Clinical trial NCT02425891
Conditions: Triple Negative Breast Cancer
Sponsor: Hoffmann-La Roche
Start date: 2015-06-23; Completion date: 2021-08-31
Enrollment: 902 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This multicenter, randomized, double-blind study evaluated the efficacy, safety, and pharmacokinetics of atezolizumab (MPDL3280A) administered with nab-paclitaxel compared with placebo in combination with nab-paclitaxel in participants with locally advanced or metastatic triple-negative breast cancer (TNBC) who have not received prior systemic therapy for metastatic breast cancer (mBC). The safety of single-agent nab-paclitaxel has been determined in previous studies of participants with mBC and the safety data to date suggest that atezolizumab can be safely combined with standard chemotherapy agents.

Detailed description:

Arms: arm 1: Participants assigned to atezolizumab plus nab-paclitaxel received both agents until disease progression or unacceptable toxicity. arm 2: Participants assigned to placebo plus nab-paclitaxel received both agents until disease progression or unacceptable toxicity.
Interventions: intervention 1: Atezolizumab (MPDL3280A), an engineered anti-PDL1 antibody intervention 2: Nab-Paclitaxel intervention 3: Placebo
Intervention descriptions: intervention 1: Atezolizumab at a fixed dose of 840 milligrams via intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle until disease progression or unacceptable toxicity. intervention 2: Nab-Paclitaxel at a starting dose of 100 milligrams per square meter via IV infusion on Days 1, 8, and 15 of each 28-day cycle. Nab-Paclitaxel was administered for a target of at least 6 cycles, with no maximum in the absence of disease progression or unacceptable toxicity. intervention 3: Placebo administered via IV infusion on Days 1 and 15 of each 28-day cycle until disease progression or unacceptable toxicity.

Protocol documents:
Prot_000.pdf: 
 
Official Title: A Phase III, Multicenter, Randomized, Placebo-Controlled Study of 
Atezolizumab (Anti-PD-L1 Antibody) in Combination With Nab-
Paclitaxel Compared With Placebo With Nab-Paclitaxel for Patients 
With Previously Untreated Metastatic Triple-Negative Breast Cancer 
NCT Number: NCT02425891 
Document Date: Protocol Version 9: 31-January-2020 
 
 


FINAL 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 WO29522, Version 9
PROTOCOL
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED,
PLACEBO-CONTROLLED STUDY OF 
ATEZOLIZUMAB (ANTIPD-L1 ANTIBODY) IN 
COMBINATION WITH NAB-PACLITAXEL COMPARED 
WITH PLACEBO WITH NAB-PACLITAXEL FOR
PATIENTS WITH PREVIOUSLY UNTREATED 
METASTATIC TRIPLE-NEGATIVE BREAST CANCER
PROTOCOL NUMBER:
WO29522
VERSION NUMBER:
9
EUDRACT NUMBER:
2014-005490-37
IND NUMBER:
123,277
TEST PRODUCT:
Atezolizumab
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
14 January 2015
DATES AMENDED:
Version 2 (UK only):  5 May 2015
Version 2 (Germany only):  22 May 2015
Version 3 (Global):  3 August 2015
Version 4:  20 November 2015
Version 4 (France only):  7 June 2016
Version 5 (France only):  7 September 2016
Version 5 (Global):  7 September 2016
Version 6 (France):  27 October 2017
Version 7 (Global):  2 March 2018
Version 8 (Global): 28 September 2018
Version 9 (Global):  See electronic date stamp below.
 
31-Jan-2020 18:20:26
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Atezolizumab—F. Hoffmann-La Roche Ltd
2/Protocol WO29522, Version 9
PROTOCOL AMENDMENT, VERSION 9
RATIONALE
Protocol WO29522 has been amended to align with Investigator’s Brochure, version 15,
and with the nab-paclitaxel (Abraxane®) prescribing information.  Changes to the 
protocol, along with a rationale for each change, are summarized below:

Background information on atezolizumab has been updated to account for additional 
approved indications (Section 1.2).

To align with the Atezolizumab Investigator's Brochure, Version 15, 
"immune-related" has been changed to "immune-mediated" when describing events 
associated with atezolizumab (Sections 1.2.2.2, 5.1.1, and 5.1.6 and Appendix 10).

The list of atezolizumab risks has been updated to include myositis for 
consistency with the list of identified risks in the Atezolizumab Investigator's 
Brochure (Section 5.1.1), and guidelines for managing patients who experience 
atezolizumab-associated adverse events have been revised to include myositis 
(Appendix 10).
To align with the nab-paclitaxel (Abraxane®) prescribing information (SmPC), the 
risk of tumour lysis syndrome has been included (Section 5.1.2).

To address a request by the French National Agency for the Safety of Medicines 
and Health Products (ANSM), systemic immune activation has been replaced by 
hemophagocytic lymphohistiocytosis and macrophage activation syndrome in the 
list of potential risks for atezolizumab (Section 5.1.1) and the management 
guidelines for systemic immune activation have been replaced with management 
guidelines for hemophagocytic lymphohistiocytosis and macrophage activation 
syndrome (Appendix 10).  As a result, Section 5.1.6.1 Systemic Immune Activation 
has been deleted.

Section 5.4.3 on reporting requirements for pregnancy has been updated with 
clarified definitions of spontaneous versus elective abortions.

The reference document for the expectedness of adverse event assessement for 
nab–paclitaxel has been specified. (Summary of Product Characteristics) 
(Section 5.7) 

To address a request by the French ANSM, the atezolizumab adverse event 
management guidelines have been updated to add laboratory (e.g., B-type 
natriuretic peptide) and cardiac imaging abnormalities as signs or symptoms that 
are suggestive of myocarditis (Appendix 10).

The Medical Monitor name and associated contact information has been updated 
throughout the document.
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


Atezolizumab—F. Hoffmann-La Roche Ltd
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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 11
PROTOCOL SYNOPSIS ................................................................................... 12
1.
BACKGROUND .......................................................................................... 24
1.1
Background on Breast Cancer............................................... 24
1.1.1
Triple-Negative Breast Cancer .............................................. 24
1.1.2
Taxanes and nab-Paclitaxel in Breast Cancer....................... 25
1.2
Background on Atezolizumab................................................ 26
1.2.1
Summary of Nonclinical Studies............................................ 26
1.2.2
Clinical Experience with Atezolizumab .................................. 27
1.2.2.1
Ongoing Clinical Studies........................................................ 27
1.2.2.2
Clinical Safety as a Single Agent........................................... 27
1.2.2.3
Clinical Safety in Combination with 
Chemotherapy....................................................................... 28
1.2.3
Clinical Activity....................................................................... 29
1.2.4
Clinical Pharmacokinetics and Immunogenicity..................... 31
1.2.5
Rationale for Atezolizumab Dosage ...................................... 31
1.3
Study Rationale and Benefit-Risk Assessment...................... 32
1.3.1
Atezolizumab......................................................................... 32
1.3.2
nab-Paclitaxel and Combination Treatment with 
Atezolizumab......................................................................... 33
2.
OBJECTIVES.............................................................................................. 34
2.1
Efficacy Objectives ................................................................ 34
2.1.1
Co-Primary Efficacy Objectives ............................................. 34
2.1.2
Secondary Efficacy Objectives .............................................. 35
2.2
Safety Objectives................................................................... 35
2.3
Pharmacokinetic Objectives .................................................. 35
2.4
Exploratory Objectives........................................................... 35
3.
STUDY DESIGN......................................................................................... 36
3.1
Description of Study .............................................................. 36
3.1.1
Independent Data Monitoring Committee .............................. 38
3.2
End of Study.......................................................................... 39


