  
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
treatment or the female partner of a male patient exposed to study treatment should be 
classified as a serious adverse event, recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study treatment or trial-related 
procedures until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome. 

 
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5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
After the end of the reporting period for serious adverse events and adverse events of 
special interest (defined as 90 days after the final cycle or until initiation of new systemic 
anti-cancer therapy, whichever occurs first), all deaths, regardless of cause, should be 
reported through use of the Long-Term Survival Follow-Up eCRF.   
In addition, if the investigator becomes aware of a serious adverse event that is believed 
to be related to prior exposure to study treatment, the event should be reported through 
use of the Adverse Event eCRF.  However, if the EDC system is not available, the 
investigator should report these events directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the paper Clinical Trial Adverse Event/Special 
Situations Form using the fax number or email address provided to investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the documents listed below: 
Drug 
Document 
Atezolizumab 
Atezolizumab Investigator's Brochure  
Bevacizumab 
Bevacizumab Investigator's Brochure 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 

 
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An iDMC will monitor the incidence of the adverse events during the study.  An 
aggregate report of any clinically relevant imbalances that do not favor the test product 
will be submitted to health authorities. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The statistical considerations and analysis plan are summarized below.  Further details 
will be provided in the Statistical Analysis Plan (SAP) as part of the Data Analysis Plan. 
The global population will include all patients enrolled during the global enrollment phase 
(including patients enrolled in China during that phase), and the China subpopulation will 
include all patients enrolled at sites in China (i.e., during both the global enrollment 
phase and the extended China enrollment phase).  Separate analyses will be performed 
for the global population (see Sections 6.16.10) and the China subpopulation 
(see Section 6.11).   
6.1 
DETERMINATION OF SAMPLE SIZE 
A total of approximately 662 patients will be randomized in the global enrollment phase 
of this study using a 1:1 randomization ratio to allocate patients to either the 
atezolizumab plus bevacizumab arm (Arm A) or the active surveillance arm (Arm B).  
The primary efficacy endpoint for this study is IRF-assessed RFS, defined as the time 
from randomization to the first documented occurrence of intrahepatic or extrahepatic  
HCC, or death from any cause (whichever occurs first). 
The sample size of this study is based on the number of RFS events required to 
demonstrate efficacy with regard to the primary efficacy endpoint of IRF-assessed RFS.  
To detect an improvement in RFS using a log-rank test at a two-sided significance level 
of 0.05, approximately 323 RFS events will be required to achieve 80% overall power 
assuming a target HR of 0.73 (median RFS improvement over active surveillance of 
7.4 months).  The minimum detectable difference (MDD) for RFS is a HR of 0.8 (median 
RFS improvement of 5 months).  
The calculation of sample size and estimates of the RFS analysis timelines are based on 
the following assumptions: 
 
Patients will be randomized to Arm A and Arm B in a 1:1 ratio. 
 
RFS follows a one-piece exponential distribution. 
 
The median RFS in Arm B is 20 months. 
 
The O’BrienFleming boundaries approximated by the LanDeMets method (Lan 
and DeMets 1983) will be used as stopping boundaries for the interim and final 
analyses of RFS.  
 
The dropout rate is 15% for Arm A and 20% for Arm B over 12 months.  
The recruitment of approximately 662 patients will take place over approximately 
17 months. 

 
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See Section 6.11 for sample size considerations for the China subpopulation.  
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Study enrollment, study treatment administration, reasons for discontinuation from the 
study treatment, and reasons for study discontinuation will be summarized by study arm 
for all randomized patients (the ITT population).  Major protocol deviations, including 
major deviations with regard to the inclusion and exclusion criteria, will be summarized 
by study arm for the ITT population. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Demographic characteristics such as age, sex, race/ethnicity, and baseline disease 
characteristics (e.g., ECOG Performance Status) will be summarized by study arm for 
the ITT population.  Descriptive statistics (mean, median, standard deviation, and range) 
will be presented for continuous data, and frequencies and percentages will be 
presented for categorical data. 
Baseline measurements are the last available data obtained prior to initiation of 
treatment or surveillance on Day 1 of Cycle 1. 
6.4 
EFFICACY ANALYSES 
The analyses of RFS, OS, time to recurrence (TTR), and time to extrahepatic spread 
(EHS) or macrovascular invasion will be performed on the basis of all randomized 
patients (the ITT population), with patients grouped according to the treatment assigned 
at randomization, regardless of whether they receive any assigned study drug.   
Hypotheses will be formally tested on primary (IRF-assessed RFS) and the key 
secondary endpoints (OS).  Implementation of the statistical testing procedure will 
strongly control the overall Type 1 error at 5% (two-sided).  Additional details will be 
provided in the SAP. 
The analysis of RFS after the first HCC recurrence will be performed on the basis of 
patients in Arm B who cross over to treatment with atezolizumab plus bevacizumab after 
documented HCC recurrence with NED at the time of crossover.  The analyses of PFS 
and ORR will be performed on the basis of patients in Arm B who cross over to 
treatment with atezolizumab plus bevacizumab after documented HCC recurrence with 
measurable disease at the time of crossover.  
6.4.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is IRF-assessed RFS, defined as the time from 
randomization to the first documented occurrence of intrahepatic or extrahepatic HCC, 
or death from any cause (whichever occurs first).  Patients who have not experienced 
disease recurrence or death at the time of analysis will be censored at the date of the 
last assessment for HCC occurrence.  Patients with no postbaseline radiographic 

 
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assessment will be censored at the date of randomization.  For the purposes of analysis 
of RFS in the ITT population, in the rare event that the IRF identifies baseline disease, 
this patient will be assessed as having a recurrence event at the time of randomization. 
Analysis of RFS will be performed on basis of the ITT population using the ITT principle:  
with patients grouped according to the study arm assigned at randomization, regardless 
of whether they receive any assigned study drug, cause of going off protocol treatment, 
crossover from Arm B to treatment with atezolizumab plus bevacizumab etc. 
RFS will be tested with the overall type I error controlled at a two-sided significance level 
of 0.05.  The null and alternative hypotheses regarding RFS can be phrased in terms of 
survival functions SA(t) and SB(t) for Arm A (atezolizumab  bevacizumab) and Arm B 
(active surveillance), respectively: 
 
H0: SA(t) SB(t) versus H1: SA(t) ≠ SB(t) 
 
The two-sided stratified log-rank test, stratified by the same stratification factors 
specified for randomization, will be used as the primary analysis to compare RFS 
between the two arms.  The stratification factor leading to the largest number of empty 
cells may be excluded from the analysis.  The unstratified log-rank test will be used to 
check the robustness of the results of the stratified log-rank test.  
The KaplanMeier method will be used to estimate the median RFS for each study arm.  
The BrookmeyerCrowley method will be used to construct the 95% CI for the median 
RFS for each study arm.  Stratified Cox proportional-hazards models will be used to 
estimate the HR and its 95% CI.  The unstratified HR will also be estimated.  
A group sequential design will be implemented for testing the RFS primary endpoint to 
account for the conduct of one interim analysis, which is to be conducted when 
approximately 236 RFS events have occurred (see Section 6.10).  The overall type I 
error rate of 0.05 for testing of the RFS primary efficacy endpoint will be controlled 
through use of an -spending function that utilizes the LanDeMets method 
approximating the O’BrienFleming boundaries (O'Brien and Fleming 1979).  
The final analysis of RFS will be conducted when approximately 323 IRF-assessed RFS 
events have occurred, which is expected to take place approximately 39 months after 
the first patient is randomized. 
Sensitivity analyses to assess the robustness of the analysis of RFS will be pre-specified 
in the SAP.  
To assess the homogeneity of the treatment effect with respect to the primary efficacy 
endpoint of RFS across important subgroups, Forest plots (including the estimated HRs) 

 
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will be provided.  A full list of all pre-specified exploratory subgroup analyses for RFS for 
this study will be provided in the SAP. 
Further details regarding the primary efficacy analysis will be provided in the SAP. 
6.4.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are OS, investigator-assessed RFS, 
investigator-assessed and IRF-assessed TTR, , investigator- and IRF-assessed RFS 
rate at 24 months and 36 months, OS rate at 24 months and 36 months, 
investigator-assessed time to EHS or macrovascular invasion, and 
investigator-assessed and IRF-assessed RFS among patients in the PD-L1high 
subgroup.  OS will be a key secondary endpoint of this study.  
6.4.2.1 
Overall Survival  
The OS will be defined as the time from randomization to death from any cause.  
Patients who are alive at the time of the analysis will be censored at the last date the 
patient was known to be alive.  Patients with no postbaseline information will be 
censored at the date of randomization.  The analysis performed for OS will follow the 
methods described for the primary endpoint.   
To detect an improvement in OS using a log-rank test at a two-sided significance level of 
0.05, approximately 319 deaths will be required to achieve 80% overall power assuming 
a target HR of 0.73 (median OS improvement over active surveillance of 22 months).  
The final OS analysis will be conducted when approximately 319 deaths have occurred 
and is expected to take place approximately 91 months after the first patient is 
randomized.  Formal statistical treatment comparison for OS will only be performed after 
IRF-assessed RFS results have reached statistical significance. See Section 6.10 for 
additional details.  
6.4.2.2 
InvestigatorAssessed Recurrence Free Survival 
The analysis methods for investigator-assessed RFS are analogous to those described 
for IRF-assessed RFS (see Section 6.4.1).  
6.4.2.3 
Time to Recurrence 
The TTR is defined as the time from randomization to first documented occurrence of 
intrahepatic or extrahepatic HCC.  Patients who have not experienced disease 
recurrence at the time of the analysis will be censored at the date of the last assessment 
for HCC occurrence.  Patients with no postbaseline information will be censored at the 
date of randomization.  The analysis of TTR will be conducted separately based on 
investigator-assessed and IRF-assessed data and will follow the methods described for 
the primary endpoint (see Section 6.4.1). 

 
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6.4.2.4 
IRF-Assessed and Investigator-Assessed RFS at 24-Month and 
36-Month Landmark Analysis 
The IRF- and investigator-assessed RFS rates at 24 months and 36 months will be 
estimated for each study arm through use of the Kaplan-Meier method, with 95% CIs 
calculated through use of Greenwood’s formula. 
6.4.2.5 
Overall Survival 24-Month and 36-Month Landmark Analysis 
The OS rates at 24 months and 36 months will be estimated for each study arm through 
use of the Kaplan-Meier method, with 95% CIs calculated through use of Greenwood’s 
formula. 
6.4.2.6 
Time to Extrahepatic Spread or Macrovascular Invasion 
Time to EHS or macrovascular invasion is defined as the time from randomization to the 
first appearance of EHS or macrovascular invasion.  The analysis of time to EHS or 
macrovascular invasion will be conducted for the study period prior to crossover.  Events 
that occurred in the study period post-crossover will not be considered. Patients who 
have not experienced either EHS or macrovascular invasion at the time of the analysis 
or before crossover will be censored at the date of the last assessment for HCC 
occurrence prior to the analysis data cutoff date and before crossover when applicable.  
Patients with no postbaseline information will be censored at the date of randomization.  
The analysis of time to EHS or macrovascular invasion will be conducted based on 
investigator-assessed data and will follow the methods described for the primary 
endpoint (see Section 6.4.1). 
6.4.2.7 
Recurrence-Free Survival among Patients with PD-L1High 
Tumors 
The RFS among patients in the PD-L1high subgroup is defined in an analogous 
manner to the primary endpoint and will be analyzed through use of same methods 
described for the primary endpoint (see Section 6.4.1).  The analysis of RFS in the 
PD-L1high subgroup will be conducted separately based on investigator-assessed RFS 
data and IRF-assessed data. 
6.4.3 
Exploratory Efficacy Endpoints 
Exploratory Overall Survival Analyses 
The OS among patients in the PD-L1high subgroup is defined in an analogous manner 
to OS in the ITT population and will be analyzed through use of the same methods 
described for OS in the ITT population (see Section 6.4.2.1).  The cutoff to define 
PD-L1high tumors will be informed by association of clinical outcome with PD-L1 status 
in Studies GO30140 and YO40245 (IMbrave150) and will be pre-specified in the SAP. 
Exploratory Patient-Reported Outcome Analyses 
Change from baseline in physical functioning, emotional functioning, role functioning, 
social functioning, and GHS/QoL scores as assessed by the IL42–EORTC QLQ-C30 
(Reduced).  Summary statistics (number of patients, mean, mean change, standard 

 
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deviation, median, minimum, maximum, and 95% CI) of linearly transformed scores (per 
the EORTC scoring manual, Fayers et al. 2001) will be calculated at all assessment 
timepoints for each study arm.  Published minimally important differences 
(e.g., 10 points) will be used to identify meaningful changes for each scale within each 
treatment group (Osoba et al. 1998).   
Completion rates and reasons for missing data will be summarized for the 
IL42EORTC QLQ-C30 (Reduced) questionnaire at each assessment timepoint for both 
arms.  Details of the analysis, including methods for handling missing data, will be 
specified in the SAP. 
Exploratory Efficacy Analyses in Arm B Patients Who Cross Over to 
Treatment with Atezolizumab Plus Bevacizumab 
The following exploratory efficacy endpoints will be analyzed in patients in Arm B who 
cross over to treatment with atezolizumab plus bevacizumab after documented HCC 
recurrence:  
 
For patients with NED at the time of crossover: 
– 
RFS after the first HCC recurrence, defined as the time from first exposure to 
any dose of crossover treatment to the second documented HCC recurrence or 
death from any cause (whichever occurs first), as determined by the 
investigator.  HCC recurrence is defined as occurrence of intrahepatic or 
extrahepatic HCC. 
 
For patients with measurable disease at the time of crossover:  
– 
PFS after first HCC recurrence, defined as the time from first exposure to any 
dose of crossover treatment to the first documented occurrence of disease 
progression beyond the initial unresectable disease recurrence as determined 
by the investigator according to RECIST v1.1, or death from any cause 
(whichever occurs first)  
– 
ORR, defined as the proportion of patients with a CR or PR as determined by 
the investigator according to RECIST v1.1 
 
The 95% CI for ORR will be calculated using the Clopper-Pearson method 
(Clopper and Pearson 1934).  
Methodological details will be provided in the SAP.  
6.5 
SAFETY ANALYSES 
The safety analysis population will consist of all patients randomized to Arm A who 
received at least one full or partial dose of study treatment (atezolizumab and/or 
bevacizumab) and all patients randomized to Arm B who underwent at least one safety 
assessment. 

 
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Safety analyses will be conducted separately for the study periods prior to crossover and 
post-crossover. 
Verbatim adverse event terms will be mapped to MedDRA thesaurus terms, and adverse 
event severity will be graded according to NCI CTCAE v5.0. 
Drug exposure will be summarized by descriptive statistics to include treatment duration, 
number of doses, and dose intensity. 
The following events occurring during or after initiation of study treatment or surveillance 
on Day 1 of Cycle 1 will be summarized by study arm and NCI CTCAE grade: 
 
All adverse events 
 
All adverse events leading to death 
 
Serious adverse events 
 
Grade 3 adverse events 
 
Adverse event of special interest 
 
Adverse events leading to study drug discontinuation or interruption 
 
Multiple occurrences of the same event will be counted once at the maximum severity.  
Laboratory data with values outside the normal ranges will be identified.  In addition, 
selected laboratory data will be summarized by study arm and grade. 
Descriptive statistics will be used to summarize changes in vital signs by study arm.   
Deaths and causes of death reported during the study treatment period and those 
reported during the follow-up period after treatment or surveillance 
completion/discontinuation will be summarized by arm. 
Additional analyses may be performed as indicated. 
6.6 
PHARMACOKINETIC ANALYSES 
The PK analysis population will consist of all patients with at least one PK assessment. 
Serum concentrations of atezolizumab will be reported as individual values and 
summarized (geometric mean and geometric mean coefficient of variation) by cycle, 
when appropriate and as data allow.  Individual and median serum atezolizumab 
concentrations will be plotted for PK-evaluable patients by day.   
Atezolizumab concentration data may be pooled with data from other studies using an 
established population PK model to derive PK parameters such as clearance, volume of 
distribution, and area under the curve, as warranted by the data.  Potential correlations 
of relevant PK parameters with dose, safety, efficacy, or biomarker outcomes may be 
explored. 

