Conditions: Renal Cell Carcinoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 915
Healthy volunteers: no

Brief summary:
This multi-center, randomized, open-label study will evaluate the efficacy and safety of atezolizumab plus bevacizumab versus sunitinib in participants with inoperable, locally advanced, or metastatic RCC who have not received prior systemic active or experimental therapy, either in the adjuvant or metastatic setting.

Detailed description:

Arms:
arm 1: Participants will receive both atezolizumab and bevacizumab until loss of clinical benefit, unacceptable toxicity or symptomatic deterioration attributed to disease progression, withdrawal of consent, or death, whichever occurs first. arm 2: Participants will receive sunitinib until loss of clinical benefit, unacceptable toxicity or symptomatic deterioration attributed to disease progression, withdrawal of consent, or death, whichever occurs first.

Interventions: intervention 1: Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody intervention 2: Bevacizumab intervention 3: Sunitinib
Intervention descriptions: intervention 1: Atezolizumab will be administered at a fixed dose of 1200 milligrams (mg) via intravenous (IV) infusion on Days 1 and 22 of each 42-day cycle. intervention 2: Bevacizumab will be administered at a dose of 15 milligrams per kilogram (mg/kg) via IV infusion on Days 1 and 22 of each 42-day cycle. intervention 3: Sunitinib will be administered at a dose of 50 mg once daily, orally via capsule, on Day 1 through Day 28 of each 42-day cycle.

Protocol document:
Prot_SAP_000.pdf: 
 
Official Title: 
A PHASE III, OPEN-LABEL, RANDOMIZED STUDY 
OF ATEZOLIZUMAB (ANTIPD-L1 ANTIBODY) IN 
COMBINATION WITH BEVACIZUMAB VERSUS 
SUNITINIB IN PATIENTS WITH UNTREATED ADVANCED 
RENAL CELL CARCINOMA 
NCT Number: 
NCT02420821 
Document Date(s): 
Protocol Version 7: 03-April-2018  
SAP Version 2: 04-April-2018 
 
 


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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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 WO29637, Version 7
PROTOCOL
TITLE:
A PHASE III, OPEN-LABEL, RANDOMIZED STUDY 
OF ATEZOLIZUMAB (ANTIPD-L1 ANTIBODY) IN 
COMBINATION WITH BEVACIZUMAB VERSUS 
SUNITINIB IN PATIENTS WITH UNTREATED 
ADVANCED RENAL CELL CARCINOMA
PROTOCOL NUMBER:
WO29637
VERSION NUMBER:
7
EUDRACT NUMBER:
2014-004684-20
IND NUMBER:
119039
TEST PRODUCT:
Atezolizumab (RO5541267)
MEDICAL MONITOR:
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
24 December 2014
DATES AMENDED:
Version 2:  10 January 2015
Version 3:  8 May 2015
Version 4:  10 October 2015
Version 5:  10 December 2015
Version 6:  14 July 2016
Version 7:  See electronic date stamp below.
 
03-Apr-2018 15:31:43
Title
Approver's Name
Company Signatory
Date and Time (UTC)




AtezolizumabF. Hoffmann-La Roche Ltd
3/Protocol WO29637, Version 7
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 12
PROTOCOL SYNOPSIS .................................................................................... 13
1.
BACKGROUND .......................................................................................... 27
1.1
Background on Renal Cell Carcinoma................................... 27
1.1.1
First-Line Treatment for Renal Cell Carcinoma ..................... 27
1.1.1.1
Anti-VEGF Therapies in Renal Cell Carcinoma..................... 27
1.1.1.2
Immune-Based Therapy in Renal Cell Carcinoma................. 29
1.2
Background on PD-L1 Biology and Atezolizumab ................. 30
1.3
Rationale for Testing Atezolizumab and the 
Combination Atezolizumab Bevacizumab........................... 30
1.4
Clinical Experience with Atezolizumab in Renal 
Cell Carcinoma...................................................................... 31
1.4.1
Phase Ia Study PCD4989g.................................................... 31
1.4.1.1
Safety Analysis of Study PCD4989g ..................................... 31
1.4.1.2
Phase Ib Study GP28328 ...................................................... 36
1.4.1.3
Clinical Activity in Renal Cell Carcinoma in Arm A 
of Study GP28328 ................................................................. 39
1.4.2
Phase II Study WO29074 ...................................................... 41
1.5
Study Rationale and Benefit-Risk Assessment...................... 41
2.
OBJECTIVES.............................................................................................. 43
2.1
Efficacy Objectives ................................................................ 43
2.1.1
Primary Efficacy Objective..................................................... 44
2.1.2
Secondary Efficacy Objectives .............................................. 44
2.2
Safety Objectives................................................................... 44
2.3
Pharmacokinetic Objectives .................................................. 45
2.4
Patient-Reported Outcome Objectives .................................. 45
2.5
Exploratory Objectives........................................................... 45
3.
STUDY DESIGN......................................................................................... 45
3.1
Description of Study .............................................................. 45
3.1.1
Independent Data Monitoring Committee .............................. 49
3.2
End of Study.......................................................................... 50


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3.3
Rationale for Study Design.................................................... 50
3.3.1
Rationale for Primary and Secondary Endpoints................... 50
3.3.2
Rationale for Inclusion of All Patients (All Levels 
of PD-L1 Expression by Immunohistochemistry) 
in the Study............................................................................ 51
3.3.3
Rationale for Stratification Factors......................................... 51
3.3.4
Rationale for Evaluating Atezolizumab in Renal 
Cell Carcinoma...................................................................... 51
3.3.5
Rationale for Testing 
Atezolizumab Bevacizumab in Renal Cell 
Carcinoma ............................................................................. 52
3.3.6
Rationale for Atezolizumab Dose and Schedule.................... 52
3.3.7
Rationale to Allow Dosing PostRECIST v1.1 
Progression and Use of Modified RECIST............................. 53
3.3.8
Rationale for Pharmacokinetic Evaluation 
Schedule................................................................................ 54
3.3.9
Rationale for Blood Sampling for Biomarkers........................ 54
3.3.10
Rationale for the Collection of Archival and/or 
Fresh Tumor Specimens ....................................................... 55
3.3.11
Rationale for the Collection of Tumor Specimens 
at the Time of Initial Radiological Progression....................... 55
3.3.12
Rationale for Comparator Arm............................................... 56
3.3.13
Rationale for Patient-Reported Outcomes............................. 57
3.3.14
Rationale for Open-Label Design .......................................... 58
3.4
Outcome Measures ............................................................... 58
3.4.1
Efficacy Outcome Measures.................................................. 58
3.4.2
Safety Outcome Measures .................................................... 58
3.4.3
Pharmacokinetic Outcome Measures.................................... 59
3.4.4
Patient-Reported Outcome Measures ................................... 59
3.4.5
Exploratory Outcome Measures ............................................ 59
4.
MATERIALS AND METHODS .................................................................... 59
4.1
Patients.................................................................................. 59
4.1.1
Inclusion Criteria.................................................................... 59
4.1.2
Exclusion Criteria................................................................... 62
4.1.2.1
Disease-Specific Exclusions.................................................. 62


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4.1.2.2
General Medical Exclusions .................................................. 63
4.1.2.3
Exclusion Criteria Related to Medications ............................. 65
4.1.2.4
Bevacizumab- and Sunitinib-Specific Exclusions .................. 65
4.2
Method of Treatment Assignment and Blinding..................... 66
4.3
Study Treatment.................................................................... 67
4.3.1
Formulation, Packaging, and Handling.................................. 67
4.3.1.1
Atezolizumab......................................................................... 67
4.3.1.2
Bevacizumab......................................................................... 67
4.3.1.3
Sunitinib................................................................................. 67
4.3.2
Dosage, Administration, and Compliance.............................. 68
4.3.2.1
Atezolizumab......................................................................... 68
4.3.2.2
Bevacizumab......................................................................... 70
4.3.2.3
Sunitinib................................................................................. 70
4.3.3
Investigational Medicinal Product Accountability ................... 71
4.3.4
Post-Study Access to Atezolizumab ...................................... 71
4.4
Concomitant Therapy ............................................................ 72
4.4.1
Permitted Therapy................................................................. 72
4.4.2
Cautionary Therapy for Atezolizumab-Treated 
Patients.................................................................................. 73
4.4.3
Excluded Therapy.................................................................. 73
4.4.3.1
Excluded and Cautionary Therapy for 
Atezolizumab-Treated Patients.............................................. 73
4.5
Study Assessments ............................................................... 74
4.5.1
Informed Consent Forms and Screening Log........................ 74
4.5.2
Medical History and Demographic Data ................................ 74
4.5.3
Physical Examinations........................................................... 75
4.5.4
Vital Signs.............................................................................. 75
4.5.5
Tumor and Response Evaluations......................................... 75
4.5.6
Patient-Reported Outcomes .................................................. 77
4.5.7
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 78
4.5.8
Cardiac Tests ........................................................................ 81


AtezolizumabF. Hoffmann-La Roche Ltd
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4.5.8.1
Electrocardiograms and Evaluations of Left 
Ventricular Ejection Fraction (Echocardiograms 
or MUGA) .............................................................................. 81
4.5.9
Anti-Therapeutic Antibody Testing......................................... 82
4.5.10
Assessments during Treatment............................................. 82
4.5.11
End of Treatment Visit ........................................................... 83
4.5.12
Follow-Up Assessments ........................................................ 83
4.5.12.1
Ongoing Tumor Assessments ............................................... 83
4.5.12.2
Survival Follow-Up................................................................. 83
4.5.12.3
Adverse Events ..................................................................... 83
4.5.13
Samples for Roche Clinical Repository.................................. 84
4.5.13.1
Overview of the Roche Clinical Repository............................ 84
4.5.13.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 84
4.5.13.3
Sample Collection.................................................................. 85
4.5.13.4
Confidentiality........................................................................ 85
4.5.13.5
Consent to Participate in the Roche Clinical 
Repository ............................................................................. 86
4.5.13.6
Withdrawal from the Roche Clinical Repository..................... 86
4.5.13.7
Monitoring and Oversight....................................................... 86
4.6
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 87
4.6.1
Patient Discontinuation.......................................................... 87
4.6.2
Study Treatment Discontinuation........................................... 87
4.6.3
Study and Site Discontinuation.............................................. 90
5.
ASSESSMENT OF SAFETY....................................................................... 90
5.1
Safety Plan ............................................................................ 90
5.1.1
Risks Associated with Atezolizumab ..................................... 91
5.1.2
General Plan to Manage Safety Concerns ............................ 91
5.1.2.1
Eligibility Criteria .................................................................... 91
5.1.2.2
Monitoring.............................................................................. 91
5.1.3
Atezolizumab Dose ModificationGeneral Notes................... 92
5.1.4
Management of Atezolizumab-Specific Adverse 
Events.................................................................................... 92


AtezolizumabF. Hoffmann-La Roche Ltd
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5.1.4.1
Immune-Mediated Reactions................................................. 92
5.1.4.2
Systemic Immune Activation.................................................. 93
5.1.5
Bevacizumab Dose and Dose Interval 
Modification ........................................................................... 94
5.1.6
Sunitinib Dose and Dose Interval Modification ...................... 94
5.1.7
Recommended Guidelines for Management of 
Suspected Bevacizumab or Sunitinib Toxicities .................... 95
5.1.8
Sunitinib- and Bevacizumab-Related Cardiac 
Toxicities................................................................................ 99
5.2
Safety Parameters and Definitions ...................................... 100
5.2.1
Adverse Events ................................................................... 101
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 101
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................. 102
5.2.4
Selected Adverse Events..................................................... 103
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 103
5.3.1
Adverse Event Reporting Period ......................................... 103
5.3.2
Eliciting Adverse Event Information..................................... 104
5.3.3
Assessment of Adverse Events........................................... 104
5.3.4
Assessment of Causality of Adverse Events ....................... 105
5.3.5
Procedures for Recording Adverse Events.......................... 105
5.3.5.1
Diagnosis versus Signs and Symptoms............................... 106
5.3.5.2
Infusion-Related Reactions.................................................. 106
5.3.5.3
Adverse Events Occurring Secondary to Other 
Events.................................................................................. 106
5.3.5.4
Persistent or Recurrent Adverse Events.............................. 106
5.3.5.5
Abnormal Laboratory Values ............................................... 107
5.3.5.6
Abnormal Liver Function Tests............................................ 108
5.3.5.7
Abnormal Vital Sign Values ................................................. 108
5.3.5.8
Deaths ................................................................................. 109
5.3.5.9
Preexisting Medical Conditions............................................ 109
5.3.5.10
Worsening of Renal Cell Carcinoma.................................... 109
5.3.5.11
Hospitalization or Prolonged Hospitalization........................ 110


AtezolizumabF. Hoffmann-La Roche Ltd
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5.3.5.12
Adverse Events Associated with an Overdose or
Error in Drug Administration ................................................ 110
5.3.5.13
Adverse Events in Individuals Not Enrolled in the 
Study ................................................................................... 110
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 111
5.4.1
Emergency Medical Contacts.............................................. 111
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 111
5.4.2.1
Events That Occur prior to Study Drug Initiation.................. 111
5.4.2.2
Events That Occur after Study Drug Initiation...................... 112
5.4.3
Reporting Requirements for Pregnancies............................ 112
5.4.3.1
Pregnancies in Female Patients.......................................... 112
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 113
5.4.3.3
Abortions ............................................................................. 113
5.4.3.4
Congenital Anomalies/Birth Defects and 
Abortions ............................................................................. 113
5.5
Follow-Up of Patients after Adverse Events ........................ 113
5.5.1
Investigator Follow-Up......................................................... 113
5.5.2
Sponsor Follow-Up .............................................................. 114
5.6
Post-Study Adverse Events................................................. 114
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees........................................................ 114
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 115
6.1
Determination of Sample Size ............................................. 115
6.1.1
Type I Error Control............................................................. 115
6.1.2
Co-Primary Endpoint:  Progression-Free Survival 
in the PD-L1Selected Population....................................... 117
6.1.3
Co-Primary Endpoint:  Overall Survival in the ITT 
Population............................................................................ 117
6.2
Summaries of Conduct of Study.......................................... 118
6.3
Summaries of Treatment Group Comparability ................... 118
6.4
Efficacy Analyses ................................................................ 119
6.4.1
Co-Primary Efficacy Endpoints............................................ 119


AtezolizumabF. Hoffmann-La Roche Ltd
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6.4.2
Secondary Efficacy Endpoints............................................. 120
6.4.2.1
Progression-Free Survival ................................................... 121
6.4.2.2
Objective Response Rate.................................................... 121
6.4.2.3
Duration of Response.......................................................... 122
6.4.2.4
Change from Baseline in Symptoms Interference ............... 122
6.4.3
Handling of Missing Data..................................................... 122
6.5
Safety Analyses................................................................... 123
6.6
Pharmacokinetic Analyses................................................... 123
6.7
Patient-Reported Outcome Analyses .................................. 124
6.7.1
MDASI, and BFI, and FKSI-19............................................. 124
6.7.2
Health Economic Data......................................................... 124
6.8
Exploratory Analyses........................................................... 124
6.8.1
Analyses at Landmark Time Points ..................................... 124
6.8.2
Subgroup Analyses ............................................................. 124
6.8.3
Biomarker Analyses............................................................. 125
6.9
Interim Analyses .................................................................. 125
6.9.1
Progression-Free Survival ................................................... 125
6.9.2
Overall Survival ................................................................... 125
6.9.3
Optional Interim Analysis..................................................... 127
7.
DATA COLLECTION AND MANAGEMENT ............................................. 128
7.1
Data Quality Assurance....................................................... 128
7.2
Electronic Case Report Forms............................................. 128
7.3
Source Data Documentation................................................ 128
7.4
Use of Computerized Systems ............................................ 129
7.5
Retention of Records........................................................... 129
8.
ETHICAL CONSIDERATIONS.................................................................. 129
8.1
Compliance with Laws and Regulations .............................. 129
8.2
Informed Consent................................................................ 130
8.3
Institutional Review Board or Ethics Committee.................. 131
8.4
Confidentiality...................................................................... 131
8.5
Financial Disclosure ............................................................ 132


AtezolizumabF. Hoffmann-La Roche Ltd
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9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 132
9.1
Study Documentation .......................................................... 132
9.2
Protocol Deviations.............................................................. 132
9.3
Site Inspections ................................................................... 132
9.4
Administrative Structure....................................................... 132
9.5
Publication of Data and Protection of Trade 
Secrets ................................................................................ 133
9.6
Protocol Amendments ......................................................... 134
10. REFERENCES ......................................................................................... 135
LIST OF TABLES
Table 1
Approved First-Line Targeted Therapies for Advanced Renal 
Cell Carcinoma ........................................................................... 28
Table 2
Efficacy of Bevacizumab Monotherapy in Renal Cell 
Carcinoma................................................................................... 29
Table 3
Adverse Events in ≥10% of Atezolizumab-Treated Patients in 
the Renal Cell Carcinoma Cohort of Study PCD4989g............... 33
Table 4
Grade 35 Adverse Events Reported in 2 or More Patients:  
Atezolizumab-Treated Renal Cell Carcinoma Cohort in 
Study PCD4989g ........................................................................ 34
Table 5
Criteria for PD-L1 Expression ..................................................... 35
Table 6
Efficacy in Patients with Clear-Cell Renal Cell Carcinoma in 
Study PCD4989g:  Best Overall Response Rate and 24-
Week PFS Rate by PD-L1 Expression (n 62) .......................... 36
Table 7
All Reported Adverse Events in Arm A of Study GP28328 ......... 37
Table 8
All Reported Adverse Events in ≥10% Patients in Arm A of 
Study GP28328........................................................................... 38
Table 9
Grade ≥3 Toxicities and Discontinuations of First-Line Renal 
Cell Carcinoma Agents ............................................................... 42
Table 10
Administration of First and Subsequent Infusions 
of Atezolizumab .......................................................................... 69
Table 11
Bevacizumab and Sunitinib Dose Management for Adverse 
Events......................................................................................... 96
Table 12
Adverse Event Severity Grading Scale ..................................... 104
Table 13
Causal Attribution Guidance ..................................................... 105
Table 14
Interim and Final OS Analyses for the ITT Population .............. 126


AtezolizumabF. Hoffmann-La Roche Ltd
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LIST OF FIGURES
Figure 1
Best Change from Baseline in SLD per RECIST v1.1:  
Unconfirmed Best Response in Efficacy-Evaluable Arm A 
Patients in Study GP28328 with First-Line Clear-Cell Renal 
Cell Carcinoma ........................................................................... 40
Figure 2
Tumor Burden over Time by Investigator-Assessed 
Unconfirmed Response and Corresponding PD-L1 IC Status .... 41
Figure 3
Study Schema............................................................................. 46
Figure 4
Conditions for Continuing Atezolizumab/Bevacizumab or 
Sunitinib in the Presence of Progression by RECIST v1.1 
Criteria ........................................................................................ 89
Figure 5
PFS and OS Analysis Hierarchy, Alpha Allocation and Alpha 
Recycling .................................................................................. 116
LIST OF APPENDICES
Appendix 1
Schedule of Assessments........................................................ 141
Appendix 2
Anti-Therapeutic Antibody, TBNK, Biomarker, 
and Pharmacokinetic Sampling Schedule................................ 148
Appendix 3
Response Evaluation Criteria in Solid Tumors:   Version 1.1... 150
Appendix 4
Modified Response Evaluation Criteria in Solid Tumors .......... 161
Appendix 5
Karnofsky Performance Score ................................................. 169
Appendix 6
Preexisting Autoimmune Diseases .......................................... 170
Appendix 7
New York Heart Association Functional Classification............. 171
Appendix 8
Biopsy Procedure..................................................................... 172
Appendix 9
MSKCC (Motzer) Criteria ......................................................... 173
Appendix 10
Anaphylaxis Precautions.......................................................... 174
Appendix 11
M.D. Anderson Symptom Inventory ......................................... 175
Appendix 12
Brief Fatigue Inventory............................................................. 177
Appendix 13
National Comprehensive Cancer Network Functional 
Assessment of Cancer Therapy Kidney Symptom Index-19..... 178
Appendix 14
EQ-5D-3L Health Questionnaire .............................................. 179
Appendix 15
Definition of Sarcomatoid Renal Cell Carcinoma:  Modified 
Stanford Surgical Pathology Criteria......................................... 182
Appendix 16
Common CYP3A4 Inducers..................................................... 183
Appendix 17
Common Drugs Which May Increase QTc Interval.................. 184


AtezolizumabF. Hoffmann-La Roche Ltd
12/Protocol WO29637, Version 7
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE III, OPEN-LABEL, RANDOMIZED STUDY 
OF ATEZOLIZUMAB (ANTIPD-L1 ANTIBODY) IN 
COMBINATION WITH BEVACIZUMAB VERSUS 
SUNITINIB IN PATIENTS WITH UNTREATED 
ADVANCED RENAL CELL CARCINOMA
PROTOCOL NUMBER:
WO29637
VERSION NUMBER:
7
EUDRACT NUMBER:
2014-004684-20
IND NUMBER:
119039
TEST PRODUCT:
Atezolizumab (RO5541267)
MEDICAL MONITOR:
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 the 
signed original of this form as instructed by F. Hoffmann-La Roche Ltd.


AtezolizumabF. Hoffmann-La Roche Ltd
13/Protocol WO29637, Version 7
PROTOCOL SYNOPSIS
TITLE:
A PHASE III, OPEN-LABEL, RANDOMIZED STUDY OF 
ATEZOLIZUMAB (ANTIPD-L1 ANTIBODY) IN COMBINATION 
WITH BEVACIZUMAB VERSUS SUNITINIB IN PATIENTS WITH 
UNTREATED ADVANCED RENAL CELL CARCINOMA
PROTOCOL NUMBER:
WO29637
VERSION NUMBER:
7
EUDRACT NUMBER:
2014-004684-20
IND NUMBER:
119039
TEST PRODUCT:
Atezolizumab (RO5541267)
PHASE:
Phase III
INDICATION:
Renal cell carcinoma
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
Analyses of the following objectives will be performed for the population of patients with 
inoperable, locally advanced, or metastatic renal cell carcinoma (RCC), unless otherwise 
indicated.  Where specified, a comparison of the treatment arms will be performed in the patient 
population defined according to tumor programmed deathligand 1 (PD-L1) expression as 
evaluated by immunohistochemistry (IHC).
Efficacy Objectives
The primary and secondary efficacy objectives will be evaluated in the PD-L1selected 
population (tumor-infiltrating immune cell [IC]1/2/3) as well as in the intent-to-treat (ITT) 
population (includes all IC scores).
The primary efficacy objective of the study is as follows:

To evaluate the efficacy of atezolizumab bevacizumab compared with sunitinib as 
measured by the co-primary endpoints of investigator-assessed progression-free survival 
(PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and overall 
survival (OS).
The secondary efficacy objectives for this study are as follows:

To evaluate the efficacy of atezolizumab bevacizumab versus sunitinib as measured by 
Independent Review Committee (IRC)assessed PFS according to RECIST v1.1

To evaluate the efficacy of atezolizumab bevacizumab versus sunitinib as measured by 
investigator-assessed objective response rate (ORR) (complete partial response rates) per 
RECIST v1.1

To evaluate the efficacy of atezolizumab bevacizumab versus sunitinib as measured by 
investigator-assessed duration of response (DOR) among patients with an objective 
response per RECIST v1.1

To evaluate the efficacy of atezolizumab bevacizumab versus sunitinib as measured by 
IRC-assessed ORR and DOR according to RECIST v1.1

To evaluate the efficacy of atezolizumab bevacizumab versus sunitinib as measured by 
investigator-assessed PFS, DOR, and ORR per modified RECIST


AtezolizumabF. Hoffmann-La Roche Ltd
14/Protocol WO29637, Version 7

To evaluate the efficacy of atezolizumab bevacizumab versus sunitinib among patients 
with sarcomatoid histology (defined by investigator-assessed conventional histopathology) 
as measured by investigator assessed PFS per RECIST v1.1 and OS

To evaluate the efficacy of atezolizumab bevacizumab versus sunitinib on symptom 
interference as measured by the M.D. Anderson Symptom Inventory [MDASI Part II])
Safety Objectives
The safety objectives for this study are as follows:

To evaluate the safety and tolerability of atezolizumab bevacizumab versus sunitinib

To evaluate the incidence of anti-therapeutic antibodies (ATAs) against atezolizumab and to 
explore the potential relationship of immunogenicity response with pharmacokinetics, safety, 
and efficacy
Pharmacokinetic Objectives
The pharmacokinetic objectives for this study are as follows:

To characterize the pharmacokinetics of atezolizumab when administered in combination 
with bevacizumab

To characterize the pharmacokinetics of bevacizumab when administered in combination 
with atezolizumab
Patient-Reported Outcome Objectives
The additional patient-reported outcome (PRO) objectives of the study are as follows:

To assess symptom severity associated with atezolizumab bevacizumab versus sunitinib 
in patients with RCC as measured by the MDASI and Brief Fatigue Inventory (BFI)

To document patients’ perspective regarding the tolerability of the treatments (from the 
treatment side-effects subscale from the Functional Assessment of Cancer Therapy Kidney 
Symptom Index [FKSI-19])

To obtain general measures of health as measured by the EuroQoL 5 Dimensions (EQ-5D) 
questionnaire for health economic modeling of atezolizumab bevacizumab versus sunitinib 
in patients with RCC
Exploratory Objectives
The exploratory objectives for this study are as follows:

To evaluate the relationship between the expression of other candidate predictive immune, 
angiogenic, or hypoxia biomarkers, as defined by IHC or quantitative polymerase chain 
reaction (qPCR), and efficacy as defined by PFS and ORR

To evaluate the efficacy of atezolizumab bevacizumab versus sunitinib among patients 
with tumor Fuhrman Grade 4 or sarcomatoid histology (defined by investigator-assessed 
conventional histopathology) as measured by PFS and ORR

To assess immune-mediated predictive and prognostic exploratory biomarkers in tumor 
tissue and blood from archival specimens, fresh biopsy specimens, or specimens obtained 
during the study and their association with disease status and/or efficacy as defined by PFS 
and ORR
Study Design
Description of Study
This is a Phase III, multicenter, randomized, open-label study designed to evaluate the efficacy 
and safety of atezolizumab bevacizumab versus sunitinib in patients with inoperable, locally 
advanced, or metastatic RCC who have not received prior systemic active or experimental 
therapy, either in the adjuvant or metastatic setting.


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Number of Patients
The study will enroll approximately 900 patients, including a minimum of 351 patients with a 
PD-L1 IHC of IC score of 1/2/3 (PD-L1selected population), at approximately 150180 centers 
globally.  A maximum of approximately 180 patients (20%) with a Memorial Sloan Kettering 
Cancer Center (MSKCC [Motzer]) score of 0 (good risk) will be enrolled.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Unresectable advanced or metastatic RCC with clear-cell histology and/or component of 
sarcomatoid carcinoma
Renal cell carcinoma with any component of high-grade malignant spindle cells 
consistent with sarcomatoid histology is eligible.  (See the protocol for further 
guidelines regarding defining sarcomatoid histology.)

Evaluable MSKCC risk score (i.e., “Motzer” score)
All MSKCC risk scores are included
Patients with good risk MSKCC (risk score 0) will comprise no more than 20% of the 
study population

Definitive diagnosis of RCC on the basis of a representative, formalin-fixed, 
paraffin-embedded tumor specimen accompanied by an associated pathology report 
collected within 24 months prior to Cycle 1, Day 1 available at the study site that allows 
determination of PD-L1 expression status (IC) (required prior to randomization)
The archival specimen must contain adequate viable tumor tissue to establish PD-L1 
expression status by a central laboratory prior to randomization.
The specimen may consist of a tissue block (preferred) or at least 15 unstained, 
serial sections.
Fine-needle aspiration, brushing, cell pellet from pleural effusion, bone metastases, 
and lavage samples are not acceptable.  For core needle biopsy specimens, at least 
three cores embedded into a single paraffin block should be submitted for evaluation.  
Tumor tissue from bone metastases is not evaluable for PD-L1 expression and is 
therefore not acceptable.
If the archival tissue was acquired 24 months prior to Cycle 1, Day 1, the patient may 
still be eligible provided the patient is willing to consent to and undergo a pre-treatment 
core or excisional biopsy of the tumor.  If the location of the tumor renders the tumor 
biopsy medically unsafe, eligibility may be provided with Medical Monitor approval.  A 
local analysis to confirm the diagnosis of RCC is required.

Measurable disease, as defined by RECIST v1.1

Age 18 years

Karnofsky performance status 70

Ability and capacity to comply with study and follow-up procedures

Adequate hematologic and end-organ function, defined by the following laboratory results 
obtained within 28 calendar days prior to randomization:
ANC 1500 cells/L (without granulocyte colony-stimulating factor support within 2 
weeks prior to Cycle 1, Day 1)
WBC counts 2500 cells/L
Lymphocyte count 300 cells/L
Platelet count 100,000 cells/L (without transfusion within 2 weeks prior 
to Cycle 1, Day 1)
Hemoglobin 9.0 g/dL
AST, ALT, and alkaline phosphatase 2.5 ULN, with the following exceptions:
Patients with documented liver metastases:  AST and ALT 5 ULN


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Patients with documented liver or bone metastases:  alkaline phosphatase 
5 ULN
Serum bilirubin 1.5 ULN
Patients with known Gilbert disease who have serum bilirubin level 3 ULN 
may be enrolled.
INR and aPTT 1.5 ULN, unless on a stable dose of warfarin
Serum albumin 2.5 g/dL
Creatinine clearance 30 mL/min (Cockcroft-Gault formula or based on 24-hour urine 
collection)

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate of 1% 
per year during the treatment period and for at least 6 months after the last dose of 
atezolizumab and bevacizumab or 30 days after the last dose of sunitinib.
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, established, proper use of 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 at least 6 months after the last dose 
of bevacizumab or 30 days after the last dose of sunitinib.  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 the duration of the pregnancy 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.

Patients with a history of treated asymptomatic CNS metastases are eligible, provided they 
meet all of the following criteria:
Evaluable or measurable disease outside the CNS
Only supratentorial and cerebellar metastases allowed (i.e., no metastases to midbrain, 
pons, medulla or spinal cord)
No history of intracranial or spinal cord hemorrhage
No evidence of significant vasogenic edema
No ongoing requirement for corticosteroids as therapy for CNS disease
No stereotactic radiation within 14 days
No evidence of interim progression between the completion of CNS-directed therapy 
and the screening radiographic study
Patients with new asymptomatic CNS metastases detected at the screening scan must 
receive radiation therapy and/or surgery for CNS metastases.  Following treatment, 


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these patients may then be eligible without the need for an additional brain scan prior 
to enrollment [or randomization], if all other criteria are met.
Exclusion Criteria
Disease-Specific Exclusions

Prior treatment with active or experimental systemic agents, including treatment in the 
neoadjuvant or adjuvant setting.  Prior treatment with placebo in adjuvant setting is allowed.

Radiotherapy for RCC within 14 calendar days prior to Cycle 1, Day 1

Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or 
metastases causing nerve impingement) should be treated at least 14 days prior to Cycle 1, 
Day 1.

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently)

Uncontrolled hypercalcemia (1.5 mmol/L ionized calcium or calcium 12 mg/dL) or 
symptomatic hypercalcemia refractory to bisphosphonate therapy or denosumab
Patients who are currently receiving bisphosphonate therapy without current 
hypercalcemia (corrected serum calcium greater than the upper limit of normal) are 
eligible.

Malignancies other than RCC within 5 years prior to Cycle 1, Day 1
Patients with localized low risk prostate cancer (defined as stage T2b, Gleason score 
7, and PSA at prostate cancer diagnosis 20 ng/mL) treated with curative intent and 
without prostate-specific antigen (PSA) recurrence are eligible 
Patients with low risk prostate cancer (defined as Stage T1/T2a, Gleason score 6,
and PSA 10 ng/mL) who are treatment-naive and undergoing active surveillance are 
eligible
Patients with malignancies of a negligible risk of metastasis or death (e.g., risk of 
metastasis or death 5% at 5 years) are eligible provided they meet all of the following 
criteria:
Malignancy treated with expected curative intent (such as adequately treated 
carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal 
carcinoma in situ treated surgically with curative intent)
No evidence of recurrence or metastasis by follow-up imaging and any 
disease-specific tumor markers
General Medical Exclusions

Life expectancy of 12 weeks

Current, recent (within 4 weeks of Cycle 1, Day 1), or planned participation in another 
experimental drug study

Pregnant and lactating , or intending to become pregnant during the study

Women who are not postmenopausal (12 months of non-therapy-induced amenorrhea) or 
surgically sterile must have a negative serum pregnancy test result within 7 days prior to 
initiation of study drug.

History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins

Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary 
cells or any component of the atezolizumab formulation

History of autoimmune disease, including but not limited to myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory 
bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s 
granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, 
or glomerulonephritis (see the protocol for a more comprehensive list of autoimmune 
diseases)


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Patients with a history of autoimmune-related hypothyroidism on a stable dose of 
thyroid replacement hormone are eligible for this study.
Patients with controlled Type I diabetes mellitus on a stable dose of insulin regimen 
may be eligible for this study.

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), 
drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on 
screening chest computed tomography (CT) scan; however, history of radiation pneumonitis 
in the radiation field (fibrosis) is permitted.

Positive test for HIV

Patients with active or chronic hepatitis B (defined as having a positive hepatitis B surface 
antigen [HBsAg] test at screening)
Patients with past/resolved HBV infection (defined as having a negative HBsAg test 
and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible.  
A negative HBV DNA test must be obtained in patients with positive hepatitis B core 
antibody prior to Cycle 1, Day 1.

Patients with active hepatitis C
Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) 
analysis is negative for HCV RNA.

Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia

Signs or symptoms of infection (including active tuberculosis) within 2 weeks prior to 
Cycle 1, Day 1

Received therapeutic oral or intravenous antibiotics within 2 weeks prior to Cycle 1, Day 1
Patients receiving routine antibiotic prophylaxis (e.g., to prevent chronic obstructive 
pulmonary disease exacerbation or for dental extraction) are eligible.

Significant cardiovascular or cerebrovascular disease, such as New York Heart Association 
cardiac disease (Class II or greater), unstable angina, myocardial infarction or 
cerebrovascular events within the previous 6 months or unstable arrhythmias within the 
previous 3 months.
Patients with known coronary artery disease, arrhythmias, congestive heart failure not 
meeting the above criteria must be on a stable medical regimen that is optimized in the 
opinion of the treating physician, in consultation with a cardiologist if appropriate.  
Baseline evaluation of left ventricular ejection fraction (LVEF) should be considered for 
all patients, especially in those with cardiac risk factors and/or history of coronary 
artery disease.
Patients with known LVEF 50%

Major surgical procedure other than for diagnosis within 21 days prior to Cycle 1, Day 1, or 
planned procedure or surgery during the study

Prior allogeneic stem cell or solid organ transplant

Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1
Influenza vaccination should be given during influenza season only (approximately 
October through May in the Northern Hemisphere and approximately April through 
September in the Southern Hemisphere).  Patients must agree not to receive live, 
attenuated influenza vaccine (e.g. FluMist) within 28 days prior to randomization, 
during treatment or within 5 months following the last dose of atezolizumab (for 
patients randomized to atezolizumab).

Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that contraindicates 
the use of an investigational drug or that may affect the interpretation of the results or 
render the patient at high risk from treatment complications


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Exclusion Criteria Related to Medications

Prior treatment with CD137 agonists, antiCTLA-4, antiprogrammed death-1 (PD-1), or 
antiPD-L1 therapeutic antibody or pathway-targeting agents

Treatment with systemic immunostimulatory agents (including but not limited to interferon , 
interleukin-2) for the treatment of non-malignant conditions within 6 weeks or five half-lives 
of the drug, whichever is shorter, prior to Cycle 1, Day 1

Any prior use of systemic immunostimulatory agents for the management of metastatic 
RCC is excluded.

Treatment with systemic immunosuppressive medications (including but not limited to 
prednisone, dexamethasone cyclophosphamide, azathioprine, methotrexate, thalidomide, 
and antitumor necrosis factor [antiTNF] agents) within 2 weeks prior to Cycle 1, Day 1. 
Patients who have received acute, low-dose, systemic immunosuppressant 
medications (e.g., a one-time dose of dexamethasone for nausea) or physiologic 
replacement doses (i.e., prednisone 57.5 mg/day) for adrenal insufficiency may be 
enrolled in the study.
The use of inhaled corticosteroids, physiologic replacement doses of glucocorticoids 
(i.e., for adrenal insufficiency), and mineralocorticoids (e.g., fludrocortisone) is allowed.
Bevacizumab- and Sunitinib-Specific Exclusions

Inadequately controlled hypertension (defined as systolic blood pressure 150 mmHg 
and/or diastolic blood pressure 100 mmHg)
Anti-hypertensive therapy to maintain a systolic blood pressure 150 mmHg and/or 
diastolic blood pressure 100mmHg is permitted. 

Prior history of hypertensive crisis or hypertensive encephalopathy

New York Heart Association Class II or greater congestive heart failure

History of stroke or transient ischemic attack within 6 months prior to Cycle 1, Day 1

Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent 
peripheral arterial thrombosis) within 6 months prior to Cycle 1, Day 1

Patients with a baseline ECG demonstrating a QTc 460 ms

Evidence of bleeding diathesis or clinically significant coagulopathy (in the absence of 
therapeutic anticoagulation)

Current or recent (within 10 calendar days prior to Cycle 1, Day 1) use of dipyramidole, 
ticlopidine, clopidogrel, or cilostazol.

Prophylactic or therapeutic use of low molecular weight heparin (e.g., enoxaparin), direct 
thrombin inhibitors, or warfarin are permitted, provided, where appropriate anticoagulation 
indices are stable.  Patients should have been on a stable dose (for therapeutic use) for at 
least 2 weeks (or until reaching steady state level of the drug) prior to the first study 
treatment

Core biopsy or other minor surgical procedure, excluding placement of a vascular access 
device, within 7 calendar days prior to the first dose of bevacizumab

History of abdominal or tracheoesophageal fistula or gastrointestinal perforation 
within 6 months prior to Cycle 1, Day 1

Clinical signs or symptoms of gastrointestinal obstruction or requirement for routine 
parenteral hydration, parenteral nutrition, or tube feeding

Evidence of abdominal free air not explained by paracentesis or recent surgical procedure

Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture

Proteinuria, as demonstrated by urine dipstick or 1.0 g of protein in a 24-hour 
urine collection
All patients with 2protein on dipstick urinalysis at baseline must undergo a 24-hour 
urine collection for protein.


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Length of Study
On the basis of accrual projections and projected median OS for each treatment arm, the final 
analysis of OS is projected to occur at Month 63 from the time the first patient is randomized.
End of Study
The end of study will occur when the number of deaths required for the final analysis of OS has 
been observed.  On the basis of accrual projections and projected median OS for each 
treatment arm, the final analysis of OS is projected to occur at Month 63 from the time the 
first patient is randomized.
Outcome Measures
Efficacy Outcome Measures
The co-primary efficacy outcome measures are: 

PFS, defined as the time from randomization to the first occurrence of disease progression, 
as determined by the investigator from tumor assessments based on RECIST v1.1, or 
death from any cause and 

OS, defined as the time from randomization to death due to any cause
The secondary efficacy outcome measures for this study are as follows:

PFS based on IRC assessment of radiographic progression per RECIST v1.1

ORR, defined as the proportion of patients with an objective response (either complete 
response or partial response, confirmation not required) as determined by investigator per 
RECIST v1.1

Duration of response (DOR), defined as the time from the first documented response to 
documented disease progression as determined by the investigator per RECIST v1.1 or 
death due to any cause, whichever occurs first

ORR and DOR based on IRC assessment per RECIST v1.1

PFS, ORR, and DOR based on investigator assessment per modified RECIST criteria 

Change from baseline in symptom interference (from MDASI Part II)
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Incidence, nature, and severity of all adverse events, including Grade 3 laboratory 
toxicities (grading per National Cancer Institute Common Terminology Criteria for Adverse 
Events version 4.0; laboratory toxicities based on local laboratory assessments), during 
first-line treatment

Incidence of ATA response to atezolizumab and potential correlation with pharmacokinetics, 
safety, and efficacy parameters
Pharmacokinetic Outcome Measures
The pharmacokinetic outcome measures for this study are as follows:

Maximum atezolizumab serum concentration (Cmax) after infusion on Cycle 1, Day 1 

Minimum atezolizumab serum concentration (Cmin) prior to the infusion on Day 1 of Cycles 1, 
2, 4, 8 and every eight cycles thereafter; Day 22 of Cycles 1, 2, and 4; and at study 
termination

Bevacizumab Cmax after infusion on Day 1 of Cycles 1 and 2

Bevacizumab Cmin prior to the infusion on Day 1 of Cycles 1 and 2 and at study termination
Patient-Reported Outcome Measures
The other PRO outcome measures for this study are as follows:

Change from baseline in symptom severity as measured by the MDASI and BFI 

Change from baseline in treatment side effects subscale (from FKSI-19)


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In addition, health status will be collected the EuroQoL 5 Dimensions (EQ-5D) questionnaire to 
derive utilizes for health economic modeling.
Exploratory Outcome Measures
The exploratory outcome measures for this study are as follows:

Status of PD-L1, immune-, angiogenic-, and RCC-related and other exploratory biomarkers 
in archival and/or freshly obtained tumor tissues and blood collected before, during, or after 
treatment with atezolizumab bevacizumab or sunitinib or at progression

PFS and ORR in patients with tumor Fuhrman Grade 4 or sarcomatoid histology (defined by 
investigator-assessed conventional histopathology)

Status of tumor-infiltrating immune cells and biomarkers in biopsy specimens and blood 
collected at the first evidence of radiographic disease progression
Investigational Medicinal Products
Test Product (Investigational Drugs)
Atezolizumabbevacizumab will be dosed in 6-week cycles.  Atezolizumab will be administered 
intravenously at a fixed dose of 1200 mg on Days 1 and 22 of each 42-day cycle.  Bevacizumab 
will be administered intravenously at 15 mg/kg on Days 1 and 22 of each 42-day cycle.
Comparator
Sunitinib will be administered in 6-week cycles at 50 mg/day given orally for 4 weeks, followed 
by 2 weeks of rest.
Statistical Methods
Primary Analysis
The co-primary efficacy endpoints are investigator-assessed PFS per RECIST v1.1 and OS.  
Because type I error will be controlled accounting for two co-primary endpoints, the study will be 
considered a positive study if statistical significance is achieved for either of the co-primary 
endpoints.
PFS will be analyzed in the PD-L1selected population and OS will be analyzed first in the ITT 
population; additional analyses of OS will be performed in a hierarchical fashion.
PFS is defined as the time from randomization to disease progression, as determined by the 
investigator per RECIST v1.1, or death from any cause, whichever occurs first.  Data for 
patients who have not experienced disease progression or death will be censored at the last 
tumor assessment date.  Data for patients with no post-baseline tumor assessments will be 
censored at the randomization date 1 day.
For United States registrational purposes, the co-primary efficacy endpoint of PFS will be 
defined as described above with an additional censoring rule for missed visits.  Data for patients 
with a PFS event who missed two or more scheduled assessments immediately prior to the 
PFS event will be censored at the last tumor assessment prior to the missed visits.
OS is defined as the time from randomization to death due to any cause.  Data for patients who 
are not reported as having died at the date of analysis will be censored at the date when they 
were last known to be alive.  Patients who do not have post-baseline information will be 
censored at the date of randomization 1 day.
The following analyses will be performed for both PFS endpoints described above and OS.  
PFS and OS will be compared between treatment arms with use of the stratified log-rank test.  
The HR will be estimated using a stratified Cox proportional hazards model.  The 95% CI for the 
HR will be provided.  The stratification factors will be the same as the randomization 
stratification factors:  presence of liver metastasis (yes/no); tumor PD-L1 status (IC0 vs. IC1/2/3); 
and the MSKCC (Motzer) score (0, 12, 3).  The stratification factors will be obtained from the 
IxRS at the time of randomization.  Results from an unstratified analysis will also be provided.  
Kaplan-Meier methodology will be used to estimate the median PFS and OS for each treatment 
arm, and Kaplan-Meier curves will be produced.  The Brookmeyer-Crowley methodology will be 
used to construct the 95% CI for the median PFS and OS for each treatment arm.