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3.3
Rationale for Study Design.................................................... 39
3.3.1
Rationale for Atezolizumab Dosage ...................................... 39
3.3.2
Rationale for Use of nab-Paclitaxel Comparator.................... 39
3.3.3
Rationale for nab-Paclitaxel Dosage and 
Regimen ................................................................................ 40
3.3.4
Rationale for Collection of Archival and Pre-
Treatment Tumor Specimens ................................................ 41
3.3.5
Rationale for the Collection of Biopsy at the Time 
of Radiographic Progression ................................................. 42
3.3.6
Rationale for Optional Biopsies ............................................. 42
3.3.7
Rationale for Blood Sampling for Biomarkers........................ 42
3.3.8
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 43
3.4
Outcome Measures ............................................................... 43
3.4.1
Efficacy Outcome Measures.................................................. 43
3.4.1.1
Co-Primary Efficacy Outcome Measures............................... 43
3.4.1.2
Secondary Efficacy Outcome Measures................................ 43
3.4.2
Safety Outcome Measures .................................................... 44
3.4.3
Pharmacokinetic Outcome Measures.................................... 44
3.4.4
Exploratory Outcome Measures ............................................ 44
4.
MATERIALS AND METHODS .................................................................... 44
4.1
Patients.................................................................................. 44
4.1.1
Inclusion Criteria.................................................................... 45
4.1.2
Exclusion Criteria................................................................... 47
4.1.2.1
Cancer-Specific Exclusion Criteria ........................................ 47
4.1.2.2
General Medical Exclusion Criteria........................................ 49
4.1.2.3
Exclusion Criteria Related to Atezolizumab........................... 49
4.2
Method of Treatment Assignment and Blinding..................... 51
4.2.1
Unblinding.............................................................................. 52
4.3
Study Treatment.................................................................... 52
4.3.1
Formulation, Packaging, and Handling.................................. 52
4.3.1.1
Atezolizumab/Placebo ........................................................... 52
4.3.1.2
nab-Paclitaxel........................................................................ 53
4.3.2
Dosage, Administration, and Compliance.............................. 53


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4.3.2.1
Atezolizumab or Placebo....................................................... 53
4.3.2.2
nab-Paclitaxel........................................................................ 54
4.3.3
Investigational Medicinal Product Accountability ................... 55
4.3.4
Post-Study Access to Atezolizumab ...................................... 55
4.4
Concomitant Therapy ............................................................ 56
4.4.1
Permitted Therapy................................................................. 56
4.4.2
Excluded and Cautionary Therapy ........................................ 57
4.4.3
Concomitant Medications with nab-Paclitaxel........................ 58
4.5
Study Assessments ............................................................... 58
4.5.1
Informed Consent Forms and Screening Log........................ 59
4.5.2
Description of Study Assessments ........................................ 59
4.5.2.1
Medical History and Demographic Data ................................ 59
4.5.2.2
Physical Examinations........................................................... 59
4.5.2.3
Vital Signs.............................................................................. 59
4.5.2.4
Tumor and Response Evaluations......................................... 60
4.5.2.5
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 61
4.5.3
Anti-Therapeutic Antibody Testing......................................... 64
4.5.4
Electrocardiograms and Cardiac Function 
Assessment........................................................................... 64
4.5.5
Patient-Reported Outcomes .................................................. 64
4.5.6
Samples for Roche Clinical Repository.................................. 66
4.5.6.1
Overview of the Roche Clinical Repository............................ 66
4.5.6.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 66
4.5.6.3
Sample Collection.................................................................. 66
4.5.6.4
Confidentiality........................................................................ 67
4.5.6.5
Consent to Participate in the Roche Clinical 
Repository ............................................................................. 68
4.5.6.6
Withdrawal from the Roche Clinical Repository..................... 68
4.5.6.7
Monitoring and Oversight....................................................... 68
4.6
Patient, Study, and Site Discontinuation................................ 69
4.6.1
Patient Discontinuation.......................................................... 69
4.6.1.1
Discontinuation from Study Drug........................................... 69


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4.6.2
Study and Site Discontinuation.............................................. 69
5.
ASSESSMENT OF SAFETY....................................................................... 70
5.1
Safety Plan ............................................................................ 70
5.1.1
Risks Associated with Atezolizumab ..................................... 70
5.1.2
Risks Associated with nab-Paclitaxel .................................... 71
5.1.3
General Plan to Manage Safety Concerns ............................ 71
5.1.3.1
Eligibility Criteria .................................................................... 71
5.1.3.2
Monitoring.............................................................................. 71
5.1.4
Dose Modification.................................................................. 72
5.1.4.1
General Notes Regarding Dose Modification......................... 72
5.1.5
Atezolizumab/Placebo Dose Modification.............................. 73
5.1.6
Management of Atezolizumab/Placebo-Specific 
Adverse Events ..................................................................... 73
5.1.7
nab-Paclitaxel Dose Modification and 
Management of Specific Adverse Events .............................. 74
5.1.7.1
Hematologic Toxicity ............................................................. 74
5.1.7.2
Gastrointestinal Toxicity......................................................... 75
5.1.7.3
Neurological Toxicity ............................................................. 76
5.1.7.4
Hepatic Toxicity ..................................................................... 76
5.1.7.5
Pulmonary events/Pneumonitis:  
Atezolizumab/Placebo and nab-Paclitaxel............................. 77
5.1.7.6
Other Toxicities...................................................................... 78
5.2
Safety Parameters and Definitions ........................................ 79
5.2.1
Adverse Events ..................................................................... 79
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 80
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 80
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 81
5.3.1
Adverse Event Reporting Period ........................................... 81
5.3.2
Eliciting Adverse Event Information....................................... 82
5.3.3
Assessment of Severity of Adverse Events ........................... 82
5.3.4
Assessment of Causality of Adverse Events ......................... 83


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5.3.5
Procedures for Recording Adverse Events............................ 83
5.3.5.1
Infusion-Related Reactions.................................................... 83
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 83
5.3.5.3
Adverse Events Occurring Secondary to Other 
Events.................................................................................... 84
5.3.5.4
Persistent or Recurrent Adverse Events................................ 84
5.3.5.5
Abnormal Laboratory Values ................................................. 84
5.3.5.6
Abnormal Liver Function Tests.............................................. 85
5.3.5.7
Abnormal Vital Sign Values ................................................... 86
5.3.5.8
Deaths ................................................................................... 86
5.3.5.9
Preexisting Medical Conditions.............................................. 87
5.3.5.10
Lack of Efficacy or Worsening of Breast Cancer ................... 87
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 87
5.3.5.12
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 88
5.3.5.13
Patient-Reported Outcome Data ........................................... 88
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 88
5.4.1
Emergency Medical Contacts................................................ 89
5.4.2
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest...................................................................... 89
5.4.2.1
Events that Occur Prior to Study Drug Initiation .................... 89
5.4.2.2
Events that Occur After Study Drug Initiation ........................ 90
5.4.3
Reporting Requirements for Pregnancies.............................. 90
5.4.3.1
Pregnancies in Female Patients............................................ 90
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 90
5.4.3.3
Abortions ............................................................................... 91
5.4.3.4
Congenital Anomalies/Birth Defects ...................................... 91
5.5
Follow-Up of Patients after Adverse Events .......................... 91
5.5.1
Investigator Follow-Up........................................................... 91
5.5.2
Sponsor Follow-Up ................................................................ 92
5.6
Post-Treatment Adverse Events............................................ 92


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5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 93
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 93
6.1
Determination of Sample Size ............................................... 94
6.1.1
Type I Error Control............................................................... 94
6.1.2
Co-Primary Endpoint:  Progression-Free Survival................. 95
6.1.3
Co-Primary Endpoint:  Overall Survival ................................. 96
6.2
Summaries of Conduct of Study............................................ 97
6.3
Summaries of Treatment Group Comparability ..................... 97
6.4
Efficacy Analyses .................................................................. 97
6.4.1
Co-Primary Efficacy Endpoints.............................................. 97
6.4.1.1
Progression-Free Survival ..................................................... 97
6.4.1.2
Overall Survival ..................................................................... 98
6.4.2
Secondary Efficacy Endpoints............................................... 98
6.4.2.1
Objective Response Rate...................................................... 98
6.4.2.2
Duration of Objective Response............................................ 99
6.4.2.3
Time to Deterioration in Global Health Status........................ 99
6.4.3
Handling of Missing Data....................................................... 99
6.5
Safety Analyses..................................................................... 99
6.6
Pharmacokinetic Analyses................................................... 100
6.7
Patient-Reported Outcome Analyses .................................. 100
6.7.1
Analysis of Time to Deterioration in Global Heath 
Status .................................................................................. 100
6.7.2
Exploratory Patient-Reported Outcomes 
Analyses.............................................................................. 101
6.7.2.1
Health Economic Data......................................................... 101
6.8
Exploratory Analyses........................................................... 102
6.8.1
Subgroup Analyses ............................................................. 102
6.8.2
Exploratory Biomarker Analysis........................................... 102
6.9
Interim Analyses .................................................................. 102
6.9.1
Progression-Free Survival ................................................... 102
6.9.2
Overall Survival ................................................................... 102
6.9.3
Safety Monitoring................................................................. 102


