Clinical trial NCT03434379
Conditions: Carcinoma, Hepatocellular
Sponsor: Hoffmann-La Roche
Start date: 2018-03-15; Completion date: 2022-11-17
Enrollment: 558 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the efficacy and safety of atezolizumab in combination with bevacizumab compared with sorafenib in participants with locally advanced or metastatic Hepatocellular Carcinoma (HCC) who have received no prior systemic treatment.

Detailed description:
The participants will be randomized in a 2:1 ratio to one of the two treatment arms: Arm A (experimental arm): Atezolizumab +bevacizumab; Arm B (control arm): Sorafenib

Arms: arm 1: Participants will receive Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator arm 2: Participants will receive Sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator
Interventions: intervention 1: Atezolizumab intervention 2: Bevacizumab intervention 3: Sorafenib
Intervention descriptions: intervention 1: Atezolizumab will be administered by IV, 1200 mg on day 1 of each 21 day cycle intervention 2: Bevacizumab will be administered by IV, 15 mg/kg on day 1 of each 21 day cycle intervention 3: Sorafenib will be administered by mouth, 400 mg twice per day, on days 1-21 of each 21-day cycle

Protocol documents:
Prot_000.pdf: 
PROTOCOL AMENDMENT APPROVAL
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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and; therefore,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—F. Hoffmann-La Roche Ltd
Protocol YO40245, Version 6
PROTOCOL
TITLE:
A PHASE III, OPEN-LABEL, RANDOMIZED STUDY 
OF ATEZOLIZUMAB IN COMBINATION WITH 
BEVACIZUMAB COMPARED WITH SORAFENIB IN 
PATIENTS WITH UNTREATED LOCALLY 
ADVANCED OR METASTATIC HEPATOCELLULAR 
CARCINOMA
PROTOCOL NUMBER:
YO40245
VERSION NUMBER:
6
EUDRACT NUMBER:
2017-003691-31
IND NUMBER:
135913
NCT NUMBER:
NCT03434379
TEST PRODUCTS:
Atezolizumab (RO5541267)
Bevacizumab (RO4876646)
MEDICAL MONITOR:
M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1:  18 October 2017
DATES AMENDED:
Version 2:  14 March 2018
Version 3:  15 September 2018
Version 4:  20 February 2019
Version 5: 15 January 2020
Version 6: See electronic date stamp below.
 
01-Feb-2021 17:34:51
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Atezolizumab—F. Hoffmann-La Roche Ltd
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PROTOCOL AMENDMENT, VERSION 6:
RATIONALE
Protocol YO40245 has been amended primarily to align with updates in the 
Atezolizumab Investigator’s Brochure, Version 17.  Changes to the protocol, along with a 
rationale for each change, are summarized below.

The descriptive and optional nature of subsequent overall survival (OS) analyses 
once statistical significance is reached at any of the pre-planned interim analyses of 
OS was clarified (Sections 6.1, 6.4.1.1, and 6.10)

Severe Cutaneous Adverse Reactions (SCARs) were added as a risk associated 
with atezolizumab (Section 5.1.1) and a statement was added to Appendix 8 to 
communicate that caution should be used in patients who have previously 
experienced a severe or life-threatening atezolizumab skin adverse reaction

The Management Guidelines for Dermatologic Events section of Appendix 12 was 
updated to include updated management guidelines for Grade 3 dermatologic 
events and new guidelines for Stevens-Johnson syndrome or toxic epidermal 
necrolysis of any grade were added

Section 1.6.3, COVID-19 Considerations, has been added to describe
COVID19-related risks

Exclusion criteria in Section 4.1.2 Severe infection within 4 weeks prior to initiation 
of study treatment, including, but not limited to, hospitalization for complications of 
infection, bacteremia, or severe pneumonia has been updated to include any active 
infection that, the opinion of the investigator, could impact patient safety

COVID-19 risk language has been included in Section 5.1, Safety Plan, to state that 
patients with an active infection will be excluded from study participation

The Management Guidelines for Infusion-Related Reactions and Cytokine-Release 
Syndrome were updated to include COVID-19 risk language

The Management Guidelines for Hepatic Events for Patients with Hepatocellular 
Carcinoma section of Appendix 12 has been updated to align with the updated 
management guidelines in the Atezolizumab Investigator’s Brochure v17
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.


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TABLE OF CONTENTS
PROTOCOL SYNOPSIS .................................................................................... 12
1.
BACKGROUND .......................................................................................... 29
1.1
Background on Hepatocellular Carcinoma ............................ 29
1.2
Current Systemic Treatment for Advanced 
Hepatocellular Carcinoma ..................................................... 29
1.3
Background on Atezolizumab................................................ 30
1.4
Background on Bevacizumab................................................ 31
1.5
Overview of Clinical Development Program in 
Hepatocellular Carcinoma ..................................................... 31
1.5.1
Atezolizumab Monotherapy ................................................... 31
1.5.2
Bevacizumab Monotherapy ................................................... 33
1.6
Study Rationale and Benefit-Risk Assessment...................... 34
1.6.1
Rationale for the Combination of Anti-PD-L1 and 
Anti-VEGF Therapy in Hepatocellular Carcinoma ................. 34
1.6.2
Clinical Data of Atezolizumab in Combination 
with Bevacizumab in Hepatocellular Carcinoma.................... 35
1.6.3
COVID-19 Considerations ..................................................... 37
1.6.4
Summary ............................................................................... 38
2.
OBJECTIVES AND ENDPOINTS ............................................................... 38
3.
STUDY DESIGN......................................................................................... 42
3.1
Description of the Study......................................................... 42
3.1.1
Overview of Study Design ..................................................... 42
3.1.2
Independent Data Monitoring Committee .............................. 44
3.2
End of Study.......................................................................... 45
3.3
Rationale for Study Design.................................................... 45
3.3.1
Rationale for Atezolizumab Dose and Schedule.................... 45
3.3.2
Rationale for Bevacizumab Dose and Schedule.................... 45
3.3.3
Rationale for Patient Population ............................................ 45
3.3.4
Rationale for Control Arm ...................................................... 46
3.3.5
Rationale for Open-Label Study ............................................ 46
3.3.6
Rationale for Overall Survival and Progression-
Free Survival as Co-Primary Endpoints................................. 47


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3.3.7
Rationale for Stratification...................................................... 47
3.3.7.1
Geographic Region................................................................ 47
3.3.7.2
Macrovascular Invasion and/or Extrahepatic 
Spread (Presence vs. Absence)............................................ 48
3.3.7.3
Baseline -Fetoprotein(400 ng/mL 
vs. 400 ng/mL).................................................................... 48
3.3.7.4
Eastern Cooperative Oncology Group 
Performance Status (0 vs. 1)................................................. 49
3.3.8
Rationale for Study Treatment beyond Initial 
Radiographic Progression ..................................................... 49
3.3.9
Rationale for Biomarker Assessments................................... 49
3.3.10
Rationale for Patient-Reported Outcomes 
Assessments ......................................................................... 50
4.
MATERIALS AND METHODS .................................................................... 51
4.1
Patients.................................................................................. 51
4.1.1
Inclusion Criteria.................................................................... 51
4.1.2
Exclusion Criteria................................................................... 54
4.2
Method of Treatment Assignment.......................................... 59
4.2.1
Treatment Assignment........................................................... 59
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 59
4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 59
4.3.1.1
Atezolizumab......................................................................... 59
4.3.1.2
Bevacizumab......................................................................... 59
4.3.1.3
Sorafenib ............................................................................... 60
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 60
4.3.2.1
Atezolizumab......................................................................... 61
4.3.2.2
Bevacizumab......................................................................... 62
4.3.2.3
Sorafenib ............................................................................... 63
4.3.3
Investigational Medicinal Product Accountability ................... 63
4.3.4
Continued Access to Atezolizumab and 
Bevacizumab......................................................................... 64
4.4
Concomitant Therapy (Prohibited Food and 
Other Restrictions)................................................................. 64


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4.4.1
Permitted Therapy................................................................. 65
4.4.2
Cautionary Therapy ............................................................... 66
4.4.2.1
Herbal Therapies................................................................... 66
4.4.2.2
Cautionary Therapy for Atezolizumab-Treated 
Patients.................................................................................. 66
4.4.2.3
Corticosteroids, Immunosuppressive Medications, 
and TNF-Inhibitors.............................................................. 66
4.4.2.4
Cautionary Therapy for Sorafenib-Treated 
Patients.................................................................................. 67
4.4.3
Prohibited Therapy ................................................................ 68
4.5
Study Assessments ............................................................... 69
4.5.1
Informed Consent Forms and Screening Log........................ 69
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 69
4.5.3
Physical Examinations........................................................... 70
4.5.4
Vital Signs.............................................................................. 70
4.5.5
Tumor and Response Evaluations......................................... 71
4.5.6
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 72
4.5.7
Electrocardiograms................................................................ 74
4.5.8
Patient-Reported Outcomes .................................................. 74
4.5.8.1
EORTC QLQ-C30.................................................................. 75
4.5.8.2
EORTC QLQ-HCC18............................................................. 75
4.5.8.3
EQ-5D-5L .............................................................................. 75
4.5.9
Tumor Samples at Screening ................................................ 76
4.5.10
Optional Samples for Research Biosample 
Repository ............................................................................. 76
4.5.10.1
Overview of the Research Biosample Repository.................. 76
4.5.10.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 77
4.5.10.3
Sample Collection.................................................................. 77
4.5.10.4
Confidentiality........................................................................ 78
4.5.10.5
Consent to Participate in the Research 
Biosample Repository............................................................ 78
4.5.10.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 79


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4.5.10.7
Monitoring and Oversight....................................................... 79
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 79
4.6.1
Study Treatment Discontinuation........................................... 79
4.6.2
Patient Discontinuation from Study........................................ 80
4.6.3
Study Discontinuation............................................................ 81
4.6.4
Site Discontinuation............................................................... 81
5.
ASSESSMENT OF SAFETY....................................................................... 81
5.1
Safety Plan ............................................................................ 81
5.1.1
Risks Associated with Atezolizumab ..................................... 82
5.1.2
Risks Associated with Bevacizumab ..................................... 82
5.1.3
Risks Associated with Sorafenib............................................ 82
5.1.4
Risks Associated with Combination Use of 
Atezolizumab and Bevacizumab............................................ 83
5.2
Safety Parameters and Definitions ........................................ 83
5.2.1
Adverse Events ..................................................................... 83
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 84
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 85
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 86
5.3.1
Adverse Event Reporting Period ........................................... 86
5.3.2
Eliciting Adverse Event Information....................................... 87
5.3.3
Assessment of Severity of Adverse Events ........................... 87
5.3.4
Assessment of Causality of Adverse Events ......................... 87
5.3.5
Procedures for Recording Adverse Events............................ 88
5.3.5.1
Infusion-Related Reactions.................................................... 88
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 89
5.3.5.3
Adverse Events that are Secondary to Other 
Events.................................................................................... 89
5.3.5.4
Persistent or Recurrent Adverse Events................................ 89
5.3.5.5
Abnormal Laboratory Values ................................................. 90
5.3.5.6
Abnormal Vital Sign Values ................................................... 91


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5.3.5.7
Abnormal Liver Function Tests.............................................. 91
5.3.5.8
Deaths ................................................................................... 92
5.3.5.9
Preexisting Medical Conditions.............................................. 92
5.3.5.10
Lack of Efficacy or Worsening of Hepatocellular 
Carcinoma ............................................................................. 92
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 93
5.3.5.12
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 93
5.3.5.13
Patient-Reported Outcomes Data.......................................... 94
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 94
5.4.1
Emergency Medical Contacts................................................ 94
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 95
5.4.2.1
Events That Occur prior to Study Treatment 
Initiation ................................................................................. 95
5.4.2.2
Events That Occur after Study Treatment 
Initiation ................................................................................. 95
5.4.3
Reporting Requirements for Pregnancies.............................. 96
5.4.3.1
Pregnancies in Female Patients............................................ 96
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 96
5.4.3.3
Abortions ............................................................................... 96
5.4.3.4
Congenital Anomalies/Birth Defects ...................................... 97
5.5
Follow-Up of Patients after Adverse Events .......................... 97
5.5.1
Investigator Follow-Up........................................................... 97
5.5.2
Sponsor Follow-Up ................................................................ 97
5.6
Adverse Events that Occur after the Adverse 
Event Reporting Period.......................................................... 97
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 98
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 98
6.1
Determination of Sample Size ............................................... 99
6.2
Summaries of Conduct of Study.......................................... 101
6.3
Summaries of Treatment Group Comparability ................... 101


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6.4
Efficacy Analyses ................................................................ 101
6.4.1
Co-Primary Efficacy Endpoints............................................ 101
6.4.1.1
Overall Survival ................................................................... 101
6.4.1.2
Independent Review Facility-Assessed 
Progression-Free Survival ................................................... 102
6.4.2
Secondary Efficacy Endpoints............................................. 103
6.4.3
Exploratory Efficacy Endpoints............................................ 105
6.5
Safety Analyses................................................................... 106
6.6
Pharmacokinetic Analyses................................................... 107
6.7
Immunogenicity Analyses.................................................... 108
6.8
Exploratory Biomarker Analyses.......................................... 108
6.9
Exploratory Health Status Analysis...................................... 108
6.10
Interim Analysis ................................................................... 108
6.11
China Subpopulation Analyses............................................ 109
7.
DATA COLLECTION AND MANAGEMENT ............................................. 110
7.1
Data Quality Assurance....................................................... 110
7.2
Electronic Case Report Forms............................................. 111
7.3
Source Data Documentation................................................ 111
7.4
Use of Computerized Systems ............................................ 112
7.5
Retention of Records........................................................... 112
8.
ETHICAL CONSIDERATIONS.................................................................. 112
8.1
Compliance with Laws and Regulations .............................. 112
8.2
Informed Consent................................................................ 112
8.3
Institutional Review Board or Ethics Committee.................. 114
8.4
Confidentiality...................................................................... 114
8.5
Financial Disclosure ............................................................ 115
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 115
9.1
Study Documentation .......................................................... 115
9.2
Protocol Deviations.............................................................. 115
9.3
Site Inspections ................................................................... 115
9.4
Administrative Structure....................................................... 116


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9.5
Dissemination of Data and Protection of Trade 
Secrets ................................................................................ 116
9.6
Protocol Amendments ......................................................... 117
10. REFERENCES ......................................................................................... 118
LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints................................... 38
Table 2
Study Treatment Regimens ........................................................ 60
Table 3
Administration of First and Subsequent Atezolizumab 
Infusions...................................................................................... 61
Table 4
Administration of First and Subsequent Bevacizumab 
Infusions...................................................................................... 62
Table 5
Timing for Vital Sign Measurements for First and 
Subsequent Infusions in Arm A................................................... 70
Table 6
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 87
Table 7
Causal Attribution Guidance ....................................................... 88
Table 8
Analysis Timing and Stopping Boundaries for Overall 
Survival ..................................................................................... 109
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 44
LIST OF APPENDICES
Appendix 1
Schedule of Activities................................................................ 123
Appendix 2
Schedule of Biomarker, Pharmacokinetic, and 
Immunogenicity Samples.......................................................... 128
Appendix 3
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1)........................................................ 129
Appendix 4
Immune-Modified Response Evaluation Criteria in Solid 
Tumors (imRECIST) ................................................................. 138
Appendix 5
European Organisation for Research and Treatment of
Cancer Quality-of-Life Questionnaire:  EORTC QLQ-C30 ........ 148
Appendix 6
EORTC QLQ-HCC18 Module ................................................... 150
Appendix 7
EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) ....... 151
Appendix 8
Preexisting Autoimmune Diseases and Immune Deficiencies .. 153
Appendix 9
Anaphylaxis Precautions........................................................... 154
Appendix 10
Child-Pugh Classification .......................................................... 155


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Appendix 11
Overall Guidelines for Management of Patients who 
Experience Adverse Events...................................................... 156
Appendix 12
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab ............................................................................ 162
Appendix 13 American Association for the Study of Liver Diseases Criteria:  
Algorithm for Investigation of Small Nodules Found on 
Screening in Patients at Risk for HCC ...................................... 189


Atezolizumab—F. Hoffmann-La Roche Ltd
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PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE III, OPEN-LABEL, RANDOMIZED STUDY 
OF ATEZOLIZUMAB IN COMBINATION WITH 
BEVACIZUMAB COMPARED WITH SORAFENIB IN 
PATIENTS WITH UNTREATED LOCALLY 
ADVANCED OR METASTATIC HEPATOCELLULAR 
CARCINOMA
PROTOCOL NUMBER:
YO40245
VERSION NUMBER:
6
EUDRACT NUMBER:
2017-003691-31
IND NUMBER:
135913
NCT NUMBER:
NCT03434379
TEST PRODUCTS:
Atezolizumab (RO5541267)
Bevacizumab (RO4876646)
MEDICAL MONITOR:
 M.D.
SPONSOR:
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—F. Hoffmann-La Roche Ltd
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PROTOCOL SYNOPSIS
TITLE:
A PHASE III, OPEN-LABEL, RANDOMIZED STUDY OF 
ATEZOLIZUMAB IN COMBINATION WITH BEVACIZUMAB 
COMPARED WITH SORAFENIB IN PATIENTS WITH UNTREATED 
LOCALLY ADVANCED OR METASTATIC HEPATOCELLULAR 
CARCINOMA
PROTOCOL NUMBER:
YO40245
VERSION NUMBER:
6
EUDRACT NUMBER:
2017-003691-31
IND NUMBER:
135913
NCT NUMBER:
NCT03434379
TEST PRODUCTS:
Atezolizumab (RO5541267)
Bevacizumab (RO4876646)
PHASE:
III
INDICATION:
Metastatic hepatocellular carcinoma (HCC)
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy and safety of atezolizumab in combination with 
bevacizumab compared with sorafenib in patients with locally advanced or metastatic 
hepatocellular carcinoma (HCC) who have received no prior systemic treatment.  
Specific objectives and corresponding endpoints for the study are outlined below.
Primary Efficacy Objective
Corresponding Endpoint
To evaluate the efficacy of 
atezolizumab bevacizumab 
compared with sorafenib

OS, defined as the time from randomization to death 
from any cause

PFS, defined as the time from randomization to the first 
occurrence of disease progression or death from any 
cause (whichever occurs first), as determined by an IRF 
according to RECIST v1.1
Secondary Efficacy Objectives
Corresponding Endpoints
To evaluate the efficacy of 
atezolizumab bevacizumab 
compared with sorafenib

OR, defined as a complete or partial response, as 
determined by the investigator according to 
RECIST v1.1

PFS as determined by the investigator according to 
RECIST v1.1

TTP, defined as the time from randomization to the first 
occurrence of disease progression, as determined by 
the investigator according to RECIST v1.1


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Secondary Efficacy Objectives
Corresponding Endpoints

DOR, defined as the time from the first occurrence of a 
documented objective response to disease progression 
or death from any cause (whichever occurs first), as 
determined by the investigator according to 
RECIST v1.1

Objective response as determined by an IRF according 
to RECIST v1.1

TTP as determined by an IRF according to 
RECIST v1.1

DOR as determined by an IRF according to 
RECIST v1.1

Objective response as determined by an IRF according 
to HCC mRECIST

PFS as determined by an IRF according to HCC 
mRECIST

TTP as determined by an IRF according to HCC 
mRECIST

DOR as determined by an IRF according to HCC 
mRECIST
To evaluate the association of 
pre-specified biomarkers with 
efficacy of 
atezolizumab bevacizumab 
compared with sorafenib

PFS as determined by the investigator and by an IRF 
according to RECIST v1.1 and OS by baseline serum 
AFP level (400 ng/mL vs. 400 ng/mL)
To evaluate PROs of 
disease/treatment-related 
symptoms, GHS/QoL, and function 
experienced by patients on 
atezolizumab bevacizumab versus 
sorafenib

TTD, defined as the time from randomization to first 
deterioration (decrease from baseline of 10 points), 
maintained for 2 consecutive assessments or 
1 assessment followed by death from any cause within 
3 weeks in the following EORTC QLQ-C30 subscales:
–
Physical functioning (PF)
–
Role functioning (RF)
–
GHS/QoL
Exploratory Efficacy Objectives
Corresponding Endpoints
To evaluate the efficacy of 
atezolizumabbevacizumab 
compared with sorafenib

Objective response as determined by the investigator 
according to imRECIST

PFS as determined by the investigator according to 
imRECIST

TTP as determined by the investigator according to 
imRECIST

DOR as determined by the investigator according to 
imRECIST


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Exploratory Efficacy Objectives
Corresponding Endpoints
To evaluate PROs of 
disease/treatment-related symptoms 
(including abdominal pain and 
itching), GHS/QoL, and function 
experienced by patients on 
atezolizumab bevacizumab versus 
sorafenib

Mean and mean changes from baseline score (by cycle) 
in all the subscales of the EORTC QLQ-C30 and 
QLQ-HCC18

Proportion of patients with clinically meaningful change 
in select scales of the QLQ-C30 (GHS/QoL, physical 
function, role function, appetite loss, diarrhea, fatigue, 
pain) and QLQ-HCC18 (fatigue, jaundice, pain)

TTD maintained for 2 consecutive timepoints, or 
1 timepoint followed by death from any cause within 
3 weeks, in select scales of the QLQ-C30 (appetite loss, 
diarrhea, fatigue, pain) and QLQ-HCC18 (jaundice, 
fatigue, pain)

TTD maintained for 2 consecutive timepoints, or 
1 timepoint followed by death from any cause, within 
3 weeks in HRQoL/GHS, physical function, and role 
function of the QLQ-C30

Proportion of responses for abdominal pain item 
(of QLQ-HCC18 pain subscale) and itching item 
(of QLQ-HCC18 jaundice subscale)
Safety Objective
Corresponding Endpoints
To evaluate the safety of 
atezolizumab bevacizumab 
compared with sorafenib

Incidence and severity of adverse events, with severity 
determined according to NCI CTCAE v4.0

Vital signs

Clinical laboratory test results
Pharmacokinetic Objective
Corresponding Endpoint
To characterize the PK profile of 
atezolizumab bevacizumab

Serum concentration of atezolizumab at specified 
timepoints
Immunogenicity Objective
Corresponding Endpoint
To evaluate the immune response to 
atezolizumab

Presence of ADAs to atezolizumab during the study 
relative to the presence of ADAs at baseline
Exploratory Immunogenicity 
Objective
Corresponding Endpoint
To evaluate potential effects of 
ADAs to atezolizumab on the 
efficacy, safety, and 
pharmacokinetics of 
atezolizumab bevacizumab

Efficacy, safety, or PK endpoints by ADA status


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Exploratory Biomarker Objective
Corresponding Endpoint
To identify tissue or blood-based 
biomarkers that are associated with 
response to 
atezolizumab bevacizumab versus 
sorafenib, or can increase the 
understanding of HCC disease evolution 
under atezolizumab bevacizumab 
treatment

PFS as determined by the investigator according 
to RECIST v 1.1 and OS based on the following 
biomarkers in tumor tissue:
–
Baseline expression of T effector gene 
signature in tumor tissue
–
Baseline PD-L1 protein expression in 
tumor tissue
–
CD8 protein expression level or 
CD8T-cell localization
–
IHCs or genes/gene signatures (by gene 
expression profiling) related to tumor 
microenvironments
–
T cell receptor sequence profile in 
tumor-associated T cells

Objective response as determined by the 
investigator according to RECIST v1.1 and OS 
based on the following biomarkers in blood:
–
Immune-related biomarkers profiling in 
plasma and serum (e.g., interleukin 2, 
interferon-)
Exploratory Health Status Objective
Corresponding Endpoint
To evaluate health status experienced by 
patients on atezolizumab bevacizumab 
versus sorafenib to generate utility 
scores for use in economic evaluations

Health utility and VAS scores of the EQ-5D-5L 
questionnaire
ADA anti-drug antibody; AFP -fetoprotein; DOR duration of response; EORTC European 
Organisation for Research and Treatment of Cancer; EQ-5D-5L EuroQol 5-Dimension 
Questionnaire, 5-Level version; GHS global health status; HCC hepatocellular carcinoma; 
HCC mRECIST modified RECIST for HCC; imRECIST immune-modified RECIST; 
IRF independent review facility; NCI CTCAE v4.0 National Cancer Institute Common 
Terminology Criteria for Adverse Events, v4.0; OS overall survival; PFS progression-free
survival; PK pharmacokinetic; PRO patient-reported outcome; QLQ-C30 quality-of-life 
questionnaire for cancer; QLQ-HCC18 HCC disease-specific module; QoL quality-of-life; 
RECIST v1.1 Response Evaluation Criteria in Solid Tumors, Version 1.1; TTD time to 
deterioration; TTP time to progression; VAS visual analog scale.
Study Design
Description of Study
This is a Phase III, randomized, multicenter, open-label, two-arm study designed to evaluate the 
efficacy and safety of atezolizumab and bevacizumab versus sorafenib in patients with locally 
advanced or metastatic HCC who have received no prior systemic treatment.
This study will enroll approximately 480 patients randomized in a 2:1 ratio to one of two
treatment arms:

Arm A (experimental arm):  Atezolizumab 1200 mg IV infusion every 3 weeks (Q3W; dosed 
in 3-week cycles) and bevacizumab 15 mg/kg Q3W (dosed in 3-week cycles)

Arm B (control arm):  Sorafenib 400 mg by mouth, twice a day (BID), continuously
Randomization will be stratified according to the following stratification factors:

Geographic region (Asia excluding Japan vs. rest of world)

Macrovascular invasion and/or extrahepatic spread (presence vs. absence)

Baseline -fetoprotein (400 vs. 400 ng/mL)


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
Eastern Cooperative Oncology Group Performance Status (0 vs. 1)
Patients randomized to the atezolizumab and bevacizumab arm (Arm A) who transiently 
withhold or permanently discontinue either atezolizumab or bevacizumab may continue on 
single-agent therapy as long as the patients are experiencing clinical benefit in the opinion of 
the investigator and after discussion with the Medical Monitor (i.e., patients transiently withheld 
or permanently discontinued from bevacizumab treatment for adverse effects may continue 
atezolizumab monotherapy and vice versa).
Patients will receive atezolizumab and/or bevacizumab or sorafenib 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).  In the absence of unacceptable toxicity, patients who meet criteria 
for disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
while receiving atezolizumab and/or bevacizumab or sorafenib will be permitted to continue the 
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

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
Tumor assessments will be performed at baseline and at regular intervals during study 
treatment.  Additional scans will be performed as clinically indicated. Tumor assessments will 
continue until disease progression, regardless of whether treatment has been discontinued 
(e.g., for toxicity).  Patients who meet RECIST v1.1 criteria for progression will undergo tumor 
assessments until disease progression (per immune-modified RECIST [imRECIST]) or loss of 
clinical benefit, whichever occurs later.  In the absence of disease progression, tumor 
assessments should continue regardless of whether patients start new anti-cancer therapy, until 
consent is withdrawn, death, or the study is terminated by the Sponsor, whichever occurs first.  
Following disease progression, patients will be followed for survival and subsequent anti-cancer 
therapies until death, loss to follow-up, withdrawal of consent, or study termination by Sponsor, 
whichever occurs first.
Sites will provide imaging used for tumor assessments to an IRF to enable centralized, 
independent review of response and progression endpoints.  These reviews will be performed 
prior to the pre-specified efficacy analyses.  Independent Review Facility membership and 
procedures will be detailed in an IRF Charter.
Safety assessments will include the incidence, nature, and severity of adverse events and 
laboratory abnormalities graded per the National Cancer Institute Common Terminology Criteria 
for Adverse Events, v4.0 (NCI CTCAE v4.0).  Laboratory safety assessments will include the 
regular monitoring of hematology and blood chemistry.  Serum samples will be collected to 
monitor the pharmacokinetics of atezolizumab when administered in combination with 
bevacizumab.  Patient samples, including archival tumor tissues as well as serum and plasma, 
will be collected for future exploratory biomarker assessments.
Number of Patients
The study will enroll approximately 480 patients at approximately 120 study sites.  
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 approximately 135 patients from 
mainland China in a China subpopulation.
The Sponsor is targeting a total enrollment of approximately 135 patients from mainland China.
After completion of the global enrollment phase, in the event that less than 135 patients from 
mainland China are enrolled, additional patients in China may be subsequently randomized into 
the two treatment arms in a 2:1 ratio in an extended China enrollment phase to ensure a total of 
approximately 135 patients from mainland China in a China subpopulation.  The China 


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subpopulation will include all patients enrolled in China (i.e., during both the global enrollment 
phase and the extended China enrollment phase).  The patients enrolled in the China extension 
phase will undergo the same schedule of activities and will receive atezolizumab and
bevacizumab, or sorafenib as in the global study.  The China subgroup analysis will be 
performed based on the China subpopulation.
Target Population
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, in the investigator's judgment

Locally advanced or metastatic and/or unresectable HCC with diagnosis confirmed by 
histology/cytology or clinically by American Association for the Study of Liver Diseases 
(AASLD) criteria in cirrhotic patients
Patients without cirrhosis require histological confirmation of diagnosis.

Disease that is not amenable to curative surgical and/or locoregional therapies, or 
progressive disease after surgical and /or locoregional therapies

No prior systemic therapy (including systemic investigational agents) for HCC
Previous use of herbal therapies/traditional Chinese medicines with anti-cancer activity 
included in the label is allowed, provided that these medications are discontinued prior to 
randomization.

At least 1 measurable (per RECIST 1.1) untreated lesion

Patients who received prior local therapy (e.g., radiofrequency ablation, percutaneous 
ethanol or acetic acid injection, cryoablation, high-intensity focused ultrasound, transarterial 
chemoembolization, transarterial embolization, etc.) are eligible provided the target lesion(s) 
have not been previously treated with local therapy or the target lesion(s) within the field of 
local therapy have subsequently progressed in accordance with RECIST v1.1

Pretreatment tumor tissue sample (if available)
If tumor tissue is available, a formalin-fixed, paraffin-embedded (FFPE) tumor specimen 
in a paraffin block (preferred) or approximately 1015 slides containing unstained, 
freshly cut, serial sections should be submitted along with an associated pathology 
report within 4 weeks of randomization.
If FFPE specimens described above are not available, any type of specimens (including 
fine-needle aspiration, cell pellet specimens [e.g., from pleural effusion], and lavage 
samples) are also acceptable.  This specimen should be accompanied by the associated 
pathology report.
If tumor tissue is not available (e.g., depleted because of prior diagnostic testing), 
patients are still eligible.

Eastern Cooperative Oncology Group Performance Status of 0 or 1 within 7 days prior to 
randomization

Child-Pugh Class A within 7 days prior to randomization

Adequate hematologic and end-organ function, defined by the following laboratory test 
results, obtained within 7 days prior to randomization, unless otherwise specified:

ANC 1.5 109/L (1500/L) without granulocyte colony-stimulating factor support

Lymphocyte count 0.5 109/L (500/L)
–
Platelet count 75109/L (75,000/L) without transfusion 
–
Hemoglobin 90 g/L (9 g/dL)
Patients may be transfused to meet this criterion.
–
AST, ALT, and alkaline phosphatase (ALP) 5upper limit of normal (ULN)
–
Serum bilirubin 3ULN


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–
Serum creatinine 1.5ULN or creatinine clearance 50 mL/min (calculated using the 
Cockcroft-Gault formula)
–
Serum albumin 28 g/L (2.8 g/dL) without transfusion
–
For patients not receiving therapeutic anticoagulation:  INR or aPTT 2ULN
–
Urine dipstick for proteinuria 2(within 7 days prior to initiation of study treatment)
Patients discovered to have 2proteinuria on dipstick urinalysis at baseline 
should undergo a 24-hour urine collection and must demonstrate 1 g of protein in 
24 hours.

Resolution of any acute, clinically significant treatment-related toxicity from prior therapy to 
Grade 1 prior to study entry, with the exception of alopecia

Negative HIV test at screening

Documented virology status of hepatitis, as confirmed by screening hepatitis B virus (HBV)
and hepatitis C virus (HCV) serology test

For patients with active HBV:
HBV DNA 500 IU/mL obtained within 28 days prior to initiation of study treatment, and
Anti-HBV treatment (per local standard of care; e.g., entecavir) for a minimum of 14 days 
prior to study entry and willingness to continue treatment for the length of the study

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods with a failure rate of 1% per year 
during the treatment period and for at least 5 months after the last dose of atezolizumab,
6 months after the last dose of bevacizumab, or 6 months after the last dose of sorafenib.  
Women must refrain from donating eggs during this 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 has not undergone surgical sterilization 
(removal of ovaries and/or uterus).
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 acceptable methods of contraception.

For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential, men must remain abstinent or use a 
condom plus an additional contraceptive method that together result in a failure rate of 
1% per year during the treatment period and for 6 months after the last dose of 
bevacizumab or 3 months after the last dose of sorafenib.  Men must refrain from 
donating sperm during this same period.
With pregnant female partners, men must remain abstinent or use a condom during the 
treatment period and for 6 months after the last dose of bevacizumab or 3 months after 
the last dose of sorafenib to avoid exposing the embryo.
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 acceptable methods of contraception.

For the extended China enrollment phase:  Chinese ancestry and residence in Mainland 
China, Hong Kong, or Taiwan with enrollment at sites recognized by the China Center for 
Drug Evaluation


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Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

History of leptomeningeal disease

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, 
Wegener granulomatosis, 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
–
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 previous 12 months

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 computed tomography (CT) scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Known active tuberculosis

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 
initiation of study treatment), unstable arrhythmia, or unstable angina 

History of congenital long QT syndrome or corrected QT interval 500 ms (calculated with 
use of the Fridericia method) at screening

History of uncorrectable electrolyte disorder affecting serum levels of potassium, calcium, or 
magnesium

Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study 
treatment, or anticipation of need for a major surgical procedure during the study

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 overall survival 
[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

Severe infection within 4 weeks prior to initiation of study treatment, 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 initiation of study 
treatment
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

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


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
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, 
or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months 
after the last dose of atezolizumab

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 formulation 

Pregnant or breastfeeding, or intention of becoming pregnant during study treatment or 
within at least 5 months after the last dose of atezolizumab, 6 months after the last dose of 
bevacizumab, or 6 months after the last dose of sorafenib
Women of childbearing potential must have a negative serum pregnancy test result 
within 14 days prior to initiation of study treatment.

Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC

Untreated or incompletely treated esophageal and/or gastric varices with bleeding or high 
risk for bleeding
Patients must undergo an esophagogastroduodenoscopy (EGD), and all size of varices 
(small to large) must be assessed and treated per local standard of care prior to 
enrollment.  Patients who have undergone an EGD within 6 months of prior to initiation 
of study treatment do not need to repeat the procedure. 

A prior bleeding event due to esophageal and/or gastric varices within 6 months prior to 
initiation of study treatment

Moderate or severe ascites

History of hepatic encephalopathy

Coinfection of HBV and HCV
Patients with a history of HCV infection but who are negative for HCV RNA by PCR will 
be considered non-infected with HCV.

Symptomatic, untreated, or actively progressing CNS metastases
Asymptomatic patients with treated CNS lesions are eligible, provided that all of the 
following criteria are met:
–
Measurable disease, per RECIST v1.1, must be present outside the CNS.
–
The patient has no history of intracranial hemorrhage or spinal cord hemorrhage.
–
Metastases are limited to the cerebellum or the supratentorial region (i.e., no 
metastases to the midbrain, pons, medulla, or spinal cord).
–
There is no evidence of interim progression between completion of CNS-directed 
therapy and initiation of study treatment.
–
The patient has not undergone stereotactic, whole-brain radiotherapy, and/or 
neurosurgical resection within 28 days prior to initiation of study treatment.
–
The patient has no ongoing requirement for corticosteroids as therapy for CNS 
disease.  Anticonvulsant therapy at a stable dose is permitted.

Asymptomatic patients with CNS metastases newly detected at screening are eligible for 
the study after receiving radiotherapy or surgery, with no need to repeat the screening brain 
scan.

Uncontrolled tumor-related pain
Patients requiring pain medication must be on a stable regimen at study entry.
Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) 
amenable to palliative radiotherapy should be treated prior to enrollment.  Patients 
should be recovered from the effects of radiation.  There is no required minimum 
recovery period.
Asymptomatic metastatic lesions that would likely cause functional deficits or intractable 
pain with further growth (e.g., epidural metastasis that is not currently associated with 


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spinal cord compression) should be considered for locoregional therapy if appropriate 
prior to enrollment.

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently)
Patients with indwelling catheters (e.g., PleurX) are allowed.

Uncontrolled or symptomatic hypercalcemia (ionized calcium 1.5 mmol/L, 
calcium 12 mg/dL or corrected serum calcium ULN)

Treatment with investigational therapy within 28 days prior to initiation of study treatment

Treatment with strong CYP3A4 inducers within 14 days prior to initiation of study treatment, 
including rifampin (and its analogs) or St. John's wort

Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including 
antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic antibodies 

Treatment with systemic immunostimulatory agents (including, but not limited to, interferon 
and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior 
to initiation of study treatment

Treatment with systemic immunosuppressive medication (including, but not limited 
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
antiTNF-agents) within 2 weeks prior to initiation of study treatment, 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 for the study after Medical Monitor 
approval has been obtained.
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for 
chronic obstructive pulmonary disease (COPD) 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 blood pressure 100 mmHg), based on an average of 
3 BP readings on 2 sessions
Anti-hypertensive therapy to achieve these parameters is allowable.

Prior 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 initiation of study treatment

History of hemoptysis (2.5 mL of bright red blood per episode) within 1 month prior to 
initiation of study treatment

Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic 
anticoagulation)

Current or recent (within 10 days of first dose of study treatment) use of aspirin 
(325 mg/day) or treatment with dipyramidole, ticlopidine, clopidogrel, and cilostazol

Current or recent (within 10 days prior to study treatment start) use of full-dose oral or 
parenteral anti-coagulants 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 within 14 days prior to initiation of study treatment.
For prophylactic use of anti-coagulants or thrombolytic therapies, local label approved 
dose levels may be used.

Core biopsy or other minor surgical procedure, excluding placement of a vascular access 
device, within 3 days prior to the first dose of bevacizumab

History of abdominal or tracheoesophageal fistula, gastrointestinal (GI) perforation, or 
intra-abdominal abscess within 6 months prior to initiation of study treatment


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
History of intestinal obstruction and/or clinical signs or symptoms of GI obstruction including 
sub-occlusive disease related to the underlying disease or requirement for routine 
parenteral hydration, parenteral nutrition, or tube feeding prior to initiation of study treatment
Patients with signs/symptoms of sub-/occlusive syndrome/intestinal obstruction at time 
of initial diagnosis may be enrolled if they had received definitive (surgical) treatment for 
symptom resolution.