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The following analyses will be performed for both PFS endpoints described above and (as 
applicable) for OS: 

Analyses described in the protocol for landmark timepoints

Analyses described in the protocol for subgroups 

Secondary endpoint of PFS by IRC assessment, PD-L1selected population and ITT 
population, based on RECIST v1.1

Secondary endpoint of PFS by investigator assessment in the ITT population, based on 
RECIST v1.1
Patient-Reported Outcome Analysis
MDASI, and BFI, and FKSI-19
Scoring for the MDASI and BFI questionnaires will be based on their corresponding user 
manuals.  For MDASI and BFI scales with more than 50% of the constituent items 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 missing. 
The impact of symptoms on patients’ functioning will be compared between treatment arms as a 
change from baseline on the interference items in the MDASI Part II. 
The severity of symptoms captured in the MDASI and the BFI will be summarized using 
descriptive analyses including summary statistics and change from baseline at each 
assessment by treatment arm.
Determination of Sample Size
This study will randomize approximately 900 patients, including a minimum of approximately 
351 patients with a PD-L1 IHC IC score of 1/2/3.
Type I Error Control
The type I error () for this study is 0.05 (two-sided).  There are two co-primary efficacy 
endpoints for this study:  PFS by investigator assessment per RECIST v1.1 and OS.  To control 
the overall type I error rate at 0.05 (two-sided) while accounting for two co-primary endpoints, 
will be split between PFS (0.04) and OS (0.01).  Because type I error will be controlled 
accounting for two co-primary endpoints, the study will be considered a positive study if 
statistical significance is achieved for either of the co-primary endpoints.
Formal treatment comparisons will be performed in a hierarchical fashion in which may be 
recycled as follows:
1.
PFS in the PD-L1selected population will be evaluated at 0.04 (two-sided).
2.
If PFS results in the PD-L1selected population are statistically significant at 0.04, then 
0.04 will be recycled to OS in the ITT population, and OS in the ITT population will be 
evaluated at 0.05 (two-sided).  If PFS results in the PD-L1selected population are not 
statistically significant at 0.04, then no recycling of will occur, and OS in the ITT
population will be evaluated at 0.01 (two-sided).
3.
OS will be compared between treatment arms in a hierarchical fashion as follows.  If OS 
results in the ITT population are statistically significant at the appropriate level, then OS in 
the PD-L1selected population will be evaluated at same -level as for OS in the ITT
population.  If OS results in the ITT population are not statistically significant, formal 
treatment comparison of OS in the PD-L1selected population will not be performed.
Interim analyses of OS and the final analysis of OS will be based on the allocated to the 
comparison of OS, as described above.  Statistical significance at interim analyses of OS will be 
evaluated.
Co-Primary Endpoint:  Progression-Free Survival in the PD-L1Selected Population
The analysis of the co-primary endpoint of PFS will take place when approximately 228 PFS 
events in the PD-L1selected population (65% of the estimated 351 PD-L1population) as 
defined for the primary analysis of PFS have occurred based on the following assumptions:

Two-sided, stratified log-rank test 

0.04 (two-sided)


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
Approximately 88% power

Median PFS for the sunitinib arm of 11 months and estimated median PFS in the 
atezolizumab bevacizumab arm of 17 months (corresponding to HR of 0.65)

5% annual loss to follow-up for PFS

No interim analysis
Accrual is projected to occur over 20months, assuming a ramp-up period of 9 months.  
On the basis of these assumptions, the required number of PFS events in the PD-L1selected 
population is projected to occur at Month 34 from the time the first patient is randomized.  Also 
on the basis of these assumptions, it is projected that an observed HR of 0.76 or lower will 
result in a statistically significant difference between treatment arms (i.e., an HR of 0.76 will be 
the minimally detectable difference for the analysis; this corresponds to an improvement of 
3.5 months in median PFS from 11 months in the sunitinib arm to 14.5 months in the 
atezolizumab bevacizumab arm).
Co-Primary Endpoint:  Overall Survival in the ITT Population
The final analysis of the co-primary endpoint of OS will take place at the later of the time points 
when the required number of events has occurred in the PD-L1selected population and in the 
ITT population, where the required number of events is as follows:

639 OS events in the ITT population (71% of the estimated 900 patients)

246 OS events in the PD-L1selected population (70% of the estimated 351 patients)
The number of events required for the final OS analysis in these populations is based on the 
following assumptions:

Two-sided, stratified log-rank test 

0.01 (two-sided)

1% annual loss to follow-up for OS

For the ITT population:  
85% power
Median OS in the control arm of 24 months
Estimated median OS in the atezolizumab bevacizumab arm of 32 months (an 
increase of 8 months, corresponding to an HR of 0.75

For the PD-L1selected population:  
53% power
Median OS in the control arm of 24 months
Estimated median OS in the atezolizumab bevacizumab arm of 33.8 months (an 
increase of 9.8 months, corresponding to an HR of 0.71)
On the basis of these assumptions, the required number of OS events for the final analysis of 
OS in both the PD-L1selected population and the ITT population is projected to occur at 
Month 63 from the time the first patient is randomized. 
At the final OS analysis, on the basis of these assumptions, it is projected that an observed OS 
HR of 0.83 or lower in the ITT population will result in a statistically significant difference 
between treatment arms (i.e., the minimally detectable difference at the analysis; this 
corresponds to an improvement of 4.9 months in median OS, from 24 months in the control arm 
to 28.9 months in the atezolizumab bevacizumab arm).
Also at the final OS analysis, on the basis of these assumptions, it is projected that an observed 
OS HR of 0.72 or lower in the PD-L1selected population will result in a statistically significant 
difference between treatment arms (i.e., an HR of 0.72 will be the minimally detectable 
difference at the analysis; this corresponds to an improvement of 9.5 months in median OS, 
from 24 months in the control arm to 33.5 months in the atezolizumab bevacizumab arm).




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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
anti-HBc
antibody to hepatitis B core antigen
antiTNF
anti-tumor necrosis factor
ATA
anti-therapeutic antibody
BFI
Brief Fatigue Inventory
Cmin
minimum serum concentration
CR
complete response
CRP
c-reactive protein
CT
computed tomography
Ctrough
trough concentration
DOR
duration of response
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
EQ-5D
EuroQoL 5 Dimensions
FACIT-F
Functional Assessment of Chronic Illness Therapy-Fatigue
FKSI-19
Functional Assessment of Cancer Therapy Kidney Symptom Index
FDA
U.S. Food and Drug Administration
HBsAg
hepatitis B surface antigen
HIPAA
Health Insurance Portability and Accountability Act
HR
hazard ratio
IC
tumor-infiltrating immune cells
ICH
International Conference on Harmonisation
iDMC
independent Data Monitoring Committee
IFN
interferon
IHC
immunohistochemistry
IL
interleukin
IMP
Investigational Medicinal Product
IND
Investigational New Drug 
IRB
Institutional Review Board
IRC
Independent Review Committee
ITT
intent-to-treat
IV
intravenous
IxRS
interactive voice/Web response system
KPS
Karnofsky performance status
LFT
liver function test


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Abbreviation
Definition
LLN
lower limit of normal
LVEF
left ventricular ejection fraction
MDASI
M.D. Anderson Symptom Inventory
MDSC
myeloid-derived suppressor cells
MRI
magnetic resonance imaging
MSKCC
Memorial Sloan Kettering Cancer Center
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events
NGS
next-generation sequencing
OBF
O'Brien-Fleming
ORR
objective response rate
OS
overall survival
PCR
polymerase chain reaction
PD-1
programmed death1
PD-L1
programmed deathligand 1
PFS
progression-free survival
PK
pharmacokinetic
PR
partial response
PRO
patient-reported outcome
q2w
every 2 weeks
q3w
every 3 weeks
qPCR
quantitative polymerase chain reaction
RCC
renal cell carcinoma
RCR
Roche Clinical Repository
RECIST
Response Evaluation Criteria in Solid Tumors
SPD
sum of the product of the longest perpendicular dimensions
SQLQ
Supplementary Quality of Life Questionnaire
TBNK
T, B, and natural killer cells
TNF
tumor necrosis factor
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
VEGF
vascular endothelial growth factor
VHL
von Hippel-Lindau


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1.
BACKGROUND
1.1
BACKGROUND ON RENAL CELL CARCINOMA
Metastatic renal cell carcinoma (RCC) is the most lethal urologic cancer and the 
sixth leading cause of cancer deaths in industrialized countries.  Worldwide, in 
2012, there were an estimated 337,860 new diagnoses and approximately 
143,369 deaths secondary to RCC (GLOBOCAN 2012).  The average age-adjusted 
incidence of RCC is approximately 12 in 100,000 men and 5 in 100,000 women 
(Patel et al. 2006):  RCC age-adjusted incidence has been rising for the past 30 years 
within the United States and most European countries at an annual rate of approximately 
3% (Chow et al. 2010).
RCC has several histologic types, each arising from distinct regions of the renal epithelia 
caused by a separate set of gene mutations and exhibiting a unique clinical course.  The 
most common types of epithelial renal tumors include the following:  clear-cell RCC 
(75%), Type I (5%) and Type II (10%) papillary, chromophobe (5%), and oncocytoma 
(5%; Motzer et al. 1996).  Both sporadic and inherited forms of clear-cell RCC are 
strongly associated with mutations in the von Hippel-Lindau (VHL) gene.  Clear-cell RCC 
is a highly vascular tumor arising from epithelial elements within proximal tubules of 
nephrons.  An early event during the evolution of clear-cell RCC leads to loss of function 
mutation of the VHL gene (Latif et al. 1993).  Inactivation of the VHL gene leads to 
overexpression of vascular endothelial growth factor (VEGF), a growth hormone that 
stimulates growth and angiogenesis.
Radical nephrectomy is the treatment of choice for early-stage RCC; however, 30% of 
these patients will relapse and develop future metastasis.  Cytotoxic chemotherapy and 
radiotherapy have been largely ineffective for treating for RCC (Motzer et al. 1996).  
Several agents that target the VEGF pathway (sunitinib, pazopanib, axitinib, 
bevacizumab) and mTor pathway inhibitors (temsirolimus, everolimus) are approved in 
the treatment of RCC.  Additionally, RCC is responsive to immunomodulation (interleukin
[IL]-2, interferon alfa, antiprogrammed death1 [antiPD-1], and antiprogrammed
deathligand 1 [antiPD-L1]) (McDermott 2009; Brahmer et al. 2012; 
Topalian et al. 2012).  Immunotherapy with IL-2 is associated with a low response rate, 
yet durable long-term benefit in patients who respond (approximately 10% durable 
response rate); however, as a result of toxicity, high-dose IL-2 is generally only feasible 
in young patients with good performance status.  To date, RCC is typically managed with 
VEGF-directed therapy, as well as immune therapy. 
1.1.1
First-Line Treatment for Renal Cell Carcinoma
1.1.1.1
Anti-VEGF Therapies in Renal Cell Carcinoma
Clear-cell RCC is associated with an overproduction of VEGF as a result of the 
mutation/inactivation of the VHL tumor-suppressor gene (George and Kaelin 2003; 
Kaelin 2003).  Thus, there has been substantial effort for more than 10 years to test 
agents that target VEGF in RCC.  These studies have demonstrated significant 


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anti-tumor activity (e.g., by objective responses and prolonged progression-free survival 
[PFS]), placing VEGF blockade strategies at the forefront of RCC therapy.  Approved 
therapies in the first-line metastatic setting now include, among others, sunitinib, 
pazopanib, and the combination of bevacizumabinterferon alfa-2a.  Treatment with 
each of these agents results in a median PFS of approximately 9.210.8 months and an 
objective response rate (ORR) of approximately 35% (see Table 1).  However, these 
therapies are associated with significant adverse events and do not result in a sustained, 
durable clinical benefit (Patel et al. 2006).
Table 1
Approved First-Line Targeted Therapies for Advanced Renal Cell 
Carcinoma
Agent and 
Population
Comparison
PFS
(months)
HR
p-Value
OS
(months)
HR
(95% CI)
Sunitinib
(first-line, all a)
IFN 
10.8 vs. 5.1
0.44 b
0.01
24.5 vs. 20.4
0.82
0.671.00
BevIFN 
(first-line, all a)
IFN 
10.2 vs. 5.4
0.60 c
0.01
23 vs. 21
0.96
0.731.04
Pazopanib
(first-line or prior 
cytokine, all a)
Placebo
9.2 vs. 4.2
0.46 d
0.001
22.9 vs. 20.5
0.91
0.711.16
Temsirolimus 
(first-line, poor risk)
IFN 
5.5 vs. 3.1
0.66 e
0.008
10.9 vs. 7.3
0.73
0.580.92
HRhazard ratio; momonths; IFNinterferon; OSoverall survival; PFSprogression-free 
survival.
a “All” refers goodintermediatepoor risk.
b Motzer et al. 2007, 2009.
c Escudier et al. 2007.
d Sternberg et al. 2010.
e Hudes et al. 2007.
Avastin(bevacizumab) is a recombinant, humanized therapeutic antibody directed 
against VEGF that has demonstrated single agent activity in a series of studies.  In the 
first seminal study at the National Institutes of Health published in 
2003 (Yang et al. 2003), 116 patients with RCC who were refractory to IL-2 were 
randomized to receive bevacizumab at a high dose (10 mg/kg every 2 weeks [q2w]), a 
low dose (3 mg/kg q2w), or placebo.  In this IL-2 refractory population, the median PFS 
was 4.8, 3.0, and 2.5 months in the three treatment groups, respectively.  In a more 
recent study (see Table 2), bevacizumab monotherapy as first-line therapy was 
examined in comparison studies of bevacizumab combined with erlotinib versus 
bevacizumab alone (Bukowski et al. 2007).  Bevacizumab monotherapy in patients with 
untreated RCC demonstrated an ORR of 13% and a PFS of 8.5 months.  In the most 
recent study (BEST Study) comparing single-agent bevacizumab (ORR of 12% and PFS 
of 8.7 months) with the combination of bevacizumab and either sorafenib or temsirolimus, 


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single-agent bevacizumab was found to be as efficacious as the combinations and less 
toxic (McDermott et al. 2013).
Table 2
Efficacy of Bevacizumab Monotherapy in Renal Cell Carcinoma
No. of 
Patients
PFS
(months)
ORR
(%)
Patient 
Population
Placebo a
40
2.5
0
IL-2 
Refractory
Bev 3 mg/kg q2w a
37
3.0
0
Bev 10 mg/kg q2w a
39
4.8
10
Bev 10 mg/kg q2w b
53
8.5
13
1st line
Bev 10 mg/kg q2werlotinib b
51
9.9
14
Bev 10 mg/kg q2w c
87
8.7
12
1st line
Bevbevacizumab; ILinterleukin; ORRoverall response rate; 
PFSprogression-free survival q2wevery 2 weeks.
a Yang et al. 2002.
b Bukowski et al. 2007.
c Mc Dermott et al. 2013.
The role of combining bevacizumab with immunomodulation with interferon (IFN) in 
RCC is well established.  In combination studies of bevacizumab with interferon alfa-2a 
compared with interferon alfa-2a alone, the PFS (approximately 10 months vs. 
approximately 5 months; hazard ratio [HR] 0.60), as well as tumor shrinkage (ORR 31% 
vs. 13%), were improved (Escudier et al. 2007; Rini et al. 2010), suggesting an 
incremental benefit when anti-VEGF and immune therapies are combined.
The efficacy of VEGF antagonism highlights the central role of VEGF in RCC 
pathogenesis.  In addition, VEGF may also modulate the immune response through 
diverse mechanisms described in Section 1.3.
1.1.1.2
Immune-Based Therapy in Renal Cell Carcinoma
Immunotherapy historically has had a significant role in the management of metastatic 
RCC.  Treatment with interferon alfa and/or IL-2 results in objective responses in 
approximately 5% of patients with RCC and 10% of patients treated with IL-2 exhibit 
durable disease stabilization or remission (Yang and Childs 2006).  Data from the 
Phase I antiPD-L1 antibody (atezolizumab, MPDL3280A) Study PCD4989g in RCC is 
outlined in Section 1.4.1.  This agent, atezolizumab, blocks the inhibitory receptors 
expressed on tumor cells called programmed deathligand 1 (PD-L1), resulting in 
enhanced anti-tumor immune activity.  The observed level of activity with this agent 
suggests that the enhancement of immune function by targeting the PD-L1 axis may be 
of critical importance in RCC.


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1.2
BACKGROUND ON PD-L1 BIOLOGY AND ATEZOLIZUMAB
PD-L1 is an extracellular protein that downregulates immune responses primarily in 
peripheral tissues through binding to its two receptors, programmed death1 (PD-1) and 
B7.1.  Many human tumors have been found to overexpress PD-L1, which acts to 
suppress anti-tumor immunity.  PD-1 is an inhibitory receptor expressed on T cells 
following T-cell activation, which is sustained in states of chronic stimulation, such as in 
chronic infection or cancer (Blank et al. 2005; Keir et al. 2008). Ligation of PD-L1 with 
PD-1 inhibits T-cell proliferation, cytokine production, and cytolytic activity, leading to the 
functional inactivation or exhaustion of T cells.  B7.1 is a molecule expressed on 
antigen-presenting cells and activated T cells.  PD-L1 binding to B7.1 on T cells and 
antigen-presenting cells can mediate the downregulation of immune responses, 
including inhibition of T-cell activation and cytokine production (Butte et al. 2007; 
Yang et al. 2011; Chen et al. 2012).
Aberrant expression of PD-L1 on tumor cells has been reported to impede anti-tumor 
immunity, resulting in immune evasion (Blank and Mackensen 2007).  Therefore, 
interruption of the PD-L1/PD-1 pathway represents an attractive strategy to reinvigorate 
tumor-specific T-cell immunity.  PD-L1 expression is prevalent in many human tumors 
and may be associated with poor prognosis in certain cancers (Mu et al. 2011).
Atezolizumab is a humanized IgG1 monoclonal antibody consisting of two heavy chains 
(448 amino acids) and two light chains (214 amino acids) and is produced in Chinese 
hamster ovary cells.  Atezolizumab was engineered to eliminate Fc-effector function via 
a single amino acid substitution at position 298 on the heavy chain, which results in a 
non-glycosylated antibody that has minimal binding to Fc receptors and, consequently, 
eliminates detectable Fc‑effector function and depletion of cells expressing PD-L1.  
Atezolizumab targets human PD-L1 and inhibits its interaction with its receptors, PD-1 
and B7.1 (CD80, B7-1).  Both of these interactions are reported to provide inhibitory 
signals to T cells.
See the Atezolizumab Investigator's Brochure for details on nonclinical and clinical 
studies. 
1.3
RATIONALE FOR TESTING ATEZOLIZUMAB AND THE 
COMBINATION ATEZOLIZUMABBEVACIZUMAB
In multiple murine tumor models, the interruption of the interaction between PD-L1 and 
PD-1 resulted in anti-tumor effects (Iwai et al. 2002; Strome et al. 2003). 
 
 
 
In addition to promoting tumor angiogenesis, there is increasing evidence that VEGF 
plays a role in cancer immune evasion through several different mechanisms.  VEGF is 
believed to be involved in immune response via the induction of myeloid-derived 


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suppressor cells (MDSCs).  These VEGF-induced MDSCs can suppress both T-cell and 
dendritic-cell function (Gabrilovich 2012).  Anti-VEGF therapies may elicit immune 
responses through diverse mechanisms, including increased trafficking of T cells into 
tumors (Manning et al. 2007; Shrimali et al. 2010), reduced frequency of MDSC 
(Kusmartsev et al. 2008), reduction of suppressive cytokines and tumor-infiltrating 
T regulatory cells and MDSCs (Roland et al. 2009), and increased CD8+ and CD4
central memory T cells (Hodi et al. 2011).
PD-L1 expression is prevalent in many human tumors (e.g., lung, ovarian, melanoma, 
colon carcinoma, and RCC).  This elevated PD-L1 expression is often associated with a 
worse prognosis in RCC (Choueiri et al. 2014).  Atezolizumab has demonstrated activity 
in advanced refractory cancer patients in the Phase I monotherapy Study PCD4989g 
(Cho et al. 2013; Herbst et al. 2013), as well as in combination with bevacizumab, 
(McDermott et al. 2014; see Section 1.4).
Collectively, the role of VEGF in the immune response and its critical role in RCC 
pathogenesis provide a compelling rationale to test whether inhibition of the PD-L1/PD-1 
pathway with a human antiPD-L1 IgG1 effectorless antibody with anti-VEGF therapies 
will result in improved clinical benefit for patients with RCC.
1.4
CLINICAL EXPERIENCE WITH ATEZOLIZUMAB IN RENAL 
CELL CARCINOMA
The experience to date with atezolizumab in RCC consists of three ongoing studies:  an 
atezolizumab monotherapy Phase Ia study (Study PCD4989g) and 
two atezolizumabbevacizumab combination studies (a Phase Ib Study GP28328 and a 
randomized Phase II Study WO29074).
1.4.1
Phase Ia Study PCD4989g
Study PCD4989g is an ongoing Phase Ia, open-label, dose-escalation trial assessing the 
safety and pharmacokinetics of atezolizumab administered as a single agent to patients 
with solid tumors and hematologic malignancies.  
1.4.1.1
Safety Analysis of Study PCD4989g
As of 10 May 2014, atezolizumab has been administered to approximately 775 patients 
with solid tumors and hematologic malignancies.  The safety profile of atezolizumab is 
primarily based on data from this ongoing Phase Ia study.  Refer to the Atezolizumab
Investigator’s Brochure for the safety profile of all patients enrolled in this study.  The 
safety profile for the subset of patients enrolled in this study (patients with renal cell 
cancer) is summarized below.
1.4.1.1.1
Clinical Safety in Renal Cell Carcinoma Cohort 
(Study PCD4989g)
Study PCD4989g included 69 patients with RCC.  As of the 10 May 2014 data 
cutoff date, the median duration of treatment for this cohort was 239.0 days 


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(range: 21855 days) and the median number of atezolizumab cycles administered was 
12 cycles (range: 236 cycles).
As of May 10 2014, 66 of 69 treated RCC patients (95.7%) reported one or more 
adverse events.  The most frequently observed adverse events (occurring in 10% of 
treated patients) are presented in Table 3.  The most frequently observed adverse 
events (occurring in 10% of treated patients) included fatigue, cough, arthralgia, 
pyrexia, constipation, nausea, decreased appetite, dyspnea, rash, diarrhea, chills, 
pruritus, anemia, back pain, headache, insomnia, upper respiratory tract infection, pain 
in extremity, vomiting, asthenia, edema peripheral, dizziness, oropharyngeal pain, dry 
skin, hypothyroidism, and influenza-like illness.
No new safety concerns were observed in this cohort and RCC findings are consistent 
with the overall larger population in Study PCD4989g.


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Table 3
Adverse Events in ≥10% of Atezolizumab-Treated Patients in the 
Renal Cell Carcinoma Cohort of Study PCD4989g
No. (%) of Adverse Events
Preferred Term
Total
Treatment-Related
Fatigue
24 (34.8)
14 (20.3)
Cough
21 (30.4)
1 (1.4)
Arthralgia
20 (29.0)
10 (14.5)
Pyrexia
18 (26.1)
8 (11.6)
Constipation
18 (26.1)
2 (2.9)
Nausea
16 (23.2)
7 (10.1)
Decreased appetite
16 (23.2)
11 (15.9)
Dyspnoea
14 (20.3)
4 (5.8)
Rash
13 (18.8)
10 (14.5)
Diarrhoea
12 (17.4)
8 (11.6)
Chills
12 (17.4)
7 (10.1)
Pruritus
12 (17.4)
8 (11.6)
Anaemia
12 (17.4)
5 (7.2)
Back pain
12 (17.4)
2 (2.9)
Headache
11 (15.9)
5 (7.2)
Insomnia
11 (15.9)
2 (2.9)
Upper respiratory tract infection
10 (14.5)
1 (1.4)
Pain in extremity
9 (13.0)
0 (0.0)
Vomiting
8 (11.6)
4 (5.8)
Asthenia
8 (11.6)
5 (7.2)
Oedema peripheral
8 (11.6)
3 (4.3)
Dizziness
8 (11.6)
1 (1.4)
Oropharyngeal pain
8 (11.6)
1 (1.4)
Dry skin
8 (11.6)
6 (8.7)
Hypothyroidism
8 (11.6)
6 (8.7)
Influenza-like illness
7 (10.1)
6 (8.7)
RCCrenal cell carcinoma.
Grade 3 adverse events occurred in 32 patients (46.4%; see Table 4).  The most 
frequently reported related Grade 3 adverse events included fatigue, anemia, 
dehydration, and hypophosphatemia.


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Table 4
Grade 35 Adverse Events Reported in 2 or More Patients:  
Atezolizumab-Treated Renal Cell Carcinoma Cohort in 
Study PCD4989g 
No. (%) of Grade 3 Adverse Events
Preferred Term
Total
Treatment-Related
Anaemia
4 (5.8)
2 (2.9)
Asthenia
2 (2.9)
0 (0.0)
Fatigue
2 (2.9)
2 (2.9)
Dehydration
2 (2.9)
2 (2.9)
Hyperglycaemia
2 (2.9)
1 (1.4)
Hyponatraemia
2 (2.9)
0 (0.0)
Hypophosphataemia
2 (2.9)
2 (2.9)
Malignant neoplasm progression
2 (2.9)
0 (0.0)
Proteinuria
2 (2.9)
0 (0.0)
Dyspnoea
4 (5.8)
1 (1.4)
Hypoxia
2 (2.9)
0 (0.0)
Pleural effusion
2 (2.9)
0 (0.0)
RCCrenal cell carcinoma.
1.4.1.1.2
Clinical Activity in Renal Cell Carcinoma in Study PCD4989g
As of 21 April 2014, a total of 69 patients with RCC have been treated with atezolizumab 
monotherapy at the following dose levels:  3 mg/kg (n2), 10 mg/kg (n12), 15 mg/kg 
(n19), and 20 mg/kg (n36).  Best responses in the 62 patients with clear-cell RCC 
evaluable for efficacy who were dosed prior to 21 October 2013 included the following:  
9 patients (15%) with confirmed partial responses (PRs)/complete responses (CRs), 
35 patients (57%) with stable disease, and 17 patients (27%) with disease progression.  
The 24-week PFS rate was 51%, and stable disease was maintained for 24 weeks in 
31% of patients with RCC.  As of 21 April 2014, 5 of 9 responding patients with clear-cell 
RCC have continued to respond.  The median duration of response (DOR) is 75.7 weeks.  
In addition, 4 of 18 patients (22%) with Fuhrman Grade 4 clear-cell or sarcomatoid 
histology achieved a response by Response Evaluation Criteria in Solid Tumors 
version 1.1 (RECIST v1.1) criteria.  
Preliminary results suggest that PD-L1 expression in tumor tissue is likely to be 
associated with response to atezolizumab.  A prototype immunohistochemistry (IHC) 
assay that measures specific PD-L1 signals in tumor-infiltrating immune cells (ICs) was 
used in Study PCD4989g.  PD-L1 staining categories in ICs are defined as IC0, IC1, 
IC2, and IC3 (see Table 5).  In the efficacy-evaluable patients with clear-cell RCC 
(n62), an ORR of 20.0% (7 of 35 patients, 95% CI: 8.7%36.6%) was observed in 
the PD-L1positive patients (IC1/2/3 group) compared with an ORR of 9.5% 


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(2 of 21 patients, 95% CI: 1.7%29.8%) in patients with low PD-L1 staining or who were 
PD-L1 negative (IC0 group) (Table 6).  Note that protocol enrollment criteria for PD-L1 
expression status varied over time; as a result, the IC1/2/3 group (n35 patients) is 
enriched for IC2/3 patients (n20 patients) and interpretation of results for the overall 
RCC population and PD-L1selected groups must take this into consideration.  A total of 
3 of 15 (20%) IC1 patients and 4 of 20 (20%) had an overall response of CR or PR.
Table 5
Criteria for PD-L1 Expression
Description of IC Scoring Algorithm
PD-L1
Expression 
Level
Presence of discernible PD-L1 staining of any intensity in tumor infiltrating immune 
cells covering 10% of tumor area occupied by tumor cells, associated 
intratumoral, and contiguous peri-tumoral desmoplastic stroma
IC3
Presence of discernible PD-L1 staining of any intensity in tumor-infiltrating immune 
cells covering between 510% of tumor area occupied by tumor 
cells, associated intratumoral, and contiguous peri-tumoral desmoplastic stroma
IC2
Presence of discernible PD-L1 staining of any intensity in tumor-infiltrating immune 
cells covering between 15% of tumor area occupied by tumor cells, associated
intratumoral, and contiguous peri-tumoral desmoplastic stroma
IC1
Absence of any discernible PD-L1 staining OR Presence of discernible PD-L1 
staining of any intensity in tumor-infiltrating immune cells covering 1% of tumor 
area occupied by tumor cells, associated intratumoral, and contiguous peri-tumoral 
desmoplastic stroma
IC0
ICtumor-infiltrating immune cells; PD-L1programmed deathligand 1.


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Table 6
Efficacy in Patients with Clear-Cell Renal Cell Carcinoma in 
Study PCD4989g:  Best Overall Response Rate and 24-Week PFS 
Rate by PD-L1 Expression (n62)
PD-L1 IHC 
Expression 
Level
No. of 
Patients
ORR by RECIST, 
Version 1.1
(95% CI)
CR
PR
SD
24-Week 
PFS Rate
(95%CI) a
All patients
62
9 (14.5%) 
7.5%, 25.2%
1
(1.6%)
8 
(12.9%)
35 
(56.5%)
50.9% 
38.4, 63.4
IC0
21
2 (9.5%)
1.7%, 29.8%
0
2
(9.5%)
11 
(52.4%)
45.2%
23.4, 67.1
IC1/2/3 b
35
7 (20.0%)
8.7%, 36.6%
1
(2.9%)
6 
(17.1%)
20 
(57.1%)
54.3%
37.8, 70.8
Fuhrman
Grade 4/ 
sarcomatoid
18
4 (22.2%)
8.0%, 46.5%
1
(5.6%)
3 
(16.7%)
8 
(44.4%)
NA
IC tumor-infiltrating immune cell; IHC immunohistochemistry; ORR objective response rate; 
CR complete response; NAnot available; PFS progression–free survival; PR partial 
response; SD stable disease; PD-L1 programmed deathligand 1; RCCrenal cell carcinoma; 
RECIST Response Evaluation Criteria in Solid Tumors.
Note: This table is based on a data cutoff date of 21 April 2014. Patients with RCC were dosed 
by 21 October 2013.
a Kaplan-Meier estimates.
b Partially enriched for patients with IC2/3; IC1:  3 of 15 (ORR 20%), IC 2/3:  4 of 20 (ORR 20%).
1.4.1.2
Phase Ib Study GP28328
Study GP28328 is an ongoing Phase Ib study evaluating the safety and 
pharmacokinetics of atezolizumab administered in combination with bevacizumab 
(Arm A) or in combination with bevacizumab plus chemotherapy (Arms BE) in patients 
with advanced solid tumors.
1.4.1.2.1
Safety Analysis of Arm A of Study GP28328
Restricting the safety discussion to components of Study GP28328 without cytotoxic 
chemotherapy (i.e., Arm A), atezolizumabbevacizumab has been generally well 
tolerated.  No dose-limiting toxicities have been reported during the dose-escalation 
stage (only one dose level of atezolizumab was tested).  As of 7 July 2014, clinical data 
were available for 35 patients who received at least one dose of the combination of 
atezolizumabbevacizumab (Arm A).  Table 7 and Table 8 summarize all reported 
events among the 35 patients enrolled in Arm A.


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Table 7
All Reported Adverse Events in Arm A of Study GP28328
No. (%) of Adverse Events
(n=35)
Parameter
Total
Treatment-Related 
Any adverse event
35 (100.0)
27 (77.1)
Grade 35 adverse event
18 (51.4)
1 (2.9)
Serious adverse event
14 (40.0)
0 (0.0)
Adverse event leading to death (Grade 5)
1 (2.9)
0 (0.0)


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Table 8
All Reported Adverse Events in ≥10% Patients in Arm A of 
Study GP28328
No. (%) of Adverse Events
Preferred Term
Total
Treatment-Related 
Any adverse event
35 (100.0)
27 (77.1)
Fatigue
16 (45.7)
7 (20.0)
Nausea
13 (37.1)
7 (20.0)
Pyrexia
13 (37.1)
6 (17.1)
Diarrhea
11 (31.4)
8 (22.9)
Decreased appetite
9 (25.7)
5 (14.3)
Abdominal pain
7 (20.0)
(0.0)
Chills
7 (20.0)
4 (11.4)
Hypertension
7 (20.0)
0 (0.0)
Vomiting
7 (20.0)
2 (5.7)
Cough
6 (17.1)
3 (8.6)
Dyspnoea
6 (17.1)
2 (5.7)
Oedema peripheral
6 (17.1)
0 (0.0)
Upper respiratory tract infection
6 (17.1)
0 (0.0)
Anaemia
5 (14.3)
2 5.7)
Anxiety
5 (14.3)
0 (0.0)
Epistaxis
5 (14.3)
1 (2.9)
Headache
5 (14.3)
0 (0.0)
Pain in extremity
5 (14.3)
1 (2.9)
Pneumonia
5 (14.3)
0 (0.0)
Pruritus
5 (14.3)
3 (8.6)
Rash
5 (14.3)
3 (8.6)
Arthralgia
4 (11.4)
1 (2.9)
Constipation  
4 (11.4)
0 (0.0)
Insomnia
4 (11.4)
0 (0.0)
Productive cough
4 (11.4)
0 (0.0)
Bone pain
3 (8.6)
2 (5.7)
Musculoskeletal pain 
3 (8.6)
1 (2.9)
AEadverse event.
Of the 35 patients enrolled in Arm A, 100% reported one or more adverse events.  
Adverse events reported in 10% of patients included anemia, nausea, diarrhea, 
constipation, vomiting, abdominal pain, fatigue, pyrexia, chills, edema peripheral, upper 
respiratory tract infection, pneumonia, arthralgia, pain in extremity, bone pain, 


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musculoskeletal pain, headache, anxiety, insomnia, cough, epistaxis, dyspnea, 
productive cough, rash, pruritus, hypertension, and decreased appetite.
Adverse events attributed to the atezolizumabbevacizumab combination occurred in 
27 patients (77%).  The majority of these related events were Grade 1 and 2 in severity, 
with Grade 3 related adverse events occurring in only 1 patient with neutropenia.  The 
five most commonly reported related adverse events included fatigue, nausea, diarrhea, 
decreased appetite, and pyrexia.  Two patients developed adverse events leading to 
treatment discontinuation (liver function test [LFT] abnormalities, hypercalcemia).  Other 
adverse events included upper respiratory tract infection, flu-like symptoms, vomiting, 
constipation, and sinus infection.  The majority of these events were Grade 1 or 2 in 
severity.
Grade 3 AEs (regardless of attribution) were reported for 18 patients (51.4%) in Arm A.  
The most frequently reported related Grade 3 AE included abdominal pain, pneumonia, 
and hypertension (each occurring in 3 patients [8.6%]).  Only 1 patient had a Grade 3 
event of neutropenia that was assessed as related to the study treatment by the 
investigator.  Other Grade 3 events included reduced lymphocyte count, increased 
alkaline phosphatase, chest pain, colonic perforation, and abdominal pain.  The event of 
colonic perforation occurred in a patient with a history of abscess and prior radiation to 
the affected area; the investigator attributed the event to bevacizumab and not to 
atezolizumab.
There were no deaths attributed to atezolizumab.
Fourteen serious adverse events were reported including abdominal pain, catheter site 
infection, dyspnea, pneumonia, colonic perforation, and pyrexia.  None of these serious 
adverse events were attributed to atezolizumab.
1.4.1.3
Clinical Activity in Renal Cell Carcinoma in Arm A of 
Study GP28328
Study GP28328 is a Phase Ib trial of atezolizumab administered with bevacizumab (in 
Arm A) in patients with advanced solid tumors.  Ten first-line RCC patients enrolled and 
dosed by 7 April 2014 were evaluable for efficacy by the cutoff date of 7 July 2014. 
An ORR of 40% (4 of 10 patients, 95% CI: 15.0%, 73.3%) was observed in patients with 
the combination therapy of atezolizumab and bevacizumab (see Figure 1).  Given a 
median duration of follow-up of 7.8 months, 9 of 10 patients have remained in the 
combination treatment with 4 patients achieving at least stable disease in 24 weeks 
(2442 weeks) and 4 patients achieving at least a PR (1736 weeks; see Figure 2).  
Among the 9 patients evaluable for PD-L1 IHC staining at baseline, 2 of 5 (40%) 
responded in the IC1/2/3 group, while 1 of 4 (25%) responded in the IC0 group.  
One responder was unevaluable for PD-L1 IHC staining. 


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Figure 1
Best Change from Baseline in SLD per RECIST v1.1:  Unconfirmed Best Response in Efficacy-Evaluable 
Arm A Patients in Study GP28328 with First-Line Clear-Cell Renal Cell Carcinoma
RECIST Response Evaluation Criteria in Solid Tumors; SLDsum of longest diameter. 
Note:  The efficacy-evaluable patients were dosed by 7 April 2014.


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Figure 2
Tumor Burden over Time by Investigator-Assessed Unconfirmed 
Response and Corresponding PD-L1 IC Status
CRcomplete response; ICtumor-infiltrating immune cell; PDprogressive disease; 
PD-L1programmed deathligand 1; PRpartial response; SDstable disease; TCtumor cell.
1.4.2
Phase II Study WO29074
The ongoing Phase II RCC Study WO29074 randomized 305 patients in a 1:1:1 fashion 
to either the combination of atezolizumab bevacizumab, atezolizumab monotherapy, or 
sunitinib.  The study is still ongoing.  A preliminary review by the Internal Monitoring 
Committee demonstrated no safety or efficacy concerns with the combination of 
atezolizumab and bevacizumab study arm and no impact upon the conduct of 
Study WO29637.
1.5
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
Despite recent advancements, metastatic RCC cancer remains an incurable disease 
because a substantial majority of patients develop resistance to standard therapies, 
including VEGF-directed and/or immunotherapy.  Furthermore, patients exhibit poor 
tolerance with current oral VEGF-directed receptor tyrosine kinase inhibitors, as well as 
current immune-based therapy.  Approved therapies with current VEGF-directed 
receptor tyrosine kinase inhibitors (including sunitinib) are associated with significant 
toxicities (e.g., fatigue, diarrhea, mucositis, hand-foot syndrome, and mucositis) that 
negatively impact quality of life and often limit treatment continuation (see Table 9).  In a 


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recent comparative study of sunitinib and pazopanib, an equal percentage of both 
groups of patients (74%) developed Grade 3 toxicities, and 20% and 24% of these 
patients, respectively, discontinued the study drug because of adverse events 
(Motzer et al. 2013).  Therefore, there is an ongoing need for more efficacious and 
better-tolerated treatments.
Table 9
Grade ≥3 Toxicities and Discontinuations of First-Line Renal Cell 
Carcinoma Agents
Agent
Grade 3
Hypertension
Grade 3 
Asthenia
Any Grade 3 
Adverse Event
Discontinuation 
Due to Study Drug
Sunitinib 
(n548) a
15%
17%
74%
20%
Pazopanib 
(n554) a
15%
10%
74%
24%
BevIFN 
(n337) b
3%
10%
60%
28%
Temsirolimus 
(n209) c
N/A
11%
67%
7%
Atezolizumab Bev
(n59) d
14%
2%
34%
3%
Bevbevacizumab; IFNinterferon; N/Anot available; RCCrenal cell carcinoma.
a Motzer et al.2013.
b Escudier et al. 2007.
c Hudes et al. 2007.
d Preliminary, unpublished, internal data from Arm A of the Phase II Study WO29074.
Encouraging clinical data emerging in the field of tumor immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant survival benefit in patients with advanced malignancies 
(Hodi et al. 2010; Kantoff et al. 2010; Chen et al. 2012).  
Overexpression of PD-L1 on tumor cells has been reported to impede anti-tumor 
immunity, resulting in immune evasion (Blank and Mackensen 2007).  Therefore, 
interruption of the PD-L1/PD-1 pathway represents an attractive strategy to reinvigorate 
tumor-specific T-cell immunity.  PD-L1 expression is prevalent in many human tumors 
and elevated PD-L1 expression on tumor or immune cells are associated with a poor 
prognosis in patients with RCC (Choueiri et al. 2014).
Importantly, preliminary evidence suggests that patients with RCC and 
PD-L1expressing tumors are more likely to benefit from PD-L1 pathwaytargeted 
therapies than are patients with low PD-L1expressing (IC0) tumors.  Data from the 
Phase Ia Study PCD4989g showed that patients with RCC and PD-L1positive (IC1/2/3) 


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tumors have a numerically higher ORR than patients with PD-L1negative (IC0) tumors 
(see Table 6 and McDermott et al. 2014).
The safety profile and associated benefit and risk of atezolizumab as a single agent 
(Phase Ia Study PCD4989g) and in combination with bevacizumab (Phase Ib 
Study GP28328 and Phase II Study WO29074) support its continued development in 
metastatic RCC.  In a cohort of predominantly heavily pre-treated patients with RCC, 
single-agent atezolizumab demonstrated evidence for single-agent activity with tumor 
shrinkage (ORR of approximately 15%) and/or disease stabilization 6 months 
(approximately 50% of patients).  Responses have been durable, and the median 
duration of response for atezolizumab monotherapy was 75.7 weeks.  In the Phase Ib 
study of atezolizumabbevacizumab (Study GP28328), the combination has been well 
tolerated, with 4 of 10 patients achieving a PR and another 4 of 10 maintaining stable 
disease for 24 weeks.
In contrast to the current approved targeted agents or combinations, 
atezolizumabbevacizumab has been generally well tolerated (see Table 9), and the 
preliminary response rates for atezolizumabbevacizumab compare favorably to the 
30%35% historical ORR for sunitinib, pazopanib, and the bevacizumab/interferon 
combination. 
In summary, treatment with atezolizumabbevacizumab offers the potential for clinical 
benefit in patients with RCC.  
Given that both the VEGF and PD-L1 pathways are important in RCC pathogenesis, this 
study is designed to test the hypothesis that inhibition of VEGF signaling will enhance 
the efficacy of immunotherapy in the front-line treatment of patients with metastatic RCC.  
On the basis of the information summarized above, the Sponsor believes that the 
assessment of atezolizumab in combination with bevacizumab for the treatment of 
metastatic RCC presents a positive benefit-risk.
2.
OBJECTIVES
Analyses of the following objectives will be performed for the population of patients with 
inoperable, locally advanced, or metastatic RCC, unless otherwise indicated.  Where 
specified, a comparison of the treatment arms will be performed in the patient population 
defined according to tumor PD-L1 expression as evaluated by IHC.
2.1
EFFICACY OBJECTIVES
The primary and secondary efficacy objectives will be evaluated in the PD-L1selected 
population (IC1/2/3) as well as in the ITT population (includes all IC scores; see Table 5
for a description of IC score).


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2.1.1
Primary Efficacy Objective
The primary efficacy objective of the study is as follows:

To evaluate the efficacy of atezolizumabbevacizumab compared with sunitinib as 
measured by the co-primary endpoints of investigator-assessed PFS per 
RECIST v1.1 and overall survival (OS).
2.1.2
Secondary Efficacy Objectives
The secondary efficacy objectives of the study are as follows:

To evaluate the efficacy of atezolizumabbevacizumab versus sunitinib as 
measured by Independent Review Committee (IRC)assessed PFS according to 
RECIST v1.1

To evaluate the efficacy of atezolizumabbevacizumab versus sunitinib as 
measured by investigator-assessed ORR (completepartial response rates) per 
RECIST v1.1

To evaluate the efficacy of atezolizumabbevacizumab versus sunitinib as 
measured by investigator-assessed DOR among patients with an objective 
response per RECIST v1.1

To evaluate the efficacy of atezolizumabbevacizumab versus sunitinib as 
measured by IRC-assessed ORR and DOR according to RECIST v1.1

To evaluate the efficacy of atezolizumabbevacizumab versus sunitinib as 
measured by investigator-assessed PFS, DOR, and ORR per modified RECIST 
(see Appendix 4)

To evaluate the efficacy of atezolizumabbevacizumab versus sunitinib among 
patients with sarcomatoid histology (defined by investigator-assessed conventional 
histopathology) as measured by investigator assessed PFS per RECIST v1.1 and 
OS

To evaluate the efficacy of atezolizumabbevacizumab versus sunitinib on 
symptom interference as measured by the M.D. Anderson Symptom Inventory 
[MDASI Part II])
2.2
SAFETY OBJECTIVES
The safety objectives of the study are as follows:

To evaluate the safety and tolerability of atezolizumabbevacizumab versus 
sunitinib

To evaluate the incidence of anti-therapeutic antibodies (ATAs) against 
atezolizumab and to explore the potential relationship of immunogenicity response 
with pharmacokinetics, safety, and efficacy


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2.3
PHARMACOKINETIC OBJECTIVES
The pharmacokinetic (PK) objectives of the study are as follows:

To characterize the pharmacokinetics of atezolizumab when administered in 
combination with bevacizumab

To characterize the pharmacokinetics of bevacizumab when administered in 
combination with atezolizumab
2.4
PATIENT-REPORTED OUTCOME OBJECTIVES
The additional patient-reported outcome (PRO) objectives of the study are as follows:

To assess symptom severity associated with atezolizumabbevacizumab versus 
sunitinib in patients with RCC as measured by the MDASI and Brief Fatigue 
Inventory (BFI)

To document patients’ perspective regarding the tolerability of the treatments (from 
the treatment side-effects subscale from the Functional Assessment of Cancer 
Therapy Kidney Symptom Index [FKSI-19])

To obtain general measures of health as measured by the EuroQoL 5 Dimensions 
(EQ-5D) questionnaire for health economic modeling of 
atezolizumabbevacizumab versus sunitinib in patients with RCC
2.5
EXPLORATORY OBJECTIVES
The exploratory objectives of the study are as follows:

To evaluate the relationship between the expression of other candidate predictive 
immune, angiogenic, or hypoxia biomarkers, as defined by IHC or quantitative 
polymerase chain reaction (qPCR), and efficacy as defined by PFS and ORR

To evaluate the efficacy of atezolizumabbevacizumab versus sunitinib among 
patients with tumor Fuhrman Grade 4 or sarcomatoid histology (defined by 
investigator-assessed conventional histopathology) as measured by PFS and ORR

To assess immune-mediated predictive and prognostic exploratory biomarkers in 
tumor tissue and blood from archival specimens, fresh biopsy specimens, or 
specimens obtained during the study and their association with disease status 
and/or efficacy as defined by PFS and ORR
3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
This is a Phase III, multicenter, randomized, open-label study designed to evaluate the 
efficacy and safety of atezolizumabbevacizumab versus sunitinib in patients with 
inoperable, locally advanced, or metastatic RCC who have not received prior systemic 
active or experimental therapy, either in the adjuvant or metastatic setting.  The study 
will enroll approximately 900 patients, including a minimum of 351 patients with a PD-L1 
IHC of IC score of 1/2/3 (PD-L1selected population), at approximately 150180 centers 
globally.  A maximum of approximately 180 patients (20%) with a Memorial Sloan 




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The key inclusion criteria include:

Male and female patients aged 18 years with Karnofsky performance status (KPS) 
70% who have histologically proven, unresectable locally advanced or metastatic 
RCC with clear cell histology and/or a component of sarcomatoid histology and who 
have not received prior treatment in the metastatic setting 

Tumor specimens from patients meeting eligibility criteria will be prospectively 
tested for PD-L1 expression by a central laboratory.  PD-L1 expression must be 
determined prior to randomization.
Patients will be randomized in a 1:1 ratio to one of two treatment arms:

Arm A (experimental arm):  Atezolizumab 1200 mg intravenous (IV) infusions 
every 3 weeks (q3w; dosed in 6-week cycles)bevacizumab 15 mg/kg q3w (dosed 
in 6-week cycles) 

Arm B (control arm):  Sunitinib 50 mg/day orally for 4 weeks, followed by 2 weeks of 
rest (dosed in 6-week cycles)
Randomization will be stratified by:

Presence of liver metastasis (yes vs. no)

MSKCC (Motzer) score (low, intermediate, or high risk; 0, 12, or 3), which 
comprises the following five risk factors:  KPS 80%, LDH 1.5upper limit of 
normal (ULN), hemoglobin less than the lower limit of normal (LLN), corrected 
serum calcium 10 mg/dL, and time from nephrectomy to systemic therapy 
(12 months vs. 12 months) (see Appendix 9).