Atezolizumab—F. Hoffmann-La Roche Ltd 
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6.9.4 
Optional Interim Analysis ..................................................... 102 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 103 
7.1 
Data Quality Assurance ....................................................... 103 
7.2 
Electronic Case Report Forms ............................................. 103 
7.3 
Source Data Documentation ................................................ 104 
7.4 
Use of Computerized Systems ............................................ 104 
7.5 
Retention of Records ........................................................... 104 
8. 
ETHICAL CONSIDERATIONS .................................................................. 105 
8.1 
Compliance with Laws and Regulations .............................. 105 
8.2 
Informed Consent ................................................................ 105 
8.3 
Institutional Review Board or Ethics Committee .................. 106 
8.4 
Confidentiality ...................................................................... 107 
8.5 
Financial Disclosure ............................................................ 107 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 107 
9.1 
Study Documentation .......................................................... 107 
9.2 
Protocol Deviations .............................................................. 108 
9.3 
Site Inspections ................................................................... 108 
9.4 
Administrative Structure ....................................................... 108 
9.5 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 108 
9.6 
Protocol Amendments ......................................................... 109 
10. REFERENCES ......................................................................................... 110 
 
 
LIST OF TABLES 
Table 1  
Administration of First and Subsequent Infusions of 
Atezolizumab/Placebo ................................................................ 54 
Table 2  
nab-Paclitaxel Permanent Dose Reductions for Hematologic 
Toxicity ........................................................................................ 75 
Table 3  
nab-Paclitaxel Dose Modification Based on Gastrointestinal 
Toxicities in the Preceding Cycle ................................................ 75 
Table 4  
nab-Paclitaxel Permanent Dose Reductions for Neurological 
Toxicity ........................................................................................ 76 


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Table 5  
nab-Paclitaxel Dose Modification for Hepatic Toxicity ................. 77 
Table 6  
Management Guidelines for Pulmonary Events, including 
Pneumonitis:  Atezolizumab/Placebo and nab-Paclitaxel, or 
nab-Paclitaxel Alone ................................................................... 78 
Table 7  
nab-Paclitaxel Permanent Dose Reductions for Non-
Hematologic, Non-GI, Non-Neurologic, and Non-Hepatic, 
Toxicity ........................................................................................ 79 
Table 8  
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 82 
 
 
LIST OF FIGURES 
Figure 1  
Study Schema ............................................................................. 36 
Figure 2  
Overview of the Type I Error Control ........................................... 95 
 
 
LIST OF APPENDICES 
Appendix 1  Schedule of Assessments ......................................................... 115 
Appendix 2  Anti-Therapeutic Antibody, Pharmacodynamic, 
and Pharmacokinetic Sampling Schedule ................................. 121 
Appendix 3  Response Evaluation Criteria in Solid Tumors:  Modified 
Excerpt from Original Publication .............................................. 122 
Appendix 4  Patient-Reported Outcome Instruments .................................... 134 
Appendix 5  Preexisting Autoimmune Diseases ........................................... 140 
Appendix 6  Anaphylaxis Precautions ........................................................... 141 
Appendix 7  Eastern Cooperative Oncology Group (ECOG) Performance 
Status Scale .............................................................................. 142 
Appendix 8  Patient Eligibility per Archival and Fresh Tumor Tissue 
Quantity and Histology .............................................................. 143 
Appendix 9  Interim and Final Analyses for Overall Survival ......................... 144 
Appendix 10 Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab ............................................................................ 146 


Atezolizumab—F. Hoffmann-La Roche Ltd
11/Protocol WO29522, Version 9
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED,
PLACEBO-CONTROLLED STUDY OF 
ATEZOLIZUMAB (ANTIPD-L1 ANTIBODY) IN 
COMBINATION WITH NAB-PACLITAXEL COMPARED
WITH PLACEBO WITH NAB-PACLITAXEL FOR 
PATIENTS WITH PREVIOUSLY UNTREATED 
METASTATIC TRIPLE-NEGATIVE BREAST CANCER
PROTOCOL NUMBER:
WO29522
VERSION NUMBER:
9
EUDRACT NUMBER:
2014-005490-37
IND NUMBER:
123,277
TEST PRODUCT:
Atezolizumab
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name (print)
Principal Investigator’s Signature
Date
Please return the signed original of this form to the Sponsors or their designee. Contact 
details will be provided to the investigator prior to study start.  Please retain a copy for 
your study files.


Atezolizumab—F. Hoffmann-La Roche Ltd
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PROTOCOL SYNOPSIS
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, PLACEBO-
CONTROLLED STUDY OF ATEZOLIZUMAB (ANTIPD-L1 
ANTIBODY) IN COMBINATION WITH NAB-PACLITAXEL 
COMPARED WITH PLACEBO WITH NAB-PACLITAXEL FOR 
PATIENTS WITH PREVIOUSLY UNTREATED METASTATIC 
TRIPLE-NEGATIVE BREAST CANCER
PROTOCOL NUMBER:
WO29522
VERSION NUMBER:
9
EUDRACT NUMBER:
2014-005490-37
IND NUMBER:
123,277
TEST PRODUCT:
Atezolizumab
PHASE:
III
INDICATION:
Triple-negative breast cancer (TNBC)
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy, safety, and pharmacokinetics of atezolizumab with 
nab-paclitaxel compared with placebo with nab-paclitaxel in patients with metastatic or locally 
advanced triple-negative adenocarcinoma of the breast who have not received prior systemic 
therapy for metastatic breast cancer (mBC).  Specific objectives and corresponding endpoints 
for the study are outlined below.
Efficacy Objectives
The following efficacy objectives will be evaluated in both the intent-to-treat (ITT) population (i.e., 
all randomized patients) and the subpopulation with programmed deathligand 1 
(PD-L1)selected tumor status.
The co-primary efficacy objectives for this study are as follows:

To evaluate the efficacy of atezolizumab nab-paclitaxel compared with 
placebonab-paclitaxel as measured by PFS

To evaluate the efficacy of atezolizumabnab-paclitaxel compared with 
placebonab-paclitaxel as measured by overall survival (OS)
The secondary efficacy objectives for this study are as follows:

To evaluate the efficacy of atezolizumabnab-paclitaxel compared with 
placebonab-paclitaxel as measured by objective response rate (ORR; per investigator 
assessment using RECIST v1.1)

To evaluate the efficacy of atezolizumabnab-paclitaxel compared with 
placebonab-paclitaxel as measured by duration of objective response (DOR; per 
investigator using RECIST v1.1) among patients with an objective response

To evaluate patient-reported outcomes (PROs) of health status/health-related quality of life 
(HRQoL) associated with atezolizumabnab-paclitaxel compared with 
placebonab-paclitaxel, as measured by the time to deterioration (TTD) in Items 29 and 
30 of the European Organisation for Research and Treatment of Cancer (EORTC) Quality 
of Life Questionnaire Core 30 (QLQ-C30)


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Safety Objectives
The safety objectives for this study are as follows:

To evaluate the safety and tolerability of atezolizumabnab-paclitaxel compared with 
placebonab-paclitaxel

To evaluate the incidence of anti-therapeutic antibodies (ATAs) against atezolizumab and to 
explore the potential relationship of the immunogenicity response with pharmacokinetics, 
pharmacodynamics, safety, and efficacy
Pharmacokinetic Objectives
The pharmacokinetic (PK) objectives for this study are as follows:

To characterize the pharmacokinetics of atezolizumab when administered with 
nab-paclitaxel

To characterize the pharmacokinetics of nab-paclitaxel when administered with 
atezolizumab
Exploratory Objectives 
The exploratory objectives for this study are as follows:

To evaluate PROs of function and disease/treatment-related symptoms associated with 
atezolizumabnab-paclitaxel compared with placebonab-paclitaxel, as measured by the 
EORTC QLQ-C30 and its breast cancer module (QLQ-BR23)

To evaluate health utility as measured by the EuroQoL 5 Dimension (EQ-5D-5L) 
questionnaire for health economic modeling of atezolizumabnab-paclitaxel compared with 
placebonab-paclitaxel