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

Metastatic disease that involves major airways or blood vessels, or centrally located 
mediastinal tumor masses (30 mm from the carina) of large volume
Patients with vascular invasion of the portal or hepatic veins may be enrolled.  

History of intra-abdominal inflammatory process within 6 months prior to initiation of study 
treatment, including but not limited to active peptic ulcer disease, diverticulitis, or colitis

Radiotherapy within 28 days and abdominal/ pelvic radiotherapy within 60 days prior to 
initiation of study treatment, except palliative radiotherapy to bone lesions within 7 days 
prior to initiation of study treatment

Local therapy to liver (e.g., radiofrequency ablation, percutaneous ethanol or acetic acid 
injection, cryoablation, high-intensity focused ultrasound, transarterial chemoembolization, 
transarterial embolization, etc.) within 28 days prior to initiation of study treatment or 
non-recovery from side effects of any such procedure

Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to 
initiation of study treatment, or abdominal surgery, abdominal interventions or significant 
abdominal traumatic injury within 60 days prior to initiation of study treatment or anticipation 
of need for major surgical procedure during the course of the study or non-recovery from 
side effects of any such procedure

Chronic daily treatment with a nonsteroidal anti-inflammatory drug (NSAID)
Occasional use of NSAIDs for the symptomatic relief of medical conditions such as 
headache or fever is allowed.
End of Study
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs 
(i.e., last patient in the global and extended China enrollment phases combined) or safety 
follow-up is received from the last patient (global and extended China enrollment phases 
combined), whichever occurs later.
In addition, the Sponsor may decide to terminate the study at any time.
Investigational Medicinal Products
Patients will receive treatment as outlined below 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).


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Arm
Cycle 
Length
Dose, Route, and Regimen
(drugs listed in order of 
administration)
Infusion Rate
A a
21 days
Atezolizumab 1200 mg IV on Day 1
Over 60 (15) minutes (for the 
first infusion); 30 (10) minutes for 
subsequent infusions if tolerated
Bevacizumab 15 mg/kg IV on Day 1
Over 90 (15) minutes (for the 
first infusion); shortening to 
60 (10) then 30 (10) minutes
for subsequent infusions if 
tolerated
B
21 days
Sorafenib 400 mg BID, by mouth, 
continuously
Not applicable
BIDtwice per day.
a For patients randomized to Arm A, on Day 1 of each cycle, atezolizumab will be administered 
first, followed by bevacizumab, with a minimum of 5 minutes between dosing.
Statistical Methods
Primary Analysis
The primary efficacy objective for this study is to evaluate the efficacy of atezolizumab in 
combination with bevacizumab compared with sorafenib on the basis of the co-primary efficacy 
endpoints of OS and IRF-assessed PFS according to RECIST v1.1.
Overall survival and PFS will be tested initially in parallel with the overall type I error controlled 
at a 2-sided significance level of 0.05, where OS will be tested at a 2-sided significance level of 
0.048 and PFS will be tested at a 2-sided significance level of 0.002.
Overall Survival
Overall survival is defined as the time from the date of randomization to the date of death from 
any cause. Patients who are alive at the time of the analysis data cutoff will be censored at the 
last date they were known to be alive. Patients with no post-baseline information will be 
censored at the date of randomization.
The 2-sided log-rank test, stratified by geographic region (Asia excluding Japan vs. rest of 
world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and 
baseline -fetoprtein (AFP; 400 vs. 400 ng/mL), will be used as the primary analysis to 
compare OS between the two treatment arms. The results from the unstratified log-rank test 
will also be provided as a sensitivity analysis to check the robustness of the results of the 
stratified log-rank test.
The Kaplan-Meier method will be used to estimate median OS for each treatment arm. 
Brookmeyer-Crowley methodology will be used to calculate the 95% CI for the median OS for 
each treatment arm.  Stratified Cox proportional-hazards models will be used to estimate the 
hazard ratio (HR) and its 95% CIs. The stratification factors will be the same as those used for 
the primary stratified log-rank test.  The unstratified HR will also be provided.
A group sequential design will be used for testing the co-primary efficacy endpoint OS to 
account for the conduct of 2 interim analyses.  An -spending with use of the Lan-De Mets
method approximating O'Brien-Fleming boundaries will be utilized to control the overall type I 
error rate of 0.048 for the OS co-primary efficacy endpoint.  The first interim OS analysis will be 
conducted at time of the co-primary analysis of IRF-assessed PFS.  The second interim OS 
analysis is planned to be conducted when approximately 243 OS events have been observed.
The final analysis of OS is expected to occur after approximately 312 deaths have occurred. 
If statistical significance is reached at one of the pre-planned interim analyses of OS, then 
that interim OS analysis will be regarded as the definitive analysis of OS and subsequent 
analyses of OS, including the final OS analysis, will be descriptive and considered as optional.
IRF-Assessed Progression-Free Survival
Independent Review Facility-assessed PFS is defined as the time from randomization to the 
occurrence of disease progression as determined by the IRF according to RECIST v1.1, or 


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death from any cause, whichever occurs first.  Patients who have not experienced disease 
progression or death at the time of the clinical cutoff date will be censored at the time of the last 
tumor assessment on or prior to the clinical cutoff date.  Patients with no post-baseline tumor 
assessment will be censored at the date of randomization.
Methods for PFS analyses are similar to those described for the OS endpoint.
Determination of Sample Size
A total of approximately 480 patients will be randomized in the global enrollment phase of this 
study, with use of a 2:1 randomization ratio to allocate patients to either the atezolizumab and 
bevacizumab arm (Arm A) or the sorafenib arm (Arm B).  The final OS analysis will be 
conducted at approximately 33 months after the first patient is randomized (first patient in [FPI]).
The final OS analysis will be descriptive and considered as optional if statistical significance 
is achieved at one of the pre-planned interim analyses of OS.
The co-primary efficacy endpoints for this study are as follows:

OS, defined as the time from randomization to death from any cause

IRF-assessed PFS, defined as the time from randomization to the occurrence of disease 
progression per RECIST v1.1 or death from any cause, whichever occurs first. 
The overall type I error rate for this study will be controlled at a 2-sided significance level of 0.05 
by a graphical approach (i.e., -splitting and recycling).  The overall 2-sided significance level of 
0.05 will be split into a 2-sided significance level of 0.048 for the testing of OS and a 2-sided
significance level of 0.002 for the testing of PFS as a first step.
The sample size of the study was determined based on the number of deaths required to
demonstrate efficacy in terms of OS.  To detect an improvement in OS using a log-rank test at a 
2-sided significance level of 0.048, approximately 312 deaths will be required to achieve 80% 
overall power assuming a target HR of 0.71 (median OS improvement vs. control is 4.9 months). 
The minimum detectable difference (MDD) of OS is an HR of 0.783 (median OS improvement is 
3.3 months). Three-hundred and twelve deaths are expected to occur approximately 33 months 
after FPI.
The calculation of sample size and estimates of the OS analysis timelines are based on the 
following assumptions:

Patients will be randomized to the atezolizumab bevacizumab and sorafenib arms in a 
2:1 ratio.

OS follows a one-piece exponential distribution.

The median OS in the control arm is 12 months.

The stopping boundaries of the interim and final analyses of OS use the O'Brien-Fleming 
boundaries approximated using the Lan-DeMets method.

The dropout rate is 5% for the atezolizumab bevacizumab arm and 10% for the sorafenib 
arm over 12 months for OS.

The recruitment of approximately 480 patients will take place over approximately 10 months
Interim Analysis
No interim analysis is planned for PFS in this study.
Two interim analyses of OS are planned to be performed.  The first interim analysis will be 
performed at the time of the primary PFS analysis, estimated to occur at approximately 
16 months after FPI.  It is anticipated that at this time approximately 172 deaths will have been 
observed.  The respective MDD OS HR is 0.633 (median OS improvement is 6.9 months).  
The second OS interim analysis is planned to be conducted when approximately 243 deaths are 
accumulated, estimated to occur at approximately 24 months after FPI.  The respective MDD 
OS HR is 0.728 (median OS improvement is 4.6 months).
To control the 2-sided significance level at 0.048 for the interim and final OS analyses, the 
Lan-DeMets method will be used to approximate the O'Brien-Fleming boundaries.
The planned interim analyses for OS will be conducted by the Sponsor.


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Analysis 
Timing
Planned 
Information 
Fraction
Required 
Events/
Analysis timing
(estimated)
Stopping Boundary
(2-Sided p-value)
can be recycled to 
OS (i.e., OS 0.05)
cannot be recycled 
to OS 
(i.e., OS 0.048)
1st OS 
interim 
analysis
55%
172/16 months
MDD.HR 0.636
(p-value 0.005)
MDD.HR 0.633
(p-value 0.005)
2nd OS 
interim 
analysis
78%
243/24 months
MDD.HR 0.73
(p-value 0.021)
MDD.HR 0.728
(p-value 0.02)
OS final 
analysis
100%
312/33 months
MDD.HR 0.784
(p-value 0.043)
MDD.HR 0.783
(p-value 0.041)
HR hazard ratio; MDD minimum detectable difference; OS overall survival; 
PFS=progression-free survival.
Analysis timing shown in the table is projected based on protocol assumptions. Actual timing 
depends on the exact time that the required events have accrued.
The 1st OS interim analysis will be conducted when approximately 308 PFS events have 
happened.  If statistical significance is reached at one of the pre-planned interim analyses of 
OS, then that interim OS analysis will be regarded as the definitive analysis of OS and 
subsequent analyses of OS, including the final OS analysis, will be descriptive and considered 
as optional.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
16W-DCR
disease-control rate at 16 weeks 
AASLD
American Association for the Study of Liver Diseases
ADA
anti-drug antibody
AFP
-fetoprotein
APASL
Asian-Pacific Association for the Study of the Liver
ASCO
American Society of Clinical Oncology
BID
twice a day
BP
blood pressure
CDE
Center of Drug Evaluation (China)
COPD
chronic obstructive pulmonary disease
CR
complete response
CRC
carcinoma of the colon or rectum
CSR
Clinical Study Report
CT
computed tomography
DOR
duration of response
EC
Ethics Committee
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EGD
esophagogastroduodenoscopy
EOC
epithelial ovarian cancer
EORTC
European Organisation for Research and Treatment of Cancer
EQ-5D-5L
EuroQol 5-Dimension, 5-Level Questionnaire
FDA
(U.S.) Food and Drug Administration
FPI
first patient in
FFPE
formalin-fixed, paraffin-embedded
FTC
fallopian tube cancer
GBM
glioblastoma multiforme
GHS
global health status
GI
gastrointestinal
HBcAb
hepatitis B core antibody
HBV
hepatitis B virus
HBsAg
hepatitis B surface antigen
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act


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Abbreviation
Definition
HR
hazard ratio
HRQoL
health-related quality-of-life
ICH
International Council for Harmonisation
iDMC
independent Data Monitoring Committee
IL-2
interleukin-2
IMP
investigational medicinal product
imRECIST
immune-modified RECIST
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
IRF
Independent Review Facility
IRR
infusion-related reaction
ITT
intent-to-treat
IxRS
interactive voice or Web-based response system
LMWH
low molecular weight heparin
LPLV
last patient, last visit
MDD
minimum detectable difference
MID
minimally important differences
mRECIST
modified Response Evaluation Criteria in Solid Tumors
MRI
magnetic resonance imaging
NCCN
National Comprehensive Cancer Network
NCI CTCAE
National Cancer Institute Common Terminology Criteria for 
Adverse Events
NE
not evaluable
NGS
next-generation sequencing
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
nonsmall-cell lung cancer
ORR
objective response rate
OS
overall survival
PCR
polymerase chain reaction
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic
PPC
primary peritoneal cancer
PR
partial response
PRO
patient-reported outcome
Q2W
every 2 weeks
Q3W
every 3 weeks


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Abbreviation
Definition
QLQ-C30
quality-of-life questionnaire for cancer
QLQ-HCC18
quality-of-life questionnaire for cancer HCC disease-specific 
module
QoL
quality-of-life
RBR
Research Biosample Repository
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
SAP
Statistical Analysis Plan
SD
stable disease
SHARP
Sorafenib HCC Assessment Randomized Protocol (trial)
TTD
time to deterioration
TTP
time to progression
UC
urothelial carcinoma
ULN
upper limit of normal
VAS
visual analog scale
VEGF
vascular endothelial growth factor
VTE
venous thromboembolism
WES
whole-exome sequencing
WGS
whole-genome sequencing


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1.
BACKGROUND
1.1
BACKGROUND ON HEPATOCELLULAR CARCINOMA
Hepatocellular carcinoma (HCC) is the sixth most common cancer globally and is the 
second most deadly cancer (International Agency for Research on Cancer 2012). 
There are over 700,000 new cases diagnosed each year worldwide with large 
geographic variation in both risk factors and incidence (Ferlay et al. 2010; 
El-Serag 2011). The majority (80%) of cases occur in sub-Saharan Africa and eastern 
Asia, and China alone accounts for 55% of cases worldwide. Hepatitis B virus (HBV) 
infection is the main risk factor for HCC in Asia and Africa, while in Western countries 
and Japan, the main risk factor is hepatitis C virus (HCV) infection and excessive alcohol 
intake, along with other causes of cirrhosis.
Hepatocellular carcinoma is a highly lethal disease with the highest 
mortality-to-incidence rate ratio of 0.98 of any solid tumor (Kamangar et al. 2006). Up to 
80% of patients first presenting with HCC have advanced unresectable or metastatic 
disease because of the late appearance of symptoms. It is a medically complex and 
difficult to treat disease because the majority of patients with HCC have underlying 
cirrhosis requiring management of both the malignancy and the cirrhosis. In the 
United States, at 5 years, the overall survival (OS) rate of patients with HCC is 17% and 
falls substantially to only 3% if present with distant metastasis (Siegel et al. 2016).  
In China, at 5 years, the OS rate of patients with HCC is 10.1% (Chen et al. 2016).
1.2
CURRENT SYSTEMIC TREATMENT FOR ADVANCED 
HEPATOCELLULAR CARCINOMA
Prior to the approval of sorafenib (Nexavar), there was no globally approved systemic 
treatment for patients presenting with unresectable advanced or metastatic HCC.
Doxorubicin was the most widely used cytotoxic agent, and is reported to have an 
11%15% response rate (Mok et al. 1999; Zhu 2006; Lind et al. 2007). More aggressive 
combinations of cytotoxic chemotherapy have not been shown to increase OS rates and 
have been associated with considerable toxicity (Yeo et al. 2005).
Sorafenib, an oral multi-kinase inhibitor, was first approved in 2007 by the U.S. Food and 
Drug Administration (FDA) and is currently considered the global standard of care for the 
first-line treatment of patients with advanced HCC.  The efficacy of sorafenib has been 
demonstrated in 2 large multicenter, randomized, double-blind, placebo-controlled 
Phase III trials:  the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial 
and a trial conducted in the Asia-Pacific region.  Both studies demonstrated a survival 
benefit of sorafenib versus placebo.  In the SHARP trial, median OS was 10.7 months 
with sorafenib versus 7.9 months with placebo (hazard ratio [HR]0.69 [95% CI: 0.55, 
0.87]); in the Asia-Pacific trial, median OS was 6.5 months versus 4.2 months (HR0.68 
[95% CI: 0.50, 0.93]).  Benefit in median time to radiographic progression was also 
demonstrated:  5.5 months versus 2.8 months in the SHARP trial (HR0.58 
[95% CI: 0.5, 0.7]) and 2.8 months versus 1.4 months in the Asia-Pacific trial 


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(HR0.6 [95% CI: 0.4, 0.8]).  The objective response rate (ORR; per RECIST v1.0) was 
2.3% (7 of 299 patients) in the SHARP trial and 3.3% (5 of 150 patients) in the 
Asia-Pacific trial. The numerically shorter OS and duration of benefit in the Asia-Pacific 
trial may be largely attributed to the fact that patients had more advanced disease at the 
time of recruitment, and potentially also to the regional difference in etiology and 
supportive care (Llovet et al. 2008; Cheng et al. 2009).
Despite the survival benefit reported from these 2 Phase III studies, the overall 
benefit-risk ratio of sorafenib is modest given the known toxicity.  Adverse events
commonly reported across both sorafenib studies included handfoot skin reaction, 
diarrhea, hypertension, weight loss, fatigue, anorexia, alopecia, nausea, and 
rash/desquamation.  Drug-related adverse events reported were predominantly 
Grade 1 or 2 in severity.  The drug discontinuation rate in patients receiving sorafenib 
was 38% in the SHARP trial compared with 20% in the Asia-Pacific trial.  The frequency 
of dose reductions due to adverse events was similar between the 2 studies
(26% in SHARP and 30.9% in the Asia-Pacific trial; Llovet et al. 2008; Cheng et al. 2009).  
Despite additional clinical experience with the use of sorafenib, the GIDEON study, 
which evaluated sorafenib in the real-world setting, showed the drug discontinuation 
rates due to adverse events in patients starting at the label-recommended dose of 
800 mg was 27%, indicating that tolerability has not improved.  Moreover, GIDEON 
showed that in real-life practice, the starting dose of 800 mg daily (400 mg twice a day 
[BID]) is halved to 400 mg daily in over 22% of patients (Lencioni et al. 2014).
Since the approval of sorafenib, there have been a number of Phase III trial failures in 
first-line HCC in head-to-head comparisons with sorafenib, including sunitinib, brivanib,
and linifanib (Cheng et al. 2013; Johnson et al. 2013; Cainap et al. 2015).  Recently, 
front-line treatment with lenvatinib, a multi-targeted receptor tyrosine kinase inhibitor, 
was shown to be non-inferior to sorafenib in terms of OS (lenvatinib vs. sorafenib: 
median OS 13.6 months vs. 12.3 months; HR0.92 [95% CI: 0.79, 1.06]; 
Cheng et al. 2017) though a clinically meaningful difference in OS from the accepted 
standard of care remains elusive.  Therefore, there remains an ongoing high unmet 
medical need for patients with advanced unresectable HCC, requiring further evaluation 
of treatment with novel, more efficacious, and less toxic agents.
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.


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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 for the treatment of urothelial carcinoma (UC), nonsmall-cell 
lung cancer (NSCLC), small-cell lung cancer, and triple-negative breast cancer.
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and 
clinical studies.
1.4
BACKGROUND ON BEVACIZUMAB
Avastin(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 contains human framework 
regions and the complementarity-determining regions of a murine antibody that binds to 
VEGF, and has an approximate molecular weight of 149 kD.  Bevacizumab is produced 
in a mammalian Chinese hamster ovary cell line.
Bevacizumab was first granted marketing approval in the United States on 
26 February 2004 (international birth date) in combination with IV 5-fluorouracil 
(5-FU)based chemotherapy for the first-line treatment of patients with metastatic 
carcinoma of the colon or rectum (CRC).  As of November 2016, bevacizumab has been 
approved for use in over 100 countries worldwide in a variety of indications, including 
locally recurrent or metastatic breast cancer; advanced, metastatic, or recurrent NSCLC;
advanced and/or metastatic renal cell cancer (RCC); newly diagnosed glioblastoma 
multiforme (GBM) and GBM after relapse or disease progression; persistent, recurrent, 
or metastatic cervical cancer; front-line treatment of epithelial ovarian cancer (EOC), 
primary peritoneal cancer (PPC), or fallopian tube cancer (FTC); and treatment of 
platinum-sensitive and platinum-resistant recurrent EOC, PPC, or FTC.
1.5
OVERVIEW OF CLINICAL DEVELOPMENT PROGRAM IN 
HEPATOCELLULAR CARCINOMA
1.5.1
Atezolizumab Monotherapy
A comprehensive overview of atezolizumab efficacy across all indications is provided in 
the Atezolizumab Investigator's Brochure.  This section provides an overview of the 
available efficacy data in patients with HCC treated with atezolizumab as a monotherapy.  
To date, atezolizumab used as a single agent has shown minimal activity in the 
treatment of patients with HCC with similar characteristics as those that would be 
included in this study. Safety findings in the HCC cohort are in line with expectations for
an HCC population and with the atezolizumab safety profile observed in the overall study 


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population across multiple tumor types. No new safety signals related to atezolizumab 
monotherapy were observed in the HCC population.
Study PCD4989g
Study PCD4989g is a Phase Ia, multicenter, first-in-human, open-label, dose-escalation 
study evaluating the safety, tolerability, immunogenicity, pharmacokinetics, exploratory 
pharmacodynamics, and preliminary evidence of biologic activity of atezolizumab 
administered as a single agent by IV infusion every 3 weeks (Q3W) to patients with 
locally advanced or metastatic solid malignancies or hematologic malignancies.  
The largest cohorts enrolled into this trial consisted of patients with NSCLC, RCC, and 
UC.  Expansion cohorts have included patients with CRC, melanoma, NSCLC, 
pancreatic cancer, UC, breast cancer, esophageal cancer, prostate cancer, small-cell 
lung cancer, malignant lymphoma, multiple myeloma, HCC, and other less common 
tumor types.
In the analysis of Study PCD4989g (clinical cutoff date of 31 December 2016) conducted 
in 15 patients with first- and later-line HCC, the median duration of treatment was 
2.0 months (range: 0.76.3 months).  At the time of the clinical cutoff date, 1 patient 
remained on treatment, 12 patients had discontinued treatment due to disease 
progression, 1 patient discontinued because of an adverse event, and 1 patient was 
discontinued as per the physician's decision.
Of the 15 response-evaluable patients, none had an objective response (confirmed 
complete response [CR] or partial response [PR] as assessed by the investigator per the
Response Evaluation Criteria in Solid Tumors [RECIST] v1.1).  Four patients (33.3%) 
had stable disease (SD) 24 weeks.  No patients had SD 24 weeks.  
Median progression-free survival (PFS) per the investigator assessment per 
RECIST v1.1 was 2.3 months (95% CI: 1.3, 3.4) and median OS was 5.3 months 
(95% CI: 2.4, NE).
Study YO29233
Study YO29233 is a Phase I, open-label, multicenter study evaluating the
pharmacokinetics, safety, and preliminary anti-tumor activity of atezolizumab as a 
monotherapy in Chinese patients with locally advanced or metastatic gastric cancer, 
nasopharyngeal carcinoma, esophageal cancer, HCC and other solid tumors, and the 
safety and preliminary anti-tumor activity of atezolizumab in combination with 
gemcitabine and cisplatin in Chinese patients with Stage IV, treatment-naive NSCLC. 
For monotherapy cohorts, atezolizumab is administered as a single agent at a dose of 
1200 mg IV Q3W.
Based on a clinical cutoff date of 1 April 2018, 21 patients with HCC had received 
atezolizumab monotherapy. At the time of the clinical cutoff date, 7 patients remained 
on treatment (3 first-line patients with HCC), while 7 patients had discontinued treatment 
due to disease progression, 2 patients discontinued treatment due to an adverse event, 


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2 patients discontinued treatment due to non-compliance with study drug, and 1 patient 
each discontinued treatment due to a protocol deviation, physician decision, and death 
due to progression of disease.
Of the 21 efficacy-evaluable patients (first-line and second-line or greater), 2 patients 
(9.5% [95% CI: 1.17%, 30.38%]) had a confirmed objective response and 11 patients 
(52.4% [95% CI: 29.78%, 74.29%]) had the best response of SD.  Median PFS 
was 2.8 months (95% CI: 1.4, 7.8) and median OS was 11.1 months 
(95% CI: 4.7 months, NE).
1.5.2
Bevacizumab Monotherapy
A comprehensive overview of bevacizumab efficacy across all indications is provided in 
the Bevacizumab Investigator's Brochure.  This section provides an overview of the 
available efficacy data in patients with HCC treated with bevacizumab as a monotherapy.  
Overall, bevacizumab as a single agent demonstrated minimal activity in HCC, and is
unlikely to demonstrate a meaningful clinical benefit over the current standard of care 
(sorafenib) based on the survival data observed. Bevacizumab monotherapy was 
generally safe and well-tolerated in the HCC population, and safety findings were 
consistent with the HCC population and the established safety profile of bevacizumab.  
No new safety signals related to bevacizumab monotherapy were observed in this 
patient population.
Phase II Study of Bevacizumab in Unresectable Hepatocellular Carcinoma
This study was a Phase II, single-center, single-arm trial designed to evaluate the clinical 
and biological effects of bevacizumab in unresectable HCC (Siegel et al. 2008).  
Adult patients with organ-confined HCC, an Eastern Cooperative Oncology Group 
(ECOG) Performance Status of 02, and compensated liver function 
(Child-Pugh Class A or B7), received bevacizumab 5 mg/kg or 10 mg/kg every 2 weeks 
(Q2W) until disease progression or treatment-limiting toxicity.  Of note, patients with 
extrahepatic disease or tumor invasion of the main portal vein or inferior vena cava were 
excluded. Given the known prognostic value of these factors, the study likely enrolled a 
population with a more favorable prognosis and treatment outcome compared with a 
population that would typically be enrolled in a first-line HCC study. The primary 
objective was to determine whether bevacizumab improved the 6-month PFS rate from 
40% to at least 60%.  Overall, 46 patients were enrolled, including 12 patients who 
received bevacizumab 5 mg/kg and 34 patients who received bevacizumab 10 mg/kg 
Q2W.
Clinical activity of bevacizumab was observed in patients with non-metastatic HCC.  
Of the 46 patients, 6 patients (13%) had objective responses (95% CI: 3%, 23%), and 
65% (95% CI: 51%, 79%) of patients were progression-free at 6 months.  Median PFS 
was 6.9 months (95% CI: 6.5, 9.1) and median OS was 12.4 months (95% CI: 9.4, 19.9).  
No significant changes were seen with respect to dose and outcome.  The response 
rates for the 5 mg/kg and 10 mg/kg groups were 8.3% and 14.7%, respectively 


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(p0.99 by Fisher's exact test).  Median OS times for patients receiving 5 mg/kg and 
10 mg/kg were 15.1 months and 12.2 months, respectively (p0.64 by the log-rank test;
Siegel et al. 2008).
Phase II Study of Bevacizumab in Advanced Hepatocellular Carcinoma
This study was a Phase II, single-center, single-arm trial designed to evaluate the 
efficacy, safety, and potential biomarkers of the activity of bevacizumab in patients with 
advanced HCC (Boige et al. 2012).  Patients with histologically-confirmed advanced 
HCC that was not amenable to curative-intent therapies (e.g., resection, liver 
transplantation, or percutaneous ablation) received bevacizumab 5 mg/kg or 10 mg/kg 
Q2W until disease progression or unacceptable toxicity.  The primary objective was to 
determine the disease-control rate at 16 weeks (16W-DCR) defined as the proportion of 
patients with a CR, PR, or SD at 16 weeks after study entry, according to RECIST v1.0.
Overall, 48 patients were enrolled, of which 25 patients were planned to receive 
bevacizumab 5 mg/kg and 23 patients were planned to receive bevacizumab 10 mg/kg,
Q2W. Of the 48 patients enrolled, 43 patients received at least 1 dose of bevacizumab.
Among the 38 response-evaluable patients, 6 patients achieved a PR (intent-to-treat 
[ITT] ORR, 14% [95% CI: 4%, 24%]); the median duration of response (DOR) was 
148 days (range, 55362 days); 18 patients had SD (DCR, 56%), including 12 patients 
who experienced SD for 16 weeks. The 16W-DCR was 42% (95% CI: 27%, 57%) in 
the overall population, 39% (95% CI: 19%, 59%) in patients treated with 5 mg/kg 
bevacizumab, and 45% (95% CI: 23%, 67%) in those treated at the 10 mg/kg dose.
In the overall population (N43), median PFS was 3 months (95% CI: 2, 4); median OS
was 8 months (95% CI: 4, 9; Boige et al. 2012).
1.6
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
1.6.1
Rationale for the Combination of Anti-PD-L1 and Anti-VEGF 
Therapy in Hepatocellular Carcinoma
Strong scientific rationale and emerging clinical data suggest that the combined 
VEGF/PD-L1 blockade may be clinically beneficial in a number of tumor types,
including HCC.
It is known that HCC is a highly vascularized tumor, and that several pro-angiogenic 
factors play a role in HCC pathogenesis.  For example, in HCC, increased VEGF 
correlates with vascular density, tumor invasiveness and metastasis, and poor prognosis 
(Boige et al. 2012; Frenette 2012).  The VEGF pathway also plays a crucial role in 
exerting and maintaining an immunosuppressive tumor microenvironment through 
several mechanisms.  For instance, VEGF-A has been shown to induce FasL expression 
on endothelial cells, which have the ability to kill effector CD8T cells, but not T-reg 
cells.  Administration of anti-VEGF-A attenuated tumor endothelial FasL expression and 
produced a significant increase in the influx of tumor-rejecting CD8over 
FoxP3T cells, which was FasL-dependent, and led to CD8-dependent tumor growth 


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suppression (Motz et al. 2014).  Furthermore, bevacizumab can restore and/or maintain 
the antigen presentation capacity of dendritic cells, leading to enhanced T-cell infiltration 
in tumors (Oelkrug and Ramage 2014; Wallin et al. 2016). In addition to increased 
trafficking of T cells into tumors (Manning et al. 2007), several publications have 
illustrated that anti-VEGF therapies can also reduce the frequency of myeloid-derived 
suppressor cells, decrease production of suppressive cytokines, and lower the 
expression of inhibitory checkpoints on CD8T cells in tumors (Roland et al. 2009; 
Voron et al. 2015). Therefore, the immunomodulatory effect of bevacizumab is expected 
to increase CD8T-cell recruitment and relieve intra-tumoral immunosuppression, 
thereby boosting the effects of atezolizumab.
1.6.2
Clinical Data of Atezolizumab in Combination with 
Bevacizumab in Hepatocellular Carcinoma
Preliminary data from Study GO30140 indicates substantial numerical improvement in 
ORR for the combination of atezolizumab and bevacizumab compared with sorafenib, 
the current global standard of care, in patients with locally advanced or metastatic HCC, 
supporting the hypothesis of a synergistic/complementary effect of atezolizumab and 
bevacizumab.
Efficacy:  Study GO30140
Study GO30140 is a Phase Ib, multicenter study of atezolizumab in combination with 
bevacizumab and/or first-line chemotherapy for patients with metastatic cancer.  Arm A 
is designed to test the combination of atezolizumab and bevacizumab in patients with 
locally advanced or metastatic HCC who have not received prior systemic therapy. 
Patients received 1200 mg of atezolizumab and 15 mg/kg of bevacizumab on Day 1 of 
every 21-day cycle (Q3W).
Based on a clinical cutoff date of 26 July 2018, 103 patients (recruited from the 
United States and South Korea) with HCC received atezolizumab and bevacizumab 
combination therapy.  All patients received atezolizumab and bevacizumab as first-line 
therapy.  At the time of the clinical cutoff date, 70 patients remained on treatment, 
18 patients had discontinued treatment due to disease progression, 2 patients 
discontinued treatment due to symptomatic deterioration, 6 patients discontinued 
treatment due to an adverse event, 4 patients discontinued treatment due to death, and 
3 patients discontinued treatment due to patient decision or for other reasons.
Efficacy analyses were performed in the efficacy-evaluable population, defined as all 
patients who received any amount of the combination treatment and have been followed 
in the study for at least 16 weeks.  Based on a clinical cutoff date of 26 July 2018, 
73 patients enrolled into Arm A were efficacy-evaluable with a median duration of 
survival follow-up of 7.2 months.
Based on IRF-assessment per RECIST v1.1, the confirmed ORR was 27.4% 
(95% CI: 17.6, 39.1).  Among the 20 responders, 4 patients (20%) achieved a CR and 


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the remaining 16 patients (80%) achieved a PR.  The ORR based on the investigator’s 
assessment per RECIST v1.1 was numerically similar to the ORR based on the 
IRF-assessment per RECIST v1.1.  According to the investigator assessment per 
RECIST v1.1, 23 of 73 efficacy-evaluable patients (31.5% [95% CI: 21.1, 43.4]) achieved 
confirmed objective responses, with 1 patient (1.4%) achieving a CR.  When tumor 
scans were assessed by the IRF according to HCC modified RECIST (mRECIST)
criteria, 25 of 73 efficacy-evaluable patients (34.2% [95% CI: 23.5, 46.3]) achieved a
confirmed objective response, 8 of those 25 responders (32%) achieved a best overall 
response of CR, and 17 of 25 responders (68%) achieved a best overall response of PR.  
Importantly, responses were observed in all assessed patient subgroups, including 
etiology, region, baseline -fetoprotein (AFP), and tumor burden.
At the time of the clinical cutoff date, 80% (16 of 20 patients) of the IRF-assessed 
responses per RECIST v1.1 were ongoing, with durations ranging from 1.6to 
22.0months (denotes censored data).  Nine patients had responses of 6 months or 
longer per IRF-assessment by RECIST v1.1.
The median DOR has not been reached by IRF-assessment (per RECIST v.1.1 or HCC 
mRECIST) or investigator assessment (per RECIST v1.1), nor has the median OS been 
reached.  The median PFS by IRF-assessment per RECIST v1.1 and per HCC 
mRECIST was 7.5 months (95% CI: 5.414.9) and the median PFS by investigator 
assessment per RECIST v1.1 was 14.9 months (95% CI: 7.4NE).  The 6-month PFS 
rate was 56% by IRF-assessment per RECIST v1.1, 65% by investigator assessment 
per RECIST v1.1, and 58% by IRF-assessment per HCC mRECIST.  These estimates 
of median PFS are considered to be unstable and expected to change with longer 
follow-up.
Safety:  Study GO30140
In the analysis of safety data from Study GO30140 (clinical cutoff date 26 July 2018) in 
103 patients with HCC (median treatment duration with atezolizumab was 3.5 months 
[range: 024 months]; median treatment duration with bevacizumab was 3.5 months 
[range: 023 months]), the combination of atezolizumab and bevacizumab was 
generally safe and 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.
Overall, 95 patients (92.2%) experienced at least 1 adverse event.  The most common 
adverse events (20%) were decreased appetite (28.2%) and fatigue, pyrexia, and rash 
(20.4% each).  Forty-one patients (39.8%) experienced a Grade 34 adverse event, with 
the most common Grade 34 adverse events (4%) being hypertension (11.7%) and
increased AST (4.9%). Treatment-related Grade 34 adverse events were reported in 
28 patients (27.2%), the most common being hypertension (9.7%) and neutrophil count 
decreased (2.9%).


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A total of 36 patients (35%) experienced serious adverse events.  Treatment-related 
serious adverse events occurred in 19 patients (18.4%), most of which were a single 
occurrence except colitis, esophageal varices hemorrhage and pneumonitis (1.9% each).
Five patients (4.9%) experienced Grade 5 adverse events, of which 2 patients (1.9%) 
experienced Grade 5 treatment-related adverse events.
Six patients (5.8%) discontinued both atezolizumab and bevacizumab treatment due to 
adverse events. Eight patients (7.8%) discontinued atezolizumab and 10 patients (9.7%) 
discontinued bevacizumab due to adverse events. All adverse events leading to any 
atezolizumab and/or bevacizumab discontinuation were single occurrences except for
esophageal varices hemorrhage in 2 patients (1.9%), which led to discontinuation of
bevacizumab only.
1.6.3
COVID-19 Considerations
In the setting of the 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 COVID-19.  However, it is unclear whether or how 
systemic cancer therapies such as chemotherapy, targeted therapy, or immunotherapy 
impact the incidence or severity of COVID-19.
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 COVID-19 is altered by cancer immunotherapy.
Severe COVID-19 appears to be associated with a cytokine-release syndrome (CRS) 
involving the inflammatory cytokines IL-6, IL-10, IL-2, and interferon-
(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 COVID-19.
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 COVID19-related interstitial pneumonia.  Thus, investigators should use 
their clinical judgment when evaluating and managing patients with pulmonary 
symptoms.