PD-L1 status:  IC1/2/3 versus IC0
Atezolizumab will be administered intravenously at a fixed dose of 1200 mg on 
Days 1 and 22 of each 42-day cycle.  Bevacizumab will be administered intravenously at 
15 mg/kg on Days 1 and 22 of each 42-day cycle.  Patients randomized to the 
atezolizumabbevacizumab arm who transiently withhold or permanently discontinue 
either atezolizumab or bevacizumab may continue on single-agent therapy until disease 
progression (i.e., patients holding bevacizumab transiently for adverse effects may 
continue atezolizumab monotherapy and vice versa).  Guidelines for dosage 
modification, treatment interruption or discontinuation, and the management of specific 
adverse events are provided in Sections 5.1.3, 5.1.4, and 5.1.5.  
Sunitinib will be administered at the starting dose of 50 mg/day orally on Day 1 through 
Day 28 of each 42-day cycle.
Patients will receive atezolizumab and/or bevacizumab or sunitinib as long as they 
continue to experience clinical benefit in the opinion of the investigator until 
unacceptable toxicity or symptomatic deterioration attributed to disease progression 
(e.g., pain secondary to disease or unmanageable ascites) as determined by the 


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investigator after an integrated assessment of radiographic data, biopsy results (if 
available), and clinical status.
Patients in both study arms will be permitted to continue their treatments after 
RECIST v1.1 criteria for progressive disease are met if they meet all of the following 
criteria:

Evidence of clinical benefit as assessed by the investigator

Absence of symptoms and signs (including worsening of laboratory values [e.g., 
new or worsening hypercalcemia]) indicating unequivocal progression of disease

No decline in KPS that can be attributed to disease progression

Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions
Patients in whom radiographic disease progression is confirmed at a subsequent tumor 
assessment may be considered for continued study treatment at the discretion of the 
investigator if they continue to meet the criteria above (see Figure 4).  Collection of a 
tumor biopsy tissue sample at the time of first radiographic progression for all consenting 
patients in both treatment arms is required, if clinically feasible per the investigator and 
not prohibited by country or institution, in order to evaluate the utility of the biopsy tissue 
sample in distinguishing pseudoprogression/tumor immune infiltration from true disease 
progression.  These data will be analyzed for the association between changes in tumor 
tissue and clinical outcome.
No crossover will be allowed from the control arm to the experimental arm.
Patients will undergo scheduled tumor assessment at baseline, Week 12, and then 
every 6 weeks through Week 78 followed by every 12 weeks thereafter.  Tumor 
assessments will continue until disease progression per both RECIST v1.1 and modified 
RECIST (see Appendix 4), 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 modified RECIST.  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.  The 
following information regarding all subsequent anti-neoplastic agents upon treatment 
discontinuation will be collected:  line of therapy, date of first dose of agent, date of last 
dose of agent (or if ongoing), patient's best response, and date of disease progression.
Schedules of assessments are provided in Appendix 1 and Appendix 2.


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Sites will provide imaging used for tumor assessment to the IRC to enable centralized, 
independent review of response and progression endpoints.  IRC membership and 
procedures will be detailed in an IRC 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 atezolizumab and bevacizumab 
pharmacokinetics and to detect the presence of antibodies to atezolizumab and 
bevacizumab.  Patient samples, including archival tumor tissues, as well as serum, 
plasma, and blood will be collected for future exploratory biomarker assessments.
PRO data will be obtained from patients with use of the MDASI (see Appendix 11), the 
BFI (see Appendix 12), the treatment side-effect subscale (FKSI-19; see Appendix 13), 
and the EQ-5D (see Appendix 14) (see Section 4.5.6).
The co-primary efficacy endpoints are investigator-assessed PFS using RECIST v1.1 
and OS.  PFS will be analyzed in the PD-L1selected population, and OS will be 
analyzed first in the ITT population; additional analyses of OS will be performed in a 
hierarchical fashion (see Section 6.1.1).  See Sections 6.1.2 and 6.1.3 for a description 
of the timing of analyses of PFS and OS.  No interim analyses of PFS are planned.  See 
Section 3.4 for other outcome measures.
3.1.1
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 
analysis of the co-primary efficacy endpoint of PFS according to policies and procedures 
detailed in an iDMC Charter.  No interim efficacy analyses are planned for PFS.
Staff at an independent Data Coordinating Center (iDCC) will prepare all summaries and 
analyses for iDMC review.  The safety summaries will include demographic data, 
adverse events, serious adverse events, and relevant laboratory data.
Members of the iDMC will be external to the Sponsor and will follow a charter that 
outlines their roles and responsibilities.  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/Ethics Committees (IRBs/ECs).


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3.2
END OF STUDY
The end of study will occur when the number of deaths required for the final analysis of 
OS has been observed (see Section 6.1.3).  On the basis of accrual projections and 
projected median OS for each treatment arm, the final analysis of OS is projected to 
occur at Month 63 from the time the first patient is randomized.
In addition, the Sponsor may decide to terminate the study at any time.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Primary and Secondary Endpoints
The co-primary efficacy endpoints are investigator-assessed PFS using RECIST v1.1
and OS.  PFS will be analyzed in the PD-L1selected population (defined as IC1/2/3), 
and OS will be analyzed first in the ITT population; additional analyses of OS will be 
performed in a hierarchical fashion in the PD-L1selected population (see Section 6.1.1).  
On the basis of other immunotherapy studies, including Studies PCD4989g and 
GP28328, as well as other studies involving renal, lung, and bladder tumors, the 
treatment benefit of atezolizumab may be greater among patients with higher PD-L1 
expression (IC1/2/3).  OS benefit may also be observed in the ITT population.
PFS of sufficient magnitude constitutes clinical benefit to the patient.  PFS also allows 
evaluation of treatment benefit without possible confounding effects of subsequent 
therapies.  This has historically been the standard measure of effectiveness in RCC 
trials given the availability of secondary and tertiary lines of therapy for metastatic RCC.  
The hypothesis that treatment with atezolizumab and bevacizumab will prolong PFS 
compared with treatment with sunitinib is based on the durable response rates observed 
in both the Phase I Study PCD4989g with atezolizumab monotherapy and the Phase Ib 
Study GP28328 of atezolizumab and bevacizumab.  Patients will be evaluated for 
disease progression at predefined, standard intervals to minimize evaluation-time biases.
OS is an accepted measure of clinical benefit for patients.
Centralized independent PFS assessment will be performed by the IRC and will be used 
to support results of the investigator-assessed PFS.  ORR and DOR measurements will 
permit the evaluation of differences in response and progression patterns between the 
two treatment arms.  Given the potential limitations of conventional response criteria to 
assess activity of immunotherapeutic agents (see Section 3.3.7) modified RECIST 
assessments will also be performed.
Patients’ rating of their symptom interference on daily functioning will provide further 
evidence of the clinical benefit between the two treatment groups.


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3.3.2
Rationale for Inclusion of All Patients (All Levels of PD-L1 
Expression by Immunohistochemistry) in the Study
In Study PCD4989g, the Phase Ia monotherapy study of atezolizumab, the response 
rate in patients with PD-L1 IC1/2/3 RCC has been higher (20%) than that observed for 
the PD-L1 IC0 patients (10%; see Section 1.4.1.1.2).
Responses to the combination of atezolizumab with bevacizumab have been observed 
in both PD-L1 IC1/2/3 and PD-L1 IC0 patients.  In the Phase Ib Study GP28328, among 
patients who received atezolizumab in combination with bevacizumab and assessed for 
PD-L1 expression level, responses were seen in 2 of 5 PD-L1 IC1/2/3 (40%) and 1 of 
4 PD-L1 IC0 (25%) patients.  Therefore, given available evidence, it is too early to 
exclude PD-L1 IC0 patients from potential benefit from the combination.
3.3.3
Rationale for Stratification Factors
In order to balance the distribution of risk factors between the treatment arms, the 
randomization will be stratified for the following factors:

The presence of liver metastases (yes/no) is included as a stratification factor 
because it is a well-described clinical factor portending a poor prognosis 
(Motzer et al. 1999) and specifically noted to be predictive for poorer survival in the 
CALBG 90206 bevacizumab and interferon study (Rini et al. 2010).

MKSCC (Motzer) risk score is a well-established prognostic index stratifying patients 
into three categories:  good, intermediate, and poor risk depending upon five criteria 
(see Appendix 9) (Motzer et al. 1999).

The PD-L1 status (i.e., IC0 vs. IC1/2/3) is included as a stratification factor to 
account for potential differences in efficacy between patients with varying PD-L1 
expression levels at study entry.  Both investigators and the Sponsor will remain 
blinded to the results of an individual patient’s PDL1 status.
3.3.4
Rationale for Evaluating Atezolizumab in Renal Cell Carcinoma
Immune checkpoint inhibitors, including atezolizumab, have demonstrated the potential 
to deliver significant clinical benefit to patients with advanced cancer (see 
Section 1.1.1.2).  In this respect, atezolizumab is an example of an agent that is well 
tolerated and has the potential to deliver an excellent therapeutic index.  In addition, 
because these therapies have the potential to induce potent anti-tumor immunity, there 
exists the potential for long-term durable responses.
Early unpublished data from the Phase Ia Study PCD4989g suggest that tumor PD-L1 
status (as determined by IC0 vs. IC1/2/3) in patients with RCC correlates with response 
to single-agent atezolizumab, with 15% of patients (9 of 62 efficacy-evaluable patients 
with clear-cell RCC) achieving a PR (confirmed PR or unconfirmed PR) or CR and 57% 
of patients achieving stable disease.  Thirty-one percent of patients had stable disease 
at 24 weeks.  The 24-week PFS was 51%.  Notably, 7 of 35 patients (20%) with PD-L1 
IC1/2/3 RCC achieved an objective response compared with 2 of 21 patients (10%) who 


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were PD-L1 IC0.  A potential benefit in terms of PFS or OS remains to be tested in 
controlled studies. 
These data provide a rationale for evaluating the efficacy of atezolizumab in patients 
with RCC.
3.3.5
Rationale for Testing AtezolizumabBevacizumab in Renal 
Cell Carcinoma
Bevacizumab is a recombinant, humanized therapeutic antibody directed against VEGF.  
In addition to promoting tumor angiogenesis, there is increasing evidence that VEGF 
plays a role in cancer immune evasion through several different mechanisms.  For 
example, experiments with activated endothelial cells suggest that in the tumor 
microenvironment, VEGF may reduce lymphocyte adhesion to vessel walls, thus 
contributing to decreased immune-cell recruitment to the tumor site (Bouzin et al. 2007).  
Some immunosuppressive activities of VEGF can be reversed by inhibition of VEGF 
signaling.  Thus, mice exposed to pathophysiologic levels of VEGF exhibited impaired 
dendritic cell function, which could be restored by blockade of VEGFR2 
(Huang et al. 2007).  In a murine melanoma model, VEGF blockade synergized with 
adoptive immunotherapy, as evidenced by improved anti-tumor activity, prolonged 
survival, and increased trafficking of T cells into tumors (Shrimali et al. 2010).  
Synergistic effects have also been observed in a clinical study of melanoma patients 
combining an immunomodulatory antibody (antiCTLA-4; ipilimumab) and 
bevacizumab (Hodi et al. 2011).  In this study of an immunomodulatory agent and 
bevacizumab, best overall responses were PR in 8 of 22 patients (35%) and stable 
disease in 6 of 22 patients (27%).  All responses were durable for 6 months.  Therefore, 
the combined treatment with atezolizumab and bevacizumab may augment the anti-
tumor immune response, resulting in improved and more durable clinical benefit.
3.3.6
Rationale for Atezolizumab Dose and Schedule
The fixed dose of 1200 mg (equivalent to an average body weightbased dose of 
15 mg/kg) was selected on the basis of both nonclinical studies and available clinical 
data from Study PCD4989g as described below.
The target exposure for atezolizumab was projected on the basis of nonclinical tissue 
distribution data in tumor-bearing mice, target-receptor occupancy in the tumor, the 
observed atezolizumab interim pharmacokinetics in humans, and other factors.  The 
target trough concentration (Ctrough) was projected to be 6 g/mL on the basis of several 
assumptions, including:  1) 95% tumor-receptor saturation is needed for efficacy and 
2) the tumor-interstitial concentration to plasma ratio is 0.30 based on tissue distribution 
data in tumor-bearing mice. 
The atezolizumab dose is also informed by available clinical activity, safety, 
pharmacokinetic, and immunogenicity data.  Anti-tumor activity has been observed 
across doses from 1 mg/kg to 20 mg/kg.  The maximum tolerated dose of atezolizumab 


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was not reached, and no dose-limiting toxicities have been observed at any dose in 
Study PCD4989g.  Available preliminary pharmacokinetic (PK) data (0.0320 mg/kg) 
from Study PCD4989g suggest that for doses 1 mg/kg, overall atezolizumab exhibits 
pharmacokinetics that are both linear and consistent with typical IgG1 antibodies.  
Detectable ATAs were observed in patients at all dose levels, but were associated with 
changes in pharmacokinetics for some patients in only the lower dose cohorts 
(0.3, 1, and 3 mg/kg).  It is unclear from currently available data in these lower dose 
cohorts whether administration of higher doses to patients with both detectable ATAs 
and reduced exposure would necessarily restore exposure to expected levels.  No clear 
relationship between the development of measurable ATAs and safety or efficacy has 
been observed.  Available data suggest that development of detectable ATAs does not 
appear to have a significant impact on pharmacokinetics for doses from 10 to 20 mg/kg 
in most patients.  Correspondingly, patients dosed at the 10-, 15-, and 20-mg/kg dose 
levels have maintained target trough levels of drug despite the detection of ATAs.  
Currently available PK and ATA data suggest that the 15-mg/kg atezolizumab q3w 
regimen (or fixed-dose equivalent) for Phase II and Phase III studies would be sufficient 
to both maintain Ctrough 6 g/mL and further safeguard against both interpatient 
variability and potential effect of ATAs that could lead to subtherapeutic levels of 
atezolizumab relative to the 10-mg/kg atezolizumab q3w regimen (or fixed-dose 
equivalent).  From inspection of available observed Ctrough data, moving further to the 
20 mg/kg atezolizumab q3w regimen does not appear to be warranted to maintain 
targeted Ctrough levels relative to the proposed 15-mg/kg atezolizumab q3w level.
Simulations (Bai et al. 2012) do not suggest any clinically meaningful differences in 
exposure following fixed dose or dose adjusted for weight.  On the basis of this analysis, 
a fixed dose of 1200 mg is selected (equivalent to a body weightbased dose of 
15 mg/kg).
Selection of an every 21-day dosing interval both is supported by this preliminary 
pharmacokinetics evaluation and allows for a convenient integration with common 
chemotherapeutic regimens.
3.3.7
Rationale to Allow Dosing PostRECIST v1.1 Progression and 
Use of Modified RECIST
Immunotherapy approaches to the treatment of solid tumors has resulted in distinct 
patterns of response different from those of traditional cytotoxic therapies and other 
targeted therapies.  Traditional response criteria may be insufficient to characterize 
clinical benefit with use of this class of compounds.  In a review of clinical data from the 
ipilimumab Phase II melanoma study, four distinct response patterns were observed:  
a) shrinkage of baseline lesions without new lesions, b) durable stable disease, 
sometimes followed by prolonged gradual decline in total tumor burden, c) response 
after an increase in tumor burden, and d) response in the presence of new lesions 
(Wolchok et al. 2009; O’Regan et al. 2011).  In the ipilimumab study, patients with 


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disease progression before Week 12 (first tumor assessment) who did not have 
evidence of clinical deterioration were allowed to continue on study at the discretion of 
the investigator.  Some of these patients were noted to have objective responses or 
stable disease at later tumor assessments without the addition of other anti-cancer 
therapies.  This led to the proposal for immune-related (i.e., modified) response criteria, 
taking into account index and measurable new lesions.  The sum of the product of the 
longest perpendicular dimensions (SPD) of index lesions and any new, measurable 
lesions (tumor burden) are taken into account for each tumor assessment.  Disease 
progression must be confirmed by a repeat, consecutive assessment no fewer than 
4 weeks after the initial, unconfirmed disease progression, provided the patient is 
experiencing no evidence of clinical deterioration.  With use of these criteria, 9.7% of 
subjects initially characterized as disease progression by the World Health Organization 
criteria had evidence of clinical benefit (PR or stable disease). 
In the preliminary experience of atezolizumab in Study PCD4989g, similar patterns of 
response have been observed.  Evidence of tumor growth followed by response has 
been observed in several tumor types including RCC.  Because of the complexity of 
response patterns observed with immunotherapeutic approaches, efficacy parameters 
will be evaluated by investigator assessment with use of both standard RECIST v1.1, as 
well as modified RECIST (see Appendix 4).
There may also be benefit to continuing sunitinib beyond RECIST v1.1 radiographic 
progression provided the patient remains clinically stable.  This has been described by 
several studies as a protracted stabilization of the tumor growth rate 
(Teo and McDermott 2012; Burotto et al. 2014).  The PFS benefit with continuing 
sunitinib in this retrospective evaluation appears to be comparable, if not superior, to 
current second-line options (Burotto et al. 2014).
Patients will be permitted to continue study treatment on either study arm after 
progression by RECIST v 1.1, provided there is believed to be clinical benefit and a 
careful assessment of the risks by investigators and patients.  
3.3.8
Rationale for Pharmacokinetic Evaluation Schedule
The proposed sampling scheme for atezolizumab and bevacizumab concentration 
assessments will contribute to the characterization of atezolizumab and bevacizumab 
pharmacokinetics, respectively.  The atezolizumab and bevacizumab concentration 
results may be compared with available data from other clinical studies and correlated 
with safety events in this study as appropriate.
3.3.9
Rationale for Blood Sampling for Biomarkers
Changes in biomarkers in blood may provide evidence for biologic activity of 
atezolizumab in humans and may allow for the development of a blood-based biomarker 
to help predict which patients may benefit from atezolizumab.  An exploratory objective 
of this study is to evaluate baseline levels and potential changes upon treatment in 


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surrogate pharmacodynamic markers (including but not limited to cytokines, such as 
IFN-) in blood samples.  
In addition, potential correlations of these pharmacodynamic markers with the dose, 
safety, and anti-tumor activity of atezolizumab will be explored.
3.3.10
Rationale for the Collection of Archival and/or Fresh Tumor 
Specimens
Pathway activation in tumors, as demonstrated by PD-L1 levels, may be an important 
predictive diagnostic for atezolizumab.  A fraction of patients with RCC appear to derive 
a long-term benefit from PD-L1based therapy.  The pathway biomarkers responsible for 
this long-term benefit are unknown.  Published results suggest that expression of 
PD-L1 in tumors correlates with response to antiPD-1 therapy (Topalian et al. 2012).  
This correlation is also observed with atezolizumab in preliminary data from 
Study PCD4989g such that patients with PD-L1 expression appear to derive the most 
benefit from atezolizumab, as judged by RECIST response and/or prolonged stable 
disease (see Section 3.3.4).  In this study, PD-L1 status will be used initially for 
stratification; tumor specimens from patients meeting eligibility criteria will be 
prospectively tested for PD-L1 expression by a central laboratory.  In addition, PD-L1 
status (as defined by expression of PD-L1 on tumor cells and/or tumor-infiltrating 
cells), will be correlated to treatment efficacy as defined by PFS and ORR.
In order to determine PD-L1 status, prior to study initiation, patients will be required to 
submit tumor tissue that was collected within 24 months of Cycle 1, Day 1.  If a recent 
archival sample is not available, patients must undergo fresh tumor biopsy to meet 
eligibility.  An archival specimen that was collected 24 months prior, if available, should 
also be submitted to evaluate change in PD-L1 status over time.  Biopsy tissue samples
must be obtained in a manner that minimizes risk (see Appendix 8).
These archival and/or fresh biopsy samples will be used to determine level of 
PD-L1 expression in tumor and tumor-infiltrating (i.e., immune) cells.  Other exploratory 
markers, such as potential predictive and prognostic markers that are related to 
response or clinical benefit of atezolizumab, tumor immunobiology, angiogenesis, 
hypoxia, or tumor type, may also be analyzed.
3.3.11
Rationale for the Collection of Tumor Specimens at the Time 
of Initial Radiological Progression 
Following documented RECIST v1.1 disease progression, patients are required to 
undergo tumor biopsy tissue sample collection of a progressing lesion (unless the 
location of the tumor renders tumor biopsy tissue sample collection unsafe or not 
clinically feasible per the investigator or is prohibited by the institution or country) in 
patients providing consent.  Biopsy tissue sample collection must be obtained in a 
manner that minimizes risk (see Appendix 8).  Anti-tumor immune responses such as 
those associated with atezolizumab may result in objective responses that are delayed 


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and can be preceded by initial apparent radiological progression.  This initial apparent 
progression, called pseudoprogression, may occur as a result of either delayed 
anti-tumor activity and/or robust tumor immune infiltration of the tumor with a 
concomitant increase in tumor size.  In addition, lesions that would otherwise be 
undetectable with conventional imaging (i.e., micrometastatic disease) may increase in 
size as a result of these processes and be recorded as new lesions (Hales et al. 2010).  
In order to characterize the kinetics and biological basis of the potential anti-tumor 
activity of atezolizumab, all consenting patients will be required to undergo a tumor 
biopsy tissue sample collection (with exceptions as described above).  Data will be 
analyzed for the association between changes in tumor tissue and clinical outcome to 
further understand the potential mechanisms of resistance and progression to 
atezolizumab bevacizumab when compared to such mechanisms after treatment with 
sunitinib.  Biopsy tissue samples collected at progression will be analyzed to determine 
changes in PD- expression, CD8 T-cell infiltration, next generation DNA targeted 
sequencing related to tumor biology (Foundation Medicine), as well as vascular density 
(e.g., CD31).  DNA and/or RNA extraction may be performed to enable identification of 
somatic mutations, with use of next-generation sequencing (NGS), that are associated 
with disease progression or acquired resistance to atezolizumab and to increase 
understanding of disease pathobiology. In addition, markers related to tumor biology 
may also be analyzed.
NGS may be performed by Foundation Medicine. If performed by Foundation Medicine, 
the investigator can obtain results from the samples collected at the time of disease 
progression in the form of an NGS report, which is available directly from Foundation 
Medicine upon request. The investigator may share and discuss the results with the 
patient, unless the patient chooses otherwise. The Foundation Medicine NGS assay 
has not been cleared or approved by the U.S. Food and Drug Administration (FDA); 
results from these investigational tests should not be used to guide future treatment 
decisions. 
3.3.12
Rationale for Comparator Arm
Targeted therapy with tyrosine kinase inhibitors is widely used in the management of 
RCC in the first-line setting.  Sunitinib is a multi-targeted receptor kinase inhibitor 
targeting several receptor tyrosine kinases, including VEGF receptors (VEGFR-1, -2, 
and -3), platelet-derived growth factor receptors, stem cell factor receptor (c-KIT), and 
FMS-like tyrosine kinase (FLT-3).  Sunitinib is the most widely used agent globally for 
the management of RCC in the first-line setting.
Sunitinib was granted accelerated approval by the FDA in January 2006 for the 
treatment of patients with advanced RCC following the demonstration of favorable ORR 
in two separate Phase II trials.  Sunitinib was approved by the European Commission in 
July 2006 under conditional approval, and was later granted full approval in 
January 2007 on the basis of a large multi-institutional, randomized Phase III trial in 


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which 750 patients with clear-cell RCC were randomized 1:1 to receive either sunitinib or 
IFN .  The results of the pivotal Phase III trial demonstrated better outcomes in the 
sunitinib arm compared to the IFN arm (PFS of 11 months vs. 5 months; HR: 0.42; 
Motzer et al. 2007).  The study enrolled patients with all MSKCC (Motzer) risk categories 
and the results demonstrated PFS benefit regardless of the prognostic category 
(HR: 0.37, 0.39, and 0.53 in good, intermediate, and poor-risk strata, respectively).  In 
comparison, the pivotal temsirolimus study in exclusively patients with poor risk 
demonstrated a HR of 0.66 compared to IFN and remains the only RCC study to 
demonstrate an overall survival benefit (Hudes et al. 2007).  With longer follow-up, 
sunitinib further demonstrated a trend toward an OS benefit (HR: 0.82; p0.05), 
extending OS from 21.8 months to 26.4 months (Motzer et al. 2009).  A recent trial 
comparing pazopanib and sunitinib in front-line metastatic RCC demonstrated a median 
PFS of approximately 8.4 months for pazopanib and 9.5 months for sunitinib (HR 1.05; 
Motzer et al. 2013).  The study enrolled patients with all MSKCC (Motzer) risk categories 
and the results suggested similar efficacy between the two agents.
Furthermore, sunitinib is considered by the National Comprehensive Cancer Network 
(NCCN) a Category 1 option for the management of metastatic RCC in previously 
untreated patients.  Similarly, European Society for Medical Oncology (ESMO) 
Guidelines recommend sunitinib for good or intermediate risk (Category I) and poor risk 
(Category II) patients (Escudier et al. 2012).  Sunitinib is widely administered for all 
MSKCC (Motzer) risk categories.
3.3.13
Rationale for Patient-Reported Outcomes
Treatment tolerability is a key issue in the treatment of first-line advanced RCC.  The 
progression of RCC is often asymptomatic, and the symptoms, functional interference, 
and impact of quality of life that patients experience may be attributable in large part to 
treatment-related side effects.  The treatment-related symptoms associated with the 
current standard of care for first-line RCC, VEGF-directed tyrosine kinase inhibitors 
(including sunitinib), are extensive and well documented (Motzer et al. 2013, 
Escudier et al. 2014) and include fatigue, gastrointestinal symptoms, such as diarrhea, 
hand-foot syndrome, dysgeusia, and stomatitis, among others.  Despite the superior 
safety and quality-of-life profile of pazopanib compared with sunitinib demonstrated in 
the COMPARZ trial, approximately 20% of patients in both treatment arms discontinued 
study drug as a result of adverse events and patients in both study arms reported 
increased fatigue, functional interference from treatment-related side effects and 
physical symptoms, and worsened mouth, hand and foot soreness, as measured by the 
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), the treatment 
side-effects subscale of the FKSI-19 and the Supplementary Quality of Life 
Questionnaire (SQLQ), respectively (Motzer et al. 2013).  Therefore, characterizing the 
tolerability of the atezolizumabbevacizumab combination compared with sunitinib from 
the patient’s perspective is important in demonstrating overall comparative treatment 
benefit.  


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3.3.14
Rationale for Open-Label Design
An open-label design was considered appropriate for this patient population because of 
the unique characteristics associated with the sunitinib control arm, including toxicities 
(i.e., hand-foot syndrome, mucositis, and dysgeusia) and delivery method (i.e., oral 
agent vs. IV administration) that would make it difficult to maintain the treatment blind.  In 
the COMPARZ study, hand-foot syndrome, stomatitis, dysgeusia, and yellow skin of any 
grade occurred in 50%, 36%, 27%, and 15% respectively, in the sunitinib arm 
(Motzer et al. 2013) and have not been observed with the combination of atezolizumab 
and bevacizumab.  Validation of tumor assessments by investigators will also be 
conducted with a centralized IRC as a secondary endpoint to evaluate any potential bias.
3.4
OUTCOME MEASURES
3.4.1
Efficacy Outcome Measures
The co-primary efficacy outcome measures are: 

PFS, defined as the time from randomization to the first occurrence of disease 
progression, as determined by the investigator from tumor assessments based on 
RECIST v1.1, or death from any cause and 

OS, defined as the time from randomization to death due to any cause
The secondary efficacy outcome measures for this study are as follows:

PFS based on IRC assessment of radiographic progression per RECIST v1.1

ORR, defined as the proportion of patients with an objective response (either CR or 
PR, confirmation not required) as determined by investigator per RECIST v1.1

DOR, defined as the time from the first documented response to documented 
disease progression as determined by the investigator per RECIST v1.1 or death 
due to any cause, whichever occurs first

ORR and DOR based on IRC assessment per RECIST v1.1

PFS, ORR, and DOR based on investigator assessment per modified RECIST 
criteria (see Appendix 4)

Change from baseline in symptom interference (from MDASI Part II)
3.4.2
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Incidence, nature, and severity of all adverse events, including Grade 3 laboratory 
toxicities (grading per NCI CTCAE v4.0; laboratory toxicities based on local 
laboratory assessments), during first-line treatment

Incidence of ATA response to atezolizumab and potential correlation with 
pharmacokinetics, safety, and efficacy parameters


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3.4.3
Pharmacokinetic Outcome Measures
The PK outcome measures for this study are as follows:

Maximum atezolizumab serum concentration (Cmax) after infusion on Cycle 1, Day 1 

Minimum atezolizumab serum concentration (Cmin) prior to the infusion on Day 1 
of Cycles 1, 2, 4, 8 and every eight cycles thereafter; Day 22 of Cycles 1, 2, and 4; 
and at study termination

Bevacizumab Cmax after infusion on Day 1 of Cycles 1 and 2

Bevacizumab Cmin prior to the infusion on Day 1 of Cycles 1 and 2 and at study 
termination
3.4.4
Patient-Reported Outcome Measures
The other PRO outcome measures for this study are as follows:

Change from baseline in symptom severity as measured by the MDASI and BFI 

Change from baseline in treatment side effects subscale (from FKSI-19)
In addition, health status will be collected the EuroQoL 5 Dimensions (EQ-5D) 
questionnaire to derive utilizes for health economic modeling. 
3.4.5
Exploratory Outcome Measures
The exploratory outcome measures for this study are as follows:

Status of PD-L1, immune-, angiogenic-, and RCC-related and other exploratory 
biomarkers in archival and/or freshly obtained tumor tissues and blood collected 
before, during, or after treatment with atezolizumabbevacizumab or sunitinib or at 
progression

PFS and ORR in patients with tumor Fuhrman Grade 4 or sarcomatoid histology 
(defined by investigator-assessed conventional histopathology)

Status of tumor-infiltrating immune cells and biomarkers in biopsy specimens and 
blood collected at the first evidence of radiographic disease progression
4.
MATERIALS AND METHODS
4.1
PATIENTS
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Unresectable advanced or metastatic RCC with clear-cell histology and/or 
component of sarcomatoid carcinoma
Renal cell carcinoma with any component of high-grade malignant spindle cells 
consistent with sarcomatoid histology is eligible. (See Appendix 15 for further 
guidelines regarding defining sarcomatoid histology.)


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
Evaluable MSKCC risk score (i.e., “Motzer” score, see Appendix 9)
All MSKCC risk scores are included
Patients with good risk MSKCC (risk score 0) will comprise no more than 20% 
of the study population

Definitive diagnosis of RCC on the basis of a representative, formalin-fixed, 
paraffin-embedded tumor specimen accompanied by an associated pathology report 
collected within 24 months prior to Cycle 1, Day 1 available at the study site that 
allows determination of PD-L1 expression status (IC) (required prior to 
randomization)
The archival specimen must contain adequate viable tumor tissue to establish 
PD-L1 expression status by a central laboratory prior to randomization.
The specimen may consist of a tissue block (preferred) or at least 15 unstained, 
serial sections.
Fine-needle aspiration, brushing, cell pellet from pleural effusion, bone 
metastases, and lavage samples are not acceptable.  For core needle biopsy 
specimens, at least three cores embedded into a single paraffin block should be 
submitted for evaluation.  Tumor tissue from bone metastases is not evaluable 
for PD-L1 expression and is therefore not acceptable.
If the archival tissue was acquired 24 months prior to Cycle 1, Day 1, the 
patient may still be eligible provided the patient is willing to consent to and 
undergo a pre-treatment core or excisional biopsy of the tumor.  If the location 
of the tumor renders the tumor biopsy tissue sample collection medically unsafe, 
eligibility may be provided with Medical Monitor approval.  A local analysis to 
confirm the diagnosis of RCC is required.

Measurable disease, as defined by RECIST v1.1 (see Appendix 3)

Age 18 years

KPS 70 (see Appendix 5)

Ability and capacity to comply with study and follow-up procedures

Adequate hematologic and end-organ function, defined by the following laboratory 
results obtained within 28 calendar days prior to randomization:
ANC 1500 cells/L (without granulocyte colony-stimulating factor support 
within 2 weeks prior to Cycle 1, Day 1)
WBC counts 2500 cells/L
Lymphocyte count 300 cells/L
Platelet count 100,000 cells/L (without transfusion within 2 weeks prior 
to Cycle 1, Day 1)
Hemoglobin 9.0 g/dL
AST, ALT, and alkaline phosphatase 2.5ULN, with the following exceptions:
Patients with documented liver metastases:  AST and ALT 5ULN


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Patients with documented liver or bone metastases:  alkaline phosphatase 
5ULN
Serum bilirubin 1.5ULN
Patients with known Gilbert disease who have serum bilirubin level 
3ULN may be enrolled.
INR and aPTT 1.5ULN, unless on a stable dose of warfarin
Serum albumin 2.5 g/dL
Creatinine clearance 30 mL/min (Cockcroft-Gault formula or based on 24-hour 
urine collection)

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate 
of 1% per year during the treatment period and for at least 6 months after the last 
dose of atezolizumab and bevacizumab or 30 days after the last dose of sunitinib.
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, established, proper use of 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 at least 
6 months after the last dose of bevacizumab or 30 days after the last dose of 
sunitinib.  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 the duration of the pregnancy 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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
Patients with a history of treated asymptomatic CNS metastases are eligible, 
provided they meet all of the following criteria:
Evaluable or measurable disease outside the CNS
Only supratentorial and cerebellar metastases allowed (i.e., no metastases to 
midbrain, pons, medulla or spinal cord)
No history of intracranial or spinal cord hemorrhage
No evidence of significant vasogenic edema
No ongoing requirement for corticosteroids as therapy for CNS disease
No stereotactic radiation within 14 days
No evidence of interim progression between the completion of CNS-directed
therapy and the screening radiographic study
Patients with new asymptomatic CNS metastases detected at the screening 
scan must receive radiation therapy and/or surgery for CNS metastases.  
Following treatment, these patients may then be eligible without the need for an 
additional brain scan prior to enrollment [or randomization], if all other criteria 
are met.
4.1.2
Exclusion Criteria
4.1.2.1
Disease-Specific Exclusions

Prior treatment with active or experimental systemic agents, including treatment in 
the neoadjuvant or adjuvant setting.  Prior treatment with placebo in adjuvant setting 
is allowed.

Radiotherapy for RCC within 14 calendar days prior to Cycle 1, Day 1

Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or 
metastases causing nerve impingement) should be treated at least 14 days prior to 
Cycle 1, Day 1.

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently)

Uncontrolled hypercalcemia (1.5 mmol/L ionized calcium or calcium 12 mg/dL) or 
symptomatic hypercalcemia refractory to bisphosphonate therapy or denosumab
Patients who are currently receiving bisphosphonate therapy without current 
hypercalcemia (corrected serum calcium greater than the upper limit of normal) 
are eligible.

Malignancies other than RCC within 5 years prior to Cycle 1, Day 1
Patients with localized low risk prostate cancer (defined as Stage T2b, 
Gleason score 7, and PSA at prostate cancer diagnosis 20 ng/mL) treated 
with curative intent and without prostate-specific antigen (PSA) recurrence are 
eligible


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Patients with low risk prostate cancer (defined as Stage T1/T2a, Gleason score 
6, and PSA 10 ng/mL) who are treatment-naive and undergoing active 
surveillance are eligible
Patients with malignancies of a negligible risk of metastasis or death (e.g., risk 
of metastasis or death 5% at 5 years) are eligible provided they meet all of the 
following criteria:
Malignancy treated with expected curative intent (such as adequately 
treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, 
or ductal carcinoma in situ treated surgically with curative intent)
No evidence of recurrence or metastasis by follow-up imaging and any 
disease-specific tumor markers
4.1.2.2
General Medical Exclusions

Life expectancy of 12 weeks

Current, recent (within 4 weeks of Cycle 1, Day 1), or planned participation in 
another experimental drug study

Pregnant and lactating, or intending to become pregnant during the study

Women who are not postmenopausal (12 months of non-therapy-induced 
amenorrhea) or surgically sterile must have a negative serum pregnancy test result 
within 7 days prior to initiation of study drug.

History of severe allergic, anaphylactic, or other hypersensitivity reactions 
to chimeric or humanized antibodies or fusion proteins

Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese 
hamster ovary cells or any component of the atezolizumab formulation

History of autoimmune disease, including but not limited to myasthenia gravis, 
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, 
inflammatory bowel disease, vascular thrombosis associated with antiphospholipid 
syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré 
syndrome, multiple sclerosis, vasculitis, or glomerulonephritis (see Appendix 6 for a 
more comprehensive list of autoimmune diseases)
Patients with a history of autoimmune-related hypothyroidism on a stable dose 
of thyroid replacement hormone are eligible for this study.
Patients with controlled Type I diabetes mellitus on a stable dose of insulin 
regimen may be eligible for this study.

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest computed tomography (CT) scan; however, history 
of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Positive test for HIV


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
Patients with active or chronic hepatitis B (defined as having a positive hepatitis B 
surface antigen [HBsAg] test at screening)
Patients with past/resolved HBV infection (defined as having a negative HBsAg 
test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) 
are eligible.  A negative HBV DNA test must be obtained in patients with 
positive hepatitis B core antibody prior to Cycle 1, Day 1.

Patients with active hepatitis C
Patients positive for HCV antibody are eligible only if polymerase chain reaction 
(PCR) analysis is negative for HCV RNA.

Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia

Signs or symptoms of infection (including active tuberculosis) within 2 weeks prior to 
Cycle 1, Day 1

Received therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1 
Patients receiving routine antibiotic prophylaxis (e.g., to prevent chronic 
obstructive pulmonary disease exacerbation or for dental extraction) are eligible.

Significant cardiovascular or cerebrovascular disease, such as New York Heart 
Association cardiac disease (Class II or greater), unstable angina, myocardial 
infarction or cerebrovascular events within the previous 6 months or unstable 
arrhythmias within the previous 3 months.
Patients with known coronary artery disease, arrhythmias, congestive heart 
failure not meeting the above criteria must be on a stable medical regimen that 
is optimized in the opinion of the treating physician, in consultation with a 
cardiologist if appropriate.  Baseline evaluation of left ventricular ejection 
fraction (LVEF) should be considered for all patients, especially in those with 
cardiac risk factors and/or history of coronary artery disease.
Patients with known LVEF 50%

Major surgical procedure other than for diagnosis within 21 days prior to 
Cycle 1, Day 1, or planned procedure or surgery during the study

Prior allogeneic stem cell or solid organ transplant

Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 
Influenza vaccination should be given during influenza season only
(approximately October through May in the Northern Hemisphere and 
approximately April through September in the Southern Hemisphere). Patients 
must agree not to receive live, attenuated influenza vaccine (e.g. FluMist) 
within 28 days prior to randomization, during treatment or within 5 months
following the last dose of atezolizumab (for patients randomized to 
atezolizumab).

Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug or that may affect the 


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interpretation of the results or render the patient at high risk from treatment 
complications
4.1.2.3
Exclusion Criteria Related to Medications

Prior treatment with CD137 agonists, antiCTLA-4, antiPD-1, or antiPD-L1 
therapeutic antibody or pathway-targeting agents

Treatment with systemic immunostimulatory agents (including but not limited to 
IFN , IL-2) for the treatment of non-malignant conditions within 6 weeks or 
five half-lives of the drug, whichever is shorter, prior to Cycle 1, Day 1

Any prior use of systemic immunostimulatory agents for the management of 
metastatic RCC is excluded.

Treatment with systemic immunosuppressive medications (including but not limited 
to prednisone, dexamethasone cyclophosphamide, azathioprine, methotrexate, 
thalidomide, and anti-tumor necrosis factor [antiTNF] agents) within 2 weeks prior 
to Cycle 1, Day 1. 
Patients who have received acute, low-dose, systemic immunosuppressant 
medications (e.g., a one-time dose of dexamethasone for nausea) or 
physiologic replacement doses (i.e., prednisone 57.5 mg/day) for adrenal 
insufficiency may be enrolled in the study.
The use of inhaled corticosteroids, physiologic replacement doses of 
glucocorticoids (i.e., for adrenal insufficiency), and mineralocorticoids (e.g., 
fludrocortisone) is allowed.
4.1.2.4
Bevacizumab- and Sunitinib-Specific Exclusions

Inadequately controlled hypertension (defined as systolic blood pressure 
150 mmHg and/or diastolic blood pressure 100 mmHg).
Anti-hypertensive therapy to maintain a systolic blood pressure 150 mmHg 
and/or diastolic blood pressure 100 mmHg is permitted.

Prior history of hypertensive crisis or hypertensive encephalopathy

New York Heart Association Class II or greater congestive heart failure 
(see Appendix 7)

History of stroke or transient ischemic attack within 6 months prior to Cycle 1, Day 1

Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent 
peripheral arterial thrombosis) within 6 months prior to Cycle 1, Day 1

Patients with a baseline ECG demonstrating a QTc 460 ms

Evidence of bleeding diathesis or clinically significant coagulopathy (in the absence 
of therapeutic anticoagulation)

Current or recent (within 10 calendar days prior to Cycle 1, Day 1) use of 
dipyramidole, ticlopidine, clopidogrel, or cilostazol.

Prophylactic or therapeutic use of low molecular weight heparin (e.g., enoxaparin), 
direct thrombin inhibitors, or warfarin are permitted, provided, where appropriate 
anticoagulation indices are stable.  Patients should have been on a stable dose (for 


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therapeutic use) for at least 2 weeks (or until reaching steady state level of the drug) 
prior to the first study treatment

Core biopsy or other minor surgical procedure, excluding placement of a vascular 
access device, within 7 calendar days prior to the first dose of bevacizumab

History of abdominal or tracheoesophageal fistula or gastrointestinal perforation 
within 6 months prior to Cycle 1, Day 1

Clinical signs or symptoms of gastrointestinal obstruction or requirement for routine 
parenteral hydration, parenteral nutrition, or tube feeding

Evidence of abdominal free air not explained by paracentesis or recent 
surgical procedure

Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture

Proteinuria, as demonstrated by urine dipstick or 1.0 g of protein in a 24-hour 
urine collection
All patients with 2protein on dipstick urinalysis at baseline must undergo a 
24-hour urine collection for protein.
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is an open-label study.  The investigator and patient will not be blinded to treatment 
assignment.  The Sponsor study team will be blinded to the treatment assigned by 
randomization until the analysis of the primary endpoint is performed.
After written informed consent has been obtained and eligibility has been established, 
the study site will obtain the patient’s identification number and treatment assignment 
from the Interactive Voice/Web Response System (IxRS).  For patients who are eligible 
for enrollment, the study site will obtain the patient’s randomization number and 
treatment assignment from the IxRS.
Patients will be randomized to one of the following two treatment arms in a 1:1 ratio:

Arm A:  Atezolizumabbevacizumab

Arm B:  Sunitinib
Randomization will be stratified by the following factors: 
1.
Presence of liver metastasis (yes vs. no)
2.
MSKCC (Motzer) score (0, 12, or 3; corresponding to low, intermediate, or high 
risk), which comprises the following five risk factors:  KPS 80%, LDH 1.5ULN, 
hemoglobin less than LLN, corrected serum calcium 10 mg/dL, and time from 
nephrectomy to systemic therapy (12 months vs. 12 months) (see Appendix 9)
3.
PD-L1 status:  IC1/2/3 versus IC0
A stratified, permuted-block randomization will be implemented in order to obtain a 
balanced assignment to each treatment within levels of the stratification factors.  


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4.3
STUDY TREATMENT
Atezolizumab and bevacizumab are considered the investigational medicinal products 
(IMP) in this study.
Sunitinib is considered a non-IMP in this study.  Depending on local legislation, sunitinib 
may be considered an IMP.  If considered an IMP, then appropriate information on 
formulation, packaging, handling, and administration will be provided.
Patients should receive their first dose of assigned study treatment no later than 
5 business days after randomization.
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Atezolizumab
Atezolizumab will be supplied by the Sponsor as sterile liquid in 20-mL glass vials.  The 
vial is designed to deliver 20 mL (1200 mg) of atezolizumab solution but may contain 
more than the stated volume to enable delivery of the entire 20 mL volume.  For 
information on the formulation and handling of atezolizumab, refer to the Investigator's 
Brochure and Pharmacy Manual.
4.3.1.2
Bevacizumab
Bevacizumab is supplied by Roche/Genentech as a clear-to-slightly-opalescent, sterile 
liquid ready for parenteral administration.  Each 400-mg (25-mg/mL) glass vial contains 
16 mL of bevacizumab (25 mg/mL) with a vehicle consisting of sodium phosphate, 
trehalose, polysorbate 20, and Sterile Water for Injection, USP.  Vials contain no 
preservative and are for single use only.  For further details, see the Bevacizumab 
Investigator’s Brochure.
Bevacizumab is intended for use solely in clinical trials.  The drug provided for clinical 
trial use is expected to be very similar in safety and activity to the commercially 
marketed drug (Avastin).
For additional details, see the Avastinlocal label.
4.3.1.3
Sunitinib
Sutent is the malate salt of sunitinib.  Sunitinib malate is described chemically as 
butanedioic acid, hydroxy- (2S)-, compounded with N-[2-(diethylamino)ethyl]-5-[(Z)-(5-
fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidine)methyl]-2,4-dimethyl-1Hpyrrole-3-
carboxamide (1:1).  The molecular formula is C22H27FN4O2 C4H6O5.  It will be provided 
by the Sponsor if it is considered an IMP by local regulations (see Section 4.3.3).  
Sunitinib capsules will be supplied as printed, hard-shell capsules containing sunitinib 
malate equivalent to 12.5 mg, 25 mg, or 50 mg of Sutent with mannitol, croscarmellose 
sodium, povidone (K-25), and magnesium stearate as inactive ingredients.


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For additional details, see the Sutentlocal label for Dosage, Administration, and 
Storage.
4.3.2
Dosage, Administration, and Compliance
4.3.2.1
Atezolizumab
The fixed dose of 1200 mg (equivalent to an average body weightbased dose of 
15 mg/kg) was selected on the basis of both nonclinical studies and available clinical 
data from Study PCD4989g.
Patients randomized to atezolizumab will receive 1200 mg of atezolizumab administered 
by IV infusion every 21 days in a monitored setting where there is immediate access to 
trained personnel and adequate equipment/medicine to manage potentially serious 
reactions.  For more detailed information regarding administration, refer to the 
Atezolizumab Investigator’s Brochure and Pharmacy Manual.
For patients randomized to Arm A, atezolizumab will be administered first, followed by 
bevacizumab, with a minimum of 5 minutes between dosing.  
Atezolizumab infusions will be administered per the instructions outlined in Table 10.
For additional details regarding management of infusion-related reactions, please refer 
to the Atezolizumab Investigator’s Brochure:  Guidelines for the Management of 
Infusion-Related Reactions during Cycle 1. 


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Table 10 Administration of First and Subsequent Infusions 
of Atezolizumab
First Infusion
Subsequent Infusions
No premedication is administered
Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) within 60 minutes before 
starting infusion.
Infuse atezolizumab (one vial in 250 mL 
NaCl) over 60 (15) minutes.
Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) during the infusion at 15, 30, 
45, and 60 minutes (5-minute windows are 
allowed for all timepoints).
Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) at 30 (10) minutes and 
2 hours (15 minutes) after the infusion.
Patients will be informed about the possibility 
of delayed post-infusion symptoms and 
instructed to contact their study physician if 
they develop such symptoms.
If patient experienced infusion-related 
reaction during any previous infusion, 
premedication with antihistamines may be 
administered for Cycles 2 at the discretion 
of the treating physician.
Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) within 60 minutes before 
starting infusion.
If the patient tolerated the first infusion well 
without infusion-associated adverse events, 
the second infusion may be delivered over 
30 (10) minutes.
If the patient had an infusion-related 
reaction during the previous infusion, the 
subsequent infusion must be delivered over 
60 (15) minutes.
Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) during the infusion if clinically 
indicated or patient experienced symptoms 
during the previous infusion. 
Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) 60 (10) minutes after the 
infusion.
If no reaction occurs, continue subsequent 
infusions over 30 (10) minutes with same 
schedule for recording vital signs.
For anaphylaxis precautions, see Appendix 10.  Patients in Arm A may discontinue 
either atezolizumab or bevacizumab (e.g., for adverse events) and may continue on 
single-agent therapy until disease progression.  Guidelines for dosage modification, 
treatment interruption or discontinuation, and the management of specific adverse 
events are provided in Sections 5.1.3 and 5.1.4.
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of study treatment should be 
recorded on the Adverse Event eCRF.
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration.