To assess predictive, prognostic, and pharmacodynamic (PD) exploratory biomarkers in 
archival and/or fresh tumor tissue and blood and their association with disease status 
and/or response to study treatment
Study Design
Description of Study
This is a Phase III, global, multicenter, double-blind, two-arm, randomized, placebo-controlled 
study designed to evaluate the efficacy and safety of atezolizumab administered with 
nab-paclitaxel compared with placebo in combination with nab-paclitaxel in patients with locally 
advanced or metastatic TNBC who have not received prior systemic therapy for mBC. 
Eligible patients will be randomized in a 1:1 ratio to receive atezolizumab (840 mg) or placebo 
IV infusions on Days 1 and 15 of every 28-day cycle plus nab-paclitaxel (100 mg/m2) 
administered via IV infusion on Days 1, 8, and 15 of every 28-day cycle.  Randomization will be 
stratified by the following three factors:  presence of liver metastases (yes vs. no); prior taxane 
treatment (yes vs. no); and tumor PD-L1 status (IC0 vs. IC1/2/3).
In the absence of disease progression or unacceptable toxicity, nab-paclitaxel will be 
administered for a target of at least 6 cycles, with no maximum.  nab-Paclitaxel and 
atezolizumab or placebo may be discontinued for toxicity independently of each other in the 
absence of disease progression.  The Sponsor, patients, and investigators will not be aware of 
each patient’s treatment assignment prior to unblinding.  Once treatment unblinding has 
occurred, investigators may request crossover to the atezolizumabnab-paclitaxel arm for 
patients who were randomized to the placebo nab-paclitaxel arm, who have not yet 
experienced disease progression, and who have not started any other systemic anti-cancer 
agents beyond those offered in this study.  Patients must still meet the safety-related eligibility 
criteria for the study prior to initiating atezolizumab.
In order to interrogate the mechanism of action of the drug combination in the tumor 
microenvironment and possible resistance mechanisms, tumor tissue may be optionally 
collected before dosing on Cycle 2, Day 1.  
To test the mechanisms of resistance to the drug combination in the tumor microenvironment, 
all patients will undergo a mandatory tumor biopsy collection (if clinically feasible) at first 


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evidence of radiographic disease progression per RECIST v1.1.  DNA sequencing of cancer-
related genes will be performed on these specimens by Foundation Medicine, Inc. (Cambridge, 
MA). The research report may be obtained by the Investigator, if desired, directly from 
Foundation Medicine, Inc. and will describe results from investigational tests that are not 
intended to be used to guide future treatment decisions.
Tumor assessments per RECIST v1.1 will be performed approximately every 8 weeks (1 week) 
for the first 12 months after Cycle 1, Day 1 and every 12 weeks (1 week) thereafter until 
disease progression or treatment discontinuation, whichever is later.  Tumor assessments will 
be performed on the specified schedule regardless of treatment delays.
Treatment will be discontinued upon radiographic disease progression per RECIST v1.1.  For 
equivocal findings of progression (e.g., very small or uncertain new lesions or lymph nodes; 
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. 
For estimation of PFS, ORR, and DOR, tumor response will be based on RECIST v1.1.  The 
imaging data used for tumor assessment will be collected by the Sponsor to enable centralized, 
independent review of response endpoints by an Independent Review Committee (IRC) in the 
future, if necessary.
All patients will be followed for survival approximately every 3 months after the treatment 
discontinuation visit until death, withdrawal of consent, loss to follow-up, or study termination by 
the Sponsor.  In addition, information regarding use of subsequent anti-cancer agents for 
metastatic TNBC during the survival follow-up period will be collected.
The pharmacokinetics of atezolizumab and nab-paclitaxel will be determined.
Safety assessments will include the incidence, nature, and severity of adverse events and 
laboratory abnormalities graded per 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 pharmacokinetics and to detect the presence of antibodies to 
atezolizumab.  Patient samples, including tumor tissues, as well as serum and plasma and 
whole blood, will be collected for exploratory biomarker assessments.
Number of Patients
Up to 900 patients will be enrolled at approximately 257 sites globally.
Target Population
Patients with metastatic or locally advanced TNBC who have not received prior systemic 
cytotoxic therapy for mBC may be eligible for this study.  Locally advanced disease must not be 
amenable to resection with curative intent.  Patients may have received prior chemotherapy in 
the neoadjuvant/adjuvant setting if treatment was completed 12 months prior to randomization.  
Patients must comply with all eligibility criteria to be enrolled.
Inclusion Criteria
Patients must meet all of the following criteria to be eligible for study entry:

Signed Informed Consent Form

Women or men aged 18 years

Metastatic or locally advanced, histologically documented TNBC (absence of HER2, ER, 
and PR expression)
HER2 negativity is defined as either of the following by local laboratory assessment:
In situ hybridization (ISH) non-amplified (ratio of HER2 to CEP17 2.0 or single 
probe average HER2 gene copy number 4 signals/cell), or
IHC 0 or IHC 1+ (if more than one test result is available and not all results meet 
the inclusion criterion definition, all results should be discussed with the Medical 
Monitor to establish eligibility of the patient)
ER and PR negativity are defined as 1% of cells expressing hormonal receptors via 
IHC analysis.

No prior chemotherapy or targeted systemic therapy for inoperable locally advanced or 
metastatic TNBC 


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Radiation therapy for metastatic disease is permitted.  There is no required minimum 
washout period for radiation therapy.  Patients should be recovered from the effects of 
radiation.
Prior chemotherapy (including taxanes) in the neoadjuvant or adjuvant setting is 
allowable if treatment was completed 12 months prior to randomization.

Eligible for taxane monotherapy (i.e., absence of rapid clinical progression, life-threatening 
visceral metastases, or the need for rapid symptom and/or disease control)

Representative FFPE tumor specimens (either an archival specimen or fresh pre-treatment 
tissue from relapsed disease) in paraffin blocks (preferred) or at least 15 unstained slides, 
with an associated pathology report documenting ER, PR, and HER2 negativity 
Patients with fewer than 20 unstained slides available at baseline (but no fewer than 
12) may be eligible upon discussion with the Medical Monitor.
Tumor tissue should be of good quality based on total and viable tumor content and 
must be evaluated for PD-L1 expression prior to enrollment.  Patients whose tumor 
tissue is not evaluable for PD-L1 expression are not eligible.  
If multiple tumor specimens are submitted (e.g., an archival specimen and tissue from 
relapsed disease), patients may be eligible if at least one specimen is evaluable for 
PD-L1.  For the purpose of stratification, the PD-L1 score of the patient will be the 
maximum PD-L1 score among the samples.
A tumor specimen obtained from relapsed metastatic or locally advanced disease 
(if applicable) must also be submitted, if clinically feasible. 
Acceptable samples include core needle biopsies for deep tumor tissue (minimum 
three cores) or excisional, incisional, punch, or forceps biopsies for cutaneous, 
subcutaneous, or mucosal lesions.
FFPE tumor specimens in paraffin blocks are preferred
Fine-needle aspiration, brushing, cell pellet from pleural effusion, bone 
metastases, and lavage samples are not acceptable.  
Tumor tissue from bone metastases is not evaluable for PD-L1 expression and is 
therefore not acceptable.

ECOG performance status of 0 or 1

Life expectancy 12 weeks

Measurable disease, as defined by RECIST v1.1
Previously irradiated lesions can be considered as measurable disease only if disease 
progression has been unequivocally documented at that site since radiation. 

Adequate hematologic and end-organ function, defined by the following laboratory results 
obtained within 14 days prior to the first study treatment (Cycle 1, Day 1):
ANC 1500 cells/L (without granulocyte colony-stimulating factor [G-CSF] support 
within 2 weeks prior to Cycle 1, Day 1)
Lymphocyte count 500/L
Platelet count 100,000/L (without transfusion within 2 weeks prior to Cycle 1, Day 1)
Hemoglobin 9.0 g/dL
Patients may be transfused or receive erythropoietic treatment to meet this 
criterion.
AST, ALT, and alkaline phosphatase 2.5the upper limit of normal (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 1.25ULN
Patients with known Gilbert disease who have serum bilirubin level 3ULN may 
be enrolled.


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INR and aPTT 1.5ULN
This applies only to patients who are not receiving therapeutic anticoagulation; 
patients receiving therapeutic anticoagulation should be on a stable dose.
Calculated creatinine clearance 30 mL/min

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 5 months after the last dose of 
atezolizumab/placebo or 1 month after the last dose of nab-paclitaxel, whichever is later.
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 (IUDs), and copper IUDs.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical study 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 or pregnant female partners, men must 
remain abstinent or use a condom during the treatment period and for at least 6 months 
after the last dose of nab-paclitaxel.  Men must refrain from donating sperm during this 
same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical study 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.