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1.6.4
Summary
Overall, the combination of atezolizumab and bevacizumab may be a promising 
treatment option for patients with HCC.  To address the ongoing high unmet medical 
need for patients with HCC, Study YO40245 aims to evaluate the efficacy and safety of 
atezolizumab and bevacizumab against the current standard of care, sorafenib, in 
patients with locally advanced or metastatic HCC.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy and safety of atezolizumab in combination with 
bevacizumab compared with sorafenib in patients with locally advanced or metastatic 
HCC who have received no prior systemic treatment.  Specific objectives and 
corresponding endpoints for the study are outlined below.
In this protocol, "study treatment" refers to the treatments assigned to patients as part of 
this study (i.e., atezolizumab and bevacizumab, or sorafenib).
Table 1
Objectives and Corresponding Endpoints
Primary Efficacy Objective
Corresponding Endpoint
To evaluate the efficacy of 
atezolizumab bevacizumab 
compared with sorafenib

OS, defined as the time from randomization to death 
from any cause

PFS, defined as the time from randomization to the first 
occurrence of disease progression or death from any 
cause (whichever occurs first), as determined by an IRF 
according to RECIST v1.1


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Table 1
Objectives and Corresponding Endpoints (cont.)
Secondary Efficacy Objectives
Corresponding Endpoints
To evaluate the efficacy of 
atezolizumabbevacizumab 
compared with sorafenib

OR, defined as a complete or partial response, as 
determined by the investigator according to 
RECIST v1.1

PFS as determined by the investigator according to 
RECIST v1.1

TTP, defined as the time from randomization to the first 
occurrence of disease progression, as determined by 
the investigator according to RECIST v1.1

DOR, defined as the time from the first occurrence of a 
documented objective response to disease progression 
or death from any cause (whichever occurs first), as 
determined by the investigator according to 
RECIST v1.1

Objective response as determined by an IRF according 
to RECIST v1.1

TTP as determined by an IRF according to 
RECIST v1.1

DOR as determined by an IRF according to 
RECIST v1.1

Objective response as determined by an IRF according 
to HCC mRECIST

PFS as determined by an IRF according to HCC 
mRECIST

TTP as determined by an IRF according to HCC 
mRECIST

DOR as determined by an IRF according to HCC 
mRECIST
To evaluate the association of 
pre-specified biomarkers with 
efficacy of 
atezolizumabbevacizumab 
compared with sorafenib

PFS as determined by the investigator and by an IRF 
according to RECIST v1.1 and OS by baseline serum 
AFP level (400 ng/mL vs. 400 ng/mL)
To evaluate PROs of 
disease/treatment-related 
symptoms, GHS/QoL, and function 
experienced by patients on 
atezolizumabbevacizumab versus 
sorafenib

TTD, defined as the time from randomization to first 
deterioration (decrease from baseline of 10 points), 
maintained for 2 consecutive assessments or 
1 assessment followed by death from any cause within 
3 weeks in the following EORTC QLQ-C30 subscales:
–
Physical functioning (PF)
–
Role functioning (RF)
–
GHS/QoL


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Table 1
Objectives and Corresponding Endpoints (cont.)
Exploratory Efficacy Objectives
Corresponding Endpoints
To evaluate the efficacy of 
atezolizumabbevacizumab 
compared with sorafenib

Objective response as determined by the investigator 
according to imRECIST

PFS as determined by the investigator according to 
imRECIST

TTP as determined by the investigator according to 
imRECIST

DOR as determined by the investigator according to 
imRECIST
To evaluate PROs of 
disease/treatment-related symptoms 
(including abdominal pain and 
itching), GHS/QoL, and function 
experienced by patients on 
atezolizumabbevacizumab versus 
sorafenib

Mean and mean changes from baseline score (by cycle) 
in all the subscales of the EORTC QLQ-C30 and 
QLQ-HCC18

Proportion of patients with clinically meaningful change 
in select scales of the QLQ-C30 (GHS/QoL, physical 
function, role function, appetite loss, diarrhea, fatigue, 
pain) and QLQ-HCC18 (fatigue, jaundice, pain)

TTD maintained for 2 consecutive timepoints, or 
1 timepoint followed by death from any cause within 
3 weeks, in select scales of the QLQ-C30 (appetite loss, 
diarrhea, fatigue, pain) and QLQ-HCC18 (jaundice, 
fatigue, pain)

TTD maintained for 2 consecutive timepoints, or 
1 timepoint followed by death from any cause, within 
3 weeks in HRQoL/GHS, physical function, and role 
function of the QLQ-C30

Proportion of responses for abdominal pain item 
(of QLQ-HCC18 pain subscale) and itching item 
(of QLQ-HCC18 jaundice subscale)
Safety Objective
Corresponding Endpoints
To evaluate the safety of 
atezolizumabbevacizumab 
compared with sorafenib

Incidence and severity of adverse events, with severity 
determined according to NCI CTCAE v4.0

Vital signs

Clinical laboratory test results
Pharmacokinetic Objective
Corresponding Endpoint
To characterize the PK profile of 
atezolizumabbevacizumab

Serum concentration of atezolizumab at specified 
timepoints
Immunogenicity Objective
Corresponding Endpoint
To evaluate the immune response to 
atezolizumab

Presence of ADAs to atezolizumab during the study 
relative to the presence of ADAs at baseline


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Table 1
Objectives and Corresponding Endpoints (cont.)
Exploratory Immunogenicity Objective
Corresponding Endpoint
To evaluate potential effects of ADAs to 
atezolizumab on the efficacy, safety, and 
pharmacokinetics of
atezolizumabbevacizumab

Efficacy, safety, or PK endpoints by ADA status
Exploratory Biomarker Objective
Corresponding Endpoint
To identify tissue or blood-based 
biomarkers that are associated with 
response to atezolizumabbevacizumab 
versus sorafenib, or can increase the 
understanding of HCC disease evolution 
under atezolizumabbevacizumab 
treatment

PFS as determined by the investigator according 
to RECIST v 1.1 and OS based on the following 
biomarkers in tumor tissue:
–
Baseline expression of T effector gene 
signature in tumor tissue
–
Baseline PD-L1 protein expression in 
tumor tissue
–
CD8 protein expression level or 
CD8T-cell localization
–
IHCs or genes/gene signatures (by gene 
expression profiling) related to tumor 
microenvironments
–
T cell receptor sequence profile in 
tumor-associated T cells

Objective response as determined by the 
investigator according to RECIST v1.1 and OS 
based on the following biomarkers in blood:
–
Immune-related biomarkers profiling in 
plasma and serum (e.g., interleukin-2, 
interferon-)
Exploratory Health Status Objective
Corresponding Endpoint
To evaluate health status experienced by 
patients on atezolizumabbevacizumab 
versus sorafenib to generate utility 
scores for use in economic evaluations

Health utility and VAS scores of the EQ-5D-5L 
questionnaire
ADAanti-drug antibody; AFP-fetoprotein; DORduration of response; EORTCEuropean 
Organisation for Research and Treatment of Cancer; EQ-5D-5LEuroQol 5-Dimension 
Questionnaire, 5-Level version; GHSglobal health status; HCChepatocellular carcinoma; 
HCC mRECIST modified RECIST for HCC; imRECISTimmune-modified RECIST; 
IRFindependent review facility; NCI CTCAE v4.0National Cancer Institute Common 
Terminology Criteria for Adverse Events, v4.0; OSoverall survival; PFSprogression-free 
survival; PKpharmacokinetic; PROpatient-reported outcome; QLQ-C30quality-of-life 
questionnaire for cancer; QLQ-HCC18HCC disease-specific module; QoLquality-of-life; 
RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1; TTDtime to 
deterioration; TTPtime to progression; VASvisual analog scale.


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3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
3.1.1
Overview of Study Design
This is a Phase III, randomized, multicenter, open-label, two-arm study designed to 
evaluate the efficacy and safety of atezolizumab and bevacizumab versus sorafenib in 
patients with locally advanced or metastatic HCC who have received no prior systemic 
treatment.
This study will enroll approximately 480 patients randomized in a 2:1 ratio to one of two
treatment arms:

Arm A (experimental arm):  Atezolizumab 1200 mg IV infusion Q3W (dosed in 
3-week cycles) and bevacizumab 15 mg/kg Q3W (dosed in 3-week cycles)

Arm B (control arm):  Sorafenib 400 mg by mouth, BID, continuously
Randomization will be stratified according to the following stratification factors:

Geographic region (Asia excluding Japan vs. rest of world)

Macrovascular invasion and/or extrahepatic spread (presence vs. absence)

Baseline AFP (400 vs. 400 ng/mL)

ECOG Performance Status (0 vs. 1)
The study schema is shown in Figure 1.
Patients randomized to the atezolizumab andbevacizumab arm (Arm A) who transiently 
withhold or permanently discontinue either atezolizumab or bevacizumab may continue 
on single-agent therapy as long as the patients are experiencing clinical benefit in the 
opinion of the investigator and after discussion with the Medical Monitor (i.e., patients 
transiently withheld or permanently discontinued from bevacizumab treatment for 
adverse effects may continue atezolizumab monotherapy and vice versa).
Patients will receive atezolizumab and/or bevacizumab or sorafenib 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).  In the absence of unacceptable 
toxicity, patients who meet criteria for disease progression per RECIST v1.1 while 
receiving atezolizumab and/or bevacizumab or sorafenib will be permitted to continue 
the 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 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
Tumor assessments will be performed at baseline and at regular intervals during study 
treatment (see Section 4.5.5 and Appendix 1).  Additional scans will be performed as 
clinically indicated. Tumor assessments will continue until disease progression, 
regardless of whether treatment has been discontinued (e.g., for toxicity).  Patients who 
meet RECIST v1.1 criteria for progression will undergo tumor assessments until disease 
progression (per immune-modified RECIST [imRECIST]) or loss of clinical benefit,
whichever occurs later.  In the absence of disease progression, tumor assessments 
should continue regardless of whether patients start new anti-cancer therapy, until 
consent is withdrawn, death, or the study is terminated by the Sponsor, whichever 
occurs first.  Following disease progression, patients will be followed for survival and 
subsequent anti-cancer therapies until death, loss to follow-up, withdrawal of consent, or 
study termination by Sponsor, whichever occurs first.
Sites will provide imaging used for tumor assessments to an IRF to enable centralized, 
independent review of response and progression endpoints.  These reviews will be 
performed prior to the pre-specified efficacy analyses.  Independent Review Facility
membership and procedures will be detailed in an IRF Charter.
Safety assessments will include the incidence, nature, and severity of adverse events 
and laboratory abnormalities graded per the National Cancer Institute Common 
Terminology Criteria for Adverse Events, v4.0 (NCI CTCAE v4.0).  Laboratory safety 
assessments will include the regular monitoring of hematology and blood chemistry.  
Serum samples will be collected to monitor the pharmacokinetics of atezolizumab when 
administered in combination with bevacizumab.  Patient samples, including archival 
tumor tissues as well as serum and plasma, will be collected for future exploratory 
biomarker assessments.
This study will initially enroll approximately 480 patients across all sites in a global 
enrollment phase.
The Sponsor is targeting a total enrollment of approximately 135 patients from mainland 
China. After completion of the global enrollment phase, in the event that less than
135 patients from mainland China are enrolled, additional patients in China may be 
subsequently randomized into the two treatment arms in a 2:1 ratio in an extended 
China enrollment phase to ensure a total of approximately 135 patients from mainland 
China in a China subpopulation.  The China subpopulation will include all patients 
enrolled in China (i.e., during both the global enrollment phase and the extended China 
enrollment phase).  The patients enrolled in the China extension phase will undergo the 
same schedule of activities and will receive atezolizumab and bevacizumab, or sorafenib 


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as in the global study.  The China subgroup analysis will be performed based on the 
China subpopulation.
Figure 1 presents an overview of the study design.  The schedule of activities is provided 
in Appendix 1.
Figure 1
Study Schema
AFP-fetoprotein; BIDtwice a day; ECOGEastern Cooperative Oncology Group; 
EHSextrahepatic spread; HCChepatocellular carcinoma; MVImacrovascular invasion; 
PS Performance Status; Q3W every 3 weeks.
3.1.2
Independent Data Monitoring Committee
An external independent Data Monitoring Committee (iDMC) will evaluate safety data 
during the study on a periodic basisapproximately every 6 monthsuntil the time of 
the co-primary efficacy PFS final analysis and the first OS interim analysis. No efficacy
interim analyses are planned to be conducted by the iDMC.
Staff at an independent Data Coordinating Center will prepare all safety analyses for 
iDMC review.  The safety summaries will include demographic data, adverse events, 
serious adverse events, and relevant laboratory data.
Patients with untreated 
advanced/metastatic HCC
(n=480 patients)
Arm A
Atezolizumab 1200 mg Q3W + 
Bevacizumab 15 mg/kg Q3W
Arm B
Sorafenib 400 mg BID
Treatment until 
loss of clinical benefit or 
unacceptable toxicity
Treatment until 
loss of clinical benefit or 
unacceptable toxicity
Survival follow-up
Survival follow-up
Randomization (2:1)
Stratification factors:
•
Geographic region 
(Asia excluding Japan 
vs. rest of world)
•
MVI and/or EHS 
(yes vs. no)
•
Baseline AFP
(<400 vs. ≥400 ng/mL)
•
Baseline ECOG PS 
(0 vs. 1)


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Following the data review, the iDMC will provide a recommendation to the Sponsor 
whether to continue the study, amend the protocol, or stop the study.  The final decision 
will rest with the Sponsor.  Any outcomes of these safety reviews that affect study 
conduct will be communicated in a timely manner to the investigators for notification of 
the Institutional Review Boards (IRBs)/Ethics Committees (ECs). Members of the iDMC 
will be external to the Sponsor.  An iDMC charter will outline roles and responsibilities of 
the iDMC members as well as the policies and procedures to be followed by the iDMC.
3.2
END OF STUDY
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs 
(i.e., last patient in the global and extended China enrollment phases combined) or 
safety follow-up is received from the last patient (global and extended China enrollment 
phases combined), whichever occurs later.
In addition, the Sponsor may decide to terminate the study at any time.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
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 the approved dosage for atezolizumab (Tecentriq).  
Anti-tumor activity has been observed across doses ranging from 1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).
3.3.2
Rationale for Bevacizumab Dose and Schedule
Bevacizumab will be administered at a fixed dose of 15 mg/kg Q3W on Day 1 of each 
21-day cycle, which is the approved dosage for bevacizumab.  This dose schedule 
aligns with the atezolizumab dose schedule highlighted above and is the dose used in 
combination with atezolizumab in Study GO30140.  In this study, the combination of 
atezolizumab and 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.
3.3.3
Rationale for Patient Population
This study will enroll patients with untreated locally advanced or metastatic HCC, 
regardless of PD-L1 expression or HCC etiology.  The broad patient population selected 
is similar to the population enrolled in Study GO30140, the initial study testing this 
combination first-line in patients with HCC.


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Although sorafenib is approved for the first-line treatment of patients with advanced HCC,
the prognosis of these patients remains poor with a median OS reported of 
6.510.7 months.  Treatment with sorafenib is also associated with significant toxicity 
including hand-foot skin reaction, diarrhea, hypertension, weight loss, fatigue, anorexia, 
alopecia, nausea, and rash/desquamation, all of which negatively impact the quality-of-
life.  Therefore, there is a continuing need for more efficacious, better tolerated 
treatments for the first-line treatment of patients with locally advanced or metastatic HCC.
Patients accrued on the study are also required to have adequate liver function, defined 
as Child-Pugh Class A. Patients with a Child-Pugh Class B or C rating have an 
increased risk of death due to underlying cirrhosis, which could potentially confound the 
appropriate evaluation of treatment-related anti-tumor efficacy; these patients are thus,
excluded from the study. The proposed study population is the recommended patient 
population in the initial study of a new agent or combination of agents for HCC, as noted 
by an expert panel convened by the American Association for the Study of Liver 
Diseases (AASLD; Llovet et al. 2008).
3.3.4
Rationale for Control Arm
Patients in the control arm will receive sorafenib.  Sorafenib is the only globally approved 
targeted therapy for patients with unresectable HCC who have not received prior 
systemic therapy and is considered the acceptable standard of care globally.  
The survival benefit of sorafenib was demonstrated in 2 randomized Phase III trials 
versus placebo, one in a Western population and one in an Asian-Pacific population as 
discussed in Section 1.2.  Sorafenib is the standard of care and the NCCN-, European 
Association for the Study of the Liver (EASL)-, and Asian-Pacific Association for the 
Study of the Liver (APASL)-recommended initial therapy regimen for patients with HCC 
(Omata et al. 2010; EASL-EORTC 2012; NCCN 2017).  As such, this study will utilize 
sorafenib 400 mg BID continuously, the approved dose and schedule.
While lenvatinib recently demonstrated non-inferiority versus sorafenib in terms of OS in 
patients with advanced HCC (13.6 months for lenvatinib versus 12.3 months for 
sorafenib) in a randomized Phase III trial (Cheng et al. 2017), it has not been approved 
globally for this indication.  Therefore, the Sponsor believes that the choice of using 
sorafenib as control treatment is appropriate.
3.3.5
Rationale for Open-Label Study
An open-label study design was chosen for this Phase III study given the unique toxicity 
profiles of the treatments in each study arm; patients as well as physicians may be 
capable of identifying treatment assignment if the treatment was assigned blinded.  
Furthermore, a blinded study would require patients randomized to sorafenib to receive 
placebo infusions of atezolizumab and bevacizumab which the Sponsor believes would 
impose unnecessary burden and excessive risk to patients.


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As part of the study design, adequate steps have been taken to ensure the validity of the
data in this open-label study (i.e., IRF-assessed PFS co-primary objective and 
IRF-assessed ORR as secondary endpoints).
3.3.6
Rationale for Overall Survival and Progression-Free Survival
as Co-Primary Endpoints
In this study, the co-primary efficacy endpoints will be OS and IRF-assessed PFS.
Overall survival was chosen as one of the co-primary endpoints for this study because
the measurement of this endpoint is clearly defined, and patients can be evaluated 
objectively.
Progression-free survival was chosen as a co-primary endpoint for this study because
PFS is an important, clinically meaningful metric to demonstrate the efficacy of 
anti-cancer regimens in many first-line disease settings, particularly where additional 
lines of therapy are common.  In addition, data from several tumor types have suggested 
a strong correlation between PFS and OS, thus supporting PFS as a robust surrogate 
predictor of OS and clinical benefit (Adunlin et al. 2015; Dabbous et al. 2017).
3.3.7
Rationale for Stratification
To balance the disease-related prognostic factors across treatment arms, randomization 
of patients into the study will be stratified.  The proposed stratification factors are the 
following:

Geographic region (Asia excluding Japan vs. rest of world)

Macrovascular invasion and/or extrahepatic spread (presence vs. absence)

Baseline AFP (400 vs. 400 ng/mL)

ECOG Performance Status (0 vs. 1)
3.3.7.1
Geographic Region
Although HCC is a global disease, there is significant geographic heterogeneity in terms 
of efficacy outcomes.  In the SHARP trial, which recruited patients from Europe, 
Australia, and the Americas, median OS in the sorafenib and placebotreated arm was 
10.7 and 7.9 months, respectively (Llovet et al. 2008).  In the Asia-Pacific trial, which 
recruited patients from China, South Korea, and Hong Kong, the median OS in the 
sorafenib and placebotreated arm was 6.5 and 4.2 months, respectively
(Cheng et al. 2009).  In a subgroup analyses of Phase III trials evaluating sorafenib
versus other multi-kinase inhibitors (sunitinib, brivanib, and linifanib), similar trends of 
differences in median OS were observed consistently between the 2 regions (sunitinib 
study: median OS 7.9 months [Asia] vs. 15.3 months [non-Asia]; brivanib study: 
median OS 8.7 months [Asia] vs. 10.9 months [non-Asia]; linifanib study: median OS 
8.2 months [Asia] vs. 11.3 months [non-Asia]; Cheng et al. 2013; Johnson et al. 2013; 
Cainap et al. 2015).


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These differences in outcome may be attributed to several potential causes that include 
regional differences in etiology and clinical practice patterns.  Hepatitis B virus infection 
is the main risk factor for HCC in Asia (70%), while in Western countries and Japan, 
the main risk factor is HCV infection (50%70%) and excessive alcohol intake (20%), 
along with other causes of cirrhosis (10%), and literature has long cited that 
clinicopathologic features and prognoses differ among the different etiologies of HCC
(Llovet et al. 2003; Sanyal et al. 2010; Nault 2014).  Furthermore, even with the same 
etiology, the OS of patients differs, which can be attributed to the difference in clinical 
practice between the 2 regions (Cheng et al. 2013).  Patients recruited from Asian 
regions, who may be considered ineligible for surgery or other localized treatments 
because of extent of disease, may have been treated more aggressively, with more
transarterial chemoembolization and surgical treatment than patients recruited from 
other regions.  Therefore, Asian-region patients recruited into clinical trials for first-line 
treatment may have more advanced disease and thus, worse outcomes than patients 
from other regions (Cheng et al. 2009).
Given this geographic heterogeneity, randomization into the study will be stratified by
geographic region (Asia excluding Japan vs. rest of world).  The median OS of advanced 
HCC for patients in Japan more closely resembles those of Western countries, and;
therefore, Japan will not be included in the Asia region subgroup (Kudo et al. 2016).
3.3.7.2
Macrovascular Invasion and/or Extrahepatic Spread 
(Presence vs. Absence)
Randomization of patients will be stratified by presence or absence of extrahepatic 
spread or macrovascular invasion because these 2 factors have been shown to be 
strong independent prognostic factors associated with shorter OS.  Patients with 
extrahepatic spread and/or macrovascular invasion have a worse prognosis than 
patients without either of these 2 factors, and stratification by these 2 variables has been 
recommended by an expert panel convened by the AASLD (Llovet et al. 2008; 
Bruix et al. 2012; Cheng et al. 2012; Bruix et al. 2017).
3.3.7.3
Baseline -Fetoprotein(400 ng/mL vs. 400 ng/mL)
Very high serum AFP level (400 ng/mL) is a strong prognostic factor of shorter OS time 
for patients with HCC, including those receiving sorafenib (Bronowicki et al. 2015; 
Bruix et al. 2017). Though serum AFP level may be an indirect measure of tumor 
burden, multivariate analysis has shown that even when tumor morphology is accounted 
for, AFP levels greater than 400 ng/mL still have independent prognostic value, 
suggesting that it could be a marker of a biologically more aggressive phenotype
(Cancer of the Liver Italian Program Investigators 1998). Therefore, given the 
prognostic impact of serum AFP level, randomization of patients in this study will be 
stratified by their baseline serum AFP level (400 ng/mL vs.400 ng/mL).


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3.3.7.4
Eastern Cooperative Oncology Group Performance Status 
(0 vs. 1)
Eastern Cooperative Oncology Group performance status is regarded as an acceptable 
and comprehensive parameter to determine the degree of health status in patients with 
cancer. In patients with HCC, a poor performance status is associated with larger tumor 
burden and more severe cirrhosis and is an indispensable surrogate to reflect the 
general condition of patients. Deterioration of performance status was identified as an
independent predictor of decreased survival, and patients with a performance status of 1
had a 34% increased risk of mortality compared with patients with a performance status 
of 0 (Hsu et al. 2013). In the Phase III trials evaluating linifanib, brivanib, and most 
recently levatinib, patients with a performance status of 1 had a decreased medial OS
compared with patients with a performance status of 0 in both the experimental and 
control arms (Johnson et al. 2013; Cainap et al. 2015; Cheng et al. 2017). Stratification 
by ECOG Performance Status has also been recommended by an expert panel 
convened by the AASLD (Llovet et al. 2008).
3.3.8
Rationale for Study Treatment beyond Initial Radiographic 
Progression
In studies of immunotherapeutic agents, CR, PR, and SD have each been shown to 
occur after radiographic evidence of an apparent increase in tumor burden.  This initial 
increase in tumor burden caused by immune-cell infiltration in the setting of a T-cell
response has been termed pseudoprogression (Hales et al. 2010).  In Study PCD4989g, 
evidence of tumor growth followed by a response was observed in several tumor types.  
In addition, in some responding patients with radiographic evidence of progression, 
biopsies of new lesions or areas of new growth in existing lesions revealed immune cells
and no viable cancer cells.  For sorafenib treatment, as noted in the prescribing 
information, it can be continued until the patient is no longer clinically benefitting from 
therapy or until unacceptable toxicity occurs.  Therefore, this study will allow all patients 
to continue their assigned treatment after apparent radiographic progression per 
RECIST v1.1, provided the benefit-risk ratio is judged to be favorable by the investigator 
(see criteria in Section 3.1).  Patients should be discontinued for unacceptable toxicity or 
loss of clinical benefit as determined by the investigator after an integrated assessment 
of radiographic and biochemical data, and clinical status (see Section 3.1 for details).
3.3.9
Rationale for Biomarker Assessments
Several exploratory biomarkers may correlate with clinical response of atezolizumab in 
combination with bevacizumab. Since the VEGF pathway plays a crucial role in exerting 
and maintaining an immunosuppressive tumor microenvironment through several 
mechanisms, the abundance of preexisting CD8T-cell infiltrates, the expression of 
PD-L1 in tumors, or gene signatures related to the tumor stromal environment may be 
important determinants of clinical responses. In the current study, archival or baseline 
tumor specimens will be collected from patients and tested retrospectively with protein or 
genomic/transcriptomic platforms to explore the potential relationship to clinical 


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responses.  In addition to the assessment of PD-L1 expression and CD8 T-cell status, 
other exploratory biomarkers, such as potential predictive and prognostic biomarkers 
related to the clinical benefit of atezolizumab in combination with bevacizumab, tumor 
immunobiology, mechanisms of resistance, or tumor type, may be analyzed.
Archival tumor tissue will be collected at baseline if available.  These baseline tissues 
will enable exploratory analysis of tumor tissue biomarkers related to clinical response, 
resistance, or disease progression.
Plasma and serum samples will be collected at baseline and during the study to evaluate 
changes in peripheral biomarkers such as immune-related biomarkers (e.g., interleukin-2
[IL-2], interferon-).  Changes in biomarkers may provide evidence of biologic activity of 
atezolizumab in combination with bevacizumab 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 
and bevacizumab combination therapy.
Tumor tissue and blood samples will be analyzed through use of next-generation 
sequencing (NGS), and/or additional protein detection methods to identify signatures 
and/or other biomarkers that are predictive of response to the combination, are 
associated with progression to a more severe disease state, are associated with 
acquired resistance to the combination, are associated with susceptibility to developing 
adverse events, or can increase the knowledge and understanding of disease biology.
3.3.10
Rationale for Patient-Reported Outcomes Assessments
Both cancer- and treatment-related symptoms and the associated impact on 
health-related quality-of-life (HRQoL) in patients with HCC are complex.  Historically, 
hepatobiliary cancers have been associated with poor prognosis and HRQoL 
(Heffernan et al. 2002).  Patients with HCC have reported worsened physical, 
psychological, functional well-being, and hepatobiliary symptoms (pain, fatigue, 
anorexia/weight loss, obstructive jaundice/ascites) compared with the general 
population.  Similarly, patients with HCC have reported worsened physical well-being 
and overall HRQoL compared with patients who have chronic liver disease 
(Fan et al. 2010).  While there have been many advances in HCC treatment, and 
survival data and information about side effects of treatment are becoming more readily 
available, much less is known about the impact HCC treatments have on the patients’
HRQoL.
Patient-reported information regarding treatment-related symptoms and other aspects of 
quality-of-life are valuable for both patients and clinicians in decision-making and may
also predict survival.  Common patient-reported symptoms of disease in this patient 
population include abdominal pain, fatigue, weight loss, poor appetite, and jaundice 
(Sun et al. 2008).  The concepts of symptom burden and HRQoL are best documented 


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through standardized patient-reported outcomes (PROs), and validated measures will be 
used to assess these aspects at pre-specified timepoints in the study (see Appendix 1).
The European Organisation for Research and Treatment of Cancer Quality-of-Life 
Questionnaire (EORTC QLQ-C30; see Section 4.5.8.1) and its HCC diseasespecific 
module (EORTC QLQ-HCC18; see Section 4.5.8.2) have been selected on the basis of 
their content validity, performance, and breadth of concepts measured.
In addition, the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L;
see Section 4.5.8.3) will be completed to inform pharmacoeconomic models and, as 
such, will not be included in the Clinical Study Report (CSR).
4.
MATERIALS AND METHODS
4.1
PATIENTS
The study will enroll approximately 480 patients at approximately 120 study sites.  
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 approximately 
135 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 the Informed Consent Form

Ability to comply with the study protocol, in the investigator's judgment

Locally advanced or metastatic and/or unresectable HCC with diagnosis confirmed 
by histology/cytology or clinically by AASLD criteria (see Appendix 13) in cirrhotic 
patients
Patients without cirrhosis require histological confirmation of diagnosis.

Disease that is not amenable to curative surgical and/or locoregional therapies, or 
progressive disease after surgical and/or locoregional therapies

No prior systemic therapy (including systemic investigational agents) for HCC
Previous use of herbal therapies/traditional Chinese medicines with anti-cancer 
activity included in the label is allowed, provided that these medications are 
discontinued prior to randomization.

At least 1 measurable (per RECIST v1.1) untreated lesion

Patients who received prior local therapy (e.g., radiofrequency ablation, 
percutaneous ethanol or acetic acid injection, cryoablation, high-intensity focused 
ultrasound, transarterial chemoembolization, transarterial embolization, etc.) are 
eligible provided the target lesion(s) have not been previously treated with local 
therapy or the target lesion(s) within the field of local therapy have subsequently 
progressed in accordance with RECIST v1.1


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
Pretreatment tumor tissue sample (if available)
If tumor tissue is available, a formalin-fixed, paraffin-embedded (FFPE) tumor 
specimen in a paraffin block (preferred) or approximately 1015 slides containing 
unstained, freshly cut, serial sections should be submitted along with an 
associated pathology report within 4 weeks of randomization.
If FFPE specimens described above are not available, any type of specimens 
(including fine-needle aspiration, cell pellet specimens [e.g., from pleural 
effusion], and lavage samples) are also acceptable.  This specimen should be 
accompanied by the associated pathology report (see Section 4.5.6 for 
further details).
If tumor tissue is not available (e.g., depleted because of prior diagnostic testing), 
patients are still eligible.

Eastern Cooperative Oncology Group performance status of 0 or 1 within 7 days 
prior to randomization

Child-Pugh Class A (see Appendix 10) within 7 days prior to randomization

Adequate hematologic and end-organ function, defined by the following laboratory 
test results, obtained within 7 days prior to randomization, unless otherwise 
specified:
–
ANC 1.5109/L (1500/L) without granulocyte colony-stimulating factor 
support
–
Lymphocyte count 0.5109/L (500/L)
–
Platelet count 75109/L (75,000/L) without transfusion
–
Hemoglobin 90 g/L (9 g/dL)
Patients may be transfused to meet this criterion.
–
AST, ALT, and ALP 5upper limit of normal (ULN)
–
Serum bilirubin 3ULN
–
Serum creatinine 1.5ULN or creatinine clearance 50 mL/min (calculated 
with use of the Cockcroft-Gault formula)
–
Serum albumin 28 g/L (2.8 g/dL) without transfusion
–
For patients not receiving therapeutic anticoagulation:  INR or aPTT 2ULN
–
Urine dipstick for proteinuria 2(within 7 days prior to initiation of study 
treatment)
Patients discovered to have 2proteinuria on dipstick urinalysis at baseline 
should undergo a 24-hour urine collection and must demonstrate 1 g of 
protein in 24 hours.

Resolution of any acute, clinically significant treatment-related toxicity from prior 
therapy to Grade 1 prior to study entry, with the exception of alopecia

Negative HIV test at screening


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
Documented virology status of hepatitis, as confirmed by screening HBV and HCV 
serology test

For patients with active HBV:
HBV DNA 500 IU/mL obtained within 28 days prior to initiation of study 
treatment, and
Anti-HBV treatment (per local standard of care; e.g., entecavir) for a minimum of 
14 days prior to study entry and willingness to continue treatment for the length 
of the study

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods with a failure rate of 
1% per year during the treatment period and for at least 5 months after the last 
dose of atezolizumab, 6 months after the last dose of bevacizumab, or 6 months
after the last dose of sorafenib.  Women must refrain from donating eggs during this 
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 has not undergone surgical 
sterilization (removal of ovaries and/or uterus).
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 acceptable methods of contraception.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm, as 
defined below:
With female partners of childbearing potential, men must remain abstinent or use 
a condom plus an additional contraceptive method that together result in a failure 
rate of 1% per year during the treatment period and for 6 months after the last 
dose of bevacizumab or 3 months after the last dose of sorafenib.  Men must 
refrain from donating sperm during this same period.
With pregnant female partners, men must remain abstinent or use a condom 
during the treatment period and for 6 months after the last dose of bevacizumab 
or 3 months after the last dose of sorafenib to avoid exposing the embryo.
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 acceptable methods of contraception.


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
For the extended China enrollment phase: Chinese ancestry and residence in 
Mainland China, Hong Kong, or Taiwan with enrollment at sites recognized by 
China’s Center of Drug Evaluation (CDE)
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

History of leptomeningeal disease

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, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré 
syndrome, or multiple sclerosis (see Appendix 8 for a more comprehensive list of 
autoimmune diseases and immune deficiencies), 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
–
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 
previous 12 months

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 computed tomography (CT) scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Known active tuberculosis

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 initiation of study treatment), unstable arrhythmia, or 
unstable angina

History of congenital long QT syndrome or corrected QT interval 500 ms 
(calculated with use of the Fridericia’s formula) at screening

History of uncorrectable electrolyte disorder affecting serum levels of potassium, 
calcium, or magnesium


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
Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation 
of study treatment, or anticipation of need for a major surgical procedure during 
the study

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

Severe infection within 4 weeks prior to initiation of study treatment, 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 initiation of 
study treatment
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection 
or chronic obstructive pulmonary disease [COPD] exacerbation) are eligible for 
the study.

Prior allogeneic stem cell or solid organ 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

Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during atezolizumab treatment 
or within 5 months after the last dose of atezolizumab

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 formulation

Pregnant or breastfeeding, or intention of becoming pregnant during study treatment 
or within at least 5 months after the last dose of atezolizumab, 6 months after the 
last dose of bevacizumab, or 6 months after the last dose of sorafenib
Women of childbearing potential must have a negative serum pregnancy test 
result within 14 days prior to initiation of study treatment.

Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and 
HCC

Untreated or incompletely treated esophageal and/or gastric varices with bleeding or 
high risk for bleeding
Patients must undergo an esophagogastroduodenoscopy (EGD), and all size of 
varices (small to large) must be assessed and treated per local standard of care 


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prior to enrollment.  Patients who have undergone an EGD within 6 months of 
prior to initiation of study treatment do not need to repeat the procedure.

A prior bleeding event due to esophageal and/or gastric varices within 6 months 
prior to initiation of study treatment

Moderate or severe ascites

History of hepatic encephalopathy

Coinfection of HBV and HCV
Patients with a history of HCV infection but who are negative for HCV RNA by 
PCR will be considered non-infected with HCV.

Symptomatic, untreated, or actively progressing CNS metastases
Asymptomatic patients with treated CNS lesions are eligible, provided that all of 
the following criteria are met:
–
Measurable disease, per RECIST v1.1, must be present outside the CNS
–
The patient has no history of intracranial hemorrhage or spinal cord 
hemorrhage
–
Metastases are limited to the cerebellum or the supratentorial region (i.e., no 
metastases to the midbrain, pons, medulla, or spinal cord)
–
There is no evidence of interim progression between completion of 
CNS-directed therapy and initiation of study treatment
–
The patient has not undergone stereotactic, whole-brain radiotherapy, and/or
neurosurgical resection within 28 days prior to initiation of study treatment
–
The patient has no ongoing requirement for corticosteroids as therapy for 
CNS disease.  Anticonvulsant therapy at a stable dose is permitted.

Asymptomatic patients with CNS metastases newly detected at screening are 
eligible for the study after receiving radiotherapy or surgery, with no need to repeat 
the screening brain scan.

Uncontrolled tumor-related pain
Patients requiring pain medication must be on a stable regimen at study entry.
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to 
enrollment.  Patients should be recovered from the effects of radiation.  There is 
no required minimum recovery period.
Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not currently 
associated with spinal cord compression) should be considered for locoregional 
therapy if appropriate prior to enrollment.

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently)
Patients with indwelling catheters (e.g., PleurX®) are allowed.


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
Uncontrolled or symptomatic hypercalcemia (ionized calcium 1.5 mmol/L, 
calcium12 mg/dL or corrected serum calcium ULN)

Treatment with investigational therapy within 28 days prior to initiation of study 
treatment

Treatment with strong CYP3A4 inducers within 14 days prior to initiation of study 
treatment, including rifampin (and its analogs) or St. John's wort

Prior treatment with CD137 agonists or immune checkpoint blockade therapies, 
including antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic antibodies

Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferon and IL-2) within 4 weeks or 5 half-lives of the drug (whichever is longer) 
prior to initiation of study treatment

Treatment with systemic immunosuppressive medication (including, but not limited 
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
antiTNF-agents) within 2 weeks prior to initiation of study treatment, 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 for the study 
after Medical Monitor approval has been obtained.
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids 
for COPD 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 3 BP 
readings on 2 sessions
Antihypertensive therapy to achieve these parameters is allowable.

Prior 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 initiation of study treatment

History of hemoptysis (2.5 mL of bright red blood per episode) within 1 month prior 
to initiation of study treatment

Evidence of bleeding diathesis or significant coagulopathy (in the absence of 
therapeutic anticoagulation)

Current or recent (within 10 days of first dose of study treatment) use of aspirin 
(325 mg/day) or treatment with dipyramidole, ticlopidine, clopidogrel, and cilostazol

Current or recent (within 10 days prior to study treatment start) use of full-dose oral 
or parenteral anti-coagulants or thrombolytic agents for therapeutic (as opposed to 
prophylactic) purpose


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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 within 14 days prior to initiation of study treatment.
For prophylactic use of anti-coagulants or thrombolytic therapies, local label 
approved dose levels may be used.

Core biopsy or other minor surgical procedure, excluding placement of a vascular 
access device, within 3 days prior to the first dose of bevacizumab

History of abdominal or tracheoesophageal fistula, gastrointestinal (GI) perforation, 
or intra-abdominal abscess within 6 months prior to initiation of study treatment

History of intestinal obstruction and/or clinical signs or symptoms of GI obstruction 
including sub-occlusive disease related to the underlying disease or requirement for 
routine parenteral hydration, parenteral nutrition, or tube feeding prior to initiation of 
study treatment
Patients with signs/symptoms of sub-occlusive syndrome/intestinal obstruction 
at time of initial diagnosis may be enrolled if they had received definitive 
(surgical) treatment for symptom resolution.

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

Metastatic disease that involves major airways or blood vessels, or centrally located 
mediastinal tumor masses (30 mm from the carina) of large volume
Patients with vascular invasion of the portal or hepatic veins may be enrolled.

History of intra-abdominal inflammatory process within 6 months prior to initiation of 
study treatment, including but not limited to active peptic ulcer disease, diverticulitis,
or colitis

Radiotherapy within 28 days and abdominal/pelvic radiotherapy within 60 days prior 
to initiation of study treatment, except palliative radiotherapy to bone lesions within 
7 days prior to initiation of study treatment

Local therapy to liver (e.g., radiofrequency ablation, percutaneous ethanol or acetic 
acid injection, cryoablation, high-intensity focused ultrasound, transarterial 
chemoembolization, transarterial embolization, etc.) within 28 days prior to initiation 
of study treatment or non-recovery from side effects of any such procedure

Major surgical procedure, open biopsy, or significant traumatic injury within 28 days 
prior to initiation of study treatment, or abdominal surgery, abdominal interventions 
or significant abdominal traumatic injury within 60 days prior to initiation of study 
treatment or anticipation of need for major surgical procedure during the course of 
the study or non-recovery from side effects of any such procedure

Chronic daily treatment with a nonsteroidal anti-inflammatory drug (NSAID)
Occasional use of NSAIDs for the symptomatic relief of medical conditions such 
as headache or fever is allowed.


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4.2
METHOD OF TREATMENT ASSIGNMENT
4.2.1
Treatment Assignment
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).
Patients will be randomized to one of two treatment arms, atezolizumab and 
bevacizumab or sorafenib, according to a 2:1 randomization ratio with use of a 
permuted-block randomization method. Randomization will be stratified according to the 
following stratification factors:

Geographic region (Asia excluding Japan vs. rest of world)

Macrovascular invasion and/or extrahepatic spread (presence vs. absence)

Baseline AFP (400 vs. 400 ng/mL)

ECOG Performance Status (0 vs 1) 
Patients should receive their first dose of study drug on the day of randomization if 
possible.  If this is not possible, the first dose should occur within 3 business days after 
randomization, with the exception of the emergence of an adverse event, for which 
dosing may be postponed.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal products (IMPs) for this study are atezolizumab, 
bevacizumab, and sorafenib.
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 100-mg and 400-mg preservative-free glass vials to deliver 4 mL or 16 mL of 
bevacizumab (25 mg/mL).  The vial contains approximately 4 mL or 16 mL of 
bevacizumab solution.