 
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6.7 
IMMUNOGENICITY ANALYSES 
The immunogenicity analysis population will consist of all patients with at least one ADA 
assessment.  Patients will be grouped according to treatment received or, if no treatment 
is received prior to study discontinuation, according to treatment assigned. 
The numbers and proportions of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) and after drug administration (postbaseline incidence) 
will be summarized for ADA-evaluable patients.  When determining postbaseline 
incidence, patients are considered to be postbaseline ADA positive if they are ADA 
negative or have missing data at baseline but develop an ADA response following study 
drug exposure (treatment-induced ADA response), or if they are ADA positive at 
baseline and the titer of one or more postbaseline samples is at least 0.60 titer unit 
greater than the titer of the baseline sample (treatment-enhanced ADA response).  
Patients are considered to be postbaseline ADA negative if they are ADA negative or 
have missing data at baseline and all postbaseline samples are negative, or if they are 
ADA positive at baseline but do not have any postbaseline samples with a titer that is at 
least 0.60 titer unit greater than the titer of the baseline sample (treatment unaffected). 
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
may be analyzed and reported. 
6.8 
BIOMARKER ANALYSES  
Although no formal statistical analysis of exploratory biomarkers will be performed, 
biomarker data may be analyzed in the context of this study and in aggregate with data 
from other studies.   
6.9 
HEALTH UTILITY ANALYSES 
Health utility data from the EQ-5D-5L will be evaluated in pharmacoeconomic models.  
The results from the health economic data analyses will be reported separately from the 
clinical study report. 
6.10 
INTERIM ANALYSES 
6.10.1 
Interim Analyses of RFS 
One interim analysis of IRF-assessed RFS will be performed.  The interim analysis will 
be performed when approximately 236 RFS events have occurred, which is expected to 
take place approximately 26 months after the first patient is randomized.  For the interim 
analysis, the MDD for RFS is a HR of 0.734 (median RFS improvement over active 
surveillance of 7.2 months).  
For the interim analysis, efficacy stopping boundaries will be determined through use of 
the LanDeMets method to approximate the O’BrienFleming boundaries.  Analysis 
timing and stopping boundaries for the interim and final RFS analyses are summarized 
in Table 9.   

 
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The planned interim analysis of RFS will be conducted by an independent Data 
Coordinating Center and reviewed by the iDMC.  Interactions between the iDMC and 
Sponsor will be carried out as specified in the iDMC Charter. 
6.10.2 
Interim Analyses of OS 
A group sequential design will be implemented for testing OS to account for the conduct 
of up to two interim analyses.  The boundary for statistical significance at each interim 
analysis and the final analysis will be determined based on the Lan-DeMets 
implementation of the O’Brien-Fleming function (Lan and DeMets 1983) to maintain the 
overall type 1 error rate at 0.05 level.  The O’Brien-Fleming boundary for statistical 
significance is provided in Table 10.  Formal statistical treatment comparison for OS will 
only be performed after IRF-assessed RFS results have reached statistical significance 
at either the interim or final RFS analyses. 
If RFS is statistically significant at the interim analysis, then three analyses of the key 
secondary endpoint of OS are planned (see Table 10).  The two interim analyses of OS 
will be conducted at the time of the planned interim and final analyses of the primary 
efficacy endpoint of IRF-assessed RFS.  The final OS analysis will be conducted when 
approximately 319 deaths occurs. 
If RFS is not statistically significant at the interim analysis, the study will continue to the 
RFS final analysis without conducting an interim analysis for OS.  If RFS is statistically 
significant at the final analysis, then only one interim analysis of the secondary endpoint 
of OS is planned at the time of the IRF-assessed RFS final analysis (see Table 11).  The 
final OS analysis will be conducted when approximately 319 deaths occurs. 
If RFS is not statistically significant in either interim or final analysis, the secondary 
endpoint of the OS will not be formally tested and will be descriptive only. 
The boundaries for statistical significance at the planned IRF-assessed RFS and OS 
interim and final analyses will be determined based on the actual number of events 
observed. 
Further details will be provided in the SAP. 

 
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Table 9 
Analysis Timing and Stopping Boundaries for Recurrence-Free 
Survival Analyses 
Analysis 
Timing a 
Planned 
Information 
Fraction 
Required No. 
of Events 
(Estimated) 
Estimated 
Analysis Timing 
Stopping 
Boundary (Two-
Sided p-Value) b 
RFS interim 
analysis 
73% 
236 
26 months after 
first patient is 
randomized 
MDD HR  0.734 
(p-value  0.017) 
RFS final 
analysis 
100% 
323 
39 months after 
first patient is 
randomized 
MDD HR  0.8 
(p-value   0.045) 
HR  hazard ratio; ITT  intent-to-treat; MDD  minimum detectable difference (based on an 
exponential distribution); RFS  recurrence-free survival. 
a Analysis timing is estimated on the basis of protocol assumptions.  Actual timing depends 
on the exact time that the required events have accrued. 
b The actual stopping boundaries will be calculated at the time of the interim and final RFS 
analysis on the basis of the observed information fraction, that is, the actual number of 
RFS events observed at the time of analysis over the total planned target number of RFS 
events in the ITT population.  
 

 
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Table 10 Projected Interim and Final OS Analysis Characteristics When 
Statistical Significance is Reached at the Interim Analysis for 
RFS 
Analysis 
No. of 
events 
% 
information 
Event to 
Patient 
Ratio 
Cutoff Date 
a 
MDD b 
Boundary 
(p-value) c 
First OS interim 
(Performed at 
time of RFS 
interim analysis) 
107 
33.5% 
16% 
Month 26 
0.489 
p  0.0002 
Second OS 
interim 
(Performed at 
time of RFS final 
analysis) 
164 
51.4% 
25% 
Month 39 
0.634 
p  0.0035 
Final OS (Event 
driven) 
319 
100% 
48% 
Month 91 
0.802 
p  0.0488 
MDD  minimally detectable difference; OS  overall survival; RFS  recurrence free survival. 
Note:  Assumes 5% dropout rate over 12 months for OS analyses. 
a Study month at which required number of events are projected to occur, where Study 
Month 1 is the month the first patient is enrolled.  Analysis results will be available after data 
cleaning. 
b The largest observed hazard ratio that is projected to be statistically significant.  
c The projected boundary for statistical significance for the number of events shown (actual 
boundary to be calculated at time of analysis based on actual number of events). 
 

 
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Table 11 Projected Interim and Final OS Analysis Characteristics When 
Statistical Significance is Reached at the Final Analysis for RFS 
Analysis 
No. of 
events 
% 
information 
Event to 
Patient 
Ratio 
Cutoff Date a 
MDD b 
Boundary 
(p-value) c 
First OS interim 
(performed at 
time of RFS 
final analysis) 
164 
51.4% 
25% 
Month 39 
0.634 
p  0.0035 
Final OS (Event 
driven) 
319 
100% 
48% 
Month 91 
0.802 
p  0.0488 
MDD  minimally detectable difference; OS  overall survival; RFS  recurrence free survival. 
Note:  Assumes 5% dropout rate over 12 months for OS analyses. 
a Study month at which required number of events are projected to occur, where Study 
Month 1 is the month the first patient is enrolled.  Analysis results will be available after data 
cleaning. 
b The largest observed hazard ratio that is projected to be statistically significant.  
c The projected boundary for statistical significance for the number of events shown (actual 
boundary to be calculated at time of analysis based on actual number of events). 
 
6.11 
CHINA SUBPOPULATION ANALYSES 
The Sponsor is targeting a total enrollment of a minimum of 250 patients from mainland 
China.  The sample size of the China subpopulation was determined by characterizing 
the efficacy and safety profile of atezolizumab plus bevacizumab.  After approximately 
662 patients have been randomized into the global portion of the study, in the event that 
fewer than 250 patients from mainland China are enrolled, additional patients in China 
may be subsequently randomized into the two study arms in a 1:1 ratio in an extended 
China enrollment phase to ensure a total of approximately 250 patients from mainland 
China for the China subpopulation. 
The primary efficacy objective of the China subpopulation analysis is to assess efficacy, 
as measured by the primary endpoint of IRF-assessed RFS of atezolizumab plus 
bevacizumab compared with active surveillance in the Chinese patients.  The China 
subpopulation is not powered to demonstrate statistical significance in terms of efficacy, 
and no formal hypothesis testing will be performed. 
The China subpopulation analyses will be conducted when sufficient RFS events have 
occurred to demonstrate approximately 80% probability of maintaining 50% of RFS risk 
reduction compared with that estimated from the global population.  The exact timing of 
analyses will be specified in the SAP. 

 
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The analysis methods for China subpopulation will be the same as for the global 
population unless elsewhere noted.  The results of the China subpopulation analyses will 
be summarized in a separate report from the clinical study report for the global 
population.  The statistical details for such analyses in the China subpopulation will be 
documented in the SAP. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data. Central laboratory data and any other 
externally generated electronic study data will be sent directly to the Sponsor, using the 
Sponsor's standard procedures to handle and process the electronic transfer of these 
data. 
The eCRFs and correction documentation will be maintained in the EDC system's audit 
trail.  System backups for data stored by the Sponsor and records retention for the study 
data will be consistent with the Sponsor's standard procedures. 
PRO data will be collected on paper questionnaires.  The data from the questionnaires 
will be entered into the EDC system by site staff. 
7.2 
ELECTRONIC CASE REPORT FORMS  
The eCRFs are to be completed through use of a Sponsor-designated EDC system.  
Sites will receive training and have access to a manual for appropriate eCRF 
completion.  The eCRFs will be submitted electronically to the Sponsor and should be 
handled in accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  The eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required. 

 
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7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper PRO data (if applicable), Informed Consent 
Forms, laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for 15 years after completion or discontinuation of the study or for 

 
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the length of time required by relevant national or local health authorities, whichever is 
longer.  After that period of time, the documents may be destroyed, subject to local 
regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a 
U.S. Investigational New Drug (IND) Application will comply with U.S. FDA regulations 
and applicable local, state, and federal laws.  Studies conducted in the European Union 
or European Economic Area will comply with the E.U. Clinical Trials Directive 
(2001/20/EC) or Clinical Trial Regulation (536/ 2014) and applicable local, regional, and 
national laws. 
8.2 
INFORMED CONSENT 
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site.  If applicable, it will be provided in a certified translation of 
the local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/ECapproved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 

 
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The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
If the Consent Forms are revised (through an amendment or an addendum) while a 
patient is participating in the study, the patient or a legally authorized representative 
must re-consent by signing the most current version of the Consent Forms or the 
addendum, in accordance with applicable laws and IRB/EC policy.  For any updated or 
revised Consent Forms, the case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
using the updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the 
U.S. Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site 
utilizes a separate Authorization Form for patient authorization for use and disclosure of 
personal health information under the HIPAA regulations, the review, approval, 
and other processes outlined above apply except that IRB review and approval may not 
be required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments 
(see Section 9.7). 

 
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In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file.  
8.4 
CONFIDENTIALITY 
Information technology systems used to collect, process, and store study- related data 
are secured by technical and organizational security measures designed to protect such 
data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access. In the event of a data security breach, appropriate mitigation measures will be 
implemented. 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.6). 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
Study data, which may include data on genomic variants, may be submitted to 
government or other health research databases or shared with researchers, government 
agencies, companies, or other groups that are not participating in this study.  These data 
may be combined with or linked to other data and used for research purposes, to 
advance science and public health, or for analysis, development, and commercialization 
of products to treat and diagnose disease.  In addition, redacted Clinical Study Reports 
and other summary reports will be provided upon request (see Section 9.6). 

 
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8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator 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, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes 
to data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
9.3 
MANAGEMENT OF STUDY QUALITY 
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  The 
Sponsor will identify potential risks associated with critical trial processes and data and 
will implement plans for evaluating and controlling these risks.  Risk evaluation and 
control will include the selection of risk-based parameters (e.g., adverse event rate, 
protocol deviation rate) and the establishment of quality tolerance limits for these 
parameters.  Detection of deviations from quality tolerance limits will trigger an 
evaluation to determine if action is needed.  Details on the establishment and monitoring 
of quality tolerance limits will be provided in a Quality Tolerance Limit Management Plan. 
9.4 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 

 
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permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.5 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring. 
Approximately 175 sites globally will participate to randomize approximately 
662 patients.  Screening and enrollment will occur through an IxRS.   
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker analyses, and PK analyses), as specified in 
Section 4.5.6.  Accredited local laboratories will be used for routine monitoring; local 
laboratory ranges will be collected.  
An iDMC will evaluate patient safety and efficacy during the study.  An IRF will be used 
to enable centralized, independent reviews of images.  
9.6 
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals.  The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and/ or other summaries of clinical study results may be 
available in the health authority database for public access, as required by local 
regulation, and will be made available upon request. For more information, refer to the 
Roche Global Policy on Sharing or Clinical Study Information at the following website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/ 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 

 
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In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.7 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only. 

 
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10. 
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Appendix 1  
Schedule of Activities 
 
Both Arms 
Arm A 
(Atezolizumab  
Bevacizumab) 
Arm B 
(Active Surveillance) 
Both Arms 
Both Arms 
Assessment Timing 
Screening a 
Day 1 of Each 
Cycle b 
Day 1 of Cycles 1, 3, 
5, 7, 9, 11, 13, 
15, 17 b 
Day 1 of Cycles 2, 
4, 6, 8, 10, 12, 
14, 16 b 
Treatment/ 
Surveillance Discon.c 
Long-Term 
Follow-Up 
Days –28 
to –1 
Days –7 
to –1 
 30 Days after Final 
Cycle 
Informed consent a 
x 
 
 
 
 
 
 
Review of eligibility criteria 
x 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
Medical history and baseline 
conditions 
x 
 
 
 
 
 
 
ECOG Performance Status 
 
x 
x d 
x d 
 
x 
 
Patient-reported outcomes  
 
 
Odd Cycles  
only, starting at 
Cycle 1 d, e 
x d, e 
 
x f 
x f 
Complete physical 
examination g 
x 
 
 
 
 
 
 
Limited physical examination h 
 
 
x d 
x d 
 
x 
 
Weight 
x i 
 
x i 
x 
 
x 
 
Height 
x 
 
 
 
 
 
 
Vital signs j 
x 
 
x 
x 
 
x 
 
12-lead ECG k 
x 
 
Perform as clinically indicated 
 

Appendix 1: Schedule of Activities (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
115/Protocol WO41535, Version 6 
 
Both Arms 
Arm A 
(Atezolizumab  
Bevacizumab) 
Arm B 
(Active Surveillance) 
Both Arms 
Both Arms 
Assessment Timing 
Screening a 
Day 1 of Each 
Cycle b 
Day 1 of Cycles 1, 3, 
5, 7, 9, 11, 13, 
15, 17 b 
Day 1 of Cycles 2, 
4, 6, 8, 10, 12, 
14, 16 b 
Treatment/ 
Surveillance Discon.c 
Long-Term 
Follow-Up 
Days –28 
to –1 
Days –7 
to –1 
 30 Days after Final 
Cycle 
EGD l 
x 
 
 
 
 
 
 
HIV, HBV, HCV serology m 
x 
 
 
 
 
 
 
Quantitative HBsAg, HBV DNA, 
HCV RNA n 
x 
 
Cycles 5 and 9 
only d 
Cycles 5 and 9 only d 
 
x 
 
Hematology o 
 
x 
x d, p 
x d 
 
x 
 
Serum chemistry q 
 
x 
x d, p 
x d 
 
x 
 
Coagulation (aPTT, INR) 
 
x 
x d, p 
xd 
 
x 
 
Child-Pugh assessment r 
 
x 
x d 
x d 
 
x 
 
Pregnancy test s 
x 
 
x d 
 
 
x t 
x s 
Urinalysis u 
 
x v 
x d, p, v 
x d 
 
x 
 
C-reactive protein 
 
 
Cycle 1 only d 
Cycle 1 only d 
 
 
 
-fetoprotein 
x 
 
x d 
x d 
 
 
 
TSH, free T3 (or total T3), 
free T4 w 
x 
 
Cycles 5, 9, 13, 
and 17 only d 
 
 
 
 
Tumor tissue sample for 
biomarker analysis x 
x 
 
 
 
 
 
 

Appendix 1: Schedule of Activities (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
116/Protocol WO41535, Version 6 
 
Both Arms 
Arm A 
(Atezolizumab  
Bevacizumab) 
Arm B 
(Active Surveillance) 
Both Arms 
Both Arms 
Assessment Timing 
Screening a 
Day 1 of Each 
Cycle b 
Day 1 of Cycles 1, 3, 
5, 7, 9, 11, 13, 
15, 17 b 
Day 1 of Cycles 2, 
4, 6, 8, 10, 12, 
14, 16 b 
Treatment/ 
Surveillance Discon.c 
Long-Term 
Follow-Up 
Days –28 
to –1 
Days –7 
to –1 
 30 Days after Final 
Cycle 
Serum PK sample 
 
 
See Appendix 3 
 
 
See Appendix 3 
 
Serum ADA sample 
 
 
See Appendix 3 
 
 
See Appendix 3 
 
Blood, serum, and plasma 
biomarker samples 
See Appendix 3 
Blood sample for WES y 
 
 
Cycle 1 only. 
See Appendix 3 
Cycle 1 only. See 
Appendix 3 
 
 
 
Study treatment infusion z 
 
 
X 
 
 
 
 
Adverse events aa 
x 
 
x bb 
x bb 
x bb, cc 
x 
 
Concomitant medications dd 
 
x 
x bb 
x bb 
x bb, cc 
x 
 
Imaging assessments ee 
x 
 
Every 12 weeks ( 7 days) for the first 3 years following randomization and every 24 weeks 
( 10 days) thereafter, regardless of treatment delays, until the end of Year 7 after randomization 
or until IRF-confirmed disease recurrence ff, whichever occurs first  
Tumor tissue sample, if 
clinically feasible 
 