Women who are not postmenopausal (12 months of nontherapy-induced amenorrhea) or 
surgically sterile must have a negative serum pregnancy test result within 14 days prior to 
initiation of study drug
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
Cancer-Specific Exclusion Criteria

Spinal cord compression not definitively treated with surgery and/or radiation, or previously 
diagnosed and treated spinal cord compression without evidence that disease has been 
clinically stable for 2 weeks prior to randomization

Known CNS disease, except for treated asymptomatic CNS metastases, provided all of the 
following criteria are met:
Only supratentorial and cerebellar metastases allowed (i.e., no metastases to midbrain,
pons, medulla, or spinal cord)
No ongoing requirement for corticosteroids as therapy for CNS disease 
No stereotactic radiation within 7 days or whole brain radiation within 14 days prior to 
randomization
No evidence of interim progression between the completion of CNS-directed therapy 
and the screening radiographic study
Note:  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, if all other criteria are met.

Leptomeningeal disease


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
Uncontrolled pleural effusion, pericardial effusion, or ascites 
Patients with indwelling catheters (e.g., PleurX) are allowed.

Uncontrolled tumor-related pain
Patients requiring narcotic pain medication must be on a stable regimen at study entry.
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to 
randomization.  Patients should be recovered from the effects of radiation.  There is no 
required minimum recovery period.
Asymptomatic metastatic lesions whose further growth would likely cause functional 
deficits or intractable pain (e.g., epidural metastasis that is not presently associated 
with spinal cord compression) should be considered for loco-regional therapy if 
appropriate prior to randomization.

Uncontrolled hypercalcemia (1.5 mmol/L ionized calcium or calcium 12 mg/dL or 
corrected serum calcium ULN) or symptomatic hypercalcemia requiring continued use of 
bisphosphonate therapy 
Patients who are receiving denosumab must discontinue denosumab use and replace 
it with a bisphosphonate instead while on study.  There is no required minimum 
washout period for denosumab. 
Patients who are receiving bisphosphonate therapy specifically to prevent skeletal 
events and who do not have a history of clinically significant hypercalcemia are eligible.

Malignancies other than TNBC within 5 years prior to randomization, with the exception of 
those with a negligible risk of metastasis or death and treated with expected curative 
outcome (such as adequately treated carcinoma in situ of the cervix or basal or squamous 
cell skin cancer)
General Medical Exclusion Criteria

Pregnancy or lactation

Evidence of significant uncontrolled concomitant disease that could affect compliance with 
the protocol or interpretation of results, including significant liver disease (such as cirrhosis, 
uncontrolled major seizure disorder, or superior vena cava syndrome)

Significant cardiovascular disease, such as New York Heart Association (NYHA) cardiac 
disease (Class II or greater), myocardial infarction within 3 months prior to randomization, 
unstable arrhythmias, or unstable angina
Patients with a known left ventricular ejection fraction (LVEF) 40% will be excluded.
Patients with known coronary artery disease, congestive heart failure not meeting the 
above criteria, or LVEF 50% must be on a stable medical regimen that is optimized in 
the opinion of the treating physician, in consultation with a cardiologist if appropriate.

Severe infection within 4 weeks prior to randomization, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia

Received 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.

Major surgical procedure within 28 days prior to randomization or anticipation of the 
need for a major surgical procedure during the course of the study other than for diagnosis
Placement of central venous access catheter(s) (e.g., port or similar) is not considered 
a major surgical procedure and is therefore permitted

Known hypersensitivity to nab-paclitaxel or to any of the excipients.
Exclusion Criteria Related to Atezolizumab

History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or
humanized antibodies or fusion proteins


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
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
Patients with a history of autoimmune-mediated hypothyroidism on a stable dose of 
thyroid replacement hormone are eligible for this study.
Patients with controlled Type 1 diabetes mellitus on a stable insulin dosing regimen are 
eligible for this study.
Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with dermatologic 
manifestations only (e.g., no psoriatic arthritis) are permitted provided that they meet 
the following conditions:
Rash must cover less than 10% of body surface area (BSA)
Disease is well controlled at baseline and only requiring low potency topical 
steroids
No acute exacerbations of underlying condition within the last 12 months (not 
requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids, 
biologic agents, oral calcineurin inhibitors, high potency or oral steroids)

Prior allogeneic stem cell or solid organ transplantation

History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, 
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or 
evidence of active pneumonitis on screening chest CT scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Positive test for HIV

Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test at 
screening) or hepatitis C 
Patients with past hepatitis B virus (HBV) infection or 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.
Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase 
chain reaction (PCR) is negative for HCV RNA.

Active tuberculosis

Receipt of a live, attenuated vaccine within 4 weeks prior to randomization or anticipation 
that such a live, attenuated vaccine will be required during the study
Patients must agree not to receive live, attenuated vaccine (e.g., FluMist) within 28 
days prior to randomization, during treatment, or within 5 months following the last 
dose of atezolizumab/placebo.

Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including 
antiCTLA-4, antiPD-1, or antiPD-L1 therapeutic antibodies

Treatment with systemic immunostimulatory agents (including but not limited to interferons 
or IL-2) within 4 weeks or five half-lives of the drug (whichever is shorter) prior to 
randomization

Treatment with systemic corticosteroids or other systemic immunosuppressive medications 
(including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, 
methotrexate, thalidomide, and antitumor necrosis factor [TNF] agents) within 2 weeks 
prior to randomization, or anticipated requirement for systemic immunosuppressive 
medications during the study
Patients who have received acute, low-dose, systemic immunosuppressant 
medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled in 
the study 


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Patients with a history of allergic reaction to IV contrast requiring steroid pre-treatment
should have baseline and subsequent tumor assessments performed using MRI.
The use of inhaled corticosteroids for chronic obstructive pulmonary disease,
mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and 
low-dose supplemental corticosteroids for adrenocortical insufficiency are allowed.
End of Study
The end of the study is expected to occur about 53 months after FPI when approximately the 
pre-planned number of deaths will have been observed. 
OS events will be monitored throughout the course of the study, and study timelines might be 
updated as indicated.
Length of Study
The end of the study is expected to occur about 53 months after FPI.
Investigational Medicinal Products
Test Products

Atezolizumab 840-mg flat dose or placebo administered via IV infusion on Day 1 and 
Day 15 of every 28-day cycle

nab-Paclitaxel 100 mg/m2 administered via IV infusion on Days 1, 8, and 15 of every 28-day 
cycle.  Doses of nab-paclitaxel should not be administered more frequently than every 
7 days.
Statistical Methods
Primary Analysis
Efficacy analyses will be performed separately for the ITT population and the PD-L1selected
subpopulation.
Progression-Free Survival
PFS is defined as the time from randomization to the occurrence of disease progression, as 
determined by investigators from tumor assessments per RECIST v1.1 or death from any cause, 
whichever occurs first.  PFS is simultaneously assessed in the ITT and PD-L1selected 
subgroup.
For United States registration 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.  Type I error control will 
be applied to this analysis of PFS.  The following analyses will be performed for both PFS
endpoints described above.  PFS will be compared between treatment arms with use of the 
stratified log-rank test.  The HR for disease progression or death 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 metastases (yes vs. no), prior taxane treatment (yes vs. no), and tumor PD-L1 status (IC0 
vs. IC1/2/3).  Results from an unstratified analysis will also be provided.  Kaplan-Meier 
methodology will be used to estimate the median PFS 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 for each treatment arm.
Overall Survival
OS is defined as the time from the date of randomization to the date of death from any cause.  
Testing of OS is outlined in the protocol and analysis of OS is performed analogously to PFS.
OS will be analyzed in a similar manner as PFS.
Determination of Sample Size
Up to 900 patients in total will be randomized into the study.