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For information on the formulation and handling of bevacizumab, see the pharmacy 
manual and the Bevacizumab Investigator's Brochure.
4.3.1.3
Sorafenib
Sorafenib tablets will be supplied by the Sponsor (where required by local health 
authority regulations) in a wallet containing 28 tablets.
For further details on the formulation, packaging, and handling, refer to the local 
prescribing information for sorafenib.
4.3.2
Study Treatment Dosage, Administration, and Compliance
Patients will receive treatment as outlined in Table 2 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; see Section 3.1 for details).  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.  If treatment was postponed 
for fewer than 3 days, the patient can resume the original schedule.
After 6 complete cycles, 1 of 3 cycles may be delayed by 1 week (28 days instead of 
21 days for 1 cycle) to allow for vacations/holidays.  Following the delay, the next cycle 
visit must be 21 days from the previous Day 1 visit: 2 consecutive 28 cycles are not 
permitted.
Table 2
Study Treatment Regimens
Arm
Cycle 
Length
Dose, Route, and Regimen a
Infusion Rate
A b
21 days
Atezolizumab 1200 mg IV on 
Day 1
Over 60 (15) minutes (for the first 
infusion); 30 (10) minutes for 
subsequent infusions if tolerated
Bevacizumab 15 mg/kg IV on 
Day 1
Over 90 (15) minutes (for the first 
infusion); shortening to 60 (10) then 
30 (10) minutes for subsequent 
infusions if tolerated
B
21 days
Sorafenib 400 mg BID, by 
mouth, continuously
Not applicable
BIDtwice per day.
a Drugs listed in order of administration.
b For patients randomized to Arm A, on Day 1 of each cycle, atezolizumab will be 
administered first, followed by bevacizumab, with a minimum of 5 minutes between dosing.


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Any overdose or incorrect administration of the study treatments should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of any of the study treatments 
should be recorded on the Adverse Event eCRF.
No safety data related to overdosing of atezolizumab and bevacizumab are available 
to date.
Guidelines for treatment interruption or discontinuation and dosage modification 
(sorafenib arm only) for patients who experience adverse events are provided in 
Appendix 11 and Appendix 12.
Patients who are still receiving study treatment at the time of the end of this study will 
continue to be offered study treatment until disease progression or unacceptable 
toxicity. Patients may receive study treatment as part of an open-label extension study, 
if eligible.
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 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 (see Section 3.1 for details).
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 9.  
Atezolizumab infusions will be administered per the instructions outlined in Table 3.
Table 3
Administration of First and Subsequent Atezolizumab Infusions
First Infusion
Subsequent Infusions

No premedication is permitted

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, anti-pyretics, 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


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Table 3
Administration of First and Subsequent Atezolizumab Infusions
(cont.)
First Infusion
Subsequent Infusions

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
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration.
Guidelines for medical management of infusion-related reactions (IRRs) are provided in 
the Atezolizumab Investigator's Brochure.
No dose modification for atezolizumab is allowed.
4.3.2.2
Bevacizumab
Bevacizumab will be administered by IV infusion at a fixed dose of 15 mg/kg on Day 1 of 
each 21-day Cycle (see Table 2).
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 9.  
Bevacizumab infusions will be administered per the instructions outlined in Table 4.  
Guidelines for dosage modification and treatment interruption or discontinuation because 
of toxicities are provided in Appendix 11.
Table 4
Administration of First and Subsequent Bevacizumab Infusions
First Infusion
Subsequent Infusions

No premedication is permitted prior to the 
Bevacizumab infusion

Vital signs (heart rate, respiratory rate, 
blood pressure, and temperature) should be 
recorded within 60 minutes prior to the 
infusion

Bevacizumab should be infused over 
90 (15) minutes

Vital signs should be at the end of infusion 
and 2 (1) hours after the infusion

If the patient experienced an 
infusion-related reaction with any 
previous infusion, premedication with 
antihistamines, anti-pyretics, and/or 
analgesics may be administered for 
subsequent doses at the discretion of the 
investigator

Vital signs should be recorded within 
60 minutes prior to the infusion


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Table 4
Administration of First and Subsequent Bevacizumab Infusions
(cont.)
First Infusion
Subsequent Infusions

Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms

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 at the end of infusion 
and 2 (1) hours after the infusion
4.3.2.3
Sorafenib
A dose of 400 mg sorafenib (2 200 mg tablets) will be given by mouth BID, starting on 
Cycle 1, Day 1. Tablets should be taken with approximately 240 mL (1 cup or 8 ounces) 
of water, without food (at least 1 hour before or 2 hours after a meal). The evening dose 
should be taken approximately 12 hours after the morning dose.
Guidelines for dose modification and study treatment interruption or discontinuation are 
provided in Appendix 11.
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (atezolizumab, bevacizumab, sorafenib) 
will be provided by the Sponsor where required by local health authority regulations.  
The study site will acknowledge receipt of IMPs supplied by the Sponsor with use of the 
IxRS to confirm the shipment condition and content.  Any damaged shipments will be 
replaced.
Investigational medicinal products 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 
(if supplied by the Sponsor) with the appropriate 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.


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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:
https://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY (PROHIBITED FOOD AND 
OTHER RESTRICTIONS)
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 initiation of study treatment to the treatment discontinuation visit.  All such 
medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF.


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4.4.1
Permitted Therapy
Patients are permitted to use the following therapies during the study:

Oral contraceptives

Hormone replacement therapy

Inactivated influenza vaccinations

Megestrol acetate administered as an appetite stimulant 

Mineralocorticoids (e.g., fludrocortisone)

Corticosteroids administered for COPD or asthma

Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency

Low-dose aspirin (325 mg/day) is permitted.  Co-administration of proton pump 
inhibitors is strongly recommended to reduce potential GI damage

Prophylactic use of low-dose anticoagulation, unfractionated heparin, or low 
molecular weight heparin (LMWH) is permitted.  The preferred choice for 
anticoagulation treatment should be LMWH as per American Society of Clinical 
Oncology (ASCO) guidelines (Lyman et al. 2015).

Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic 
relief of pain) as outlined below:
Palliative radiotherapy is permitted, provided it does not interfere with the 
assessment of tumor target lesions (e.g., the lesion to be irradiated must not be 
the only site of measurable disease).  Treatment with atezolizumab may be 
continued during palliative radiotherapy. Bevacizumab or sorafenib treatment 
must be held during palliative radiotherapy treatment.  Upon completion of 
palliative radiotherapy treatment, continuation of bevacizumab or sorafenib 
treatment may be allowed after Medical Monitor approval has been obtained.

Radiotherapy to the brain as outlined below:
Patients whose extracranial tumor burden is stable or responding to study 
treatment and who are subsequently found to have 3 or fewer brain metastases 
may receive radiotherapy to the brain (either stereotactic radiosurgery or 
whole-brain radiation therapy) provided that all of the following criteria are met:
–
The patient has no evidence of progression or hemorrhage after completion 
of CNS-directed therapy
–
The patient has no ongoing requirement for corticosteroids as therapy for 
CNS disease
Patients who require corticosteroid therapy for more than 7 days after 
completion of radiotherapy must be discontinued from study treatment.
–
Anti-convulsant therapy, if required, is administered at a stable dose


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Note:  Treatment with atezolizumab and bevacizumab should be withheld 
during CNS-directed radiation therapy.

Other local therapy (e.g., surgery, stereotactic radiosurgery, radiotherapy, 
radiofrequency ablation) as outlined below:
Patients experiencing a mixed response requiring local therapy for control of 3 or 
fewer non-target lesions may still be eligible to continue study treatment after 
Medical Monitor approval has been obtained.
Premedication with antihistamines, anti-pyretics, 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 4.4.2.2) 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 9).
4.4.2
Cautionary Therapy
4.4.2.1
Herbal Therapies
Concomitant use of herbal therapies 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.
4.4.2.2
Cautionary Therapy for Atezolizumab-Treated Patients
4.4.2.3
Corticosteroids, Immunosuppressive Medications, and TNF-
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 
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 


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associated with atezolizumab therapy (see Appendix 12 and the
Atezolizumab Investigator's Brochure for details).
4.4.2.4
Cautionary Therapy for Sorafenib-Treated Patients
Medications Given with Precaution due to Effects Related to 
Cytochrome P450 Enzymes
In vitro data suggest that sorafenib inhibits CYP2B6 and CYP2C8. Systemic exposure 
to substrates of CYP2B6 and CYP2C8 is expected to increase when co-administered 
with sorafenib. Therefore, the medications listed below should be avoided.  If use of one 
of these medications is necessary, the risks and benefits should be discussed with the 
Medical Monitor prior to concomitant administration with sorafenib.

CYP2B6 substrates, including, but not limited to, bupropion and efavirenz

CYP2C8 substrates, including, but not limited to, repaglinide, montelukast, 
pioglitazone, and rosiglitazone
The above lists of medications are not necessarily comprehensive.  The investigator 
should consult the prescribing information when determining whether a concomitant 
medication can be safely administered with study treatment.  In addition, the investigator 
should contact the Medical Monitor if questions arise regarding medications not 
listed above.
UGT1A1 and UGT1A9 Substrates
Caution is recommended when administering sorafenib with compounds that are 
metabolized/eliminated predominantly by the UGT1A1 pathway (e.g., irinotecan).  
Sorafenib inhibits glucuronidation by the UGT1A1 and UGT1A9 pathways.  Systemic 
exposure to substrates of UGT1A1 and UGT1A9 may increase when co-administered
with sorafenib.  For additional detail, see local prescribing information.
Anti-Arrhythmic Medications or Other Medications that Lead to QT 
Prolongation
Sorafenib has been shown to prolong the QT/QTc interval, which may lead to an 
increased risk of ventricular arrhythmia.  Caution is recommended when administering 
sorafenib with certain anti-arrhythmic medicines or other medicinal products that lead to 
QT prolongation.
Strong CYP3A4 Inducers
Inducers of CYP3A4 may increase metabolism of sorafenib and thus decrease the 
systemic exposure to sorafenib.  Caution is recommended for concomitant use of strong 
CYP3A4 inducers (including, but not limited to, phenytoin, St. John's Wort, 
dexamethasone, carbamazepine, rifampin, rifabutin, and phenobarbital) with sorafenib.  
For additional details, see local prescribing information.


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4.4.3
Prohibited Therapy
Use of the following concomitant therapies is prohibited as described below:

Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy), whether health authorityapproved or experimental, is prohibited for 
various time periods prior to starting study treatment, depending on the agent 
(see Section 4.1.2), and during study treatment, until disease progression is 
documented and the patient has discontinued study treatment, with the exception of 
palliative radiotherapy and local therapy under certain circumstances 
(see Section 4.4.1 for details)

Investigational therapy is prohibited within 28 days prior to initiation of study 
treatment and during study treatment

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 last dose of atezolizumab

Systemic immunostimulatory agents (including, but not limited to, interferons 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

Systemic immunosuppressive medications (including, but not limited to, 
cyclophosphamide, azathioprine, methotrexate, and thalidomide) are prohibited
during study treatment because these agents could potentially alter the efficacy and 
safety of atezolizumab

Current use of full-dose anti-coagulants, thrombolytic therapy at therapeutic doses, 
or anti-platelet therapy are prohibited
Local label-recommended doses for prophylactic use of anti-coagulants or 
thrombolytic therapies is allowed.
Low-dose aspirin (325 mg/day) is permitted.  Coadministration of proton pump 
inhibitors is strongly recommended to reduce potential GI damage.
If a patient experiences a venous thromboembolism (VTE) event while still 
receiving study drug 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 Coumadin-like products (includes for prophylactic use) is 
prohibited
Prophylactic use of low-dose anticoagulation, unfractionated heparin or LMWH is 
permitted.  The preferred choice for anticoagulation treatment should be LMWH 
as per ASCO guidelines (Lyman et al. 2015).

Concomitant chronic use of NSAIDs while receiving study drugs 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) intermittent or 


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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 during the study is provided in Appendix 1.  
The schedule of biomarker, PK, and immunogenicity sampling is provided in Appendix 2.  
All activities must be performed and documented for each patient.
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.  If treatment was postponed 
for fewer than 3 days, the patient can resume the original schedule.
After 6 complete cycles, 1 of 3 cycles may be delayed by 1 week (28 days instead of 
21 days for 1 cycle) to allow for vacations/holidays.  Following the delay, the next cycle 
visit must be 21 days from the previous Day 1 visit: 2 consecutive 28 cycles are not 
permitted.
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.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.  Patients who fail their first screening for study eligibility 
may qualify for 1 re-screening opportunity (for a total of 2 screenings per patient) at the 
investigator’s discretion.  All re-screening requests will require approval by the 
Medical Monitor or designee.
4.5.2
Medical History, 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 initiation of study treatment will be recorded.  At the time of each follow-up physical 


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examination, 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 
post-baseline 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.
As part of the tumor assessment, 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.
Vital signs are to be measured before, during, and after infusions for Arm A as outlined 
in Table 5, and at other specified timepoints as outlined in the schedule of activities 
(see Appendix 1).
Table 5
Timing for Vital Sign Measurements for First and Subsequent 
Infusions in Arm A
Drug
Timing for Vital Sign Measurements
First Infusion
Subsequent Infusions
Arm A
Atezolizumab

Within 60 minutes prior to the 
atezolizumab infusion

Record patient's vital signs 
during or after the infusion if 
clinically indicated

Within 60 minutes prior to the 
atezolizumab infusion

Record patient's vital signs during 
or after the infusion if clinically 
indicated
Bevacizumab

Within 60 minutes prior to the 
bevacizumab infusion

At the end of infusion and 
2 (1) hours after the infusion

Within 60 minutes prior to the 
bevacizumab infusion

At the end of infusion and 
2 (1) hours after the infusion


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4.5.5
Tumor and Response Evaluations
Patients will undergo tumor assessments at baseline, then every 6 weeks (1 week) for 
the first 54 weeks following treatment initiation, and every 9 weeks (1 week) thereafter, 
regardless of dose delays, until radiographic disease progression per RECIST v1.1 or 
(for patients who continue treatment after radiographic disease progression) loss of 
clinical benefit as determined by the investigator (see Section 3.1 for details).  
Patients who meet RECIST v1.1 criteria for progression will undergo tumor assessments 
until disease progression per imRECIST or loss of clinical benefit, whichever occurs later.  
In the absence of disease progression, tumor assessments should continue regardless 
of whether patients start new anti-cancer therapy, until consent is withdrawn, death, or 
the study is terminated by the Sponsor, whichever occurs first.  At the investigator's 
discretion, tumor assessments may be repeated at any time if progressive disease is 
suspected.
All measurable and evaluable lesions should be assessed and documented at screening.  
Tumor assessments performed as standard of care prior to obtaining informed consent 
and within 28 days prior to initiation of study treatment do not have to be repeated at 
screening.
Screening assessments must include CT scans (with oral or IV contrast) or magnetic 
resonance imaging (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 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 multi-phase imaging 
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.  Patients with a 
history of irradiated brain metastases and without measurable brain lesion at screening 
are not required to undergo brain scans at subsequent tumor evaluations, unless scans 
are clinically indicated per local standard of care.
Bone scans or PET scans and CT scans of the neck should also be performed if 
clinically indicated.  At the investigator's discretion, other methods of assessment of 
measurable disease as per RECIST v1.1 may be used.
If a CT scan for tumor assessment is performed in a positron emission tomography 
(PET)/CT scanner, the CT acquisition must be consistent with the standards for a 
full-contrast diagnostic CT scan.


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All measurable and evaluable lesions should be re-assessed at each subsequent tumor 
evaluation.  The same radiographic procedures used to assess disease sites at 
screening should be used for subsequent tumor assessments (e.g., the same contrast 
protocol for CT scans).
Response will be assessed by the investigator with use of RECIST v1.1 (see Appendix 3) 
and imRECIST (see Appendix 4).  Assessments should be performed by the same 
evaluator, if possible, to ensure internal consistency across visits.  Results must be 
reviewed by the investigator before dosing at the next cycle.
Scans will be submitted to an IRF for central review for evaluation of secondary 
progression and response efficacy endpoints.
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, 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
other cells)

Chemistry panel (serum or plasma):  bicarbonate or total carbon dioxide 
(if considered standard of care for the region), sodium, potassium, magnesium, 
chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, 
calcium, total bilirubin, alkaline phosphatase, ALT, AST, LDH

Coagulation:  INR, aPTT

Thyroid function testing: thyroid-stimulating hormone, free triiodothyronine (T3) 
(or total T3 for sites where free T3 is not performed), free thyroxine (also known 
as T4)

AFP testing in blood 

HIV serology

HBV serology:  Hepatitis B surface antigen (HBsAg), hepatitis B surface antibody, 
total hepatitis B core antibody (HBcAb)
If a patient has a positive HBsAg test and/or a positive total HBcAb test at 
screening, an HBV DNA test should be performed at screening.

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 active HCV infection.

Pregnancy test
All women of childbearing potential will have a serum pregnancy test at 
screening.  Urine pregnancy tests will be performed at specified subsequent 
visits.  If a urine pregnancy test is positive, it must be confirmed by a serum 
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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 has not undergone surgical 
sterilization (removal of ovaries and/or uterus).

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:

Pharmacokinetic assays
Serum samples will be assayed for atezolizumab concentration with use of
validated immunoassays.

Anti-drug antibody (ADA) assays
Serum samples will be assayed for the presence of ADAs to atezolizumab with 
use of validated immunoassays.

Quantitative HBsAg

Serum and plasma samples for exploratory research on biomarkers
Exploratory biomarker research may include, but not be limited to, analysis of 
genes or gene signatures associated with tumor immunobiology, PD-L1, or 
cytokines associated with T-cell activation and may involve extraction of 
circulating tumor DNA, or RNA, analysis of somatic mutations by NGS.
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 
when the final CSR has been completed, with the following exceptions:

Serum samples collected for PK or immunogenicity analysis may be needed for 
additional immunogenicity characterization and PK and immunogenicity assay 
development and validation; therefore, these samples will be destroyed no later than 
5 years after the final CSR has been completed

Serum, plasma, and tumor tissue samples collected for biomarker research will be 
destroyed no later than 5 years after the final CSR has been completed

For enrolled patients, remaining archival tissue blocks will be returned to the site 
upon request or 18 months after 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 


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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 will be subject to the confidentiality standards 
described in Section 8.4.
4.5.7
Electrocardiograms
An ECG is required at screening and when clinically indicated.  Electrocardiograms for 
each patient should be obtained from the same machine wherever possible.  
Lead placement should be as consistent as possible.  Electrocardiogram 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 
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, PRO data will be obtained through use of the following instruments: 
the EORTC QLQ-C30, HCC disease-specific treatment questionnaire 
(EORTC QLQ-HCC18), and the EQ-5D-5L.  The questionnaires will be translated as 
appropriate (if necessary) in the country language(s) and as feasible in the local 
language.
To ensure instrument validity and that data standards meet health authority 
requirements, questionnaires must be completed by the patient during a clinic visit 
before discussion of the patient’s health state, laboratory results, or health record, before 
administration of study treatment, and/or prior to any other study assessment(s).
Patients will complete paper versions of the EORTC QLQ-C30, EORTC QLQ-HCC18, 
and EQ-5D-5L questionnaires at the clinic site on Cycle 1, Day 1 and Day 1 of every 
cycle thereafter until the treatment discontinuation visit (included); after treatment
discontinuation or disease progression, whichever comes first, questionnaires will be 
completed every 3 months (for 1 year), unless the patient withdraws consent or the 
Sponsor terminates the study as is denoted in Appendix 1.  Paper PRO questionnaires 
will be provided and collected by site staff.  Questionnaires should be self-administered, 
or they can be interviewer-administered by staff prior to other study assessments.
Study personnel should review all questionnaires for completeness before a patient 
leaves the investigational site.  Patients for whom PRO questionnaires are not available 
in their native language or who are deemed by the investigator incapable of completing
their PRO assessment may be exempt from all PRO assessments.  In the event that 


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PRO questionnaires are not administered, site staff will record the reasons for why the 
measure was not completed in the eCRF.
4.5.8.1
EORTC QLQ-C30
The EORTC QLQ-C30 is a validated, reliable self-reported measure 
(Aaronson et al. 1993; Fitzsimmons et al. 1999; see Appendix 5).  It consists of 
30 questions that assess 5 aspects of patient functioning (physical, emotional, role, 
cognitive, and social), 3 symptom scales (fatigue, nausea and vomiting, pain), global 
health/QoL, and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, 
and financial difficulties) with a recall period of the previous week.  
The EORTC QLQ-C30 module takes approximately 10 minutes to complete. Each score 
is transformed on to a 0 to 100point scale. In the 5 functional scales and the Global 
Health Status (GHS) scale, a high score means a "high level of functioning or global 
health status." For the symptom scales and single items scales, a higher score implies a 
"high level of symptoms or problems."  Previously published minimally important 
differences will be used to identify meaningful changes from baseline in each treatment 
group on the disease and treatment-related symptom scales (Osoba et al. 1998).
4.5.8.2
EORTC QLQ-HCC18
The EORTC QLQ-HCC18 is a disease-specific measure designed for use along with 
the EORTC QLQ-C30 in patients with HCC (Blazeby et al. 2004; Chie et al. 2012).  
It contains 6 multi-item symptom scales (fatigue, body image, jaundice, nutrition, fevers, 
and pain), and 2 single-item scales (abdominal swelling and sexual interest) for a total of 
18 questions with a recall period the past week.  The EORTC QLQ-HCC18 module 
takes approximately 5 minutes to complete.  All item responses are scored according 
to the EORTC guidelines for scoring and the supplementary manuscript on the 
QLQ-HCC18 module (Fayers et al. 2001; Chie et al. 2012).
4.5.8.3
EQ-5D-5L
The EQ-5D-5L is a validated self-reported 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 7).  There are 2 components to the EQ-5D-5L: a 5-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.  
Published weighting systems allow for creation of a single composite score of a patient's 
health status.  The EQ-5D-5L takes approximately 3 minutes to complete. 
The EQ-5D-5L will be included to derive utility to inform pharmacoeconomic models.


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4.5.9
Tumor Samples at Screening
If available, archival tissue samples will be obtained at baseline for exploratory research 
on biomarkers.
Although any available tumor tissue sample can be submitted, sites are strongly 
encouraged 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.
Exploratory biomarker research may include, but not be limited to, analysis of genes or 
gene signatures associated with tumor immunobiology, PD-L1, or cytokines associated 
with T-cell activation and may involve extraction of circulating tumor DNA, or RNA, 
analysis of somatic mutations by NGS.
If there is no available archival tissue sample at baseline, an optional screening biopsy 
may be performed. The Informed Consent Form will contain a separate section that 
addresses this optional screening biopsy.  A separate, specific signature will be required 
to document a patient's agreement to undergo optional biopsies.  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 Optional Biopsy Sample 
Informed Consent eCRF.
See Section 4.5.6 for details on sample storage, use of samples after patient withdrawal, 
and confidentiality standards for data.
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 biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection, 
storage, and analysis of RBR specimens 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.
Specimens for the RBR will be collected from patients who give specific consent to 
participate in this optional research. Research Biosample Repository specimens will be 
used to achieve the following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology


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
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 and submission of biological samples to the RBR 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 (see Section 4.5.10) will not be applicable at that site.
4.5.10.3
Sample Collection
In addition to the RBR plasma sample collected during treatment, the following samples 
will also be stored in the RBR and used for research purposes, including, but not limited 
to, research on biomarkers related to atezolizumab and bevacizumab combination or 
HCC:

Serum and plasma samples collected at Day 1 of Cycles 1, 2, and 4 and at time of 
radiographic progression

Archival tumor tissue samples (e.g., from an earlier biopsy) collected at screening

Tumor tissue samples collected on treatment at the investigator's discretion during 
the study

Tumor tissue samples from biopsies collected after disease progression at the 
investigator's discretion during the study

Leftover 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), including leftover tissue samples from 
medically indicated procedures (e.g., bronchoscopy, EGD, colonoscopy) performed 
at the investigator's discretion during the course of the study
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic mutations via whole-genome sequencing (WGS), whole-exome sequencing 
(WES), NGS, or other genomic analysis methods.
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
Whole-genome sequencing and 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.  Data will be 
analyzed in the context of this study but will also be explored in aggregate with data from 
other studies.  The availability of a larger dataset will assist in identification of important 
pathways, guiding the development of new targeted agents.


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For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Research Biosample Repository specimens 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
Specimens and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR specimens 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 specimens, 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 specimens 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 specimens.  
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 
specimens 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 specimens 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 specimens 
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 specimens, the investigator must inform the Medical Monitor in writing of the 
patient's wishes through use of the appropriate RBR Subject Withdrawal Form and, if the 
trial is ongoing, must enter the date of withdrawal on the RBR Research Sample 
Withdrawal of Informed Consent eCRF.  A patient's withdrawal from Study YO40245
does not, by itself, constitute withdrawal of specimens from the RBR.  Likewise, a 
patient's withdrawal from the RBR does not constitute withdrawal from Study YO40245.
If a patient wishes to withdraw consent to the testing of his or her specimens after 
closure of the site, the investigator must inform the Sponsor by e-mailing the study 
number and patient number to the following e-mail address:
global_rcr-withdrawal@roche.com
4.5.10.7
Monitoring and Oversight
Research Biosample Repository specimens 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 specimens 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 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 determines it is in the best interest of the patient

Use of another non-protocol anti-cancer therapy

Pregnancy


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
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) 
(see Section 3.1 for details)
Arm A patients: If one component of study treatment is discontinued permanently 
because of tolerability concerns, the patient may continue with the other components of 
study treatment until loss of clinical benefit as long as the patients are experiencing 
clinical benefit in the opinion of the investigator and after discussion with the 
Medical Monitor if agreed upon by the investigator and patient.
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 discontinuation visit 30 days after the 
last dose of study treatment.  The visit at which response assessment shows 
progressive disease may be used as the treatment discontinuation visit.  Patients who 
discontinue study treatment for any reason other than progressive disease or loss of 
clinical benefit will continue to undergo tumor response assessments and PRO 
assessments as outlined in the schedule of activities (see Appendix 1).
After treatment discontinuation, information on survival status and new anti-cancer 
therapy will be collected via telephone calls, patient medical records, and/or clinic visits 
approximately every 3 months until death (unless the patient withdraws consent or the 
Sponsor terminates the study).
4.6.2
Patient Discontinuation from 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 withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent

Study termination or site closure

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal 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.


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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, 5.1.2, 5.1.3, and 5.1.4).
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria, close monitoring of 
patients during the study, and regular monitoring by the iDMC (see Section 3.1.2).  
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 
anticipated adverse events, including criteria for treatment interruption or discontinuation
and dosage modification (sorafenib only), are provided in Appendix 11 and Appendix 12.  
See Sections 5.25.6 for details on safety reporting (e.g., adverse events, pregnancies) 
for this study.


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Patients with active infection 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., ASCO or 
European Society for Medical Oncology).
Severe COVID-19 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 COVID-19, 
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 COVID-19 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, nephritis, 
myocarditis, myositis, and severe cutaneous adverse reactions.  Immune-mediated 
reactions may involve any organ system and may lead to hemophagocytic 
lymphohistiocytosis and macrophage activation syndrome (considered to be potential 
risks for atezolizumab). See Appendix 12 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, 
hemorrhage, arterial thromboembolic events, fistulae, wound-healing complications, 
hypertension, VTE, and proteinuria.
Refer to Section 6 of the Bevacizumab Investigator's Brochure for a detailed description 
of anticipated safety risks for bevacizumab.
5.1.3
Risks Associated with Sorafenib
The most common side effects reported in patients receiving sorafenib include diarrhea, 
nausea, weight loss, hand-foot skin reaction, alopecia, anorexia, and voice changes.  
The most common Grade 3 or higher adverse reactions include diarrhea, hand-foot skin 
reaction, hypertension, abdominal pain, cardiac ischemia and/or infarction, hemorrhage, 
hypertension, hand-foot skin reactions and rash, and GI perforation.
For more details regarding the safety profile of sorafenib, refer to the prescribing 
information for sorafenib.


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5.1.4
Risks Associated with Combination Use of Atezolizumab and 
Bevacizumab
The risk of overlapping toxicities between atezolizumab and bevacizumab is anticipated
to be minimal.  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 not be unambiguous 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.
Toxicities should initially be managed according to the recommendations in Appendix 11
with dose holds and modifications (if applicable) applied to the component of the study 
treatment judged to be the primary cause.  If individual component causality for the 
toxicity cannot be adequately determined, then the most conservative management 
recommendation should be applied (in addition to Appendix 11, refer to adverse event 
management guidelines in Appendix 12 and in the most recent version of the 
Atezolizumab and Bevacizumab Investigator's Brochures).
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.  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


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
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)
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).


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5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
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 elevated bilirubin or clinical jaundice, as defined by Hy's Law 
(see Section 5.3.5.7)

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:  diabetes mellitus, pancreatitis, adrenal insufficiency, 
hyperthyroidism, and hypophysitis

Hepatitis, including AST or ALT 10ULN

Systemic lupus erythematosus

Neurological disorders:  Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis

Events suggestive of hypersensitivity, IRRs, CRS, influenza--like illness, and
systemic inflammatory response syndrome

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)

Grade 3 hypertension

Grade 3 proteinuria


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
Any grade GI perforation, abscesses, or GI fistulae

Grade 2 non-GI fistula or abscess

Tracheoesophageal fistula

Grade 3 wound-healing complication

Hemorrhage
Any grade CNS bleeding.
Grade 2 hemoptysis.
Other Grade 3 hemorrhagic event.

Any arterial thromboembolic event

Grade 3 venous thromboembolic event

Any grade posterior reversible encephalopathy syndrome

Grade 3 congestive heart failure
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.  
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, 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, all adverse events will be reported until 30 days after 
the last dose of study treatment 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 last dose of study treatment or 
until initiation of new systemic anti-cancer therapy, whichever occurs first.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.


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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 v4.0 will be used for 
assessing adverse event severity. Table 6 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 6
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 (v4.0), which can be found at:  
https://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" 


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accordingly.  The following guidance should be taken into consideration (see also 
Table 7):

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
Table 7
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 1 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,


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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 eCRF.  If a diagnosis is subsequently established, all previously reported 
adverse events based on signs and symptoms should be nullified and replaced by 
1 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 3 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 


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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.
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).


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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
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).  The patient population for this study consists of patients with 
decreased hepatic function who may exhibit abnormal liver function test results, some of 
which may meet Hy's law criteria prior to enrollment in the trial. The following modified 
Hy's law criteria are for the purpose of determining what may constitute a drug-induced 
liver injury for this trial population and define those cases which require expedited 
reporting to the health authorities in relation to Hy's law.  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).


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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).  An 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 
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 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.


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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.
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 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
Adverse Events Associated with an Overdose or Error in Drug 
Administration
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study treatment should be 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, 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).
No safety data related to overdosing of atezolizumab or bevacizumab are available. 
The highest dose of sorafenib studied was 800 mg BID, at this dose, adverse events 
observed were primarily diarrhea and dermatologic.  No information is available on 
adverse events associated with an overdose of sorafenib in nonclinical studies.


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5.3.5.13
Patient-Reported Outcomes Data
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data. 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 (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)
The investigator must report new significant follow-up information for these events 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
Global Medical Monitor Contact Information
Medical Monitor:
 M.D. (Primary)
Telephone No.:
Mobile Telephone No.:
Back-up Medical Monitor:
, Ph.D. (Primary)
Mobile Telephone No.:


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To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche 
Medical Responsible (listed above and/or on the Roche Medical Emergency List), and 
track all calls.  The Emergency Medical Call Center Help Desk will be available 24 hours 
per day, 7 days per week.  Toll-free numbers for the Help Desk, as well as 
Medical Monitor and Medical Responsible contact information, will be distributed to all 
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, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting 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 e-mailing the form using the fax number or 
e-mail address provided to investigators.
5.4.2.2
Events That Occur after Study Treatment Initiation
After initiation of study treatment, all adverse events will be reported until 30 days after 
the last dose of study treatment or until initiation of new systemic anti-cancer therapy, 
whichever occurs first, and serious adverse events and adverse events of special 
interest will be reported until 90 days after the last dose of study treatment or until 
initiation of new systemic anti-cancer therapy, whichever occurs first.  Investigators 
should record all case details that can be gathered immediately (i.e., within 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 Serious Adverse 
Event/Adverse Event of Special Interest Reporting 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 e-mailing
the form using the fax number or e-mail 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 90 days after the last dose 
of study treatment are provided in Section 5.6.


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5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 5 months after the last 
dose of atezolizumab or 6 months after the last dose of bevacizumab, or within 6 months
after the last dose of sorafenib.  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 
e-mailing the form using the fax number or e-mail 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 last dose of bevacizumab or within 3 months after the last dose of 
sorafenib.  A 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 e-mailing the form using 
the fax number or e-mail 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.  The pregnant partner will need to sign 
an Authorization for Use and Disclosure of Pregnancy Health Information to allow for 
follow-up on her pregnancy.  After the authorization has been signed, the investigator 
will submit a Clinical Trial Pregnancy Reporting Form when updated information on the 
course and outcome of the pregnancy 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 investigator 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).


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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, new systemic
anti-cancer treatment is initiated, the patient is lost to follow-up, the patient withdraws 
consent, or it is determined that the study treatment or participation is not the cause of the 
adverse event.  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.
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, e-mail, 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 last dose of study treatment or until 


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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 e-mailing the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form using the fax number or e-mail
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 with use of the following reference documents:

Atezolizumab Investigator's Brochure

Bevacizumab Investigator's Brochure

Summary of Product Characteristics for sorafenib
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.
An iDMC will monitor the incidence of the above-listed anticipated 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 
on the statistical considerations and analysis plan will be provided in the 
Statistical Analysis Plan (SAP) as part of the Data Analysis Plan.


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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 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6.9) and the China subpopulation (see Section 6.11).  
Any deviations to this will be noted.
The analyses of PFS, time to progression (TTP), and OS 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.  Objective response rate will be analyzed on the basis of all randomized 
patients who have measurable disease at baseline.  Duration of response will be 
assessed only in patients who have an objective response.  Time to deterioration (TTD)
analyses will be conducted in the ITT population.  Change from baseline analysis of
PROs will be performed with use of patients who have both a baseline assessment and 
at least 1 post-baseline assessment, with patients grouped according to the treatment 
assigned at randomization.
Safety analyses will be performed on the basis of all randomized patients who received 
any amount of study drug (the safety population), with patients grouped according to the 
treatment the patient actually received.
6.1
DETERMINATION OF SAMPLE SIZE
A total of approximately 480 patients will be randomized in the global enrollment phase 
of this study, with use of a 2:1 randomization ratio to allocate patients to either the 
atezolizumab and bevacizumab arm (Arm A) or the sorafenib arm (Arm B).  The final OS 
analysis will be conducted at approximately 33 months after the first patient is 
randomized (first patient in [FPI]). The final OS analysis will be descriptive and 
considered as optional if statistical significance is achieved at one of the pre-planned 
interim analyses of OS.
The co-primary efficacy endpoints for this study are as follows:

Overall survival, defined as the time from randomization to death from any cause

Independent Review Facility-assessed PFS, defined as the time from randomization 
to the occurrence of disease progression per RECIST v1.1 or death from any cause, 
whichever occurs first
The overall type I error rate for this study will be controlled at a 2-sided significance level 
of 0.05 by a graphical approach (i.e., -splitting and recycling; Bretz et al. 2009;
Burman et al. 2009).  The overall 2-sided significance level of 0.05 will be split into a 
2-sided significance level of 0.048 for the testing of OS and a 2-sided significance level 
of 0.002 for the testing of PFS as a first step.  For further details, see Section 6.4.1.


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The sample size of the study was determined based on the number of deaths required to
demonstrate efficacy in terms of OS.  To detect an improvement in OS using a log-rank 
test at a 2-sided significance level of 0.048, approximately 312 deaths will be required to 
achieve 80% overall power assuming a target HR of 0.71 (median OS improvement vs.
control is 4.9 months). The minimum detectable difference (MDD) of OS is an HR of 
0.783 (median OS improvement is 3.3 months). Three-hundred and twelve deaths are
expected to occur approximately 33 months after FPI.
Overall Survival
The calculation of sample size and estimates of the OS analysis timelines are based on 
the following assumptions:

Patients will be randomized to the atezolizumab and bevacizumab and sorafenib 
arms in a 2:1 ratio

Overall survival follows a 1-piece exponential distribution

The median OS in the control arm is 12 months

The stopping boundaries of the interim and final analyses of OS use the
O'Brien-Fleming boundaries approximated with use of the Lan-DeMets method
(DeMets and Lan 1994)

The dropout rate is 5% for the atezolizumab and bevacizumab arm and 10% for the 
sorafenib arm over 12 months for OS

The recruitment of approximately 480 patients will take place over approximately 
10 months
Independent Review Facility-Assessed Progression-Free Survival
To detect an improvement in IRF-assessed PFS using a log-rank test at a 2-sided 
significance level of 0.002, approximately 308 events will be accrued for the primary PFS 
analysis, which will provide approximately 97% power with a target HR of 0.55 
(median PFS improvement of 3.3 months from 47.3 months).  This is to ensure a 
minimal follow-up of approximately 6 months for all patients (i.e., to have a clinical cutoff 
date at approximately 6 months after the last patient is randomized to the study).  
The MDD is a PFS HR of 0.688 (median PFS improvement of 1.8 months from 
45.8 months).  The clinical cutoff date for this primary PFS analysis is expected to 
occur approximately 16 months after the first patient was enrolled in the study.  
The following assumptions were made for PFS based on the ITT population:

Patients will be randomized to the atezolizumab and bevacizumab and sorafenib 
arms in a 2:1 ratio

Progression-free survival follows a 1-piece exponential distribution

The median duration of PFS in the control arm is 4 months

The dropout rate is 5% for the atezolizumab and bevacizumab arm and 10% for the 
sorafenib arm over 12 months for PFS

The recruitment of 480 patients will take place over 10 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 drug administration, reasons for discontinuation from the study 
drug, and reasons for study termination will be summarized by treatment arm for the ITT 
population.  Major protocol deviations, including major deviations of inclusion/exclusion 
criteria, will be reported and summarized by treatment 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 treatment 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 the patient receiving 
the first dose of any component of study treatment.
6.4
EFFICACY ANALYSES
Hypotheses will be formally tested on co-primary and key secondary endpoints (to be 
identified in the SAP) and details on the -recycling method, including -recycling 
sequence, will be specified in the SAP.  Implementation of the statistical testing 
procedure will strongly control the overall type I error at 5% (2-sided).  Additional details 
will be provided in the SAP.
6.4.1
Co-Primary Efficacy Endpoints
The primary efficacy objective for this study is to evaluate the efficacy of atezolizumab in 
combination with bevacizumab compared with sorafenib on the basis of the co-primary 
efficacy endpoints of OS and IRF-assessed PFS according to RECIST v1.1.
Overall survival and PFS will be tested initially in parallel with the overall type I error 
controlled at a 2-sided significance level of 0.05, where OS will be tested at a 2-sided 
significance level of 0.048 and PFS will be tested at a 2-sided significance level of 0.002.
6.4.1.1
Overall Survival
Overall survival is defined as the time from the date of randomization to the date of 
death from any cause. Patients who are alive at the time of the analysis data cutoff will 
be censored at the last date they were known to be alive. Patients with no post-baseline 
information will be censored at the date of randomization.