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4.3.2.2
Bevacizumab
The dose of bevacizumab in this study is 15 mg/kg administered by IV infusion every 
3 weeks on Days 1 and 22 of each 42-day (6-week) cycle.  The interval between 
infusions must not be 10 days.  The bevacizumab dose will be based on the patient’s 
weight at randomization and will remain the same throughout the study unless there is a 
weight change of 10% from baseline.  It is not necessary to correct dosing based on 
ideal weight, unless warranted per institutional guidelines/standard. 
The initial dose of bevacizumab will be delivered over 90 (15) minutes.  If the first 
infusion is tolerated without infusion-associated adverse events (fever and/or chills), 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, the patient should be observed for at least 2 hours after 
the first administration of the combination and for at least 1 hour for subsequent 
infusions.
If a patient experiences an infusion-associated adverse event, he or she may be 
premedicated for the next bevacizumab infusion; however, the infusion time may not be 
decreased for the subsequent infusion.  If the next infusion is well tolerated with 
premedication, the subsequent infusion time may then be decreased by 30 minutes as 
long as the patient continues to be premedicated.  If a patient experiences a second 
episode of an infusion-associated adverse event with the 60-minute infusion, all 
subsequent doses should be given over 90 (15) minutes.  Similarly, if a patient 
experiences a second episode of an infusion-associated adverse event with the 
30-minute infusion, all subsequent doses should be given over 60 (10) minutes.
Upon receipt of the bevacizumab, vials are to be refrigerated at 2C8°C (36F46°F) 
and should remain refrigerated until use.  Vials should be protected from light.  DO NOT 
FREEZE.  DO NOT SHAKE.  VIALS ARE FOR SINGLE USE ONLY.  Vials used for 
one patient may not be used for any other patient.
4.3.2.3
Sunitinib
The comparator, sunitinib, will be used in the commercially available formulation, 
packaging, and handling. It will be provided by the Sponsor if it is considered an IMP by 
local regulations (see Section 4.3.3).  Bottles of the appropriate dose will be dispensed
on Day 1 of each cycle, and patients will be required to return empty bottles to the clinic 
on Day 1 of each cycle, starting at Cycle 2, for drug accountability by site study 
personnel.
Sunitinib will be taken at the approved dose level of 50 mg/day for 4 weeks followed by a 
2-week rest period.  For the purposes of this trial, a cycle is defined as 4 weeks of 
sunitinib and 2 weeks of rest (6 weeks).  Under no circumstances may a patient receive 
sunitinib for 28 days (4 weeks) without a subsequent 2-week rest period.  Capsules 
should be taken once daily with a glass of water and may be taken without regard to 


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meals.  The study investigator may implement dose interruption or dose reduction 
(i.e., 50 mg to 37.5 mg or 37.5 mg to 25 mg) in order to ensure patient safety (see 
Section 5.1.7, Section 5.1.8, and Table 11). 
For further details, see the Sutentlabel. 
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for the completion of this study (atezolizumab, bevacizumab, and 
sunitinib if considered an IMP by local regulations) will be provided (or reimbursed) by 
the Sponsor.  The investigational site will acknowledge receipt of atezolizumab and 
bevacizumab with use of the IxRS to confirm the shipment condition and content.  Any 
damaged shipments will be replaced.  Where sunitinib is supplied by the Sponsor, 
shipment receipt will be documented using IxRS; otherwise, it will be documented per 
local practice.
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed upon by the 
Sponsor.  The site must obtain written authorization from the Sponsor before any IMP is 
destroyed, and IMP destruction must be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log.
4.3.4
Post-Study Access to Atezolizumab
A patient will be eligible to receive the study drug (atezolizumab) and bevacizumab after 
the end of the study if all of the following conditions are met: 

The patient has a life-threatening or severe medical condition and require continued 
study drug 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
The patient will not be eligible to receive the study drug after the end of the study if any 
of the following conditions are met: 

The study drug 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) 

Roche has discontinued development of the study drug or data suggest that the 
study drug is not effective for kidney cancer

Roche has reasonable safety concerns regarding the study drug as treatment for 
kidney cancer


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
Continued access to study drug is not permitted under the laws and regulations of 
the patient’s country
4.4
CONCOMITANT THERAPY
4.4.1
Permitted Therapy
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
7 days prior to screening until the treatment discontinuation visit.  All such medications 
should be reported to the investigator.
Premedication with antihistamines may be administered for any atezolizumab infusions 
after Cycle 1.
The following therapies should continue while patients are in the study:

Oral contraceptives

Hormone-replacement therapy

Prophylactic or therapeutic anticoagulation therapy (such as low molecular weight
heparin, direct thrombin inhibitors, or warfarin at a stable dose level)

Megestrol administered as an appetite stimulant 

Inhaled corticosteroids for chronic obstructive pulmonary disease

Mineralocorticoids (e.g., fludrocortisone) 

Low-dose corticosteroids (10 mg prednisone equivalent) for patients with 
orthostatic hypotension or adrenocortical insufficiency
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated, as per local standards.  Patients who experience infusion-associated 
symptoms may be treated symptomatically with acetaminophen, ibuprofen, 
diphenhydramine, and/or famotidine or another H2 receptor antagonist as per standard 
practice (for sites outside the United States, equivalent medications may be substituted 
per local 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 10). 
The use of systemic corticosteroids is discouraged.  A limited course of systemic 
steroids is permitted to treat immune-mediated adverse events when associated with
atezolizumab therapy, at the discretion of the treating physician.  For full details of the 
management of immune related events, refer to the Investigator’s Brochure, Section 6.6.
All medications must be recorded on the Concomitant Medications eCRF.


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4.4.2
Cautionary Therapy for Atezolizumab-Treated Patients
Systemic corticosteroids and tumor necrosis factor-(TNF-) inhibitors may attenuate 
potential beneficial immunologic effects of treatment with atezolizumab.  Therefore, in 
situations where systemic corticosteroids or TNF-inhibitors would be routinely 
administered, alternatives, including antihistamines, should be considered first by the 
treating physician.  If the alternatives are not feasible, systemic corticosteroids and 
TNF-inhibitors may be administered at the discretion of the treating physician.  
4.4.3
Excluded Therapy
Any concomitant therapy intended for the treatment of cancer, whether health 
authorityapproved or experimental, is prohibited.  This includes but is not limited to the 
following:

Chemotherapy, immunotherapy, radiotherapy, investigational agents
After Cycle 1, Day 14, radiotherapy may be considered for pain palliation if 
patients are deriving benefit (e.g., treatment of known bony metastases) and 
provided they do not compromise assessments of tumor target lesions.  Study 
drug administration may be continued during radiotherapy for patients being 
treated with atezolizumab.  Study drug should be suspended for patients being 
treated with sunitinib per institutional guidelines.
4.4.3.1
Excluded and Cautionary Therapy for Atezolizumab-Treated 
Patients
The following guidance applies only to patients randomized to receive atezolizumab.  
The following medications are excluded while the patient is receiving study treatment: 

Traditional herbal medicines; these therapies are not fully studied and their use may 
result in unanticipated drug-drug interactions that may cause or confound the 
assessment of toxicity

Immunomodulatory agents, including but not limited to interferons or 
interleukin-2 during the entire study; these agents could potentially increase the risk 
for autoimmune conditions when received in combination with atezolizumab

Immunosuppressive medications, including but not limited to cyclophosphamide, 
azathioprine, methotrexate, and thalidomide; these agents could potentially alter the 
activity and the safety of atezolizumab
Influenza vaccinations (inactivated forms only) should be given only during influenza 
season (approximately October to March in the Northern hemisphere; April to 
September in the Southern Hemisphere).  Patients randomized to receive atezolizumab 
must agree not to receive live, attenuated influenza vaccines (such as FluMist) 28 days 
prior to randomization, at any time during the study, or within 5 months following the last 
dose of atezolizumab (for patients randomized to atezolizumab) but may receive 
inactivated influenza vaccines.


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In addition, patients treated with atezolizumab should not receive other 
immunomodulatory agents for 10 weeks after study treatment discontinuation.
4.5
STUDY ASSESSMENTS
Flowcharts of scheduled study assessments are provided in Appendix 1 and Appendix 2.  
Patients will be closely monitored for safety and tolerability throughout the study.  All 
assessments must be performed and documented for each patient. 
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.
If the timing of a protocol-mandated study visit coincides with a holiday and/or weekend 
that precludes the visit, the visit should be scheduled on the nearest following feasible 
date.
4.5.1
Informed Consent Forms and Screening Log
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.
Re-screening is required if a patient has not met all of the eligibility criteria within 
28 days from the original date of the screening visit.  Re-screening refers to repeating 
the entire screening process with the exception of performing a repeat biopsy to collect a 
tumor tissue sample to be used to determine PD-L1 status and repeating CT and/or MRI 
imaging scans used for tumor assessment, provided the biopsy tissue sample and 
imaging scans were obtained during the original screening visit.  Patients are only 
allowed to be re-screened twice.  Blood samples may be redrawn due to sample 
handling problems, breakage, or sample integrity, without being considered a re-screen.
4.5.2
Medical History and Demographic Data
Medical history includes clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), and all medications (e.g., prescription 
drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) 
used by the patient within 7 days prior to the screening.  A history of pleural or 
pericardial effusion or of ascites requiring intervention should be entered in the medical 
history.
Demographic data will include age, sex, and self-reported race/ethnicity. 
Cancer history will include an assessment of tumor histology.


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4.5.3
Physical Examinations
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, and throat and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, and neurological systems.  Any abnormality identified at baseline should 
be recorded on the General Medical History and Baseline Conditions eCRF.  Height and 
weight should be measured and recorded in the eCRF.
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  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.
4.5.4
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, systolic and 
diastolic blood pressures while the patient is in a seated position, and body temperature.
For patients randomized to Arm A, atezolizumab will be administered first, followed by 
bevacizumab, with a minimum of 5 minutes between dosing.  For the first infusion of 
atezolizumab for patients in Arm A, the patient’s vital signs (heart rate, respiratory rate, 
blood pressures, and temperature) should be determined within 60 minutes before, 
during (every 15 [5] minutes), and 30 (10) minutes and 2 hours (15 minutes) after 
the infusion.  For subsequent infusions, vital signs will be collected within 60 minutes 
before the infusion, during the infusion if clinically indicated, and 1 hour (10 minutes) 
after the infusion.  For patients randomized to Arm A, observation should be for at least 
2 hours after the first administration of the combination and for at least 1 hour for 
subsequent infusions.  Patients will be informed about the possibility of delayed 
post-infusion symptoms and instructed to contact their study physician if they develop 
such symptoms.
4.5.5
Tumor and Response Evaluations
Measurable and non-measurable disease must be documented at screening and 
re-assessed at each subsequent tumor evaluation.  Tumor assessments are to be 
performed regardless of drug delays or interruptions (i.e., independent of treatment 
cycles) as specified in Appendix 1 5 business days.  
Screening assessments must include CT scans (with oral and IV contrast unless 
contraindicated) or magnetic resonance imaging (MRI) of the chest, abdomen, and 
pelvis, and a brain scan (CT or MRI).  For patients undergoing MRI, a non-contrast spiral 
CT scan of the chest should be obtained to evaluate lung parenchyma.  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.
A CT (with contrast if not contraindicated) or MRI scan of the brain must be done at 
screening to exclude CNS metastasis.  An MRI scan of the brain is required to confirm or 


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refute the diagnosis of CNS metastases at baseline in the event of an equivocal scan.  
Patients with definitively treated stable CNS metastases may be eligible for the study 
(see Sections 4.1.1 and 4.1.2.1).
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.
Bone scans (technetium-99m [TC-99m]) or sodium fluoride PET (NaF-PET) should be 
performed at screening if bone metastases are clinically suspected.  If bone metastases 
are present at screening and cannot be seen on CT or MRI scans, bone scans should 
be performed at any time when progression in bone is suspected.  Bone scans should 
be repeated when CR is identified in target disease or when progression in bone is 
suspected and not visualized by CT/MRI.
For subsequent tumor assessments, the same radiographic procedure used to assess 
disease sites at screening should be used throughout the study (e.g., the same contrast 
protocol for CT scans).  If IV contrast cannot be given, then the patient should undergo 
MRI of the abdomen and pelvis and non-contrast CT of the chest.  If CT with contrast is 
used for baseline imaging, but subsequently IV contrast cannot be given, then 
non-contrast CT scans may be used.
All known sites of disease must be documented at screening and re-assessed at each 
subsequent tumor evaluation.  Response will be assessed by the investigator with use of 
RECIST v1.1, as well as modified RECIST criteria (see Appendix 3 and Appendix 4).  
Assessments should be performed by the same evaluator if possible to ensure internal 
consistency across visits.  At the investigator’s discretion, CT scans should be repeated 
at any time if progressive disease is suspected.  
Patients permitted to continue study therapy beyond radiographic disease progression 
per RECIST v1.1 (see Section 4.6.2) will be monitored with a follow-up scan at the next 
scheduled tumor assessment when the scan frequency is every 6 weeks.  If the scan 
frequency is every 12 weeks (see Appendix 1), the follow-up scan must be performed 
every 12 weeks (5 business days), or earlier if clinically indicated.
If study treatment discontinues prior to disease progression per RECIST v1.1, tumor 
assessment should be followed according to Section 4.5.12.1.
All scans, as outlined above, should be submitted to the IRC for independent review.  
For patients who discontinue study therapy after investigator assessed, radiographic 
progression per RECIST v1.1, at least one scan, after RECIST v1.1 progression should 
continue to be submitted to the IRC.


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4.5.6
Patient-Reported Outcomes
PRO data will be collected using an electronic PRO method, both during the trial and at 
post-progression assessments.  Site staff will review PRO questionnaires for 
completeness ONLY.
PRO data will be obtained from patients with use of the MDASI (see Appendix 11), the 
BFI (see Appendix 12), the treatment side-effect subscale (FKSI-19; see Appendix 13), 
and the EQ-5D (see Appendix 14) to more fully characterize the clinical profile of 
atezolizumab.
The MDASI (Cleeland et al. 2000) is a cancer-related, multisymptom, valid, and reliable 
self-report questionnaire for clinical and research use.  It consists of 23 items over 
two scales that assess symptom severity and symptom interference with different 
aspects of a patient’s life.  Seventeen items (pertaining to pain, fatigue, nausea, 
disturbed sleep, distressed, shortness of breath, remembering things, lack of appetite, 
drowsy, dry mouth, sad, vomiting, diarrhea, and numbness or tingling) ask patients to 
rate how severe the symptoms were when “at their worst” in the last 24 hours.  An 
additional six items ask patients to rate how much the symptoms have interfered with 
six areas of function (general activity, walking, work, mood, relations with other people, 
and enjoyment of life) in the last 24 hours.  Additionally, the MDASI contains 
tumor-specific modules to assess symptoms of disease and treatment.  For this study, to 
specifically assess RCC symptoms and treatment side effects, patients will rate 
four additional symptoms (skin rash or change, sores in throat and mouth, diarrhea, and 
headache).  The MDASI items are rated from 0 to 10, with 0 indicating that the symptom 
is either not present or does not interfere with the patient’s activities and 10 indicating 
that the symptom is “as bad as you can imagine” or “interfered completely” with the 
patient’s life.  The MDASI takes approximately 5 minutes to complete.  
The BFI is a valid and reliable self-report questionnaire used to rapidly assess the 
severity and impact of cancer-related fatigue.  It consists of three items to assess the 
severity of fatigue over 24 hours and an additional six items to assess the impact of 
fatigue on global domains (i.e., general activity, mood, walking ability, normal work, 
relations with other people, and enjoyment of life) in the last 24 hours.  Similar to the 
MDASI, items are rated from 0 to 10, with 0 indicating that the symptom is either not 
present or does not interfere with the patient’s activities and 10 indicating that the 
symptom is “as bad as you can imagine” or “interfered completely” with the patient’s life.  
For most patients, the BFI takes fewer than 5 minutes to complete.  
The EQ-5D questionnaire is a generic, preference-based health utility measure with 
questions about mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression that are used to build a composite of the patient’s health status 
(EQ-5D-3L User Guide Version 5.0).  The EQ-5D will be utilized in this study for 
economic modeling.  The EQ-5D questionnaire takes 5 minutes or less to complete.


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The FKSI-19 is a 19-item tool designed to assess the most important symptoms and 
concerns related to evaluating treatment effectiveness in advanced kidney cancer 
(Butt et al. 2013).  The FKSI-19 includes the following items:  lack of energy, pain, losing 
weight, fatigue, shortness of breath, fever, bone pain, coughing, weakness, hematuria, 
appetite, sleeping, worry, nausea, diarrhea, bother from side effects of treatment, ability 
to work, ability to enjoy life, and contentment. The nausea, diarrhea and bother from 
side effects of treatment items together comprise the side effects from treatment 
subscale.  Each item is scored on a five-point scale (04) with each level corresponding 
to:  0“Not at all,” 1“A little bit,” 2“Somewhat,” 3“Quite a bit,” and 4“Very much.”  
It takes approximately 5 minutes to complete.
The PRO questionnaires will be translated as required in the local language, distributed 
by the investigator staff, and completed in their entirety by the patient.  
PRO questionnaires should be self-administered using an electronic device prior to the 
completion of other study assessments and the administration of study treatment.  The 
PRO questionnaires should be completed at Day 1 and Day 22 of each cycle, at the 
end-of-treatment visit, in case of early treatment discontinuation, as well as at 6, 12, 24, 
and 36 weeks after the end-of-treatment visit.  In addition, the BFI ePRO questionnaire 
will be collected weekly during the first 12 weeks.  Assessments on days when the 
patient does not come to the clinic (e.g., Days 8, 15, 29, 36) will be completed by the 
patient at home.
Adverse event reports will not be derived from PRO data by the Sponsor.  However, any 
PRO responses suggestive of a possible adverse event that are identified during site 
review of the PRO data should be reported.
4.5.7
Laboratory, Biomarker, and Other Biological Samples
Samples for hematology, serum chemistries, coagulation, urinalysis, and the pregnancy 
test will be analyzed at the study site’s local laboratory, as listed below.  
Central laboratories will coordinate the collection of archival tumor, fresh tumor, 
and leftover tumor tissue and blood samples for the assessment of atezolizumab 
pharmacokinetics and biomarkers, ATA assays, and auto-antibody testing.  Instruction 
manuals and supply kits will be provided for all central laboratory assessments.
Local laboratory assessments will include the following:

Hematology (CBC, including RBC count, hemoglobin, hematocrit, WBC count with 
differential [neutrophils, eosinophils, lymphocytes, monocytes, basophils, and other 
cells], and platelet count)

Serum chemistries (glucose, BUN or urea, creatinine, sodium, potassium, 
magnesium, chloride, bicarbonate, calcium, phosphorus, total bilirubin, ALT, AST, 
alkaline phosphatase, LDH, total protein, serum ferritin, and albumin)

Coagulation (aPTT and INR)


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
Serum pregnancy test (for women of childbearing potential, including women who 
have had a tubal ligation) 

Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood)

Thyroid function testing (thyroid stimulating hormone [TSH], free T3, free T4)

HBV serology (HBsAg, antibody to HBsAg [anti-HBs], anti-HBc)

HBV DNA required prior to Cycle 1, Day 1 in patients who are antihepatitis B core 
antibodypositive

HCV serology (anti-HCV)

All patients will be tested for HIV prior to the inclusion into the study and 
HIV-positive patients will be excluded from the clinical trial.
Instruction manuals and supply kits will be provided for all central laboratory 
assessments.  The following assessments will be performed at a central laboratory 
or Roche:

T, B, and natural killer (TBNK) blood sample
Samples will be assayed for T cells, B cells, and NK cells.

C-reactive protein (CRP)

ATA assays
Serum samples will be assayed for the presence of ATAs to atezolizumab with 
use of validated immunoassays.

PK assays
Serum samples will be assayed for atezolizumab concentration (and 
bevacizumab concentration, if applicable) with the use of a 
validated immunoassay.

Auto-antibody testing
Anti-nuclear antibody
Antidouble-stranded DNA
Circulating antineutrophil cytoplasmic antibody
Perinuclear antineutrophil cytoplasmic antibody

Biomarker assays in blood samples
Blood samples will be obtained for biomarker evaluation from all eligible 
patients at screening, before treatment, on treatment, and at the end of 
treatment visits.  Samples will used for the determination of changes in 
surrogate pharmacodynamic biomarkers, including but not limited to cytokines 
such as IFN-, T-cell markers such as CD8, and other exploratory biomarkers.  
Whole blood samples may be processed to obtain peripheral blood 
mononuclear cells (PBMCs) and their derivatives (e.g., RNA and DNA).  DNA 
samples will only tested for targeted analysis of genes involved in renal cancer 
such as Von-Hippel Lindau or the related immune response.  If health 


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authorities or ethics committees do not approve the use of the blood for PBMCs 
and/or their derivatives (e.g., DNA, RNA), the related analysis will not be 
applicable.  For example, in countries where DNA analysis is not permitted, 
then investigators may opt out of the DNA portion of the testing.
Any remaining samples collected for PK, biomarker assays, and ATAs may be used for 
exploratory biomarker profiling, identification, and pharmacodynamic assay development 
purposes and additional safety assessments (e.g., ATA assay) as appropriate. 

Archival and fresh tumor tissue samples
Representative tumor specimens in paraffin blocks (preferred) or at least 
15 unstained slides (or 1014 slides with monitor approval), with an associated 
pathology report, must be submitted for determination of PD-L1 status prior to
study enrollment.  
All patients must have a tumor biopsy specimen acquired 24 months prior to 
Cycle 1 for the PD-L1 pathway assessment, unless, following discussion with 
the Medical Monitor, the location of the tumor renders the tumor biopsy 
medically unsafe or infeasible.
If an archival sample acquired 24 months prior to Cycle 1, Day 1 is not 
available, patients must undergo fresh tumor biopsy to meet eligibility 
requirements.  If a patient’s PD-L1 status is determined on the basis of a fresh 
tumor specimen, the archival tissue sample, if available, should also be 
submitted.
Tumor tissue should be of good quality based on total and viable tumor content 
(sites will be informed if the quality of the submitted specimen is inadequate to 
determine tumor PD-L1 status).  Fine-needle aspiration, brushing, cell pellets 
from pleural effusion, bone metastases, and lavage samples are not acceptable.  
For core needle biopsy specimens, at least three cores embedded in a single 
paraffin block should be submitted for evaluation.  Tumor tissue from bone 
metastases that is subject to de-calcification is not acceptable.
For fresh metastatic biopsy specimens, acceptable samples include core 
needle biopsies for deep tumor tissue or excisional, incisional, punch, or 
forceps biopsies for cutaneous, subcutaneous, or mucosal lesions.  
In addition, exploratory biomarkers (including, but not limited to markers related 
to immune or RCC biology or non-inherited biomarkers identified through NGS 
on extracted DNA and/or RNA) may be evaluated.
At the time of progression by RECIST v1.1, patients randomized to the 
atezolizumabbevacizumab arm or sunitinib arm, if clinically feasible and 
permitted by institution and country, are required to undergo a biopsy of a site 
of progression.
NGS may be performed by Foundation Medicine. If performed by Foundation 
Medicine, the investigator can obtain results from the samples collected at the 
time of disease progression in the form of an NGS report, which is available 
directly from Foundation Medicine upon request. The investigator may share 


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and discuss the results with the patient, unless the patient chooses 
otherwise. The Foundation Medicine NGS assay has not been cleared or 
approved by the FDA; results from these investigational tests should not be 
used to guide future treatment decisions. 
For archival samples, the remaining tumor tissue block for all patients enrolled 
will be returned to the site upon request or 18 months after final closure of the 
study database, whichever is sooner.  Tissue samples from patients who are 
not eligible to enroll in the study will be returned no later than 6 weeks after 
eligibility determination.

For patients who consent to the optional collection of samples for the Roche Clinical 
Repository (RCR):
Core needle biopsies for deep tumor tissue or organs or excisional, incisional, 
punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions will 
be obtained from consenting patients.  Biopsy at the time of radiographic 
progression is highly recommended if there is any concern that it could 
represent pseudo-progression as opposed to true progression.  Additional 
biopsy samples may be collected at any time during the study per investigator 
discretion.

Use and storage of remaining samples from study-related procedures:
The remainder of samples obtained for study-related procedures will be 
destroyed no later than 5 years after the end of the study or earlier depending 
on local regulations.  If the patient provides optional consent for storing samples 
into the RCR for future research, the samples will be destroyed no later than 
15 years after the date of final closure of the clinical database.
Refer to the laboratory manual for additional details on laboratory assessments and 
sample handling.  Samples collected during the study may be evaluated for 
immune-related, tumor type-related, and other exploratory biomarkers (e.g., alterations 
in gene expression or targeted DNA sequencing of renal cancer-related genes in 
countries where this is permitted).
4.5.8
Cardiac Tests
4.5.8.1
Electrocardiograms and Evaluations of Left Ventricular 
Ejection Fraction (Echocardiograms or MUGA)
A twelve-lead ECG is required at screening, at the end of treatment visit, and when 
clinically indicated.  ECGs for each patient should be obtained from the same machine 
whenever possible.
Patients receiving sunitinib or bevacizumab should be carefully monitored for clinical 
signs and symptoms of congestive heart failure, especially in patients with cardiac risk 
factors and/or history of coronary artery disease.  Baseline and periodic evaluations of 
LVEF should also be considered (echocardiogram or MUGA).  In patients receiving 
sunitinib who do not have any cardiac risk factors, a baseline evaluation of ejection 
fraction should also be considered.  In countries where additional cardiac monitoring is 


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considered standard (e.g., France), additional cardiac monitoring as described below will 
be required:

A baseline evaluation of LVEF in those patients with cardiac risk factors and/or an 
abnormal baseline ECG

Electrocardiogram (ECG) on Cycle 1, Day 22 for patients randomized to the 
sunitinib arm 
4.5.9
Anti-Therapeutic Antibody Testing
Atezolizumab may elicit an immune response.  Patients with signs of any potential 
immune response to atezolizumab will be closely monitored.  Validated screening and 
confirmatory assays will be employed to detect ATAs at multiple timepoints before, 
during, and after treatment with atezolizumab (see Appendix 1 and Appendix 2 for the 
schedule).  The immunogenicity evaluation will utilize a risk-based immunogenicity 
strategy (Rosenberg and Worobec 2004; Koren et al. 2008) to characterize 
ATA responses to atezolizumab in support of the clinical development program.  
This tiered strategy will include an assessment of whether ATA responses correlate with 
relevant clinical endpoints.  Implementation of ATA characterization assays will depend 
on the safety profile and clinical immunogenicity data.
4.5.10
Assessments during Treatment
Assessments across the two treatment arms will be conducted using the same visit 
schedule.  If treatment is delayed for an adverse event, assessments should continue to 
be performed while treatment is on hold.  All visits must occur within 3 days from the 
scheduled date unless otherwise noted (see Appendix 1 and Section 4.5).  All 
assessments will be performed on the day of the specified visit unless a time window is 
specified.  Assessments scheduled on the day of study treatment administration (Day 1) 
of each cycle should be performed prior to study treatment infusion unless otherwise 
noted.  Local laboratory assessments from each cycle must be reviewed prior to study 
treatment administration for each cycle.
See the schedule of assessments provided in Appendix 1 and Appendix 2 for the 
schedule of treatment period assessments.
Karnofsky performance status and limited physical examination may be obtained 
96 hours prior to Days 1 and 22 of each cycle.
For any study arm, 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 regular dosing schedule.  If 
treatment was postponed for fewer than 2 days, the patient can resume the original 
schedule.
After two complete cycles, treatment can be delayed by 1 week to allow for vacations.


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Blood samples for pharmacodynamic biomarker analysis and pharmacokinetics will be 
obtained according to the schedules in Appendix 1 and Appendix 2.
4.5.11
End of Treatment Visit
Patients who discontinue from treatment will be asked to return to the clinic not more 
than 30 days after the last treatment for an end of treatment visit.  The visit at which a 
response assessment shows progressive disease resulting in patient discontinuation 
may be used as the end of treatment visit.  
See the schedule of assessments provided in Appendix 1 and Appendix 2 for 
assessments to be performed at the end of treatment visit.
4.5.12
Follow-Up Assessments
Patients who discontinue from treatment will be followed as outlined below.
4.5.12.1
Ongoing Tumor Assessments
Patients who discontinue study treatment (atezolizumabbevacizumab, or sunitinib) for 
reasons other than disease progression (e.g., toxicity) should continue to undergo 
scheduled tumor assessments as if the patients were still on study treatment until the 
patient dies, experiences disease progression per RECIST v1.1 and modified RECIST, 
withdraws consent, or until the study closes, whichever occurs first.  Patients who start a 
new anti-cancer therapy in the absence of disease progression per RECIST v1.1 should 
continue to undergo tumor assessments according to the protocol schedule unless they 
withdraw consent, die, experience disease progression per RECIST v1.1 and modified 
RECIST, or study closes, whichever occurs first.
4.5.12.2
Survival Follow-Up 
Survival follow-up information will be collected by the Sponsor via telephone calls, 
patient medical records, and/or clinic visits approximately every 3 months until death, 
loss to follow-up, or study termination, whichever occurs first.  All patients will be 
followed for survival and new anti-cancer therapy 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 consent to be 
followed on the study, the study staff may use a public information source (e.g., county 
records) to obtain information about survival status only.  During survival follow-up, the 
following information regarding all subsequent anti-neoplastic agents upon treatment 
discontinuation will be collected:  line of therapy, agent, date of first dose of agent, date 
of last dose of agent (or if ongoing), patient's best response, and date of disease 
progression.
4.5.12.3
Adverse Events
Serious adverse events (see Section 5.2.2) and adverse events of special interest (see 
Section 5.2.3), regardless of attribution, will be recorded until the end of the special 
reporting period (defined as 90 days after the last dose of atezolizumab or bevacizumab 


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or 30 days after the last dose of sunitinib or until the initiation of another anti-cancer 
therapy, whichever occurs first).  All other adverse events will be recorded until 30 days 
after the last dose of atezolizumab, bevacizumab or sunitinib or until the initiation of 
another anti-cancer therapy, whichever occurs first.  Ongoing adverse events thought to 
be related to study treatment will be followed until resolution of the adverse event, until 
an alternate cause has been identified, the patient is lost to follow-up, the patient 
withdraws consent, or it has been determined that study treatment or participation is not 
the cause of the adverse event.  The Sponsor should be notified if the investigator 
becomes aware of any serious adverse event that occurs after the end of the special 
reporting period, if the event is believed to be related to prior study drug treatment (see 
Section 5.6).
See the schedule of assessments provided in Appendix 1 for specified follow-up 
assessments. 
4.5.13
Samples for Roche Clinical Repository
Roche participates in the collection and/or submission of biological samples to the RCR.
4.5.13.1
Overview of the Roche Clinical Repository
The RCR 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 and analysis of RCR 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 RCR will be collected from patients who give specific consent 
to participate in this optional research.  RCR 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

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
4.5.13.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection and submission of biological samples to the RCR is contingent upon the 
review and approval of the exploratory research and the RCR portion of the Informed 
Consent Form by each site's IRB or EC and, if applicable, an appropriate regulatory 
body.  If a site has not been granted approval for RCR sampling, this section of the 
protocol (Section 4.5.13) will not be applicable at that site.


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4.5.13.3
Sample Collection
The following samples may be collected for patients who have signed the RCR optional 
consent:

Optional fresh biopsy samples as clinically indicated.  Optional tumor biopsies may 
be obtained at other timepoints at the investigator’s discretion.

Whole blood constitutive (inherited) DNA:  single-nucleotide polymorphism array 
testing on DNA

Remaining serum and plasma after study-related tests have been performed

Remaining formalin-fixed, paraffin-embedded tissue (with the exception of archival 
FFPE blocks, which will be returned to sites) after study-related tests have been 
performed
For all samples, dates of consent should be recorded on the associated RCR page of 
the eCRF.  For sampling procedures, storage conditions, and shipment instructions, see 
the Laboratory Manual.  
RCR specimens will be stored for 15 years or until they are exhausted.  The RCR 
storage period will be in accordance with the IRB/EC-approved Informed Consent Form 
and applicable laws (e.g., health authority requirements).
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4.  The genetic biomarker specimens will undergo additional 
processes to ensure confidentiality, as described below.  
4.5.13.4
Confidentiality 
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens and associated data.  Upon receipt 
by the RCR, each specimen is "double-coded" by replacing the patient identification 
number with a new independent number.  Data generated from the use of these 
specimens and all clinical data transferred from the clinical database and considered 
relevant are also labeled with this same independent number.  A "linking key" between 
the patient identification number and this new independent number is stored in a secure 
database system.  Access to the linking key is restricted to authorized individuals and is 
monitored by audit trail.  Legitimate operational reasons for accessing the linking key are 
documented in a standard operating procedure.  Access to the linking key for any other 
reason requires written approval from the Pharma Repository Governance Committee 
and Roche's Legal Department, as applicable.
Data generated from RCR specimens must be available for inspection upon request 
by representatives of national and local health authorities and Roche monitors, 
representatives, and collaborators, as appropriate.


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Patient medical information associated with RCR 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.
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using RCR specimens will be available 
in accordance with the effective Roche policy on study data publication.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise.
4.5.13.5
Consent to Participate in the Roche Clinical Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RCR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens 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 RCR specimens. 
Patients who decline to participate will not provide a separate signature.
The investigator should document whether the patient has given consent to participate 
by completing the RCR Research Sample Informed Consent eCRF.
In the event of an RCR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research.
4.5.13.6
Withdrawal from the Roche Clinical Repository
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  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 with use of the RCR Subject Withdrawal Form 
and, if the trial is ongoing, must enter the date of withdrawal on the RCR Research 
Sample Withdrawal of Informed Consent eCRF.  The patient will be provided with 
instructions on how to withdraw consent after the trial is closed.  A patient's withdrawal 
from Study WO29637 does not, by itself, constitute withdrawal of specimens from the 
RCR.  Likewise, a patient's withdrawal from the RCR does not constitute withdrawal 
from Study WO29637.
4.5.13.7
Monitoring and Oversight
RCR specimens will be tracked in a manner consistent with Good Clinical Practice by 
a quality-controlled, auditable, and appropriately validated laboratory information 


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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.  Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to Roche.  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 RCR samples.
4.6
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation
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 at any time

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study

Investigator or Sponsor determines it is in the best interest of the patient

Patient non-compliance
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.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced.
4.6.2
Study Treatment Discontinuation
Patients must discontinue study treatment if they experience any of the following:

Symptomatic deterioration attributed to disease progression as determined by the 
investigator after integrated assessment of radiographic data, biopsy results, and 
clinical status.

Intolerable toxicity related to atezolizumabbevacizumab or sunitinib, determined 
by the investigator and Medical Monitor 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 
on study treatment

Use of another anti-cancer therapy with the exception of anti-cancer therapies 
specified in the protocol (see Section 4.4.3)

Pregnancy


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Patients randomized to either study arm will be permitted to continue study treatment 
after RECIST v1.1 criteria for investigator-assessed progressive disease are met, at the 
discretion of the investigator, if they meet all of the following criteria:

Evidence of clinical benefit as assessed by the investigator

Absence of symptoms and signs (including worsening of laboratory values 
[e.g., new or worsening hypercalcemia]) indicating unequivocal progression 
of disease

No decline in KPS that can be attributed to disease progression

Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be readily managed and stabilized by protocol-allowed medical 
interventions prior to repeat dosing.
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  


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Figure 4
Conditions for Continuing Atezolizumab/Bevacizumab or Sunitinib in the Presence of Progression 
by RECIST v1.1 Criteria
Bevbevacizumab; KPSKarnofsky performance status; RECISTResponse Evaluation Criteria in Solid Tumors.


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4.6.3
Study and Site 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.
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 Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice 

No study activity (i.e., all patients have completed and all obligations have been 
fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
Atezolizumab is not approved and is currently in clinical development.  Human 
experience is currently limited and the entire safety profile is not known at this time.  
The following information is based on results from nonclinical and clinical studies and 
published data on similar molecules.
Measures will be taken to ensure the safety of patients participating in this trial, including 
the use of stringent inclusion and exclusion criteria (see Sections 4.1.1, 4.1.2, 
and 5.1.2.1) and close monitoring (as indicated below and in Section 4.5).  
See Section 5.3 (Methods and Timing for Capturing and Assessing Safety Parameters) 
for complete details regarding safety reporting for this study.
The administration of atezolizumab will be performed in a setting with emergency 
medical facilities and staff who are trained to monitor for and respond to medical 
emergencies.  Serious adverse events (see Section 5.2.2) and adverse events of special 
interest (see Section 5.2.3), regardless of attribution, will be recorded during the trial until 
the end of the special reporting period (defined as 90 days after the last dose of 
atezolizumab or bevacizumab or 30 days after the last dose of sunitinib [see 
Section 5.6]).  All other adverse events will be recorded until 30 days after the last dose 
of atezolizumab, bevacizumab, or sunitinib or until the initiation of another anti-cancer 
therapy, whichever occurs first.  The potential safety issues anticipated in this trial, as 


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well as measures intended to avoid or minimize such toxicities, are outlined in the 
following sections.
5.1.1
Risks Associated with Atezolizumab
The PD-L1/PD-1 pathway is involved in peripheral tolerance; therefore, such therapy 
may increase the risk of immune-mediated adverse events, specifically the induction or 
exacerbation of autoimmune conditions.  As of 10 May 2015, adverse events with 
potentially immune-mediated causes, including rash, hypothyroidism, adrenal 
insufficiency, hepatitis/transaminitis, colitis, myositis, influenza-like illness, and 
neurologic disorders, have been observed in Study PCD4989g.  A more comprehensive 
list of observed adverse events observed with atezolizumab is available in Section 1 and 
the Atezolizumab Investigator’s Brochure.
Although most immune-mediated adverse events s observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications (Di Giacomo et al. 2010).  
Suggested workup and management guidelines for suspected immune-mediated 
adverse events are provided in Section 6 (Guidance for the Investigator) of the 
Atezolizumab Investigator’s Brochure.
5.1.2
General Plan to Manage Safety Concerns
5.1.2.1
Eligibility Criteria
Eligibility criteria were selected to guard the safety of patients in this trial.  Results from 
the nonclinical toxicology studies with atezolizumab, the nonclinical/clinical data from 
other PD-L1/PD-1 inhibitors, and clinical data from bevacizumab and sunitinib were 
taken into account.  Specifically, patients at risk for study-emergent autoimmune 
conditions or with a prior diagnosis of autoimmune disease, patients with evidence of 
acute infections, and patients who have received a live-attenuated viral vaccine within 
4 weeks before Day 1 are excluded from the study (see Section 4 for additional details).
5.1.2.2
Monitoring
Laboratory values must be reviewed prior to each infusion.
General safety assessments will include serial interval histories, physical examinations, 
and specific laboratory studies, including serum chemistries and blood counts
(see Appendix 1 and Appendix 2 for the list and timing of study assessments). 
During the study, patients will be closely monitored for the development of any signs or 
symptoms of autoimmune conditions and infection.
All serious adverse events and protocol-defined events of special interest 
(see Sections 5.2.2 and 5.2.3) will be reported in an expedited fashion (see Section 5.4).  
In addition, the Medical Monitor and investigators will review and evaluate observed 
adverse events on a regular basis.


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Patients who have an ongoing study treatmentrelated adverse event upon study 
completion or at discontinuation from the study will be followed until the event has 
resolved to baseline grade, 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 has been determined that study treatment or participation is not the cause 
of the adverse event.
5.1.3
Atezolizumab Dose ModificationGeneral Notes
There will be no dose reduction for atezolizumab in this study.  Patients may temporarily 
suspend study treatment if they experience toxicity that is considered to be related to 
study drug and requires a dose to be withheld.  If atezolizumab is withheld because of 
related adverse events for 42 days beyond when the next dose would have been given, 
then the patient will be discontinued from atezolizumab and will be followed up for safety 
and efficacy as specified in Section 4.5.12.  If, in the judgment of the investigator, the 
patient is likely to derive clinical benefit from resuming atezolizumab after a hold of 
42 days, the study drug may be restarted with the approval of the Medical Monitor.
If patients must be tapered off steroids used to treat adverse events, study treatment 
may be withheld for 42 days until steroids are discontinued or reduced to prednisone 
dose (or dose equivalent) 10 mg/day.  The acceptable length of interruption will depend 
on agreement between the investigator and the Medical Monitor.
Dose interruptions for reason(s) other than adverse events, such as surgical procedures, 
may be allowed with Medical Monitor approval.  The acceptable length of interruption will 
depend on agreement between the investigator and the Medical Monitor.
Patients who discontinue atezolizumab either transiently or permanently (e.g., for 
adverse events) may continue on bevacizumab until disease progression if there is felt 
to be clinical benefit.  
Management of atezolizumab-specific adverse events is presented in in Section 5.1.4.  
See Section 4.3 for guidelines for the management of infusion-related reactions and 
Appendix 10 for precautions for anaphylaxis.
5.1.4
Management of Atezolizumab-Specific Adverse Events
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 determine a possible immunogenic etiology.  
5.1.4.1
Immune-Mediated Reactions
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 


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may not have an immediate therapeutic effect, and in severe cases, immune-mediated 
toxicities may be acutely managed with topical corticosteroids, systemic corticosteroids,
or other immunosuppressive agents.
The primary approach to Grade 12 immune-mediated adverse events is supportive and 
symptomatic care with continued treatment with atezolizumab; for higher grade 
immune-mediated adverse events, atezolizumab should be withheld and oral/parenteral 
steroids administered.  Recurrent Grade 2 immune-mediated adverse events may also 
mandate holding atezolizumab or the use of steroids.  Consideration for benefit-risk 
balance should be made by the investigator, with consideration of the totality of 
information as it pertains to the nature of the toxicity and the degree of clinical benefit a 
given patient may be experiencing prior to further administration of atezolizumab.  
Atezolizumab should be permanently discontinued in patients with life-threatening 
immune-mediated adverse events.
Management of systemic immune activation is presented in Section 5.1.4.2.  See the 
current Atezolizumab Investigator’s Brochure for details on management of 
gastrointestinal, dermatologic, endocrine, pulmonary toxicity, hepatotoxicity, potential 
pancreatic or eye toxicity and other immune-mediated adverse events.  See 
Section 4.3.2.1 for guidelines for the management of infusion-related reactions (see 
Appendix 10 for precautions for anaphylaxis).
5.1.4.2
Systemic Immune Activation
Systemic immune activation is a rare condition characterized by an excessive immune 
response.  Given the mechanism of action of atezolizumab, systemic immune activation 
is considered a potential risk when given in combination with other immunomodulating 
agents.  Systemic immune activation should be included in the differential diagnosis for 
patients who develop a sepsis-like syndrome after administration of atezolizumab and 
the initial evaluation should include the following:

CBC with peripheral smear

PT, PTT, fibrinogen, and D-dimer

Ferritin

Triglycerides

AST, ALT, and total bilirubin

LDH

Complete neurologic and abdominal examination (assess for hepatosplenomegaly)
If systemic immune activation is still suspected after the initial evaluation, contact the 
Medical Monitor for additional recommendations.


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5.1.5
Bevacizumab Dose and Dose Interval Modification
The bevacizumab dose will be based on the patient’s weight at randomization and will 
remain the same throughout the study, unless there is a weight change of 10% from 
baseline.  It is not necessary to correct dosing on the basis of ideal weight, unless 
warranted per institutional guidelines/standard.  Management of bevacizumab may be 
performed according to the label.  Suggested guidelines for management are 
summarized in Table 11.  If adverse events occur that necessitate holding bevacizumab, 
the weight-based dose in mg/kg will remain unchanged after treatment resumes.
Patients who discontinue bevacizumab transiently or permanently for adverse events 
may continue on single-agent atezolizumab until disease progression if there is felt to be 
clinical benefit.  Patients with Grade 3 toxicities attributable to bevacizumab should 
withhold atezolizumab until those toxicities have improved to Grade 2 (exception for 
Grade 3 hypertension).  If bevacizumab is permanently discontinued but there is felt to 
be clinical benefit from atezolizumab, the latter may be continued.
Temporary suspension of bevacizumab must occur if a patient experiences a serious 
adverse event or a Grade 3 or 4 adverse event assessed by the investigator as related 
to bevacizumab.  If the event resolves to Grade 1, bevacizumab may be restarted at 
the same dose level.  Patients who develop Grade 4 toxicities related to bevacizumab 
for 21 days should permanently discontinue bevacizumab.
The appropriate interval between the last dose of bevacizumab and major surgery is 
unknown.  Because bevacizumab has a half-life of approximately 21 days, elective 
surgery should be delayed whenever possible, but if necessary, bevacizumab should be 
withheld for 28 days prior to the procedure.  Re-initiation of bevacizumab should occur 
28 days after surgery and after wounds have fully healed.  Re-initiation of bevacizumab 
after surgery requires documented approval from the Medical Monitor.
Infusion of bevacizumab should be interrupted in patients who develop dyspnea 
or clinically significant hypotension.  Patients who experience an NCI CTCAE Grade 3 or 
4 allergic reaction/hypersensitivity, adult respiratory distress syndrome, or 
bronchospasm (regardless of grade) will be discontinued from bevacizumab treatment.  
If possible, a sample for ATA assessment will be collected at the time of discontinuation.
Bevacizumab infusion should be slowed to 50% or interrupted for patients who 
experience any infusion-associated symptoms not specified above.  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.
5.1.6
Sunitinib Dose and Dose Interval Modification
Dose interruption and/or dose modification in 12.5-mg increments or decrements is 
recommended based on individual safety and tolerability.  Modification to sunitinib 


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administration may be done according to the label.  The starting dose of sunitinib is 
50 mg, unless otherwise specified (below). 
Strong CYP3A4 inhibitors such as ketoconazole may increase sunitinib plasma 
concentrations.  Selection of an alternate concomitant medication with no or minimal 
enzyme inhibition potential is recommended.  A dose reduction for sunitinib to a 
minimum of 37.5 mg daily should be considered if sunitinib must be co-administered with 
a strong CYP3A4 inhibitor (see sections on drug interactions and clinical pharmacology 
from the Sutentlabel). 
CYP3A4 inducers such as rifampin may decrease sunitinib plasma concentrations.  
Selection of an alternate concomitant medication with no or minimal enzyme induction 
potential is recommended.  A dose increase for sunitinib to a maximum of 87.5 mg daily 
should be considered if sunitinib must be co-administered with a CYP3A4 inducer (see 
Appendix 16).  If dose is increased, the patient should be monitored carefully for toxicity 
(see sections on drug interactions and clinical pharmacology from the Sutent label).
Sunitinib should be used with caution in patients with a known history of QT interval 
prolongation, patients who are taking antiarrhythmics, or medicinal products that can 
prolong QT interval, or patients with relevant pre-existing cardiac disease, bradycardia, 
or electrolyte disturbances.  QT interval prolongation may lead to an increased risk of 
ventricular arrhythmias including Torsade de pointes. Torsade de pointes has been 
observed in 0.1% of sunitinib-exposed patients.  A comprehensive list of drugs that 
have the potential to increase QT interval is provided in Appendix 17.
5.1.7
Recommended Guidelines for Management of Suspected 
Bevacizumab or Sunitinib Toxicities
Table 11 describes recommended guidelines for dose modification to sunitinib or 
bevacizumab for selected events.