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Type I Error Control
The type I error () for this study is 0.05 (two-sided).  Type I error will be controlled for the 
following efficacy endpoints: 

Co-primary efficacy endpoint of investigator-assessed PFS by RECIST v1.1 (as defined for 
United States registrational purposes; ITT and PD-L1selected subgroups) 

Co-primary efficacy endpoint of OS (ITT and PD-L1selected subgroups)

Secondary efficacy endpoint: Investigator-assessed ORR by RECIST v1.1 (measurable 
disease population) 
Type I error will be controlled by comparing these endpoints between treatment arms according 
to the following testing procedure.
At the time of the analysis of PFS, the co-primary endpoints of PFS and OS and the secondary 
endpoint of ORR are tested in the ITT population and in the PD-L1selected subpopulation, as 
follows:
1.
(0.05) will be allocated between PFS (0.01) and OS (0.04).  The allocated type I error for 
PFS is further allocated to PFS in the ITT (0.005) and PFS in the PD-L1selected subgroup 
(0.005).
Testing of PFS and ORR
2.
Test the null hypothesis of no difference in PFS between the two arms using the stratified 
log-rank test in the ITT population and the PD-L1selected subgroup with the allocated type 
I error.
3.
If one or both of the null hypotheses from the step above is rejected, ORR will subsequently 
be compared between the two arms in the corresponding populations (one or both) using the 
stratified Cochran-Mantel-Haenszel test using a Type I error of 0.001 for each 
correspondingly.
Testing of OS
4.
At the time of the analysis of PFS, an interim analysis of OS in the ITT (OS [ITT]) will be 
performed.  The interim analysis of OS (ITT) will be performed regardless of the results of 
the analyses of PFS and ORR.  The interim analysis boundary for statistical significance will 
be determined based on the Lan-DeMets implementation of the O’Brien-Fleming use 
function according to the type I error allocated to the comparison of OS (ITT).  Allocation of 
the type I error to the comparison of OS (ITT) will depend on the outcome of the testing of 
PFS and ORR outlined in the Steps 13 above.  Details for the different type I error 
allocations to the OS (ITT) testing are provided in the protocol.
5.
If hypothesis of no difference in OS in the ITT population can be rejected, OS in the 
PD-L1selected subgroup will be compared by recycling the type I error used for OS (ITT) 
testing.  
Interim Analyses
There are no planned interim analyses of the co-primary endpoint of PFS.
Overall Survival
A total of three analyses of OS will be performed (two interim analyses and one final analysis).  
The timing and the two interim analyses and the final analysis for OS depends on the results of 
the definitive analysis of the co-primary endpoint PFS as well as the secondary endpoint ORR 
as described in the protocol, where the pre-specified boundaries for OS of all different scenarios 
are also presented.
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 use function.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
anti-HBc
antibody to hepatitis B core antigen
anti-HBs
antibody to hepatitis B surface antigen
ASCO
American Society of Clinical Oncology
ATA
anti-therapeutic antibody
CL
clearance
Cmax
maximum observed serum concentration
Cmin
minimum observed serum concentration
CR
complete response
CRC
colorectal cancer
CRP
C-reactive protein
CT
computed tomography
Ctrough
trough concentration
CYP
cytochrome P450
DLT
dose-limiting toxicity
DOR
duration of objective response
DRB
Data Review Board
EC
Ethics Committee
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EORTC
European Organisation for Research and Treatment of 
Cancer
ePRO
electronic patient-reported outcome
EQ-5D-5L
European Quality of Life 5 Dimension, 5-level version
ER
estrogen receptor
ESMO
European Society of Medical Oncology
FDA
U.S. Food and Drug Administration
FFPE
formalin-fixed paraffin-embedded
FOLFOX
oxaliplatin, leucovorin, and 5-fluorouracil
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HER2
human epidermal growth factor 2
HIPAA
Health Insurance Portability and Accountability Act
HR
hazard ratio


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Abbreviation
Definition
HRQoL
health-related quality of life
IC
tumor-infiltrating immune cell
ICH
International Conference on Harmonisation
iDCC
independent Data Coordinating Committee
iDMC
independent Data Monitoring Committee
IHC
immunohistochemistry
Ig
immunoglobulin
IL
interleukin
IMP
investigational medicinal product
IND
Investigational New Drug application
ISH
in situ hybridization
ITT
intent to treat
IV
intravenous
IxRS
interactive voice or Web response system
LFT
liver function test
LVEF
left ventricular ejection fraction
mBC
metastatic breast cancer
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCCN
National Comprehensive Cancer Network
NCI CTCAE v4.0
National Cancer Institute Common Terminology Criteria 
for Adverse Events, Version 4.0
NSCLC
nonsmall cell lung cancer
ORR
objective response rate
OS
overall survival
pCR
pathologic complete response
PCR
polymerase chain reaction
PD
pharmacodynamic
PD1
programmed death1
PDL1
programmed deathligand 1
PFS
progression-free survival
PK
pharmacokinetic
PR
progesterone receptor/partial response
PRO
patient-reported outcome
PVC
polyvinylchloride
q2w
every 2 weeks
q3w
every 3 weeks


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Abbreviation
Definition
QLQ-BR23
breast cancer module for QLQ-C30
QLQ-C30
Quality-of-Life Questionnaire Core 30
RCC
renal cell carcinoma
RCR
Roche Clinical Repository
RECIST
Response Evaluation Criteria in Solid Tumors
SAP
Statistical Analysis Plan
sb
solvent based
SD
stable disease
TIF
tumor interstitial fluid
TNBC
triple-negative breast cancer
TNF
tumor necrosis factor
TSH
thyroid-stimulating hormone
TTD
time to deterioration
ULN
upper limit of normal
Vss
volume of distribution at steady state


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1.
BACKGROUND
1.1
BACKGROUND ON BREAST CANCER
Globally, breast cancer is the second most common invasive malignancy and the most 
common cause of cancer-related mortality in women, with a 5-year survival rate 
following metastatic diagnosis of approximately15% (Jemal et al. 2011; Ferlay et al. 
2012).
The treatment algorithm for patients with metastatic breast cancer (mBC) is based on 
several factors that include clinical, pathologic, and histologic characteristics such as the 
presence or absence of human epidermal growth factor 2 (HER2) amplification; 
hormone receptor status; prior response to and/or failure of hormonal agents; number 
and specific sites of metastatic disease; and treatment history in both the metastatic and 
adjuvant settings. 
Several cytotoxic chemotherapy agents have shown activity in mBC, including 
anthracyclines, taxanes, gemcitabine, capecitabine, vinorelbine, eribulin, and 
ixabepilone. The response rates and progression-free intervals observed with these 
agents vary depending on the extent and type of prior therapy and extent of metastatic 
disease, as well as the biology of the disease. In general, anthracycline-based 
combination therapy and taxanes such as paclitaxel and docetaxel are believed to show 
the greatest activity (Piccart-Gebhart et al. 2008). Given the use of regimens containing 
anthracyclines in the adjuvant setting and the risk of cardiotoxicity associated with 
repeated courses, taxanes are now the most commonly used agent for patients with 
locally advanced or metastatic disease, particularly in the front-line setting
(Greene and Hennessy 2014).
1.1.1
Triple-Negative Breast Cancer
Triple-negative breast cancer (TNBC) may be simply defined by the absence of 
immunostaining for estrogen receptor (ER), progesterone receptor (PR), and HER2. 
Overall, approximately 15%20% of breast cancers are classified as TNBC. Large-scale 
comprehensive genomic analyses have characterized the heterogeneous nature of 
TNBCs and their diverse gene-expression patterns and underlying genomic changes, 
but these insights have not yet provided clear guidance for the identification of clinically 
effective targeted therapies currently under laboratory and clinical investigation. 
Unfortunately, TNBCs are more likely to have aggressive features, such as a high 
proliferative rate, and exhibit an invasive phenotype.  Patients with metastatic TNBCs 
exhibit a poor clinical outcome, generally with rapid progression and a median overall 
survival (OS) of less than 1 year (Rodler et al. 2010).
Although TNBC may respond to chemotherapy, including taxanes, there are no targeted 
therapies with widespread global approval available for patients with this specific 
subtype of breast cancer. Recent Phase II and III clinical studies in TNBC have been 
disappointing, with the failure of iniparib and targeted therapies in combination with 