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The null and alternative hypotheses regarding OS can be phrased in terms of the 
survival functions SA(t) and SB(t) for Arm A (atezolizumab andbevacizumab) and Arm B 
(sorafenib), respectively:
H0:  SA(t)SB(t) versus H1: SA(t) ≠ SB(t)
The 2-sided log-rank test, stratified by geographic region (Asia excluding Japan vs. rest 
of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), 
and baseline AFP (400 vs. 400 ng/mL), will be used as the primary analysis to 
compare OS between the two treatment arms. The results from the unstratified log-rank 
test will also be provided as a sensitivity analysis to check the robustness of the results
of the stratified log-rank test.
The Kaplan-Meier method will be used to estimate median OS for each treatment arm. 
Brookmeyer-Crowley methodology will be used to calculate the 95% CI for the median 
OS for each treatment arm.  Stratified Cox proportional-hazards models will be used to 
estimate the HR and its 95% CIs. The stratification factors will be the same as those 
used for the primary stratified log-rank test.  The unstratified HR will also be provided.
A group sequential design will be used for testing the co-primary efficacy endpoint OS to 
account for the conduct of 2 interim analyses.  An -spending with use of the 
Lan-De Mets method approximating O'Brien-Fleming boundaries (DeMets and Lan 1994) 
will be utilized to control the overall type I error rate of 0.048 for the OS co-primary 
efficacy endpoint.  The first interim OS analysis will be conducted at time of the 
co-primary analysis of IRF-assessed PFS (see Section 6.4.1.2).  The second interim OS 
analysis is planned to be conducted when approximately 243 OS events have been 
observed. The final analysis of OS is expected to occur after approximately 312 deaths 
have occurred. If statistical significance is reached at one of the pre-planned interim 
analyses of OS, then that interim OS analysis will be regarded as the definitive analysis 
of OS and subsequent analyses of OS, including the final OS analysis, will be 
descriptive and considered as optional.
In order to assess the homogeneity of the treatment effect with respect to the co-primary 
efficacy endpoint of OS across important subgroups, Forest plots (including the 
estimated HRs) will be provided.  A full list of all pre-specified exploratory subgroup 
analyses for OS for this study will be provided in the SAP.
Further methodological details will be provided in the SAP.
6.4.1.2
Independent Review Facility-Assessed Progression-Free 
Survival
Independent Review Facility-assessed PFS is defined as the time from randomization to 
the occurrence of disease progression as determined by the IRF according to 
RECIST v1.1, or death from any cause, whichever occurs first.  Patients who have not 
experienced disease progression or death at the time of the clinical cutoff date will be 


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censored at the time of the last tumor assessment on or prior to the clinical cutoff date.  
Patients with no post-baseline tumor assessment will be censored at the date of 
randomization.
Methods for PFS analyses are similar to those described for the OS endpoint.
6.4.2
Secondary Efficacy Endpoints
Investigator-Assessed Objective Response Rate
An objective response, defined as a CR or PR, will be determined by the investigator
according to RECIST v1.1.  Patients not meeting these criteria, including patients without 
any post-baseline tumor assessment, will be considered non-responders.  A confirmed 
objective response is a response (CR or PR) seen at 2 consecutive tumor assessments
at least 28 days apart.
Investigator-assessed ORR is defined as the percentage of patients who have an 
objective response per the investigator according to RECIST v1.1.  The analysis 
population for ORR will be all randomized patients with measurable disease at baseline
per the investigator according to RECIST v1.1.
The 2-sided Cochran-Mantel-Haenszel test, stratified by geographic region 
(Asia excluding Japan vs. rest of world), macrovascular invasion and/or extrahepatic 
spread (presence vs. absence), and baseline AFP (400 vs. 400 ng/mL), will be used 
to compare ORR between the two treatment arms.
Objective response rate will be estimated for each treatment arm.  The respective 
95% CIs will be calculated with use of the Clopper-Pearson method
(Clopper and Pearson 1934). Finally, the difference in ORR between treatment arms will 
be computed with the associated 95% CI by normal approximation.
Investigator-Assessed Progression-Free Survival
Progression-free survival analyses will be performed separately based on 
investigator-assessed tumor response according to RECIST v1.1.  The analysis 
methods are similar to those described for OS.
Investigator-Assessed Time to Progression
Time to progression is defined as the time from the date of randomization to the date of 
the first documented tumor progression. Patients without tumor progression, including 
death, will be censored at the last tumor assessment date.  Patients who have no 
post-baseline tumor assessment will be censored at the date of randomization.
Investigator-assessed TTP analyses will be performed based on investigator-assessed 
tumor response according to RECIST v1.1.  The analysis methods are similar to those 
described for OS.


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Independent Review Facility-Assessed Objective Response
An objective response per IRF is defined as a CR or PR as determined by an IRF,
according to RECIST v1.1 and separately according to HCC mRECIST. Patients not 
meeting these criteria, including patients without any post-baseline tumor assessment, 
will be considered non-responders.  A confirmed objective response is a response 
(CR or PR) seen at 2 consecutive tumor assessments at least 28 days apart).
Objective response rate is defined as the proportion of patients who had an objective 
response.  The analysis population for ORR per IRF will be all randomized patients with 
measurable disease at baseline per IRF according to RECIST v1.1 and HCC mRECIST. 
The analysis methods are similar to those described for the investigator-assessed ORR.
Duration of Response
Duration of response will be assessed in patients who had an objective response. 
Duration of response is defined as the time interval from the date of the first occurrence 
of a documented objective response (CR or PR, whichever status is recorded first) until 
the first date that disease progression or death is documented, whichever occurs first.
Patients who have not progressed and who have not died at the time of the clinical cutoff 
date will be censored at the time of the last tumor assessment on or prior to the clinical 
cutoff date.
Duration of response analyses will be performed separately based on IRF- and 
investigator-assessed tumor response according to RECIST v1.1, and IRF-assessed 
tumor response according to HCC mRECIST.  The analysis methods are similar to those 
described for OS.
Independent Review Facility-Assessed Time to Progression
Independent Review Facility-assessed TTP is defined the same as 
investigator-assessment TTP, except that analyses will be performed based on 
IRF-assessed tumor response according to RECIST v1.1. and HCC mRECIST.  
The analysis methods are similar to those described for OS.
Independent Review Facility-Assessed Progression-Free Survival
Progression-free survival analyses will be performed separately based on IRF-assessed 
tumor response according to HCC mRECIST.  The analysis methods are similar to those 
described for OS.
Progression-Free Survival and Overall Survival by Baseline -Fetoprotein
Investigator- and IRF-assessed PFS according to RECIST v1.1 and OS will be analyzed 
by subgroups of baseline serum AFP level (400 ng/mL vs. 400 ng/mL).  The analysis 
methods are similar to those described for the co-primary endpoints.  Geographic region 
(Asia excluding Japan vs. rest of world) and macrovascular invasion and/or extrahepatic 
spread (presence vs. absence) will be used as stratification factors for stratified analyses.


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Time to Deterioration
The primary analysis population for evaluation of TTD will be the ITT population.
Time to deterioration is defined as the time from randomization to first deterioration 
(decrease from baseline of 10 points) in the patient-reported GHS/QoL, physical 
function, or role function scales of the EORTC QLQ-C30, maintained for 2 consecutive 
assessments, or 1 assessment followed by death from any cause within 3 weeks.
The Kaplan-Meier analysis methods for the analysis of TTD are similar to those 
described for PFS.  Patients who do not have an observed deterioration at the time of 
discontinuation from study treatment or at the clinical cutoff date will be censored at the 
last available assessment date prior to or at the time of discontinuation from study 
treatment or clinical cutoff date, whichever is earlier.  Patients without a post-baseline 
assessment will be censored at randomization date.
6.4.3
Exploratory Efficacy Endpoints
Objective response rate, PFS, TTP, and DOR will be determined by the investigator 
according to imRECIST, using the same definitions as for the primary/secondary 
endpoints determined by RECIST v1.1 and analyzed using the same analysis methods.
Independent Review Facility-assessed PFS according to RECIST v 1.1 and OS based 
on the following biomarkers in tumor tissue will be analyzed using similar statistical 
methods:

Baseline expression of T effector gene signature in tumor tissue

Baseline PD-L1 protein expression in tumor tissue

CD8 protein expression level or CD8T-cell localization

Immunohistochemistry or genes/gene signatures (by gene expression profiling) 
related to tumor microenvironments

T-cell receptor sequence profile in tumor-associated T cells
Patient-Reported Outcomes Analyses
Completion rates and reasons for missing data will be summarized for each of the 
EORTC QLQ-C30 and EORTC QLQ-HCC18 measures at each cycle by treatment arm.
In addition, the following analyses will be conducted by treatment arm.
Exploratory TTD analyses will be conducted utilizing Kaplan-Meier methods, with TTD
defined as the time from randomization to first deterioration (increase from baseline 
of 10 points), maintained for 2 consecutive timepoints, or 1 timepoint followed by death 
from any cause within 3 weeks for select subscales of the EORTC QLQ-C30 
(appetite loss, diarrhea, fatigue, pain) and the EORTC QLQ-HCC18 (jaundice, fatigue, 
pain). Patients who do not have an observed deterioration at the time of discontinuation 
from study treatment or at the clinical data cutoff date will be censored at the last 
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or clinical cutoff date, whichever is earlier. Patients without a post-baseline assessment 
will be censored at the randomization date.
Kaplan-Meier analysis methods similar to those described for OS will be used to assess 
long-term impact on GHS/HRQoL, physical function, and role function.  For this 
exploratory analysis, TTD will be defined as the time from randomization to first 
deterioration (decrease from baseline of 10 points), maintained for 2 consecutive 
timepoints, or 1 timepoint followed by death from any cause within 3 weeks.
Patients who do not have an observed deterioration at the time of the clinical data cutoff 
will be censored at the last available assessment date. Patients without a post-baseline 
assessment will be censored at randomization.
Visit mean summary and change from baseline analyses will be performed for all 
subscales of the EORTC QLQ-C30 and EORTC QLQ-HCC18.  Summary statistics 
(number of patients, mean, standard deviation, median, minimum, maximum, 95% CI) of 
score(s) and score change(s) from baseline to each timepoint will be determined.  
Previously published minimally important differences (MID; e.g., 10-point MID) will be 
used to identify meaningful change from baseline within each treatment group on all 
scales of the EORTC QLQ-C30 and EORTC QLQ-HCC18 (Osoba et al. 1998).
Proportion of patients with a clinically meaningful change (improved, deteriorated, 
remained stable) in select scales of the QLQ-C30 (GHS/QoL, physical function, role 
function, appetite loss, diarrhea, fatigue, pain) and QLQ-HCC18 (jaundice, fatigue, pain)
will be summarized by treatment arm.
Proportion of responses for the itching item of the QLQ-HCC18 jaundice subscale, the 
abdominal pain item of the QLQ-HCC18 pain subscale, and each timepoint while 
patients are on treatment will be summarized.
In the event of incomplete data for any questionnaire subscales, if more than 50% of 
the constituent items are completed, a prorated score will be computed, consistent with 
the scoring manuals and validation papers.  For subscales with less than 50% of the 
items completed, the subscale will be considered as missing (Fayers et al. 2001; 
Chie et al. 2012).
6.5
SAFETY ANALYSES
The safety analysis population will consist of all randomized patients who received at 
least 1 full or partial dose of study treatment, with patients grouped according to 
treatment received.
Verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms, and adverse event severity will be graded 
according to NCI CTCAE v4.0.


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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 the first dose of study treatment will be 
summarized by treatment arm and NCI CTCAE grade:

All adverse events

All adverse leading to death

All serious adverse events

All severe adverse events (Grade 3)

All adverse event of special interest

All 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 treatment arm and grade.
Descriptive statistics will be used to summarize changes in vital signs by treatment arm.
Deaths with causes of death reported during the study will be summarized by 
treatment arm.
Additional analyses may be performed as indicated.
6.6
PHARMACOKINETIC ANALYSES
The PK analysis population will consist of all patients with at least 1 PK assessment.
Samples will be collected for PK analyses and serum concentrations of atezolizumab will 
be reported as individual values and summarized (mean, standard deviation, coefficient 
of variation, median, range, geometric mean, and geometric mean coefficient of variation) 
by treatment arm and 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.
Additional PK and pharmacodynamic analyses will be conducted as appropriate.


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6.7
IMMUNOGENICITY ANALYSES
The immunogenicity analysis population will consist of all patients with at least 1 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 (post-baseline incidence) 
will be summarized for ADA-evaluable patients.  When determining post-baseline 
incidence, patients are considered to be 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 1 or more post-baseline samples is at least 0.60 titer units greater than the titer of the 
baseline sample (treatment-enhanced ADA response).  Patients are considered to be
post-treatment ADA-negative if they are ADA-negative or have missing data at baseline
and all post-baseline samples are negative, or if they are ADA-positive at baseline but 
do not have any post-baseline samples with a titer that is at least 0.60 titer units 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
EXPLORATORY BIOMARKER ANALYSES
Exploratory biomarker analyses will be performed in an effort to understand the
association of tissue or blood-based biomarkers (see Table 1) with response to 
atezolizumab in combination with bevacizumab versus sorafenib, or increase the 
understanding of HCC disease evolution under atezolizumab and bevacizumab 
treatment.  Progression-free survival and OS will be analyzed using the methods 
outlined in Section 6.4.  This may include appropriate multivariate analyses.  
Further details will be provided in the SAP.
6.9
EXPLORATORY HEALTH STATUS ANALYSIS
Health utility data from the EQ-5D-5L (see Appendix 7) will be evaluated in 
pharmacoeconomic models.  The results from the health economic data analyses will be 
reported separately from the CSR.
6.10
INTERIM ANALYSIS
No interim analysis is planned for PFS in this study.
Two interim analyses of OS are planned to be performed.  The first interim analysis will 
be performed at the time of the primary PFS analysis, estimated to occur at 
approximately 16 months after FPI.  It is anticipated that at this time approximately 
172 deaths will have been observed.  The respective MDD OS HR is 0.633 (median OS 
improvement is 6.9 months).  The second OS interim analysis is planned to be 


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conducted when approximately 243 deaths are accumulated, estimated to occur at 
approximately 24 months after FPI.  The respective MDD OS HR is 0.728 (median OS 
improvement is 4.6 months).
To control the 2-sided significance level at 0.048 for the interim and final OS analyses, 
the Lan-DeMets method will be used to approximate the O'Brien-Fleming boundaries.
The planned interim analyses for OS will be conducted by the Sponsor.
Further details are given in Section 6.4.1.1.
Table 8
Analysis Timing and Stopping Boundaries for Overall Survival
Analysis 
Timing
Planned 
Information 
Fraction
Required Events/
Analysis Timing
(estimated)
Stopping Boundary
(2-Sided p-value)
can be 
recycled to OS 
(i.e., OS 0.05)
cannot be recycled 
to OS
(i.e., OS 0.048)
1st OS 
interim 
analysis
55%
172/16 months
MDD.HR 0.636
(p-value 0.005)
MDD.HR 0.633
(p-value 0.005)
2nd OS 
interim 
analysis
78%
243/24 months
MDD.HR 0.73
(p-value 0.021)
MDD.HR 0.728
(p-value 0.02)
OS final 
analysis
100%
312/33 months
MDD.HR 0.784
(p-value 0.043)
MDD.HR 0.783
(p-value 0.041)
HR hazard ratio; MDD minimum detectable difference; OS overall survival; 
PFS progression-free survival.
Analysis timing shown in the table is projected based on protocol assumptions. Actual timing 
depends on the exact time that the required events have accrued.
The 1st OS interim analysis will be conducted when approximately 308 PFS events have 
happened.  If statistical significance is reached at one of the pre-planned interim analyses of 
OS, then that interim OS analysis will be regarded as the definitive analysis of OS and 
subsequent analyses of OS, including the final OS analysis, will be descriptive and considered 
as optional.
6.11
CHINA SUBPOPULATION ANALYSES
The Sponsor is targeting a total enrollment of approximately 135 patients from mainland 
China. The sample size of the China subpopulation was determined by characterizing
the efficacy and safety profile of atezolizumab in combination with bevacizumab. 
After approximately 480 patients have been randomized into the global portion of the 
study, in the event that fewer than 135 patients from mainland China are enrolled, 
additional patients in China may be subsequently randomized into the two treatment 


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arms in a 2:1 ratio in an extended China enrollment phase to ensure a total of 
approximately 135 patients from mainland China for inclusion in the China subpopulation.
The primary efficacy objective of the China subpopulation analysis is to assess efficacy,
as measured by the co-primary endpoints of PFS by an IRF-assessment per 
RECIST v1.1 and OS, of atezolizumab and bevacizumab compared with sorafenib 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 PFS and/or OS 
events have occurred to demonstrate at least 80% probability of maintaining 50% of risk 
reduction compared with that estimated from the global population. The exact timing of
analyses will be specified in the SAP.
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 CSR 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.
Electronic Case Report Forms 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.
Patient-reported outcomes data will be collected on paper questionnaires.  The data 
from the questionnaires will be entered into the EDC system by site staff.


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7.2
ELECTRONIC CASE REPORT FORMS
Electronic Case Report Forms 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.  Electronic Case Report Forms 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.  Electronic Case Report 
Forms 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 on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
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.


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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, paper PRO data, 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 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 Trial Directive (2001/20/EC) 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 a Child's Informed Assent Form or Mobile Nursing


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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.
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.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  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, 


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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 9.6).
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
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 Roche policy on study data publication 
(see Section 9.5).
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.


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Study data, which may include data on germline mutations, 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 CSRs and other 
summary reports will be provided upon request.
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
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 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.


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9.4
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 120 sites globally will participate to randomize approximately 480 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 be employed to monitor and evaluate patient safety throughout the study.  
Tumor response and progression will be evaluated by the investigator as well as an IRF.
9.5
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 more details), and 
redacted CSRs and other summary reports will be made available upon request.  
For more information, refer to the Roche Global Policy on Sharing of Clinical Trials Data 
at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
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 CSR.  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.
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.


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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.
9.6
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 (e.g., change in Medical Monitor or contact information).


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10.
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Atezolizumab—F. Hoffmann-La Roche Ltd
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Appendix 1 Schedule of Activities
Assessment Window (Days) a
Screening b
Treatment Phase (Q3W)
Treatment 
Discontinuation c
Survival 
Follow-Up
–28 to –1
–7 to –1
Day 1 of Each Cycle c
30 Days after 
Last Dose
Signed Informed Consent Form(s) b
x
Review of eligibility criteria
x
Medical, surgical, and cancer histories, 
including demographic information d
x
Complete physical examination e
x
Limited physical examination f
x g
x
ECOG Performance Status
x
x g
x
Patient-reported outcomes h
x g
x
x h
Tumor assessment i
x
See footnote i
x
x
Vital signs j
x
x
x
Weight
x
x k
x
Height
x
12-lead ECG l
x
Perform as clinically indicated
EGD m
x
Hematology n, z
x
x g
x
Serum chemistry o, z
x
x g
x
HIV, HBV, HCV serology p
x
Quantitative HBsAg, HBV DNA, HCV 
RNA q
x
x
x
-fetoprotein 
x
x
x
Coagulation panel (aPTT, INR) z
x
x g
x
Urinalysis r, z
x
x g
x


Appendix 1:  Schedule of Activities (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
124/Protocol YO40245, Version 6
Assessment Window (Days) a
Screening b
Treatment Phase (Q3W)
Treatment 
Discontinuation c
Survival 
Follow-Up
–28 to –1
–7 to –1
Day 1 of Each Cycle c
30 Days after 
Last Dose
TSH, free T3, free T4
x
Cycles 5, 9, 13, etc. (every 4 cycles) 
x
Pregnancy test
x s
x t
x
Serum PK sample
See Appendix 2
Serum ADA sample
See Appendix 2
Pharmacodynamic samples for 
biomarkers
See Appendix 2
x
Plasma sample for RBR (optional)
Any time (at investigator's discretion)
Archival tumor tissue sample (or optional 
fresh biopsy if archival tissue is not 
available) for biomarkers
x
Concomitant medications u
x
x
x
Adverse events v
x
x
x
Study treatment infusion w
x
Sorafenib dispensing x
x
Survival and anti-cancer therapy 
follow-up y
x
ADAanti-drug antibody; CTcomputed tomography; EGDesophagogastroduodenscopy; EORTCEuropean Organisation for Research and 
Treatment of Cancer; EQ-5D-5LEuroQol 5-Dimension Questionnaire, 5-level version; HBcAbhepatitis B core antibody; HBsAbhepatitis B 
surface antibody; HBsAghepatitis B surface antigen; HBVhepatitis B virus; HCVhepatitis C virus; imRECIST immune-modified RECIST; 
MRImagnetic resonance imaging; PET positron emission tomography; PKpharmacokinetic; PROpatient-reported outcome; Q3W every 
3 weeks; QLQ-C30quality-of-life questionnaire for cancer; QLQ-HCC18HCC disease-specific module; RBRResearch Biosample Repository; 
RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1; T3triiodothyronine; T4thyroxine; TSHthyroid-stimulating hormone.
Note:  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.
a
The first dosing date (Cycle 1, Day 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.  All visits and infusions thereafter may be administered with a window of 3 days.


Appendix 1:  Schedule of Activities (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
125/Protocol YO40245, Version 6
b
Written informed consent can be obtained up to 30 days prior to study entry 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 protocol relevant 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.
c
Patients will be asked to return to the clinic 30 days after the last dose of study treatment for an end-of-treatment visit.  After this visit, serious 
adverse events and protocol defined adverse events of special interest, regardless of attribution, will be recorded until 90 days after the last dose 
of study treatment or until initiation of another systemic anti-cancer therapy, whichever occurs first.  Ongoing adverse events thought to be 
related to study treatment will be followed until the event has resolved to baseline grade or better, the event is assessed by the investigator as 
stable, new anti-cancer treatment is initiated, the patient is lost to follow-up, the patient withdraws consent, or it is determined that the study 
treatment or participation is not the cause of the adverse event.  Scans performed within 6 weeks prior to the treatment discontinuation visit do 
not need to be repeated.
d
Cancer history includes stage, date of diagnosis, and prior anti-tumor treatment.  Demographic information includes age and self-reported 
race/ethnicity.  Reproductive status and smoking history should also be captured.
e
A complete physical examination at screening should include the evaluation of head, eye, ear, nose, and throat and cardiovascular, 
dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  Changes in abnormalities noted at baseline 
should be recorded at the end of the visit.  New or worsened abnormalities should be recorded as adverse events if appropriate.
f
A limited physical examination will be performed at other visits to assess changes from baseline abnormalities and any new abnormalities and to 
evaluate patient-reported symptoms.  New or worsened abnormalities should be recorded as adverse events if appropriate.
g
ECOG Performance Status, limited physical examination, local laboratory assessments, and PROs may be obtained 96 hours before Day 1 of 
each cycle.
h
The EORTC QLQ-C30, EORTC QLQ-HCC18, and EQ-5D-5L questionnaires will be completed by all patients on paper starting on Day 1 of 
Cycle 1 and Day 1 of every cycle thereafter.  All PRO questionnaires scheduled for administration during a clinic visit are required to be 
completed by the patient at the investigational site at the start of the clinic visit before discussion of the patient's health state, lab results or health 
record, before administration of study treatment, and/or prior to any other study assessment(s).  This is to avoid any potential bias to patients’ 
responses to ensure that the validity of the instrument is not compromised and that data quality meets regulatory requirements.  Interview 
assessment by a member of the clinic staff will be allowed if the patient is not able to complete the measure on their own.  Study personnel 
should review all questionnaires for completeness before the patient leaves the investigational site.  During survival follow-up, all PRO 
questionnaires will be completed every 3 months (for 1 year), unless the patient withdraws consent or the Sponsor terminates the study.  
PRO questionnaires during the survival follow-up period may be completed at the investigational site should the patient come in for a clinic visit 
or be administered via interview in telephone calls.
i
All measurable and evaluable lesions should be assessed and documented at the screening visit.  Radiologic imaging performed during the 
screening period should consist of 1) CT and/or MRI of the chest/abdomen/pelvis and brain, 2) bone scan or PET scan as clinically indicated, 
and 3) any other imaging studies (CT scan of the neck, plain films, etc.) as clinically indicated by the treating physician. The same radiographic 
procedures and technique must be used throughout the study for each patient (e.g., if the patient had CT chest/abdomen/pelvis performed 
during screening, then she should subsequently undergo CT performed with use of the same radiologic protocol throughout the remainder of the 
study).  Results must be reviewed by the investigator before dosing at the next cycle.  Tumor assessments will be performed at baseline, every 
6 weeks (1 week) for the first 54 weeks following the initiation of study treatment, and every 9 weeks (1 week) thereafter, with additional 


Appendix 1:  Schedule of Activities (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
126/Protocol YO40245, Version 6
scans as clinically indicated.  All known sites of disease documented at screening should be re-assessed at each subsequent tumor evaluation.  
Tumor response will be evaluated by the investigator with use of RECIST version 1.1 and imRECIST.  In the absence of disease progression, 
tumor assessments should continue regardless of whether patients discontinue study treatment or start new anti-cancer treatment, unless the 
patient dies, withdraws consent, or the study is terminated by the Sponsor, whichever occurs first. 
j
Vital signs include heart rate, respiratory rate, blood pressure, and temperature.  For patients randomized to Arm A, on days of study treatment 
administration (atezolizumab and bevacizumab), the patient's vital signs should be determined up to 60 minutes before all infusions.  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 after every 
infusion of atezolizumab if clinically indicated.
k
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 baseline.  If re-baseline is needed the 
latest baseline weight should always be used to calculate percent change in weight for all subsequent doses.
l
Patients should be resting and in a supine position for at least 10 minutes prior to each ECG collection.
m
All patients must undergo an EGD and all size of varices (small to large) must be assessed and treated per local standard of care prior to 
enrollment.
n
Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with differential (neutrophils, eosinophils, lymphocytes, 
monocytes, basophils, and other cells), and platelet count.  A manual differential can be done if clinically indicated.  
o
Serum chemistry includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, potassium, magnesium, 
chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, alkaline phosphatase, ALT, AST, and LDH.
p
All patients will be tested for HIV locally prior to the inclusion into the study and if not in contradiction with local legislation; HIV-positive patients 
will be excluded from the clinical study.  HBsAg, HBcAb, and HBsAb should be collected during screening and tested locally.  HBV DNA must be 
collected prior to Cycle 1, Day 1 in patients who have negative serology for HBsAg and positive serology for anti-HBcAb.
q
Only if patient tests positive for HBsAg, HBcAb, quantitative HBsAg and HBV DNA will be tested during screening; Cycle 5, Day 1; Cycle 9, 
Day 1; and at treatment discontinuation.  Quantitative HBsAg will be tested by central laboratory.  If a patient tests positive for HCV antibody at 
screening, quantitative HCV RNA must be tested locally at screening, Cycle 5 Day 1, Cycle 9 Day 1, and at treatment discontinuation.
r
Urine dipstick includes specific gravity, pH, glucose, protein, ketones, and blood and should be repeated before every cycle during treatment.  
Urine dipstick for proteinuria must be 2+ within 7 days prior to initiation of study treatment.  Patients discovered to have 2+ proteinuria on 
dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate 1 g of protein in 24 hours.  
s
Serum pregnancy test within 14 days before Cycle 1, Day 1.
t
Urine pregnancy test; if a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.
u
Concomitant medications include any prescription medications or over-the-counter medications.  At screening, any medications the patient has 
used within the 7 days prior to initiation of study treatment should be documented.  At subsequent visits, changes to current medications or 
medications used since the last documentation of medications will be recorded.
v
After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 30 days after the last dose of study 
treatment or until initiation of another anti-cancer therapy, whichever occurs first.  Serious adverse events and adverse events of special interest 
will continue to be reported until 90 days after the last dose of study treatment or until initiation of new anti-cancer therapy, whichever occurs first.  
After this period, investigators should report any serious adverse events and adverse events of special interest that are believed to be related to 


Appendix 1:  Schedule of Activities (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
127/Protocol YO40245, Version 6
prior treatment with study drug. 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, new systemic anti-cancer treatment is initiated, the patient is lost to follow-up, the patient
withdraws consent, or it is determined that the study treatment or participation is not the cause of the adverse event.  Every effort should be 
made to follow all serious adverse events considered to be related to study drug or study-related procedures until a final outcome can be 
reported.
w
The initial dose of atezolizumab will be delivered over 60 (15) minutes.  If the first infusion is tolerated without infusion-associated adverse 
events, the second infusion may be delivered over 30 (10) minutes.  If the 30-minute infusion is well-tolerated, all subsequent infusions may be 
delivered over 30 (10) minutes.  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.  If the 60-minute infusion is well-
tolerated, all subsequent infusions may be delivered over 30 (10) minutes.  For patients randomized to Arm A, atezolizumab will be 
administered first followed by bevacizumab, with a minimum of 5 minutes between dosing.  In the absence of unacceptable toxicity, patients may 
continue study treatment until there is evidence of disease progression or lack of clinical benefit.  
x
Sorafenib is taken by mouth twice a day continuously.
y
Survival follow-up information will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months 
(21 days) until death, loss to follow-up, or until study termination by the Sponsor.  All patients will be followed for survival and new anti-cancer 
therapy (including targeted therapy and immunotherapy) information unless the patient requests to be withdrawn from follow-up; this request 
must be documented in the source documents and signed by the investigator.  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.
z
Local laboratory assessments from each cycle must be reviewed prior to study treatment administration for each cycle.


Atezolizumab—F. Hoffmann-La Roche Ltd
128/Protocol YO40245, Version 6
Appendix 2 Schedule of Biomarker, Pharmacokinetic, and 
Immunogenicity Samples
Visit
Timepoint
Sample Type
Day 1 of Cycle 1
Prior to any drug administration

Atezolizumab PK 
(serum) a

Atezolizumab ADA 
(serum) a

Biomarker (plasma, 
serum) b
30 min after end of atezolizumab infusion 
Atezolizumab PK 
(serum) a
Day 1 of Cycle 2
Prior to any drug administration

Atezolizumab PK 
(serum) a

Atezolizumab ADA 
(serum) a

Biomarker (plasma, 
serum) b
Day 1 of Cycle 3, 
Cycle 8, Cycle 12, 
Cycle 16
Prior to any drug administration

Atezolizumab PK 
(serum) a

Atezolizumab ADA 
(serum) a
Day 1 of Cycle 4
Prior to any drug administration

Atezolizumab PK 
(serum) a

Atezolizumab ADA 
(serum) a

Biomarker (plasma, 
serum) b
Treatment 
discontinuation visit 
(30 days after last 
dose)
At visit

Atezolizumab PK 
(serum) a

Atezolizumab ADA 
(serum) a

Biomarker (plasma, 
serum)
ADAanti-drug antibody; PKpharmacokinetic.
a For Arm A only.
b Biomarker samples must be collected for both arms before dosing.  For Arm B: If the patient 
takes the morning dose before coming to the visit, samples should be taken before the evening 
dose.


Atezolizumab—F. Hoffmann-La Roche Ltd
129/Protocol YO40245, Version 6
Appendix 3 Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1)
Selected sections from the Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1; 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 1 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.


Appendix 3:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
130/Protocol YO40245, Version 6
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 locoregional therapy are usually not considered measurable unless there has 
been demonstrated progression in the lesion.


Appendix 3:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
131/Protocol YO40245, Version 6
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
Computed tomography 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.  Magnetic resonance imaging 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 


Appendix 3:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
132/Protocol YO40245, Version 6
be taken in measurement of target lesions and interpretation of non-target disease or 
new 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 1 measurable lesion is present at baseline, all lesions up to a maximum 
of 5 lesions total (and a maximum of 2 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 1 or 2 organ sites 
involved, a maximum of 2 lesions (1 site) and 4 lesions (2 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 2 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 


Appendix 3:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
(cont.)
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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 
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 (CR) 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 


Appendix 3:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
(cont.)
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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).
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 in the study 
(including baseline)
In addition to the relative increase of 20%, the sum of diameters must also 
demonstrate an absolute increase of 5 mm.


Appendix 3:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
(cont.)
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
Stable disease (SD):  Neither sufficient shrinkage to qualify for CR or PR nor 
sufficient increase to qualify for PD
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 1 or more non-target lesions and/or (if applicable) 
maintenance of tumor marker level above the normal limits

Progressive disease:  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.
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 a 
tumor (for example, some "new" bone lesions may be simply healing or flare of 
pre-existing 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.


Appendix 3:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
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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.
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.
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 would be most likely to 
happen in the case of PD.  For example, if a patient had a baseline sum of 50 mm with 
3 measured lesions and during the study only 2 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.


Appendix 3:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
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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.
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 4 Immune-Modified Response Evaluation Criteria in 
Solid Tumors (imRECIST)
Conventional response criteria may not be adequate to characterize the anti-tumor 
activity of immunotherapeutic agents, which can produce delayed responses that may 
be preceded by initial apparent radiographic progression, including the appearance of 
new lesions.  Therefore, immune-modified response criteria have been developed to 
incorporate new lesions into the assessment of total tumor burden and allow 
radiographic progression to be confirmed at a subsequent assessment.  
Immune-modified Response Evaluation Criteria in Solid Tumors (imRECIST), as 
described within this appendix, were adapted from RECIST, Version 1.1 (v1.1; 
Eisenhauer et al. 2009), in the same manner that immune-related response criteria were 
adapted from World Health Organization criteria (Wolchok et al. 2009) and RECIST v1.0 
(Nishino et al. 2014).  When not otherwise specified, RECIST v1.1 conventions will apply.  
Differences between imRECIST and RECIST v1.1 are summarized in Table 1.
Table 1
Comparison of RECIST v1.1 and imRECIST
RECIST v1.1
imRECIST
Measurable new lesions
Always represent progression
Incorporated into the total tumor 
burden a and followed
Non-measurable new 
lesions
Always represent progression
Do not represent progression, but 
preclude CR
Non-target lesions
Contribute to defining CR, PR, 
SD, and PD
Contribute to defining CR only
CR
Disappearance of all lesions
Disappearance of all lesions
PR
30% decrease in sum of 
diameters of target lesions, in 
the absence of CR, new 
lesions, and unequivocal 
progression in non-target 
lesions
30% decrease in tumor burden, a
in the absence of CR
PD
20% increase in sum of 
diameters of target lesions, 
unequivocal progression in 
non-target lesions, and/or 
appearance of new lesions
20% increase in tumor burden a
SD
Neither sufficient shrinkage to 
qualify for CR or PR nor 
sufficient increase to qualify for 
PD
Neither sufficient shrinkage to 
qualify for CR or PR nor sufficient 
increase to qualify for PD
CRcomplete response; imRECISTimmune-modified RECIST; PDprogressive disease; 
PRpartial response; RECIST Response Evaluation Criteria in Solid Tumors; SD stable 
disease.
a Tumor burden is the sum of diameters of target lesions and measurable new lesions.


Appendix 4:  Immune-Modified Response Evaluation Criteria in Solid Tumors (imRECIST)
(cont.)
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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 1 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," "New Lesions," and 
"Calculation of Sum of Diameters").
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.


Appendix 4:  Immune-Modified Response Evaluation Criteria in Solid Tumors (imRECIST)
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
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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 locoregional therapy are usually not considered measurable unless there has 
been demonstrated progression in the lesion.
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.


Appendix 4:  Immune-Modified Response Evaluation Criteria in Solid Tumors (imRECIST)
(cont.)
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141/Protocol YO40245, Version 6
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
Computed tomography 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.  Magnetic resonance imaging 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 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 
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.


Appendix 4:  Immune-Modified Response Evaluation Criteria in Solid Tumors (imRECIST)
(cont.)
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IDENTIFICATION OF TARGET AND NON-TARGET LESIONS
When more than 1 measurable lesion is present at baseline, all lesions up to a maximum 
of 5 lesions total (and a maximum of 2 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 1 or 2 organ sites 
involved, a maximum of 2 lesions (1 site) and 4 lesions (2 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 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 2 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 
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").


Appendix 4:  Immune-Modified Response Evaluation Criteria in Solid Tumors (imRECIST)
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
143/Protocol YO40245, Version 6
NEW LESIONS
New lesions identified after baseline will be evaluated for measurability with use of the 
same criteria applied to prospective target lesions at baseline per RECIST v1.1 
(e.g., nonlymph node lesions must be 10 mm on the longest diameter; new lymph 
nodes must be 15 mm on the short axis [see note below]).  All new lesions 
(measurable or non-measurable) must be assessed and recorded at the time of 
identification and at all subsequent tumor assessment timepoints.
Up to a maximum of 5 measurable new lesions total (and a maximum of 2 lesions per 
organ) can be included in the calculation of tumor burden that is performed as part of the 
tumor response evaluation.  New lesion types that would not qualify as target lesions per 
RECIST v1.1 cannot be included in the calculation of tumor burden and thus will not 
affect overall tumor response evaluation.  New lesions that are not measurable at first 
appearance but meet measurability criteria at a subsequent timepoint can be included in 
the tumor response evaluation from that point on, if the maximum number of measurable 
new lesions has not been reached.
Note regarding new lymph node lesions:  If at first appearance the short axis of a lymph 
node lesion is 15 mm, it will be considered a measurable new lesion.  If at first 
appearance the short axis of a lymph node lesion is 10 mm and 15 mm, the lymph 
node will not be considered measurable but will still be considered a new lesion and 
should be identified as a non-measurable new lesion.  If at first appearance the short 
axis of a lymph node is 10 mm, the lymph node should not be considered pathological 
and should not be considered a new lesion.  A lymph node can subsequently become 
measurable, when the short axis is 15 mm.
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 as a measure of 
tumor burden.  At each subsequent tumor assessment, 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 plus measurable new lesions (up to 5 new lesions, with a 
maximum of 2 new lesions per organ) that have emerged after baseline.  Hence, each 
net percentage change in tumor burden per assessment accounts for the size and 
growth kinetics of both old lesions and new lesions as they appear.
Measuring Lymph Nodes
If at first appearance the short axis of a new lymph node lesion is 15 mm, it will be 
considered a measurable new lesion and may be included in the sum of the diameters.  
If the new lymph node lesion is included in the sum of diameters, it will continue to be 


Appendix 4:  Immune-Modified Response Evaluation Criteria in Solid Tumors (imRECIST)
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
144/Protocol YO40245, Version 6
measured and included in the sum of diameters at subsequent timepoints, even if the 
short axis decreases to 15 mm (or even 10 mm).  However, if it subsequently 
decreases to 10 mm and all other lesions are no longer detectable or have also 
decreased to a short axis of 10 mm (if lymph nodes), a response assessment of 
complete response (CR) may be assigned.
Lymph nodes 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 in the 
sum of diameters, the sum may not be zero even if CR 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 and up to 5 measurable new lesions (lymph node and 
nonlymph node) should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm).  However, sometimes lesions or lymph 
nodes 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).
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.