 
At the time of radiographic confirmation of disease recurrence gg 
 
Survival and anti-cancer 
therapy follow-up hh 
 
 
 
 
 
 
x 
 

Appendix 1: Schedule of Activities (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
117/Protocol WO41535, Version 6 
ADA  anti-drug antibody; CT  computed tomography; Discon  discontinuation; ECOG  Eastern Cooperative Oncology Group; 
EGD  esophagogastroduodenscopy; FFPE  formalin-fixed, paraffin-embedded; GI  gastrointestinal; HBcAb  hepatitis B core antibody; 
HBsAb  hepatitis B surface antibody; HBsAg  hepatitis B surface antigen; HBV  hepatitis B virus; HCV  hepatitis C virus; HGRAC  Human 
Genetic Resources Administration of China; IL42EORTC  IL42European Organisation for the Research and Treatment of Cancer; 
LTFU long-term follow-up; MRI  magnetic resonance imaging; PK  pharmacokinetic; PRO  patient-reported outcome; WES  whole exome 
sequencing. 
Notes:  Assessments scheduled on the days of study treatment infusions should be performed before the infusion unless otherwise noted.  
Each cycle is 21 days in length.  If scheduled dosing and study assessments are precluded because of a holiday, weekend, or other event, 
then dosing may be postponed to the soonest following date, with subsequent dosing continuing on a 21-day schedule, with one exception:  If 
treatment was postponed for fewer than 3 days, the patient can resume the original schedule. 
a Written informed consent may be obtained more than 28 days prior to randomization and is required before performing any study-specific 
tests or procedures.  Results of standard-of-care tests or examinations performed prior to obtaining informed consent and per the relevant 
protocol-defined window may be used for screening assessments rather than repeating such tests.  Screening local laboratory 
assessments obtained   96 hours prior to Day 1 of Cycle 1 do not have to be repeated for Cycle 1.  Test results should be reviewed prior to 
administration of study treatment. 
b Day 1 of Cycle 1 should occur within 3 business days from randomization, with the exception of the emergence of an adverse event for 
which dosing may be postponed.  Day 1 of subsequent cycles should occur within a window of  3 days. 
c Patients will return to the clinic for a treatment/surveillance discontinuation visit not more than 30 days after the final dose of study 
treatment (patients who receive active treatment) or final visit or telephone contact (patients who do not receive active treatment), or at the 
end of the 12-month treatment/surveillance period.   
d Indicated assessments may be obtained  96 hours before Day 1 of each cycle.  C-reactive protein may be obtained  96 hours before 
Day 1 of Cycle 1. 
e PRO assessments (IL42–EORTC QLQ-C30 [Reduced] and EQ-5D-5L questionnaires) will be completed at the site or by means of 
telephone call at each odd cycle visit before the patient receives any information on disease status, and prior to the completion of all other 
study assessments and the administration of study treatment.  Patients who experience disease recurrence will complete PRO 
assessments at the visit when disease recurrence is determined by the investigator if operationally feasible, at the treatment/surveillance 
discontinuation visit, and at the first four LTFU visits.  Study personnel should review all questionnaires for completeness before the patient 
leaves the investigational site.  If the patient is unable to complete the measure on her or his own, interview assessment is allowed but can 
only be conducted by site staff (see Section 4.5.8.1). 
f PRO assessments (IL42–EORTC QLQ-C30 [Reduced] and EQ-5D-5L questionnaires) will be administered by trained staff at the 
treatment/surveillance discontinuation visit, and at the first four LTFU visits.  In scenarios where PRO assessments cannot be done on 
scheduled LTFU visits, PRO assessments may be done  96 hours prior to the scheduled LTFU visits; when imaging assessments are 

Appendix 1: Schedule of Activities (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
118/Protocol WO41535, Version 6 
done at a different day or location than the LTFU visit, PRO assessments may be done after imaging assessments, as long as results have 
not been discussed with patients.  For patients who experience disease recurrence after the collection of the first four LTFU PRO 
assessments, PRO assessments do not need to be collected again. 
g Complete physical examination includes evaluation of the head, eyes, ears, nose, and throat and cardiovascular, dermatologic, 
musculoskeletal, respiratory, GI, genitourinary, and neurologic systems.   
h Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated.   
i The dose of bevacizumab will be based on the patient's weight (in kilograms) measured  14 days prior to baseline (the initiation of study 
treatment) and will remain the same throughout the study unless there is a weight change of  10% from the baseline body weight, in which 
case the bevacizumab dose should be modified.  Body weight will be re-baselined at the time of dose change, and dose modifications 
should occur if the patient’s weight changes  10% from the new baseline.  
j Vital signs include pulse rate, respiratory rate, systolic and diastolic blood pressure, and temperature.  For patients receiving active 
treatment, vital signs should be measured within 60 minutes prior to each infusion.  Vital signs will be measured at the end of bevacizumab 
infusion and 2 ( 1) hours after end of the infusion and will also be collected during and at 30 ( 10) minutes after every infusion of 
atezolizumab if clinically indicated. 
k Patients should be resting and in a supine position for at least 10 minutes prior to each ECG collection. 
l EGD is required only for patients who did not undergo an EGD prior to surgical resection or ablation.  
m At screening, patients will be tested for HIV, HBsAg, HBcAb, and HBsAb.  HBV DNA test must be performed during screening in patients 
who have positive serology for HBsAg and/or positive serology for HBcAb. 
n If patient tests positive for HBsAg and/or HBcAb, quantitative HBsAg and HBV DNA will be tested at screening, Day 1 of Cycles 5 and 9, 
and at the discontinuation visit.  If patient tests positive for HCV antibody at screening, quantitative HCV RNA must be tested locally at 
screening, on Day 1 of Cycles 5 and 9, and at the discontinuation visit.  If local quantitative HBsAg test is not available, a qualitative HBsAg 
followed by quantitative HBV DNA can be performed as an alternative. 
o Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, 
basophils, monocytes, lymphocytes, and other cells).  A manual differential can be done if clinically indicated.  
p The indicated local laboratory assessments from each cycle must be reviewed prior to study treatment administration for each cycle. 
q Serum chemistry includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, potassium, chloride, 
glucose, BUN or urea, creatinine, total protein, albumin, phosphate, calcium, total bilirubin, ALP, ALT, AST, and lactate dehydrogenase.  
r Patients will undergo assessment of Child-Pugh status at screening and Day 1 of each cycle for patients in Arm A and Day 1 of each odd 
cycle for patients in Arm B (see Appendix 4) as well as at the Treatment/Surveillance discontinuation visit. 

Appendix 1: Schedule of Activities (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
119/Protocol WO41535, Version 6 
s All women of childbearing potential will have a serum pregnancy test within 14 days before Day 1 of Cycle 1.  Urine pregnancy tests will be 
performed at specified subsequent visits for patients in Arm A including prior to Day 1 of each cycle and at the treatment discontinuation 
visit.  An additional pregnancy test should be performed 6 months after last administration of study drug.  Pregnancy test results should be 
reviewed and confirmed as negative prior to administration of treatment at each cycle.  If a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test. 
t A pregnancy test at the treatment/surveillance discontinuation visit is only required for patients in Arm A. 
u Urine dipstick includes specific gravity, pH, glucose, protein, ketones, and blood. 
v Patients must have  2  proteinuria on dipstick within 7 days prior to Day 1 of Cycle 1.  Patients with  2  proteinuria on dipstick urinalysis 
at baseline must undergo a 24-hour urine collection (or protein:creatinine ratio as an alternative per local guidance) and demonstrate  1 g 
of protein in 24 hours.  24 hour urine collection (or protein:creatinine ratio as an alternative per local guidance) should be done prior to 
bevacizumab administration according to the guidelines in Appendix 12. 
w TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed at screening and on Day 1 of Cycles 5, 9, 
13, and 17.   
x Mandatory for resected patients:  representative FFPE tumor from the resected specimen in a paraffin block (preferred) or at least 15 slides 
containing unstained, freshly cut, serial sections.  If available for ablated patients: a representative FFPE tumor specimen in a paraffin block 
(preferred) or approximately 1015 slides containing unstained, freshly cut, serial sections along with an associated pathology report.  
Samples collected via resection, core-needle biopsy, or excisional, incisional, punch, or forceps biopsy are preferred.  However, all 
specimen types (e.g., fine-needle aspiration, brushing, cell pellets from pleural effusion, and lavage samples) are acceptable.  
Tissue samples should be submitted within four weeks following randomization.  For patients in China, tissue samples may be submitted 
retrospectively upon HGRAC approval of sample submission. 
y Not applicable for a site that has not been granted approval for WES.  
z For patients receiving active treatment, atezolizumab will be administered first followed by bevacizumab, with a minimum of 5 minutes 
between dosing.  The initial dose of atezolizumab will be delivered over 60 ( 15) minutes.  Subsequent infusions will be delivered over 
30 ( 10) minutes if the previous infusion was tolerated without infusion-associated adverse events, or 60 ( 15) minutes if the patient 
experienced an infusion-associated adverse event with the previous infusion.  The initial dose of bevacizumab will be delivered over 
90 ( 15) minutes.  If the first infusion is tolerated without infusion-associated adverse events, the second infusion may be delivered over 
60 ( 10) minutes or 90 ( 15) minutes if the patient experienced an infusion-related reaction with the previous infusion.  If the 60-minute 
infusion is well tolerated, all subsequent infusions may be delivered over 30 ( 15) minutes.  In the absence of unacceptable toxicity, 
patients may continue study treatment for up to 12 months or until disease recurrence. 
 

Appendix 1: Schedule of Activities (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
120/Protocol WO41535, Version 6 
aa After informed consent has been obtained but prior to initiation of study treatment or surveillance on Day 1 of Cycle 1, only serious adverse 
events caused by a protocol-mandated intervention should be reported.  After initiation of study treatment or surveillance on Day 1 of 
Cycle 1, all adverse events will be reported until 30 days after the final cycle (i.e., final cycle of treatment or surveillance) or until initiation of 
new systemic anti-cancer therapy, whichever occurs first, and serious adverse events and adverse events of special interest will continue to 
be reported until 90 days after the final cycle or until initiation of new systemic anti-cancer therapy, whichever occurs first.  After this period, 
all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be notified if the investigator becomes aware of any 
serious adverse event that is believed to be related to prior exposure to study treatment. 
bb In the event that a patient cannot attend a clinic visit, telemedicine may be used to collect adverse event and concomitant medications. 
cc Adverse events and concomitant medications at cycles can be assessed either via telephone call or clinic visit. 
dd Concomitant medications includes any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic 
remedies, nutritional supplements) used by a patient in addition to protocol-mandated treatment from 7 days prior to Day 1 of Cycle 1 to the 
treatment/surveillance discontinuation visit.   
ee Imaging performed during screening should consist of CT and/or MRI of the chest, abdomen, pelvis, and head,and any other imaging 
studies (CT scan of the neck, plain films, etc.) as clinically indicated by the treating physician (see Section 4.5.5 for details).  Patients will 
undergo imaging assessments every 12 weeks ( 7 days) for the first 3 years following randomization and every 24 weeks ( 10 days) 
thereafter, regardless of treatment delays, until the end of Year 7 after randomization or IRF-confirmed disease recurrence,  whichever 
occurs first (see Section 4.5.5 for details).  Thus, imaging assessments are to continue according to schedule in patients who discontinue 
treatment for reasons other than disease recurrence, even if they start new, nonprotocol-specified anti-cancer therapy.  The same 
radiographic procedures and technique should be used throughout the study for each patient (e.g., if the patient had CT 
chest/abdomen/pelvis performed during screening, then he or she should subsequently undergo CT performed using the same radiologic 
protocol throughout the remainder of the study).  Results must be reviewed by the investigator before dosing at the next cycle.   
ff Criteria for diagnosis of recurrence are described in Section 4.5.5. 
gg Patients will undergo a mandatory tumor biopsy sample collection at the time of first evidence of clinical or radiographic disease recurrence 
if deemed clinically feasible by the investigator.  Biopsies at the time of recurrence should be performed within 12 weeks after recurrence or 
prior to the next anti-cancer therapy, whichever is sooner.  Samples collected via resection, core-needle biopsy (at least three cores 
preferred), or excisional, incisional, punch, or forceps biopsy are preferred.  
hh Information on survival follow-up and new anti-cancer therapy (including targeted therapy and immunotherapy) will be collected by means 
of telephone calls or telemedicine, patient medical records, and/or clinic visits approximately every 12 weeks ( 21 days) until death (unless 
the patient withdraws consent or the Sponsor terminates the study).  If the patient experiences disease recurrence during the 
treatment/surveillance period, the first LTFU should be done 12 weeks ( 21 days) from the last scheduled imaging assessment.  If the 
patient has not experienced disease recurrence in the treatment/surveillance period, the first LTFU should be done at the first scheduled 

Appendix 1: Schedule of Activities (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
121/Protocol WO41535, Version 6 
imaging assessment after the treatment/surveillance period.  The visit window for the LTFU is   21 days.  If the patient withdraws from 
study, the study staff may use a public information source (e.g., county records) to obtain information about survival status only. 

 
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
122/Protocol WO41535, Version 6 
Appendix 2  
Schedule of Activities for Patients in Arm B Who Cross Over to Treatment with Atezolizumab plus 
Bevacizumab 
Assessment Timing 
Screening a 
Treatment Period 
Treatment 
Discontinuation c 
Long-Term 
Follow-Up 
Days –28 to  
–1 
Days –7 to –1 
Day 1 of Each 21-Day 
Cycle b 
 30 Days after Final 
Dose 
Review of eligibility criteria 
x 
 
 
 
 
ECOG Performance Status 
 
x 
x d 
x 
 
Limited physical examination e 
x 
 
x d 
 
 
Weight f 
x 
 
X 
x 
 
Vital signs g 
x 
 
X 
x 
 
12-lead ECG h 
x 
 
Perform as clinically indicated 
 
EGD 
x i 
 
 
 
 
Quantitative HBsAg, HBV DNA, 
HCV RNA j 
 
 
As clinically indicated 
x 
 
Hematology k 
 
x 
x d, l 
 
 
Serum chemistry m 
 
x 
x d, l 
 
 
Coagulation panel (aPTT, INR) 
 
x 
x d, l 
 
 
Child-Pugh assessment n  
 
x d 
x d 
x n 
 
Pregnancy test o 
x 
 
x d 
x 
x o 
Urinalysis p 
 
x q 
x d, l 
 
 
-fetoprotein 
x 
 
x d 
 
 

Appendix 2: Schedule of Activities for Patients in Arm B who Cross Over to Treatment with Atezolizumab plus Bevacizumab (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
123/Protocol WO41535, Version 6 
Assessment Timing 
Screening a 
Treatment Period 
Treatment 
Discontinuation c 
Long-Term 
Follow-Up 
Days –28 to  
–1 
Days –7 to –1 
Day 1 of Each 21-Day 
Cycle b 
 30 Days after Final 
Dose 
TSH, free T3 (or total T3), free T4 r 
x 
 
Every 4 cycles starting at 
Cycle 5 d 
 
 
Study treatment infusion s 
 
 
X 
 
 
Adverse events t, u 
x 
 
X 
x 
 
Concomitant medications u, v 
 
x 
X 
x 
 
Imaging assessments w 
x x 
 
Every 12 weeks after Crossover Day 1 of Cycle 1 ( 7 days; at 
approximately every 4 cycles), regardless of treatment delays, until 
disease recurrence y (for patients with NED at the time of crossover) or 
loss of clinical benefit as determined by the investigator (for patients 
with measurable disease at crossover) 
Survival and anti-cancer therapy 
follow-up z 
 
 
 
 
x 
 
CT  computed tomography; ECOG  Eastern Cooperative Oncology Group; EGD  esophagogastroduodenoscopy; HBsAg  hepatitis B 
surface antigen; HBV  hepatitis B virus; HCV  hepatitis C virus; NED  no evidence of disease.  
Notes:  Assessments scheduled on the days of study treatment infusions should be performed before the infusion unless otherwise 
noted.  Each cycle is 21 days in length.  If scheduled dosing and study assessments are precluded because of a holiday, weekend, or 
other event, then dosing may be postponed to the soonest following date, with subsequent dosing continuing on a 21-day schedule, with 
one exception:  If treatment was postponed for fewer than 3 days, the patient can resume the original schedule. 
a Results of tests or examinations performed per the relevant protocol-defined window may be used for screening assessments rather 
than repeating such tests.  Screening local laboratory assessments obtained  96 hours prior to the initiation of study treatment do not 
have to be repeated for Cycle 1.  Test results should be reviewed prior to administration of study treatment. 