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chemotherapy (Carey et al. 2012; O’Shaughnessy et al. 2014). There is a pressing 
need for clinically active agents for the triple-negative subtype of mBC.
1.1.2
Taxanes and nab-Paclitaxel in Breast Cancer
Taxane-based regimens are considered a standard of care in first-line therapy for 
patients with mBC, including TNBC (Cardoso et al. 2012). No standard approach exists 
for second or further-line treatment, and options for cytotoxic chemotherapy are the 
same as those for other subtypes. Single-agent cytotoxic chemotherapeutic agents are 
generally regarded as the primary option for patients with metastatic TNBC, although 
combination chemotherapy may be used when there is aggressive disease and visceral 
involvement.
The role of paclitaxel in the treatment of breast cancer has been well established.  
The response rates for paclitaxel administered as a single agent to patients with mBC 
are approximately 25% in first-line treatment (Wilson et al. 1994; Seidman et al. 1995; 
Nabholtz et al. 1996; Gradishar et al. 2005).
Nanoparticle albumin-bound (nab)-paclitaxel is an albumin-bound formulation of 
paclitaxel that was developed to avoid the toxicities associated with the vehicles that are 
necessary for parenteral administration of solvent-based (sb)-paclitaxel (polyethylated 
castor oil and polysorbate 80). nab-Paclitaxel has a shorter infusion time (30 minutes) 
than sb-paclitaxel and can be administered without steroid or antihistamine 
premedication. In addition, it has an advantageous PK profile compared with
sb-paclitaxel and achieves a 33% higher tumor uptake in preclinical models 
(Yardley et al. 2013). nab-Paclitaxel was approved for the treatment of mBC on the 
basis of a randomized Phase III study in which patients received either nab-paclitaxel or 
sb-paclitaxel (control) administered every 3 weeks (q3w) (n460; Gradishar et al. 2005). 
The primary efficacy endpoint of the study was response rate.  Patients receiving 
nab-paclitaxel achieved a higher response rate (21.5% vs. 11.1% for those receiving 
sb-paclitaxel). The median time to disease progression was longer for patients who 
received nab-paclitaxel than for those randomized to the sb-paclitaxel arm (23.0 vs.
16.9 weeks, respectively). Although a higher paclitaxel dose was achieved in the 
nab-paclitaxel arm, the incidence of Grade 4 neutropenia was significantly lower in the 
nab-paclitaxel arm than in the sb-paclitaxel (control) arm (9% vs. 22%, respectively). 
Grade 3 sensory neuropathy was more common with nab-paclitaxel than with 
sb-paclitaxel (10% vs. 2%, respectively) but was reported to be manageable and 
self-limiting with treatment interruption and dose reduction.
The pivotal study for nab-paclitaxel (Gradishar et al. 2005) enrolled patients who had not 
received a taxane for metastatic disease and who had not relapsed within 1 year of 
receiving a taxane for adjuvant disease. Forty-one percent (n186) of the patients in the
study received study drug as a first-line therapy. Among first-line patients, those who 
received nab-paclitaxel achieved a significantly higher response rate than those in the 
sb-paclitaxel group (34% vs. 18%, p0.013) (Abraxis BioScience, Inc. 2006; EMA 2007). 


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There was also a trend for prolonged progression-free survival (PFS) among first-line
patients in the experimental group, although this was not statistically significant (23.7 vs.
19.7 weeks, p0.173). There was no benefit in OS among first-line patients (71.0 vs. 
77.9 weeks, HR1.215, p0.264).
Based on the results of the pivotal study, nab-paclitaxel was approved for the treatment 
of mBC after failure of front-line combination chemotherapy for metastatic disease or 
relapse within 6 months of adjuvant chemotherapy.  Although it is not labeled for use in 
the front-line metastatic setting, National Comprehensive Cancer Network (NCCN) and 
European Society for Medical Oncology (ESMO) clinical practice guidelines include 
nab-paclitaxel as a standard of care that may be administered as a single agent to 
patients with recurrent or metastatic breast cancer (Cardoso et al. 2014; NCCN 2014; 
see Section 3.3.2).
1.2
BACKGROUND ON ATEZOLIZUMAB
Atezolizumab (TECENTRIQ, formerly known as MPDL3280A) is a humanized 
immunoglobulin IgG1 mAb 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 (asparagine to alanine) at position 298 on the heavy chain, which results in a 
non-glycosylated antibody that has minimal binding to Fc receptors and prevents 
Fc-effector function at expected concentrations in humans. Atezolizumab targets human 
programmed deathligand 1 (PD-L1) and inhibits its interaction with its receptors, 
programmed death1 (PD-1) and B7.1 (CD80, B7-1).  Both of these interactions are 
reported to provide inhibitory signals to T cells.
Atezolizumab is being investigated as a potential therapy against solid tumors and 
hematologic malignancies in humans.  Atezolizumab is approved for the treatment of 
urothelial carcinoma, nonsmall cell lung cancer, small-cell lung cancer, and TNBC.
1.2.1
Summary of Nonclinical Studies
The nonclinical strategy of the atezolizumab program was to demonstrate in vitro and 
in vivo activity, to determine in vivo pharmacokinetic (PK) behavior, to demonstrate an 
acceptable safety profile, and to identify a Phase I starting dose.  Comprehensive 
pharmacology, PK, and toxicology evaluations were, thus, undertaken with atezolizumab.
The safety, pharmacokinetics, and toxicokinetics of atezolizumab were investigated in 
mice and cynomolgus monkeys to support intravenous (IV) administration and to aid 
in projecting the appropriate starting dose in humans.  Given the similar binding of 
atezolizumab with cynomolgus monkey and human PD-L1, the cynomolgus monkey was 
selected as the primary and relevant nonclinical model for understanding the safety, 
pharmacokinetics, and toxicokinetics of atezolizumab. 


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Overall, the nonclinical pharmacokinetics and toxicokinetics observed for atezolizumab
supported entry into clinical studies, including providing adequate safety factors for the 
proposed Phase I starting doses.  The results of the toxicology program were consistent 
with the anticipated pharmacologic activity of downmodulating the PD-L1/PD-1 pathway 
and supported entry into clinical studies in patients.
Refer to the atezolizumab Investigator’s Brochure for details on the nonclinical studies.
1.2.2
Clinical Experience with Atezolizumab
1.2.2.1
Ongoing Clinical Studies
Atezolizumab is currently being tested in multiple Phase I, II, and III studies, both as 
monotherapy and in combination with several anti-cancer therapies (see the 
atezolizumab Investigator’s Brochure for study descriptions). Much of the safety and 
efficacy data summarized below are from Phase Ia Study PCD4989g, a multicenter, 
first-in-human, open-label, dose-escalation study evaluating the safety, tolerability, 
immunogenicity, pharmacokinetics, exploratory pharmacodynamics, and preliminary 
evidence of biologic activity of atezolizumab administered as a single agent by IV 
infusion q3w to patients with locally advanced or metastatic solid malignancies or 
hematologic malignancies.
1.2.2.2
Clinical Safety as a Single Agent
As of 15 December 2015, single-agent safety information was available for 629 
safety-evaluable patients enrolled in the Phase Ia Study PCD4989g from all lines of 
therapy, including for the following tumor types: NSCLC89, urothelial carcinoma95, renal 
cell carcinoma (RCC)72, TNBC111, and small-cell lung cancer17.  These 
safety-evaluable patients received a range of atezolizumab doses: mg/kg q3w9, 
3 mg/kg q3w3, 10 mg/kg q3w36, 15 mg/kg q3w236, 20 mg/kg q3w46, and 1200 mg 
q3w199. To date, no maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), or
clear dose-related trends in the incidence of adverse events have been determined.  
Adverse Events
Of the 629 treated patients in Study PCD4989g, 619 patients (98.4%) experienced an 
adverse event regardless of attribution to atezolizumab.  Treatment-related adverse 
events (per investigator’s assessment of causality) were reported in 444 patients 
(70.6%).  Approximately half of the 629 patients (50.2%) experienced an adverse event 
of Grade 34 in severity, based on the National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0).
The most frequently observed adverse events (10% of patients) included fatigue, 
decreased appetite, nausea, pyrexia, constipation, cough, dyspnea, diarrhea, headache, 
back pain, vomiting, anemia, arthralgia, rash, insomnia, asthenia, abdominal pain, chills, 
pruritus, generalized pain, and peripheral edema.