Appendix 4:  Immune-Modified Response Evaluation Criteria in Solid Tumors (imRECIST)
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
145/Protocol YO40245, Version 6
EVALUATION OF NON-TARGET LESIONS AND NON-MEASURABLE NEW 
LESIONS
Measurements are not required for non-target lesions or non-measurable new lesions.  
Non-target lesions should be noted at baseline, and non-measurable new lesions should 
be noted at the time of identification.  At subsequent evaluations, non-target lesions and 
non-measurable new lesions will be categorized as "present" or "absent."
After baseline, changes in non-target lesions or non-measurable new lesions 
(or measurable new lesions in excess of 5 total or 2 per organ) will contribute only in the 
assessment of CR (i.e., a CR is attained only with the complete disappearance of all 
tumor lesions, including non-target lesions and non-measurable new lesions) and will not 
be used to assess progressive disease.
RESPONSE CRITERIA
Definitions of the criteria used to determine objective tumor response are provided below:

Complete response (CR):  Disappearance of all 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 plus measurable new lesions (up to a maximum of 5 total or 2 per organ), 
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 all 
target lesions plus measurable new lesions (up to a maximum of 5 total or 2 per 
organ), taking as reference the smallest sum of diameters in the study (including 
baseline)
In addition to the relative increase of 20%, the sum of diameters must also 
demonstrate an absolute increase of 5 mm.
New lesions alone do not qualify as progressive disease.  However, their 
contribution to total tumor burden is factored into the sum of the diameters, which 
is used to determine the overall imRECIST tumor response.

Stable disease (SD):  Neither sufficient shrinkage to qualify for CR or PR nor 
sufficient increase to qualify for PD


Appendix 4:  Immune-Modified Response Evaluation Criteria in Solid Tumors (imRECIST)
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
146/Protocol YO40245, Version 6
CRITERIA FOR OVERALL RESPONSE AT A SINGLE TIMEPOINT
Table 2 provides a summary of the overall response status calculation at each response 
assessment timepoint for patients who have measurable disease at baseline.
Table 2
Criteria for Overall Response at a Single Timepoint:  Patients 
with Target Lesions (with or without Non-Target Lesions)
Target Lesions and Measurable 
New Lesions a
Non-Target Lesions and 
Non-Measurable New Lesions b
Overall Response
CR
Absent
CR
CR
Present or not all evaluated
PR
PR
Any
PR
SD
Any
SD
Not all evaluated
Any
NE
PD
Any
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial response; 
SDstable disease.
a Up to a maximum of 5 measurable new lesions total (and a maximum of 2 lesions per organ) 
can be included in the calculation of tumor burden, in addition to the target lesions identified at 
baseline.
b Also includes measurable new lesions in excess of 5 total or 2 per organ.
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 or 
measurable new 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 would be most likely to happen in the case of PD.  For example, if a patient had a 
baseline sum of 50 mm with 3 measured lesions and during the study only 2 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 
having "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.  


Appendix 4:  Immune-Modified Response Evaluation Criteria in Solid Tumors (imRECIST)
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
147/Protocol YO40245, Version 6
The objective response status of such patients is to be determined by evaluation of 
target and non-target lesions, as well as new lesions, as shown in Table 2.
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.
Nishino M, Gargano M, Suda M, et al. Optimizing immune-related tumor response 
assessment: does reducing the number of lesions impact response assessment in 
melanoma patients treated with ipilimumab? J Immunother Cancer 2014;2:17.
Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune-related response criteria. Clin Cancer Res 
2009;15:741220.


Atezolizumab—F. Hoffmann-La Roche Ltd
148/Protocol YO40245, Version 6
Appendix 5 European Organisation for Research and Treatment 
of Cancer Quality-of-Life Questionnaire:  EORTC QLQ-C30
Do not reproduce or distribute:  The Sponsor will provide sites with all instruments to 
be completed in this study.


Appendix 5: European Organisation for Research and Treatment of Cancer Quality-of-Life 
Questionnaire:  EORTC QLQ-C30 (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
149/Protocol YO40245, Version 6


Atezolizumab—F. Hoffmann-La Roche Ltd
150/Protocol YO40245, Version 6
Appendix 6 EORTC QLQ-HCC18 Module
Do not reproduce or distribute:  The Sponsor will provide sites with all instruments to 
be completed in this study.


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Appendix 7 EuroQol 5-Dimension, 5-Level Questionnaire
(EQ-5D-5L)
Do not reproduce or distribute:  The Sponsor will provide sites with all instruments to 
be completed in this study.


Appendix 7: EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
152/Protocol YO40245, Version 6


Atezolizumab—F. Hoffmann-La Roche Ltd
153/Protocol YO40245, Version 6
Appendix 8 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 while receiving another immunostimulatory anti-cancer agent.  
Contact the Medical Monitor regarding 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 myocarditis

Autoimmune nephritis

Autoimmune oophoritis

Autoimmune orchitis

Autoimmune 
thrombocytopenic 
purpura

Behçet disease

Bullous pemphigoid

Chronic fatigue syndrome

Chronic inflammatory 
demyelinating 
polyneuropathy

Churg-Strauss syndrome

Crohn disease 

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 cirrhosis

Psoriasis

Reiter syndrome

Rheumatoid arthritis

Sarcoidosis

Scleroderma

Sjögren syndrome

Stiff-Person syndrome

Takayasu arteritis

Ulcerative colitis

Vitiligo

Vogt-Koyanagi-Harada 
disease

Wegener granulomatosis


Atezolizumab—F. Hoffmann-La Roche Ltd
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Appendix 9 Anaphylaxis Precautions
EQUIPMENT NEEDED

Oxygen

Epinephrine for subcutaneous, IV, and/or endotracheal use in accordance with 
standard practice

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.
Maintain an adequate airway.
3.
Administer antihistamines, epinephrine, or other medications as required by patient 
status and directed by the physician in charge.
4.
Continue to observe the patient and document observations.


Atezolizumab—F. Hoffmann-La Roche Ltd
155/Protocol YO40245, Version 6
Appendix 10 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
International normalized ratio
1.03.0
1.7
4.06.0
1.72.3
6.0
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.


Atezolizumab—F. Hoffmann-La Roche Ltd
156/Protocol YO40245, Version 6
Appendix 11 Overall Guidelines for Management of Patients who 
Experience Adverse Events
PATIENTS TREATED WITH ATEZOLIZUMAB AND BEVACIZUMAB (ARM A)
DOSE MODIFICATIONS:  ARM A
There will be no dose modifications for atezolizumab or bevacizumab in this study.
TREATMENT INTERRUPTION:  ARM A
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 10 mg/day oral prednisone or 
equivalent 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 Medical Monitor agrees that the patient is likely to derive 
clinical benefit.
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 Medical Monitor agrees that the patient is likely to 
derive clinical benefit.
Atezolizumab or bevacizumab treatment may be suspended for reasons other than 
toxicity (e.g., surgical procedures), with Medical Monitor approval.  The investigator and 
the Medical Monitor will determine the acceptable length of treatment interruption.
If either study drug is withheld or discontinued, the other study drug can be continued as 
long as the patient is experiencing clinical benefit, as determined by the investigator per 
medical judgment.
See Section 4.3.2 for information on dose interruptions for reasons other than toxicity.
MANAGEMENT GUIDELINES:  ARM A
Guidelines for the management of patients who experience specific adverse events are 
provided as outlined below. For cases in which management guidelines are not covered 
in the Atezolizumab or Bevacizumab Investigator's Brochures or this protocol, patients 
should be managed as deemed appropriate by the investigator according to best 
medical judgment.


Appendix 11:
Overall Guidelines for Management of Patients Who Experience Adverse 
Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
157/Protocol YO40245, Version 6
Atezolizumab
Appendix 12 provides guidelines for the management of patients who experience 
atezolizumab-associated IRRs and immune-mediated adverse events (e.g., pulmonary, 
hepatic, gastrointestinal, endocrine, ocular, myocarditis, pancreatic, dermatologic, 
neurologic, meningoencephalitis, renal, myositis, hemophagocytic lymphohistiocytosis, 
and macrophage activation syndrome events).
Bevacizumab
Table 1 provides guidelines for the management of patients who experience adverse 
events associated with bevacizumab.
Table 1
Management Guidelines for Adverse Events Associated with 
Bevacizumab
Event
Action to Be Taken
Infusion-Related Reaction
IRR to bevacizumab, Grade 1

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 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 
Grade 4

Stop infusion

Discontinue bevacizumab.
Gastrointestinal events
Gastrointestinal perforation, any 
grade

Discontinue bevacizumab

Initiate treatment per institutional guidelines
Bowel obstruction, Grade 2

Hold bevacizumab for partial obstruction requiring 
medical intervention

Bevacizumab may be restarted upon complete 
resolution of event


Appendix 11:
Overall Guidelines for Management of Patients Who Experience Adverse 
Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
158/Protocol YO40245, Version 6
Table 1
Management Guidelines for Adverse Events Associated with 
Bevacizumab (cont.)
Event
Action to Be Taken
Bowel obstruction, Grade 34

Hold bevacizumab for complete obstruction
If surgery is necessary, patient may restart bevacizumab 
after full recovery from surgery and at investigator's 
discretion
Hypersensitivity/allergic 
reactions

Permanently discontinue bevacizumab
Hypertension
General Guidance

Grade 2 or above, start antihypertensive therapy
Hypertension Grade 2

Hold bevacizumab

Once blood pressure 150/100 mmHg, patient may 
continue bevacizumab therapy
Hypertension Grade 3

If blood pressure is not controlled to 150/100 mmHg 
with medication, discontinue bevacizumab
Hypertension Grade 4
(includes hypertensive 
encephalopathy)

Discontinue bevacizumab
Hemorrhage
Grade 2 hemoptysis
(2.5 mL of bright red blood per 
episode)

Discontinue bevacizumab
Grade 3, 4 bleeding

Discontinue bevacizumab
Bleeding in patients on full-dose 
anticoagulant therapy

Discontinue bevacizumab a
CNS bleeding, any grade

Discontinue bevacizumab
Venous Thromboembolic Events
Venous thromboembolic event 
Grade 3

For Grade 3 thromboembolic events, hold 
bevacizumab for 3 weeks.  Bevacizumab treatment 
may be resumed during the period of therapeutic-dose 
anticoagulant therapy once the level of anticoagulation 
therapy is stabilized

Anticoagulant treatment should be administered per 
institutional guidelines

After administration of bevacizumab is restarted, if the 
patient experiences another Grade 3 venous 
thromboembolic event, bevacizumab should be 
discontinued

For Grade 4 thromboembolic events, discontinue 
bevacizumab


Appendix 11:
Overall Guidelines for Management of Patients Who Experience Adverse 
Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
159/Protocol YO40245, Version 6
Table 1
Management Guidelines for Adverse Events Associated with 
Bevacizumab (cont.)
Event
Action to Be Taken
Arterial thromboembolic event, 
any Grade

Discontinue bevacizumab
Arterial Thromboembolic Events
Arterial thromboembolic event, 
any Grade

Discontinue bevacizumab
Proteinuria
Grade 1
(1proteinuria; urinary protein 
1.0 g/24 hour)

Administer bevacizumab
Grade 2
(2proteinuria; urinary protein 
1.03.4 g/24 hour)

For 2dipstick: may administer bevacizumab and 
collect 24-hour urine prior to subsequent bevacizumab 
administration

For 3dipstick: must obtain 24-hour urine prior to 
administering bevacizumab

Withhold bevacizumab for urinary protein 
2 g/24 hour.  Resume bevacizumab when 
proteinuria is 2 g/24 hour.
Grade 3
(urinary protein 3.5 g/24 hour)

Withhold bevacizumab. Resume bevacizumab when 
proteinuria is 2 g/24 hour.
Proteinuria with diagnosis of 
nephrotic syndrome

Permanently discontinue bevacizumab
Fistula
Tracheoesophageal fistula, any 
grade

Discontinue bevacizumab
Fistula (non-racheoesophageal), 
Grade 4

Discontinue bevacizumab
Wound Dehiscence
Wound dehiscence, any grade 
requiring medical or surgical 
therapy

Discontinue bevacizumab
Posterior Reversible Encephalopathy Syndrome/Reversible Posterior 
Leukoencephalopathy Syndrome
PRES/RPLS, any grade 
confirmed by MRI

Discontinue bevacizumab
IRR infusion-related reaction; MRI magnetic resonance imaging.
a Follow guidelines of the treating institution.


Appendix 11:
Overall Guidelines for Management of Patients Who Experience Adverse 
Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
160/Protocol YO40245, Version 6
PATIENTS TREATED WITH SORAFENIB (ARM B)
DOSE MODIFICATIONS AND TREATMENT INTERRUPTIONS:  ARM B
Temporary interruption or dose modification may be required for management of 
toxicities. Any toxicity associated or possibly associated with sorafenib treatment should 
be managed according to standard medical practice. Suggested dose modifications for 
hand-foot skin reaction toxicities are provided in Table 2. Management of suspected 
adverse drug reactions may require temporary interruption and/or dose reduction of 
sorafenib. When dose reduction is necessary, the sorafenib dose may be reduced to 
400 mg once daily. If additional dose reduction is required, sorafenib may be reduced to 
a single 400 mg dose every other day.  Once a dose reduction is made, the sorafenib 
dose may be re-escalated at the discretion of the investigator if the patient has been on 
a stable dose for 3 weeks or more without further toxicities requiring dose modification.


Appendix 11:
Overall Guidelines for Management of Patients Who Experience Adverse 
Events (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
161/Protocol YO40245, Version 6
Table 2
Suggested Sorafenib Dose Modification for HandFoot Skin
Grade
Occurrence
Sorafenib Dose Modification
Grade 1:
Numbness, 
dysesthesia, 
paresthesia, tingling, 
painless swelling, 
erythema, or 
discomfort of the 
hands or feet which 
does not disrupt the 
patient's normal 
activities
Any occurrence

Continue treatment and consider topical 
therapy for symptomatic relief
Grade 2:
Painful erythema and 
swelling of the hands 
or feet and/or 
discomfort affecting 
the patient's normal 
activities
1st occurrence

Continue treatment and consider topical 
therapy for symptomatic relief

Interrupt sorafenib treatment until toxicity 
resolves to Grade 0 or 1
No improvement 
within 7 days or 2nd
or 3rd occurrence

Interrupt sorafenib treatment until toxicity 
resolves to Grade 0 or 1

When resuming treatment, decrease dose 
to 400 mg daily
4th occurrence

Discontinue sorafenib treatment
Grade 3:
Moist desquamation, 
ulceration, blistering or 
severe pain of the 
hands or feet, or 
severe discomfort that 
causes the patient to 
be unable to work or 
perform daily activities
1st or 2nd occurrence

Interrupt sorafenib treatment until toxicity 
resolves to Grade 0 or 1

When resuming treatment, decrease dose 
to 400 mg daily
3rd occurrence

Discontinue sorafenib treatment
For adverse events associated with sorafenib that are not listed in Table 2, refer to 
guidelines in the applicable local prescribing information (if available). 


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162/Protocol YO40245, Version 6
Appendix 12 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.
Although most immune-mediated adverse events observed with immunomodulatory 
agents 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 investigator should consider the benefitrisk balance a given patient may be 
experiencing prior to further administration of atezolizumab.  In patients who have met 
the criteria for permanent discontinuation, resumption of atezolizumab may be 
considered if the patient is deriving benefit and has fully recovered from the 
immune-mediated event.  Patients can be re-challenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and 
the Medical Monitor.
PULMONARY EVENTS
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been 
associated with the administration of atezolizumab.  Patients will be assessed for 
pulmonary signs and symptoms throughout the study and will also 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.  Management guidelines for pulmonary events are provided in Table 1.


Appendix 12:
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
163/Protocol YO40245, 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
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

Initiate treatment with 12 mg/kg/day oral prednisone or equivalent

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, treat as a Grade 3 or 4 event
Pulmonary 
event, Grade 3 
or Grade 4

Permanently discontinue atezolizumab and contact Medical Monitor c

Bronchoscopy or BAL is recommended

Initiate treatment with 12 mg/kg/day oral prednisone or equivalent

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.
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 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent 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.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.


Appendix 12:
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
164/Protocol YO40245, Version 6
HEPATIC EVENTS FOR PATIENTS WITH HEPATOCELLULAR CARCINOMA
Immune-mediated hepatitis has been associated with the administration of atezolizumab.  
Patients eligible for study treatment must have adequate liver function, as manifested 
by measurements of total bilirubin and hepatic transaminases; 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 12:
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
165/Protocol YO40245, Version 6
Table 2
Management Guidelines for Hepatic Events for Patients with HCC
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
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 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be agreed upon by 
the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent 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.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


Appendix 12:
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
166/Protocol YO40245, Version 6
GASTROINTESTINAL EVENTS
Immune-mediated colitis has been associated with the administration of atezolizumab.  
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 3 to 5 specimens for standard paraffin block to check for 
inflammation and lymphocytic infiltrates to confirm colitis diagnosis.
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

Patient referral to GI specialist is recommended

For recurrent events or events that persist 5 days, initiate treatment 
with 12 mg/kg/day oral prednisone or equivalent

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 12 mg/kg/day IV methylprednisolone or 
equivalent 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


Appendix 12:
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
167/Protocol YO40245, Version 6
Table 3
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) (cont.)
Event
Management
Diarrhea or 
colitis, Grade 4

Permanently discontinue atezolizumab and contact Medical Monitor c

Refer patient to GI specialist for evaluation and confirmation biopsy

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent 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.
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 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent 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.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.
ENDOCRINE EVENTS
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have 
been associated with the administration of atezolizumab.  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.  The patient should be referred to an 
endocrinologist if an endocrinopathy is suspected.  Thyroid-stimulating hormone (TSH) 
and free triiodothyronine and thyroxine 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 12:
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
168/Protocol YO40245, Version 6
Table 4
Management Guidelines for Endocrine Events
Event
Management
Asymptomatic 
hypothyroidism

Continue atezolizumab

Initiate treatment with thyroid replacement hormone

Monitor TSH weekly
Symptomatic 
hypothyroidism

Withhold atezolizumab

Initiate treatment with thyroid replacement hormone

Monitor TSH weekly

Consider patient referral to endocrinologist

Resume atezolizumab when symptoms are controlled and 
thyroid function is improving
Asymptomatic 
hyperthyroidism
TSH 0.1 mU/L and 0.5 mU/L:

Continue atezolizumab

Monitor TSH every 4 weeks
TSH 0.1 mU/L:

Follow guidelines for symptomatic hyperthyroidism
Symptomatic 
hyperthyroidism

Withhold 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

Permanently discontinue atezolizumab and contact 
Medical Monitor for life-threatening immune-mediated
hyperthyroidism c
Symptomatic adrenal 
insufficiency, 
Grade 24 

Withhold atezolizumab for up to 12 weeks after event onset a

Refer patient to endocrinologist

Perform appropriate imaging

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent 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 
Medical Monitor c
Hyperglycemia, 
Grade 1 or 2 

Continue atezolizumab

Initiate treatment with insulin if needed

Monitor for glucose control


Appendix 12:
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
169/Protocol YO40245, Version 6
Table 4
Management Guidelines for Endocrine Events (cont.)
Event
Management
Hyperglycemia, 
Grade 3 or 4

Withhold atezolizumab

Initiate treatment with insulin

Monitor for glucose control

Resume atezolizumab when symptoms resolve and glucose 
levels are stable
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 12 mg/kg/day IV methylprednisolone or 
equivalent 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 Medical Monitor c

For recurrent hypophysitis, treat as a Grade 4 event
Hypophysitis 
(pan-hypopituitarism), 
Grade 4

Permanently discontinue atezolizumab and contact 
Medical Monitor c

Refer patient to endocrinologist

Perform brain MRI (pituitary protocol)

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent 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.
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 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be agreed upon by 
the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent 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.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.


Appendix 12:
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
170/Protocol YO40245, 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 
Medical Monitor c
Ocular event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical Monitor c

Refer patient to ophthalmologist

Initiate treatment with 12 mg/kg/day oral prednisone or equivalent

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month
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 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent 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.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.


Appendix 12:
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
171/Protocol YO40245, Version 6
IMMUNE-MEDIATED MYOCARDITIS
Immune-mediated myocarditis has been associated with the administration of 
atezolizumab.  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.  
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.


Appendix 12:
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
172/Protocol YO40245, Version 6
Table 6
Management Guidelines for Immune-Mediated Myocarditis
Event
Management
Immune-mediated
myocarditis, Grade 1

Refer patient to cardiologist

Initiate treatment as per institutional guidelines
Immune-mediated
myocarditis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset a and 
contact Medical Monitor

Refer patient to cardiologist

Initiate treatment as per institutional guidelines and consider anti-
arrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate

Consider treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement a

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
Immune-mediated
myocarditis,
Grade 3 or 4

Permanently discontinue atezolizumab and contact 
Medical Monitor c

Refer patient to cardiologist

Initiate treatment as per institutional guidelines and consider anti-
arrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement a, b

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.
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 10 mg/day oral prednisone or equivalent.  
The acceptable length of the extended period of time must be agreed upon by the investigator 
and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent 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.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.


Appendix 12:
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
173/Protocol YO40245, 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 atezozlizumab may receive premedication with antihistamines or 
anti-pyretics/analgesics (e.g., acetaminophen) for subsequent infusions.  Metamizole
(dipyrone) is prohibited in treating atezolizumab-associated IRRs because of its potential 
for causing agranulocytosis.
Infusion-related reactions 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.
Cytokine-release syndrome 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).  Cytokine-release syndrome  
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 medical management of IRRs and CRS are provided 
in Table 7.
Severe COVID-19 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 COVID-19, 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 COVID-19 is confirmed, the disease should be 
managed as per local or institutional guidelines.


Appendix 12:
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
174/Protocol YO40245, 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, anti-pyretics, 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 e

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 
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, anti-pyretics, and/or 
analgesics and monitor closely for IRRs and/or CRS.


Appendix 12:
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
175/Protocol YO40245, Version 6
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.)
Event
Management

If symptoms do not resolve to Grade 1 or better for 3 consecutive 
days, contact Medical Monitor
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 
Medical Monitor f

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 e

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.


Appendix 12:
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
176/Protocol YO40245, Version 6
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.)
Event
Management
Grade 4 a
Fever b with 
hypotension 
requiring multiple 
vasopressors 
(excluding 
vasopressin)
and/or
Hypoxia requiring 
oxygen by positive 
pressure 
(e.g., CPAP, 
Bi-PAP, 
intubation and 
mechanical 
ventilation)

Permanently discontinue atezolizumab and contact 
Medical Monitor f

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. e  For patients who are 
refractory to anti-cytokine therapy, experimental treatments g
may be considered at the discretion of the investigator and in 
consultation with the Medical Monitor.

Hospitalize patient until complete resolution of symptoms
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, anti-pyretics, 
analgesics, bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or 
dyspnea, additional treatment may be administered as per institutional practice.


Appendix 12:
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
177/Protocol YO40245, Version 6
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.)
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
There are case reports where anti-cytokine therapy has been used for treatment of 
CRS with immune checkpoint inhibitors (Rotz et al. 2017; 
Adashek and Feldman 2019), but data are limited, and the role of such treatment in 
the setting of antibody-associated CRS has not been established.
f
Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator 
(or an appropriate delegate) and the Medical Monitor.  For subsequent infusions, 
administer oral premedication with antihistamines, anti-pyretics, and/or analgesics, 
and monitor closely for IRRs and/or CRS.  Premedication with corticosteroids and 
extending the infusion time may also be considered after consulting the 
Medical Monitor and considering the benefitrisk ratio.
g
Refer to Riegler et al. (2019) for information on experimental treatments for CRS.


Appendix 12:
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
178/Protocol YO40245, Version 6
PANCREATIC EVENTS
Symptoms of abdominal pain associated with elevations of amylase and lipase, 
suggestive of pancreatitis, have been associated with the administration of atezolizumab.  
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.
Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis
Event
Management
Amylase and/or lipase 
elevation, Grade 2

Continue atezolizumab

Monitor amylase and lipase weekly

For prolonged elevation (e.g., 3 weeks), consider treatment 
with 10 mg/day oral prednisone or equivalent
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 12 mg/kg/day 
oral prednisone or equivalent

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 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 12 mg/kg/day IV methylprednisolone 
or equivalent 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 Medical Monitor c


Appendix 12:
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
179/Protocol YO40245, 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 12 mg/kg/day IV 
methylprednisolone or equivalent 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.
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 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be agreed upon by 
the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent 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.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.
DERMATOLOGIC EVENTS
Treatment-emergent rash has been associated with atezolizumab.  The majority of 
cases of rash were mild in severity and self-limited, 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 12:
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
180/Protocol YO40245, 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
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 10 mg/day oral prednisone or equivalent, 
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 
Medical Monitor c
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
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 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent 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.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


Appendix 12:
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
181/Protocol YO40245, Version 6
NEUROLOGIC DISORDERS
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab.  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.
Table 10 Management Guidelines for Neurologic Disorders
Event
Management
Immune-mediated
neuropathy, Grade 1

Continue atezolizumab

Investigate etiology
Immune-mediated
neuropathy, Grade 2 

Withhold atezolizumab for up to 12 weeks after event onset a

Investigate etiology

Initiate treatment as per institutional guidelines

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
Immune-mediated
neuropathy,
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical Monitor c 

Initiate treatment as per institutional guidelines
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 12 mg/kg/day oral or IV prednisone or 
equivalent
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 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent 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.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 
IMMUNE-MEDIATED MENINGOENCEPHALITIS
Immune-mediated meningoencephalitis is an identified risk associated with the 
administration of atezolizumab.  Immune-mediated meningoencephalitis should be 


Appendix 12:
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
182/Protocol YO40245, Version 6
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 11
Table 11 Management Guidelines for Immune-Mediated
Meningoencephalitis
Event
Management
Immune-mediated
meningoencephalitis, 
all grades

Permanently discontinue atezolizumab and contact 
Medical Monitor a

Refer patient to neurologist

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent 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
a Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.
RENAL EVENTS
Immune-mediated nephritis has been associated with the administration of atezolizumab.  
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 post-renal causes, and concomitant medications such as 
non-steroidal anti-inflammatory drugs).  Refer the patient to a renal specialist if clinically 


Appendix 12:
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
183/Protocol YO40245, Version 6
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 12.
Table 12 Management Guidelines for Renal Events
Event
Management
Renal event, 
Grade 1

Continue atezolizumab

Monitor kidney function, including creatinine, 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
Renal event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical Monitor

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
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 agreed upon by the 
investigator and the Medical Monitor.
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.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.


Atezolizumab—F. Hoffmann-La Roche Ltd
184/Protocol YO40245, Version 6
IMMUNE-MEDIATED MYOSITIS
Immune-mediated myositis has been associated with the administration of atezolizumab.  
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 signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 13.


Appendix 12:
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
185/Protocol YO40245, Version 6
Table 13 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 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 
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 
Medical Monitor c

For recurrent events, treat as a Grade 4 event


Appendix 12:
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
186/Protocol YO40245, Version 6
Table 13 Management Guidelines for Immune-Mediated Myositis (cont.)
Event
Management
Immune-mediated 
myositis, Grade 4

Permanently discontinue atezolizumab and contact 
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
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 agreed upon by the investigator and the Medical Monitor.
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.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 
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).
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 5 of the 
following 8 criteria are met:

Fever 38.5°C

Splenomegaly

Peripheral blood cytopenia consisting of at least 2 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)


Appendix 12:
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
187/Protocol YO40245, Version 6
–
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 2 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 14.
Table 14 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome
Event
Management
Suspected HLH 
or MAS

Permanently discontinue atezolizumab and contact Medical Monitor

Consider patient referral to hematologist

Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines

Consider initiation of IV corticosteroids and/or an 
immunosuppressive agent

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
HLH hemophagocytic lymphohistiocytosis; MAS macrophage activation syndrome.


Appendix 12:
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
188/Protocol YO40245, Version 6
REFERENCES
Adashek ML, Feldman M. Cytokine release syndrome resulting from antiprogrammed 
death-1 antibody: raising awareness among community oncologist. J Oncol 
Practice 2019;15:5024.
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.
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.
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—F. Hoffmann-La Roche Ltd
189/Protocol YO40245, Version 6
Appendix 13 American Association for the Study of Liver 
Diseases Criteria: Algorithm for Investigation of Small Nodules 
Found on Screening in Patients at Risk for HCC
AASLDAssociation for the Study of Liver Diseases; CTcomputed tomography; 
MDCT multi-detector CT scan; MRImagnetic resonance imaging; HCChepatocellular 
carcinoma.
REFERENCES
Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology 
2011;53:10202.

SAP_001.pdf: 
 
Official Title: 
A Phase III, Open-Label, Randomized Study of Atezolizumab in 
Combination With Bevacizumab Compared With Sorafenib in Patients 
With Untreated Locally Advanced or Metastatic Hepatocellular 
Carcinoma 
NCT Number: 
NCT03434379 
Document Date: 
SAP Version 1: 22-February-2019 
 
 


STATISTICAL ANALYSIS PLAN APPROVAL
CONFIDENTIAL
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd.
Atezolizumab—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan YO40245
STATISTICAL ANALYSIS PLAN
TITLE:
A PHASE III, OPEN-LABEL, RANDOMIZED STUDY OF 
ATEZOLIZUMAB IN COMBINATION WITH BEVACIZUMAB 
COMPARED WITH SORAFENIB IN PATIENTS WITH 
UNTREATED LOCALLY ADVANCED OR METASTATIC
HEPATOCELLULAR CARCINOMA
PROTOCOL NUMBER:
YO40245
STUDY DRUG:
Atezolizumab
Bevacizumab
VERSION NUMBER:
1
IND NUMBER:
135913
EUDRACT NUMBER:
2017-003691-31
SPONSOR:
F. Hoffmann-La Roche Ltd.
PLAN PREPARED BY:
 Ph.D.
DATE FINAL:
See electronic date stamp below
Name                                                             Reason for Signing                              Date and Time
(UTC)
22-Feb-2019 16:19:43
Company Signatory


Atezolizumab—F. Hoffmann-La Roche Ltd
2/Statistical Analysis Plan YO40245
TABLE OF CONTENTS
1.
BACKGROUND ............................................................................................ 5
2.
STUDY DESIGN........................................................................................... 5
2.1
Protocol Synopsis.................................................................... 7
2.2
Determination of Sample Size ................................................. 7
2.2.1
Type I Error Control................................................................. 7
2.2.2
Co-Primary Endpoint: OS ........................................................ 8
2.2.3
Co-Primary Endpoint: PFS by IRF-Assessment 
(PFS-IRF) per RECIST v1.1 .................................................... 9
2.3
INTERIM AND PRIMARY ANALYSIS TIMING........................ 9
2.3.1
Primary Analysis Timing .......................................................... 9
2.3.2
Interim Analyses Timing .......................................................... 9
3.
STUDY CONDUCT..................................................................................... 10
3.1
Randomization....................................................................... 10
3.2
Data Monitoring ..................................................................... 11
3.3
Independent Review Facility.................................................. 11
4.
STATISTICAL METHODS .......................................................................... 11
4.1
Analysis Populations ............................................................. 11
4.1.1
Intent-to-Treat Population...................................................... 11
4.1.2
Pharmacokinetic-Evaluable Population ................................. 11
4.1.3
PRO-Evaluable Population.................................................... 11
4.1.4
Safety Population .................................................................. 12
4.1.5
Anti-Drug-Antibody-Evaluable Population.............................. 12
4.2
Analysis of Study Conduct..................................................... 12
4.3
Analysis of Treatment Group Comparability .......................... 12
4.4
Efficacy Analysis.................................................................... 13
4.4.1
Co-Primary Efficacy Endpoints.............................................. 13
4.4.1.1
Overall Survival (OS)............................................................. 13
4.4.1.2
PFS by IRF-Assessment (PFS-IRF) per RECIST 
v1.1........................................................................................ 14
4.4.2
Secondary Efficacy Endpoints............................................... 14
4.4.2.1
Objective Response Rate (ORR)........................................... 14


Atezolizumab—F. Hoffmann-La Roche Ltd
3/Statistical Analysis Plan YO40245
4.4.2.2
Duration of Response (DOR)................................................. 15
4.4.2.3
Progression-Free Survival (PFS)........................................... 15
4.4.2.4
Time to Progression (TTP) .................................................... 16
4.4.2.5
PFS and OS by Baseline AFP............................................... 16
4.4.2.6
Time to Deterioration (TTD)................................................... 16
4.4.2.7
Overall Multiplicity Control for Key Secondary 
Endpoints............................................................................... 16
4.4.3
Exploratory Efficacy Endpoints.............................................. 17
4.4.4
Patient-Reported Outcome (PRO) Analyses ......................... 17
4.4.5
Exploratory Biomarker Analysis............................................. 18
4.4.6
Sensitivity Analyses............................................................... 18
4.4.7
Subgroup Analyses ............................................................... 19
4.5
Pharmacokinetic and Pharmacodynamic 
Analyses................................................................................ 19
4.6
Safety Analyses..................................................................... 20
4.6.1
Exposure of Study Medication............................................... 20
4.6.2
Adverse Events ..................................................................... 20
4.6.3
Laboratory Data..................................................................... 20
4.6.4
Vital Signs.............................................................................. 20
4.6.5
Electrocardiograms................................................................ 21
4.7
Immunogenicity Analyses...................................................... 21
4.8
Exploratory Health Status Analysis........................................ 21
4.9
Missing Data.......................................................................... 21
4.10
Interim Analyses .................................................................... 21
5.
CHINA SUBPOPULATION ANALYSIS....................................................... 21
REFERENCES................................................................................................... 23


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LIST OF TABLES
Table 1
Study YO40245 Treatment Arms.................................................. 5
Table 2
Analysis Timing and Stopping Boundaries for Overall 
Survival ....................................................................................... 10
LIST OF FIGURES
Figure 1
Study Schema............................................................................... 6
Figure 2
Overview of the Type I Error Control for Co-Primary and Key 
Secondary Endpoints.................................................................... 8
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ....................................................................... 24
Appendix 2
Schedule of Activities.................................................................. 38
Appendix 3
Schedule of Biomarker, Pharmacokinetic, and 
Immunogenicity Samples............................................................ 44


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1.
BACKGROUND
This Statistical Analysis Plan (SAP) is based on Protocol YO40245 (IMbrave150), “A
Phase III, randomized, multicenter, open-label, two-arm study designed to evaluate the 
efficacy and safety of atezolizumabbevacizumab versus sorafenib in patients with 
untreated locally advanced or metastatic hepatocellular carcinoma (HCC)”.  This SAP 
provides details of the planned analyses and statistical methods for Study YO40245 to 
support potential registration for atezolizumab in combination with bevacizumab for 
patients with unresectable or advanced HCC who have received no prior systemic 
therapy.  The background for the study can be found in the study protocol. Analyses 
that are beyond those outlined in the protocol are delineated in this document.
In this study, the global population will include all patients enrolled during the global 
enrollment phase, and the China subpopulation will include all patients enrolled at sites 
that are recognized by the China Food and Drug Administration during both the global 
enrollment phase and the extended China enrollment phase.  This SAP documents 
details of the statistical analyses planned for the global study population (Section 4) and 
the China subpopulation (Section 5).
2.
STUDY DESIGN
This is a Phase III, randomized, multicenter, open-label, two-arm study designed to 
evaluate the efficacy and safety of atezolizumabbevacizumab versus sorafenib in 
patients with locally advanced or metastatic HCC who have received no prior systemic 
treatment.
This study will randomize approximately 480 eligible patients in a 2:1 ratio to one of the 
two treatment regimens as shown in Table 1.
Table 1
Study YO40245 Treatment Arms
Treatment 
Arm
Dose, Route, and Regimen a
A
Atezolizumab 1200 mg IV infusions Q3W (dosed in 3-week 
cycles)bevacizumab 15 mg/kg Q3W (dosed in 3-week cycles)
B
Sorafenib 400 mg PO, BID, continuously
BIDtwice per day; IVintravenous; PO by mouth; Q3W every 3 weeks.
Note: No dose modification for atezolizumab or bevacizumab is allowed.
a
21-day treatment cycles until unacceptable toxicity or loss of clinical benefit.
Randomization details, including stratification factors, are outlined in Section 3.1.
Figure 1 illustrates the study design.