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Table 11 Bevacizumab and Sunitinib Dose Management for Adverse 
Events
Event
Action to Be Taken
Hypertension 
Grade 1 (asymptomatic, 
transient [24 hr] blood 
pressure increase by 
20 mmHg (diastolic) or to 
150/100 mmHg if previously 
within normal limits)
No bevacizumab or sunitinib dose modifications.
Grade 2 (recurrent or 
persistent [24 hr] or 
symptomatic increase by 
20 mmHg (diastolic) or to 
150/100 mmHg if previously 
within normal limits)
Withhold bevacizumab or sunitinib.  Start antihypertensive therapy 
per institutional guidelines.  After blood pressure is 
150/100 mmHg, patient may continue bevacizumab or sunitinib 
therapy.
Grade 3
Requires more than one antihypertensive drug or more intensive 
therapy than previously:  If not controlled to 150/100 mmHg with 
medication, discontinue bevacizumab or sunitinib.
Grade 4 (including 
hypertensive encephalopathy)
Discontinue bevacizumab or sunitinib.
Hemorrhage 
Grade 1 or 2 non-pulmonary 
or non-CNS events
No bevacizumab or sunitinib modifications.
Grade 3 non-pulmonary or 
non--brain or non-spinal cord 
hemorrhage
Withhold bevacizumab or sunitinib until all of the following criteria 
are met:

The bleeding has resolved and hemoglobin is stable.

There is no bleeding diathesis that would increase the risk of 
therapy.

There is no anatomic or pathologic condition that significantly 
increases the risk of hemorrhage recurrence.
Patients who experience a repeat Grade 3 hemorrhagic event will 
be discontinued from bevacizumab or sunitinib.


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Table 11 Bevacizumab and Sunitinib Dose Management for Adverse 
Events (cont.)
Event
Action to Be Taken
Hemorrhage (cont.)
Grade 4 non-pulmonary or 
non-brain or non-spinal 
cord hemorrhage
Discontinue bevacizumab or sunitinib.
Grade 1 pulmonary or brain 
or spinal cord hemorrhage
Withhold bevacizumab or sunitinib until all of the following criteria 
are met:

The bleeding has resolved and hemoglobin is stable.

There is no bleeding diathesis that would increase the risk of 
therapy.

There is no anatomic or pathologic condition that significantly 
increases the risk of hemorrhage recurrence.
Grade 2, 3, or 4 pulmonary 
or brain or spinal cord 
hemorrhage
Discontinue bevacizumab or sunitinib.
Venous thromboembolic event 
Grade 1 or 2
No bevacizumab or sunitinib modifications.
Grade 3 or 
asymptomatic Grade 4
If the planned duration of full-dose anticoagulation is 2 weeks, 
bevacizumab or sunitinib should be withheld until the full-dose 
anticoagulation period is over.  If the planned duration of full-dose 
anticoagulation is 2 weeks, bevacizumab or sunitinib may be 
resumed after 2 weeks of full-dose anticoagulation if all of the 
following criteria are met:

The patient must have an in-range INR (usually between 2 and 
3) if on warfarin; LMWH, warfarin, or other anticoagulant 
dosing must be stable prior to restarting study treatment.  

The patient must not have had a Grade 3 or 4 hemorrhagic 
event while on anticoagulation.
Symptomatic Grade 4
Discontinue bevacizumab or sunitinib.
Arterial thromboembolic event
(new onset, worsening, or unstable angina, myocardial infarction, transient ischemic attack, 
cerebrovascular accident, and any other arterial thromboembolic event)
Any grade
Discontinue bevacizumab or sunitinib.
Congestive heart failure (left ventricular systolic dysfunction)
Grade 1 or 2
No bevacizumab modifications or sunitinib.
Grade 3
Withhold bevacizumab until resolution to Grade 1; discontinue 
sunitinib.
Grade 4
Discontinue bevacizumab or sunitinib.


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Table 11 Bevacizumab and Sunitinib Dose Management for Adverse 
Events (cont.)
Event
Action to Be Taken
Proteinuria
Grade 1 (urine dipstick 1
or urine collection 0.15 to 
1.0 g/24 hr)
No bevacizumab or sunitinib modifications.
Grade 2 (urine dipstick 
2to 3or urine collection 
1.0 to 3.5 g/24 hr)
For 2 dipstick, may administer bevacizumab and obtain 24-hour 
urine prior to next dose; no sunitinib modification.
For 3 dipstick, obtain 24-hour urine prior to administration of 
bevacizumab; no sunitinib modification.
Withhold bevacizumab for proteinuria >2 g/24 hr and resume when 
proteinuria is ≤2 g/24 hr; no sunitinib modification.a
Grade 3 
(urine dipstick 4or urine 
collection 3.5 g/24 hr) 
No sunitinib modification.
Withhold bevacizumab.  Resume when proteinuria is ≤2 g/24 hr.a
Grade 4 
(nephrotic syndrome)
Discontinue bevacizumab or sunitinib.
GI perforation
Any grade
Discontinue bevacizumab or sunitinib.
Fistula
Any grade 
tracheoesophageal fistula
Discontinue bevacizumab.
Grade 4 fistula (other than 
tracheoesophageal)
Discontinue bevacizumab.
Bowel obstruction
Grade 1
Continue patient on study for partial obstruction not requiring 
medical intervention.
Grade 2
Discontinue bevacizumab.  Withhold sunitinib for partial/complete 
obstruction requiring medical intervention. Patient may restart 
upon complete resolution. 
Wound dehiscence 
Any grade
(requiring medical or 
surgical therapy)
Discontinue bevacizumab or sunitinib.
Reversible posterior leukoencephalopathy
Any grade
(confirmed by MRI)
Discontinue bevacizumab or sunitinib.


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Table 11 Bevacizumab and Sunitinib Dose Management for Adverse 
Events (cont.)
Event
Action to Be Taken
Fatigue/asthenia
Grade 1 or 2
No bevacizumab or sunitinib modification
Grade 3
No bevacizumab modification; withhold sunitinib until resolves to 
Grade 2.  Discontinue sunitinib if fatigue does not resolve 
within 42 days or if Grade 3 fatigue/asthenia reoccurs upon 
resumption
Grade 4
No bevacizumab modification; discontinue sunitinib
Hand-foot syndrome
Grade 1 or 2
No bevacizumab modification; no sunitinib modification.
Grade 3
No bevacizumab modification; withhold sunitinib dose until 
resolves to Grade 2. 
If it resolves to Grade 1 between 7 and 42 days, resume at 
1 dose level (if possible).
Discontinue sunitinib if Grade 3 hand-foot syndrome does not 
resolve within 42 days or if recurs following resumption of 
sunitinib.
Stomatitis
Grade 1 or 2
No bevacizumab modification; no sunitinib modification.
Grade 3
No bevacizumab modification; withhold sunitinib until resolves to 
Grade ≤ 2.
If resolves in 7 days, resume sunitinib at current dose.  If 
resolves between 7 and 42 days, resume sunitinib at 1 dose 
level (if possible).
Discontinue sunitinib if Grade 3 stomatitis recurs following 
resumption of sunitinib or if does not resolve within 42 days.
Grade 4
No bevacizumab modification; discontinue sunitinib.
Hematologic toxicities (excluding anemia)
Grade 1 or 2
No bevacizumab modification; no sunitinib modification.
Grade 3 or 4
No bevacizumab modification; withhold sunitinib until recovered to 
Grade 2, then resume at –1 dose level (if possible).
GIgastrointestinal; LMWHlow molecular-weight heparin; MRImagnetic resonance imaging.
a All proteinuria values are from 24-hour urine collection.
5.1.8
Sunitinib- and Bevacizumab-Related Cardiac Toxicities
Potential cardiac risks of sunitinib include risk of ejection fraction decline, which may 
lead to congestive heart failure and QTc interval prolongation, which may lead to 
ventricular arrhythmias, including Torsades de pointes.  Torsade de pointes has been
observed in 0.1% of sunitinib-exposed patients.  These risks are described in the 
sunitinib label. 


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Patients should be carefully monitored for clinical signs and symptom of CHF while 
receiving sunitinib or bevacizumab, especially in patients with cardiac risk factors and/or 
history of coronary artery disease.  Physicians are advised to weigh this risk against the 
potential benefits.  Baseline and periodic evaluations of LVEF should also be considered 
while these patients are receiving sunitinib.  In patients without cardiac risk factors, a 
baseline evaluation of ejection fraction should be considered.  
If congestive heart failure symptoms appear, sunitinib and bevacizumab should be 
withheld.  Sunitinib dose should be interrupted or reduced in patients without clinical 
evidence of congestive heart failure but with ejection fraction 50% but 20% below 
baseline.
QT interval prolongation may lead to an increased risk of ventricular arrhythmias 
including Torsade de pointes.  Torsade de pointes has been observed in 0.1% of 
sunitinib-exposed patients.  Sunitinib should be used with caution in patients with a 
known history of QT interval prolongation, patients who are taking antiarrhythmics, or 
medicinal products that can prolong QT interval, or patients with relevant preexisting 
cardiac disease, bradycardia, or electrolyte disturbances. Concomitant administration of 
sunitinib with potent CYP3A4 inhibitors should be limited because of the possible 
increase in sunitinib plasma concentrations.
Patients who develop QTc interval prolongation 500 ms should undergo continuous 
cardiac monitoring to evaluate their QTc and this monitoring should continue until 
normalization of the QTc 460 ms and clearance by a cardiologist or equivalent 
physician. 
In countries where additional cardiac monitoring is considered standard (e.g., France), 
additional cardiac monitoring will be required: 

A baseline evaluation of LVEF in those patients with cardiac risk factors and/or an 
abnormal baseline ECG

ECG on Day 22 of Cycle 1 for patients randomized to the sunitinib arm 
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; performing protocol-specified vital 
signs; and 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.


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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), except as described in 
Section 5.3.5.9

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

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 drug

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 (rated as mild, moderate, or severe, or according to NCI CTCAE 


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criteria; 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
for reporting instructions).
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 for reporting instructions).  Adverse events of special interest for this study 
include the following:

The following confirmed treatment-emergent autoimmune conditions:
Pneumonitis
Hypoxia or dyspnea Grade 3
Colitis
Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency, 
hyperthyroidism, or hypothyroidism
Vasculitis
Hepatitis
Transaminitis:  Grade 2 (AST or ALT 3ULN and bilirubin 2ULN) OR 
AST/ALT 10ULN
Systemic lupus erythematosus
Neurologic: Guillain-Barré syndrome, myasthenia gravis, meningoencephalitis
Nephritis

Events suggestive of hypersensitivity, cytokine release, influenza-like illness, 
systemic inflammatory response system (SIRS), systemic immune activation, or 
infusion reaction syndromes 

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy’s law, see Section 5.3.5.6.

Suspected transmission of an infectious agent by the study drug, defined as the 
following:
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 


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suspected from clinical symptoms or laboratory test findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected.
5.2.4
Selected Adverse Events
Additional data will be collected for the following selected adverse events:

Immune-mediated adverse events, including conditions (regardless of grade) 
suggestive of an autoimmune disorder, such as Grade 3 rash or pruritus, 
Grade 3 diarrhea or Grade 2 colitis

Cases of potential drug-induced liver injury that include Grade 3 asymptomatic 
AST/ALT/total bilirubin elevations, or Grade 2 AST/ALT/total bilirubin elevations 
with constitutional symptoms (Hy’s law, see Section 5.3.5.6)
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 drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported 
(e.g., serious adverse events related to invasive procedures such as biopsies).
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported during the trial until the end of the special reporting period 
(defined as 90 days after the last dose of atezolizumab or bevacizumab or 30 days after 
the last dose of sunitinib).  All other adverse events will be reported until 30 days after 
the last dose of atezolizumab, bevacizumab, or sunitinib or until the initiation of another 
anti-cancer therapy, whichever occurs first.  After this period, the investigator should 
report any serious adverse events that are believed to be related to prior study drug 
treatment (see 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 Adverse Events
For each adverse event, the investigator will make an assessment of seriousness (see 
Section 5.2.2 for seriousness criteria), severity, and causality on the Adverse Event 
eCRF.
The adverse event severity grading scale for the NCI CTCAE v4.0 will be used for 
assessing adverse event severity.  Table 12 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 12 Adverse Event Severity Grading Scale
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:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding one's self, 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.


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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 the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also 
Table 13):

Temporal relationship of event onset to the initiation of study drug

Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (where applicable)

Known association of the event with the study drug 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 13 Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug based on 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 the study drug, 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 the 
study drug; and/or the adverse event abates or resolves upon discontinuation of 
the study drug or dose reduction and, if applicable, reappears upon re-challenge.
NO
Adverse events will be considered related, unless they fulfill the criteria as 
specified below. 
Evidence exists that the adverse event has an etiology other than the study drug 
(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 the study drug (e.g., cancer diagnosed 2 days 
after Cycle 1, Day 1).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.


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5.3.5.1
Diagnosis versus Signs and Symptoms
For adverse events, 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 one adverse event report based on the single diagnosis, with a starting date that 
corresponds to the starting date of the first symptom of the eventual diagnosis.
5.3.5.2
Infusion-Related Reactions
An exception to the above is symptoms that occur during or within 24 hours after an 
atezolizumab infusion.  These may be part of an acute infusion reaction and should not 
be recorded under the diagnosis of “infusion-related reaction.”  Rather, these symptoms 
should be recorded as separate adverse events on the AE eCRF.  Serious symptoms 
should be reported as one serious adverse event on the AE eCRF with the most 
medically significant sign or symptom as the primary event term.  Additional signs and 
symptoms should be reported in the Additional Case Details section of the AE eCRF.
5.3.5.3
Adverse Events Occurring Secondary to Other Events
In general, adverse events occurring 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.  However, medically significant adverse events 
occurring secondary to an initiating event that are separated in time should be recorded 
as independent events 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 gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 


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Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded 
separately 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
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., alkaline phosphatase 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.”


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Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3baseline value) in combination with either 
an elevated total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy’s law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3baseline value in combination with total 
bilirubin 2ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3baseline value in combination with clinical 
jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).
5.3.5.7
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 blood pressure), 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).


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5.3.5.8
Deaths
Deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1) that are attributable by the investigator solely to the progression of RCC 
should be recorded only on the Study Discontinuation eCRF.  All other deaths during 
study treatment, regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4).
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.  The term “sudden death” should be used only for the occurrence of an abrupt 
and unexpected death due to presumed cardiac causes in a patient with or without 
preexisting heart disease, within 1 hour of the onset of acute symptoms or, in the case of 
an unwitnessed death, within 24 hours after the patient was last seen alive and stable.  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.
During survival follow-up, deaths attributed to progression of RCC should be recorded 
only on the Survival eCRF.
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,” “worsening,” or “exacerbation”).
5.3.5.10
Worsening of Renal Cell Carcinoma
The term disease progression (i.e., worsening and/or progression of RCC) should not be 
recorded as an adverse event.  The underlying symptoms should be captured as 
adverse events and assessed accordingly for seriousness, severity, and causality.  Data 
for disease progression will be captured as efficacy assessment data only.
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 criteria.  In rare cases, the determination of clinical 


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progression will be based on symptomatic deterioration.  However, every effort should 
be made to document progression with use of objective criteria.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., in-patient 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.  
The following hospitalization scenarios are not considered to be adverse events:

Hospitalization for respite care

Hospitalization to perform 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 condition
The patient has not suffered an adverse event
The following hospitalization scenarios are not considered to be serious adverse events, 
but should be reported as adverse events instead:

Hospitalization for outpatient care outside of normal clinic operating hours that is 
required per protocol or per local standard of care
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 drug 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). 
5.3.5.13
Adverse Events in Individuals Not Enrolled in the Study
If an adverse event inadvertently occurs in an individual not enrolled in the study 
(e.g., during administration of study drug), the Adverse Event Form provided to 
investigators should be completed and submitted to the Sponsor or its designee, either 
by faxing or by scanning and emailing the form with use of the fax number or email 
address provided to investigators.


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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 drug:

Serious adverse events (see Section 5.4.2 for further details)

Adverse events of special interest (see Section 5.4.2 for further details)

Pregnancies (see Section 5.4.3 for further details)
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
Medical Monitor Contact Information for All Sites
Medical Monitor:
Telephone No.:
Mobile Telephone No.:
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 
Monitor, 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 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 Drug Initiation
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.  


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The 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 emailing the form with use of the fax number or email address provided 
to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 90 days after the last dose of atezolizumab or bevacizumab 
and 30 days after the last dose of sunitinib.  All other adverse events will be reported 
until 30 days after the last dose of atezolizumab, bevacizumab, or sunitinib or until the 
initiation of another anti-cancer therapy, whichever occurs first.  After this period, the 
investigator should report any serious adverse events that are believed to be related to 
prior study drug treatment (see Section 5.6).  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 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 emailing the form with 
use of the fax number or email address provided to investigators.  Once the EDC system 
is available, all information will need to be entered and submitted via the EDC system.  
Instructions for reporting post-study adverse events are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 6 months after the last 
dose of atezolizumab or bevacizumab or within 30 days after the last dose of sunitinib. 
A Pregnancy Report eCRF should be completed by the investigator immediately (i.e., no 
more than 24 hours after learning of the pregnancy) and submitted via the EDC system.  
A pregnancy report will automatically be generated and sent to Safety Risk Management.  
Pregnancy should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study drug 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.


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In the event that the EDC system is unavailable, the Clinical Trial Pregnancy 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 pregnancy), 
either by faxing or by scanning and emailing the form with use of the fax number or 
email address provided to investigators.  Once the EDC system is available, all 
information will need to be entered and submitted via the EDC system.
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 30 days after the last dose of 
sunitinib.  A Pregnancy Report eCRF should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted 
via the EDC system.  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 drug.  
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.  Once the 
authorization has been signed, the investigator will update the Pregnancy Report eCRF 
with additional information on the course and outcome of the pregnancy.  An investigator 
who is contacted by the male patient or his pregnant partner may provide information on 
the risks of the pregnancy and the possible effects on the fetus, to support an informed 
decision in cooperation with the treating physician and/or obstetrician.
In the event that the EDC system is unavailable, follow reporting instructions provided in 
Section 5.4.3.1.
5.4.3.3
Abortions
Any abortion should be classified as a serious adverse event (because 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).
5.4.3.4
Congenital Anomalies/Birth Defects and Abortions
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).  
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow up, or the patient withdraws consent.  Every effort should be made to 


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follow all serious adverse events considered to be related to study drug 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.  If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF. 
All pregnancies reported during the study should be followed until pregnancy or fetal 
outcome.  If the EDC system is not available at the time of pregnancy outcome, follow 
reporting instructions provided in Section 5.4.3.1.
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, electronic 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
POST-STUDY ADVERSE EVENTS
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the special reporting period (defined as 
90 days after the last dose of atezolizumab or bevacizumab and 30 days after the last 
dose of sunitinib), if the event is believed to be related to prior study drug treatment.  All 
other adverse events will be reported until 30 days after the last dose of atezolizumab, 
bevacizumab, or sunitinib or until the initiation of another anti-cancer therapy, whichever 
occurs first.
The investigator should report these events directly to Roche or its designee, by either 
faxing or by scanning and emailing the Serious Adverse Event/Adverse Event of Special 
Interest Reporting Form with use of the fax number or email address provided to 
investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events with use of the following reference documents:

The Atezolizumab Investigator’s Brochure 


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
The Bevacizumab Investigator’s Brochure

Local prescribing information for sunitinib 
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.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
This is a randomized, Phase III, open-label study designed to evaluate the safety and 
efficacy of atezolizumabbevacizumab as compared with sunitinib. 
Analysis populations are defined as follows:

The ITT population is defined as all randomized patients whether or not the 
assigned study treatment was received.

The PD-L1selected population is defined as patients in the ITT population whose 
PD-L1 status is IC1/2/3 at the time of randomization

The measurable disease population is defined as patients in the ITT population with 
measurable disease at baseline.

The DOR-evaluable population is defined as patients with objective response.

The PRO-evaluable population is defined as patients with a non-missing baseline 
PRO assessment.

The safety-evaluable population is defined as patients who received any amount of 
any component of the study treatments.
All analyses will be performed for patients in the PD-L1selected population and the ITT 
population, unless specified otherwise.
6.1
DETERMINATION OF SAMPLE SIZE
This study will randomize approximately 900 patients, including a minimum of 
approximately 351 patients with a PD-L1 IHC IC score of 1/2/3.
6.1.1
Type I Error Control
The type I error () for this study is 0.05 (two-sided).  There are two co-primary efficacy 
endpoints for this study:  PFS by investigator assessment per RECIST v1.1 and OS.  To 
control the overall type I error rate (Bretz et al. 2009) at 0.05 (two-sided) while 
accounting for two co-primary endpoints, will be split between PFS (0.04) and OS 
(0.01).  Because type I error will be controlled accounting for two co-primary
endpoints, the study will be considered a positive study if statistical significance is 
achieved for either of the co-primary endpoints.


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Formal treatment comparisons will be performed in a hierarchical fashion in which may 
be recycled (Burman et al. 2009) as follows:
1.
PFS in the PD-L1selected population will be evaluated at 0.04 (two-sided). 
2.
If PFS results in the PD-L1selected population are statistically significant at 
0.04, then 0.04 will be recycled to OS in the ITT population, and OS in the 
ITT population will be evaluated at 0.05 (two-sided).  If PFS results in the 
PD-L1selected population are not statistically significant at 0.04, then no 
recycling of will occur, and OS in the ITT population will be evaluated at 0.01
(two-sided).
3.
OS will be compared between treatment arms in a hierarchical fashion as follows.  If 
OS results in the ITT population are statistically significant at the appropriate level, 
then OS in the PD-L1selected population will be evaluated at same -level as for 
OS in the ITT population.  If OS results in the ITT population are not statistically 
significant, formal treatment comparison of OS in the PD-L1selected population will 
not be performed. 
Interim analyses of OS and the final analysis of OS will be based on the allocated to 
the comparison of OS, as described above.  Statistical significance at interim analyses of 
OS will be evaluated as described in Section 6.9.2.
The PFS and OS analysis hierarchy and allocation including possible recycling are 
shown in Figure 5.
Figure 5
PFS and OS Analysis Hierarchy, Alpha Allocation and Alpha 
Recycling
ICtumor-infiltrating immune cell; ITTintent to treat; PFSprogression-free survival; 
OSoverall survival.


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6.1.2
Co-Primary Endpoint:  Progression-Free Survival in the 
PD-L1Selected Population
The analysis of the co-primary endpoint of PFS will take place when 
approximately 228 PFS events in the PD-L1selected population (65% of the estimated 
351 PD-L1population) as defined for the primary analysis of PFS (see Section 6.4.1) 
have occurred based on the following assumptions:

Two-sided, stratified log-rank test 

0.04 (two-sided)

Approximately 88% power

Median PFS for the sunitinib arm of 11 months and estimated median PFS in the 
atezolizumabbevacizumab arm of 17 months (corresponding to HR of 0.65)

5% annual loss to follow-up for PFS

No interim analysis
Accrual is projected to occur over 20 months, assuming a ramp-up period of 9 months.  
On the basis of these assumptions, the required number of PFS events in the 
PD-L1selected population is projected to occur at Month 34 from the time the first 
patient is randomized.  Also on the basis of these assumptions, it is projected that an 
observed HR of 0.76 or lower will result in a statistically significant difference between 
treatment arms (i.e., an HR of 0.76 will be the minimally detectable difference for the 
analysis; this corresponds to an improvement of 3.5 months in median PFS from 
11 months in the sunitinib arm to 14.5 months in the atezolizumabbevacizumab arm).
6.1.3
Co-Primary Endpoint:  Overall Survival in the ITT Population
The final analysis of the co-primary endpoint of OS will take place at the later of the time 
points when the required number of events has occurred in the PD-L1selected 
population and in the ITT population, where the required number of events is as follows:

639 OS events in the ITT population (71% of the estimated 900 patients)

246 OS events in the PD-L1selected population (70% of the estimated 351
patients)
The number of events required for the final OS analysis in these populations is based on 
the following assumptions:

Two-sided, stratified log-rank test 

0.01 (two-sided) 

1% annual loss to follow-up for OS

For the ITT population:  
85% power
Median OS in the control arm of 24 months


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Estimated median OS in the atezolizumabbevacizumab arm of 32 months (an 
increase of 8 months, corresponding to an HR of 0.75

For the PD-L1selected population:  
53% power
Median OS in the control arm of 24 months
Estimated median OS in the atezolizumabbevacizumab arm of 33.8 months 
(an increase of 9.8 months, corresponding to an HR of 0.71)
On the basis of these assumptions, the required number of OS events for the final 
analysis of OS in both the PD-L1selected population and the ITT population is 
projected to occur at Month 63 from the time the first patient is randomized.
At the final OS analysis, on the basis of these assumptions, it is projected that an 
observed OS HR of 0.83 or lower in the ITT population will result in a statistically 
significant difference between treatment arms (i.e., the minimally detectable difference at 
the analysis; this corresponds to an improvement of 4.9 months in median OS, from 
24 months in the control arm to 28.9 months in the atezolizumabbevacizumab arm).
Also at the final OS analysis, on the basis of these assumptions, it is projected that an 
observed OS HR of 0.72 or lower in the PD-L1selected population will result in a 
statistically significant difference between treatment arms (i.e., an HR of 0.72 will be the 
minimally detectable difference at the analysis; this corresponds to an improvement of 
9.5 months in median OS, from 24 months in the control arm to 33.5 months in the 
atezolizumabbevacizumab arm).
6.2
SUMMARIES OF CONDUCT OF STUDY
Enrollment, major protocol deviations including major deviations of inclusion/exclusion 
criteria, and reasons for discontinuation from the study will be summarized by treatment 
arm for the PD-L1selected population and the ITT population.  Study treatment 
administration and reasons for discontinuation from the study treatment will be 
summarized by treatment arm for all treated patients and for treated patients in the 
PD-L1selected population.  
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic variables such as age, sex, race/ethnicity, stratification factors (liver 
metastases, MSKCC [Motzer] score, PD-L1 status), and baseline characteristics (e.g., 
weight, primary tumor characteristics [Fuhrman grade, histology {clear cell; sarcomatoid}, 
etc.], time since initial diagnosis, time since metastatic diagnosis, site[s] of metastatic 
disease, number of metastatic site[s], and KPS) will be summarized by treatment arm for
the ITT population and for the PD-L1selected population.  Continuous variables will be 
summarized using means, standard deviations, medians, and ranges.  Categorical 
variables will be summarized by proportions. 


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The baseline value of any variable will be defined as the last available value prior to the 
first administration of study treatment. 
6.4
EFFICACY ANALYSES
The efficacy analyses will include patients with an IHC score of IC1/2/3 (PD-L1selected 
population) and all randomized patients grouped according to the treatment assigned at 
randomization on the basis of the ITT principle.  
6.4.1
Co-Primary Efficacy Endpoints
The co-primary efficacy endpoints are investigator-assessed PFS per RECIST v1.1 and 
OS.  Because type I error will be controlled accounting for two co-primary endpoints, the 
study will be considered a positive study if statistical significance is achieved for either of 
the co-primary endpoints.
PFS will be analyzed in the PD-L1selected population and OS will be analyzed first in 
the ITT population; additional analyses of OS will be performed in a hierarchical fashion 
(see Section 6.1.1).
PFS is defined as the time from randomization to disease progression, as determined by 
the investigator per RECIST v1.1 (see Appendix 3), or death from any cause, whichever 
occurs first.  Data for patients who have not experienced disease progression or death 
will be censored at the last tumor assessment date.  Data for patients with no 
post-baseline tumor assessments will be censored at the randomization date 1 day.  
For United States registrational purposes, the co-primary efficacy endpoint of PFS will 
be defined as described above with an additional censoring rule for missed visits.  Data 
for patients with a PFS event who missed two or more scheduled assessments 
immediately prior to the PFS event will be censored at the last tumor assessment prior to 
the missed visits.
OS is defined as the time from randomization to death due to any cause.  Data for 
patients who are not reported as having died at the date of analysis will be censored at 
the date when they were last known to be alive.  Patients who do not have post-baseline 
information will be censored at the date of randomization 1 day.
The following analyses will be performed for both PFS endpoints described above and 
OS.  PFS and OS will be compared between treatment arms with use of the stratified 
log-rank test.  The HR will be estimated using a stratified Cox proportional hazards 
model.  The 95% CI for the HR will be provided.  The stratification factors will be the 
same as the randomization stratification factors:  presence of liver metastasis (yes/no); 
tumor PD-L1 status (IC0 vs. IC1/2/3); and the MSKCC (Motzer) score (0, 12, 3).  The 
stratification factors will be obtained from the IxRS at the time of randomization.  Results 
from an unstratified analysis will also be provided. Kaplan-Meier methodology will be 
used to estimate the median PFS and OS for each treatment arm, and Kaplan-Meier 


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curves will be produced.  The Brookmeyer-Crowley methodology will be used to 
construct the 95% CI for the median PFS and OS for each treatment arm 
(Brookmeyer and Crowley 1982).  
The following analyses will be performed for both PFS endpoints described above and 
(as applicable) for OS: 

Analyses described in Section 6.8.1 (Analyses at Landmark Time Points)

Analyses described in Section 6.8.2 (Subgroup Analyses) 

Secondary endpoint of PFS by IRC assessment, PD-L1selected population and 
ITT population, based on RECIST v1.1

Secondary endpoint of PFS by investigator assessment in the ITT population, based 
on RECIST v1.1
6.4.2
Secondary Efficacy Endpoints
Secondary efficacy endpoints include the following:
The following secondary efficacy endpoints will be analyzed in the PD-L1selected 
population and the ITT population:

OS (PD-L1selected population)

PFS by IRC assessment (RECIST v1.1)

ORR by investigator assessment (ORR-evaluable population, RECIST v1.1 [see 
Appendix 3])

DOR by investigator assessment (DOR-evaluable population, RECIST v1.1)

ORR by IRC assessment (ORR-evaluable  population, RECIST v1.1)

DOR by IRC assessment (DOR-evaluable population, RECIST v1.1)

PFS by investigator assessment (modified RECIST [see Appendix 4])

ORR by investigator assessment (ORR-evaluable population, modified RECIST)

DOR by investigator assessment (DOR-evaluable population, modified RECIST)

PFS by investigator assessment (ITT population, RECIST v1.1)

PFS by investigator (patients with sarcomatoid histology, RECIST v1.1)  

OS (patients with sarcomatoid histology) 

Change from baseline in symptom interference from the MDASI Part II 
(PRO-evaluable population)


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6.4.2.1
Progression-Free Survival
Progression-Free Survival by Modified RECIST
PFS by modified RECIST is defined as the time from randomization to disease 
progression as determined by the investigator per modified RECIST (see Appendix 4) or 
death from any cause, whichever occurs first.  A patient is considered to have disease 
progression by modified RECIST if either of the following conditions were met:

Modified RECIST criteria for progression were met at a tumor assessment and no 
subsequent tumor assessment was performed.

Modified RECIST criteria for progression were met at a tumor assessment and at 
the subsequent tumor assessment the criteria for confirmed progression by modified 
RECIST were also met.
For patients who meet criterion (a), the date of progression is the date of the tumor 
assessment that met the criteria for modified RECIST.  For patients who meet 
criterion (b), the date of progression is the date of the tumor assessment at which the 
modified RECIST criteria for progression were first met.  
Patients who do not meet either of the above criteria are not considered to have had 
disease progression by modified RECIST.  For example, a patient who had a tumor 
assessment for which the criteria for progression by modified RECIST criteria were met, 
but at the subsequent tumor assessment the criteria for confirmed progression by 
modified RECIST were not met, would not be considered to have had progression by 
modified RECIST on the basis of those two tumor assessments.  The determination of 
whether such a patient subsequently met the criteria for progression by modified 
RECIST would be based only on additional subsequent tumor assessments performed 
after the two tumor assessments described in this example.
Data for patients who have not experienced disease progression by modified RECIST or 
death will be censored at the last tumor assessment date.  Data for patients with no 
post-baseline tumor assessments will be censored at the randomization date 1 day.
Analysis of Progression-Free Survival as Secondary Endpoints
Methods for comparison of PFS between treatment arms for the secondary endpoints of 
PFS will be the same as the methods for treatment comparisons for the co-primary
efficacy endpoint of PFS.
6.4.2.2
Objective Response Rate
An objective response is defined as either a CR or PR (confirmation not required) based 
on RECIST v1.1.  Patients not meeting this criterion, including patients without any 
post-baseline tumor assessments, will be considered non-responders.  
ORR is defined as the proportion of patients who had an objective response among 
patients with measurable disease at baseline.  Confirmed response rate will also be 


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evaluated, defined as patients with CR or PR at two consecutive tumor assessments at 
least 28 days apart.  
ORR will be compared between treatment arms with use of the stratified 
Cochran-Mantel-Haenszel test.  The stratification factors will be the same as those 
described in the analysis of the primary endpoint of PFS.  An estimate of ORR will be 
calculated for each treatment arm, and its 95% CI will be calculated using the 
Clopper-Pearson method.  The difference in ORR between treatment arms will be 
calculated, and its 95% CI will be calculated using the normal approximation to the 
binomial distribution.  
6.4.2.3
Duration of Response
Duration of response is defined for patients who had an objective response as the time 
from the first occurrence of response (CR or PR) to disease progression or death, 
whichever occurs first.  Data for patients who have not experienced disease progression 
or death will be censored at the last tumor assessment date.  If no tumor assessments 
were performed after the date of the first occurrence of CR or PR, data for DOR will be 
censored at the date of the first occurrence of CR or PR 1 day.
DOR is based on a non-randomized subset of patients (those who achieved an objective 
response); therefore, formal hypothesis testing will not be performed for this endpoint.  
Comparisons between treatment arms will be made for descriptive purposes only.  
Methods for comparison of DOR between treatment arms will be the same as the 
methods for treatment comparison for the co-primary efficacy endpoint of PFS. 
6.4.2.4
Change from Baseline in Symptoms Interference
See Section 6.7 for a description of this endpoint and analysis methods to be used.
6.4.3
Handling of Missing Data
For PFS, patients without a date of disease progression will be analyzed as censored 
observations on the date of last tumor assessment.  If no post-baseline tumor 
assessment is available, PFS will be censored at the date of randomization 1 day.  In 
the analysis of PFS for United States registrational purposes, data for patients with a 
PFS event who missed two or more scheduled assessments immediately prior to the 
PFS event will be censored at the last tumor assessment prior to the missed visits (see 
Section 6.4.1).
For objective response, patients without any post-baseline assessment will be 
considered non-responders.
For OS, patients who are not reported as having died will be analyzed as censored 
observations on the date they were last known to be alive.  If no post-baseline data are 
available, OS will be censored at the date of randomization 1 day.


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For PRO measures (MDASI and BFI), subscales with less than 50% of the items 
completed will be considered missing.
6.5
SAFETY ANALYSES
Safety analyses will be performed for the safety-evaluable population; selected safety 
analyses will be performed for safety-evaluable patients in the PD-L1selected 
population.  Patients will be grouped according to the treatment actually received. 
Exposure to study treatment will be summarized by treatment arm.
Safety will be evaluated through summaries of adverse events, changes in laboratory 
test results, changes in vital signs, and immunogenicity as measured by ATA, and will be 
presented by treatment arm.
Verbatim descriptions of adverse events will be mapped to MedDRA terms.  
Treatment-emergent events (defined as events occurring on or after the first dose 
of atezolizumab or bevacizumab or sunitinib) will be summarized by MedDRA term, 
appropriate MedDRA levels, and NCI CTCAE v4.0 grade.  For each patient, the 
maximum severity reported will be used in the summaries.  Adverse events will be 
summarized regardless of relationship to study drug as assessed by the investigator.  All 
adverse events, adverse events leading to withdrawal of study drug, adverse events 
leading to dose reduction or interruption, Grade 3 adverse events, serious adverse 
events, and adverse events of special interest will be summarized.  Deaths and cause 
of death will be summarized.  
Changes in NCI CTCAE grade for laboratory tests will be tabulated by treatment arm.  
Changes in selected vital signs will be summarized.  ATA results will be summarized and 
listed by patient and cycle.
6.6
PHARMACOKINETIC ANALYSES
Atezolizumab serum concentration data (Cmin and Cmax) will be tabulated and 
summarized for each cycle at which pharmacokinetics are to be measured (Cmax will be 
reported for Day 1 of Cycle 1 only; Cmin will be evaluated at Day 1 of Cycles 1, 2, 4, 8 
and every eight cycles thereafter; Day 22 of Cycles 1, 2, and 4; and at study termination).
Bevacizumab serum concentration data (Cmin and Cmax) will be tabulated and 
summarized for each cycle at which pharmacokinetics are to be measured (Cmax will be 
reported for Day 1 of Cycles 1 and 2; Cmin will be evaluated at Day 1 of Cycles 1, 2, and 
study termination).
Descriptive statistics will include means, medians, ranges, and SDs, as appropriate.
Additional PK and pharmacodynamic analyses will be conducted as appropriate.


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6.7
PATIENT-REPORTED OUTCOME ANALYSES
6.7.1
MDASI, and BFI, and FKSI-19
Scoring for the MDASI and BFI questionnaires will be based on their corresponding user 
manuals (Cleeland 2009).  For MDASI and BFI scales with more than 50% of the 
constituent items 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 missing. 
The impact of symptoms on patients’ functioning will be compared between treatment 
arms as a change from baseline on the interference items in the MDASI Part II. 
The severity of symptoms captured in the MDASI and the BFI will be summarized using 
descriptive analyses including summary statistics and change from baseline at each 
assessment by treatment arm.
6.7.2
Health Economic Data
Health economic data, as assessed by the EQ-5D, will be evaluated for patients with a 
baseline assessment and at least one post-baseline EQ-5D assessment that generated 
a score.  Scores at baseline and change from baseline scores for each timepoint will be 
quantified using descriptive statistics.
The results from the health economic data analysis will be reported separately from the 
Clinical Study Report.
6.8
EXPLORATORY ANALYSES
6.8.1
Analyses at Landmark Time Points
The PFS and OS rates at various timepoints (i.e., every 6 months after randomization) 
will be estimated by the Kaplan-Meier methodology for each treatment arm and the 
95% CI will be calculated using Greenwood’s formula.  
6.8.2
Subgroup Analyses
To assess the consistency of study results in subgroups defined by demographic and 
baseline characteristics, PFS, ORR, and OS in these subgroups will be examined.  
Summaries of PFS and OS, including unstratified HRs estimated from Cox proportional 
hazards models and Kaplan-Meier estimates of the median, will be produced separately 
for each level of the categorical variables.  ORR will be summarized for each level of the 
categorical variables.
PFS and ORR will be summarized in patients with tumor Fuhrman Grade 4 or 
sarcomatoid histology (defined by investigator-assessed conventional histopathology)


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6.8.3
Biomarker Analyses
Exploratory biomarker analyses will be performed in an effort to understand the
association of these markers with study drug response, including efficacy and/or adverse 
events.  Biomarker analyses may be reported in a separate report.
6.9
INTERIM ANALYSES
6.9.1
Progression-Free Survival
There are no planned interim analyses of the co-primary endpoint of PFS.
6.9.2
Overall Survival
A total of four analyses of OS will be performed, including three interim analyses and 
one final analysis. The level for OS testing is 0.05 given that the co-primary 
endpoint of PFS was met in the study (see Section 6.1.1). The boundary for statistical 
significance at each interim analysis and the final analysis will be determined based on 
the Lan-DeMets implementation of the O’Brien-Fleming function 
(Lan and DeMets 1983) to maintain the overall type 1 error rate (Hung et al. 2007; 
Glimm et al. 2009) at 0.05 level. The O’Brien-Fleming (OBF) boundary for statistical 
significance is provided in Table 14.  The OS endpoint will be considered positive in the 
ITT population if statistical significance is achieved for any of the three OS interim 
analyses or the final analysis.


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Table 14 Interim and Final OS Analyses for the ITT Population
OS Analyses
First interim OS (performed at time of 
PFS analysis) a
   No. of events (%) b
264 (29%)
% of final events
41%
Cutoff date
Study Month 29 c
OBF boundary for p-value
p 0.0009
Second interim OS (Time driven)
   Projected No. of events (%) b
377 (41%)
Projected % of final events
59%
Cutoff date
Study Month 40 c
Projected OBF boundary for p-value d
p 0.0067
Third interim OS (Event driven)
   No. of events (%) b
518 (57%)
% of final events
81%
Projected cutoff date
Study Month 57 c
Projected OBF boundary for p-value d
p 0.0233
Final OS (Event driven)
   No. of events (%) b  
639 (70%)
% of final events
100%
Projected cutoff date
Study Month 79 c
Projected OBF boundary for p-value d
p 0.0420
ITT intent-to-treat; OBF O’Brien-Fleming; OS overall survival; PFS progression-free 
survival.
Note:  The level for OS testing is 0.05, given that the co-primary endpoint of PFS was met 
(see Section 6.1.1).
a
The first interim analysis of OS was performed at the time of the PFS primary analysis at 
Study Month 29, with a cut-off date of 29 September 2017, which was 5 months earlier than 
the initial projection of Month 34 described in Section 6.1.2  The OBF boundary for p-value 
is calculated based on 264 OS events observed by the cutoff date.
b
The event rate is based on the actually observed ITT population with N 915.
c
Study month at which required number of events are projected to occur, where Study 
Month 1 is the month the first patient is enrolled.  
d
The projected OBF boundary for statistical significance is calculated according to the 
number of events shown.  The actual OBF boundary will be calculated at time of analysis 
based on actual number of events observed.
The first interim analysis of OS was performed at the time of the PFS primary analysis.  
A total of 264 deaths (29% of 915 patients in the ITT population) was observed at the 
first interim analysis of OS, which corresponds to 41% of the events information 


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required for the final analysis of OS in the ITT population.  The first OS interim 
analysis did not pass the OBF boundary at 0.0009. 
The second interim analysis of OS will be time driven and will occur approximately 
11 months from the clinical cutoff of the first OS interim.  
 
 
  It is projected that at the second interim OS analysis,
377 deaths (41% of 915 patients in the ITT population) will occur, corresponding to 
approximately 59% of the events required for the final analysis of OS in the ITT 
population.  Statistical significance will be declared if p 0.0067 when 377 deaths have 
occurred at the time of the second OS interim analysis.
The third interim analysis of OS is event driven and remains the same as the original 
plan (Protocol WO29637, Version 6).   The third interim analysis of OS will be 
performed when approximately 518 deaths (57% of 915 patients in the ITT population) 
have occurred, which corresponds to approximately 81% of the events information 
required for the final analysis of OS in the ITT population.  Statistical significance will 
be declared if p 0.0233 when 518 deaths have occurred at the time of the third OS 
interim analysis.
The final analysis of OS is event driven and remains the same as the original plan 
(Protocol WO29637, Version 6).   The final analysis of OS will be performed when 
639 deaths (70% of 915 patients in the ITT population) have occurred.  Statistical 
significance will be declared if p 0.0420 when 639 deaths have occurred at the time of 
the final OS analysis.
The interim and final analyses of OS, including analyses in both the ITT and 
PD-L1selected populations, will follow the testing hierarchy described in 
Section 6.1.1.  Specifically, for each OS interim and final analysis, OS in the 
PD-L1selected population will be evaluated for statistical significance only when the 
OS results in the ITT population are statistically significant at the OBF boundary.  The 
actual OBF boundary will be calculated at time of analysis based on actual number of 
events observed.  If OS results in the ITT population are not statistically significant, 
formal testing of OS in the PD-L1selected population will not be performed.
All efficacy analyses, including the interim analyses of OS, will be performed by the 
Sponsor.
6.9.3
Optional Interim Analysis
In addition to the planned interim analyses of OS, one additional interim analysis of OS 
may be performed at the discretion of the Sponsor.  The decision to conduct the optional 
interim analysis, along with the rationale, timing, and statistical details for the analysis, 
will be documented in the Statistical Analysis Plan (SAP), and the SAP will be submitted 
to relevant health authorities prior to the conduct of the interim analysis.  