Appendix 2: Schedule of Activities for Patients in Arm B who Cross Over to Treatment with Atezolizumab plus Bevacizumab (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
124/Protocol WO41535, Version 6 
b Day 1 of Cycle 1 should occur within 3 business days from the end of screening, with the exception of the emergence of an adverse 
event for which dosing may be postponed.  Day 1 of Cycle 1 must be no later than 12 weeks after documentation of recurrence.  
Day 1 of subsequent cycles should occur within a window of  3 days. 
c Patients will return to the clinic for a treatment discontinuation visit not more than 30 days after the final dose of study treatment.   
d Indicated assessments may be obtained   96 hours before Day 1 of each cycle.   
e Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated.   
f The dose of bevacizumab will be based on the patient's weight (in kilograms) measured  14 days prior to baseline (the initiation of 
study treatment) and will remain the same throughout the study unless there is a weight change of  10% from the baseline body 
weight, in which case the bevacizumab dose should be modified.  Body weight will be re-baselined at the time of dose change, and 
dose modifications should occur if the patient’s weight changes  10% from the new baseline.   
g Vital signs include pulse rate, respiratory rate, systolic and diastolic blood pressure, and temperature.  Vital signs should be measured 
within 60 minutes prior to each infusion.  Vital signs will be measured at the end of bevacizumab infusion and 2 ( 1) hours after end 
of the infusion and will also be collected during and at 30 ( 10) minutes after every infusion of atezolizumab if clinically indicated. 
h Patients should be resting and in a supine position for at least 10 minutes prior to each ECG collection. 
i As clinically indicated.  
j If patient tests positive for HBsAg and/or HBcAb at initial screening, quantitative HBsAg and HBV DNA will be tested as clinically 
indicated during crossover treatment and at the discontinuation visit.  If patient tests positive for HCV antibody at initial screening, 
quantitative HCV RNA must be tested locally as clinically indicated and at the discontinuation visit.  If local quantitative HBsAg test is 
not available, a qualitative HBsAg followed by quantitative HBV DNA can be performed as an alternative. 
k Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, 
basophils, monocytes, lymphocytes, and other cells).  A manual differential can be done if clinically indicated. 
l The indicated local laboratory assessments from each cycle must be reviewed prior to study treatment administration for each cycle. 
m Serum chemistry includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, potassium, 
chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphate, calcium, total bilirubin, ALP, ALT, AST, and lactate 
dehydrogenase.  
n Patients will undergo assessment of Child-Pugh status at screening and Day 1 of each cycle (see Appendix 4) as well as at the 
Treatment Discontinuation visit.  Laboratory tests (bilirubin, albumin, and INR) required for Child-Pugh assessment at the Treatment 
Discontinuation visit can either be repeated or taken from the most recent cycle visit if  30 days from Treatment Discontinuation visit. 

Appendix 2: Schedule of Activities for Patients in Arm B who Cross Over to Treatment with Atezolizumab plus Bevacizumab (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
125/Protocol WO41535, Version 6 
o All women of childbearing potential will have a serum pregnancy test within 14 days before Day 1 of Cycle 1.  Urine pregnancy tests 
will be performed at specified subsequent visits including prior to Day 1 of each cycle and at the treatment discontinuation visit. An 
additional pregnancy test should be performed 6 months after last administration of study drug.  Pregnancy test results should be 
reviewed and confirmed as negative prior to administration of treatment at each cycle.  If a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test. 
p Urine dipstick includes specific gravity, pH, glucose, protein, ketones, and blood.   
q Patients must have  2  proteinuria on dipstick within 7 days prior to initiation of study treatment.  Patients with  2  proteinuria on 
dipstick urinalysis at baseline must undergo a 24-hour urine collection and demonstrate  1 g of protein in 24 hours. 24 hour urine 
collection (or protein:creatinine ratio as an alternative per local guidance) should be done prior to bevacizumab administration 
according to the guidelines in Appendix 12. 
r TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed at screening and on Day 1 of Cycle 5 
and every 4 cycles thereafter (i.e., Cycles 9, 13, etc.). 
s Atezolizumab will be administered first followed by bevacizumab, with a minimum of 5 minutes between dosing.  The initial dose 
of atezolizumab will be delivered over 60 ( 15) minutes.  Subsequent infusions will be delivered over 30 ( 10) minutes if the 
previous infusion was tolerated without infusion-associated adverse events, or 60 ( 15) minutes if the patient experienced an 
infusion  associated adverse event with the previous infusion.  The initial dose of bevacizumab will be delivered over 
90 ( 15) minutes.  If the first infusion is tolerated without infusion-associated adverse events, the second infusion may be delivered 
over 60 ( 10) minutes, or 90 ( 15) minutes if the patient experienced an infusion-related reaction with the previous infusion.  If the 
60-minute infusion is well tolerated, all subsequent infusions may be delivered over 30 ( 15) minutes.  Patients may continue study 
treatment until unacceptable toxicity or second disease recurrence (for patients with NED at the time of crossover), or until 
unacceptable toxicity or loss of clinical benefit as determined by the investigator after an integrated assessment of radiographic and 
biochemical data, and clinical status (e.g., symptomatic deterioration such as pain secondary to disease) (for patients with 
measurable disease at crossover). 

Appendix 2: Schedule of Activities for Patients in Arm B who Cross Over to Treatment with Atezolizumab plus Bevacizumab (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
126/Protocol WO41535, Version 6 
t After the end of the reporting period for serious adverse events (i.e., 90 days after the final cycle of surveillance) but prior to initiation 
of study treatment, only serious adverse events caused by a protocol-mandated intervention (e.g., resection or ablation to treat 
disease recurrence, invasive procedures such as biopsies) should be reported.  After initiation of study treatment on Day 1 of Cycle 1, 
all adverse events will be reported until 30 days after the final cycle or until initiation of new systemic anti-cancer therapy, whichever 
occurs first, and serious adverse events and adverse events of special interest will continue to be reported until 90 days after the final 
cycle or until initiation of new systemic anti-cancer therapy, whichever occurs first.  After this period, all deaths, regardless of cause, 
should be reported.  In addition, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is 
believed to be related to prior exposure to study treatment. 
u In the event that a patient cannot attend a clinic visit, telemedicine may be used to collect adverse event and concomitant 
medications. 
v Concomitant medications includes any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic 
remedies, nutritional supplements) used by a patient in addition to protocol-mandated treatment from 7 days prior to Day 1 of Cycle 1 
to the treatment discontinuation visit. 
w The same radiographic procedures and technique should be used throughout the study for each patient (e.g., if the patient had CT 
chest/abdomen/pelvis performed during screening, then he or she should subsequently undergo CT performed using the same 
radiologic protocol throughout the remainder of the study).  Results must be reviewed by the investigator before dosing at the next 
cycle.  
x An imaging assessment at screening is optional; the first documented recurrence prior to crossover can serve as the baseline 
imaging assessment. 
y Criteria for diagnosis of recurrence are described in Section 4.5.5. 
z Information on survival follow-up and new anti-cancer therapy (including targeted therapy and immunotherapy) will be collected by 
means of telephone calls or telemedicine, patient medical records, and/or clinic visits approximately every 12 weeks ( 21 days) until 
death (unless the patient withdraws consent or the Sponsor terminates the study).  If the patient withdraws from study, the study staff 
may use a public information source (e.g., county records) to obtain information about survival status only. 
 

 
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
127/Protocol WO41535, Version 6 
Appendix 3  
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples  
Visit 
Timepoint 
Arm A Samples a 
Arm B Samples a 
Screening (Days 
28 to 1) 
At visit 
Biomarker (plasma) 
Biomarker (plasma) 
Day 1 of Cycle 1 
At visit (prior to any 
drug administration 
for Arm A 
Atezolizumab PK (serum) 
Atezolizumab ADA (serum) 
Biomarker (WES) (blood) b 
Biomarker (plasma, serum) c 
Biomarker (WES) 
(blood) b 
Biomarker  
(plasma, serum) c 
 
 
30 min 
( 10 minutes) after 
end of 
atezolizumab 
infusion 
Atezolizumab PK (serum) 
 
Day 1 of Cycle 2 
Prior to any drug 
administration 
Atezolizumab PK (serum) 
Atezolizumab ADA (serum) 
 
Day 1 of Cycle 3 
At visit (prior to any 
drug administration 
for Arm A) 
Atezolizumab PK (serum) 
Atezolizumab ADA (serum) 
Biomarker (plasma, serum) c 
Biomarker  
(plasma, serum) c 
Day 1 of Cycle 4 
Prior to any drug 
administration 
Atezolizumab PK (serum) 
Atezolizumab ADA (serum) 
 
Day 1 of Cycle 5 
At visit (prior to any 
drug administration 
for Arm A) 
Biomarker (plasma, serum) c 
Biomarker  
(plasma, serum) c 
Day 1 of Cycle 7 
At visit (prior to any 
drug administration 
for Arm A) 
Biomarker (plasma, serum) c 
Biomarker  
(plasma, serum) c 
Day 1 of Cycle 8 
Prior to any drug 
administration 
Atezolizumab PK (serum) 
Atezolizumab ADA (serum) 
 
Day 1 of Cycle 9 
At visit (prior to any 
drug administration 
for Arm A) 
Biomarker (plasma, serum) c 
Biomarker  
(plasma, serum) c 
Day 1 of Cycle 11 
At visit (prior to any 
drug administration 
for Arm A) 
Biomarker (plasma, serum) c 
Biomarker  
(plasma, serum) c 
Day 1 of Cycle 12 
Prior to any drug 
administration 
Atezolizumab PK (serum) 
Atezolizumab ADA (serum) 
 
Day 1 of Cycle 15 
At visit (prior to any 
drug administration 
for Arm A) 
Biomarker (plasma, serum) c 
Biomarker  
(plasma, serum) c 
Day 1 of Cycle 16 
Prior to any drug 
administration 
Atezolizumab PK (serum) 
Atezolizumab ADA (serum) 
 

Appendix 3: Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples 
(cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
128/Protocol WO41535, Version 6 
Visit 
Timepoint 
Arm A Samples a 
Arm B Samples a 
Treatment/ 
surveillance 
discontinuation 
( 30 days after 
final cycle) 
At visit 
Atezolizumab PK (serum) 
Atezolizumab ADA (serum) 
Biomarker (plasma, serum) c 
Biomarker (plasma, 
serum) c 
Long-term follow-
up period, through 
Year 3 after 
randomization d 
At imaging 
assessment visits 
Biomarker (plasma, serum) c 
Biomarker (plasma, 
serum) c 
ADA  anti-drug antibody; PK  pharmacokinetic; WES  whole exome sequencing. 
Note: PK, ADA, and biomarker samples will not be taken in patients randomized to Arm B who 
cross over to treatment with atezolizumab plus bevacizumab 
a With the exception of the PK sample to be collected 30 minutes after the infusion on Day 1 of 
Cycle 1, all other PK, ADA, and biomarker samples can be collected  96 hours before 
Day 1 of each cycle. 
b Not applicable for a site that has not been granted approval for WES.  If collection of the 
WES sample is missed at Cycle 1 Day 1, this sample may be collected at any other time 
during the study. 
c At the time of disease recurrence (or the next visit if disease recurrence occurs at an 
unscheduled visit), biomarker samples will be collected either at the treatment/surveillance 
discontinuation visit or the imaging assessment visit.  Following collection of biomarker 
samples at the time of disease recurrence, subsequent biomarker sample collection is not 
required. 
d During the long-term follow-up period, biomarker sample will be collected at the first imaging 
assessment and all subsequent imaging assessments ( 6 weeks) through Year 3 after 
randomization or until disease recurrence, whichever comes first. 
 

 
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Appendix 4  
Child-Pugh Classification 
Scoring 
Measure 
Points Scored for Observed Finding 
1 Point 
2 Points 
3 Points 
Bilirubin (mg/dL) 
 2.0 
2.03.0 
 3.0 
Albumin (g/dL) 
 3.5 
2.83.5 
 2.8 
Prothrombin time, a 
seconds over control 
1.03.0 
4.06.0  
 6.0 
International normalized 
ratio 
 1.7 
1.72.3 
 2.3
Ascites 
None 
Mild to moderate 
(diuretic responsive) 
Severe 
(diuretic 
refractory) 
Encephalopathy (grade) 
None 
Mild to moderate 
(Grade 1 or 2) 
Severe 
(Grade 3 or 4) 
a Prolonged time. 
 
Classification 
Points 
Class 
56 
A 
79 
B 
1015 
C 
 
References 
Child CG, Turcotte JG. Surgery and portal hypertension. In: The liver and portal 
hypertension. Edited by Child CG. Philadelphia, Saunders;1964:5064. 
Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus 
for bleeding oesophageal varices. Br J Surg 1973;60:6469.

 
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Appendix 5  
Classification of Hepatocellular Carcinoma 
with Vascular Invasion 
Figure 1 shows the classification of portal vein tumor invasion according to the Liver 
Cancer Study Group of Japan classification (Costentin et al. 2017). 
Figure 1 Classification of Portal Vein Tumor Invasion 
 
 
 

Appendix 5: Classification of Hepatocellular Carcinoma with Vascular Invasion (cont.) 
  
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Table 1 
Definition of Types of Vascular Invasion in HCC 
Type of 
vascular 
invasion 
Classification 
Definition 
Eligible for 
IMbrave050 
Portal vein 
Vp0 
No evidence of tumor thrombus 
invasion 
Yes a 
Vp1 
Tumor thrombus distal to but not in the 
second-order branches 
Yes a 
Vp2 
Tumor thrombus in the second-order 
branches 
Yes 
Vp3 
Tumor thrombus in the first-order 
branches 
No 
Vp4 
Tumor thrombus in the main trunk or 
contralateral or both 
No 
Hepatic vein 
Vv0 
Absence of tumor thrombus invasion of 
the hepatic vein 
Yes 
Vv1 
Tumor thrombus invasion of peripheral 
branches of the hepatic vein 
No 
Vv2 
Tumor thrombus invasion of the right, 
middle, or left hepatic vein, the inferior 
right hepatic vein, or the short hepatic 
vein 
No 
Vv3 
Tumor thrombus invasion of the inferior 
vena cava. 
No 
Microvascular 
invasion 
N/A 
Presence of microscopic thrombi within 
the central hepatic vein, the portal vein, 
or large capsular vessels 
Yes 
a Only allowed for patients undergoing resection. 
 
REFERENCES 
Costentin CE, Ferrone CR, Arellano RS, et al. Hepatocellular carcinoma with 
macrovascular invasion: defining the optimal treatment strategy. Liver Cancer 
2017;6:36074. 
 

 
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Appendix 6  
EASL Clinical Practice Guidelines:  Diagnostic Algorithm and 
Recall Policy in Cirrhotic Liver 
 
APHE  arterial phase hyper-enhancement; CT  computed tomography; EASL  European 
Association for the Study of the Liver; HCC  hepatocellular carcinoma; IRF  Independent 
Review Facility; mo  months; MR  magnetic resonance; MRI  magnetic resonance imaging; 
US  ultrasound. 
* 
Using extracellular MR contrast agents or gadobenate dimeglumine. 
** 
Using the following diagnostic criteria: APHE and washout on the portal venous phase.  
*** Using the following diagnostic criteria:  APHE and mild washout after 60 seconds.  Please 
note, contrast enhanced-US cannot be used by the IRF to determine recurrence. 
**** Lesion  1 cm stable for 12 months (three controls after 4 months) can be shifted back to 
regular 6-month surveillance.  
***** Optional for center-based programmes. 
 
REFERENCE 
EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma.  
J Hepatol. 2018;69:182236.

 
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Appendix 7  
Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1 
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1 (Eisenhauer et al. 2009) are presented below, with slight modifications from 
the original publication and the addition of explanatory text as needed for clarity.1 
TUMOR MEASURABILITY 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as described below.  All measurable and non-measurable lesions 
should be assessed at screening and at subsequent protocol-specified tumor 
assessment timepoints.  Additional assessments may be performed as clinically 
indicated for suspicion of progression. 
DEFINITION OF MEASURABLE LESIONS 
Tumor Lesions 
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size as follows:  
 
10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval  5 mm) 
 
10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable) 
 
20 mm by chest X-ray 
 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be 
 15 mm in the short axis when assessed by CT scan (CT scan slice thickness 
recommended to be  5 mm).  At baseline and follow-up, only the short axis will be 
measured and followed.  Additional information on lymph node measurement is provided 
below (see "Identification of Target and Non-Target Lesions" and "Calculation of Sum of 
Diameters"). 
                                            
 
1 For clarity and for consistency within this document, the section numbers and cross-references 
to other sections within the article have been deleted and minor changes have been made. 

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DEFINITION OF NON-MEASURABLE LESIONS 
Non-measurable tumor lesions encompass small lesions (longest diameter  10 mm or 
pathological lymph nodes with short axis  10 mm but  15 mm) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques. 
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
Bone Lesions: 
 
Technetium-99m bone scans, sodium fluoride positron emission tomography scans, 
and plain films are not considered adequate imaging techniques for measuring bone 
lesions.  However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
 
Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue 
components that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered measurable lesions if the soft tissue component 
meets the definition of measurability described above. 
 
Blastic bone lesions are non-measurable. 
 
Cystic Lesions: 
 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 
Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 
Lesions with Prior Local Treatment: 
 
Tumor lesions situated in a previously irradiated area or in an area subjected to 
other loco-regional therapy are usually not considered measurable unless there has 
been demonstrated progression in the lesion.  
 

Appendix 7: Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 (cont.) 
  