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Figure 1
Study Schema
AFP-fetoprotein; BIDtwice per day; ECOG PS Eastern Cooperative Oncology Group 
Performance Status; EHSextrahepatic spread; HCC hepatocellular carcinoma;
MVImacrovascular invasion; PS Performance Status; Q3W every 3 weeks.
Patients will receive atezolizumab and/or bevacizumab or sorafenib 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). In the absence of unacceptable 
toxicity, patients who meet criteria for disease progression per Response Evaluation 
Criteria in Solid Tumors (RECIST) v1.1 while receiving atezolizumab and/or 
bevacizumab or sorafenib will be permitted to continue the 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

Absence of decline in Eastern Co-operative Oncology Group Performance (ECOG)
Performance Status that can be attributed to disease progression
Patients with untreated 
advanced/metastatic HCC
(n=480 patients)
Arm A
Atezolizumab 1200 mg Q3W + 
Bevacizumab 15 mg/kg Q3W
Arm B
Sorafenib 400 mg BID
Treatment until 
loss of clinical benefit or 
unacceptable toxicity
Treatment until 
loss of clinical benefit or 
unacceptable toxicity
Survival follow-up
Survival follow-up
Randomization (2:1)
Stratification factors:
•
Geographic region 
(Asia excluding Japan 
vs. rest of world)
•
MVI and/or EHS 
(yes vs. no)
•
Baseline AFP
(<400 vs. ≥400 ng/mL)
•
Baseline ECOG PS 
(0 vs. 1)


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
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions
The co-primary efficacy endpoints of this study are overall survival (OS) and 
progression-free survival as assessed by Independent Review Facility (PFS-IRF)
according to RECIST v1.1.  See Section 4.4.1 for further details on the co-primary 
efficacy endpoints, as well as other subsections of 4.4 on the secondary efficacy 
endpoints and the safety, pharmacokinetic (PK), immunogenicity, and exploratory 
endpoints. Unless otherwise specified, the term “PFS” in this SAP refers to PFS-IRF 
according to RECIST v1.1.
2.1
PROTOCOL SYNOPSIS
The protocol synopsis can be found in Appendix 1, including the study objectives, 
inclusion and exclusion criteria, outcome measures, and statistical methods as stated in 
the protocol.  Schedule of Activities is in Appendix 2 and schedule of biomarker, 
pharmacokinetic, and immunogenicity samples is in Appendix 3.
2.2
DETERMINATION OF SAMPLE SIZE
Approximately 480 patients are planned for enrollment during the global enrollment 
phase.
2.2.1
Type I Error Control
The overall type I error rate for this study will be strongly controlled at a two-sided 
significance level of 0.05 by a graphical approach, i.e., alpha splitting and recycling
(Bretz et al. 2009, Burman et al. 2009).  The overall two-sided significance level of 0.05 
will be split into a two-sided significance level of 0.048 for the testing of OS and a 
two-sided significance level of 0.002 for the testing of PFS initially. If OS is statistically 
significant, the allocated two-sided significance level of 0.048 can be recycled to PFS 
such that PFS can be tested at a two-sided significance level of 0.05 instead of 0.002. If 
the analysis of PFS is statistically significant, then the two-sided significance level of 
0.002 (or 0.05 if OS is statistically significant) will be recycled to key secondary 
endpoints to be formally tested in a hierarchical fashion (See Section 4.4.2.7 for details 
on secondary endpoints to be included for formal statistical testing). If PFS and all key
secondary endpoints are statistically significant at a two-sided significance level of 0.002, 
then OS can be tested at a two-sided significance level of 0.05 instead of 0.048; the 
detailed testing boundaries are provided in Section 2.3. An overview of the type I error 
rate control strategy for the co-primary and key secondary efficacy endpoints is shown in 
Figure 2.




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2.2.3
Co-Primary Endpoint: PFS by IRF-Assessment (PFS-IRF) per 
RECIST v1.1
To detect an improvement in PFS-IRF per RECIST v1.1 using a log-rank test at a 
two-sided significance level of 0.002, approximately 308 events will be required for the 
primary PFS analysis, which will provide approximately 97% power with a target HR of 
0.55 (median PFS improvement vs. control of 3.3 months).  The MDD is a PFS HR of 
0.688 (median PFS improvement vs. control of 1.8 months).  The clinical cutoff date for 
this primary PFS analysis is expected to occur approximately 16 months after the first 
patient was enrolled in the study.  The following assumptions were made for PFS based 
on the ITT population:

Patients will be randomized to the atezolizumabbevacizumab and sorafenib arms 
in a 2:1 ratio

PFS follows a one-piece exponential distribution

The median PFS in the control arm is 4 months

The dropout rate is 5% for the atezolizumab plus bevacizumab arm and 10% for the 
sorafenib arm over 12 months for PFS

The recruitment of approximately 480 patients will take place over approximately
10 months.
See Section 5 for sample size considerations for the China subpopulation.
2.3
INTERIM AND PRIMARY ANALYSIS TIMING
2.3.1
Primary Analysis Timing
The primary analysis of the co-primary endpoint PFS-IRF per RECIST v1.1 based on 
randomized patients enrolled during the global enrollment phase will be performed when 
approximately 308 PFS events are observed.  This is to have a minimal follow-up of 
approximately 6 months for patients randomized in the global enrollment phase (i.e., to 
have a clinical cutoff date at approximately 6 months after global last patient in [LPI]).
2.3.2
Interim Analyses Timing
No interim analysis (IA) is planned for the co-primary endpoint PFS in this study.
Two interim analyses of OS will be performed.  The first IA will be performed at the time 
of the primary PFS analysis, estimated to occur at approximately 16 months after FPI.  It 
is anticipated that at this time, approximately 172 deaths will have been observed.  The 
respective MDD OS HR is 0.633 (median OS improvement vs. control of 6.9 months).  
The second OS IA is planned to be conducted when approximately 243 deaths are 
accumulated, estimated to occur at approximately 24 months after FPI.  The respective 
MDD OS HR is 0.728 (median OS improvement vs. control of 4.6 months).
To control the type I error for OS, the stopping boundaries for the OS interim and final 
analyses are to be computed with use of the LanDeMets approximation to the 


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O’Brien-Fleming boundary (DeMets and Lan 1994) as shown in Table 2. The projected 
p-value and MDD boundaries were computed based on the number of OS events 
required at each OS analysis; the actual boundaries will be calculated at the time of OS 
analysis based on the observed information fraction, i.e., actual number of events 
observed at time of analysis over the total planned target number of events in the ITT 
population.
The planned IAs for OS will be conducted by the Sponsor.
Table 2
Analysis Timing and Stopping Boundaries for Overall Survival
Analysis 
Timing
Planned 
Information 
Fraction
Number of Events/
Analysis timing
(estimated)
Stopping Boundary
(Two-Sided p-Value)
Alpha can be 
recycled to OS (i.e. 
OS alpha0.05)
Alpha cannot be 
recycled to OS (i.e. 
OS alpha0.048)
1st OS 
interim 
analysis
55%
172/16 months*
MDD HR0.636
(p-value0.005)
MDD HR0.633
(p-value0.005)
2nd OS 
interim 
analysis
78%
243/24 months
MDD HR0.73
(p-value0.021)
MDD HR0.728
(p-value0.02)
OS final 
analysis
100%
312/33 months
MDD HR0.784
(p-value0.043)
MDD HR0.783
(p-value0.041)
HR hazard ratio; MDD minimum detectable difference; OS overall survival;
PFS progression-free survival.
Analysis timing shown in the table is projected based on protocol assumptions. Actual timing 
depends on the exact time that the required events have accrued.
*The 1st OS interim analysis will be conducted when approximately 308 PFS events have 
occurred. It is anticipated that approximately 172 OS events have been observed at time of 
primary PFS analysis.
MDD HR is estimated based on proportional hazard assumption.
3.
STUDY CONDUCT
3.1
RANDOMIZATION
Eligible patients will be randomized in a 2:1 ratio to receive either 
atezolizumabbevacizumab or sorafenib with the use of a stratified permuted-block 
randomization.  The randomization will be stratified according to the following 
stratification factors:

Geographic region (Asia excluding Japan vs. rest of world)

Macrovascular invasion and/or extrahepatic spread (presence vs. absence)

Baseline AFP (-fetoprotein [400 vs.400 ng/mL])

ECOG Performance Status (0 vs. 1)


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3.2
DATA MONITORING
An independent Data Monitoring Committee (iDMC) will be implemented to evaluate 
safety during the study on a regular basis.  All summaries and analyses by treatment 
arm for the iDMC review are prepared by an external independent Data Coordinating 
Center.  Members of the iDMC are external to the Sponsor and follow a separate iDMC 
Charter that outlines their roles and responsibilities, as well as a detailed monitoring plan.  
The meetings are scheduled approximately every 6 months for the review of the accrued 
safety data, with the first review meeting based on a data cut approximately 6 months 
after FPI.  iDMC membership will extend until the study is unblinded to the Sponsor. 
Further details will be provided in the iDMC charter.
All efficacy analyses including primary PFS analysis, interim and final OS analyses will 
be conducted by the Sponsor.
3.3
INDEPENDENT REVIEW FACILITY
An IRF will be used to conduct a blinded centralized radiology review of the imaging data 
and will provide an independent assessment of tumor response data for all patients 
according to an IRF charter. PFS assessment by IRF will be used for the co-primary 
endpoint analysis, and other IRF-assessed tumor response data will be examined for 
analyses of secondary and exploratory efficacy endpoints (Section 4.4.1.2).
4.
STATISTICAL METHODS
The analyses described in this SAP will supersede those specified in the YO40245 
protocol if there is any inconsistency between the two documents for the purpose of a 
regulatory filing.
4.1
ANALYSIS POPULATIONS
4.1.1
Intent-to-Treat Population
The ITT population is defined as all randomized patients, whether or not the patient has 
received the assigned study treatment.
Patients will be grouped according to the treatment assigned at randomization by the 
interactive voice or web-based response system (IxRS), whether or not the assigned 
treatment was received.
4.1.2
Pharmacokinetic-Evaluable Population
The pharmacokinetic (PK)-evaluable population is defined as all patients who received 
any dose of study treatment and who have at least one post-baseline PK sample 
available.
4.1.3
PRO-Evaluable Population
The patient-reported outcome (PRO)-evaluable population will include all randomized 
patients who have a baseline and at least 1 post-baseline assessment. The


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PRO-evaluable population will be used for descriptive analyses of visit summary and 
change from baseline and proportion analyses.
The ITT population will be used for the analyses of PRO completion and time-to-
deterioration (TTD).
All PRO analyses will be performed per the treatment arm assigned at randomization by 
the IxRS, whether or not the assigned treatment was received.
4.1.4
Safety Population
The safety population consists of all randomized patients who received at least one full 
or partial dose of any study treatment, with patients grouped according to the actual 
treatment received.
Patients who received any amount of atezolizumab and/or bevacizumab will be assigned 
to treatment Arm A for safety analyses even if atezolizumab/bevacizumab was given in 
error.
4.1.5
Anti-Drug-Antibody-Evaluable Population
The anti-drug-antibody (ADA)-evaluable population is defined as all patients who 
received any dose of atezolizumab and who have at least one post-baseline ADA 
assessment.
4.2
ANALYSIS OF STUDY CONDUCT
Enrollment, major protocol deviations (including major deviations of inclusions/exclusion 
criteria), and reasons for discontinuation from the study will be summarized by treatment 
arm for the ITT population.  Study treatment administration and reasons for
discontinuation from study treatment will be summarized by treatment arm for the safety 
population.
4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
Demographic characteristics such as age, sex, race/ethnicity, baseline disease 
characteristics (e.g., etiology, disease stage, Child-Pugh classification, prior treatments, 
etc) and stratification factors will be summarized by treatment arm for the ITT population.
Baseline measurements are the last available data obtained prior to the patient receiving 
the first dose of any component of study treatment; if a patient did not receive any study 
treatments, baseline measurements are the last available data obtained prior to 
randomization date unless otherwise specified.
Medical history will be summarized by arm based on the safety population.  The 
summary will be separately reported for resolved events/conditions versus ongoing 
events/conditions as collected at baseline.  Concomitant medications will also be 
summarized based on the safety population for medications taken prior to the first dose 


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of study treatment, regardless of whether medications were ongoing or not post-the start 
of treatment, and the medications taken after the first dose of study treatment.
Descriptive statistics (mean, median, standard deviation, and range) will be presented 
for continuous data, and frequencies and percentages will be presented for categorical 
data.
4.4
EFFICACY ANALYSIS
Unless otherwise specified, efficacy analyses will be conducted based on the ITT 
population.
Unless otherwise specified, geographic region (Asia excluding Japan vs. rest of world), 
macrovascular invasion and/or extrahepatic spread (presence vs. absence) and baseline 
AFP (400 vs.400 ng/mL) per IxRS at randomization will be used in all the stratified 
analysis. These are factors that are considered to be among the most prognostic factors 
for the patient population indicated in the study. ECOG PS is removed from the stratified 
analysis to avoid the potential risk of over-stratification (Akazawa et al. 1997).
4.4.1
Co-Primary Efficacy Endpoints
4.4.1.1
Overall Survival (OS)
Overall survival is defined as the time from the date of randomization to the date of 
death from any cause. Patients who are alive at the time of the analysis data cutoff will 
be censored at the last date they were known to be alive. Patients with no post-baseline 
information will be censored at the date of randomization.
The null and alternative hypotheses regarding OS can be phrased in terms of the 
survival functions SA(t) and SB(t) for Arm A (atezolizumabbevacizumab) and Arm B 
(sorafenib), respectively:
H0:  SOS_A(t) SOS_B(t) versus H1: SOS_A(t) ≠SOS_B(t)
The stratified two-sided log-rank test will be used as the primary analysis to compare OS
between the two treatment arms. The results from the unstratified log-rank test will also 
be provided.
The Kaplan-Meier method will be used to estimate median OS for each treatment arm. 
Brookmeyer-Crowley methodology will be used to calculate the 95% confidence interval 
(CI) for the median OS for each treatment arm.  Stratified Cox proportional-hazards 
models will be used to estimate the HR and its 95% CIs.  The unstratified HR will also be 
provided.
As described in Section 2.2, if the null hypotheses of the PFS and key secondary 
endpoints testing are all rejected at a two-sided significance level of 0.002, OS will be 
tested at an overall two-sided significance level of 0.05.  Otherwise, OS will be tested at 


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an overall two-sided significance level of 0.048.  As described in Section 2.3, three 
analyses for OS are planned, including two interim analyses.
4.4.1.2
PFS by IRF-Assessment (PFS-IRF) per RECIST v1.1
PFS-IRF is defined as the time from randomization to the occurrence of disease 
progression as determined by IRF according to RECIST v1.1, or death from any cause,
whichever occurs first.  Patients who have not experienced disease progression or death 
at the time of the clinical cutoff date will be censored at the time of the last tumor 
assessment on or prior to the clinical cutoff date.  Patients with no post-baseline tumor 
assessment will be censored at the date of randomization.
The null and alternative hypotheses regarding PFS-IRF can be phrased in terms of the 
PFS functions SA(t) and SB(t) for Arm A (atezolizumabbevacizumab) and Arm B 
(sorafenib), respectively:
H0:  SPFS_A(t) SPFS_B(t) versus H1: SPFS_A(t) ≠ SPFS_B(t)
PFS-IRF will be analyzed with the same methodologies as OS. Treatment comparisons 
will be based on the stratified log-rank test. If the null hypothesis of the OS testing is 
rejected at a two-sided significance level of 0.048 (as indicated in Table 2), PFS will be 
tested at the two-sided significance level of 0.05.  Otherwise, PFS will be tested at the 
two-sided significance level of 0.002.
4.4.2
Secondary Efficacy Endpoints
4.4.2.1
Objective Response Rate (ORR)
ORR by IRF-Assessment (ORR-IRF) per RECIST v1.1 and HCC mRECIST
The analysis population for the analysis of objective response rate per IRF (ORR-IRF)
according to RECIST v1.1 will be all patients in the ITT population with measurable 
disease at baseline per IRF according to RECIST v1.1. The analysis population for the 
analysis of ORR-IRF according to HCC modified RECIST (mRECIST) will be all patients
in the ITT population with measurable disease at baseline per IRF according to HCC 
mRECIST.
An objective response per IRF is defined as a complete response (CR) or partial 
response (PR) as determined by an IRF, and it is assessed separately according to 
RECIST v1.1 and HCC mRECIST. Patients not meeting these criteria, including patients
without any post-baseline tumor assessment, will be considered non-responders.
ORR-IRF is defined as the proportion of patients who had an objective response as 
assessed by IRF. Objective responses, confirmation not required and confirmation 
required (i.e., CR or PR at two consecutive tumor assessments at least 28 days apart), 
will be separately considered for the ORR analysis.


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The two-sided Cochran-Mantel-Haenszel test will be used to compare ORR between the 
two treatment arms. ORR-IRF is calculated for each treatment arm and the difference in 
ORR-IRF between treatment arms will be computed.  The 95% CI for ORR-IRF for each 
arm will be derived using the Clopper-Pearson method (Clopper and Pearson 1934).
The 95% CI for difference in ORR is computed by normal approximation.
ORR by Investigator-Assessment (ORR-INV) per RECIST v1.1
The analysis population for ORR-investigator (ORR-INV) will be all patients in the ITT 
population with measurable disease at baseline per INV according to RECIST v1.1.
Investigator-assessed objective response is defined as a CR or PR as determined by the 
investigator according to RECIST v1.1. Patients not meeting these criteria, including 
patients without any post-baseline tumor assessment, will be considered 
non-responders.
ORR-INV is defined as the percentage of patients who have an objective response per 
the investigator according to RECIST v1.1.  Objective responses, confirmation not 
required, and confirmation required (i.e., CR or PR at two consecutive tumor 
assessments at least 28 days apart), will be separately considered for the ORR analysis.
The analysis methods are similar to those described for ORR-IRF.
4.4.2.2
Duration of Response (DOR)
Duration of response will be assessed in patients who had an objective response
(confirmation not required, and confirmation required, analysis will be conducted 
separately). DOR is defined as the time interval from the date of first occurrence of a 
documented objective response (CR or PR, whichever status is recorded first) until the 
first date that disease progression or death is documented, whichever occurs first. 
Patients who have not progressed and who have not died at the time of analysis will be 
censored at the time of last tumor assessment.  If no tumor assessments were 
performed after the date of the first occurrence of a documented CR or PR, DOR will be 
censored at the date of the first occurrence of a documented CR or PR. The analysis of 
DOR is based on a non-randomized subset of patients (specifically, patients who 
achieved an objective response); therefore, comparisons between treatment arms will be 
made for descriptive purposes only.
DOR analyses will be performed separately based on IRF-assessed (DOR-IRF) tumor 
response according to RECIST v1.1 and HCC mRECIST, and investigator-assessed 
(DOR-INV) tumor response according to RECIST v1.1.  The analysis methods are 
similar to those described for PFS.
4.4.2.3
Progression-Free Survival (PFS)
PFS analyses will be performed separately based on investigator-assessed tumor 
response (PFS-INV) according to RECIST v1.1 and IRF-assessed tumor response 


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(PFS-IRF) according to HCC mRECIST.  The analysis methods are similar to those 
described for OS.
4.4.2.4
Time to Progression (TTP)
Time to progression is defined as the time from the date of randomization to the date of 
the first documented tumor progression. Patients without tumor progression will be 
censored at the last tumor assessment date.  Patients who have no post-baseline tumor 
assessment will be censored at the date of randomization.
TTP analyses will be performed separately based on IRF-assessed tumor response 
(TTP-IRF) according to RECIST v1.1 and HCC mRECIST as well as 
investigator-assessed tumor response (TTP-INV) according to RECIST v1.1. The
analysis methods are similar to those described for OS.
4.4.2.5
PFS and OS by Baseline AFP
PFS-IRF and PFS-INV according to RECIST v1.1 and OS will be analyzed by subgroups 
of baseline serum AFP level (400 ng/mL vs.400 ng/mL).  The analysis methods are 
similar to those described for the co-primary endpoints. Geographic region (Asia 
excluding Japan vs. rest of the world) and macrovascular invasion and/or extrahepatic 
spread (presence vs absence) will be used as stratification factors for stratified analyses.
4.4.2.6
Time to Deterioration (TTD)
The primary analysis population for evaluation of TTD will be the ITT population.
TTD is defined as the time from randomization to the first deterioration (decrease from 
baseline of10 points) in the patient-reported health-related global health status/quality 
of life (GHS /HRQoL), physical function or role function scales of the European 
Organization for Research and Treatment of Cancer quality-of-life questionnaire for 
cancer (EORTC) QLQ-C30, maintained for two consecutive assessments, or one 
assessment followed by death from any cause within 3 weeks. A10-point change in 
the EORTC scale score was perceived by patients as clinically significant 
(Osoba et al. 1998). The Kaplan-Meier analysis methods for the analysis of TTD are 
similar to those described for PFS. Patients who do not have an observed deterioration
prior to discontinuation from study treatment or initiation of non-protocol anti-cancer 
therapy (NPT), or at the time of the clinical data cut-off, will be censored at the last 
available assessment date prior to or at the time of discontinuation from study treatment 
or initiation of NPT or the clinical cut-off date, whatever is earlier. Patients without a 
post-baseline assessment will be censored at randomization date.
4.4.2.7
Overall Multiplicity Control for Key Secondary Endpoints
If the co-primary endpoint of PFS-IRF according to RECIST v1.1 is statistically 
significant, then ORR-IRF (confirmation required) according to RECIST v1.1 and 
ORR-IRF (confirmation required) according to HCC mRECIST will be hierarchically
tested. Specifically, ORR-IRF per RECIST v1.1 will be tested first and if it is statistically


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significant, ORR-IRF per HCC mRECIST will then be tested. If ORR-IRF per RECIST 
v1.1 is not statistically significant, ORR-IRF per HCC mRECIST will not be tested. 
Implementation of this ordered statistical testing procedure will strongly control the type I 
error at 5% (two-sided) among all key hypotheses.
4.4.3
Exploratory Efficacy Endpoints
PFS-INV, TTP-INV, ORR-INV, and DOR-INV according to immune-modified RECIST
(imRECIST), using the same definitions for these efficacy endpoints as outlined in 
Sections 4.4.1 and 4.4.2, will be analyzed using similar methodology as specified in 
Sections 4.4.1 and 4.4.2.
4.4.4
Patient-Reported Outcome (PRO) Analyses
Completion rates and reasons for missing data will be summarized for each of the 
EORTC QLQ-C30 and EORTC QLQ-HCC18 measures at each cycle by treatment arm.
In addition, the following analyses will be conducted by treatment arm.
Exploratory TTD analyses will be conducted utilizing Kaplan-Meier methods, with TTD 
defined as the time from randomization to first deterioration (decrease from baseline 
of 10 points), maintained for two consecutive timepoints, one timepoint followed by 
death from any cause within 3 weeks for select subscales of the EORTC QLQ-C30 
(appetite loss, diarrhea, fatigue, pain) and EORTC QLQ-HCC18 (jaundice, fatigue, pain).
Patients who do not have an observed deterioration prior to discontinuation from study 
treatment or initiation of NPT, or at the time of the clinical data cut-off, will be censored 
at the last available assessment date prior to or at the time of discontinuation from study 
treatment or initiation of NPT or the clinical cut-off date, whatever is earlier. Patients 
without a post-baseline assessment will be censored at randomization date.
Kaplan-Meier analysis methods similar to those described for OS will be used to assess 
long-term impact on GHS/HRQoL, physical function and role function.  For this 
exploratory analysis, TTD will be defined as the time from randomization to first 
deterioration (decrease from baseline of 10 points), maintained for two consecutive 
timepoints, or one timepoint followed by death from any cause within 3 weeks. Patients 
who do not have an observed deterioration at the time of the clinical data cut-off will be 
censored at the last available assessment date.  Patients without a post-baseline 
assessment will be censored at randomization.
Visit mean summary and change from baseline analyses will be performed for all 
subscales of the EORTC QLQ-C30 and QLQ-HCC18.  Summary statistics (number of 
patients, mean, standard deviation, median, minimum, maximum, 95% CI) of score(s) 
and score change(s) from baseline to each time point.  Previously published minimally 
important differences (MID) (e.g., 10-point MID) will be used to identify meaningful 
change from baseline within each treatment group on all scales of the EORTC QLQ-C30 
and EORTC QLQ-HCC18 (Osoba et al. 1998).


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Proportion of patients with a clinically meaningful change (improved, deteriorated, 
remained stable) in select scales of the QLQ-C30 (GHS/QoL, physical function, role 
function, appetite loss, diarrhea, fatigue, pain) and QLQ-HCC18 (jaundice, fatigue, pain) 
will be summarized by treatment arm.
Proportion of responses for itching item (of HCC18 jaundice subscale) and abdominal 
pain item (of HCC18 pain subscale) at each timepoint while patients are on treatment
will be summarized by treatment arm for each response option.
In the event of incomplete data for any questionnaire subscales, if more than 50% of the 
constituent items are completed, a prorated score will be computed, consistent with the 
scoring manuals and validation papers.  For subscales with less than 50% of the items 
completed, the subscale will be considered as missing (Fayers et al. 2001; 
Chie et al. 2012).
4.4.5
Exploratory Biomarker Analysis
Exploratory biomarker analyses may be performed in an effort to understand the
association of tissue or blood-based biomarkers with response to 
atezolizumabbevacizumab versus sorafenib, or increase the understanding of HCC 
disease evolution under atezolizumabbevacizumab treatment and may not be included 
in the CSR.  PFS and OS will be analyzed using the methods outlined in Section 4.4.1.
PFS-IRF according to RECIST v 1.1 and OS by the following biomarkers in tumor tissue 
may be analyzed:

Baseline programmed death-ligand 1 (PD-L1) protein expression in tumor tissue

Baseline expression of T effector gene signature in tumor tissue

CD8 protein expression level or CD8+ T cell localization 

IHCs or genes/gene signatures (by gene expression profiling) related to tumor 
microenvironments.
4.4.6
Sensitivity Analyses
Impact of Missing Scheduled Tumor Assessments on Co-Primary Endpoint 
PFS-IRF per RECIST v1.1
The impact of missing scheduled tumor assessments on the co-primary endpoint of
PFS-IRF per RECIST v1.1 will be assessed depending on the number of patients who 
missed consecutive assessments scheduled immediately prior to the date of disease 
progression or death. If5% of patients missed two or more consecutive tumor 
assessments scheduled immediately prior to the date of disease progression or death in 
any treatment arm, the following two sensitivity analyses may be performed:

Patients who missed two or more consecutive tumor assessments scheduled 
immediately prior to the date of disease progression by IRF-assessment per 
RECIST v1.1 or death will be censored at the last tumor assessment prior to the
missed visits.


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
Patients who missed two or more consecutive tumor assessments scheduled 
immediately prior to the date of disease progression by IRF-assessment per 
RECIST v1.1 or death will be counted as having progressed on the date of the first 
of these missing assessments.
Additional sensitivity analyses may be conducted.
4.4.7
Subgroup Analyses
In order to assess the consistency of treatment effect with respect to the co-primary 
efficacy endpoints of PFS-IRF according to RECIST v 1.1 and OS across important 
subgroups, forest plots (including estimated HRs) will be provided, including, but not 
limited to, the following variables: age, sex, race, geographic region, macrovascular 
invasion and/or extrahepatic spread, macrovascular invasion, extrahepatic spread, 
ECOG performance status, HCC etiology, BCLC staging at the time of study entry and 
baseline PD-L1 expression in tumor tissue for patients with baseline tumor samples.
Unstratified analysis results will be presented for subgroup analyses due to the 
potentially limited number of patients in each subgroup.
To assess how patient baseline characteristics such as invasion of the bile duct, 
invasion at the main portal vein, and liver occupation impacts the clinical activity of the 
combination treatment of atezolizumabbevacizumab, further exploratory efficacy 
subgroup analyses for the co-primary endpoints of PFS-IRF per RECIST v1.1 and OS
may be performed for ITT patients who do not have obvious invasion of the bile duct, 
invasion at the main portal vein, or50% liver occupation.
4.5
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
Pharmacokinetic analyses will be performed for the pharmacokinetic-evaluable 
population.
Samples will be collected for PK analyses and to compare exposure in this study with 
that attained in previous studies.  Serum concentrations of atezolizumab will be reported 
as individual values and summarized (mean, standard deviation, coefficient of variation, 
median, range, geometric mean, and geometric mean coefficient of variation) by 
treatment arm and cycle, when appropriate and as data allow.  Individual and median 
serum atezolizumab concentrations will be plotted by treatment arm and 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.
Additional PK and pharmacodynamic analyses will be conducted as appropriate.  These 
additional PK analyses may not be included in the CSR.


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4.6
SAFETY ANALYSES
Unless specified otherwise, safety analyses described in this section will be conducted 
based on the safety population.
4.6.1
Exposure of Study Medication
Study drug exposure status, which includes treatment duration, number of cycles, and 
dose intensity, will be summarized for each treatment arm with descriptive statistics.
4.6.2
Adverse Events
Verbatim description of adverse events will be mapped to Medical Dictionary for 
Regulatory Activities (MedDRA) thesaurus terms and graded by the investigator 
according to National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 4.0 (NCI CTCAE v4.0).  Treatment-emergent adverse events will be 
summarized by mapped term, appropriate thesaurus level, NCI CTCAE grade, and 
treatment arm.  For reporting purposes, “treatment-emergent” is defined as all AEs with 
an onset on or after the first exposure to the study treatment, or have AE intensity 
worsening during the treatment if onset was prior to the first exposure, until the clinical 
cutoff date. In addition, serious adverse events, severe adverse events (Grade3), 
atezolizumab adverse events of special interest (AESIs), bevacizumab AESIs, 
immune-mediated AEs (imAEs [defined as atezolizumab AESIs requiring the use of 
systemic corticosteroids]) and adverse events leading to study drug discontinuation and 
AEs leading to study drug interruption/modification will be summarized accordingly.  
Multiple occurrences of the same event will be counted once at the maximum grade. 
All deaths and causes of deaths reported during the study treatment period and the 
follow-up period after treatment completion and/or discontinuation will be summarized by 
treatment arm.
4.6.3
Laboratory Data
Laboratory data will be summarized by treatment arm.  Values outside the normal 
ranges will be summarized by treatment arm. In addition, selected laboratory data will 
be summarized by treatment arm and NCI CTCAE grade according to NCI CTCAE v4.0.
To evaluate if there is any potential risks of drug-induced liver injury (DILI) in HCC 
patients, a listing for all cases meeting the potential Hy’s law criteria, defined as total 
bilirubin increase by2ULN within 7 days after ALT or ASL increase by 3baseline
value, will be provided.
4.6.4
Vital Signs
Changes in selected vital signs will be summarized by treatment arm and by change 
over time, which includes change from baseline.  Baseline is defined as the 
measurement obtained on Cycle 1, Day 1 before the first dose of study drug is 
administered.


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4.6.5
Electrocardiograms
Post-baseline abnormal electrocardiogram (ECG) (12-lead) records over time will be 
listed by treatment arm.
4.7
IMMUNOGENICITY ANALYSES
The immunogenicity analysis population will consist of all patients with at least one 
post-baseline 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 (post-baseline incidence) 
will be summarized by treatment group.
In the ADA-evaluable population, patients are considered as treatment-emergent ADA 
positive if they were ADA negative at baseline and ADA positive at any time point post
baseline (treatment induced), or if they were ADA positive at baseline and had a post
baseline ADA positive titer that was 0.6 titer units higher than baseline (treatment 
enhanced). Otherwise, all other ADA-evaluable patients are considered as treatment
emergent ADA negative.
The safety, efficacy, PK, and biomarker endpoints by treatment-emergent ADA status 
may be analyzed and reported.
4.8
EXPLORATORY HEALTH STATUS ANALYSIS
Health utility data from the EuroQol 5 Dimension Questionnaire, 5-level version 
(EQ-5D-5L) will be evaluated in pharmacoeconomic models.  The results from the health 
economic data analyses will be reported separately from the CSR.
4.9
MISSING DATA
See Section 4.4.4 and Section 4.4.5 for methods for handling missing data for the 
primary and secondary endpoints.
4.10
INTERIM ANALYSES
Please refer to Section 2.3 for details on the planned interim analyses.
5.
CHINA SUBPOPULATION ANALYSIS
The Sponsor is targeting a total enrollment of approximately 135 patients from mainland 
China. The sample size of the China subpopulation was considered adequate to 
characterize the efficacy and safety profile of atezolizumabbevacizumab in Chinese 
patients. After approximately 480 patients have been randomized into the global portion 
of the study, in the event that fewer than 135 patients from mainland China are enrolled, 
additional patients in China may be subsequently randomized into the two treatment 


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arms in a 2:1 ratio in an extended China enrollment phase to ensure a total of 
approximately 135 mainland China patients for the China subpopulation. The same 
randomization method will be implemented for the China extension cohort in the event 
the extension cohort opens.
The primary efficacy objective of the China subpopulation analysis is to assess efficacy,
as measured by the co-primary endpoints of PFS by an IRF assessment per 
RECIST v1.1 and OS, of atezolizumabbevacizumab compared with sorafenib in 
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 PFS analysis for the China subpopulation will be conducted at the time of the 
primary PFS analysis for the global population (anticipated to occur approximately 16 
months from global FPI), at which point it is estimated that there will be a sufficient 
number of PFS events to demonstrate at least 80% probability of maintaining 50% of 
PFS risk reduction compared with that estimated from the global population. If the PFS 
data in the China subpopulation is not mature at the time of primary analysis, an 
additional PFS analysis in the China subpopulation may be conducted. 
The OS data from the China subpopulation will not be mature at the time of this PFS 
analysis. Therefore, the Sponsor may decide to conduct updated OS analyses for the 
China subpopulation at the time of the 2nd OS IA for global population, or until there is a 
sufficient number of OS events to achieve at least 80% probability of maintaining 50% 
OS risk reduction compared with that estimated for the global population.
The analysis methods for the China subpopulation will be the same as for the global 
population unless otherwise noted. Given that all patients in China subpopulation are 
from geographic region Asia excluding Japan, only macrovascular invasion and/or 
extrahepatic spread (presence vs. absence) and baseline AFP (400 vs.400 ng/mL)
will be used as stratification factors in stratified analyses conducted for the China 
subpopulation. The results from the unstratified analyses will also be provided. The 
results of the China subpopulation analyses will be summarized in a separate report 
from the CSR for the global population.


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REFERENCES
Akazawa K, Nakamura T, Palesch Y. Power of Logrank Test and Cox Regression Model 
in Clinical Trials with Heterogeneous Samples. Statistics in Medicine 
1997;16:583-97.
Bretz F, Maurer W, Brannath W, et al. A graphical approach to sequentially regective 
multiple test procedures. Statist Med 2009;28:586−604.
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982;38:2941.
Burman CF, Sonesson C, Guilbaud O, et al. A recycling framework for the construction 
of Bonferroni-based multiple tests. Stat Med 2009;28:739-61.
Chie WC, Blazeby JM, Hsiao CF, et al. International cross-cultural field validation of an 
European Organization for Research and Treatment of Cancer questionnaire 
module for patients with primary liver cancer, the European Organization for 
Research and Treatment of Cancer quality-of-life questionnaire HCC18. 
Hepatology 2012;55:11229.
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of 
the binomial. Biometrika 1934;26:404−13.
DeMets D, Lan KKG. Interim analysis: the alpha spending function approach. Stat Med 
1994;13:134152.
Fayers PM, Aaronson NK, Bjordal K, et al. The EORTC QLQ-C30 scoring manual, 3rd 
ed. Brussels: European Organisation for Research and Treatment of Cancer, 2001.
Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in
health-related quality-of-life scores. J Clin Oncol 1998;16:13944.