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 with 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 will be sent 
directly to the Sponsor.  The Sponsor’s standard procedures will be used to handle and 
process the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS
eCRFs are to be completed using a Sponsor-designated EDC system.  Sites will receive 
training and have access to a manual for appropriate eCRF completion.  eCRFs will be 
submitted electronically to the Sponsor and should be handled in accordance with 
instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format 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 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, PRO, 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.
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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, 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 investigational site must also allow 
inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with health authority requirements pertaining to computerized systems used 
in clinical research.  An acceptable computerized data collection system allows 
preservation of the original entry of data.  If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic patient-reported outcome data (if applicable), Informed 
Consent Forms, laboratory test results, and medication inventory records, must be 
retained by the Principal Investigator for at least 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.
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 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 
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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 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).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form 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.
The Informed Consent Form will contain a separate section that addresses the use of 
remaining mandatory samples for optional exploratory research.  The investigator or 
authorized designee will explain to each patient the objectives of the exploratory 
research.  Patients will be told that they are free to refuse to participate and may 
withdraw their specimens 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 allow 
any remaining specimens to be used for exploratory research.  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 
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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 of 1996 (HIPAA).  If the site 
utilizes a separate Authorization Form for patient authorization for use and disclosure of 
personal health information under the HIPAA regulations, the review, approval, 
and other processes outlined above apply except that IRB review and approval may not 
be required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
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 only be 
disclosed to third parties 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.
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Data generated by this study must be available for inspection upon request by 
representatives of the FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate.
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.
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.
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.
9.4
ADMINISTRATIVE STRUCTURE
This trial will be sponsored F. Hoffman-La Roche.  Approximately 150180 sites 
worldwide will participate to enroll approximately 830 patients.
An iDMC will be in place throughout the study and will provide oversight of safety (see 
Section 3.1.1).
After written informed consent has been obtained, the study site will obtain the patient’s 
screening number from the IxRS.  After eligibility has been established, the patient will 
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be enrolled and the study site will obtain the patient’s identification number from the 
IxRS.  
The patient will be randomized by the IxRS.  The IxRS will manage the inventory of 
atezolizumab, bevacizumab, and sunitinib (in countries where sunitinib is considered an 
IMP) at all sites.  The IxRS will be required to randomize patients, to monitor enrollment 
and patient status, and to manage atezolizumab, bevacizumab, and sunitinib (where 
applicable) requests and shipments. 
Patient data will be recorded via an EDC system with use of eCRFs.
Central laboratories, including Roche and Roche’s collaborators, will be used for PD-L1 
expression status determination and will provide kits for PK, pharmacogenomic, tissue, 
whole blood, serum, and plasma sample analyses to be conducted at central 
laboratories or Roche.  PD-L1 evaluation will be conducted prior to randomization, and 
the results will be used for stratification.
Treatment decisions will be made on the basis of the local reading of ECGs obtained 
during the study.
Sites will provide imaging used for tumor assessment to the IRC to enable centralized, 
independent review of response and progression endpoints.  IRC membership and 
procedures will be detailed in an IRC Charter.
9.5
PUBLICATION 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, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site:
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.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 clinical study report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
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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.
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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Appendix 1
Schedule of Assessments
Assessment Window (Days) a
Screening b
Days 28
to 1
AtezolizumabBevacizumab
OR
Sunitinib
End of Treatment 
30 Days after Last
Dose of Study 
Treatment d
Survival Follow-Up
Cycle 1 
Day 1
Cycle 1 
Day 22 c
Day 1, Every 
Two Cycles
Signed Informed Consent 
Form(s) b
x
Review of eligibility criteria
x
Medical, surgical, and cancer 
histories, including 
demographic information e
x
x
Cancer treatment
HBV and HCV serology
x
HIV testing f
x
Concomitant medications g
x
x
x
x
Tumor assessment h
x
At 12 weeks 5 business days, then every 6 weeks 5 business days thereafter, including 
Week 78 following randomization.  After 78 weeks from randomization, patients will undergo 
tumor assessments every 12 weeks 5 business days until treatment discontinuation.
Complete physical 
examination i
x
x
Limited physical examination j
x j, k
Karnofsky performance status
x
x k
x








Appendix 1
Schedule of Assessments (cont.)
atezolizumab or bevacizumab or 30 days after the last dose of sunitinib).  After this period, the investigator should report any serious 
adverse events that are believed to be related to prior study drug treatment (see Section 5.6).  All other adverse events will be recorded 
until 30 days after the last dose of atezolizumab, bevacizumab or sunitinib, or until initiation of another anti-cancer therapy, whichever 
occurs first.  Patients will be contacted at 30 days after the last dose of study treatment to determine if any new adverse events have 
occurred.  Ongoing adverse events thought to be related to study treatment will be followed until resolution of the adverse event, until an 
alternate cause has been identified, 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 end of treatment visit do not 
need to be repeated. The Sponsor should be notified if the investigator feels any serious adverse event occurring after the end of the 
adverse event reporting period is related to prior study drug treatment.
e Cancer history includes stage, date of diagnosis, and prior anti-tumor treatment.  Demographic information includes sex, age, 
and self-reported race/ethnicity.
f
All patients will be tested for HIV prior to the inclusion into the study and HIV-positive patients will be excluded from the clinical trial.
g Concomitant medications include any prescription or over-the-counter medications.  At screening, any medications the patient has used 
within the 7 days prior to the screening visit should be documented.  At subsequent visits, changes to current medications or 
medications used since the last documentation of medications will be recorded.
h All measurable and evaluable lesions should be assessed and documented using physical examination and image-based evaluation.  
Screening assessments should include CT scans with oral and intravenous contrast of the chest, abdomen, and pelvis, and a brain 
scan (CT or MRI).  Bone scans and CT scan of neck should also be performed if clinically indicated.  CT or MRI scans must be used to 
measure lesions selected for response assessment.  Disease status will be assessed using RECIST v1.1 and modified RECIST criteria 
(see Appendix 3 and Appendix 4).  The same radiographic procedure used to define measurable lesions at baseline must be used 
throughout the study for each patient.  Results must be reviewed by the investigator before dosing at the next cycle.  Tumor 
assessments will occur at baseline, at 12 weeks 5 business days, then every 6 weeks 5 business days thereafter including 
Week 78 following randomization.  After 78 weeks from randomization, patients will undergo tumor assessments every 12 weeks 
5 business days until treatment discontinuation, or as clinically indicated.  Patients who discontinue study treatment for reasons other
than disease progression (e.g., toxicity) should continue to undergo scheduled tumor assessments as if they were on the protocol
schedule until the patient dies, experiences disease progression per RECIST v1.1 and modified RECIST, withdraws consent, or until
the study closes, whichever occurs first.  For patients who will be permitted to continue study treatment beyond radiographic disease
progression per RECIST v1.1, tumor assessment will be monitored with a follow-up scan at the next scheduled tumor assessment
when the scan frequency is every 6 weeks.  If the scan frequency is every 12 weeks (see above), the follow-up scan must be
performed at every 12 weeks (5 business days), or earlier if clinically indicated, until loss of clinical benefit described in Section 4.6.2
or treatment discontinuation, whichever is later.
i A complete physical examination at screening and the end of treatment visit should include the evaluation of head, eye, ear, nose, and 
throat and cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, and neurologic systems.  Changes in 
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Appendix 2
Anti-Therapeutic Antibody, TBNK, Biomarker, and
Pharmacokinetic Sampling Schedule
Study Visit
Time
Sample
Cycle 1,
Day 1 
Predose
Atezolizumab ATA
Bevacizumab ATA
Atezolizumab pharmacokinetics
Bevacizumab pharmacokinetics
TBNK
Biomarkers a
30 (10) minutes 
after end of infusion c
Atezolizumab pharmacokinetics
Bevacizumab pharmacokinetics
Cycle 1, 
Day 22 
Predose
Biomarkers b
Atezolizumab pharmacokinetics
Cycles 2, 3, 4, and 8, 
and every eight 
cycles thereafter
Day 1 (3 days)
Predose
Atezolizumab ATA (Cycles 2, 4, and 8, 
and every eight cycles thereafter)
Bevacizumab ATA (Cycle 3 only)
Atezolizumab pharmacokinetics (Cycles 
2, 4, and 8 and every eight cycles 
thereafter)
Bevacizumab pharmacokinetics (Cycle 3 
only)
Biomarkers b (Cycle 2 only)
30 (10) minutes 
after end of infusion
Bevacizumab pharmacokinetics (Cycle 3 
only)
Cycles 2 and 4, 
Day 22 (3 days)
Predose
Atezolizumab pharmacokinetics 
Biomarker (Cycle 2 only) b
At time of fresh 
biopsy (during 
treatment or at 
progression)
TBNK
Biomarkers b, d
End of treatment visit
At visit
Atezolizumab ATA
Atezolizumab pharmacokinetics
Biomarkers b
Bevacizumab ATA
Bevacizumab pharmacokinetics
120 (30) days after 
last dose of 
atezolizumab e
At visit
Atezolizumab ATA
Atezolizumab pharmacokinetics
Bevacizumab ATA
Bevacizumab pharmacokinetics




Appendix 3
Response Evaluation Criteria in Solid Tumors:  
Version 1.1
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1 1 are presented below, with slight modifications and the addition of 
explanatory text as needed for clarity.2
MEASURABILITY OF TUMOR AT BASELINE
DEFINITIONS
At baseline, tumor lesions/lymph nodes will be categorized measurable or 
non-measurable as follows:
Measurable Tumor Lesions
Tumor Lesions.  Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size of: 

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan
(CT/MRI scan slice thickness/interval no greater than 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 no greater than 5 mm).  At baseline and in follow-up, 
only the short axis will be measured and followed.  See also notes below on “Baseline 
Documentation of Target and Non-Target Lesions” for information on lymph node 
measurement.
Non-Measurable Tumor Lesions
Non-measurable tumor lesions encompass small lesions (longest diameter 10 mm 
or pathological lymph nodes with 10 to 15 mm short axis), 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 
1 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.
2 For consistency within this document, the section numbers and cross-references to other 
sections within the article have been deleted and minor formatting changes have been made.
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Appendix 3
Response Evaluation Criteria in Solid Tumors:  
Version 1.1 (cont’d)
TARGET LESIONS:  SPECIFICATIONS BY METHODS OF MEASUREMENTS
Measurement of Lesions
All measurements should be recorded in metric notation, with use of calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks prior to Cycle 1, Day 1.
Method of Assessment.  The same method of assessment and the same technique 
should be used to characterize each identified and reported lesion at baseline and 
during 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, because 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, MRI.  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less.  When CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable 
lesion should be twice the slice thickness.  MRI is also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a non-contrast CT or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should 
also be based on the tumor type and the anatomic location of the disease and should be 
optimized to allow for comparison with the prior studies if possible.  Each case should be 
discussed with the radiologist to determine if substitution of these other approaches is 
possible and, if not, the patient should be considered not evaluable from that point 
forward.  Care must be taken in measurement of target lesions on a different modality 
and interpretation of non-target disease or new lesions, because the same lesion may 
appear to have a different size with use of a new modality.
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Response Evaluation Criteria in Solid Tumors:  
Version 1.1 (cont’d)
Ultrasound.  Ultrasound is not useful in the assessment of lesion size and should not 
be used as a method of measurement.
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology.  The utilization of 
these techniques for objective tumor evaluation cannot generally be advised.
TUMOR RESPONSE EVALUATION
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE
To assess objective response or future progression, it is necessary to estimate 
the overall tumor burden at baseline and to use this as a comparator for subsequent 
measurements.  Measurable disease is defined by the presence of at least 
one measurable lesion, as detailed above.
BASELINE DOCUMENTATION OF TARGET AND NON-TARGET LESIONS
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means in instances where patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions 
(two sites), respectively, will be recorded.  Other lesions (albeit measurable) in those 
organs will be recorded as non-measurable lesions (even if the size is 10 mm by 
CT scan).  
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but additionally, 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 because 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.  Nodal size is normally 
reported as two dimensions in the plane in which the image is obtained (for CT scan, 
this is almost always the axial plane; for MRI the plane of 
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Response Evaluation Criteria in Solid Tumors:  
Version 1.1 (cont’d)

Stable disease (SD):  neither sufficient shrinkage to qualify for PR nor sufficient
increase to qualify for PD, taking as reference the smallest sum on study
Special Notes on the Assessment of Target Lesions
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 nodes regress to 10 mm on study.  This means that 
when lymph nodes are included as target lesions, the sum of lesions may not be zero 
even if CR criteria are met because a normal lymph node is defined as having a short 
axis 10 mm.
Target Lesions That Become Too Small to Measure.  While patients are in the study, 
all lesions (nodal and non-nodal) 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 the CT scan that the radiologist may not feel comfortable 
assigning an exact measure 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 below measurable limit (BML) should
be ticked.  (Note:  It is less likely that this rule will be used for lymph nodes because
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 BML should also be ticked.)
To reiterate, however, if the radiologist is able to provide an actual measure, that should 
be recorded, even if it is below 5 mm, and, in that case, BML should not be ticked.
Lesions That Split or Coalesce on Treatment.  When non-nodal lesions fragment, 
the longest diameters of the fragmented portions should be added together to calculate 
the target lesion sum.  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 maximal 
longest diameter for the coalesced lesion.
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Appendix 3
Response Evaluation Criteria in Solid Tumors:  
Version 1.1 (cont’d)
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions.  Although 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 protocol.

CR:  disappearance of all non-target lesions and (if applicable) normalization
of tumor marker level)
All lymph nodes must be non-pathological in size (10 mm short axis).

Non-CR/Non-PD:  persistence of one or more non-target lesion(s) and/or (if
applicable) maintenance of tumor marker level above the normal limits

PD:  unequivocal progression of existing non-target lesions
The appearance of one or more new lesions is also considered progression.
Special Notes on Assessment of Progression of Non-Target Disease
When the Patient Also Has Measurable Disease.  In this setting, to achieve 
unequivocal progression based on the non-target disease, there must be an overall level 
of substantial worsening in non-target disease in a magnitude that, even in the presence 
of SD or PR in target disease, 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 based on change in non-target disease in the 
face of SD or PR of target disease will therefore be extremely rare.
When the Patient Has Only Non-Measurable Disease.  This circumstance arises in 
some Phase III trials when it is not a criterion of study entry to have measurable disease.  
The same general concepts apply here as noted above; however, in this instance, there 
is no measurable disease assessment to factor into the interpretation of an increase in 
non-measurable disease burden.  Because worsening in non-target disease cannot be 
easily quantified (by definition:  if all lesions are truly non-measurable), 
a useful test that can be applied when assessing patients for unequivocal progression is 
to consider if the increase in overall disease burden based on the change in 
non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease, that is, an increase in tumor burden 
representing an additional 73% increase in volume (which is equivalent to a
20% increase in diameter in a measurable lesion).  Examples include an increase in 
a pleural effusion from “trace” to “large” or an increase in lymphangitic disease from 
localized to widespread or may be described in protocols as “sufficient to require a 
change in therapy.”  If unequivocal progression is seen, the patient should be considered 
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Response Evaluation Criteria in Solid Tumors:  
Version 1.1 (cont’d)
to have had overall PD at that point.  Although it would be ideal to have objective criteria 
to apply to non-measurable disease, the very nature of that disease makes it impossible 
to do so; therefore, the increase must be substantial.
When the patient has bone lesions at baseline.  When a bone scan is the sole 
indicator of progression, progression in bone will be defined as when at least two or more 
new lesions are seen on bone scan compared with screening.  In situations where the 
scan findings are suggestive of a flare reaction or apparent new lesion(s) that may 
represent trauma, these results must be confirmed with other imaging modalities such as 
MRI or fine-cut CT to constitute progression. Only a single new bone lesion on bone scan 
is required for progression if the lesion can be correlated on CT or MRI.
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion should 
be unequivocal, that is, not attributable to differences in scanning technique, change in 
imaging modality, or findings thought to represent something other than tumor (for 
example, some “new” bone lesions may be simply healing or flare of preexisting lesions).  
This is particularly important when the patient’s baseline lesions show partial or complete 
response.  For example, necrosis of a liver lesion may be reported on a CT scan report 
as a “new” cystic lesion, which it is not.
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
initial scan.
New osteoblastic bone lesions identified on plain films, CT, or MRI will not be considered 
progression in an otherwise stable or responding subject if, in the opinion of the 
physician, the osteoblastic lesion appears to be healing or a response to therapy.
EVALUATION OF RESPONSE
Timepoint Response (Overall Response)
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline.
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Response Evaluation Criteria in Solid Tumors:  
Version 1.1 (cont’d)
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used.
Table 1
Timepoint Response:  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 evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial response; 
SDstable disease.
Table 2
Timepoint Response:  Patients with Non-Target Lesions Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/Non-PD
No
Non-CR/Non-PD a
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease.
a “Non-CR/non-PD” is preferred over “stable disease” for non-target disease because stable 
disease is increasingly used as an endpoint for assessment of efficacy in some trials; thus, 
assigning “stable disease” when no lesions can be measured is not advised.
Missing Assessments and Not-Evaluable Designation
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that timepoint, unless a 
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Appendix 3
Response Evaluation Criteria in Solid Tumors:  
Version 1.1 (cont’d)
convincing argument can be made that the contribution of the individual missing lesion(s) 
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 
three measured lesions and, during the study, only two lesions were assessed, but those 
gave a sum of 80 mm, the patient will have achieved PD status, regardless of the 
contribution of the missing lesion. 
If one or more target lesions were not assessed either because the scan was not done 
or the scan could not be assessed because of poor image quality or obstructed view, the 
response for target lesions should be “unable to assess” because the patient is not 
evaluable.  Similarly, if one or more non-target lesions are not assessed, the response 
for non-target lesions should be “unable to assess” except where there is clear 
progression.  Overall response would be “unable to assess” if either the target response 
or the non-target response is “unable to assess,” except where this is clear evidence of 
progression as this equates with the case being not evaluable at that timepoint.
Table 3
Best Overall Response When Confirmation Is Required
Overall Response 
at First Timepoint
Overall Response at 
Subsequent Timepoint
Best Overall Response
CR
CR
CR
CR
PR
SD, PD, or PR a
CR
SD
SD, provided minimum duration for SD was met; 
otherwise, PD
CR
PD
SD, provided minimum duration for SD was met; 
otherwise, PD
CR
NE
SD, provided minimum duration for SD was met; 
otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD, provided minimum duration for SD was met; 
otherwise, PD
PR
NE
SD, provided minimum duration for SD was met; 
otherwise, NE
NE
NE
NE
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial response; 
SDstable disease.
a If a CR is truly met at the first timepoint, any disease seen at a subsequent timepoint, 
even disease meeting PR criteria relative to baseline, qualifies as PD at that point 
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Appendix 3
Response Evaluation Criteria in Solid Tumors:  
Version 1.1 (cont’d)
(because disease must have reappeared after CR).  Best response would depend on 
whether the minimum duration for SD was met.  However, sometimes CR may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient 
had PR, not CR, at the first timepoint.  Under these circumstances, the original CR should 
be changed to PR and the best response is PR.
Special Notes on Response Assessment
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes.  As noted 
earlier, this means that patients with CR may not have a total sum of “zero” on the CRF.
Patients with a global deterioration of 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 disease as shown in Table 1Table 3.
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.
In studies for which patients with advanced disease are eligible (i.e., primary disease 
still or partially present), the primary tumor should also be captured as a target or non-
target lesion, as appropriate.  This is to avoid an incorrect assessment of complete 
response if the primary tumor is still present but not evaluated as a target or non-target 
lesion.
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Appendix 4
Modified Response Evaluation Criteria in Solid Tumors
Conventional response criteria may not be adequate to characterize the anti-tumor 
activity of immunotherapeutic agents like atezolizumab, which can produce delayed 
responses that may be preceded by initial apparent radiological progression, including 
the appearance of new lesions.  Therefore, modified response criteria have been 
developed that account for the possible appearance of new lesions and allow 
radiological progression to be confirmed at a subsequent assessment.  In this protocol, 
patients will be permitted to continue study treatment even after modified Response 
Evaluation Criteria in Solid Tumors (RECIST) criteria for progressive disease are met if 
the risk/benefit ratio is judged to be favorable.  
Modified RECIST is derived from RECIST, Version 1.1 conventions 1, 2, 3 and 
immune-related response criteria 3, 4, 5 (irRC). 
1
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. 
2
Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of antiPD-L1
antibody in cancer. N Engl J Med 2012;366:244354.
3
Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immunetherapy activity in 
solid tumors: immune-related response criteria Clin Can Res 2009;15:741220.
4
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 Can 2014;2:17.
5
Nishino M, Giobbie-Hurder A, Gargano M et al. Developing a common language for tumor 
response to immunotherapy: immune-related response criteria using 
unidimensional measurements. Clin Can Res 2013;19:393643.
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Appendix 4
Modified Response Evaluation Criteria in Solid Tumors (cont.)
MODIFIED RECIST AND RECIST, VERSION 1.1:  SUMMARY OF CHANGES
RECIST v1.1
Modified RECIST
New lesions after baseline
Define progression.
New measurable lesions are 
added into the total tumor 
burden and followed.
Non-target lesions
May contribute to the 
designation of overall 
progression
Contribute only in the 
assessment of a complete 
response
Radiographic progression
First instance of 20% 
increase in the sum of 
diameters or unequivocal 
progression in non-target 
disease
Determined only on the basis of 
measurable disease; may be 
confirmed by a consecutive 
assessment 4 weeks from the 
date first documented 
RECISTResponse Evaluation Criteria in Solid Tumors.
Definitions of Measurable/non-Measurable Lesions
All measurable and non-measurable lesions should be assessed at screening and at the 
protocol-specified tumor assessment timepoints.  Additional assessments may be 
performed, as clinically indicated for suspicion of progression.  The investigator will 
evaluate response to treatment with use of modified RECIST.
Measurable Lesions
Tumor Lesions.  Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size 
as follows: 
10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval no greater than 5 mm)
10-mm caliper measurement by clinical examination (lesions that cannot be accurately 
measured with calipers should be recorded as non-measurable)
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 no greater than 5 mm).  At baseline and follow-up, only 
the short axis will be measured and followed.  
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Appendix 4
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Non-Measurable Lesions
Non-measurable tumor lesions encompass small lesions (longest diameter 10 mm or 
pathological lymph nodes with short axis 10 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
Bone scan, positron emission tomography (PET) scan, or 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 as 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 as malignant lesions (neither measurable nor non-measurable) because they 
are, by definition, simple cysts.
Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above.  However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as 
target lesions.
Lesions with Prior Local Treatment
Tumor lesions situated in a previously irradiated area or in an area subjected to other 
loco-regional therapy are usually not considered measurable unless there has been 
demonstrated progression in the lesion.  Study protocols should detail the conditions 
under which such lesions would be considered measurable.
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Appendix 4
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Tumor Response Evaluation
Definitions of Target/Non-Target Lesions
Target Lesions
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only 
one or two organ sites involved, a maximum of two lesions (one site) and four lesions 
(two sites), respectively, will be recorded.  Other lesions (albeit measurable) in those 
organs will be recorded as non-measurable lesions (even if the size is 10 mm by 
CT scan).  
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 because 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.  
Nodal size is normally reported as two dimensions in the plane in which the image is 
obtained (for CT, this is almost always the axial plane; for MRI, the plane of acquisition 
may be axial, sagittal, or coronal).  The smaller of these measures is the short axis.  
For example, an abdominal node that is reported as being 20 mm 30 mm has a short 
axis of 20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm 
should be recorded as the node measurement.  All other pathological nodes (those with 
short axis 10 mm 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. 
Lesions irradiated within 3 weeks prior to Cycle 1, Day 1 may not be counted as target 
lesions.
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Appendix 4
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Non-Target Lesions
All other lesions (or sites of disease), 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”). 
After baseline, changes in non-target lesions will contribute only in the assessment 
of complete response (i.e., a complete response is attained only with the complete 
disappearance of all tumor lesions, including non-target lesions) and will not be used to 
assess progressive disease. 
Calculation of Sum of the Diameters 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated as a measure of tumor burden.  
The sum of the diameters is calculated at baseline and at each tumor assessment for 
the purpose of classification of tumor responses.
Sum of the Diameters at Baseline:  The sum of the diameters for all target lesions 
identified at baseline prior to treatment on Day 1.
Sum of the Diameters at Tumor Assessment:  For every on-study tumor assessment 
collected per protocol or as clinically indicated, the sum of the diameters at tumor 
assessment will be calculated using tumor imaging scans.  All target lesions and all new 
measurable lesions that have emerged after baseline will contribute to the sum of the 
diameters at tumor assessment.  Hence, each net percentage change in tumor burden 
per assessment with use of modified RECIST accounts for the size and growth kinetics 
of both old and new lesions as they appear.
Response Criteria
Evaluation of Target Lesions
Complete Response (CR):  Disappearance of all target lesions.  Lymph nodes that 
shrink to 10 mm short axis are considered normal.
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of all 
target and all new measurable lesions, taking as reference the baseline sum of 
diameters, in the absence of CR.
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Appendix 4
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Note:  The appearance of new measurable lesions is factored into the overall tumor 
burden but does not automatically qualify as progressive disease until the sum of the 
diameters increases by 20% when compared with the sum of the diameters at nadir.
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum of the diameters while in 
the study.
Progressive Disease (PD):  At least a 20% increase in the sum of diameters of all target 
and all new measurable lesions, taking as reference the smallest sum on study 
(this includes the baseline sum if that is the smallest on study).  In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. 
Impact of New Lesions on Modified RECIST
New lesions alone do not qualify as progressive disease.  However, their contribution 
to total tumor burden is included in the sum of the diameters, which is used to determine 
the overall modified RECIST tumor response. 
Evaluation of Best Overall Response with Use of Modified RECIST 
Timepoint Response
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline.
Missing Assessments and Inevaluable Designation
When no imaging/measurement is done at all at a particular timepoint, the patient is 
not evaluable (NE) at that timepoint.  If only a subset of lesion measurements are made 
at an assessment, usually the case is also considered NE at that timepoint, unless a 
convincing argument can be made that the contribution of the individual missing 
lesion(s) would not change the assigned time point 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 
three measured lesions and at follow-up only two lesions were assessed but those gave 
a sum of 80 mm, the patient will have achieved PD status, regardless of the contribution 
of the missing lesion.
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Appendix 4
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Table 1
Modified RECIST Timepoint Response Definitions
% Change in 
Sum of the 
Diameters 
(Including 
Measurable 
New Lesions 
When Present)
Target 
Lesion 
Definition
Non-Target 
Lesion 
Definition
New 
Measurable 
Lesions
New 
Unmeasurable 
Lesions
Overall 
Modified 
RECIST 
Timepoint 
Response
100% a
CR
CR
No
No
CR
100% a
CR
Non-CR or not 
all evaluated
No
No
PR
30%
PR
Any
Yes or No
Yes or No
PR
30% to
20%
SD
Any
Yes or No
Yes or No
SD
Not all 
evaluated
Not 
evaluated
Any
Yes or No
Yes or No
NE
20%
PD
Any
Yes or No
Yes or No
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial response; 
RECIST Response Evaluation Criteria in Solid Tumors; SDstable disease.
a When lymph nodes are included as target lesions, the % change in the sum of the diameters 
may not be 100% even if complete response criteria are met because a normal lymph node is 
defined as having a short axis of 10 mm.  Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to 10 mm in order to meet the definition of CR.
Best Overall Response:  All Timepoints
The best overall response is determined once all the data for the patient are known.
The best overall response according to modified RECIST is interpreted as described 
below:
CR:  Complete disappearance of all tumor lesions (target and non-target) and no new 
measurable or unmeasurable lesions, confirmed by a consecutive assessment 
4 weeks from the date first documented.  All lymph nodes short axes must be 10 mm.
PR:  Decrease in the sum of the diameters of all target and all new measurable lesions 
30% relative to baseline, in the absence of CR, confirmed by a consecutive
assessment 4 weeks from the date first documented.
SD: Criteria for CR, PR, and PD are not met. 
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Appendix 6
Preexisting Autoimmune Diseases
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 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 or Type I diabetes 
mellitus on a stable dose of insulin 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).  Contact the Medical 
Monitor regarding any uncertainty over autoimmune exclusions.
Acute disseminated  
   encephalomyelitis
Addison’s disease
Ankylosing spondylitis
Antiphospholipid antibody 
   syndrome
Aplastic anemia
Autoimmune hemolytic anemia
Autoimmune hepatitis
Autoimmune hypoparathyroidism
Autoimmune hypophysitis
Autoimmune myocarditis
Autoimmune oophoritis
Autoimmune orchitis
Autoimmune thrombocytopenic 
    purpura
Behcet’s disease
Bullous pemphigold
Chronic fatigue syndrome
Chronic inflammatory 
   demyelinating polyneuropathy
Chung-Strauss syndrome
Crohn’s disease
Dermatomyositis 
Diabetes mellitus type 1
Dysautonomia Epidermolysis
    bullosa acquista
Gestational pemphigoid
Giant cell arteritis
Goodpasture’s syndrome
Graves’ disease
Guillain-Barré syndrome
Hashimoto’s disease
IgA nephropathy
Inflammatory bowel disease
Interstitial cystitis
Kawasaki’s disease
Lambert-Eaton myasthenia 
   syndrome
Lupus erythematosus
Lyme disease - chronic
Meniere’s syndrome
Mooren’s ulcer
Morphea
Multiple sclerosis
Myasthenia gravis
Neuromyotonia
Opsoclonus myoclonus
     syndrome 
Optic neuritis
Ord’s thyroiditis
Pemphigus
Pernicious anemia
Polyarteritis nodusa
Polyarthritis
Polyglandular autoimmune
    syndrome
Primary biliary cirrhosis
Psoriasis
Reiter’s syndrome
Rheumatoid arthritis
Sarcoidosis
Scleroderma
Sjögren’s syndrome
Stiff-Person syndrome
Takayasu’s arteritis
Ulcerative colitis
Vitiligo
Vogt-Kovanagi-Harada 
   disease
Wegener’s granulomatosis


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Appendix 7
New York Heart Association Functional Classification
The New York Heart Association (NYHA) Functional Classification provides a 
simple way of classifying the extent of heart failure.  It places patients in one of four 
categories based on how much they are limited during physical activity; the 
limitations/symptoms are in regards to normal breathing and varying degrees in 
shortness of breath and or angina pain:
NYHA 
Class
Symptoms
I
Cardiac disease, but no symptoms and no limitation in ordinary physical activity (e.g., 
shortness of breath when walking, climbing stairs etc.)
II
Mild symptoms (mild shortness of breath and/or angina) and slight limitation during 
ordinary activity.
III
Marked limitation in activity due to symptoms, even during less-than-ordinary activity 
(e.g., walking short distances [20–100 m]).
Comfortable only at rest.
IV
Severe limitations.  Experiences symptoms even while at rest.  Mostly bedbound 
patients.


Appendix 8
Biopsy Procedure
Tumor Biopsies
Patients with archival tissue collected 24 months prior to Cycle 1, Day 1 must undergo 
fresh tumor biopsy to meet eligibility requirements unless the site of tumor renders a 
biopsy medically unsafe or not feasible.  Biopsies must be obtained in a manner that 
minimizes risk.  Tumor samples will be obtained to verify that viable tumor cells are 
present and examine expression of programmed deathligand 1 (PD-L1) in addition to 
other biomarkers.
Biopsies will be taken only if there is no intervening condition (e.g., thrombocytopenia or 
neutropenia) that, in the opinion of the investigator, increases the likelihood of 
procedural complications to an unacceptable level.  Bevacizumab should be not 
administered until 3 days following the procedure and evidence of adequate wound 
healing is observed.
For patients undergoing needle biopsies of deep-seated (e.g., liver) lesions, hemoglobin 
and hematocrit will be checked at the time of biopsy and prior to starting bevacizumab 
or sooner as clinically indicated.  For patients who have a 2-unit decrease in 
hemoglobin or a 6% decrease in hematocrit following the biopsy, bevacizumab may be 
started with appropriate clinical monitoring.  For patients who have a 2- but 3-unit 
decrease in hemoglobin or a 6% but 9% decrease in hematocrit, bevacizumab may 
be started at the discretion of the investigator after discussion with the Medical Monitor.  
Patients who have a 3-unit decrease in hemoglobin or a 9% decrease in hematocrit 
should be evaluated (e.g., by means of computed tomography [CT] scan or ultrasound), 
and bevacizumab may be started once the levels improve at the discretion of the 
investigator and after discussion with the Medical Monitor.
If a patient undergoes a medically indicated procedure any time during the course of the 
study that has the likelihood of yielding tumor tissue, any remaining samples or a portion 
of the sample not necessary for medical diagnosis may be obtained for exploratory 
analysis.  Patients must have provided specific consent on the Optional Research 
Informed Consent Form to allow discarded samples from routine care to be obtained.
Refer to the laboratory manual for additional details on laboratory assessments and 
sample handling.
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Appendix 9
MSKCC (Motzer) Criteria
Risk factors:
1.
Karnofsky performance status score 80
2.
Corrected serum calcium 10 mg/dL
3.
LDH level 1.5 times the upper limit of normal
4.
Hemoglobin level lower limit of normal
5.
Time from nephrectomy to systemic therapy 12 months a

Patient also has this risk factor if:
Initially diagnosed with metastatic disease
No nephrectomy
Risk stratification:
1.
Low:
0 risk factors
2.
Intermediate:
12 risk factors
3.
High:
3 risk factors
MSKCCMemorial Sloan Kettering Cancer Center.
Note:  The raw MSKCC score (05) should be reported in the eCRF.
a For study purposes, systemic therapy will be designated as the date of initial study 
screening.  
Corrected calcium serum calcium (mg/dL)0.8 (4serum albumin (g/dL))
Calcium (mg/dL)calcium (mmol/L)4
Albumin (g/dL)10albumin (g/L)


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Appendix 10
Anaphylaxis Precautions
EQUIPMENT NEEDED

Tourniquet

Oxygen

Epinephrine for subcutaneous, intravenous, 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 drug infusion, 
the following procedures should be performed:
1.
Stop the study drug infusion.
2.
Apply a tourniquet proximal to the injection site to slow systemic absorption of study
drug.  Do not obstruct arterial flow in the limb.
3.
Maintain an adequate airway.
4.
Administer antihistamines, epinephrine, or other medications as required by patient
status and directed by the physician in charge.
5.
Continue to observe the patient and document observations.
















Appendix 15
Definition of Sarcomatoid Renal Cell Carcinoma:  Modified 
Stanford Surgical Pathology Criteria
Sarcomatoid renal cell carcinoma is defined as any histologic type of renal cell 
carcinoma containing a focus/foci of high-grade malignant spindle cells of any 
component relative to the entire tumor area.  
Requires evidence of epithelial differentiation with concurrent areas of renal cell 
carcinoma
or
Evidence of epithelial differentiation in the spindle cells with immunohistochemical 
positivity for keratin or epithelial membrane antigen (EMA)
Spindle cells must show moderate to marked atypia and resemble any form of 
sarcoma
Frequent patterns include:  fibrosarcoma, malignant fibrous histiocytoma, 
rhabdomyosarcoma
Focal spindling because of noncohesion of tumor cells is not considered to 
represent sarcomatoid differentiation 
Any spindle component relative to the entire tumor area.  
Degree of sarcomatoid differentiation should be recorded in the eCRF as 1) any 
component, 2) 20% component, or 3) predominant sarcomatoid component.
Cheville JC, Lohse CM, Zincke H, et al. Sarcomatoid renal cell carcinoma: an 
examination of underlying histologic subtype and an analysis of associations with 
patient outcome. Am J Surg Pathol 2004;28:43541.
Delahunt B, Cheville JC, Martingoni G, et al.  The International Society of Urology 
Pathology (ISUP) Grading System for Renal Cell Carcinoma and Other Prognostic 
Parameters.  Am J Surg Pathol 2013;37:1490504.
de Peralta-Venturina M, Moch H, Amin M,et al. Sarcomatoid differentiation in renal cell 
carcinoma: a study of 101 cases. Am J Surg Pathol 2001;25:27584.
AtezolizumabF. Hoffmann-La Roche Ltd
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Appendix 16
Common CYP3A4 Inducers
Carbamezepine
Dexamethasone
Ethosuximide
Glucocorticoids
Griseofulvin
Phenytoin
Primidone
Progesterone
Rifabutin
Rifampin
Nafcillin
Nelfinavir
Nevirapine
Oxcarbazepine
Phenobarbital
Phenylbutazone


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184/Protocol WO29637, Version 7
Appendix 17
Common Drugs Which May Increase QTc Interval
Alfuzosin 
Disopyramide 
Lapatinib   
Amantadine   
Dofetilide 
Levofloxacin   
Amiodarone   
Dolasetron 
Levomethadyl Lithium   
Amisulpride   
Domperidone   
Mesoridazine 
Amitriptyline   
Doxepin   
Methadone   
Amoxapine   
Dronedarone 
Metronidazole 
Anagrelide   
Droperidol   
Mifepristone   
Apomorphine   
Eribulin 
Mirabegron 
Aripiprazole   
Erythromycin   
Mirtazapine 
Arsenic trioxide 
Escitalopram   
Remeron 
Astemizole 
Famotidine   
Moexipril/HCTZ   
Atazanavir 
Felbamate 
Moxifloxacin   
Azithromycin   
Fingolimod 
Nelfinavir 
Bedaquiline 
Flecainide   
Nicardipine 
Bepridil 
Fluconazole   
Nilotinib 
Bortezomib   
Fluoxetine   
Norfloxacin   
Bosutinib 
Foscarnet 
Nortriptyline   
Chloral hydrate    
Fosphenytoin   
Ofloxacin 
Chloroquine 
Furosemide   
Olanzapine   
Chlorpromazine   
Galantamine   
Ondansetron   
Ciprofloxacin   
Gatifloxacin 
Oxytocin
Cisapride 
Gemifloxacin 
Paliperidone
Citalopram   
Granisetron   
Clarithromycin   
Halofantrine 
Clomipramine 
Haloperidol   
Clozapine   
Hydrochlorothiazide   
Cocaine 
Ibutilide 
Crizotinib 
Iloperidone   
Dabrafenib 
Imipramine (melipramine) 
Dasatinib 
Indapamide   
Desipramine
Isradipine 
Dexmedetomidine   
Itraconazole   
Dihydroartemisininpiperaquine
Ivabradine   
Diphenhydramine   
Ketoconazole   


STATISTICAL ANALYSIS PLAN AMENDMENT 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 WO29637 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A PHASE III, OPEN-LABEL, RANDOMIZED STUDY OF 
ATEZOLIZUMAB (ANTI−PD-L1 ANTIBODY) IN 
COMBINATION WITH BEVACIZUMAB VERSUS 
SUNITINIB IN PATIENTS WITH UNTREATED ADVANCED 
RENAL CELL CARCINOMA 
PROTOCOL NUMBER: 
WO29637 
STUDY DRUG: 
Atezolizumab (MPDL3280A) 
VERSION NUMBER: 
2 
IND NUMBER: 
119039 
EUDRACT NUMBER: 
2014-004684-20 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
PLAN PREPARED BY: 
 
DATE FINAL: 
Version 1:  21 March 2017 
DATE(S) AMENDED: 
Version 2:  See electronic date stamp below. 
Name                                                             Reason for Signing                              Date and Time
(UTC)
04-Apr-2018 17:22:21
Company Signatory


Atezolizumab—F. Hoffmann-La Roche Ltd 
2/Statistical Analysis Plan WO29637 
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE 
The Statistical Analysis Plan (SAP), Version 2, for Protocol WO29637 has been 
amended 
.  Changes to the SAP along with the 
rationale are summarized below: 
• 
Section 2.4.2.2 (Co-Primary Endpoint of Overall Survival):  An additional overall 
survival (OS) interim analysis, including updated alpha adjustment of the sequential 
testing of the OS interim analyses, 
 for the IMmotion151 study.  
The overall type 1 error of OS analyses is controlled at 5% per pre-specified 
O’Brien-Fleming boundary, where the 5% alpha is determined given the co-primary 
endpoint of progression-free survival (PFS) was met.  A total of four analyses of OS 
will be performed according to the new analysis plan, including three interim 
analyses and one final analysis.  The first OS interim was performed at the PFS 
primary analysis.  The second OS interim analysis has now been added to the 
original interim analyses plan.  The third interim and final OS analyses remain 
unchanged in terms of the event rate that will trigger the analyses, as per the 
original SAP, Version 1. 
 
Additional minor changes have been made to improve clarity and consistency. 
 


Atezolizumab—F. Hoffmann-La Roche Ltd 
3/Statistical Analysis Plan WO29637 
 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE .............................. 2 
1. 
BACKGROUND ................................................................................................. 5 
2. 
STUDY DESIGN ................................................................................................ 5 
2.1 
Protocol Synopsis........................................................................ 5 
2.2 
Outcome Measures ..................................................................... 5 
2.3 
Determination of Sample Size .................................................... 5 
2.3.1 
Type I Error Control..................................................................... 6 
2.3.2 
Co-Primary Endpoint: Progression-Free Survival 
by Investigator Assessment per RECIST v1.1 in 
the PD-L1−Selected Population ................................................. 7 
2.3.3 
Co-Primary Endpoint: Overall Survival in the 
Intent-to-Treat Population ........................................................... 8 
2.4 
Interim and Primary Analysis Timing.......................................... 9 
2.4.1 
Primary Analysis Timing ............................................................. 9 
2.4.2 
Interim Analyses Timing.............................................................. 9 
2.4.2.1 
Co-Primary Endpoint of Progression-Free 
Survival ........................................................................................ 9 
2.4.2.2 
Co-Primary Endpoint of Overall Survival ................................... 9 
2.4.2.3 
Periodic Safety Monitoring ........................................................ 11 
3. 
STUDY CONDUCT.......................................................................................... 12 
3.1 
Randomization........................................................................... 12 
3.2 
Independent Review Facility and Data Monitoring .................. 12 
4. 
STATISTICAL METHODS............................................................................... 12 
4.1 
Analysis Populations ................................................................. 12 
4.2 
Analysis of Study Conduct ........................................................ 13 
4.3 
Analysis of Treatment Group Comparability ............................ 13 
4.4 
Efficacy Analyses ...................................................................... 13 
4.4.1 
Co-Primary Efficacy Endpoints ................................................. 14 
4.4.2 
Secondary Efficacy Endpoints .................................................. 14 
4.4.2.1 
Objective Response Rate ......................................................... 15 
4.4.2.2 
Duration of Response ............................................................... 16 


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4/Statistical Analysis Plan WO29637 
4.4.2.3 
Progression-Free Survival by Immune-Modified 
RECIST ...................................................................................... 16 
4.4.2.4 
Change from Baseline in Symptom Interference..................... 17 
4.4.3 
Exploratory Efficacy Endpoints ................................................. 17 
4.4.3.1 
Analyses at Landmark Timepoints of 
Progression-Free Survival and Overall Survival...................... 17 
4.4.3.2 
Subgroup Analyses ................................................................... 18 
4.4.3.3 
Biomarker Analyses .................................................................. 18 
4.5 
Safety Analyses......................................................................... 18 
4.5.1 
Exposure to Study Medication .................................................. 19 
4.5.2 
Adverse Events ......................................................................... 19 
4.5.3 
Laboratory Data......................................................................... 19 
4.5.4 
Vital Signs .................................................................................. 19 
4.5.5 
Anti-Therapeutic Antibody ........................................................ 19 
4.6 
Pharmacokinetic Analyses........................................................ 19 
4.7 
Patient-Reported Outcome Analyses ....................................... 20 
4.7.1 
Health Economic Data .............................................................. 21 
4.8 
Missing Data .............................................................................. 21 
5. 
REFERENCES ................................................................................................ 22 
 
 
LIST OF TABLES 
Table 1 
Interim and Final OS Analyses for the ITT Population ................. 10 
 
 
LIST OF FIGURES 
Figure 1 
Progression-Free Survival and Overall Survival Hierarchy 
with Type I Error Control .................................................................. 6 
 
 
LIST OF APPENDICES 
Appendix 1 
Protocol Synopsis ........................................................................... 23 
Appendix 2 
Schedule of Assessments .............................................................. 36 
Appendix 3 
Modified Response Evaluation Criteria in Solid Tumors .............. 46 


AtezolizumabF. Hoffmann-La Roche Ltd 
5/Statistical Analysis Plan WO29637 
1. 
BACKGROUND 
This Statistical Analysis Plan (SAP) provides details of the planned analyses and 
statistical methods for Study WO29637 (IMmotion151):  a Phase III, multicenter, 
randomized, open-label study designed to evaluate the efficacy and safety of 
atezolizumab + bevacizumab versus sunitinib in patients with inoperable, locally 
advanced, or metastatic renal cell carcinoma (RCC) who have not received prior 
systemic active or experimental therapy, either in the adjuvant or metastatic setting. 
2. 
STUDY DESIGN 
Approximately 900 patients, including a minimum of approximately 351 patients with a 
programmed death−ligand 1 (PD-L1) immunohistochemistry (IHC) of tumor-infiltrating 
immune cell (IC) score of 1/2/3 (PD-L1−selected population; see protocol for the 
definition), were planned for enrollment at approximately 150−180 centers globally.  
Planned enrollment included a maximum of approximately 180 patients (20%) with a 
Memorial Sloan Kettering Cancer Center (MSKCC [Motzer]) score of 0 (good risk). 
Patients will be randomized in a 1:1 ratio to one of two treatment arms: 
• 
Arm A (experimental arm):  Atezolizumab 1200 mg intravenous (IV) infusions every 
3 weeks (q3w; dosed in 6-week cycles) + bevacizumab 15 mg/kg q3w (dosed in 
6-week cycles) 
• 
Arm B (control arm):  Sunitinib 50 mg/day orally for 4 weeks, followed by 2 weeks of 
rest (dosed in 6-week cycles) 
 
The co-primary efficacy endpoints are investigator-assessed progression-free survival 
(PFS) with use of the Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1) and overall survival (OS). 
2.1 
PROTOCOL SYNOPSIS 
The Protocol Synopsis is in Appendix 1, and it includes the study objectives, inclusion 
and exclusion criteria, outcome measures, and statistical methods as stated in the 
protocol.  For additional details, see the Schedules of Assessments in Appendix 2. 
2.2 
OUTCOME MEASURES 
See the Protocol Synopsis in Appendix 1 for definitions of the outcome measures. 
2.3 
DETERMINATION OF SAMPLE SIZE 
Approximately 900 patients, including a minimum of approximately 351 patients with a 
PD-L1 IHC IC score of 1/2/3 were planned for enrollment.  Sample size calculations as 
shown in the protocol were based on the planned enrollment. 
At the time of this SAP finalization, enrollment in the study had been completed 
17 months after first patient randomized.  A total of 915 patients were randomized, of 


AtezolizumabF. Hoffmann-La Roche Ltd 
6/Statistical Analysis Plan WO29637 
which 362 patients had a PD-L1 IHC IC score of 1/2/3.  The required numbers of events 
and projected timelines for the analyses of PFS and OS have been updated in this SAP 
based on the actual enrollment.  No changes were made to study design assumptions 
for the targeted treatment benefit or type 1 error control, and the ratio of the required 
number of events to the total population has been maintained. 
2.3.1 
Type I Error Control 
The type I error (α) for the entire study is 0.05 (two-sided).  There are two co-primary 
efficacy endpoints for this study:  PFS by investigator assessment per RECIST v1.1 in 
the PD-L1−selected population and OS in the intent-to-treat (ITT) population (see 
Section 4.1 for the definition on the study population).  To control the overall type I error 
rate (Bretz et al. 2009) at α  = 0.05 while accounting for two co-primary endpoints, α is 
split between PFS (α  = 0.04) and OS (α  = 0.01).  The PFS and OS analysis hierarchy and 
α allocation including possible recycling are shown in Figure 1. 
Figure 1 Progression-Free Survival and Overall Survival Hierarchy with 
Type I Error Control 
 
IC = tumor-infiltrating immune cell; ITT = intent-to-treat; OS = overall survival; 
PFS = progression-free survival. 
 
In Figure 1, formal treatment comparisons will be performed in a hierarchical fashion in 
which α may be recycled (Burman et al. 2009) as follows: 
1. 
PFS by investigator assessment per RECIST v1.1 in the PD-L1−selected population 
will be evaluated at α  = 0.04. 
If PFS results in the PD-L1−selected population are statistically significant at 
α  = 0.04, then α  = 0.04 will be recycled to OS in the ITT population, and OS in 
the ITT population will be evaluated at α  = 0.05.  


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7/Statistical Analysis Plan WO29637 
If PFS results in the PD-L1−selected population are not statistically significant at 
α  = 0.04, then no recycling of α will occur, and OS in the ITT population will be 
evaluated at α  = 0.01.  
2. 
OS will be compared between treatment arms in a hierarchical fashion as follows:  
If OS results in the ITT population are statistically significant at the appropriate 
α level (either 0.01 or 0.05 that depends on step 1), then OS in the 
PD-L1−selected population will be evaluated at same α level as for OS in the 
ITT population.  
If OS results in the ITT population are not statistically significant, formal testing 
of OS in the PD-L1−selected population will not be performed.  
Details on the interim OS analyses and testing are described in Section 2.4. 
 