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METHODS FOR ASSESSING LESIONS 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option. 
CLINICAL LESIONS 
Clinical lesions will only be considered measurable when they are superficial and 
 10 mm in diameter as assessed using calipers (e.g., skin nodules).  For the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size 
of the lesion, is suggested. 
CHEST X-RAY 
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions.  
However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
CT AND MRI SCANS 
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  In this guideline, the definition of measurability of lesions on 
CT scan is based on the assumption that CT slice thickness is  5 mm.  When CT scans 
have slice thickness of  5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable.  
If prior to enrollment it is known that a patient is unable to undergo CT scans with IV 
contrast because of allergy or renal insufficiency, the decision as to whether a non-
contrast CT or MRI (without IV contrast) will be used to evaluate the patient at baseline 
and during the study should be guided by the tumor type under investigation and the 
anatomic location of the disease.  For patients who develop contraindications to contrast 
after baseline contrast CT is done, the decision as to whether non-contrast CT or MRI 
(enhanced or non-enhanced) will be performed should also be based on the tumor type 
and the anatomic location of the disease, and should be optimized to allow for 
comparison with the prior studies if possible.  Each case should be discussed with the 
radiologist to determine if substitution of these other approaches is possible and, if not, 
the patient should be considered not evaluable from that point forward.  Care must be 
taken in measurement of target lesions and interpretation of non-target disease or new 

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lesions on a different modality, since the same lesion may appear to have a different 
size using a new modality. 
ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOR MARKERS, 
CYTOLOGY, HISTOLOGY 
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be 
used for objective tumor evaluation. 
ASSESSMENT OF TUMOR BURDEN 
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements. 
IDENTIFICATION OF TARGET AND NON-TARGET LESIONS 
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one 
or two organ sites involved, a maximum of two lesions (one site) and four lesions 
(two sites), respectively, will be recorded.  Other lesions (albeit measurable) in those 
organs will be considered non-target lesions.   
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and should be representative of all involved organs, but in addition should lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be 
selected. 
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of  15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Lymph node size is 
normally reported as two dimensions in the plane in which the image is obtained (for CT, 
this is almost always the axial plane; for MRI, the plane of acquisition may be axial, 
sagittal, or coronal).  The smaller of these measures is the short axis.  For example, an 
abdominal node that is reported as being 20 mm  30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node.  In this example, 20 mm should be recorded 
as the node measurement.  All other pathological nodes (those with short axis  10 mm 

Appendix 7: Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 (cont.) 
  
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but  15 mm) should be considered non-target lesions.  Nodes that have a short axis of 
 10 mm are considered non-pathological and should not be recorded or followed. 
All lesions (or sites of disease) not selected as target lesions (measurable or 
non-measurable), including pathological lymph nodes, should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements are not required.  It is 
possible to record multiple non-target lesions involving the same organ as a single item 
on the Case Report Form (CRF; e.g., "multiple enlarged pelvic lymph nodes" or "multiple 
liver metastases"). 
CALCULATION OF SUM OF DIAMETERS 
A sum of the diameters (longest diameter for nonlymph node lesions, short axis for 
lymph node lesions) will be calculated for all target lesions at baseline and at each 
subsequent tumor assessment as a measure of tumor burden. 
Measuring Lymph Nodes 
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the node regresses to  10 mm during the study.  Thus, when 
lymph nodes are included as target lesions, the sum of diameters may not be zero even 
if complete response criteria are met, since a normal lymph node is defined as having a 
short axis of  10 mm. 
Measuring Lesions That Become Too Small to Measure 
During the study, all target lesions (lymph node and nonlymph node) recorded at 
baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm).  However, sometimes lesions or lymph 
nodes that are recorded as target lesions at baseline become so faint on CT scan that 
the radiologist may not feel comfortable assigning an exact measurement and may 
report them as being too small to measure.  When this occurs, it is important that a value 
be recorded on the CRF, as follows: 
 
If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. 
 
If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and "too small to measure" should be 
ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat 
such as in the retroperitoneum; however, if a lymph node is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well and "too small to measure" should also be 
ticked). 

Appendix 7: Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 (cont.) 
  
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To reiterate, however, if the radiologist is able to provide an actual measurement, that 
should be recorded, even if it is  5 mm, and in that case "too small to measure" should 
not be ticked. 
Measuring Lesions That Split or Coalesce on Treatment 
When nonlymph node lesions fragment, the longest diameters of the fragmented 
portions should be added together to calculate the sum of diameters.  Similarly, as 
lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximum longest diameter for the coalesced lesion. 
EVALUATION OF NON-TARGET LESIONS 
Measurements are not required for non-target lesions, except that malignant lymph node 
non-target lesions should be monitored for reduction to  10 mm in short axis.  
Non-target lesions should be noted at baseline and should be identified as "present" or 
"absent" and (in rare cases) may be noted as "indicative of progression" at subsequent 
evaluations.  In addition, if a lymph node lesion shrinks to a non-malignant size (short 
axis  10 mm), this should be captured on the CRF as part of the assessment of non-
target lesions. 
RESPONSE CRITERIA 
CRITERIA FOR TARGET LESIONS 
Definitions of the criteria used to determine objective tumor response for target lesions 
are provided below: 
 
Complete response (CR):  Disappearance of all target lesions 
Any pathological lymph nodes must have reduction in short axis to  10 mm. 
 
Partial response (PR):  At least a 30% decrease in the sum of diameters of all target 
lesions, taking as reference the baseline sum of diameters, in the absence of CR 
 
Progressive disease (PD):  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum of diameters at prior timepoints 
(including baseline)  
In addition to the relative increase of 20%, the sum of diameters must also 
demonstrate an absolute increase of  5 mm. 
 
Stable disease (SD):  Neither sufficient shrinkage to qualify for CR or PR nor 
sufficient increase to qualify for PD 
 

Appendix 7: Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 (cont.) 
  
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CRITERIA FOR NON-TARGET LESIONS 
Definitions of the criteria used to determine the tumor response for the group of non-
target lesions are provided below.  While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints specified in the schedule of activities. 
 
CR:  Disappearance of all non-target lesions and (if applicable) normalization of 
tumor marker level 
All lymph nodes must be non-pathological in size ( 10 mm short axis). 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits 
 
PD:  Unequivocal progression of existing non-target lesions 
 
SPECIAL NOTES ON ASSESSMENT OF PROGRESSION OF NON-TARGET 
LESIONS 
Patients with Measurable and Non-Measurable Disease 
For patients with both measurable and non-measurable disease to achieve unequivocal 
progression on the basis of the non-target lesions, there must be an overall level of 
substantial worsening in non-target lesions in a magnitude that, even in the presence of 
SD or PR in target lesions, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest increase in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status.  The 
designation of overall progression solely on the basis of change in non-target lesions in 
the face of SD or PR in target lesions will therefore be extremely rare. 
Patients with Non-Measurable Disease Only  
For patients with non-measurable disease only, the same general concepts apply as 
noted above.  However, in this instance there is no measurable disease assessment to 
factor into the interpretation of an increase in non-measurable disease burden.  Because 
worsening in non-measurable disease cannot be easily quantified (by definition, if all 
lesions are truly non-measurable), a useful test that can be applied when assessing 
patients for unequivocal progression is to consider if the increase in overall disease 
burden based on the change in non-measurable disease is comparable in magnitude to 
the increase that would be required to declare PD for measurable disease, that is, an 
increase in tumor burden representing an additional 73% increase in volume (which is 
equivalent to a 20% increase in diameter in a measurable lesion).  Examples include an 
increase in a pleural effusion from "trace" to "large" or an increase in lymphangitic 
disease from localized to widespread  If unequivocal progression is seen, the patient 
should be considered to have had overall PD at that point.  While it would be ideal to 
have objective criteria to apply to non-measurable disease, the very nature of that 
disease makes it impossible to do so; therefore, the increase must be substantial. 

Appendix 7: Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 (cont.) 
  
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NEW LESIONS 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some "new" bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient's baseline lesions show PR or 
CR.  For example, necrosis of a liver lesion may be reported on a CT scan report as a 
"new" cystic lesion, which it is not. 
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, progression should be declared using the date of the 
initial scan. 
CRITERIA FOR OVERALL RESPONSE AT A SINGLE TIMEPOINT 
Table 1 provides a summary of the overall response status calculation at each response 
assessment timepoint for patients who have measurable disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used.  

Appendix 7: Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 (cont.) 
  
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Table 1 
Criteria for Overall Response at a Single Timepoint:  Patients 
with Target Lesions (with or without Non-Target Lesions) 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR  complete response; NE  not evaluable; PD  progressive disease; PR  partial 
response; SD  stable disease. 
 
Table 2 
Criteria for Overall Response at a Single Timepoint:  Patients 
with Non-Target Lesions Only  
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD a 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or no 
PD 
Any 
Yes 
PD 
CR  complete response; NE  not evaluable; PD  progressive disease. 
a "Non-CR/non-PD" is preferred over "stable disease" for non-target 
disease since stable disease is increasingly used as an endpoint for 
assessment of efficacy in some trials; thus, assigning "stable disease" 
when no lesions can be measured is not advised. 
 
MISSING ASSESSMENTS AND NOT-EVALUABLE DESIGNATION 
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If measurements are made on only a subset of target 
lesions at a timepoint, usually the case is also considered not evaluable at that 
timepoint, unless a convincing argument can be made that the contribution of the 
individual missing lesions would not change the assigned timepoint response.  This 

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would be most likely to happen in the case of PD.  For example, if a patient had a 
baseline sum of 50 mm with three measured lesions and during the study only two 
lesions were assessed, but those gave a sum of 80 mm, the patient will have achieved 
PD status, regardless of the contribution of the missing lesion.  
SPECIAL NOTES ON RESPONSE ASSESSMENT 
Patients with a global deterioration in health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
"symptomatic deterioration."  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target lesions as shown in Table 1 and Table 2. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
REFERENCES 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:22847.  

 
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Appendix 8  
IL42–European Organisation for the Research and Treatment of 
Cancer QLQ-C30 (Reduced) 
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to 
be completed in this study. 
 

 
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Appendix 9  
EQ-5D-5L 
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to 
be completed in this study. 
 

Appendix 9: EQ-5D-5L (cont.) 
  
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Appendix 10  
Preexisting Autoimmune Diseases and Immune Deficiencies 
Patients should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease.  Patients with any history of immune 
deficiencies or autoimmune disease listed in the table below are excluded from 
participating in the study.  Possible exceptions to this exclusion could be patients with a 
medical history of such entities as atopic disease or childhood arthralgias where the 
clinical suspicion of autoimmune disease is low.  Patients with a history of 
autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone 
may be eligible for this study.  In addition, transient autoimmune manifestations of an 
acute infectious disease that resolved upon treatment of the infectious agent are not 
excluded (e.g., acute Lyme arthritis).  Caution should be used when considering 
atezolizumab for patients who have previously experienced a severe or lifethreatening 
skin adverse reaction or pericardial disorder while receiving another immunostimulatory 
anti-cancer agent.  The Medical Monitor is available to advise on any uncertainty over 
autoimmune exclusions. 
Autoimmune Diseases and Immune Deficiencies 
 Acute disseminated 
encephalomyelitis 
 Addison disease 
 Ankylosing spondylitis 
 Antiphospholipid antibody 
syndrome 
 Aplastic anemia 
 Autoimmune hemolytic 
anemia 
 Autoimmune hepatitis 
 Autoimmune 
hypoparathyroidism 
 Autoimmune hypophysitis 
 Autoimmune myelitis 
 Autoimmune myocarditis 
 Autoimmune oophoritis 
 Autoimmune orchitis 
 Autoimmune 
thrombocytopenic purpura 
 Behçet disease 
 Bullous pemphigoid 
 Chronic fatigue syndrome 
 Chronic inflammatory 
demyelinating 
polyneuropathy 
 Crohn disease  
 Churg-Strauss syndrome 
 Dermatomyositis 
 Diabetes mellitus type 1 
 Dysautonomia 
 Epidermolysis bullosa 
acquisita 
 Gestational pemphigoid 
 Giant cell arteritis 
 Goodpasture syndrome 
 Graves disease 
 Guillain-Barré syndrome 
 Hashimoto disease 
 IgA nephropathy 
 Inflammatory bowel disease 
 Interstitial cystitis 
 Kawasaki disease 
 Lambert-Eaton myasthenia 
syndrome 
 Lupus erythematosus 
 Lyme disease, chronic 
 Meniere syndrome 
 Mooren ulcer 
 Morphea 
 Multiple sclerosis 
 Myasthenia gravis 
 Neuromyotonia 
 Opsoclonus myoclonus 
syndrome 
 Optic neuritis 
 Ord thyroiditis 
 Pemphigus 
 Pernicious anemia 
 Polyarteritis nodosa 
 Polyarthritis 
 Polyglandular 
autoimmune syndrome 
 Primary biliary cholangitis 
 Psoriasis 
 Reiter syndrome 
 Rheumatoid arthritis 
 Sarcoidosis 
 Scleroderma 
 Sjögren syndrome 
 Stiff-Person syndrome 
 Takayasu arteritis 
 Ulcerative colitis 
 Vitiligo 
 Vogt-Koyanagi-Harada 
disease 
 Granulomatosis with 
Polyangiitis  

 
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Appendix 11  
Anaphylaxis Precautions 
These guidelines are intended as a reference and should not supersede pertinent local 
or institutional standard operating procedures. 
REQUIRED EQUIPMENT AND MEDICATION 
The following equipment and medication are needed in the event of a suspected 
anaphylactic reaction during study treatment infusion: 
 
Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer 
 
Oxygen 
 
Epinephrine for subcutaneous, intramuscular, intravenous, and/or endotracheal 
administration in accordance with institutional guidelines 
 
Antihistamines 
 
Corticosteroids 
 
Intravenous infusion solutions, tubing, catheters, and tape 
 
PROCEDURES 
In the event of a suspected anaphylactic reaction during study treatment infusion, 
the following procedures should be performed: 
1. 
Stop the study treatment infusion. 
2. 
Call for additional medical assistance. 
3. 
Maintain an adequate airway. 
4. 
Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring if possible. 
5. 
Administer antihistamines, epinephrine, or other medications and IV fluids as 
required by patient status and as directed by the physician in charge. 
6. 
Continue to observe the patient and document observations. 
 

 
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Appendix 12  
Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
DOSE MODIFICATIONS 
There will be no dose modifications for atezolizumab or bevacizumab in this study. 
TREATMENT INTERRUPTION 
Atezolizumab treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment.  If corticosteroids are initiated for treatment 
of the toxicity, they must be tapered over  1 month to the equivalent of  10 mg/day oral 
prednisone before atezolizumab can be resumed.  If atezolizumab is withheld for 
 12 weeks after event onset, the patient will be discontinued from atezolizumab.  
However, atezolizumab may be withheld for  12 weeks to allow for patients to taper off 
corticosteroids prior to resuming treatment.  Atezolizumab can be resumed after being 
withheld for  12 weeks if the patient is likely to derive clinical benefit.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator's 
benefitrisk assessment and documented by the investigator.  The Medical Monitor is 
available to advise as needed.  Atezolizumab treatment may be suspended for reasons 
other than toxicity (e.g., surgical procedures).  The acceptable length of treatment 
interruption must be based on of the investigator’s benefitrisk assessment and in 
alignment with the protocol requirements for the duration of treatment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
Bevacizumab treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment.  If the event resolves to Grade  1, 
bevacizumab may be restarted at the same dose level.  If bevacizumab is delayed due 
to toxicity for  42 days beyond when the next dose should have been given, the patient 
must be permanently discontinued from bevacizumab.  Bevacizumab can be resumed 
after being withheld for  42 days if the patient is likely to derive clinical benefit. 
Atezolizumab or bevacizumab treatment may be suspended for reasons other than 
toxicity (e.g., surgical procedures).  The investigator will determine the acceptable length 
of treatment interruption.  If atezolizumab is discontinued, bevacizumab should also be 
discontinued.  If bevacizumab is discontinued, atezolizumab can be continued.  If 
atezolizumab is transiently withheld for adverse events, bevacizumab should also be 
held. 
Refer to Section 4.3.2 for information on dose interruptions for reasons other than 
toxicity. 

Appendix 12: Overall Guidelines for Management of Patients Who Experience 
Adverse Events (cont.) 
  
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MANAGEMENT GUIDELINES  
Guidelines for management of patients who experience specific adverse events are 
provided in Table 1. 
Table 1 
Guidelines for Management of Patients Who Experience Specific 
Adverse Events with AtezolizumabBevacizumab 
Event 
Action to Be Taken 
IRRs, anaphylaxis, and 
hypersensitivity reactions 
 Guidelines for management of IRRs for atezolizumab are 
provided in Appendix 13. 
 Guidelines for management of IRRs for bevacizumab are 
provided below. 
 For anaphylaxis precautions, see Appendix 11. 
 For hypersensitivity reactions and allergic reactions, 
permanently discontinue the causative agent. 
IRR to bevacizumab, 
Grade 1  
 Systemic intervention is not indicated.  Continue bevacizumab. 
IRR to bevacizumab,  
Grade 2  
 Reduce infusion rate to  50% or interrupt infusion at the 
discretion of the investigator per medical judgment.  
 If the infusion is interrupted, it may be resumed at  50% of the 
rate prior to the reaction after the patient's symptoms have 
adequately resolved and increased in 50% increments up to 
the full rate if well tolerated.  Infusions may be restarted at the 
full rate during the next cycle. 
IRR to bevacizumab,  
Grade 3 or 4 
 Stop infusion and permanently discontinue bevacizumab.  
 Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, antipyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen) if clinically indicated. 
IRR  infusion-related reaction. 