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Appendix 1
Protocol Synopsis
PROTOCOL SYNOPSIS
TITLE:
A PHASE III, OPEN-LABEL, RANDOMIZED STUDY OF 
ATEZOLIZUMAB IN COMBINATION WITH BEVACIZUMAB 
COMPARED WITH SORAFENIB IN PATIENTS WITH UNTREATED 
LOCALLY ADVANCED OR METASTATIC HEPATOCELLULAR 
CARCINOMA
PROTOCOL NUMBER:
YO40245
VERSION NUMBER:
4
EUDRACT NUMBER:
2017-003691-31
IND NUMBER:
135913
TEST PRODUCTS:
Atezolizumab (RO5541267)
Bevacizumab (RO4876646)
PHASE:
III
INDICATION:
Metastatic hepatocellular carcinoma (HCC)
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy and safety of atezolizumab in combination with 
bevacizumab compared with sorafenib in patients with locally advanced or metastatic HCC who 
have received no prior systemic treatment.  Specific objectives and corresponding endpoints for 
the study are outlined below.
Primary Efficacy Objective
Corresponding Endpoint
To evaluate the efficacy of 
atezolizumab bevacizumab
compared with sorafenib
OS, defined as the time from randomization to death from 
any cause
PFS, defined as the time from randomization to the first 
occurrence of disease progression or death from any 
cause (whichever occurs first), as determined by an IRF 
according to RECIST v1.1


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Secondary Efficacy Objectives
Corresponding Endpoints
To evaluate the efficacy of 
atezolizumab bevacizumab
compared with sorafenib
Objective response, defined as a complete or partial 
response, as determined by the investigator according to 
RECIST v1.1
PFS as determined by the investigator according to 
RECIST v1.1
TTP, defined as the time from randomization to the first 
occurrence of disease progression, as determined by the 
investigator according to RECIST v1.1
DOR, defined as the time from the first occurrence of a 
documented objective response to disease progression or 
death from any cause (whichever occurs first), as 
determined by the investigator according to RECIST v1.1
Objective response as determined by an IRF according to 
RECIST v1.1
TTP as determined by an IRF according to RECIST v1.1
DOR as determined by an IRF according to RECIST v1.1
Objective response as determined by an IRF according to 
HCC mRECIST 
PFS as determined by an IRF according to HCC 
mRECIST
TTP as determined by an IRF according to HCC 
mRECIST
DOR as determined by an IRF according to HCC 
mRECIST
To evaluate the association of pre-
specified biomarkers with efficacy of 
atezolizumab bevacizumab
compared with sorafenib
PFS as determined by the investigator and by an IRF 
according to RECIST v1.1 and OS by baseline serum 
AFP level (400 ng/mL vs. 400 ng/mL)
To evaluate PROs of 
disease/treatment-related 
symptoms, GHS/QoL, and function 
experienced by patients on 
atezolizumab bevacizumab versus 
sorafenib
TTD, defined as the time from randomization to first 
deterioration (decrease from baseline of 10 points), 
maintained for two consecutive assessments or one 
assessment followed by death from any cause within 
3 weeks in the following EORTC QLQ-C30 subscales:
-
Physical functioning (PF)
-
Role functioning (RF)
-
GHS/QoL
Exploratory Efficacy Objectives
Corresponding Endpoints
To evaluate the efficacy of 
atezolizumab bevacizumab
compared with sorafenib
Objective response as determined by the investigator 
according to imRECIST 
PFS as determined by the investigator according to 
imRECIST 
TTP as determined by the investigator according to 
imRECIST
DOR as determined by the investigator according to 
imRECIST


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Exploratory Efficacy Objectives
(cont.)
Corresponding Endpoints
To evaluate PROs of 
disease/treatment-related symptoms 
(including abdominal pain and 
itching), GHS/QoL, and function 
experienced by patients on 
atezolizumab bevacizumab versus 
sorafenib
Mean and mean changes from baseline score (by cycle)
in all the subscales of the EORTC QLQ-C30 and QLQ-
HCC18
Proportion of patients with clinically meaningful change in 
select scales of the QLQ-C30 (GHS/QoL, physical 
function, role function, appetite loss, diarrhea, fatigue, 
pain) and QLQ-HCC18 (fatigue, jaundice, pain)
TTD maintained for two consecutive timepoints, or one 
timepoint followed by death from any cause within 
3 weeks, in select scales of the QLQ-C30 (appetite loss, 
diarrhea, fatigue, pain) and QLQ-HCC18 (jaundice, 
fatigue, pain)
TTD maintained for two consecutive timepoints, or one 
timepoint followed by death from any cause, within 
3 weeks in HRQoL/GHS, physical function, and role 
function of the QLQ-C30
Proportion of responses for abdominal pain item (of QLQ-
HCC18 pain subscale) and itching item (of QLQ-HCC18 
jaundice subscale)
Safety Objective
Corresponding Endpoints
To evaluate the safety of 
atezolizumab bevacizumab
compared with sorafenib
Incidence and severity of adverse events, with severity 
determined according to NCI CTCAE v4.0
Vital signs
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
Presence of ADAs to atezolizumab during the study 
relative to the presence of ADAs at baseline
Exploratory Immunogenicity 
Objective
Corresponding Endpoint
To evaluate potential effects of 
ADAs to atezolizumab on the 
efficacy, safety, and 
pharmacokinetics of atezolizumab 
bevacizumab
Efficacy, safety, or PK endpoints by ADA status


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Exploratory Biomarker Objective
Corresponding Endpoint
To identify tissue or blood based 
biomarkers that are associated with 
response to atezolizumab 
bevacizumab versus sorafenib, or 
can increase the understanding of 
HCC disease evolution under 
atezolizumab bevacizumab
treatment
PFS as determined by the investigator according to 
RECIST v 1.1 and OS based on the following biomarkers 
in tumor tissue: 
-
Baseline expression of T effector gene signature in 
tumor tissue
-
Baseline PD-L1 protein expression in tumor tissue
-
CD8 protein expression level or CD8T cell 
localization 
-
IHCs or genes/gene signatures (by gene expression 
profiling) related to tumor microenvironments 
-
T cell receptor sequence profile in tumor-associated 
T cells
Objective response as determined by the investigator 
according to RECIST v1.1 and OS based on the following 
biomarkers in blood:
-
Immune-related biomarkers profiling in plasma and 
serum (e.g., interleukin 2, interferon-) 
Exploratory Health Status Objective
Corresponding Endpoint
To evaluate health status 
experienced by patients on 
atezolizumab bevacizumab versus 
sorafenib to generate utility scores 
for use in economic evaluations
Health utility and VAS scores of the EQ-5D-5L 
questionnaire
ADA anti-drug antibody; AFP-fetoprotein; DOR duration of response; EORTC European 
Organisation for Research and Treatment of Cancer; GHS global health status; EQ-5D-
5L EuroQol 5-Dimension Questionnaire, 5-level version; HCC hepatocellular carcinoma; HCC 
mRECISTmodified RECIST for HCC; HRQoL health-related quality of life; imRECIST immune-
modified RECIST; IRFindependent review facility; NCI CTCAE v4.0 National Cancer Institute 
Common Terminology Criteria for Adverse Events, Version 4.0; OS overall survival; 
PFS progression-free survival; PROpatient-reported outcome; PK pharmacokinetic; QLQ-
C30 quality-of-life questionnaire for cancer; QLQ-HCC18 HCC disease-specific module;
QoL=quality of life; RECIST v1.1 Response Evaluation Criteria in Solid Tumors, Version 1.1; 
TTD time to deterioration; TTP time to progression; VAS visual analog scale.
Study Design
Description of Study
This is a Phase III, randomized, multicenter, open-label, two-arm study designed to evaluate the 
efficacy and safety of atezolizumab bevacizumab versus sorafenib in patients with locally 
advanced or metastatic HCC who have received no prior systemic treatment.  
This study will enroll approximately 480 patients randomized in a 2:1 ratio to one of two 
treatment arms:

Arm A (experimental arm):  Atezolizumab 1200 mg IV infusions Q3W (dosed in 3-week 
cycles) bevacizumab 15 mg/kg Q3W (dosed in 3-week cycles)  

Arm B (control arm):  Sorafenib 400 mg by mouth (PO), twice per day (BID), continuously
Randomization will be stratified according to the following stratification factors:

Geographic region (Asia excluding Japan vs. rest of world)

Macrovascular invasion and/or extrahepatic spread (presence vs. absence)

Baseline AFP (400 vs. 400 ng/mL)

ECOG performance status (0 vs. 1)
Patients randomized to the atezolizumab bevacizumab arm (Arm A) who transiently withhold 
or permanently discontinue either atezolizumab or bevacizumab may continue on single-agent 
therapy as long as the patients are experiencing clinical benefit in the opinion of the investigator 


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and after discussion with the Medical Monitor (i.e., patients transiently withhold or permanently 
discontinue bevacizumab for adverse effects may continue atezolizumab monotherapy and vice 
versa).
Patients will receive atezolizumab and/or bevacizumab or sorafenib 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).  In the absence of unacceptable toxicity, patients who meet criteria 
for disease progression per RECIST v1.1 while receiving atezolizumab and/or bevacizumab or 
sorafenib will be permitted to continue the 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

Absence of decline in 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
Tumor assessments will be performed at baseline and at regular intervals during study 
treatment.  Additional scans will be performed as clinically indicated. Tumor assessments will 
continue until disease progression, regardless of whether treatment has been discontinued (e.g., 
for toxicity).  Patients who meet RECIST v1.1 criteria for progression will undergo tumor 
assessments until disease progression (per immune-modified RECIST [imRECIST]) or loss of 
clinical benefit, whichever occurs later.  In the absence of disease progression, tumor 
assessments should continue regardless of whether patients start new anti-cancer therapy, until 
consent is withdrawn, death, or the study is terminated by the Sponsor, whichever occurs first.  
Following disease progression, patients will be followed for survival and subsequent anti-cancer 
therapies until death, loss to follow-up, withdrawal of consent, or study termination by Sponsor, 
whichever occurs first.  
Sites will provide imaging used for tumor assessments to an IRF to enable centralized, 
independent review of response and progression endpoints.  These reviews will be performed 
prior to the pre-specified efficacy analyses.  IRF membership and procedures will be detailed in 
an IRF Charter. 
Safety assessments will include the incidence, nature, and severity of adverse events and 
laboratory abnormalities graded per the National Cancer Institute Common Terminology Criteria 
for Adverse Events, Version 4.0 (NCI CTCAE v4.0).  Laboratory safety assessments will include 
the regular monitoring of hematology and blood chemistry.  Serum samples will be collected to 
monitor the pharmacokinetics of atezolizumab when administered in combination with 
bevacizumab.  Patient samples, including archival tumor tissues as well as serum and plasma, 
will be collected for future exploratory biomarker assessments.
Number of Patients
This study will initially enroll approximately 480 patients across all sites in a global enrollment 
phase.  The final analysis of the global study will be based on the global population, which will 
include all patients enrolled during the global enrollment phase (including patients enrolled in 
China during that phase).
The Sponsor is targeting a total enrollment of approximately 135 patients from mainland China.  
After completion of the global enrollment phase, in the event that less than 135 patients from 
mainland China are enrolled, additional patients in China may be subsequently randomized into 
the two treatment arms in a 2:1 ratio in an extended China enrollment phase to ensure a total of 
approximately 135 patients from mainland China in a China subpopulation.  The China 
subpopulation will include all patients enrolled in China (i.e., during both the global enrollment 
phase and the extended China enrollment phase).  The patients enrolled in the China 
extension phase will undergo the same schedule of activities and will receive atezolizumab 
bevacizumab, or sorafenib as in the global study.  The China subgroup analysis will be 
performed based on the China subpopulation.


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29/Statistical Analysis Plan YO40245
Target Population
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, in the investigator's judgment

Locally advanced or metastatic and/or unresectable HCC with diagnosis confirmed by 
histology/ cytology or clinically by AASLD criteria in cirrhotic patients
Patients without cirrhosis require histological confirmation of diagnosis.

Disease that is not amenable to curative surgical and/or locoregional therapies, or 
progressive disease after surgical and /or locoregional therapies

No prior systemic therapy (including systemic investigational agents) for HCC
Previous use of herbal therapies/traditional Chinese medicines with anti-cancer 
activity included in the label is allowed, provided that these medications are 
discontinued prior to randomization.  

At least one measurable (per RECIST 1.1) untreated lesion

Patients who received prior local therapy (e.g., radiofrequency ablation, percutaneous 
ethanol or acetic acid injection, cryoablation, high-intensity focused ultrasound, transarterial 
chemoembolization, transarterial embolization, etc.) are eligible provided the target lesion(s) 
have not been previously treated with local therapy or the target lesion(s) within the field of 
local therapy have subsequently progressed in accordance with RECIST version 1.1.

Pre-treatment tumor tissue sample (if available)  
If tumor tissue is available, a formalin-fixed, paraffin-embedded (FFPE) tumor specimen 
in a paraffin block (preferred) or approximately 1015 slides  containing unstained, 
freshly cut, serial sections should be submitted along with an associated pathology 
report within 4 weeks of randomization.  
If FFPE specimens described above are not available, any type of specimens (including 
fine-needle aspiration, cell pellet specimens [e.g., from pleural effusion], and lavage 
samples) are also acceptable.  This specimen should be accompanied by the associated 
pathology report.  
If tumor tissue is not available (e.g., depleted because of prior diagnostic testing), 
patients are still eligible.

ECOG Performance Status of 0 or 1 within 7 days prior to randomization 

Child-Pugh class A within 7 days prior to randomization

Adequate hematologic and end-organ function, defined by the following laboratory test 
results, obtained within 7 days prior to randomization, unless otherwise specified:
–
ANC 1.5 109/L (1500/L) without granulocyte colony-stimulating factor support
–
Lymphocyte count 0.5 109/L (500/L)
–
Platelet count 75 109/L (75,000/L) without transfusion 
–
Hemoglobin 90 g/L (9 g/dL)
Patients may be transfused to meet this criterion.
–
AST, ALT, and alkaline phosphatase (ALP) 5 upper limit of normal (ULN)
–
Serum bilirubin 3ULN 
–
Serum creatinine 1.5 ULN or creatinine clearance 50 mL/min (calculated using the 
Cockcroft-Gault formula)
–
Serum albumin 28 g/L (2.8 g/dL) without transfusion
–
For patients not receiving therapeutic anticoagulation:  INR or aPTT 2ULN


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30/Statistical Analysis Plan YO40245
–
Urine dipstick for proteinuria 2(within 7 days prior to initiation of study treatment)
Patients discovered to have 2proteinuria on dipstick urinalysis at baseline 
should undergo a 24-hour urine collection and must demonstrate 1 g of protein in 
24 hours.

Resolution of any acute, clinically significant treatment-related toxicity from prior therapy to 
Grade 1 prior to study entry, with the exception of alopecia

Negative HIV test at screening

Documented virology status of hepatitis, as confirmed by screening HBV and HCV serology 
test 

For patients with active hepatitis B virus (HBV): 
HBV DNA 500 IU/mL obtained within 28 days prior to initiation of study treatment, and
Anti-HBV treatment (per local standard of care; e.g., entecavir) for a minimum of 14 days 
prior to study entry and willingness to continue treatment for the length of the study

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods with a failure rate of 1% per year 
during the treatment period and for at least 5 months after the last dose of atezolizumab, 6 
months after the last dose of bevacizumab, or 1 month after the last dose of sorafenib.  
Women must refrain from donating eggs during this same period.
A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).
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 
acceptable methods of contraception.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential, men must remain abstinent or use a 
condom plus an additional contraceptive method that together result in a failure rate of 
1% per year during the treatment period and for 6 months after the last dose of 
bevacizumab or 3 months after the last dose of sorafenib.  Men must refrain from 
donating sperm during this same period.
With pregnant female partners, men must remain abstinent or use a condom during the 
treatment period and for 6 months after the last dose of bevacizumab or 3 months after 
the last dose of sorafenib to avoid exposing the embryo.
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 
acceptable methods of contraception.

For the extended China enrollment phase:  Chinese ancestry and residence in Mainland 
China, Hong Kong, or Taiwan with enrollment at sites recognized by the China FDA
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

History of leptomeningeal disease


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
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, 
Wegener granulomatosis, 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
–
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 previous 12 months

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 computed tomography (CT) scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Known active tuberculosis

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 
initiation of study treatment), unstable arrhythmia, or unstable angina 

History of congenital long QT syndrome or corrected QT interval 500 ms (calculated with 
use of the Fridericia method) at screening

History of uncorrectable electrolyte disorder affecting serum levels of potassium, calcium, or 
magnesium

Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study 
treatment, or anticipation of need for a major surgical procedure during the study

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

Severe infection within 4 weeks prior to initiation of study treatment, including, but not 
limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia

Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study 
treatment
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

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

Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, 
or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months 
after the last dose of atezolizumab

History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or 
fusion proteins


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32/Statistical Analysis Plan YO40245

Known hypersensitivity to Chinese hamster ovary cell products or to any component of the 
atezolizumab or bevacizumab formulation 

Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or 
within at least 5 months after the last dose of atezolizumab, 6 months after the last dose of 
bevacizumab, or 1 month after the last dose of sorafenib
Women of childbearing potential must have a negative serum pregnancy test result 
within 14 days prior to initiation of study treatment.

Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC

Untreated or incompletely treated esophageal and/or gastric varices with bleeding or high 
risk for bleeding
Patients must undergo an esophagogastroduodenoscopy (EGD), and all size of varices 
(small to large) must be assessed and treated per local standard of care prior to 
enrollment.  Patients who have undergone an EGD within 6 months of prior to initiation 
of study treatment do not need to repeat the procedure. 

A prior bleeding event due to esophageal and/or gastric varices within 6 months prior to 
initiation of study treatment

Moderate or severe ascites

History of hepatic encephalopathy

Co-infection of HBV and HCV
Patients with a history of HCV infection but who are negative for HCV RNA by PCR will 
be considered non-infected with HCV.

Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases
Asymptomatic patients with treated CNS lesions are eligible, provided that all of the 
following criteria are met:
–
Measurable disease, per RECIST v1.1, must be present outside the CNS.
–
The patient has no history of intracranial hemorrhage or spinal cord hemorrhage.
–
Metastases are limited to the cerebellum or the supratentorial region (i.e., no 
metastases to the midbrain, pons, medulla, or spinal cord).
–
There is no evidence of interim progression between completion of CNS-directed 
therapy and initiation of study treatment.
–
The patient has not undergone stereotactic, whole-brain radiotherapy, and/or 
neurosurgical resection within 28 days prior to initiation of study treatment.
–
The patient has no ongoing requirement for corticosteroids as therapy for CNS 
disease.  Anticonvulsant therapy at a stable dose is permitted.
Asymptomatic patients with CNS metastases newly detected at screening are eligible for 
the study after receiving radiotherapy or surgery, with no need to repeat the screening 
brain scan.

Uncontrolled tumor-related pain
Patients requiring pain medication must be on a stable regimen at study entry.
Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) 
amenable to palliative radiotherapy should be treated prior to enrollment.  Patients 
should be recovered from the effects of radiation.  There is no required minimum 
recovery period.
Asymptomatic metastatic lesions that would likely cause functional deficits or intractable 
pain with further growth (e.g., epidural metastasis that is not currently associated with 
spinal cord compression) should be considered for loco-regional therapy if appropriate 
prior to enrollment.

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently)
Patients with indwelling catheters (e.g., PleurX) are allowed.


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33/Statistical Analysis Plan YO40245

Uncontrolled or symptomatic hypercalcemia (ionized calcium 1.5 mmol/L, 
calcium 12 mg/dL or corrected serum calcium ULN)

Treatment with investigational therapy within 28 days prior to initiation of study treatment

Treatment with strong CYP3A4 inducers within 14 days prior to initiation of study treatment, 
including rifampin (and its analogues) or St. John's wort

Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including 
antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic antibodies 

Treatment with systemic immunostimulatory agents (including, but not limited to, interferon 
and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior 
to initiation of study treatment

Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antiTNF-
agents) within 2 weeks prior to initiation of study treatment, 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 for the study after Medical Monitor 
approval has been obtained.
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for 
chronic obstructive pulmonary disease (COPD) 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 blood pressure 100 mmHg), based on an average of 
3 BP readings on 2 sessions
Anti-hypertensive therapy to achieve these parameters is allowable.

Prior 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 initiation of study treatment

History of hemoptysis (2.5 mL of bright red blood per episode) within 1 month prior to 
initiation of study treatment

Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic 
anticoagulation)

Current or recent (within 10 days of first dose of study treatment) use of aspirin 
(325 mg/day) or treatment with dipyramidole, ticlopidine, clopidogrel, and cilostazol

Current or recent (within 10 days prior to study treatment start) 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 within 14 days prior to initiation of study treatment.
For prophylactic use of anticoagulants or thrombolytic therapies, local label approved 
dose levels may be used.

Core biopsy or other minor surgical procedure, excluding placement of a vascular access 
device, within 3 days prior to the first dose of bevacizumab

History of abdominal or tracheoesophageal fistula, gastrointestinal (GI) perforation, or intra-
abdominal abscess within 6 months prior to initiation of study treatment

History of intestinal obstruction and/or clinical signs or symptoms of GI obstruction including 
sub-occlusive disease related to the underlying disease or requirement for routine 
parenteral hydration, parenteral nutrition, or tube feeding prior to initiation of study treatment


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34/Statistical Analysis Plan YO40245
Patients with signs/symptoms of sub-/occlusive syndrome/intestinal obstruction at time 
of initial diagnosis may be enrolled if they had received definitive (surgical) treatment for 
symptom resolution.

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

Metastatic disease that involves major airways or blood vessels, or centrally located 
mediastinal tumor masses (30 mm from the carina) of large volume
Patients with vascular invasion of the portal or hepatic veins may be enrolled.  

History of intra-abdominal inflammatory process within 6 months prior to initiation of study 
treatment, including but not limited to active peptic ulcer disease, diverticulitis, or colitis

Radiotherapy within 28 days and abdominal/ pelvic radiotherapy within 60 days prior to 
initiation of study treatment, except palliative radiotherapy to bone lesions within 7 days 
prior to initiation of study treatment

Local therapy to liver (e.g., radiofrequency ablation, percutaneous ethanol or acetic acid 
injection, cryoablation, high-intensity focused ultrasound, transarterial chemoembolization, 
transarterial embolization, etc.) within 28 days prior to initiation of study treatment or non-
recovery from side effects of any such procedure

Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to 
initiation of study treatment, or abdominal surgery, abdominal interventions or significant 
abdominal traumatic injury within 60 days prior to initiation of study treatment or anticipation 
of need for major surgical procedure during the course of the study or non-recovery from 
side effects of any such procedure

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.
End of Study
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs 
(i.e., last patient in the global and extended China enrollment phases combined) or safety 
follow-up is received from the last patient (global and extended China enrollment phases 
combined), whichever occurs later.  
In addition, the Sponsor may decide to terminate the study at any time.


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35/Statistical Analysis Plan YO40245
Investigational Medicinal Products
Patients will receive treatment as outlined below 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).  
Arm
Cycle 
Length
Dose, Route, and Regimen
(drugs listed in order of administration)
Infusion Rate
A a
21 days
Atezolizumab 1200 mg IV on Day 1
Over 60 (15) minutes (for the 
first infusion); 30 (10) minutes
for subsequent infusions 
if tolerated
Bevacizumab 15 mg/kg IV on Day 1
Over 90 (15) minutes (for the 
first infusion); shortening to 60 
(10) then 30 (10) minutes for 
subsequent infusions if tolerated
B
21 days
Sorafenib 400 mg BID, by mouth,
continuously
Not applicable
BIDtwice per day.
a For patients randomized to Arm A, on Day 1 of each cycle, atezolizumab will be 
administered first, followed by bevacizumab, with a minimum of 5 minutes between 
dosing.
Statistical Methods
Primary Analysis
The primary efficacy objective for this study is to evaluate the efficacy of atezolizumab in 
combination with bevacizumab compared with sorafenib on the basis of the co-primary efficacy 
endpoints of OS and IRF-assessed PFS according to RECIST v1.1.
OS and PFS will be tested initially in parallel with the overall type I error controlled at a 
two-sided significance level of 0.05, where OS will be tested at a two-sided significance level of 
0.048 and PFS will be tested at a two-sided significance level of 0.002. 
Overall Survival 
OS is defined as the time from the date of randomization to the date of death from any cause.  
Patients who are alive at the time of the analysis data cutoff will be censored at the last date 
they were known to be alive.  Patients with no post-baseline information will be censored at the 
date of randomization. 
The two-sided log-rank test, stratified by geographic region (Asia excluding Japan vs. rest of 
world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and 
baseline AFP (400 vs. 400 ng/mL), will be used as the primary analysis to compare OS
between the two treatment arms.  The results from the unstratified log-rank test will also be 
provided as a sensitivity analysis to check the robustness of the results of the stratified log-rank 
test. 
The Kaplan-Meier method will be used to estimate median OS for each treatment arm.  
Brookmeyer-Crowley methodology will be used to calculate the 95% CI for the median OS for 
each treatment arm.  Stratified Cox proportional-hazards models will be used to estimate the 
HR and its 95% CIs.  The stratification factors will be the same as those used for the primary 
stratified log-rank test.  The unstratified HR will also be provided.
The final analysis of OS will occur after approximately 312 deaths have occurred.  
A group sequential design will be used for testing the co-primary efficacy endpoint OS to 
account for the conduct of two interim analyses.  An spending using the Lan-De Mets method 
approximating O'Brien-Fleming boundaries will be utilized to control the overall Type I error rate
of 0.048 for the OS co-primary efficacy endpoint.  The first interim OS analysis will be 


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36/Statistical Analysis Plan YO40245
conducted at time of the co-primary analysis of IRF-assessed PFS.  The second interim OS 
analysis will be conducted when approximately 243 OS events have been observed.
IRF-Assessed Progression-Free Survival
IRF-assessed PFS is defined as the time from randomization to the occurrence of disease 
progression as determined by IRF according to RECIST v1.1, or death from any cause, 
whichever occurs first.  Patients who have not experienced disease progression or death at the 
time of the clinical cutoff date will be censored at the time of the last tumor assessment on or 
prior to the clinical cutoff date.  Patients with no post-baseline tumor assessment will be 
censored at the date of randomization.
Methods for PFS analyses are similar to those described for the OS endpoint.
Determination of Sample Size  
A total of approximately 480 patients will be randomized in the global enrollment phase of this 
study, using a 2:1 randomization ratio to allocate patients to either the 
atezolizumab bevacizumab arm (Arm A) or the sorafenib arm (Arm B).  The final OS analysis
will be conducted at approximately 33 months after the first patient is randomized (first patient in 
[FPI]).
The co-primary efficacy endpoints for this study are as follows:

OS, defined as the time from randomization to death from any cause

IRF-assessed PFS, defined as the time from randomization to the occurrence of disease 
progression per RECIST v1.1 or death from any cause, whichever occurs first. 
The overall Type I error rate for this study will be controlled at a two-sided significance level of
0.05 by a graphical approach (i.e., alpha splitting and recycling).  The overall two-sided 
significance level of 0.05 will be split into a two-sided significance level of 0.048 for the testing 
of OS and a two-sided significance level of 0.002 for the testing of PFS as a first step.  
The sample size of the study was determined based on the number of deaths required to
demonstrate efficacy in terms of OS.  To detect an improvement in OS using a log-rank test at a 
two-sided significance level of 0.048, approximately 312 deaths will be required to achieve 80% 
overall power assuming a target HR of 0.71 (median OS improvement vs. control is 4.9 months). 
The minimum detectable difference (MDD) of OS is an HR of 0.783 (median OS improvement is 
3.3 months). This analysis is expected to occur approximately 33 months after FPI.
The calculation of sample size and estimates of the OS analysis timelines are based on the 
following assumptions:

Patients will be randomized to the atezolizumab bevacizumab and sorafenib arms in a 
2:1 ratio.

OS follows a one-piece exponential distribution.

The median OS in the control arm is 12 months.

The stopping boundaries of the interim and final analyses of OS use the O'Brien-Fleming 
boundaries approximated using the Lan-DeMets method.

The dropout rate is 5% for the atezolizumab bevacizumab arm and 10% for the sorafenib 
arm over 12 months for OS.

The recruitment of approximately 480 patients will take place over approximately 10 months
Interim Analysis
No interim analysis is planned for PFS in this study.
Two interim analyses of OS will be performed.  The first interim analysis will be performed at 
the time of the primary PFS analysis, estimated to occur at approximately 16 months after FPI.  
It is anticipated that at this time approximately 172 deaths will have been observed.  The 
respective MDD OS HR is 0.633 (median OS improvement is 6.9 months).  The second OS 
interim analysis is planned to be conducted when approximately 243 deaths are accumulated, 


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37/Statistical Analysis Plan YO40245
estimated to occur at approximately 24 months after FPI.  The respective MDD OS HR is 
0.728 (median OS improvement is 4.6 months).
To control the two-sided significance level at 0.048 for the interim and final OS analyses, the 
Lan-DeMets method will be used to approximate the O'Brien-Fleming boundaries.  
The planned interim analyses for OS will be conducted by the Sponsor.
Analysis 
Timing
Planned 
Information 
Fraction
Required 
Events/
Analysis timing
(estimated)
Stopping Boundary
(Two-Sided p-Value)
Alpha can be recycled 
to OS (i.e., OS 
alpha 0.05)
Alpha cannot be 
recycled to OS (i.e., 
OS alpha 0.048)
1st OS 
interim 
analysis
55%
172/16 months
MDD.HR 0.636
(p-value 0.005)
MDD.HR 0.633
(p-value 0.005)
2nd OS 
interim 
analysis
78%
243/24 months
MDD.HR 0.73
(p-value 0.021)
MDD.HR 0.728
(p-value 0.02)
OS final 
analysis
100%
312/33 months
MDD.HR 0.784
(p-value 0.043)
MDD.HR 0.783
(p-value 0.041)
HR hazard ratio; MDD minimum detectable difference; OS overall survival; 
PFS=progression-free survival.
Analysis timing shown in the table is projected based on protocol assumptions. Actual 
timing depends on the exact time that the required events have accrued.
The 1st OS interim analysis will be conducted when approximately 308 PFS events have 
happened.


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38/Statistical Analysis Plan YO40245
Appendix 2 Schedule of Activities
Assessment Window (Days) a
Screening b
Treatment Phase (Q3W)
Treatment 
Discontinuation c
Survival
Follow-
Up
–28 to –1
–7 to –1
Day 1 of Each Cycle c
30 Days after 
Last Dose
Signed Informed Consent Form(s) b
x
Review of eligibility criteria
x
Medical, surgical, and cancer 
histories, including demographic 
information d
x
Complete physical examination e
x
Limited physical examination f
x g
x
ECOG Performance Status
x
x g
x
Patient-reported outcomes h
x g
x
x h
Tumor assessment i
x
See footnote i
x
x
Vital signs j
x
x
x
Weight
x
x k
x
Height
x
12-lead ECG l
x
Perform as clinically indicated
EGD m
x
Hematology n, z
x
x g
x
Serum chemistry o, z
x
x g
x
HIV, HBV, HCV serology p
x


Atezolizumab—F. Hoffmann-La Roche Ltd
39/Statistical Analysis Plan YO40245
Appendix 2 Schedule of Activities (cont.)
Assessment Window (Days) a
Screening b
Treatment Phase (Q3W)
Treatment 
Discontinuation c
Survival
Follow-
Up
–28 to –1
–7 to –1
Day 1 of Each Cycle c
30 Days after 
Last Dose
Quantitative HBsAg, HBV DNA, HCV 
RNA q
x
x
x
-fetoprotein 
x
x
x
Coagulation panel (aPTT, INR) z
x
x g
x
Urinalysis r, z
x
x g
x
TSH, free T3, free T4
x
Cycles 5, 9, 13, etc. (every 4 cycles) 
x
Pregnancy test
x s
x t
x
Serum PK sample
See Appendix 3
Serum ADA sample
See Appendix 3
Pharmacodynamic samples for 
biomarkers
See Appendix 3
x
Plasma sample for RBR (optional)
Any time (at investigator's discretion)
Archival tumor tissue sample (or 
optional fresh biopsy if archival tissue 
is not available) for biomarkers
x
Concomitant medications u
x
x
x
Adverse events v
x
x
x
Study treatment infusion w
x
Sorafenib dispensing x
x
Survival and anti-cancer therapy 
follow-up y
x


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40/Statistical Analysis Plan YO40245
Appendix 2 Schedule of Activities (cont.)
ADAanti-drug antibody; CTcomputed tomography; EGDesophagogastroduodenscopy; EORTCEuropean Organisation for Research and 
Treatment of Cancer; EQ-5D-5LEuroQol 5-Dimension Questionnaire, 5-level version; HBcAbhepatitis B core antibody; HBsAbhepatitis B 
surface antibody; HBsAghepatitis B surface antigen; HBVhepatitis B virus; HCVhepatitis C virus; imRECIST immune-modified RECIST; 
MRImagnetic resonance imaging; PET positron emission tomography; PKpharmacokinetic; PROpatient-reported outcome; Q3W every 3 
weeks; QLQ-C30quality-of-life questionnaire for cancer; QLQ-HCC18HCC disease-specific module; RBRResearch Biosample Repository; 
RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1; T3triiodothyronine; T4thyroxine; TSHthyroid-stimulating 
hormone.
Note:  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.
a
The first dosing date (Cycle 1, Day 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.  All visits and infusions thereafter may be administered with a window of 3 days.
b
Written informed consent can be obtained up to 30 days prior to study entry 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 protocol relevant 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.
c
Patients will be asked to return to the clinic 30 days after the last dose of study treatment for an end-of-treatment visit.  After this visit, serious 
adverse events and protocol defined adverse events of special interest, regardless of attribution, will be recorded until 90 days after the last dose 
of study treatment or until initiation of another anti-cancer therapy, whichever occurs first.  Ongoing adverse events thought to be related to study 
treatment will be followed until the event has resolved to baseline grade or better, the event is assessed by the investigator as stable, new anti-
cancer treatment is initiated, the patient is lost to follow-up, the patient withdraws consent, or it is determined that the study treatment or 
participation is not the cause of the adverse event.  Scans performed within 6 weeks prior to the treatment discontinuation visit do not need to be 
repeated.
d
Cancer history includes stage, date of diagnosis, and prior anti-tumor treatment.  Demographic information includes age and self-reported 
race/ethnicity.  Reproductive status and smoking history should also be captured.
e
A complete physical examination at screening should include the evaluation of head, eye, ear, nose, and throat and cardiovascular, 
dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  Changes in abnormalities noted at baseline 
should be recorded at the end of the visit.  New or worsened abnormalities should be recorded as adverse events if appropriate.
f
A limited physical examination will be performed at other visits to assess changes from baseline abnormalities and any new abnormalities and to 
evaluate patient reported symptoms.  New or worsened abnormalities should be recorded as adverse events if appropriate.


Atezolizumab—F. Hoffmann-La Roche Ltd
41/Statistical Analysis Plan YO40245
Appendix 2 Schedule of Activities (cont.)
g
ECOG Performance Status, limited physical examination, local laboratory assessments, and PROs may be obtained 96 hours before Day 1 of 
each cycle.
h
The EORTC QLQ-C30, EORTC QLQ-HCC18, and EQ-5D-5L questionnaires will be completed by all patients on paper starting on Day 1 of 
Cycle 1 and Day 1 of every cycle thereafter.  All PRO questionnaires scheduled for administration during a clinic visit are required to be 
completed by the patient at the investigational site at the start of the clinic visit before discussion of the patient's health state, lab results or health 
record, before administration of study treatment, and/or prior to any other study assessment(s).  This is to avoid any potential bias to patients’ 
responses to ensure that the validity of the instrument is not compromised and that data quality meets regulatory requirements.  Interview 
assessment by a member of the clinic staff will be allowed if the patient is not able to complete the measure on their own.  Study personnel 
should review all questionnaires for completeness before the patient leaves the investigational site.  During survival follow-up, all PRO 
questionnaires will be completed every 3 months (for 1 year), unless the patient withdraws consent or the Sponsor terminates the study.  PRO 
questionnaires during the survival follow-up period may be completed at the investigational site should the patient come in for a clinic visit or be 
administered via interview in telephone calls.
i
All measurable and evaluable lesions should be assessed and documented at the screening visit.  Radiologic imaging performed during the 
screening period should consist of 1) CT and/or MRI of the chest/abdomen/pelvis and brain, 2) bone scan or PET scan as clinically indicated, 
and 3) any other imaging studies (CT scan of the neck, plain films, etc.) as clinically indicated by the treating physician.  The same radiographic 
procedures and technique must be used throughout the study for each patient (e.g., if the patient had CT chest/abdomen/pelvis performed 
during screening, then 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.  Tumor assessments will be performed at baseline, every 6
weeks (1 week) for the first 54 weeks following the initiation of study treatment, and every 9 weeks (1 week) thereafter, with additional scans 
as clinically indicated.  All known sites of disease documented at screening should be re-assessed at each subsequent tumor evaluation.  Tumor 
response will be evaluated by the investigator using RECIST Version 1.1 and imRECIST.  In the absence of disease progression, tumor 
assessments should continue regardless of whether patients discontinue study treatment or start new anti-cancer treatment, unless the patient 
dies, withdraws consent, or the study is terminated by the Sponsor, whichever occurs first. 
j
Vital signs include heart rate, respiratory rate, blood pressure, and temperature.  For patients randomized to Arm A, on days of study treatment 
administration (atezolizumab and bevacizumab), the patient's vital signs should be determined up to 60 minutes before all infusions.  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 after every 
infusion of atezolizumab if clinically indicated.
k
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 baseline.  If re-baseline is needed the 
latest baseline weight should always be used to calculate percent change in weight for all subsequent doses.   
l
Patients should be resting and in a supine position for at least 10 minutes prior to each ECG collection.


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42/Statistical Analysis Plan YO40245
Appendix 2 Schedule of Activities (cont.)
m
All patients must undergo an EGD and all size of varices (small to large) must be assessed and treated per local standard of care prior to 
enrollment.
n
Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with differential (neutrophils, eosinophils, lymphocytes, 
monocytes, basophils, and other cells), and platelet count.  A manual differential can be done if clinically indicated.  
o
Serum chemistry includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, potassium, magnesium, 
chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, alkaline phosphatase, ALT, AST, and LDH.  
p
All patients will be tested for HIV locally prior to the inclusion into the study and if not in contradiction with local legislation; HIV-positive patients 
will be excluded from the clinical study.  HBsAg, HBcAb, and HBsAb should be collected during screening and tested locally.  HBV DNA must be 
collected prior to Cycle 1, Day 1 in patients who have negative serology for HBsAg and positive serology for anti HBcAb.
q
Only if patient tests positive for HBsAg, HBcAb, quantitative HBsAg and HBV DNA will be tested during screening; Cycle 5, Day 1; Cycle 9,
Day 1; and at treatment discontinuation.  Quantitative HBsAg will be tested by central laboratory.  If a patient tests positive for HCV antibody at 
screening, quantitative HCV RNA must be tested locally at screening, Cycle 5 Day 1, Cycle 9 Day 1, and at treatment discontinuation.
r
Urine dipstick includes specific gravity, pH, glucose, protein, ketones, and blood and should be repeated before every cycle during treatment.  
Urine dipstick for proteinuria must be 2+ within 7 days prior to initiation of study treatment.  Patients discovered to have 2+ proteinuria on 
dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate 1 g of protein in 24 hours.  
s
Serum pregnancy test within 14 days before Cycle 1, Day 1.
t
Urine pregnancy test; if a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.
u
Concomitant medications include any prescription medications or over-the-counter medications.  At screening, any medications the patient has 
used within the 7 days prior to initiation of study treatment should be documented.  At subsequent visits, changes to current medications or 
medications used since the last documentation of medications will be recorded.
v
After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 30 days after the last dose of study 
treatment or until initiation of another anti-cancer therapy, whichever occurs first.  Serious adverse events and adverse events of special interest 
will continue to be reported until 90 days after the last dose of study treatment or until initiation of new anti-cancer therapy, whichever occurs first.  
After this period, investigators should report any serious adverse events and adverse events of special interest that are believed to be related to 
prior treatment with study drug.  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, new anti-cancer treatment is initiated, the patient is lost to follow-up, the patient withdraws 
consent, or it is determined that the study treatment or participation is not the cause of the adverse event.  Every effort should be made to follow 
all serious adverse events considered to be related to study drug or study-related procedures until a final outcome can be reported.


Atezolizumab—F. Hoffmann-La Roche Ltd
43/Statistical Analysis Plan YO40245
Appendix 2 Schedule of Activities (cont.)
w
The initial dose of atezolizumab will be delivered over 60 (15) minutes.  If the first infusion is tolerated without infusion-associated adverse 
events, the second infusion may be delivered over 30 (10) minutes.  If the 30-minute infusion is well tolerated, all subsequent infusions may be 
delivered over 30 (10) minutes.  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.  If the 60-minute infusion is well 
tolerated, all subsequent infusions may be delivered over 30 (10) minutes.  For patients randomized to Arm A, atezolizumab will be 
administered first followed by bevacizumab, with a minimum of 5 minutes between dosing.  In the absence of unacceptable toxicity, patients may 
continue study treatment until there is evidence of disease progression or lack of clinical benefit.  
x
Sorafenib is taken by mouth twice a day continuously.
y
Survival follow-up information will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months 
(21 days) until death, loss to follow-up, or until study termination by the Sponsor.  All patients will be followed for survival and new anti-cancer 
therapy (including targeted therapy and immunotherapy) information unless the patient requests to be withdrawn from follow-up; this request 
must be documented in the source documents and signed by the investigator.  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.
z
Local laboratory assessments from each cycle must be reviewed prior to study treatment administration for each cycle.


Atezolizumab—F. Hoffmann-La Roche Ltd
44/Statistical Analysis Plan YO40245
Appendix 3
Schedule of Biomarker, Pharmacokinetic, and Immunogenicity Samples 
Visit
Timepoint
Sample Type
Day 1 of Cycle 1
Prior to any drug 
administration

Atezolizumab PK (serum) a

Atezolizumab ADA (serum) a

Biomarker (plasma, serum)b
30 min after end of 
atezolizumab infusion

Atezolizumab PK (serum) a
Day 1 of Cycle 2
Prior to any drug 
administration

Atezolizumab PK (serum) a

Atezolizumab ADA (serum) a

Biomarker (plasma, serum) b
Day 1 of Cycle 3, Cycle 8, 
Cycle 12, Cycle 16
Prior to any drug 
administration

Atezolizumab PK (serum) a

Atezolizumab ADA (serum) a
Day 1 of Cycle 4
Prior to any drug 
administration

Atezolizumab PK (serum) a

Atezolizumab ADA (serum) a

Biomarker (plasma, serum) b
Treatment discontinuation 
visit (30 days after last 
dose)
At visit

Atezolizumab PK (serum) a

Atezolizumab ADA (serum) a

Biomarker (plasma, serum)
a For Arm A only.
b Biomarker samples must be collected for both arms before dosing.  For Arm B: If the patient takes the morning dose before coming to the 
visit, samples should be taken before the evening dose.