The study will be considered as a positive study if statistical significance is achieved for 
either of the two co-primary endpoints, since the type I error (α) for the entire study is 
controlled at 0.05. 
2.3.2 
Co-Primary Endpoint:  Progression-Free Survival by 
Investigator Assessment per RECIST v1.1 in the 
PD-L1−Selected Population  
The analysis of the co-primary endpoint of PFS by investigator assessment per 
RECIST v1.1 in the PD-L1−selected population will take place when approximately 
236 investigator-assessed PFS events have occurred in the PD-L1−selected population 
(65% events rate of the 362 patients in PD-L1−selected population) based on the 
following assumptions: 
• 
Two-sided, stratified log-rank test 
• 
α  = 0.04 (two-sided) 
• 
Approximately 90% power 
• 
Median PFS for the sunitinib arm of 11 months and estimated median PFS in the 
atezolizumab + bevacizumab arm of 17 months (corresponding to hazard ratio [HR] 
of 0.65) 
• 
5% annual loss to follow-up for PFS 
• 
No interim analysis 
 
On the basis of these assumptions, it is projected that an observed HR of 0.76 or lower 
will result in a statistically significant difference between treatment arms (i.e., an HR of 
0.76 will be the minimally detectable difference [MDD] for the analysis; this corresponds 
to an improvement of 3.5 months in median PFS from 11 months in the sunitinib arm to 
14.5 months in the atezolizumab + bevacizumab arm). 


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8/Statistical Analysis Plan WO29637 
2.3.3 
Co-Primary Endpoint:  Overall Survival in the Intent-to-Treat 
Population 
The final analysis of the co-primary endpoint of OS will take place at the later of the 
timepoints when the required number of events has occurred in the PD-L1−selected 
population and in the ITT population, where the required number of events is as follows: 
• 
ITT population:  approximately 639 OS events (approximately 70% of the 
915 patients) 
• 
PD-L1−selected population:  approximately 250 OS events (approximately 70% of 
the 362 patients) 
 
The number of events required for the final OS analysis in these populations is based on 
the following assumptions: 
• 
Two-sided, stratified log-rank test 
• 
α  = 0.01 (two-sided) 
• 
Median OS in the sunitinib arm of 24 months 
• 
1% annual loss to follow-up for OS 
• 
For the ITT population: 
Approximately 85% power 
Estimated median OS in the atezolizumab + bevacizumab arm of 32 months (an 
increase of 8 months, corresponding to an HR of 0.75) 
• 
For the PD-L1−selected population: 
Approximately 55% power  
Estimated median OS in the atezolizumab + bevacizumab arm of 33.8 months 
(an increase of 9.8 months, corresponding to an HR of 0.71) 
 
ITT population OS MDD:  At the final OS analysis, on the basis of these assumptions, it 
is projected that an observed OS HR of 0.81 or lower in the ITT population will result in a 
statistically significant difference between treatment arms (i.e., the MDD at the analysis; 
this corresponds to an improvement of 5.6 months in median OS, from 24 months in the 
control arm to 29.6 months in the atezolizumab + bevacizumab arm). 
PD-L1−selected population OS MDD:  At the final OS analysis, on the basis of these 
assumptions, it is projected that an observed OS HR of 0.71 or lower in the 
PD-L1−selected population will result in a statistically significant difference between 
treatment arms (i.e., an HR of 0.71 will be the MDD at the analysis; this corresponds to 
an improvement of 9.8 months in median OS, from 24 months in the control arm to 
33.8 months in the atezolizumab + bevacizumab arm). 


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9/Statistical Analysis Plan WO29637 
2.4 
INTERIM AND PRIMARY ANALYSIS TIMING 
2.4.1 
Primary Analysis Timing 
The primary analysis timing is event driven.  The analysis of the co-primary endpoint of 
PFS by investigator assessment per RECIST v1.1 in the PD-L1−selected population will 
take place when approximately 236 investigator-assessed PFS events have occurred in 
the PD-L1−selected population.  Based on the assumptions described in Section 2.3.2 
and actual accrual, the required number of PFS events is projected to occur at Month 34 
from the time the first patient is randomized. 
The final analysis of the co-primary endpoint of OS will take place at the later of 639 OS 
events in ITT population and 250 OS events in PD-L1−selected population.  The 
required number of OS events for the final analysis of OS in both the PD-L1−selected 
population and the ITT population is projected to occur at Month 61 from the time the 
first patient is randomized. 
The actual number of events that occur by the data cutoff date of the primary or final 
analysis could potentially be higher than the required number of events.  
2.4.2 
Interim Analyses Timing 
2.4.2.1 
Co-Primary Endpoint of Progression-Free Survival 
There is no planned interim analysis of the co-primary endpoint of PFS. 
2.4.2.2 
Co-Primary Endpoint of Overall Survival 
A total of four analyses of OS will be performed, including three interim analyses and one final 
analysis.  The α level for OS testing is 0.05 given that the co-primary endpoint of PFS was met 
in the study (see Section 2.3.1 ).  The boundary for statistical significance at each interim 
analysis and the final analysis will be determined based on the Lan-DeMets implementation of 
the O’Brien-Fleming function (Lan and DeMets 1983) to maintain the overall type 1 error rate 
(Hung et al. 2007; Glimm et al. 2009) at 0.05 level.  The O’Brien-Fleming (OBF) boundary for 
statistical significance is provided in Table 1.  The OS endpoint will be considered positive in the 
ITT population if statistical significance is achieved for any of the three OS interim analyses or 
the final analysis. 


AtezolizumabF. Hoffmann-La Roche Ltd 
10/Statistical Analysis Plan WO29637 
Table 1 
Interim and Final OS Analyses for the ITT Population 
OS Analyses 
First interim OS (performed at time of 
PFS analysis) a 
 
   No. of events (%) b 
264 (29%) 
% of final events 
41% 
Cutoff date 
Study Month 29 c 
OBF boundary for p-value 
p≤0.0009 
Second interim OS (Time driven) 
Projected No. of events (%) b 
377 (41%) 
Projected % of final events 
59% 
Cutoff date 
Study Month 40 c 
Projected OBF boundary for p-value d 
p≤0.0067 
Third interim OS (Event driven) 
No. of events (%) b 
518 (57%) 
% of final events 
81% 
Projected cutoff date 
Study Month 57 c 
Projected OBF boundary for p-value d 
p≤0.0233 
Final OS (Event driven) 
No. of events (%) b   
639 (70%) 
% of final events 
100% 
Projected cutoff date 
Study Month 79 c 
Projected OBF boundary for p-value d 
p≤0.0420 
ITT=intent-to-treat; OBF=O’Brien-Fleming; OS=overall survival; PFS=progression-free 
survival. 
Note:  The α level for OS testing is 0.05, given that the co-primary endpoint of PFS was met (see 
Section 2.3.1 ). 
a The first interim analysis of OS was performed at the time of the PFS primary analysis at 
Study Month 29, with a cut-off date of 29 September 2017, which was 5 months earlier than 
the initial projection of Month 34 described in Section 2.4.1.  The OBF boundary for p-value is 
calculated based on 264 OS events observed by the cutoff date. 
b The event rate is based on the actually observed ITT population with N=915. 
c Study month at which required number of events are projected to occur, where Study Month 1 
is the month the first patient is enrolled. 
d The projected OBF boundary for statistical significance is calculated according to the number 
of events shown.  The actual OBF boundary will be calculated at time of analysis based on 
actual number of events observed. 
  
The first interim analysis of OS was performed at the time of the PFS primary analysis.  A total 
of 264 deaths (29% of 915 patients in the ITT population) was observed at the first interim 
analysis of OS, which corresponds to 41% of the events information required for the final 


AtezolizumabF. Hoffmann-La Roche Ltd 
11/Statistical Analysis Plan WO29637 
analysis of OS in the ITT population.  The first OS interim analysis did not pass the OBF 
boundary at 0.0009. 
The second interim analysis of OS will be time driven and will occur approximately 11 months 
from the clinical cutoff of the first OS interim.  
 
.  It is 
projected that at the second interim OS analysis, 377 deaths (41% of 915 patients in the ITT 
population) will occur, corresponding to approximately 59% of the events information required 
for the final analysis of OS in the ITT population.  Statistical significance will be declared if 
p≤0.0067 when 377 deaths have occurred at the time of the second OS interim analysis. 
The third interim analysis of OS is event driven and remains the same as the original plan (SAP, 
Version 1).  The third interim analysis of OS will be performed when approximately 518 deaths 
(57% of 915 patients in the ITT population) have occurred, which corresponds to approximately 
81% of the events information required for the final analysis of OS in the ITT population.  
Statistical significance will be declared if p≤0.0233 when 518 deaths have occurred at the time of 
the third OS interim analysis. 
The final analysis of OS is event driven and remains the same as the original plan (SAP, Version 
1).  The final analysis of OS will be performed when 639 deaths (70% of 915 patients in the ITT 
population) have occurred.  Statistical significance will be declared if p≤0.0420 when 639 deaths 
have occurred at the time of the final OS analysis. 
The interim and final analyses of OS, including analyses in both the ITT and PD-L1−selected 
populations, will follow the testing hierarchy described in Section 2.3.1 .  Specifically, for each 
OS interim and final analysis, OS in the PD-L1−selected population will be evaluated for 
statistical significance only when the OS results in the ITT population are statistically 
significant at the OBF boundary.  The actual OBF boundary will be calculated at time of analysis 
based on actual number of events observed.  If OS results in the ITT population are not 
statistically significant, formal testing of OS in the PD-L1−selected population will not be 
performed. 
All efficacy analyses, including the interim analyses of OS, will be performed by the Sponsor. 
2.4.2.3 
Periodic Safety Monitoring 
Safety data will be reviewed by the independent Data Monitoring Committee (iDMC) 
during the study on a periodic basis, approximately every 6 months from first patient 
randomized until the time of the primary analysis of PFS.  See Section 3.2 for more 
details. 


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12/Statistical Analysis Plan WO29637 
3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION 
Eligible patients were randomized in a 1:1 ratio to receive either 
atezolizumab + bevacizumab versus sunitinib.  A permuted-block randomization was 
applied to obtain balanced assignment to each treatment arm with respect to the 
following stratification factors:  
• 
Presence of liver metastasis (yes vs. no) 
• 
MSKCC (Motzer) score (low, intermediate, or high risk; 0, 1−2, or ≥ 3), which 
comprises the following five risk factors:  Karnofsky performance status (KPS) 
< 80%, LDH > 1.5 × upper limit of normal (ULN), hemoglobin less than the lower limit 
of normal (LLN), corrected serum calcium > 10 mg/dL, and time from nephrectomy 
to systemic therapy (≤ 12 months vs. > 12 months) 
• 
PD-L1 status:  IC1/2/3 versus IC0 
 
3.2 
INDEPENDENT REVIEW FACILITY AND DATA MONITORING 
An external iDMC will evaluate safety data during the study on a periodic basis, 
approximately every 6 months, until the time of the analysis of the co-primary efficacy 
endpoint of PFS according to policies and procedures detailed in an iDMC Charter.  No 
interim efficacy analyses are planned for PFS. 
Staff at an independent Data Coordinating Center (iDCC) will prepare all summaries and 
analyses for iDMC review.  The safety summaries will include demographic data, 
adverse events, serious adverse events, and relevant laboratory data. 
Members of the iDMC will be external to the Sponsor and will follow a charter that 
outlines their roles and responsibilities.  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/Ethics Committees (IRBs/ECs). 
4. 
STATISTICAL METHODS 
4.1 
ANALYSIS POPULATIONS 
Analysis populations of the study are defined as follows: 
• 
The ITT population is defined as all randomized patients whether or not the 
assigned study treatment was received 
• 
The measurable-disease population is defined as patients in the ITT population with 
measurable disease at baseline, as determined by investigator 


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13/Statistical Analysis Plan WO29637 
• 
The duration of response (DOR)-evaluable population is defined as patients with 
objective response 
• 
The safety-evaluable population is defined as patients who received any amount of 
any component of the study treatments 
• 
Atezolizumab pharmacokinetic (PK) analyses will be based on PK observations 
from all patients who received atezolizumab treatment with evaluable PK samples 
• 
Bevacizumab PK analyses will be based on PK observations from all patients who 
received bevacizumab treatment with evaluable PK samples 
• 
The patient-reported outcome (PRO)-evaluable population is defined as patients 
with a non-missing baseline PRO assessment and ≥ 1 post-baseline PRO 
assessment 
 
The PD-L1−selected population is defined as patient population whose PD-L1 status is 
IC1/2/3 at the time of randomization.  PFS and OS outcome measures will be performed 
for patients in the PD-L1−selected population and the ITT population. 
4.2 
ANALYSIS OF STUDY CONDUCT 
Enrollment, major protocol deviations including major deviations of inclusion and 
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 the study treatment will be summarized by treatment arm for the 
safety population. 
Analysis of study conduct will also be performed on the PD-L1−selected population. 
4.3 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
Demographic variables such as age, sex, race/ethnicity, stratification factors (liver 
metastases, MSKCC Motzer score, PD-L1 status), and baseline characteristics 
(including but not limited to weight, primary tumor characteristics such as Fuhrman 
grade and histology of clear cell vs. sarcomatoid, time since initial diagnosis, time since 
metastatic diagnosis, sites of metastatic disease, number of metastatic sites, and KPS) 
will be summarized by treatment arm for the ITT population and for the PD-L1−selected 
population. 
Baseline values are the last available data obtained prior to the patient receiving the first 
dose of study treatment on Cycle 1, Day 1.  Descriptive statistics (mean, median, SD, 
range) will be presented for continuous variables.  Frequencies and percentages will be 
presented for categorical variables. 
4.4 
EFFICACY ANALYSES 
The efficacy analyses will be performed for patients in the PD-L1−selected population 
and the ITT population according to the treatment assigned at randomization on the 
basis of the ITT principle. 


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4.4.1 
Co-Primary Efficacy Endpoints 
The co-primary efficacy endpoints are investigator-assessed PFS per RECIST v1.1 and 
OS.  Co-primary efficacy endpoints of investigator-assessed PFS per RECIST v1.1 will 
be analyzed in the PD-L1−selected population, co-primary efficacy endpoints of OS will 
be analyzed in the ITT population, and OS in the PD-L1−selected population (secondary 
endpoint with α control) will be analyzed in a hierarchical fashion (see Section 2.3). 
PFS is defined as the time from randomization to disease progression, as determined by 
the investigator per RECIST v1.1, or death from any cause, whichever occurs first.  Data 
for patients who have not experienced disease progression or death will be censored at 
the last tumor assessment date.  Data for patients with no post-baseline tumor 
assessments will be censored at the randomization date plus1 day. 
For United States registrational purposes, the co-primary efficacy endpoint of PFS will 
be defined as described above with an additional censoring rule for missed visits.  Data 
for patients with a PFS event who missed two or more scheduled assessments 
immediately prior to the PFS event will be censored at the last tumor assessment prior to 
the missed visits. 
OS is defined as the time from randomization to death due to any cause.  Data for 
patients who are not reported as having died at the date of analysis will be censored at 
the date when they were last known to be alive.  Patients who do not have post-baseline 
information will be censored at the date of randomization + 1 day. 
The following analyses will be performed for both PFS and OS endpoints described 
above.  PFS and OS will be compared between treatment arms with use of the stratified 
log-rank test at the two-sided level of significance as described in Section 2.3.  Hazard 
ratio will be estimated using a stratified Cox regression model with the same stratification 
variables used for the stratified log-rank test.  The 95% CI will be provided.  The 
randomization stratification factors are presence of liver metastasis (yes/no), tumor 
PD-L1 status (IC0 vs. IC1/2/3), and the MSKCC (Motzer) score (0, 1−2, ≥ 3).  The 
stratification factors will be obtained from the interactive voice/Web response system 
(IxRS) at the time of randomization.  Results from an unstratified analysis will also be 
provided.  Kaplan-Meier methodology will be used to estimate the median PFS and OS 
for each treatment arm, and Kaplan-Meier curves will be produced.  The 
Brookmeyer-Crowley methodology will be used to construct the 95% CI for the median 
PFS and OS for each treatment arm (Brookmeyer and Crowley 1982). 
4.4.2 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints include the following: 
• 
PFS by investigator assessment per RECIST v1.1 in the ITT population 
• 
OS in the PD-L1−selected population (secondary endpoint with α control) 
• 
PFS by Independent Review Committee (IRC) assessment per RECIST v1.1 


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• 
Objective response rate (ORR) by investigator assessment per RECIST v1.1 
(ORR-evaluable population) 
• 
DOR by investigator assessment per RECIST v1.1 (DOR-evaluable population) 
• 
ORR by IRC assessment per RECIST v1.1 (ORR-evaluable population) 
• 
DOR by IRC assessment per RECIST v1.1 (DOR-evaluable population) 
• 
PFS by investigator assessment per immune-modified RECIST 
• 
ORR by investigator assessment per immune-modified RECIST (ORR-evaluable 
population) 
• 
DOR by investigator assessment per immune-modified RECIST (DOR-evaluable 
population) 
• 
PFS by investigator assessment per RECIST v1.1 (patients with sarcomatoid 
histology defined by investigator-assessed conventional histopathology) 
• 
OS (patients with sarcomatoid histology) 
• 
Change from baseline in symptom interference, as measured by the M.D. Anderson 
Symptom Inventory (MDASI) symptom interference subscale (PRO-evaluable 
population) 
 
The above secondary efficacy endpoints will be analyzed in both the PD-L1−selected 
population and the ITT population, if not otherwise specified.  OS in the PD-L1−selected 
population is the only secondary endpoint with α control as described in Section 2.3.  No 
formal hypothesis testing will be conducted for the other secondary endpoints. 
4.4.2.1 
Objective Response Rate 
Objective response is defined as a complete response (CR) or partial response (PR) 
(confirmation not required) per RECIST v1.1.  Patients not meeting this criterion, 
including patients without any post-baseline tumor assessments, will be considered 
non-responders.  The analysis population for ORR will be measurable-disease 
population (defined in Section 4.1). 
ORR is defined as the proportion of patients who had an objective response among the 
measurable-disease population.  Confirmed (per RECIST v1.1) response rate will also 
be evaluated.  
ORR will be compared between treatment arms with use of the stratified 
Cochran−Mantel-Haenszel test.  The stratification factors will be the same as those 
described in the analysis of the primary endpoint of PFS.  An estimate of ORR will be 
calculated for each treatment arm, and its 95% CI will be calculated using the 
Clopper−Pearson method.  The difference in ORR between treatment arms will be 
calculated, and its 95% CI will be calculated using the normal approximation to the 
binomial distribution. 


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4.4.2.2 
Duration of Response 
DOR is defined for patients who had an objective response as the time from the first 
occurrence of response (CR or PR) to disease progression or death, whichever occurs 
first.  Data for patients who have not experienced disease progression or death will be 
censored at the last tumor assessment date.  DOR for confirmed response will also be 
evaluated.  If no tumor assessments were performed after the date of the first 
occurrence of CR or PR, data for DOR will be censored at the date of the first 
occurrence of CR or PR plus 1 day. 
Kaplan−Meier methodology will be used to estimate the median DOR for each treatment 
arm.  The Brookmeyer−Crowley methodology will be used to construct the 95% CI for 
the median DOR for each treatment arm (Brookmeyer and Crowley 1982). 
4.4.2.3 
Progression-Free Survival by Immune-Modified RECIST 
PFS by immune-modified RECIST is defined as the time from randomization to disease 
progression as determined by the investigator per immune-modified RECIST (see 
Appendix 3), or death from any cause, whichever occurs first.  A patient is considered to 
have disease progression by immune-modified RECIST if either of the following 
conditions were met: 
a) Immune-modified RECIST criteria for progression were met at a tumor assessment 
and no subsequent tumor assessment was performed. 
b) Immune-modified RECIST criteria for progression were met at a tumor assessment 
and at the subsequent tumor assessment the criteria for confirmed progression by 
immune-modified RECIST were also met. 
 
For patients who meet criterion (a), the date of progression is the date of the tumor 
assessment that met the criteria for immune-modified RECIST.  For patients who meet 
criterion (b), the date of progression is the date of the tumor assessment at which the 
immune-modified RECIST criteria for progression were first met. 
Patients who do not meet either of the above criteria are not considered to have had 
disease progression by immune-modified RECIST.  For example, a patient who had a 
tumor assessment for which the criteria for progression by immune-modified RECIST 
criteria were met, but at the subsequent tumor assessment the criteria for confirmed 
progression by immune-modified RECIST were not met, would not be considered to 
have had progression by immune-modified RECIST on the basis of those two tumor 
assessments.  The determination of whether such a patient subsequently met the criteria 
for progression by immune-modified RECIST would be based only on additional 
subsequent tumor assessments performed after the two tumor assessments described 
in this example.   
Data for patients who have not experienced disease progression by immune-modified 
RECIST or death will be censored at the last tumor assessment date.  Data for patients 


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with no post−baseline tumor assessments will be censored at the randomization date 
plus 1 day. 
Methods for comparison of PFS between treatment arms for the secondary endpoints of 
PFS (including PFS by IRC assessment per RECIST v1.1 and PFS by investigator 
assessment per immune-modified RECIST) will be the same as the methods for 
treatment comparisons for the co-primary efficacy endpoint of PFS by investigator 
assessment per RECIST v1.1.  Kaplan−Meier methodology will be used to estimate the 
median PFS for each treatment arm.  The Brookmeyer−Crowley methodology will be 
used to construct the 95% CI for the median PFS for each treatment arm 
(Brookmeyer and Crowley 1982). 
4.4.2.4 
Change from Baseline in Symptom Interference 
Change from baseline in symptom interference with daily living (captured by the 
MDASI symptom interference subscale) will be evaluated by timepoint and overall (i.e., 
including all on-treatment assessments) until disease progression (investigator-assessed 
per RECIST v1.1).  Multivariate longitudinal models (e.g., mixed models) and area under 
the curve (AUC) methods may be used to estimate treatment effects on symptom 
interference as appropriate.  These analyses will be performed on the PRO-evaluable 
population. 
The MDASI symptom interference subscale comprises six items that ask patients to rate 
how much their symptoms interfered with general activity, mood, work, relations with 
other people, walking, and enjoyment of life in the last 24 hours.  Each MDASI item is 
scored on a 0−10 scale, with 0 indicating that the patient’s symptoms “did not interfere” 
and 10 indicating that symptoms “interfered completely” with the patient’s life.  The 
symptom interference score is calculated as a mean of the six items with a score range 
of 0−10, where higher scores indicate greater symptom interference with daily living.  A 
2-point change has been used to define a clinically meaningful change in MDASI 
symptom interference scores.  Additional scoring details are described in Section 4.7. 
4.4.3 
Exploratory Efficacy Endpoints 
4.4.3.1 
Analyses at Landmark Timepoints of Progression-Free 
Survival and Overall Survival 
The PFS and OS rates at various landmark timepoints include but are not limited to: 
• 
PFS for every 6 months after randomization 
• 
OS for every 6 months after randomization 
 
PFS and OS rates will be estimated by the Kaplan−Meier methodology for each 
treatment arm and the 95% CI will be calculated using Greenwood’s formula. 


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4.4.3.2 
Subgroup Analyses 
To assess the consistency of study results in subgroups defined by demographic and 
baseline characteristics and stratification factors, PFS, ORR, and OS in the subgroups 
will be examined as appropriate. 
Subgroup analyses will include but not be limited to: 
• 
PFS and ORR in patients with tumor Fuhrman Grade 4  
• 
PFS (including PFS by IRC assessment per RECIST v1.1 and PFS by investigator 
assessment per immune-modified RECIST) and ORR in patients with sarcomatoid 
histology 
• 
PFS and OS in MSKCC (Motzer) score subgroup of low, intermediate, or high risk 
(0, 1−2, or ≥ 3) 
 
4.4.3.3 
Biomarker Analyses 
Exploratory prognostic, predictive, and pharmacodynamic biomarker analyses, including 
but not limited to subgroups defined by gene or gene expression signature expression, 
will be performed in archival and/or fresh tumor tissue and/or blood in an effort to 
understand the association of these markers with disease status and/or clinical 
outcomes, including ORR, PFS, and OS. 
The exploratory biomarker analyses are as follows: 
• 
Status of PD-L1, immune-, angiogenic-, and RCC biology-related and other 
exploratory biomarkers, as defined by but not limited to IHC or quantitative 
polymerase chain reaction (qPCR) in archival and/or freshly obtained tumor tissues 
and blood collected before, during, or after treatment with 
atezolizumab + bevacizumab or sunitinib, or at progression 
• 
Status of ICs and biomarkers in biopsy specimens and blood collected at the first 
evidence of radiographic disease progression 
 
The exploratory biomarker analyses will be prespecified and detailed in a separate 
biomarker SAP.  These exploratory analyses may not be available at the time of the 
preparation of the Clinical Study Report and may be reported separately. 
4.5 
SAFETY ANALYSES 
Safety analyses will be performed for the safety-evaluable population; selected safety 
analyses will be performed for safety-evaluable patients in the PD-L1−selected 
population.  Patients will be grouped according to the treatment actually received.  
Specifically, a patient will be included in the atezolizumab + bevacizumab arm in safety 
analyses if the patient receives any amount of atezolizumab or bevacizumab, regardless 
of the initial treatment assignment by IxRS. 


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4.5.1 
Exposure to Study Medication 
Study drug exposure, including treatment duration and number of cycles will be 
summarized for each treatment arm and study drug with descriptive statistics. 
4.5.2 
Adverse Events 
Verbatim description of adverse events will be mapped to MedDRA thesaurus terms.  
Adverse events will be graded by the investigator according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events, Version 4.0 
(NCI CTCAE v4.0). 
Treatment-emergent adverse events (defined as adverse events occurring on or after 
the first dose of study drug until the earliest of initiation of a non-protocol, anti-cancer 
therapy or clinical cutoff date) will be summarized by MedDRA term, appropriate 
MedDRA levels, NCI CTCAE v4.0 grade, and by treatment arm.  Multiple occurrences of 
the same event will be counted once at the maximum grade.  Adverse events, serious 
adverse events, treatment-related serious adverse events, severe adverse events 
(Grade ≥ 3), treatment-related severe adverse events, adverse events of special interest, 
immune-mediated adverse events (defined as adverse events requiring the use of 
systemic corticosteroids), and adverse events leading to study drug discontinuation or 
interruption will be summarized. 
Deaths during the study treatment period and those reported during the follow-up period 
after treatment completion/discontinuation and causes of death will be summarized by 
treatment arm. 
4.5.3 
Laboratory Data 
Laboratory data will be classified according to NCI CTCAE v4.0 and will be summarized 
descriptively by treatment arm.  Shift tables from baseline to worst value during the study 
post-baseline will be presented.  Baseline is defined as the measurement obtained on 
Cycle 1, Day 1 prior to first dose of study drug. 
4.5.4 
Vital Signs 
Changes in selected vital signs will be summarized by treatment arm.  
4.5.5 
Anti-Therapeutic Antibody 
Incidence of anti-therapeutic antibodies (ATAs) against atezolizumab and bevacizumab 
will be summarized.  The analyses of pharmacokinetics, key efficacy, and safety by ATA 
status may be conducted to explore the potential impact of immunogenicity. 
4.6 
PHARMACOKINETIC ANALYSES 
Atezolizumab serum concentration data (minimum serum concentration [Cmin] and 
maximum serum concentration [Cmax]) will be tabulated and summarized for each cycle 
at which pharmacokinetics are to be measured (Cmax will be reported for Day 1 of Cycle 


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1 only; Cmin will be evaluated at Day 1 of Cycles 1, 2, 4, 8, and every eight cycles 
thereafter; Day 22 of Cycles 1, 2, and 4; and at study termination). 
Bevacizumab serum concentration data (Cmin and Cmax) will be tabulated and 
summarized for each cycle at which pharmacokinetics are to be measured (Cmax will be 
reported for Day 1 of Cycles 1 and 2; Cmin will be evaluated at Day 1 of Cycles 1, 2, and 
study termination). 
Descriptive statistics will include means, medians, ranges, and SDs, as appropriate.  
Additional PK and pharmacodynamic analyses will be conducted as appropriate. 
4.7 
PATIENT-REPORTED OUTCOME ANALYSES 
The PRO objectives are to evaluate patient-reported symptom severity, interference, 
tolerability, and overall health associated with atezolizumab plus bevacizumab versus 
sunitinib.  PRO questionnaires (MDASI, Brief Fatigue Inventory [BFI], Functional 
Assessment of Cancer Therapy−Kidney Symptom Index-19 [FKSI-19], EuroQoL 
5 Dimension 3 Levels [EQ-5D-3L]) will be scored on the basis of their corresponding 
user manuals (Cleeland 2009a, 2010b; Cella 2014; Van Reenen and Oppe 2015).  For 
the MDASI, BFI, and FKSI-19, if more than 50% of the constituent items were completed, 
prorated scores will be computed consistent with the scoring manuals and validation 
papers.  If less than 50% of the items in a subscale were completed, the subscale will be 
considered missing. 
Completion rate for each PRO measure will be calculated and summarized at each 
assessment point, overall and by treatment.  The PRO completion rate is defined as the 
number of questionnaires received divided by the number of questionnaires expected 
(i.e., the number of subjects still in the study). 
Descriptive analyses will include summary statistics (e.g., mean, SD, median, 
interquartile range [IQR], minimum, maximum) for continuous PRO scale scores at each 
timepoint and score change from baseline to each timepoint, including disease 
progression and treatment discontinuation.  Descriptive analyses will be performed on 
the PRO-evaluable population for all subscales of the MDASI, BFI, and FKSI-19, as well 
as the EQ-5D-3L visual analogue scale (VAS). 
Key PROs include treatment- and disease-related symptoms, tolerability, interference, 
and overall quality of life:  pain, fatigue, distress, lack of appetite, numbness or tingling, 
rash, headache, mouth/throat sores, diarrhea, symptom interference with enjoyment of 
life and functioning more broadly (MDASI); level of bother with treatment side effects and 
function/well-being (FKSI-19), fatigue interference (BFI), and overall health state 
(EQ-5D-3L VAS).  Multivariate longitudinal models (e.g., mixed models) may be used to 
evaluate treatment effects on key PROs by timepoint and overall as appropriate. 


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Cumulative incidence of key patient-reported symptoms (as measured by the MDASI) 
will be compared between treatment arms.  
The proportion of patients who experienced clinically meaningful deterioration in 
symptom severity and interference (MDASI) and overall health (EQ-5D-3L VAS) will be 
compared between treatments.  Though multiple meaningful change estimates have 
been reported, we will use a 2-point change (increase) in MDASI scores and a 7-point 
change in EQ-5D-3L VAS scores as the primary thresholds for clinically meaningful 
change. 
Time to deterioration (or improvement) in key treatment- and disease-related symptoms 
and functional impact (listed above) will be compared between treatments.  Each time to 
deterioration endpoint is defined as the time from the date of randomization to the date 
of first clinically meaningful change in PRO score.  Cox proportional hazards models will 
be used to estimate HRs and corresponding 95% CIs.  Time to deterioration analyses 
will be performed on the ITT population.  
As appropriate, additional exploratory analyses may be conducted to further examine the 
relationships among changes in symptom severity, interference, overall quality of life, 
disease progression, PFS, and OS. 
4.7.1 
Health Economic Data 
Health economic data, as assessed by the EQ-5D-3L, will be evaluated for patients with 
a baseline assessment and at least one post-baseline EQ-5D-3L assessment that 
generated a score.  For the EQ-5D-3L health state profiles, descriptive statistics 
summarizing the proportions of patients who reported having “no,” “some,” or “extreme” 
problems at each timepoint will be reported.  A single summary index from the EQ-5D-3L 
health states will be utilized in this study for economic modeling.   
The results from the health economic data analysis will be reported separately from the 
Clinical Study Report. 
4.8 
MISSING DATA 
Refer to previous sections for details on how missing data are handled for each endpoint. 


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5. 
REFERENCES 
Bretz F, Maurer W, Brannath W, et al. A graphical approach to sequentially rejective 
multiple test procedures. Stat 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. 
Cella D. Functional Assessment of Cancer Therapy (FACT) symptom indexes for 
regulatory and other purposes. 2014. Accessible via FACIT.org. 
Cleeland CS. The M.D. Anderson symptom inventory user guide version 1 [resource on 
the internet]. 2009a [updated 19 Nov 2009; cited 8 Oct 2014]. Available from: 
http://www.mdanderson.org/education-and-research/departments-programs-and-
labs/departments-and-divisions/symptom-research/symptom-assessment-
tools/MDASI_userguide.pdf. 
Cleeland CS. The Brief Fatigue Inventory User Guide. 2009b. Accessible via 
http://www.mdanderson.org/bfi.  
Glimm E, Maurer W, Bretz F. Hierachial testing of multiple endpoints in group-sequential 
trials. Statist Med. 2010;29:219−28. Epub 2009 Dec 21. 
Hung HM, Wang SJ, O’Neil R. Statistical considerations for testing multiple endpoints in 
group sequential or adaptive clinical trials. J Biopharm Stat. 2007;14(6):1201−10. 
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. 
Biometrika 1983;70:659−63. 
Van Reenen M, Oppe M. EQ-5D-3L user guide version 5.1.2015. Rotterdam: EuroQol 
Research Foundation.  
 
 


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Appendix 1  
Protocol Synopsis 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE III, OPEN-LABEL, RANDOMIZED STUDY OF 
ATEZOLIZUMAB (ANTI−PD-L1 ANTIBODY) IN COMBINATION 
WITH BEVACIZUMAB VERSUS SUNITINIB IN PATIENTS WITH 
UNTREATED ADVANCED RENAL CELL CARCINOMA 
PROTOCOL NUMBER: 
WO29637 
VERSION NUMBER: 
7  
EUDRACT NUMBER: 
2014-004684-20 
IND NUMBER: 
119039 
TEST PRODUCT: 
Atezolizumab (RO5541267) 
PHASE: 
Phase III 
INDICATION: 
Renal cell carcinoma 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives 
Analyses of the following objectives will be performed for the population of patients with 
inoperable, locally advanced, or metastatic renal cell carcinoma (RCC), unless otherwise 
indicated.  Where specified, a comparison of the treatment arms will be performed in the patient 
population defined according to tumor programmed death−ligand 1 (PD-L1) expression as 
evaluated by immunohistochemistry (IHC). 
Efficacy Objectives 
The primary and secondary efficacy objectives will be evaluated in the PD-L1−selected 
population (tumor-infiltrating immune cell [IC]1/2/3) as well as in the intent-to-treat (ITT) 
population (includes all IC scores). 
The primary efficacy objective of the study is as follows: 
• 
To evaluate the efficacy of atezolizumab + bevacizumab compared with sunitinib as 
measured by the co-primary endpoints of investigator-assessed progression-free survival 
(PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and overall 
survival (OS). 
 
The secondary efficacy objectives for this study are as follows: 
• 
To evaluate the efficacy of atezolizumab + bevacizumab versus sunitinib as measured by 
Independent Review Committee (IRC)−assessed PFS according to RECIST v1.1 
• 
To evaluate the efficacy of atezolizumab + bevacizumab versus sunitinib as measured by 
investigator-assessed objective response rate (ORR) (complete + partial response rates) per 
RECIST v1.1 
• 
To evaluate the efficacy of atezolizumab + bevacizumab versus sunitinib as measured by 
investigator-assessed duration of response (DOR) among patients with an objective 
response per RECIST v1.1 
 


 
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Appendix 1  
Protocol Synopsis (cont.) 
• 
To evaluate the efficacy of atezolizumab + bevacizumab versus sunitinib as measured by 
IRC-assessed ORR and DOR according to RECIST v1.1 
• 
To evaluate the efficacy of atezolizumab + bevacizumab versus sunitinib as measured by 
investigator-assessed PFS, DOR, and ORR per modified RECIST 
• 
To evaluate the efficacy of atezolizumab + bevacizumab versus sunitinib among patients 
with sarcomatoid histology (defined by investigator-assessed conventional histopathology) 
as measured by investigator assessed PFS per RECIST v1.1 and OS 
• 
To evaluate the efficacy of atezolizumab + bevacizumab versus sunitinib on symptom 
interference as measured by the M.D. Anderson Symptom Inventory [MDASI Part II]) 
 
Safety Objectives 
The safety objectives for this study are as follows: 
• 
To evaluate the safety and tolerability of atezolizumab + bevacizumab versus sunitinib 
• 
To evaluate the incidence of anti-therapeutic antibodies (ATAs) against atezolizumab and to 
explore the potential relationship of immunogenicity response with pharmacokinetics, safety, 
and efficacy 
 
Pharmacokinetic Objectives 
The pharmacokinetic objectives for this study are as follows: 
• 
To characterize the pharmacokinetics of atezolizumab when administered in combination 
with bevacizumab 
• 
To characterize the pharmacokinetics of bevacizumab when administered in combination 
with atezolizumab 
 
Patient-Reported Outcome Objectives 
The additional patient-reported outcome (PRO) objectives of the study are as follows: 
• 
To assess symptom severity associated with atezolizumab + bevacizumab versus sunitinib 
in patients with RCC as measured by the MDASI and Brief Fatigue Inventory (BFI) 
• 
To document patients’ perspective regarding the tolerability of the treatments (from the 
treatment side-effects subscale from the Functional Assessment of Cancer Therapy Kidney 
Symptom Index [FKSI-19]) 
• 
To obtain general measures of health as measured by the EuroQoL 5 Dimensions (EQ-5D) 
questionnaire for health economic modeling of atezolizumab + bevacizumab versus sunitinib 
in patients with RCC 
 
Exploratory Objectives 
The exploratory objectives for this study are as follows: 
• 
To evaluate the relationship between the expression of other candidate predictive immune, 
angiogenic, or hypoxia biomarkers, as defined by IHC or quantitative polymerase chain 
reaction (qPCR), and efficacy as defined by PFS and ORR 
• 
To evaluate the efficacy of atezolizumab + bevacizumab versus sunitinib among patients 
with tumor Fuhrman Grade 4 or sarcomatoid histology (defined by investigator-assessed 
conventional histopathology) as measured by PFS and ORR 
• 
To assess immune-mediated predictive and prognostic exploratory biomarkers in tumor 
tissue and blood from archival specimens, fresh biopsy specimens, or specimens obtained 
during the study and their association with disease status and/or efficacy as defined by PFS 
and ORR 
 


 
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Appendix 1  
Protocol Synopsis (cont.) 
Study Design 
Description of Study 
This is a Phase III, multicenter, randomized, open-label study designed to evaluate the efficacy 
and safety of atezolizumab + bevacizumab versus sunitinib in patients with inoperable, locally 
advanced, or metastatic RCC who have not received prior systemic active or experimental 
therapy, either in the adjuvant or metastatic setting. 
Number of Patients 
The study will enroll approximately 900 patients, including a minimum of 351 patients with a 
PD-L1 IHC of IC score of 1/2/3 (PD-L1−selected population), at approximately 150−180 centers 
globally.  A maximum of approximately 180 patients (20%) with a Memorial Sloan Kettering 
Cancer Center (MSKCC [Motzer]) score of 0 (good risk) will be enrolled. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form 
• 
Unresectable advanced or metastatic RCC with clear-cell histology and/or component of 
sarcomatoid carcinoma 
Renal cell carcinoma with any component of high-grade malignant spindle cells 
consistent with sarcomatoid histology is eligible.  (See the protocol for further 
guidelines regarding defining sarcomatoid histology.) 
• 
Evaluable MSKCC risk score (i.e., “Motzer” score) 
All MSKCC risk scores are included 
Patients with good risk MSKCC (risk score 0) will comprise no more than 20% of the 
study population 
• 
Definitive diagnosis of RCC on the basis of a representative, formalin-fixed, 
paraffin-embedded tumor specimen accompanied by an associated pathology report 
collected within 24 months prior to Cycle 1, Day 1 available at the study site that allows 
determination of PD-L1 expression status (IC) (required prior to randomization) 
The archival specimen must contain adequate viable tumor tissue to establish PD-L1 
expression status by a central laboratory prior to randomization. 
The specimen may consist of a tissue block (preferred) or at least 15 unstained, 
serial sections. 
Fine-needle aspiration, brushing, cell pellet from pleural effusion, bone metastases, 
and lavage samples are not acceptable.  For core needle biopsy specimens, at least 
three cores embedded into a single paraffin block should be submitted for evaluation.  
Tumor tissue from bone metastases is not evaluable for PD-L1 expression and is 
therefore not acceptable. 
If the archival tissue was acquired > 24 months prior to Cycle 1, Day 1, the patient may 
still be eligible provided the patient is willing to consent to and undergo a pre-treatment 
core or excisional biopsy of the tumor.  If the location of the tumor renders the tumor 
biopsy medically unsafe, eligibility may be provided with Medical Monitor approval.  A 
local analysis to confirm the diagnosis of RCC is required. 
• 
Measurable disease, as defined by RECIST v1.1 
• 
Age ≥ 18 years 
• 
Karnofsky performance status ≥ 70 
• 
Ability and capacity to comply with study and follow-up procedures 
 
 


 
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Appendix 1  
Protocol Synopsis (cont.) 
• 
Adequate hematologic and end-organ function, defined by the following laboratory results 
obtained within 28 calendar days prior to randomization: 
ANC ≥ 1500 cells/µL (without granulocyte colony-stimulating factor support within 2 
weeks prior to Cycle 1, Day 1) 
WBC counts ≥ 2500 cells/µL 
Lymphocyte count ≥ 300 cells/µL 
Platelet count ≥ 100,000 cells/µL (without transfusion within 2 weeks prior 
to Cycle 1, Day 1) 
Hemoglobin ≥ 9.0 g/dL 
AST, ALT, and alkaline phosphatase ≤ 2.5 × ULN, with the following exceptions: 
Patients with documented liver metastases:  AST and ALT ≤ 5 × ULN 
Patients with documented liver or bone metastases:  alkaline phosphatase 
≤ 5 × ULN 
Serum bilirubin ≤ 1.5 × ULN 
Patients with known Gilbert disease who have serum bilirubin level ≤ 3 × ULN 
may be enrolled. 
INR and aPTT ≤ 1.5 × ULN, unless on a stable dose of warfarin 
Serum albumin > 2.5 g/dL 
Creatinine clearance ≥ 30 mL/min (Cockcroft-Gault formula or based on 24-hour urine 
collection) 
• 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% 
per year during the treatment period and for at least 6 months after the last dose of 
atezolizumab and bevacizumab or 30 days after the last dose of sunitinib. 
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, established, proper use of 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 at least 6 months after the last dose 
of bevacizumab or 30 days after the last dose of sunitinib.  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 the duration of the pregnancy to avoid exposing the 
embryo. 


 
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Appendix 1  
Protocol Synopsis (cont.) 
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. 
• 
Patients with a history of treated asymptomatic CNS metastases are eligible, provided they 
meet all of the following criteria: 
Evaluable or measurable disease outside the CNS 
Only supratentorial and cerebellar metastases allowed (i.e., no metastases to midbrain, 
pons, medulla or spinal cord) 
No history of intracranial or spinal cord hemorrhage 
No evidence of significant vasogenic edema 
No ongoing requirement for corticosteroids as therapy for CNS disease 
No stereotactic radiation within 14 days 
No evidence of interim progression between the completion of CNS-directed therapy 
and the screening radiographic study 
Patients with new asymptomatic CNS metastases detected at the screening scan must 
receive radiation therapy and/or surgery for CNS metastases.  Following treatment, 
these patients may then be eligible without the need for an additional brain scan prior 
to enrollment [or randomization], if all other criteria are met. 
 
Exclusion Criteria 
Disease-Specific Exclusions 
• 
Prior treatment with active or experimental systemic agents, including treatment in the 
neoadjuvant or adjuvant setting.  Prior treatment with placebo in adjuvant setting is allowed. 
• 
Radiotherapy for RCC within 14 calendar days prior to Cycle 1, Day 1 
• 
Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or 
metastases causing nerve impingement) should be treated at least 14 days prior to Cycle 1, 
Day 1. 
• 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently) 
• 
Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or calcium > 12 mg/dL) or 
symptomatic hypercalcemia refractory to bisphosphonate therapy or denosumab 
Patients who are currently receiving bisphosphonate therapy without current 
hypercalcemia (corrected serum calcium greater than the upper limit of normal) are 
eligible. 
• 
Malignancies other than RCC within 5 years prior to Cycle 1, Day 1 
Patients with localized low risk prostate cancer (defined as stage  ≤ T2b, Gleason score 
≤ 7, and PSA at prostate cancer diagnosis ≤ 20 ng/mL) treated with curative intent and 
without prostate-specific antigen (PSA) recurrence are eligible  
Patients with low risk prostate cancer (defined as Stage T1/T2a, Gleason score ≤ 6, 
and PSA ≤ 10 ng/mL) who are treatment-naive and undergoing active surveillance are 
eligible 
Patients with malignancies of a negligible risk of metastasis or death (e.g., risk of 
metastasis or death < 5% at 5 years) are eligible provided they meet all of the following 
criteria: 
Malignancy treated with expected curative intent (such as adequately treated 
carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal 
carcinoma in situ treated surgically with curative intent) 
No evidence of recurrence or metastasis by follow-up imaging and any 
disease-specific tumor markers 


 
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28/Statistical Analysis Plan WO29637 
Appendix 1  
Protocol Synopsis (cont.) 
General Medical Exclusions 
• 
Life expectancy of < 12 weeks 
• 
Current, recent (within 4 weeks of Cycle 1, Day 1), or planned participation in another 
experimental drug study 
• 
Pregnant and lactating , or intending to become pregnant during the study 
• 
Women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or 
surgically sterile must have a negative serum pregnancy test result within 7 days prior to 
initiation of study drug. 
• 
History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins 
• 
Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary 
cells or any component of the atezolizumab formulation 
• 
History of autoimmune disease, including but not limited to myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory 
bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s 
granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, 
or glomerulonephritis (see the protocol for a more comprehensive list of autoimmune 
diseases) 
Patients with a history of autoimmune-related hypothyroidism on a stable dose of 
thyroid replacement hormone are eligible for this study. 
Patients with controlled Type I diabetes mellitus on a stable dose of insulin regimen 
may be eligible for this study. 
• 
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), 
drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on 
screening chest computed tomography (CT) scan; however, history of radiation pneumonitis 
in the radiation field (fibrosis) is permitted. 
• 
Positive test for HIV 
• 
Patients with active or chronic hepatitis B (defined as having a positive hepatitis B surface 
antigen [HBsAg] test at screening) 
Patients with past/resolved HBV infection (defined as having a negative HBsAg test 
and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible.  
A negative HBV DNA test must be obtained in patients with positive hepatitis B core 
antibody prior to Cycle 1, Day 1. 
• 
Patients with active hepatitis C 
Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) 
analysis is negative for HCV RNA. 
• 
Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia 
• 
Signs or symptoms of infection (including active tuberculosis) within 2 weeks prior to 
Cycle 1, Day 1 
• 
Received therapeutic oral or intravenous antibiotics within 2 weeks prior to Cycle 1, Day 1 
Patients receiving routine antibiotic prophylaxis (e.g., to prevent chronic obstructive 
pulmonary disease exacerbation or for dental extraction) are eligible. 
• 
Significant cardiovascular or cerebrovascular disease, such as New York Heart Association 
cardiac disease (Class II or greater), unstable angina, myocardial infarction or 
cerebrovascular events within the previous 6 months or unstable arrhythmias within the 
previous 3 months. 
 