Appendix 12: Overall Guidelines for Management of Patients Who Experience 
Adverse Events (cont.) 
  
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Table 1 
Guidelines for Management of Patients Who Experience Specific 
Adverse Events with AtezolizumabBevacizumab (cont.)  
Event 
Action to Be Taken 
Gastrointestinal toxicity 
GI perforation, any 
grade 
 Withhold atezolizumab. 
 Permanently discontinue bevacizumab.  
 Initiate treatment per institutional guidelines. 
 If event improves, consider resuming atezolizumab.  If not, 
permanently discontinue atezolizumab. a 
Bowel obstruction, 
Grade 2 
 Atezolizumab may be continued at the discretion of the 
investigator. 
 Withhold bevacizumab for partial obstruction requiring medical 
intervention. 
 Bevacizumab may be restarted upon complete resolution of 
event. 
Bowel obstruction, 
Grade 3 or 4 
 Atezolizumab may be continued at the discretion of the 
investigator.  
 Withhold bevacizumab until complete resolution. 
 If surgery is necessary, patient may restart bevacizumab after full 
recovery from surgery and at the investigator's discretion. 
Posterior reversible encephalopathy syndrome 
Posterior reversible 
encephalopathy 
syndrome, any grade 
confirmed by magnetic 
resonance imaging 
 Withhold atezolizumab.  Permanently discontinue bevacizumab. 
 If event improves, consider resuming atezolizumab.  If not, 
permanently discontinue atezolizumab. a 
GI  gastrointestinal. 
a Resumption of treatment may be considered if the investigator believes the patient is likely to 
derive clinical benefit. 
 

Appendix 12: Overall Guidelines for Management of Patients Who Experience 
Adverse Events (cont.) 
  
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Table 1 
Guidelines for Management of Patients Who Experience Specific 
Adverse Events with AtezolizumabBevacizumab (cont.)  
Hypertension a, b 
General guidance  
 Treat with antihypertensive medication as needed.  
Hypertension, Grade 1 
 Continue atezolizumab and bevacizumab. 
 Consider increased BP monitoring. 
Hypertension,  
Grade 2  
 Continue atezolizumab.  
 If asymptomatic, begin or modify baseline anti-hypertensive 
therapy and continue bevacizumab.  
 If symptomatic, start or adjust anti-hypertensive therapy. 
Hypertension, Grade 3 
 Continue atezolizumab.  
 Modify existing anti-hypertensive therapy (more than one drug or 
more intensive therapy than previously indicated). 
 Withhold bevacizumab until symptoms resolve AND BP 
 160/90 mmHg 
Hypertension, Grade 4 
 Atezolizumab may be continued at the discretion of the 
investigator.  
 Permanently discontinue bevacizumab.  
Hemorrhage 
Hemorrhage, Grade 3 or 
4 (excluding cerebral 
hemorrhage) 
 Continue atezolizumab.   
 Permanently discontinue bevacizumab.  
CNS hemorrhage, any 
grade 
 Atezolizumab may be continued at the discretion of the 
investigator.   
 Permanently discontinue bevacizumab.  
Grade  2 hemoptysis 
( 2.5 mL of bright red 
blood per episode) 
 Continue atezolizumab.   
 Permanently discontinue bevacizumab. 
Bleeding in patients on 
full-dose anticoagulant 
therapy  
 Continue atezolizumab.   
 Permanently discontinue bevacizumab. 
BP  blood pressure. 
a Vascular disorders (including hypertension and hypotension) are possible adverse events of 
atezolizumab, considering the mechanism of action. 
b Based on an average of at least three blood pressure readings at two or more sessions. 
 
 

Appendix 12: Overall Guidelines for Management of Patients Who Experience 
Adverse Events (cont.) 
  
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Table 1 
Guidelines for Management of Patients Who Experience Specific 
Adverse Events with AtezolizumabBevacizumab (cont.)  
Event 
Action to Be Taken 
Thromboembolic events 
Venous thromboembolic 
event, Grade 3 
 Atezolizumab may be continued at the discretion of the 
investigator.   
 Withhold bevacizumab treatment.  If the planned duration of 
full-dose anticoagulation is  2 weeks, bevacizumab should 
be withheld until the full-dose anticoagulation period is over.  
The use of direct oral anticoagulants is not recommended. 
 If the planned duration of full-dose anticoagulation is  2 
weeks, bevacizumab may be resumed during full-dose 
anticoagulation IF all of the criteria below are met: 
– 
The patient must not have pathological conditions that 
carry high risk of bleeding (e.g., tumor involving major 
vessels or other conditions). 
– 
The patient must not have had hemorrhagic events 
Grade  2 while on study. 
– 
The patient must be on stable dose of heparin, 
low-molecular-weight heparin, or have an in-range INR 
(usually 23) on a stable dose of warfarin prior to 
restarting bevacizumab. 
 If thromboemboli worsen/recur upon resumption of study 
therapy, discontinue bevacizumab.  
Venous thromboembolic 
event, Grade 4 
 Atezolizumab may be continued at the discretion of the 
investigator.   
 Permanently discontinue bevacizumab. 
Arterial thromboembolic 
event, any grade 
 Atezolizumab may be continued at the discretion of the 
investigator. 
 Permanently discontinue bevacizumab.  
 

Appendix 12: Overall Guidelines for Management of Patients Who Experience 
Adverse Events (cont.) 
  
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Table 1 
Guidelines for Management of Patients Who Experience Specific 
Adverse Events with AtezolizumabBevacizumab (cont.)  
Event 
Action to Be Taken 
Proteinuria 
Proteinuria, Grade 1 
(1 by dipstick; urinary 
protein  1.0 g/24 hours) 
 Continue atezolizumab and bevacizumab. 
Proteinuria, Grade 2  
(2 and 3  by dipstick; 
urinary protein 1.03.4 g/24 
hours) 
 Continue atezolizumab. 
 For 2 dipstick:  Continue bevacizumab and collect 24-hour 
urine protein a prior to subsequent bevacizumab 
administration. 
 For 3 dipstick:  Obtain 24-hour urine a prior to administering 
bevacizumab. 
 Withhold bevacizumab for urinary protein  2 g/24 hours. 
 If bevacizumab is withheld and urine protein improves to 
 2 g/24 hours  42 days after event onset, resume 
bevacizumab.  If not, permanently discontinue bevacizumab.  
Proteinuria, Grade 3  
(4  by dipstick; 
urinary protein 
 3.5 g/24 hours) with no 
diagnosis of nephrotic 
syndrome 
 Atezolizumab may be continued at the discretion of the 
investigator. 
 Withhold bevacizumab. 
 If urine protein improves to  2 g/24 hours  42 days after 
event onset, resume bevacizumab.  If not, permanently 
discontinue bevacizumab.  
Nephrotic syndrome, 
Grade 3 or 4 
 Atezolizumab may be continued at the discretion of the 
investigator.   
 Permanently discontinue bevacizumab.  
Fistula 
Fistula formation 
involving an internal 
organ, any grade 
 Withhold atezolizumab.   
 Permanently discontinue bevacizumab.  
 If event improves, consider resuming atezolizumab.  If not, 
permanently discontinue atezolizumab. b 
Fistula formation 
not involving an 
internal organ, 
Grade 4 
 Withhold atezolizumab.   
 Permanently discontinue bevacizumab. 
 If event improves, consider resuming atezolizumab.  If not, 
permanently discontinue atezolizumab. b 
a An alternative method such as protein:creatinine ratio, per local guidance can be accepted.  
b Resumption of treatment may be considered if the investigator believes the patient is likely 
to derive clinical benefit. 

Appendix 12: Overall Guidelines for Management of Patients Who Experience 
Adverse Events (cont.) 
  
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154/Protocol WO41535, Version 6 
Table 1 
Guidelines for Management of Patients Who Experience Specific 
Adverse Events with AtezolizumabBevacizumab (cont.)  
Event 
Action to Be Taken 
Wound dehiscence 
Wound dehiscence, any grade 
requiring medical or surgical 
therapy 
 Atezolizumab may be continued at the discretion of the 
investigator.   
 Permanently discontinue bevacizumab.  
Congestive heart failure 
Congestive heart failure,  
Grade 3 or 4 
 Atezolizumab may be continued at the discretion of the 
investigator.   
 Permanently discontinue bevacizumab.  
Bevacizumab-related toxicities not described above 
Grade 1 or 2 
 Continue atezolizumab and bevacizumab. 
Grade 3 
 Continue atezolizumab.  Withhold bevacizumab. 
 If event resolves to Grade 2 or better  42 days after event 
onset, resume bevacizumab.  If not, permanently 
discontinue bevacizumab. a 
Grade 4 
 Withhold atezolizumab and bevacizumab. 
 If event improves, consider resuming atezolizumab.  If not, 
permanently discontinue atezolizumab. a 
 If event resolves to Grade 2 or better  42 days after event 
onset, resume bevacizumab.  If not, permanently 
discontinue bevacizumab. a 
Atezolizumab-related toxicities not described above 
Grade 1 or 2 
 Follow guidelines for atezolizumab in Appendix 13. 
 Continue bevacizumab. 
Grade 3 or 4 
 Follow guidelines for atezolizumab in Appendix 13. 
 Withhold bevacizumab. 
 If event resolves to Grade 2 or better  42 days after event 
onset, resume bevacizumab.  If not, permanently 
discontinue bevacizumab. a 
a Resumption of treatment may be considered if the investigator believes the patient is likely 
to derive clinical benefit. 

 
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155/Protocol WO41535, Version 6 
Appendix 13  
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab  
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology, 
when clinically indicated. 
Although most immune-mediated adverse events observed with atezolizumab have 
been mild and self-limiting, such events should be recognized early and treated promptly 
to avoid potential major complications.  Discontinuation of atezolizumab may not have 
an immediate therapeutic effect, and in severe cases, immune-mediated toxicities may 
require acute management with topical corticosteroids, systemic corticosteroids, or other 
immunosuppressive agents.  
The following are general recommendations for management of any other adverse 
events that may occur and are not specifically listed in the following subsections.  
 
Patients and family caregivers should receive timely and up-to-date information 
about immunotherapies, their mechanism of action, and the clinical profile of 
possible immune-related adverse events prior to initiating therapy and throughout 
treatment and survival follow-up.  There should be a high level of suspicion that new 
symptoms are treatment related. 
 
In general, atezolizumab therapy should be continued with close monitoring for 
Grade 1 toxicities, with the exception of some neurologic toxicities. 
 
Consider holding atezolizumab for most Grade 2 toxicities and resume when 
symptoms and/or laboratory values resolve to Grade 1 or better.  Corticosteroids 
(initial dose of 0.5-1 mg/kg/day of prednisone or equivalent) may be administered. 
 
For Grade 2 recurrent or persistent (lasting for more than 5 days) events, treat as a 
Grade 3 event.   
 
Hold atezolizumab for Grade 3 toxicities and initiate treatment with high-dose 
corticosteroids (1-2 mg/kg/day prednisone or equivalent).  Corticosteroids should be 
tapered over 1 month to 10 mg/day oral prednisone or equivalent, before 
atezolizumab can be resumed.  If symptoms do not improve within 48 to 72 hours of 
high-dose corticosteroid use, other immunosuppressants may be offered for some 
toxicities. 
 
In general, Grade 4 toxicities warrant permanent discontinuation of atezolizumab 
treatment, with the exception of endocrinopathies that are controlled by 
hormone-replacement therapy. 
 
The investigator should consider the benefitrisk balance a given patient prior to further 
administration of atezolizumab.  Resumption of atezolizumab may be considered in 
patients who are deriving benefit and have  fully recovered from the immune-mediated 
event.  The decision to re-challenge patients with atezolizumab should be based on the 

Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
156/Protocol WO41535, Version 6 
investigator’s assessment of the benefits and risks and documented by the investigator.  
The Medical Monitor is available to advise as needed.  
Guidelines for managing patients who experience selected adverse events are provided 
in the following sections.  Management guidelines are presented by adverse event 
severity based on the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE), Version 5.0. 
PULMONARY EVENTS 
Pulmonary events may present as new or worsening cough, chest pain, fever, dyspnea, 
fatigue, hypoxia, pneumonitis, and pulmonary infiltrates.  Patients will be assessed for 
pulmonary signs and symptoms throughout the study and will have computed 
tomography (CT) scans of the chest performed at every tumor assessment.   
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension.  COVID-19 evaluation should be performed per institutional guidelines 
where relevant. Management guidelines for pulmonary events are provided in Table 1
 
. 
 

Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
  
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157/Protocol WO41535, Version 6 
Table 1 
Management Guidelines for Pulmonary Events, Including 
Pneumonitis 
Event 
Management 
Pulmonary 
event, Grade 1  
 Continue atezolizumab and monitor closely. 
 Re-evaluate on serial imaging. 
 Consider patient referral to pulmonary specialist. 
 For Grade 1 pneumonitis, consider withholding atezolizumab. 
Pulmonary 
event, Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL with or without transbronchial biopsy. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
oral prednisone. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c, d 
 For recurrent events or events with no improvement after 
48-72 hours of corticosteroids, treat as a Grade 3 or 4 event. 
Pulmonary 
event, Grade 3 
or 4 
 Permanently discontinue atezolizumab and contact  
Medical Monitor. c 
 Oral or IV broad-spectrum antibiotics should be administered in 
parallel to the immunosuppressive treatment. 
 Bronchoscopy or BAL with or without transbronchial biopsy is 
recommended. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
BAL  bronchoscopic alveolar lavage; NCI CTCAE  National Cancer Institute Common 
Terminology Criteria for Adverse Events. 
Note: Management guidelines are presented by adverse event severity based on NCI 
CTCAE v5.0. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time 
must be based on the investigator’s benefitrisk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  
The Medical Monitor is available to advise as needed. 
 
 

Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
  
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158/Protocol WO41535, Version 6 
Table 1 
Management Guidelines for Pulmonary Events, Including 
Pneumonitis (cont.) 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator's 
benefitrisk assessment and documented by the investigator.  The Medical Monitor is 
available to advise as needed.  
d In case of pneumonitis, atezolizumab should not be resumed after permanent 
discontinuation. 
 
HEPATIC EVENTS 
Patients eligible for study treatment must have adequate liver function, as manifested by 
measurements of total bilirubin and hepatic transaminases; and liver function will be 
monitored throughout study treatment.  Management guidelines for hepatic events are 
provided in Table 2. 
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or 
vomiting should have liver function tests (LFTs) performed immediately and reviewed 
before administration of the next dose of study drug. 
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate. 
 

Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
  
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159/Protocol WO41535, Version 6 
Table 2 
Management Guidelines for Hepatic Events 
Event 
Management 
AST/ALT is within normal limits 
at baseline and increases to 
 3  ULN to  10  ULN 
or 
AST/ALT is  ULN to  3  ULN 
at baseline and increases to 
 5  ULN to  10  ULN 
or 
AST/ALT is  3  ULN to 
 5  ULN at baseline and 
increases to  8  ULN to 
 10  ULN  
 Withhold atezolizumab for up to 12 weeks after event 
onset. a 
 Monitor LFTs more frequently until return to baseline 
values. 
 For events of  5 days' duration, consider initiating 
treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone. 
 If event resolves to baseline or to Grade 1 or better, 
resume atezolizumab. b 
 If event does not resolve to baseline or to Grade 1 or 
better while withholding atezolizumab, permanently 
discontinue atezolizumab and contact Medical Monitor. c 
LFT   liver function test; ULN   upper limit of normal. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefitrisk assessment and in alignment with the protocol requirements for 
the duration of treatment and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator's benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as needed. 
 
 
 

Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
160/Protocol WO41535, Version 6 
Table 2 
Management Guidelines for Hepatic Events (cont.) 
Event 
Management 
AST or ALT increases to 
 10  ULN or total bilirubin 
increases to  3  ULN 
 
 Permanently discontinue atezolizumab and contact 
Medical Monitor. c 
 Consider patient referral to gastrointestinal specialist for 
evaluation and liver biopsy to establish etiology of 
hepatic injury.  
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
 If event resolves to baseline, taper corticosteroids over 
 1 month. 
LFT   liver function test; ULN   upper limit of normal. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefitrisk assessment and in alignment with the protocol requirements for 
the duration of treatment and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator's benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as needed. 
 
GASTROINTESTINAL EVENTS 
Management guidelines for diarrhea or colitis are provided in Table 3. 
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies.  For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute-phase reactants (e.g., increased C-reactive protein, 
platelet count, or bandemia):  Perform sigmoidoscopy (or colonoscopy, if appropriate) 
with colonic biopsy, with three to five specimens for standard paraffin block to check for 
inflammation and lymphocytic infiltrates to confirm colitis diagnosis.  
 

Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
161/Protocol WO41535, Version 6 
Table 3 
Management Guidelines for Gastrointestinal Events (Diarrhea 
or Colitis) 
Event 
Management 
Diarrhea or 
colitis,  
Grade 1 
 Continue atezolizumab. 
 Initiate symptomatic treatment. 
 Endoscopy is recommended if symptoms persist for  7 days. 
 Monitor closely. 
Diarrhea or 
colitis,  
Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Initiate symptomatic treatment. 
 If strong clinical suspicion for immune-mediated colitis, start empiric IV 
steroids while waiting for definitive diagnosis. 
 Patient referral to GI specialist is recommended. 
 For recurrent events or events that persist  5 days, initiate treatment 
with corticosteroids equivalent to 12 mg/kg/day oral prednisone. If the 
event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c 
Diarrhea or 
colitis,  
Grade 3 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to GI specialist for evaluation and confirmatory biopsy. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.  If event does not improve within 
48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c 
Diarrhea or 
colitis, Grade 
4 
 Permanently discontinue atezolizumab and contact Medical Monitor. c 
 Refer patient to GI specialist for evaluation and confirmatory biopsy. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
 
 

Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
162/Protocol WO41535, Version 6 
Table 3 
Management Guidelines for Gastrointestinal Events (Diarrhea 
or Colitis) (cont.) 
GI  gastrointestinal; NCI CTCAE  National Cancer Institute Common Terminology Criteria 
for Adverse Events. 
Note: Management guidelines are presented by adverse event severity based on NCI 
CTCAE v5.0. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be based on the investigator’s benefitrisk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator's benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as 
needed.  
 
ENDOCRINE EVENTS 
Management guidelines for endocrine events are provided in Table 4. 
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of 
thyroid, pituitary, or adrenal endocrinopathies.  Patients should be referred to an 
endocrinologist if an endocrinopathy is suspected.  The TSH, free T3, and T4 levels 
should be measured to determine whether thyroid abnormalities are present.  Pituitary 
hormone levels and function tests (e.g., TSH, growth hormone, luteinizing hormone, 
follicle-stimulating hormone, testosterone, prolactin, adrenocorticotropic hormone 
[ACTH] levels, and ACTH stimulation test) and magnetic resonance imaging (MRI) of the 
brain (with detailed pituitary sections) may help to differentiate primary pituitary 
insufficiency from primary adrenal insufficiency. 

Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
163/Protocol WO41535, Version 6 
Table 4 
Management Guidelines for Endocrine Events 
Event 
Management 
Grade 1 
hypothyroidism 
 Continue atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH closely. 
Grade 2 
hypothyroidism 
 Consider withholding atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH closely. 
 Consider patient referral to endocrinologist. 
 Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
Grade3 and 4 
hypothyroidism 
 Withhold atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH closely. 
 Refer to an endocrinologist. 
 Admit patient to the hospital for developing myxedema 
(bradycardia, hypothermia, and altered mental status). 
 Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor for life-threatening immune-mediated hypothyroidism. c 
Grade 1 
hyperthyroidism 
TSH  0.1 mU/L and  0.5 mU/L: 
 Continue atezolizumab. 
 Monitor TSH every 4 weeks. 
 Consider patient referral to endocrinologist. 
TSH  0.1 mU/L: 
 Follow guidelines for Grade 2 hyperthyroidism. 
 Consider patient referral to endocrinologist. 
Grade 2 
hyperthyroidism 
 Consider withholding atezolizumab. 
 Initiate treatment with anti-thyroid drug such as methimazole or 
carbimazole as needed. 
 Consider patient referral to endocrinologist. 
 Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
 

Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
164/Protocol WO41535, Version 6 
Table 4 
Management Guidelines for Endocrine Events (cont.)  
Event 
Management 
Grade 3 and 4 
hyperthyroidism 
 Withhold atezolizumab. 
 Initiate treatment with anti-thyroid drug such as methimazole or 
carbimazole as needed. 
 Refer to an endocrinologist. 
 Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
 Permanently discontinue atezolizumab and contact Medical 
Monitor for life-threatening immune-mediated hyperthyroidism. c 
Symptomatic 
adrenal 
insufficiency, 
Grades 24  
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to endocrinologist. 
 Perform appropriate imaging. 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon improvement. 
 If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding atezolizumab, 
permanently discontinue atezolizumab and contact the Medical 
Monitor. c 
Hyperglycemia, 
Grade 1 or 2  
 Continue atezolizumab. 
 Investigate for diabetes.  If patient has Type 1 diabetes, treat as 
a Grade 3 event.  If patient does not have Type 1 diabetes, treat 
as per institutional guidelines. 
 Monitor for glucose control. 
Hyperglycemia, 
Grade 3 or 4 
 Withhold atezolizumab. 
 Initiate treatment with insulin. 
 Evaluate for diabetic ketoacidosis and manage as per 
institutional guidelines.  
 Monitor for glucose control. 
 Resume atezolizumab when symptoms resolve and glucose 
levels are stable. 

Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
165/Protocol WO41535, Version 6 
Table 4 
Management Guidelines for Endocrine Events (cont.)  
Event 
Management 
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3  
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to endocrinologist. 
 Perform brain MRI (pituitary protocol). 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 Initiate hormone replacement if clinically indicated. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact the Medical Monitor. c 
 For recurrent hypophysitis, treat as a Grade 4 event. 
Hypophysitis 
(pan-hypopituitarism), 
Grade 4  
 Permanently discontinue atezolizumab and contact the 
Medical Monitor. c 
 Refer patient to endocrinologist. 
 Perform brain MRI (pituitary protocol). 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 Initiate hormone replacement if clinically indicated. 
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone; 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse 
Events. 
Note: Management guidelines are presented by adverse event severity based on NCI 
CTCAE 5.0. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time 
must be based on the investigator’s benefitrisk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed.  
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator's 
benefitrisk assessment and documented by the investigator.  The Medical Monitor is 
available to advise as needed.  
 

Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
166/Protocol WO41535, Version 6 
OCULAR EVENTS 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 5. 
Table 5 
Management Guidelines for Ocular Events 
Event 
Management 
Ocular event, 
Grade 1  
 Continue atezolizumab. 
 Patient referral to ophthalmologist is strongly recommended. 
 Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
 If symptoms persist, treat as a Grade 2 event. 
Ocular event, 
Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Patient referral to ophthalmologist is strongly recommended. 
 Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact the 
Medical Monitor. c 
Ocular event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab and contact Medical Monitor. c 
 Refer patient to ophthalmologist. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone.   
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note: Management guidelines are presented by adverse event severity based on NCI 
CTCAE v5.0. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be based on the investigator’s benefitrisk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event The decision to re-challenge 
patients with atezolizumab should be based on the investigator's benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as 
needed.  
 

Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
167/Protocol WO41535, Version 6 
IMMUNE-MEDIATED CARDIAC EVENTS 
Management guidelines for cardiac events are provided in Table 6. 
IMMUNE-MEDIATED MYOCARDITIS 
Immune-mediated myocarditis should be suspected in any patient presenting with signs 
or symptoms suggestive of myocarditis, including, but not limited to, laboratory (e.g., B-
type natriuretic peptide) or cardiac imaging abnormalities, dyspnea, chest pain, 
palpitations, fatigue, decreased exercise tolerance, or syncope.  Myocarditis may also be 
a clinical manifestation of myositis or associated with pericarditis (see section on 
pericardial disorders below) and should be managed accordingly.  Immune-mediated 
myocarditis needs to be distinguished from myocarditis resulting from infection 
(commonly viral, e.g., in a patient who reports a recent history of gastrointestinal illness), 
ischemic events, underlying arrhythmias, exacerbation of preexisting cardiac conditions, 
or progression of malignancy.   
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  An 
endomyocardial biopsy may be considered to enable a definitive diagnosis and 
appropriate treatment, if clinically indicated. 
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 6. 
IMMUNE-MEDIATED PERICARDIAL DISORDERS 
Immune-mediated pericarditis should be suspected in any patient presenting with chest 
pain and may be associated with immune-mediated myocarditis (see section on 
myocarditis above). 
Immune-mediated pericardial effusion and cardiac tamponade should be suspected in 
any patient presenting with chest pain associated with dyspnea or hemodynamic 
instability.  
Patients should be evaluated for other causes of pericardial disorders such as infection 
(commonly viral), cancer related (metastatic disease or chest radiotherapy), cardiac 
injury related (post myocardial infarction or iatrogenic), and autoimmune disorders, and 
should be managed accordingly. 

Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
168/Protocol WO41535, Version 6 
All patients with suspected pericardial disorders should be urgently evaluated by 
performing an ECG, chest X-ray, transthoracic echocardiogram, and cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  
Pericardiocentesis should be considered for diagnostic or therapeutic purposes, if 
clinically indicated. 
Patients with signs and symptoms of pericarditis, pericardial effusion, or cardiac 
tamponade, in the absence of an identified alternate etiology, should be treated 
according to the guidelines in Table 6 .  Withhold treatment with atezolizumab for 
Grade 1 pericarditis and conduct a detailed cardiac evaluation to determine the etiology 
and manage accordingly. 
Table 6 
Management Guidelines for Immune-Mediated Cardiac Events 
Event 
Management 
Immune-mediated 
myocarditis, Grades 
24 
 
Immune-mediated 
pericardial disorders, 
Grades 2‑4 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor.  
 Refer patient to cardiologist. 
 Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, VAD or 
pericardiocentesis as appropriate. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone and convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids 
over  1 month. 
ECMO  extracorporeal membrane oxygenation; VAD  ventricular assist device; 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note: Management guidelines are presented by adverse event severity based on NCI 
CTCAE v5.0. 
 

Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
169/Protocol WO41535, Version 6 
INFUSION-RELATED REACTIONS AND CYTOKINE RELEASE SYNDROME 
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) or cytokine release 
syndrome (CRS) with of atezolizumab may receive premedication with antihistamines or 
antipyretic medications, and/or analgesics (e.g., acetaminophen) for subsequent 
infusions.  Metamizole (dipyrone) is prohibited in treating atezolizumab-associated IRRs 
because of its potential for causing agranulocytosis. 
IRRs are known to occur with the administration of monoclonal antibodies and have 
been reported with atezolizumab.  These reactions, which are thought to be due to 
release of cytokines and/or other chemical mediators, occur within 24 hours of 
atezolizumab administration and are generally mild to moderate in severity. 
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T cells and/or 
other immune effector cells.  Symptoms can be progressive, always include fever at the 
onset, and may include hypotension, capillary leak (hypoxia), and end-organ dysfunction 
(Lee et al. 2019).  CRS has been well documented with chimeric antigen receptor T-cell 
therapies and bispecific T-cell engager antibody therapies but has also been reported 
with immunotherapies that target PD-1 or PD-L1 (Rotz et al. 2017; Adashek and 
Feldman 2019), including atezolizumab. 
There may be significant overlap in signs and symptoms of IRRs and CRS, and in 
recognition of the challenges in clinically distinguishing between the two, consolidated 
guidelines for the medical management of IRRs and CRS are provided in Table 7. 
Severe SARS-CoV-2 infection appears to be associated with a CRS involving the 
inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and IFN- (Merad and Martin 2020).  
If a patient develops suspected CRS during the study, a differential diagnosis should 
include SARS-CoV-2 infection, which should be confirmed or refuted through 
assessment of exposure history, appropriate laboratory testing, and clinical or radiologic 
evaluations per investigator’s judgment.  If a diagnosis of SARS-CoV-2 infection is 
confirmed, the disease should be managed as per local or institutional guidelines. 

Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
170/Protocol WO41535, Version 6 
Table 7 
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome 
 Event 
Management 
Grade 1 a 
Fever b with or 
without 
constitutional 
symptoms  
 Immediately interrupt infusion. 
 Upon symptom resolution, wait for 30 minutes and then restart infusion at 
half the rate being given at the time of event onset. 
 If the infusion is tolerated at the reduced rate for 30 minutes, the infusion 
rate may be increased to the original rate. 
 If symptoms recur, discontinue infusion of this dose. 
 Administer symptomatic treatment, c including maintenance of IV fluids for 
hydration. 
 In case of rapid decline or prolonged CRS ( 2 days) or in patients with 
significant symptoms and/or comorbidities, consider managing as per 
Grade 2. 
 For subsequent infusions, consider administration of oral premedication 
with antihistamines, antipyretic medications, and/or analgesics, and 
monitor closely for IRRs and/or CRS. 
Grade 2 a 
Fever b with 
hypotension not 
requiring 
vasopressors 
and/or 
Hypoxia 
requiring low-
flow oxygen d by 
nasal cannula 
or blow-by 
 Immediately interrupt infusion. 
 Upon symptom resolution, wait for 30 minutes and then restart infusion at 
half the rate being given at the time of event onset. 
 If symptoms recur, discontinue infusion of this dose. 
 Administer symptomatic treatment. c 
 For hypotension, administer IV fluid bolus as needed. 
 Monitor cardiopulmonary and other organ function closely (in the ICU, if 
appropriate).  Administer IV fluids as clinically indicated, and manage 
constitutional symptoms and organ toxicities as per institutional practice. 
 Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis).  
If no improvement within 24 hours, initiate workup and assess for signs 
and symptoms of HLH or MAS as described in this appendix. 
 Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy.  
 Consider hospitalization until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 3, that is, hospitalize 
patient (monitoring in the ICU is recommended), permanently discontinue 
atezolizumab, and contact the Medical Monitor. 
 If symptoms resolve to Grade 1 or better for 3 consecutive days, the next 
dose of atezolizumab may be administered.  For subsequent infusions, 
consider administration of oral premedication with antihistamines, 
antipyretic medications, and/or analgesics and monitor closely for IRRs 
and/or CRS. 
 If symptoms do not resolve to Grade 1 or better for 3 consecutive days, 
contact the Medical Monitor. 

Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
171/Protocol WO41535, Version 6 
Table 7 
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.) 
 
Event 
Management 
Grade 3 a 
Fever b with 
hypotension 
requiring a 
vasopressor (with 
or without 
vasopressin) 
and/or 
Hypoxia requiring 
high-flow oxygen 
d by nasal 
cannula, face 
mask, 
non-rebreather 
mask, or Venturi 
mask 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. e 
 Administer symptomatic treatment. c 
 For hypotension, administer IV fluid bolus and vasopressor as 
needed. 
 Monitor cardiopulmonary and other organ function closely; monitoring 
in the ICU is recommended.  Administer IV fluids as clinically 
indicated, and manage constitutional symptoms and organ toxicities 
as per institutional practice. 
 Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix. 
 Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day 
or dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy.  
 Hospitalize patient until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 4, that is, admit 
patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed; for patients 
who are refractory to anti-cytokine therapy, experimental treatments 
may be considered at the discretion of the investigator and in 
consultation with the Medical Monitor. 
Grade 4 a 
Fever b with 
hypotension 
requiring multiple 
vasopressors 
(excluding 
vasopressin) 
and/or 
Hypoxia requiring 
oxygen by 
positive pressure 
(e.g., CPAP, 
BiPAP, intubation 
and mechanical 
ventilation) 
 Permanently discontinue atezolizumab and contact Medical Monitor. e 
 Administer symptomatic treatment. c 
 Admit patient to ICU and initiate hemodynamic monitoring, 
mechanical ventilation, and/or IV fluids and vasopressors as needed.  
Monitor other organ function closely.  Manage constitutional 
symptoms and organ toxicities as per institutional practice. 
 Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix. 
 Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day 
or dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy.   For patients who are refractory to 
anti-cytokine therapy, experimental treatments f may be considered at 
the discretion of the investigator and in consultation with the Medical 
Monitor. 
 Hospitalize patient until complete resolution of symptoms. 

Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
172/Protocol WO41535, Version 6 
Table 7 
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.) 
 
ASTCT  American Society for Transplantation and Cellular Therapy; BiPAP  bi-level 
positive airway pressure; CAR  chimeric antigen receptor; CPAP  continuous positive 
airway pressure; CRS  cytokine release syndrome; CTCAE  Common Terminology 
Criteria for Adverse Events; eCRF  electronic Case Report Form; HLH  hemophagocytic 
lymphohistiocytosis; ICU  intensive care unit; IRR  infusion-related reaction; 
MAS  macrophage activation syndrome; NCCN  National Cancer Comprehensive 
Network; NCI  National Cancer Institute. 
Note:  The management guidelines have been adapted from NCCN guidelines for 
management of CAR T-cellrelated toxicities (Version 2.2019). 
a Grading system for management guidelines is based on ASTCT consensus grading for 
CRS.  NCI CTCAE v5.0 should be used when reporting severity of IRRs, CRS, or 
organ toxicities associated with CRS on the Adverse Event eCRF.  Organ toxicities 
associated with CRS should not influence overall CRS grading. 
b Fever is defined as temperature  38C not attributable to any other cause.  In patients 
who develop CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, 
fever is no longer required when subsequently determining event severity (grade).  In 
this case, the grade is driven by the presence of hypotension and/or hypoxia. 
c Symptomatic treatment may include oral or IV antihistamines, antipyretic medications, 
analgesics, bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or dyspnea, 
additional treatment may be administered as per institutional practice. 
d Low flow is defined as oxygen delivered at  6 L/min, and high flow is defined as 
oxygen delivered at  6 L/min. 
e Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator's benefitrisk assessment and 
documented by the investigator.  The Medical Monitor is available to advise as needed.  
For subsequent infusions, administer oral premedication with antihistamines, antipyretic 
medications, and/or analgesics, and monitor closely for IRRs and/or CRS.  
Premedication with corticosteroids and extending the infusion time may also be 
considered after assessing the benefitrisk ratio. 
f Refer to Riegler et al. (2019) for information on experimental treatments for CRS. 
 
PANCREATIC EVENTS 
The differential diagnosis of acute abdominal pain should include pancreatitis.  
Appropriate workup should include an evaluation for ductal obstruction, as well as serum 
amylase and lipase tests.  Management guidelines for pancreatic events, including 
pancreatitis, are provided in Table 8. 
 

Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
173/Protocol WO41535, Version 6 
Table 8 
Management Guidelines for Pancreatic Events Including 
Pancreatitis  
Event 
Management 
Amylase and/or 
lipase elevation, 
Grade 2 
Amylase and/or lipase  1.52.0  ULN: 
 Continue atezolizumab. 
 Monitor amylase and lipase weekly. 
 For prolonged elevation (e.g.,  3 weeks), consider treatment with 
corticosteroids equivalent to 10 mg/day oral prednisone. 
Asymptomatic with amylase and/or lipase  2.05.0  ULN: 
 Treat as Grade 3 event. 
Amylase and/or 
lipase elevation, 
Grade 3 or 4 
 Withhold atezolizumab for up to 12 weeks after  
event onset. a 
 Refer patient to GI specialist. 
 Monitor amylase and lipase every other day. 
 If no improvement, consider treatment with corticosteroids equivalent 
to 12 mg/kg/day oral prednisone. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact the 
Medical Monitor. c 
 For recurrent events, permanently discontinue atezolizumab and 
contact the Medical Monitor. c 
Immune-mediated 
pancreatitis, 
Grade 2 or 3 
 
 Withhold atezolizumab for up to 12 weeks after event  
onset. a 
 Refer patient to GI specialist. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c 
 For recurrent events, permanently discontinue atezolizumab and 
contact the Medical Monitor. c  
 

Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
174/Protocol WO41535, Version 6 
Table 8 
Management Guidelines for Pancreatic Events Including 
Pancreatitis (cont.)  
Event 
Management 
Immune-mediated 
pancreatitis, Grade 4 
 Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
 Refer patient to GI specialist. 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
 If event resolves to Grade 1 or better, taper corticosteroids 
over  1 month. 
GI  gastrointestinal; ULN  upper limit of normal; NCI CTCAE  National Cancer Institute 
Common Terminology Criteria for Adverse Events.   
Note: Management guidelines are presented by adverse event severity based on NCI 
CTCAE v5.0. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be based on the investigator’s benefitrisk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator's benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as 
needed. 
 
DERMATOLOGIC EVENTS 
The majority of cases of rash reported with the use of atezolizumab were mild in severity 
and self-limiting, with or without pruritus.  Although uncommon, cases of severe 
cutaneous adverse reactions such as Stevens-Johnson syndrome and toxic epidermal 
necrolysis have been reported with atezolizumab.  A dermatologist should evaluate 
persistent and/or severe rash or pruritus.  A biopsy should be considered unless 
contraindicated.  Management guidelines for dermatologic events are provided in 
Table 9. 

Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
175/Protocol WO41535, Version 6 
Table 9 
Management Guidelines for Dermatologic Events 
Event 
Management 
Dermatologic 
event, Grade 1  
 Continue atezolizumab. 
 Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines). 
Dermatologic 
event, Grade 2  
 Continue atezolizumab. 
 Consider patient referral to dermatologist for evaluation and, if 
indicated, biopsy. 
 Initiate treatment with topical corticosteroids. 
 Consider treatment with higher-potency topical corticosteroids if 
event does not improve. 
 If unresponsive to topical corticosteroids, consider oral prednisone 
0.5 mg/kg/day. 
Dermatologic 
event, Grade 3  
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to dermatologist for evaluation and, if indicated, biopsy. 
 Initiate treatment with corticosteroids equivalent to 10 mg/day oral 
prednisone, increasing dose to 12 mg/kg/day if event does not 
improve within 4872 hours. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
the Medical Monitor. c 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse 
Events.   
Note: Management guidelines are presented by adverse event severity based on NCI 
CTCAE v5.0. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time 
must be based on the investigator’s benefitrisk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator's 
benefitrisk assessment and documented by the investigator.  The Medical Monitor is 
available to advise as needed.  
 
 

Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
176/Protocol WO41535, Version 6 
Table 9 
Management Guidelines for Dermatologic Events (cont.) 
Event 
Management 
Dermatologic event, 
Grade 4 
 Permanently discontinue atezolizumab and contact Medical 
Monitor.  c 
Stevens-Johnson 
syndrome or toxic 
epidermal necrolysis 
(any grade) 
Additional guidance for Stevens-Johnson syndrome or toxic 
epidermal necrolysis: 
 Withhold atezolizumab for suspected Stevens-Johnson syndrome 
or toxic epidermal necrolysis. 
 Confirm diagnosis by referring patient to a specialist (dermatologist, 
ophthalmologist, or urologist as relevant) for evaluation and, if 
indicated, biopsy. 
 Follow the applicable treatment and management guidelines above. 
 If Stevens-Johnson syndrome or toxic epidermal necrolysis is 
confirmed, permanently discontinue atezolizumab. 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events.   
Note: Management guidelines are presented by adverse event severity based on NCI CTCAE 
v5.0. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefitrisk assessment and in alignment with the protocol requirements for 
the duration of treatment and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator's benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as needed. 
 
NEUROLOGIC DISORDERS 
Patients may present with signs and symptoms of sensory and/or motor neuropathy.  
Diagnostic workup is essential for an accurate characterization to differentiate between 
alternative etiologies.  Management guidelines for neurologic disorders are provided in 
Table 10, with specific guidelines for myelitis provided in  Table 11.
 

Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
177/Protocol WO41535, Version 6 
Table 10 Management Guidelines for Neurologic Disorders 
Event 
Management 
Immune-mediated 
neuropathy, Grade 1 
 Continue atezolizumab. 
 Investigate etiology. 
 Any cranial nerve disorder (including facial paresis) should be 
managed as per Grade 2 management guidelines below 
Immune-mediated 
neuropathy, 
including facial 
paresis,  Grade 2  
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Investigate etiology and refer patient to neurologist. 
 Initiate treatment as per institutional guidelines. 
 For general immune-mediated neuropathy: 
 
If event resolves to Grade 1 or better, resume 
atezolizumab. b 
 
If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact the Medical Monitor. c 
 For facial paresis: 
 
If event resolves fully, resume atezolizumab b 
 
If event does not resolve fully while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact the Medical Monitor. c 
Immune-mediated 
neuropathy, 
including facial 
paresis, Grade 3 or 4 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. c  
 Refer patient to neurologist. 
 Initiate treatment as per institutional guidelines. 
 
 
 

Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
178/Protocol WO41535, Version 6 
Table 10 Management Guidelines for Neurologic Disorders (cont.) 
Event 
Management 
Myasthenia gravis 
and Guillain-Barré 
syndrome (any 
grade) 
 Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
 Refer patient to neurologist. 
 Initiate treatment as per institutional guidelines. 
 Consider initiation of corticosteroids equivalent to 12 mg/kg/day 
oral or IV prednisone. 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events.  
Note: Management guidelines are presented by adverse event severity based on NCI 
CTCAE v5.0. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be based on the investigator’s benefitrisk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator's benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as 
needed.  
 
Table 11 Management Guidelines for Immune-Mediated Myelitis 
Event 
Management 
Immune-mediated myelitis, 
Grade 1 
 
Continue atezolizumab unless symptoms worsen or do not 
improve. 
 
Investigate etiology and refer patient to a neurologist.  
Immune-mediated myelitis, 
Grade 2 
 
Permanently discontinue atezolizumab and contact the 
Medical Monitor.  
 
Investigate etiology and refer patient to a neurologist. 
 
Rule out infection. 
 
Initiate treatment with corticosteroids equivalent to 
1-2 mg/kg/day oral prednisone. 
Immune-mediated myelitis, 
Grade 3 or 4 
 
Permanently discontinue atezolizumab and contact the 
Medical Monitor. 
 
Refer patient to a neurologist. 
 
Initiate treatment as per institutional guidelines. 
  

Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
179/Protocol WO41535, Version 6 
IMMUNE-MEDIATED MENINGOENCEPHALITIS 
Immune-mediated meningoencephalitis should be suspected in any patient presenting 
with signs or symptoms suggestive of meningitis or encephalitis, including, but not 
limited to, headache, neck pain, confusion, seizure, motor or sensory dysfunction, and 
altered or depressed level of consciousness.  Encephalopathy from metabolic or 
electrolyte imbalances needs to be distinguished from potential meningoencephalitis 
resulting from infection (bacterial, viral, or fungal) or progression of malignancy, or 
secondary to a paraneoplastic process.   
All patients being considered for meningoencephalitis should be urgently evaluated with 
a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or 
edema.  If deemed safe by the treating physician, a lumbar puncture should be 
performed and a neurologist should be consulted. 
Patients with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in Table 12. 
Table 12 Management Guidelines for Immune-Mediated 
Meningoencephalitis 
Event 
Management 
Immune-mediated 
meningoencephalitis, 
all grades 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor.  
 Refer patient to neurologist. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone and convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note: Management guidelines are presented by adverse event severity based on NCI 
CTCAE v5.0. 
 

Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
180/Protocol WO41535, Version 6 
RENAL EVENTS 
Eligible patients must have adequate renal function.  Renal function, including serum 
creatinine, should be monitored throughout study treatment.  Patients with abnormal 
renal function should be evaluated and treated for other more common etiologies 
(including prerenal and postrenal causes, and concomitant medications such as 
non-steroidal anti-inflammatory drugs).  Refer the patient to a renal specialist if clinically 
indicated.  A renal biopsy may be required to enable a definitive diagnosis and 
appropriate treatment. 
Patients with signs and symptoms of nephritis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 13. 
Table 13 Management Guidelines for Renal Events  
Event 
Management 
Renal event, 
Grade 1 
 Continue atezolizumab. 
 Monitor kidney function closely, including creatinine and urine protein, 
closely until values resolve to within normal limits or to baseline values.  
Renal event, 
Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to renal specialist. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c 
 
 
 

Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
181/Protocol WO41535, Version 6 
Table 13 Management Guidelines for Renal Event (cont.) 
Renal event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. c 
 Refer patient to renal specialist and consider renal biopsy. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone. 
 If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note: Management guidelines are presented by adverse event severity based on NCI 
CTCAE v5.0. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be based on the investigator’s benefitrisk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator's benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as 
needed. 
 
IMMUNE-MEDIATED MYOSITIS 
Myositis or inflammatory myopathies are a group of disorders sharing the common 
feature of inflammatory muscle injury; dermatomyositis and polymyositis are among the 
most common disorders.  Initial diagnosis is based on clinical (muscle weakness, muscle 
pain, skin rash in dermatomyositis), biochemical (serum creatine kinase increase), and 
imaging (electromyography/MRI) features, and is confirmed with a muscle biopsy.  
Patients with possible myositis should be referred to a rheumatologist or neurologist.  
Patients with possible myositis should be monitored for signs of myocarditis. 
Patients with signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 14. 
 

Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
182/Protocol WO41535, Version 6 
Table 14 Management Guidelines for Immune-Mediated Myositis 
Event 
Management 
Immune-
mediated 
myositis, 
Grade 1 
 Continue atezolizumab. 
 Refer patient to rheumatologist or neurologist.  
 Initiate treatment as per institutional guidelines. 
Immune-
mediated 
myositis, 
Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset a and 
contact the Medical Monitor. 
 Refer patient to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines. 
 Consider treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If corticosteroids are initiated and event does not improve within 
48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact the 
Medical Monitor. c 
Immune-
mediated 
myositis, 
Grade 3 
 Withhold atezolizumab for up to 12 weeks after event onset a and 
contact Medical Monitor. 
 Refer patient to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines.   
 Respiratory support may be required in more severe cases. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement. 
 If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact the 
Medical Monitor. c 
 For recurrent events, treat as a Grade 4 event.  Permanently 
discontinue atezolizumab and contact the Medical Monitor. c 

Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
183/Protocol WO41535, Version 6 
Table 14 Management Guidelines for Immune-Mediated Myositis (cont.) 
Immune-
mediated 
myositis,  
Grade 4 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. c 
 Refer patient to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines.   
 Respiratory support may be required in more severe cases. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events.  
Note: Management guidelines are presented by adverse event severity based on NCI 
CTCAE v5.0. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be based on the investigator’s benefitrisk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator's benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as 
needed. 
 
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MACROPHAGE 
ACTIVATION SYNDROME 
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome 
(MAS). 
Clinical and laboratory features of severe CRS overlap with HLH, and HLH should be 
considered when CRS presentation is atypical or prolonged. 

Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
184/Protocol WO41535, Version 6 
Patients with suspected HLH should be diagnosed according to published criteria by 
McClain and Eckstein (2014).  A patient should be classified as having HLH if five of the 
following eight criteria are met: 
 
Fever  38.5°C 
 
Splenomegaly 
 
Peripheral blood cytopenia consisting of at least two of the following: 
– Hemoglobin  90 g/L (9 g/dL) ( 100 g/L [10 g/dL] for infants  4 weeks old) 
– Platelet count  100  109/L (100,000/L) 
– ANC  1.0  109/L (1000/L) 
 
Fasting triglycerides  2.992 mmol/L (265 mg/dL) and/or fibrinogen  1.5 g/L 
(150 mg/dL) 
 
Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
 
Low or absent natural killer cell activity 
 
Ferritin  500 mg/L (500 ng/mL) 
 
Soluble IL-2 receptor (soluble CD25) elevated  2 standard deviations above age-
adjusted laboratory-specific norms 
 
Patients with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should be 
classified as having MAS if the following criteria are met: 
 
Ferritin  684 mg/L (684 ng/mL) 
 
At least two of the following: 
– Platelet count  181  109/L (181,000/L) 
– AST  48 U/L 
– Triglycerides  1.761 mmol/L (156 mg/dL) 
– Fibrinogen  3.6 g/L (360 mg/dL) 
 
Patients with suspected HLH or MAS should be treated according to the guidelines in 
Table 15. 
 
 

Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
185/Protocol WO41535, Version 6 
Table 15 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome 
Event 
Management 
Suspected 
HLH or MAS 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. 
 Consider patient referral to hematologist. 
 Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines. 
 Consider initiation of IV corticosteroids, an immunosuppressive 
agent, and/or anti-cytokine therapy. 
 If event does not improve within 24 hours, contact the Medical 
Monitor and initiate treatment as appropriate according to 
published guidelines (La Rosée 2015, 2019; Schram and Berliner 
2015). 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
HLH  hemophagocytic lymphohistiocytosis; MAS  macrophage activation syndrome. 
 
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Adashek ML, Feldman M. Cytokine release syndrome resulting from antiprogrammed 
death-1 antibody: raising awareness among community oncologist. J Oncol 
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La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology 
Am Soc Hematol Educ Protram 2015;1:1906. 
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of 
hemophagocytic lymphohistiocytosis in adults. Blood 2019;133:246577. 
Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine 
release syndrome and neurologic toxicity associated with immune effector cells. 
Biol Blood Marrow Transplant 2019;25:62538. 
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resource on the Internet]. 2014 [updated 
29 October 2018; cited: 17 May 2019]. Available from: 
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-
hemophagocytic-lymphohistiocytosis. 
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for 
monocytes and macrophages. Nat Rev Immunol 2020;20:35562. 

Appendix 13: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
  
Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
186/Protocol WO41535, Version 6 
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation 
syndrome complicating systemic juvenile idiopathic arthritis: a European League 
Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology 
International Trials Organisation Collaborative Initiative. Ann Rheum Dis 
2016;75:4819. 
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of 
cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin 
Risk Manag 2019;15:32335. 
Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient 
receiving PD-1-directed therapy. Pediatr Blood Cancer 2017;64:e26642. 
Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult 
patient. Blood 2015;125:290814
 

Atezolizumab and Bevacizumab—F. Hoffmann-La Roche Ltd 
187/Protocol WO41535, Version 6 
Appendix 14  
Investigational Medicinal Product and Non-Investigational 
Medicinal Product Designations (for Use in European Economic 
Area) 
Table 1 
Investigational, Authorized Auxiliary, and Unauthorized 
Auxiliary Medicinal Product Designations for European 
Economic Area
Product Name 
IMP Designation 
Marketing 
Authorization Status in 
EEA 
Used within 
Marketing 
Authorization 
Atezolizumab 
(RO5541267) 
IMP (test product)
Authorized 
No 
Bevacizumab 
(RO4876646) 
IMP (test product)
Authorized 
No 
EEA    European Economic Area; IMP     investigational medicinal product.

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