 
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29/Statistical Analysis Plan WO29637 
Appendix 1  
Protocol Synopsis (cont.) 
Patients with known coronary artery disease, arrhythmias, congestive heart failure not 
meeting the above criteria must be on a stable medical regimen that is optimized in the 
opinion of the treating physician, in consultation with a cardiologist if appropriate.  
Baseline evaluation of left ventricular ejection fraction (LVEF) should be considered for 
all patients, especially in those with cardiac risk factors and/or history of coronary 
artery disease. 
Patients with known LVEF < 50% 
• 
Major surgical procedure other than for diagnosis within 21 days prior to Cycle 1, Day 1, or 
planned procedure or surgery during the study 
• 
Prior allogeneic stem cell or solid organ transplant 
• 
Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 
Influenza vaccination should be given during influenza season only (approximately 
October through May in the Northern Hemisphere and approximately April through 
September in the Southern Hemisphere).  Patients must agree not to receive live, 
attenuated influenza vaccine (e.g. FluMist) within 28 days prior to randomization, 
during treatment or within 5 months following the last dose of atezolizumab (for 
patients randomized to atezolizumab). 
• 
Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that contraindicates 
the use of an investigational drug or that may affect the interpretation of the results or 
render the patient at high risk from treatment complications 
 
Exclusion Criteria Related to Medications 
• 
Prior treatment with CD137 agonists, anti−CTLA-4, anti−programmed death-1 (PD-1), or 
anti−PD-L1 therapeutic antibody or pathway-targeting agents  
• 
Treatment with systemic immunostimulatory agents (including but not limited to interferon α, 
interleukin-2) for the treatment of non-malignant conditions within 6 weeks or five half-lives 
of the drug, whichever is shorter, prior to Cycle 1, Day 1 
• 
Any prior use of systemic immunostimulatory agents for the management of metastatic 
RCC is excluded. 
• 
Treatment with systemic immunosuppressive medications (including but not limited to 
prednisone, dexamethasone cyclophosphamide, azathioprine, methotrexate, thalidomide, 
and anti−tumor necrosis factor [anti−TNF] agents) within 2 weeks prior to Cycle 1, Day 1.  
Patients who have received acute, low-dose, systemic immunosuppressant 
medications (e.g., a one-time dose of dexamethasone for nausea) or physiologic 
replacement doses (i.e., prednisone 5−7.5 mg/day) for adrenal insufficiency may be 
enrolled in the study. 
The use of inhaled corticosteroids, physiologic replacement doses of glucocorticoids 
(i.e., for adrenal insufficiency), and mineralocorticoids (e.g., fludrocortisone) is allowed. 
 
Bevacizumab- and Sunitinib-Specific Exclusions 
• 
Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg 
and/or diastolic blood pressure > 100 mmHg) 
Anti-hypertensive therapy to maintain a systolic blood pressure < 150 mmHg and/or 
diastolic blood pressure < 100mmHg is permitted.  
• 
Prior history of hypertensive crisis or hypertensive encephalopathy 
• 
New York Heart Association Class II or greater congestive heart failure 
• 
History of stroke or transient ischemic attack within 6 months prior to Cycle 1, Day 1 
 


 
AtezolizumabF. Hoffmann-La Roche Ltd 
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Appendix 1  
Protocol Synopsis (cont.) 
• 
Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent 
peripheral arterial thrombosis) within 6 months prior to Cycle 1, Day 1 
• 
Patients with a baseline ECG demonstrating a QTc > 460 ms 
• 
Evidence of bleeding diathesis or clinically significant coagulopathy (in the absence of 
therapeutic anticoagulation) 
• 
Current or recent (within 10 calendar days prior to Cycle 1, Day 1) use of dipyramidole, 
ticlopidine, clopidogrel, or cilostazol. 
• 
Prophylactic or therapeutic use of low molecular weight heparin (e.g., enoxaparin), direct 
thrombin inhibitors, or warfarin are permitted, provided, where appropriate anticoagulation 
indices are stable.  Patients should have been on a stable dose (for therapeutic use) for at 
least 2 weeks (or until reaching steady state level of the drug) prior to the first study 
treatment 
• 
Core biopsy or other minor surgical procedure, excluding placement of a vascular access 
device, within 7 calendar days prior to the first dose of bevacizumab 
• 
History of abdominal or tracheoesophageal fistula or gastrointestinal perforation 
within 6 months prior to Cycle 1, Day 1 
• 
Clinical signs or symptoms of gastrointestinal obstruction or requirement for routine 
parenteral hydration, parenteral nutrition, or tube feeding 
• 
Evidence of abdominal free air not explained by paracentesis or recent surgical procedure 
• 
Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture 
• 
Proteinuria, as demonstrated by urine dipstick or > 1.0 g of protein in a 24-hour 
urine collection 
All patients with ≥ 2+ protein on dipstick urinalysis at baseline must undergo a 24-hour 
urine collection for protein. 
 
Length of Study 
On the basis of accrual projections and projected median OS for each treatment arm, the final 
analysis of OS is projected to occur at Month 63 from the time the first patient is randomized. 
End of Study 
The end of study will occur when the number of deaths required for the final analysis of OS has 
been observed.  On the basis of accrual projections and projected median OS for each 
treatment arm, the final analysis of OS is projected to occur at Month 63 from the time the 
first patient is randomized. 
Outcome Measures 
Efficacy Outcome Measures 
The co-primary efficacy outcome measures are:  
• 
PFS, defined as the time from randomization to the first occurrence of disease progression, 
as determined by the investigator from tumor assessments based on RECIST v1.1, or 
death from any cause and  
• 
OS, defined as the time from randomization to death due to any cause 
 
The secondary efficacy outcome measures for this study are as follows: 
• 
PFS based on IRC assessment of radiographic progression per RECIST v1.1 
• 
ORR, defined as the proportion of patients with an objective response (either complete 
response or partial response, confirmation not required) as determined by investigator per 
RECIST v1.1 
 


 
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31/Statistical Analysis Plan WO29637 
Appendix 1  
Protocol Synopsis (cont.) 
• 
Duration of response (DOR), defined as the time from the first documented response to 
documented disease progression as determined by the investigator per RECIST v1.1 or 
death due to any cause, whichever occurs first 
• 
ORR and DOR based on IRC assessment per RECIST v1.1 
• 
PFS, ORR, and DOR based on investigator assessment per modified RECIST criteria  
• 
Change from baseline in symptom interference (from MDASI Part II) 
 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Incidence, nature, and severity of all adverse events, including Grade ≥ 3 laboratory 
toxicities (grading per National Cancer Institute Common Terminology Criteria for Adverse 
Events version 4.0; laboratory toxicities based on local laboratory assessments), during 
first-line treatment 
• 
Incidence of ATA response to atezolizumab and potential correlation with pharmacokinetics, 
safety, and efficacy parameters 
 
Pharmacokinetic Outcome Measures 
The pharmacokinetic outcome measures for this study are as follows: 
• 
Maximum atezolizumab serum concentration (Cmax) after infusion on Cycle 1, Day 1  
• 
Minimum atezolizumab serum concentration (Cmin) prior to the infusion on Day 1 of Cycles 1, 
2, 4, 8 and every eight cycles thereafter; Day 22 of Cycles 1, 2, and 4; and at study 
termination 
• 
Bevacizumab Cmax after infusion on Day 1 of Cycles 1 and 2 
• 
Bevacizumab Cmin prior to the infusion on Day 1 of Cycles 1 and 2 and at study termination 
 
Patient-Reported Outcome Measures 
The other PRO outcome measures for this study are as follows: 
• 
Change from baseline in symptom severity as measured by the MDASI and BFI  
• 
Change from baseline in treatment side effects subscale (from FKSI-19) 
 
In addition, health status will be collected the EuroQoL 5 Dimensions (EQ-5D) questionnaire to 
derive utilizes for health economic modeling. 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
Status of PD-L1, immune-, angiogenic-, and RCC-related and other exploratory biomarkers 
in archival and/or freshly obtained tumor tissues and blood collected before, during, or after 
treatment with atezolizumab + bevacizumab or sunitinib or at progression 
• 
PFS and ORR in patients with tumor Fuhrman Grade 4 or sarcomatoid histology (defined by 
investigator-assessed conventional histopathology) 
• 
Status of tumor-infiltrating immune cells and biomarkers in biopsy specimens and blood 
collected at the first evidence of radiographic disease progression 
 
Investigational Medicinal Products 
Test Product (Investigational Drugs) 
Atezolizumab + bevacizumab will be dosed in 6-week cycles.  Atezolizumab will be administered 
intravenously at a fixed dose of 1200 mg on Days 1 and 22 of each 42-day cycle.  Bevacizumab 
will be administered intravenously at 15 mg/kg on Days 1 and 22 of each 42-day cycle. 


 
AtezolizumabF. Hoffmann-La Roche Ltd 
32/Statistical Analysis Plan WO29637 
Appendix 1  
Protocol Synopsis (cont.) 
Comparator 
Sunitinib will be administered in 6-week cycles at 50 mg/day given orally for 4 weeks, followed 
by 2 weeks of rest. 
Statistical Methods 
Primary Analysis 
The co-primary efficacy endpoints are investigator-assessed PFS per RECIST v1.1 and OS.  
Because type I error will be controlled accounting for two co-primary endpoints, the study will be 
considered a positive study if statistical significance is achieved for either of the co-primary 
endpoints. 
PFS will be analyzed in the PD-L1−selected population and OS will be analyzed first in the ITT 
population; additional analyses of OS will be performed in a hierarchical fashion.  
PFS is defined as the time from randomization to disease progression, as determined by the 
investigator per RECIST v1.1, or death from any cause, whichever occurs first.  Data for 
patients who have not experienced disease progression or death will be censored at the last 
tumor assessment date.  Data for patients with no post-baseline tumor assessments will be 
censored at the randomization date + 1 day. 
For United States registrational purposes, the co-primary efficacy endpoint of PFS will be 
defined as described above with an additional censoring rule for missed visits.  Data for patients 
with a PFS event who missed two or more scheduled assessments immediately prior to the 
PFS event will be censored at the last tumor assessment prior to the missed visits. 
OS is defined as the time from randomization to death due to any cause.  Data for patients who 
are not reported as having died at the date of analysis will be censored at the date when they 
were last known to be alive.  Patients who do not have post-baseline information will be 
censored at the date of randomization + 1 day. 
The following analyses will be performed for both PFS endpoints described above and OS.  
PFS and OS will be compared between treatment arms with use of the stratified log-rank test.  
The HR will be estimated using a stratified Cox proportional hazards model.  The 95% CI for the 
HR will be provided.  The stratification factors will be the same as the randomization 
stratification factors:  presence of liver metastasis (yes/no); tumor PD-L1 status (IC0 vs. IC1/2/3); 
and the MSKCC (Motzer) score (0, 1−2, ≥ 3).  The stratification factors will be obtained from the 
IxRS at the time of randomization.  Results from an unstratified analysis will also be provided.  
Kaplan-Meier methodology will be used to estimate the median PFS and OS for each treatment 
arm, and Kaplan-Meier curves will be produced.  The Brookmeyer-Crowley methodology will be 
used to construct the 95% CI for the median PFS and OS for each treatment arm. 
The following analyses will be performed for both PFS endpoints described above and (as 
applicable) for OS:  
• 
Analyses described in the protocol for landmark timepoints 
• 
Analyses described in the protocol for subgroups  
• 
Secondary endpoint of PFS by IRC assessment, PD-L1−selected population and ITT 
population, based on RECIST v1.1 
• 
Secondary endpoint of PFS by investigator assessment in the ITT population, based on 
RECIST v1.1 
 
Patient-Reported Outcome Analysis 
MDASI, and BFI, and FKSI-19 
Scoring for the MDASI and BFI questionnaires will be based on their corresponding user 
manuals.  For MDASI and BFI scales with more than 50% of the constituent items 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 missing.  
 


 
AtezolizumabF. Hoffmann-La Roche Ltd 
33/Statistical Analysis Plan WO29637 
Appendix 1  
Protocol Synopsis (cont.) 
The impact of symptoms on patients’ functioning will be compared between treatment arms as a 
change from baseline on the interference items in the MDASI Part II.  
The severity of symptoms captured in the MDASI and the BFI will be summarized using 
descriptive analyses including summary statistics and change from baseline at each 
assessment by treatment arm. 
Determination of Sample Size 
This study will randomize approximately 900 patients, including a minimum of approximately 
351 patients with a PD-L1 IHC IC score of 1/2/3. 
Type I Error Control 
The type I error (α) for this study is 0.05 (two-sided).  There are two co-primary efficacy 
endpoints for this study:  PFS by investigator assessment per RECIST v1.1 and OS.  To control 
the overall type I error rate at α = 0.05 (two-sided) while accounting for two co-primary endpoints, 
α will be split between PFS (α = 0.04) and OS (α = 0.01).  Because type I error will be controlled 
accounting for two co-primary endpoints, the study will be considered a positive study if 
statistical significance is achieved for either of the co-primary endpoints. 
Formal treatment comparisons will be performed in a hierarchical fashion in which α may be 
recycled as follows: 
1. PFS in the PD-L1−selected population will be evaluated at α = 0.04 (two-sided).  
2. 
If PFS results in the PD-L1−selected population are statistically significant at α = 0.04, then 
α = 0.04 will be recycled to OS in the ITT population, and OS in the ITT population will be 
evaluated at α = 0.05 (two-sided).  If PFS results in the PD-L1−selected population are not 
statistically significant at α = 0.04, then no recycling of α will occur, and OS in the ITT 
population will be evaluated at α = 0.01 (two-sided). 
3. 
OS will be compared between treatment arms in a hierarchical fashion as follows.  If OS 
results in the ITT population are statistically significant at the appropriate α level, then OS in 
the PD-L1−selected population will be evaluated at same α-level as for OS in the ITT 
population.  If OS results in the ITT population are not statistically significant, formal 
treatment comparison of OS in the PD-L1−selected population will not be performed. 
 
Interim analyses of OS and the final analysis of OS will be based on the α allocated to the 
comparison of OS, as described above.  Statistical significance at interim analyses of OS will be 
evaluated. 
Co-Primary Endpoint:  Progression-Free Survival in the PD-L1−Selected Population 
The analysis of the co-primary endpoint of PFS will take place when approximately 228 PFS 
events in the PD-L1−selected population (65% of the estimated 351 PD-L1−population) as 
defined for the primary analysis of PFS have occurred based on the following assumptions: 
• 
Two-sided, stratified log-rank test  
• 
α = 0.04 (two-sided) 
• 
Approximately 88% power 
• 
Median PFS for the sunitinib arm of 11 months and estimated median PFS in the 
atezolizumab + bevacizumab arm of 17 months (corresponding to HR of 0.65) 
• 
5% annual loss to follow-up for PFS 
• 
No interim analysis 
 
Accrual is projected to occur over 20months, assuming a ramp-up period of 9 months.   
On the basis of these assumptions, the required number of PFS events in the PD-L1−selected 
population is projected to occur at Month 34 from the time the first patient is randomized.  Also 
on the basis of these assumptions, it is projected that an observed HR of 0.76 or lower will 
result in a statistically significant difference between treatment arms (i.e., an HR of 0.76 will be 
the minimally detectable difference for the analysis; this corresponds to an improvement of  


 
AtezolizumabF. Hoffmann-La Roche Ltd 
34/Statistical Analysis Plan WO29637 
Appendix 1  
Protocol Synopsis (cont.) 
3.5 months in median PFS from 11 months in the sunitinib arm to 14.5 months in the 
atezolizumab + bevacizumab arm). 
Co-Primary Endpoint:  Overall Survival in the ITT Population 
The final analysis of the co-primary endpoint of OS will take place at the later of the timepoints 
when the required number of events has occurred in the PD-L1−selected population and in the 
ITT population, where the required number of events is as follows: 
• 
639 OS events in the ITT population (71% of the estimated 900 patients) 
• 
246 OS events in the PD-L1−selected population (70% of the estimated 351 patients) 
 
The number of events required for the final OS analysis in these populations is based on the 
following assumptions: 
• 
Two-sided, stratified log-rank test  
• 
α = 0.01 (two-sided) 
• 
1% annual loss to follow-up for OS 
• 
For the ITT population:   
85% power 
Median OS in the control arm of 24 months 
Estimated median OS in the atezolizumab + bevacizumab arm of 32 months (an 
increase of 8 months, corresponding to an HR of 0.75 
• 
For the PD-L1−selected population:   
53% power 
Median OS in the control arm of 24 months 
Estimated median OS in the atezolizumab + bevacizumab arm of 33.8 months (an 
increase of 9.8 months, corresponding to an HR of 0.71) 
 
On the basis of these assumptions, the required number of OS events for the final analysis of 
OS in both the PD-L1−selected population and the ITT population is projected to occur at 
Month 63 from the time the first patient is randomized.  
At the final OS analysis, on the basis of these assumptions, it is projected that an observed OS 
HR of 0.83 or lower in the ITT population will result in a statistically significant difference 
between treatment arms (i.e., the minimally detectable difference at the analysis; this 
corresponds to an improvement of 4.9 months in median OS, from 24 months in the control arm 
to 28.9 months in the atezolizumab + bevacizumab arm).  
Also at the final OS analysis, on the basis of these assumptions, it is projected that an observed 
OS HR of 0.72 or lower in the PD-L1−selected population will result in a statistically significant 
difference between treatment arms (i.e., an HR of 0.72 will be the minimally detectable 
difference at the analysis; this corresponds to an improvement of 9.5 months in median OS, 
from 24 months in the control arm to 33.5 months in the atezolizumab + bevacizumab arm). 
Interim Analyses 
Progression-Free Survival 
There are no planned interim analyses of the co-primary endpoint of PFS. 
Overall Survival 
A total of four analyses of OS will be performed, including three interim analyses and one 
final analysis.  The α level for OS testing is 0.05 given that the co-primary endpoint of PFS 
was met in the study.  The boundary for statistical significance at each interim analysis and 
the final analysis will be determined based on the Lan-DeMets implementation of the O’Brien-
Fleming function to maintain the overall type 1 error rate at 0.05 level.  The O’Brien-Fleming 
(OBF) boundary for statistical significance is provided.  The OS endpoint will be considered  




Atezolizumab—F. Hoffmann-La Roche Ltd 
36/Statistical Analysis Plan WO29637 
Appendix 2  
Schedule of Assessments 
Assessment Window (Days) a 
Screening b 
Days − 28 
to − 1 
Atezolizumab + Bevacizumab 
OR 
Sunitinib 
End of Treatment  
≤ 30 Days after Last 
Dose of Study 
Treatment d 
Survival Follow-Up 
Cycle ≥ 1 
Day 1 
Cycle ≥ 1 
Day 22 c 
Day 1, Every 
Two Cycles 
Signed Informed Consent 
Form(s) b 
x 
 
 
 
 
 
Review of eligibility criteria 
x 
 
 
 
 
 
Medical, surgical, and cancer 
histories, including 
demographic information e 
x 
 
 
 
 
x 
Cancer treatment 
HBV and HCV serology 
x 
 
 
 
 
 
HIV testing f 
x 
 
 
 
 
 
Concomitant medications g 
x 
x 
x 
 
x 
 
Tumor assessment h 
x 
At 12 weeks ± 5 business days, then every 6 weeks ± 5 business days thereafter, including 
Week 78 following randomization.  After 78 weeks from randomization, patients will undergo 
tumor assessments every 12 weeks ± 5 business days until treatment discontinuation. 
Complete physical 
examination i 
x 
 
 
 
x 
 
Limited physical examination j 
 
x j, k 
 
 
 
 
Karnofsky performance status 
x 
x k 
 
 
x 
 


 
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Appendix 2  
Schedule of Assessments (cont.)  
Assessment Window (Days) a 
Screening b 
Days − 28 
to − 1 
Atezolizumab + Bevacizumab 
OR 
Sunitinib 
End of Treatment  
≤ 30 Days after Last 
Dose of Study 
Treatment d 
Survival Follow-Up 
Cycle ≥ 1 
Day 1 
Cycle ≥ 1 
Day 22 c 
Day 1, Every 
Two Cycles 
Vital signs l 
x 
x 
x 
 
x 
 
12-lead electrocardiogram 
and/or LVEF evaluation m 
x 
 
x 
 
x 
 
Weight  
x 
x n 
 
 
x 
 
Height 
x 
 
 
 
 
 
Hematology o 
x 
x k 
x 
 
x 
 
Serum chemistry p 
x 
x k 
x 
 
x 
 
Coagulation panel (aPTT, 
INR) 
x 
 
 
 
x 
 
Urine dipstick (+ 24-hr urine if 
dipstick protein ≥ 2+ ) q 
x 
x 
 
 
x 
 
Serum pregnancy test r 
x r 
 
 
x r 
 
 
TSH, free T3, free T4 s 
x 
 
 
x s 
x 
 
Ferritin s 
x 
 
 
x 
x 
 
C-reactive protein and 
auto-antibody testing t 
x 
 
 
x u 
x 
 
Serum sample for ATA 
assessment v 
 
x v 
 
 
x 
 
 


 
AtezolizumabF. Hoffmann-La Roche Ltd 
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Appendix 2  
Schedule of Assessments (cont.)  
Assessment Window (Days) a 
Screening b 
Days − 28 
to − 1 
Atezolizumab + Bevacizumab 
OR 
Sunitinib 
End of Treatment  
≤ 30 Days after Last 
Dose of Study 
Treatment d 
Survival Follow-Up 
Cycle ≥ 1 
Day 1 
Cycle ≥ 1 
Day 22 c 
Day 1, Every 
Two Cycles 
Atezolizumab PK serum 
sample w 
 
x 
x 
 
x 
 
Bevacizumab PK serum 
sample w 
 
x 
 
 
 
 
TBNK blood sample x 
 
x 
 
 
 
 
Plasma, serum, and whole 
blood for biomarkers y 
 
x 
x 
 
x 
 
DNA for RCR (optional) z 
 
x 
 
 
 
 
Adverse events 
 
x 
x 
 
x 
x d 
Atezolizumab infusion aa 
 
x z 
x 
 
 
 
Bevacizumab infusion aa 
 
x z 
x 
 
 
 
Sunitinib dispensing c 
 
x c 
 
 
 
 
Tumor tissue  
specimen or at least 
15 unstained slides bb 
x 
 
 
 
 
 
Tumor tissue at progression cc 
 
 
 
 
 
 
MDASI dd 
 
x 
x 
 
x 
x 


 
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Appendix 2  
Schedule of Assessments (cont.)  
Assessment Window (Days) a 
Screening b 
Days − 28 
to − 1 
Atezolizumab + Bevacizumab 
OR 
Sunitinib 
End of Treatment  
≤ 30 Days after Last 
Dose of Study 
Treatment d 
Survival Follow-Up 
Cycle ≥ 1 
Day 1 
Cycle ≥ 1 
Day 22 c 
Day 1, Every 
Two Cycles 
BFI dd 
 
x 
x 
 
x 
x 
EQ-5D dd 
 
x 
x 
 
x 
x 
FKSI-19 dd 
 
x 
x 
 
x 
x 
Anti-neoplastic agent use ee 
 
 
 
 
 
x 
ATA = anti−therapeutic antibody; BFI = Brief Fatigue Inventory; C = cycle; CA = cancer antigen; CMV = cytomegalovirus; CRP = C-reactive 
protein; CT = computed tomography; ePRO = electronic patient-reported outcome; EQ-5D = EuroQoL 5 Dimensions; FKSI-19 = Functional 
Assessment of Cancer Therapy Kidney Symptom Index-19; irRC = immune-related response criteria; MDASI = M.D. Anderson Symptom 
Inventory; LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; PD = pharmacodynamic; PET = positron emission 
tomography; PK = pharmacokinetic; PSA = prostate-specific antigen; RCR = Roche Clinical Repository; RECIST = Response Evaluation Criteria 
in Solid Tumors; TBNK = T, B, and natural killer; TSH = thyroid-stimulating hormone. 
Note:  Assessments scheduled on the days of study treatment should be performed before the infusion or dosing unless otherwise noted.  Each 
cycle is 42 days in length. 
a The first dosing date (Cycle 1, Day 1) should occur within 5 business days from randomization.  All visits and infusions may be administered 
with a window of ± 3 days.   
b Written informed consent is required for performing any study-specific tests or procedures.  Signing of the Informed Consent Form can occur 
outside the 28-day screening period.  Results of standard-of-care tests or examinations performed prior to obtaining informed consent and 
within 28 days prior to randomization may be used for screening assessments, rather than repeating such tests.  Screening local laboratory 
assessments obtained ≤ 96 hours prior to Cycle 1, Day 1 do not have to be repeated for Cycle 1.  Test results should be reviewed prior to 
administration of study treatment.  If re-screening is required, then then HBV, HCV, HIV, CRP, and autoantibody testing from initial screening 
may be acceptable for screening assessment if < 60 days from Cycle 1, Day 1.   
c Sunitinib is taken by mouth once a day on Days 1−28 of each cycle.  For patients taking sunitinib, the Day 22 visits are required for the first 
year of the study only. 
 
 


 
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Appendix 2  
Schedule of Assessments (cont.)  
d 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 the last 
administration of study treatment, serious adverse events (see [Section 5.2.2 of the protocol] and adverse events of special interest [see 
Section 5.2.3 of the protocol], regardless of attribution, will be recorded until the end of the special reporting period (defined as 90 days after the 
last dose of atezolizumab or bevacizumab or 30 days after the last dose of sunitinib).  After this period, the investigator should report any serious 
adverse events that are believed to be related to prior study drug treatment (see Section 5.6 of the protocol).  All other adverse events will be 
recorded until 30 days after the last dose of atezolizumab, bevacizumab or sunitinib, or until initiation of another anti-cancer therapy, whichever 
occurs first.  Patients will be contacted at 30 days after the last dose of study treatment to determine if any new adverse events have occurred.  
Ongoing adverse events thought to be related to study treatment will be followed until resolution of the adverse event, until an alternate cause has 
been identified, 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 end of treatment visit do not need to be repeated.  The Sponsor should 
be notified if the investigator feels any serious adverse event occurring after the end of the adverse event reporting period is related to prior study 
drug treatment. 
e Cancer history includes stage, date of diagnosis, and prior anti-tumor treatment.  Demographic information includes sex, age, 
and self-reported race/ethnicity. 
f All patients will be tested for HIV prior to the inclusion into the study and HIV-positive patients will be excluded from the clinical trial. 
g Concomitant medications include any prescription or over-the-counter medications.  At screening, any medications the patient has used within 
the 7 days prior to the screening visit should be documented.  At subsequent visits, changes to current medications or medications used since 
the last documentation of medications will be recorded. 
h All measurable and evaluable lesions should be assessed and documented using physical examination and image-based evaluation.  
Screening assessments should include CT scans with oral and intravenous contrast of the chest, abdomen, and pelvis, and a brain scan 
(CT or MRI).  Bone scans and CT scan of neck should also be performed if clinically indicated.  CT or MRI scans must be used to measure 
lesions selected for response assessment.  Disease status will be assessed using RECIST v1.1 and modified RECIST criteria (see Appendix 3 
and Appendix 4 of the protocol).  The same radiographic procedure used to define measurable lesions at baseline must be used throughout 
the study for each patient.  Results must be reviewed by the investigator before dosing at the next cycle.  Tumor assessments will occur at 
baseline, at 12 weeks ± 5 business days, then every 6 weeks ± 5 business days thereafter including Week 78 following randomization.  After 
78 weeks from randomization, patients will undergo tumor assessments every 12 weeks ± 5 business days until treatment discontinuation, or 
as clinically indicated.  Patients who discontinue study treatment for reasons other than disease progression (e.g., toxicity) should continue to 
undergo scheduled tumor assessments as if they were on the protocol schedule until the patient dies, experiences disease progression per 
RECIST v1.1 and modified RECIST, withdraws consent, or until the study closes, whichever occurs first.  For patients who will be permitted to 
continue study treatment beyond radiographic disease progression per RECIST v1.1, tumor assessment will be monitored with a follow-up 
scan at the next scheduled tumor assessment when the scan frequency is every 6 weeks.  If the scan frequency is every 12 weeks (see 
above), the follow-up scan must be performed at every 12 weeks (± 5 business days), or earlier if clinically indicated, until loss of clinical 
benefit described in Section 4.6.2 of the protocol or treatment discontinuation, whichever is later. 
 
 


 
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Appendix 2  
Schedule of Assessments (cont.)  
i A complete physical examination at screening and the end of treatment visit should include the evaluation of head, eye, ear, nose, and throat 
and cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, and neurologic systems.  Changes in abnormalities noted at 
baseline should be recorded at the end of treatment visit.  New or worsened abnormalities should be recorded as adverse events if 
appropriate. 
j 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. 
k Karnofsky performance status, limited physical examination may be obtained ≤ 96 hours prior to Day 1 of each cycle.  Local laboratory safety 
assessments may be obtained ≤ 96 hours prior to Day 1 and 22 of each cycle. 
l Vital signs include heart rate, respiratory rate, blood pressures, and temperature.  For the first atezolizumab infusion, the patient’s vital signs 
should be determined within 60 minutes before, during (every 15 [± 5] minutes), and 30 (± 10) minutes and 2 hours (± 15 minutes) after the 
infusion.  For subsequent atezolizumab infusions, vital signs will be collected within 60 minutes before the infusion, during the infusion if clinically 
indicated, and 1 hour (± 10 minutes) after the infusion.  Patients will be informed about the possibility of delayed post-infusion symptoms and 
instructed to contact their study physician if they develop such symptoms.  For patients randomized to Arm A, observation should be for at least 2 
hours after the first administration of the combination and for at least 1 hour for subsequent infusions.  
m Twelve-lead ECGs are required as part of the screening assessment and at the end of treatment visit.  ECGs will be reviewed by the 
investigator to determine patient eligibility at screening.  Baseline evaluation of LVEF should be considered for all patients, especially in those 
with cardiac risk factors and/or history of coronary artery disease.  In countries where additional cardiac monitoring is considered standard 
(e.g., France), additional cardiac monitoring including a 1) baseline evaluation of LVEF in those patients with cardiac risk factors and/or an 
abnormal baseline ECG and 2) for patients randomized to the sunitinib arm, a surveillance ECG on Day 22 of Cycle 1 will be required. 
n The dose of bevacizumab will be based on the patient’s weight (in kilograms) measured ≤ 14 days prior to baseline (Cycle 1, Day 1) and will 
remain the same throughout the study unless there is a weight change of > 10% from baseline.  
o Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with automated differential (neutrophils, lymphocytes, 
eosinophils, monocytes, basophils, and other cells), and platelet count.  A manual differential can be done if clinically indicated. 
p Serum chemistry includes BUN, creatinine, sodium, potassium, magnesium, chloride, bicarbonate, calcium, phosphorus, glucose, 
total bilirubin, ALT, AST, alkaline phosphatase, lactate dehydrogenase, total protein, and albumin.  In countries where serum bicarbonate is 
not considered a standard chemistry measurement (e.g., Japan), serum bicarbonate is not required as a laboratory study in the screening or 
on-study serum measurements. 
q Urine dipstick includes specific gravity, pH, glucose, protein, ketones, and blood.  Urine dipstick and 24-hour urine collection may be performed 
up to 7 days before Cycle 1, Day 1.  Screening urine tests performed up to 7 days before Cycle 1, Day 1 do not need to be repeated for 
Cycle 1.  Spot urine protein/creatinine ratio will not be used for this study.   
 
 


 
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Appendix 2  
Schedule of Assessments (cont.)  
r Serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and 
documented as negative within 7 days prior to Cycle 1, Day 1, every two cycles during the study treatment, and as clinically indicated 
thereafter.  In countries (e.g., United Kingdom) where urine pregnancy testing is considered a standard, urine pregnancy testing may substitute 
for serum pregnancy testing. 
s TSH, free T3, free T4, and serum ferritin, should be evaluated every two cycles (starting at Cycle 2). 
t Includes anti-nuclear antibody, anti−double-stranded DNA, circulating anti-neutrophil cytoplasmic antibody, and perinuclear anti−neutrophil 
cytoplasmic antibody.  If rescreening is required, auto-antibody testing may be performed within 60 days of Cycle 1, Day 1. 
u C-reactive protein and autoantibodies On Day 1 of Cycle 3 and every other cycle thereafter. 
v See Appendix 2 of the protocol for details of the ATA sampling schedule. 
w See Appendix 2 of the protocol for details of the PK sampling schedule. 
x See Appendix 2 of the protocol for details of the TBNK collection schedule.   
y See Appendix 2 of the protocol for details of the pharmacodynamic sampling schedule. 
z This is an optional sample and requires the patient to sign an RCR consent.  If sample is not taken during the Cycle 1, Day 1 visit, then the sample 
may be obtained at any other visit. 
aa 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.   
bb Tumor tissue (archival < 24 months or fresh) specimen may be obtained from prior tumor excision or biopsy performed during the course of 
the patient's illness. 
cc Tumor specimens are required at the time of disease progression per RECIST v1.1 (for patients in both treatment arms), preferably of a 
progression metastatic lesion, unless the location of the tumor renders the biopsy clinically unsafe or infeasible, or is prohibited by institution or 
country.  Optional tumor biopsies may be obtained at other timepoints at the investigator’s discretion. 
dd The ePRO questionnaires (MDASI, BFI, FSKI-19, and EQ-5D) will be completed by the patients on Days 1 and 22 of each cycle and at the 
end-of-treatment visit, and will be completed by patients at 6, 12, 24, and 36 weeks after the end-of-treatment visit.  In addition, the BFI ePRO 
questionnaire will be collected weekly during the first 12 weeks.  Assessments on days when the patient does not come to the clinic (e.g., Days 8, 
15, 29, 36) will be completed by the patient at home.  All ePRO questionnaires while on study treatments are required to be administered prior to 
administration of study treatment and/or prior to any other study assessment(s) to ensure that the validity of the instrument is not compromised 
and to ensure that data quality meets regulatory requirements.  


 
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Appendix 2  
Schedule of Assessments (cont.)  
ee During survival follow-up, the following information regarding all subsequent anti-neoplastic agents upon treatment discontinuation will be 
collected:  line of therapy, date of first dose of agent, date of last dose of agent (or if ongoing), patient's best response, and date of disease 
progression. 
 


 
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Appendix 2  
Schedule of Assessments (cont.)  
Anti-Therapeutic Antibody, TBNK, Biomarker, and Pharmacokinetic 
Sampling Schedule 
Study Visit 
Time 
Sample 
Cycle 1, 
Day 1  
Predose 
Atezolizumab ATA 
Bevacizumab ATA 
Atezolizumab pharmacokinetics 
Bevacizumab pharmacokinetics 
TBNK 
Biomarkers a 
30 (± 10) minutes 
after end of infusion c 
Atezolizumab pharmacokinetics 
Bevacizumab pharmacokinetics 
Cycle 1,  
Day 22  
Predose 
Biomarkers b  
Atezolizumab pharmacokinetics 
Cycles 2, 3, 4, and 8, 
and every eight 
cycles thereafter  
Day 1 (± 3 days) 
Predose 
Atezolizumab ATA (Cycles 2, 4, and 8, 
and every eight cycles thereafter) 
Bevacizumab ATA (Cycle 3 only) 
Atezolizumab pharmacokinetics (Cycles 
2, 4, and 8 and every eight cycles 
thereafter)  
Bevacizumab pharmacokinetics (Cycle 3 
only) 
Biomarkers b (Cycle 2 only) 
30 (± 10) minutes 
after end of infusion 
Bevacizumab pharmacokinetics (Cycle 3 
only) 
Cycles 2 and 4,  
Day 22 (± 3 days) 
Predose 
Atezolizumab pharmacokinetics  
Biomarker (Cycle 2 only) b 
At time of fresh 
biopsy (during 
treatment or at 
progression) 
 
TBNK 
Biomarkers b , d 
End of treatment visit 
At visit 
Atezolizumab ATA  
Atezolizumab pharmacokinetics 
Biomarkers b 
Bevacizumab ATA 
Bevacizumab pharmacokinetics 
120 (± 30) days after 
last dose of 
atezolizumab e 
At visit 
Atezolizumab ATA 
Atezolizumab pharmacokinetics 
Bevacizumab ATA 
Bevacizumab pharmacokinetics 


 
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Appendix 2  
Schedule of Assessments (cont.)  
ATA = anti-therapeutic antibody; TBNK = T, B, and natural killer. 
Note:  Plasma, serum, and whole blood collected for pharmacodynamic biomarkers. 
a Plasma, serum, and whole blood collected for pharmacodynamic biomarkers. 
b Plasma and serum for biomarkers. 
c For patients receiving both atezolizumab and bevacizumab (Arm A only), both 
postdose pharmacokinetic samples (for atezolizumab and bevacizumab) are to be 
drawn 30 minutes after the second (bevacizumab) infusion. 
d Biomarker samples at the time of biopsy do not have to be collected if the biopsy visit 
occurs ≤ 3 days before or after another protocol-defined biomarker sample collection 
timepoint. 
e Not required if the patient is lost to follow-up, withdraws request, or the study closes. 
 


Atezolizumab—F. Hoffmann-La Roche Ltd 
46/Statistical Analysis Plan WO29637 
Appendix 3  
Modified Response Evaluation Criteria in Solid Tumors 
Conventional response criteria may not be adequate to characterize the anti-tumor 
activity of immunotherapeutic agents like atezolizumab, which can produce delayed 
responses that may be preceded by initial apparent radiological progression, including 
the appearance of new lesions.  Therefore, modified response criteria have been 
developed that account for the possible appearance of new lesions and allow 
radiological progression to be confirmed at a subsequent assessment.  In this protocol, 
patients will be permitted to continue study treatment even after modified Response 
Evaluation Criteria in Solid Tumors (RECIST) criteria for progressive disease are met if 
the risk/benefit ratio is judged to be favorable.   
Modified RECIST is derived from RECIST, Version 1.1 conventions 1, 2, 3 and 
immune-related response criteria 3, 4, 5 (irRC).  
Modified RECIST and RECIST, Version 1.1:  Summary of Changes 
 
RECIST v1.1 
Modified RECIST 
New lesions after baseline Define progression. 
New measurable lesions are 
added into the total tumor 
burden and followed. 
Non-target lesions 
May contribute to the 
designation of overall 
progression 
Contribute only in the 
assessment of a complete 
response 
Radiographic progression 
First instance of ≥ 20% 
increase in the sum of 
diameters or unequivocal 
progression in non-target 
disease 
Determined only on the basis of 
measurable disease; may be 
confirmed by a consecutive 
assessment ≥ 4 weeks from the 
date first documented  
RECIST = Response Evaluation Criteria in Solid Tumors. 
 
                                              
1 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.  
2 Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti−PD-L1 
antibody in cancer. N Engl J Med 2012;366:2443−54. 
3 Wolchok JD,  Hoos A, O’Day S, et al. Guidelines for the evaluation of immunetherapy activity in 
solid tumors: immune-related response criteria Clin Can Res 2009;15:7412−20. 
4 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 Can 2014;2:17. 
5 Nishino M, Giobbie-Hurder A, Gargano M et al. Developing a common language for tumor 
response to immunotherapy: immune-related response criteria using unidimensional 
measurements. Clin Can Res 2013;19:3936−43. 


 
AtezolizumabF. Hoffmann-La Roche Ltd 
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Appendix 3  
Modified Response Evaluation Criteria in Solid Tumors (cont.) 
Definitions of Measurable/non-Measurable Lesions 
All measurable and non-measurable lesions should be assessed at screening and at the 
protocol-specified tumor assessment timepoints.  Additional assessments may be 
performed, as clinically indicated for suspicion of progression.  The investigator will 
evaluate response to treatment with use of modified RECIST. 
Measurable Lesions 
Tumor Lesions.  Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size 
as follows:  
10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval no greater than 5 mm) 
10-mm caliper measurement by clinical examination (lesions that cannot be accurately 
measured with calipers should be recorded as non-measurable) 
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 no greater than 5 mm).  At baseline and follow-up, 
only the short axis will be measured and followed.   
Non-Measurable Lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter < 10 mm or 
pathological lymph nodes with short axis ≥ 10 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 
Bone scan, positron emission tomography (PET) scan, or 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  


 
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Appendix 3  
Modified Response Evaluation Criteria in Solid Tumors (cont.) 
considered as 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 as malignant lesions (neither measurable nor non-measurable) because they 
are, by definition, simple cysts. 
Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above.  However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
Lesions with Prior Local Treatment 
Tumor lesions situated in a previously irradiated area or in an area subjected to other 
loco-regional therapy are usually not considered measurable unless there has been 
demonstrated progression in the lesion.  Study protocols should detail the conditions 
under which such lesions would be considered measurable. 
Tumor Response Evaluation 
Definitions of Target/Non-Target Lesions 
Target Lesions 
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only 
one or two organ sites involved, a maximum of two lesions (one site) and four lesions 
(two sites), respectively, will be recorded.  Other lesions (albeit measurable) in those 
organs will be recorded as non-measurable lesions (even if the size is > 10 mm by 
CT scan).   
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 because they are normal anatomical structures 
that may be visible by imaging even if not involved by tumor.  As noted above,  


 
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Appendix 3  
Modified Response Evaluation Criteria in Solid Tumors (cont.) 
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.  
Nodal size is normally reported as two dimensions in the plane in which the image is 
obtained (for CT, this is almost always the axial plane; for MRI, the plane of acquisition 
may be axial, sagittal, or coronal).  The smaller of these measures is the short axis.  For 
example, an abdominal node that is reported as being 20 mm × 30 mm has a short axis 
of 20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm 
should be recorded as the node measurement.  All other pathological nodes (those with 
short axis ≥ 10 mm 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.  
Lesions irradiated within 3 weeks prior to Cycle 1, Day 1 may not be counted as target 
lesions. 
Non-Target Lesions 
All other lesions (or sites of disease), 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”).  
After baseline, changes in non-target lesions will contribute only in the assessment 
of complete response (i.e., a complete response is attained only with the complete 
disappearance of all tumor lesions, including non-target lesions) and will not be used 
to assess progressive disease.  
Calculation of Sum of the Diameters  
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated as a measure of tumor burden.   
The sum of the diameters is calculated at baseline and at each tumor assessment for 
the purpose of classification of tumor responses. 
Sum of the Diameters at Baseline:  The sum of the diameters for all target lesions 
identified at baseline prior to treatment on Day 1. 
 


 
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Appendix 3  
Modified Response Evaluation Criteria in Solid Tumors (cont.) 
Sum of the Diameters at Tumor Assessment:  For every on-study tumor assessment 
collected per protocol or as clinically indicated, the sum of the diameters at tumor 
assessment will be calculated using tumor imaging scans.  All target lesions and all new 
measurable lesions that have emerged after baseline will contribute to the sum of the 
diameters at tumor assessment.  Hence, each net percentage change in tumor burden 
per assessment with use of modified RECIST accounts for the size and growth kinetics 
of both old and new lesions as they appear. 
Response Criteria 
Evaluation of Target Lesions 
Complete Response (CR):  Disappearance of all target lesions.  Lymph nodes that 
shrink to < 10 mm short axis are considered normal. 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of all 
target and all new measurable lesions, taking as reference the baseline sum of 
diameters, in the absence of CR. 
Note:  The appearance of new measurable lesions is factored into the overall tumor 
burden but does not automatically qualify as progressive disease until the sum of the 
diameters increases by ≥ 20% when compared with the sum of the diameters at nadir. 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum of the diameters while in 
the study. 
Progressive Disease (PD):  At least a 20% increase in the sum of diameters of all 
target and all new measurable lesions, taking as reference the smallest sum on study 
(this includes the baseline sum if that is the smallest on study).  In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.  
Impact of New Lesions on Modified RECIST 
New lesions alone do not qualify as progressive disease.  However, their contribution 
to total tumor burden is included in the sum of the diameters, which is used to determine 
the overall modified RECIST tumor response.  
Evaluation of Best Overall Response with Use of Modified RECIST 
Timepoint Response 
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline. 


 
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Appendix 3  
Modified Response Evaluation Criteria in Solid Tumors (cont.) 
Missing Assessments and Inevaluable Designation 
When no imaging/measurement is done at all at a particular timepoint, the patient is 
not evaluable (NE) at that timepoint.  If only a subset of lesion measurements are made 
at an assessment, usually the case is also considered NE at that timepoint, unless a 
convincing argument can be made that the contribution of the individual missing lesion(s) 
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 three 
measured lesions and at follow-up only two lesions were assessed but those gave a 
sum of 80 mm, the patient will have achieved PD status, regardless of the contribution of 
the missing lesion. 
 


 
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Appendix 3  
Modified Response Evaluation Criteria in Solid Tumors (cont.) 
Table 1 
Modified RECIST Timepoint Response Definitions 
% Change in 
Sum of the 
Diameters 
(Including 
Measurable 
New Lesions 
When Present) 
Target 
Lesion 
Definition 
Non-Target 
Lesion 
Definition 
New 
Measurable 
Lesions 
New 
Unmeasurable 
Lesions 
Overall 
Modified 
RECIST 
Timepoint 
Response 
− 100% a 
CR 
CR 
No 
No 
CR 
− 100% a 
CR 
Non-CR or not 
all evaluated 
No 
No 
PR 
≤ − 30% 
PR 
Any 
Yes or No 
Yes or No 
PR 
> − 30% to 
< + 20% 
SD 
Any 
Yes or No 
Yes or No 
SD 
Not all 
evaluated 
Not 
evaluated 
Any 
Yes or No 
Yes or No 
NE 
≥ ± 20% 
PD 
Any 
Yes or No 
Yes or No 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; 
RECIST = Response Evaluation Criteria in Solid Tumors; SD = stable disease. 
a When lymph nodes are included as target lesions, the % change in the sum of the diameters 
may not be 100% even if complete response criteria are met because a normal lymph node is 
defined as having a short axis of < 10 mm.  Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to < 10 mm in order to meet the definition of CR. 
 
Best Overall Response:  All Timepoints 
The best overall response is determined once all the data for the patient are known. 
The best overall response according to modified RECIST is interpreted as described 
below: 
CR:  Complete disappearance of all tumor lesions (target and non-target) and no new 
measurable or unmeasurable lesions, confirmed by a consecutive assessment 
≥ 4 weeks from the date first documented.  All lymph nodes short axes must be < 10 mm. 
PR:  Decrease in the sum of the diameters of all target and all new measurable lesions 
≥ 30% relative to baseline, in the absence of CR, confirmed by a consecutive 
assessment ≥ 4 weeks from the date first documented.   
SD:  Criteria for CR, PR, and PD are not met.  


 
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Appendix 3  
Modified Response Evaluation Criteria in Solid Tumors (cont.) 
PD:  Increase in the sum of the diameters of all target and all new measurable lesions 
≥ 20% relative to the nadir, which may be confirmed by a consecutive assessment 
≥ 4 weeks from the date first documented as follows:  
The confirmatory assessment shows an additional measurable increase in 
tumor burden as measured by the sum of the diameters of all target and all new 
measurable lesions. 
 
This protocol allows patients to continue to receive study treatment even after confirmed 
radiographic PD per modified RECIST and patients may achieve a best overall response 
of PR or CR based on tumor regression achieved at any time prior to study treatment 
discontinuation.