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Most of the Grade 34 adverse events occurred in 3 patients (0.5%).  Those that were 
reported in 10 patients (1.6%) included dyspnea (4.8%), anemia (4.6%), hyponatremia 
(3.8%), fatigue (3.2%), asthenia (2.5%), dehydration (2.4%), hyperglycemia, AST 
increased and abdominal pain (1.9% each), ALT increased (1.7%), and urinary tract 
infection (1.6%).  Related Grade 34 events were reported in 13.7% of patients, with 
fatigue and asthenia (1.3% each), AST increased and dyspnea (1.1% each), and 
hyponatremia (0.8%) as the most frequently occurring (0.8% or 5 patients).
Overall, atezolizumab as a single agent was well tolerated, with low rates of 
treatment-related Grade 34 events, Grade 5 events, treatment-related serious adverse 
events, and adverse events leading to treatment withdrawals.   Safety findings in the
TNBC cohort of Study PCD4989g are consistent with the data observed in the overall 
study population.
Refer to the Atezolizumab Investigator’s Brochure for additional details regarding clinical 
safety.
Immune-Mediated Adverse Events
Immune-mediated adverse events are consistent with the role of the PD-L1/PD-1 
pathway in regulating peripheral tolerance.  Given the mechanism of action of 
atezolizumab, events associated with inflammation and/or immune-mediated adverse 
events are closely monitored in the atezolizumab clinical program.  Immune-mediated
adverse events associated with atezolizumab include dermatologic, hepatic, endocrine, 
gastrointestinal, respiratory, and neurological events.
Refer to the Atezolizumab Investigator’s Brochure for additional details regarding 
immune-mediated adverse events observed in patients treated with atezolizumab.
1.2.2.3
Clinical Safety in Combination with Chemotherapy
Study GP28328 is a Phase Ib study of the safety and pharmacology of atezolizumab
administered with bevacizumab and/or chemotherapy in patients with advanced solid 
tumors. Arm A is evaluating 1200 mg atezolizumabbevacizumab administered q3w in 
patients with multiple solid tumor types, including separate expansion cohorts in 
colorectal cancer (CRC) and renal cell carcinoma (RCC). Arm B is evaluating
atezolizumabbevacizumab and oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX)
administered every 2 weeks (q2w) in patients with multiple solid tumor types, including 
breast cancer. Arms C, D, and E are evaluating atezolizumab administered q3w in 
chemotherapy-naïve nonsmall cell cancer (NSCLC) patients in combination with 
carboplatinpaclitaxel, carboplatinpemetrexed, and carboplatinnab-paclitaxel, 
respectively. Arm F is evaluating atezolizumab administered q2w in combination with 
weekly nab-paclitaxel in patients with TNBC. Patients in Arms B, C, D, E, and F 
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As of 14 January 2016, preliminary safety data were available from 208 patients in 
Study GP28328 (n144 in arms B, C, D, E, and F and n64 in arm A).  Of these patients, 
144 patients received cytotoxic chemotherapy in combination with atezolizumab and 
100.0% of patients reported one or more adverse effects.  The most frequently reported 
adverse effects (10% of patients), regardless of attribution to study treatment, included 
fatigue, nausea, diarrhea, neutropenia, peripheral neuropathy, constipation, vomiting, 
cough, anemia, arthralgia, headache, alopecia, pyrexia and decreased appetite. The 
most frequently reported adverse effects were mainly assessed as Grade 1 or Grade 2 
in maximum severity (excluding neutropenia).  Fifty-two patients (36.1%) discontinued a 
study treatment (i.e., chemotherapy or atezolizumab) due to an adverse effect, including 
9 patients (6.25%) who discontinued atezolizumab because of an adverse effect.  The 
most commonly reported adverse effects leading to discontinuation of a study treatment 
were bone marrow suppression (neutropenia [10.4%] and thrombocytopenia [4.2%]), 
peripheral neuropathy (5.6%), and fatigue (4.9%).
Safety data from 32 TNBC patients (Arm F) in Study GP28328 indicate that the 
combination appears to be well tolerated and is consistent with the known risks of 
nab-paclitaxel and atezolizumab (Adams et al. 2016).   Nineteen (19% of patients (6/32) 
experienced adverse events leading to discontinuation of nab-paclitaxel and 1 patient
discontinued atezolizumab after prolonged asymptomatic Grade 2 AST elevation.  The 
most frequent AEs attributed to atezolizumab (≥10%) included fatigue, pyrexia, diarrhea, 
nausea, alopecia, pruritis, headache, peripheral neuropathy and peripheral sensory 
neuropathy, and decreased neutrophil count.
The safety data to date suggest that atezolizumab can be safely combined with standard 
chemotherapy treatments.  Several combinations have been evaluated and have been 
generally well-tolerated.  Atezolizumab in combination with nab-paclitaxel has not been 
associated with additive severe (Grade 3 or higher) toxicities compared to that which is 
observed with nab-paclitaxel or atezolizumab alone.  The AEs observed for 
atezolizumab in combination with chemotherapy are consistent with the known risks of 
each study treatment.
Refer to the Atezolizumab Investigator’s Brochure for additional details regarding clinical 
safety.
1.2.3
Clinical Activity
Anti-tumor activity, including Response Evaluation Criteria in Solid Tumors 
(RECIST)based responses (i.e., RECIST v1.1 responses), have been observed in 
patients with different tumor types, including NSCLC, RCC, melanoma, bladder cancer, 
CRC, head and neck cancer, gastric cancer, breast cancer (including TNBC), and 
sarcoma treated with atezolizumab monotherapy in Study PCD4989g.  Among 
386 evaluable patients enrolled prior to 1 July 2013 (data cutoff of 1 January 2014), 
there were 47 patients with responses with a median duration of response of 75.7 weeks 
(range: 11.7to 85.9weeks, where “+” denotes a censored value).  The majority of 


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these responses have been durable, with 72.3% (34 of 47 patients) of responses
ongoing as of the clinical cutoff date.
Analyses of tumor-infiltrating immune cells (ICs) for PD-L1 expression on baseline tumor 
tissue have been performed for Study PCD4989g. Preliminary results from 
Study PCD4989g suggest that PD-L1 expression in ICs is likely to be associated with 
response to atezolizumab.
Clinical Activity in Patients with TNBC
Single Agent Activity
As of 2 September 2014, clinical activity analyses have been performed on 21 patients 
with PD-L1selected (IC2/3) TNBC in Study PCD4989g who received atezolizumab
treatment by 21 July 2014 (Emens et al. 2014).
Unconfirmed responses were recorded for 5 patients.  Two of these patients 
experienced a complete response and 3 patients experienced a partial response.  As of 
2 September 2014, 4 of these 5 patients were still responding and 1 patient experienced 
disease progression.  The median duration of response has not been reached.  The 
Kaplan-Meier estimated overall 24-week PFS rate was 33% (95% CI: 12% to 53%).
Activity in Combination with Chemotherapy
Study GP28328 is a multi-arm Phase 1b study evaluating the safety and preliminary 
efficacy of a number of combinations of atezolizumab and chemotherapy with or without 
bevacizumab in patients with locally advanced or metastatic solid tumors. Arm F of the 
study is testing the combination of atezolizumab and nab-paclitaxel in female patients 
with metastatic TNBC. Patients receive 800 mg of atezolizumab on Days 1 and 15 of 
every 28-day cycle plus nab-paclitaxel (125 mg/m2) on Days 1, 8, and 15 of every 
28-day cycle. Up to two prior cytotoxic regimens for metastatic disease are allowed. 
On the basis of a clinical cut-off of 14 January 2016, safety and preliminary efficacy data 
were available for 32 patients (Adams et al. 2016).  Of the efficacy-evaluable patients, 
13 received the treatment combination as first-line therapy, and 19 had received 1 prior 
cytotoxic regimens for metastatic disease. 88% had previously received taxanes. In the 
overall efficacy-evaluable population, 12 patients (38% [95% CI: 2% to 56%]) achieved 
confirmed RECIST v1.1 responses. Clinical responses were observed in patients with 
PD-L1 IC1/2/3/ tumors as well as in those with PD-L1 IC0.  
Six of thirteen patients (46% [95% CI: 19% to 75%]) who received atezolizumab plus 
nab-paclitaxel as 1L therapy achieved investigator-assessed confirmed responses, 
comprising one complete response and five partial responses.


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Two out of nine (22% [95% CI: 3%, to 60%]) and four out of 10 patients (40% [95% CI: 
12% to 74%]) who received study treatment as 2L and 3Ltherapy, respectively, 
achieved investigator-assessed confirmed responses.
The median progression-free survival, overall survival, and duration of response had not 
yet been reached at the time of the cut-off date.
1.2.4
Clinical Pharmacokinetics and Immunogenicity
On the basis of available preliminary PK data (0.0320 mg/kg), atezolizumab appeared 
to show linear pharmacokinetics at doses 1 mg/kg.  For the 1 mg/kg and 20 mg/kg 
dose groups, the mean apparent clearance (CL) and the mean volume of distribution at 
steady state (Vss) had a range of 3.11 to 4.14 mL/kg and 48.1 to 67.0 mL/kg, 
respectively, which is consistent with the expected profile of an IgG1 antibody in 
humans.
The development of anti-therapeutic antibodies (ATAs) has been observed in patients in 
all dose cohorts and was associated with changes in pharmacokinetics for some patients 
in the lower dose cohorts (0.3, 1, and 3 mg/kg).  The development of detectable ATAs 
has not had a significant impact on pharmacokinetics for doses from 10 to 20 mg/kg.  
Patients dosed at the 10, 15, and 20 mg/kg dose levels have maintained the expected 
target trough levels of drug despite the detection of ATAs.  To date, no clear relationship 
between detection of ATAs and adverse events or infusion reactions has been observed.
1.2.5
Rationale for Atezolizumab Dosage
The fixed dose of 840 mg (equivalent to an average body weightbased dose of 
15 mg/kg q3w) 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 the following: 1) 95% tumor-receptor saturation is needed for 
efficacy, and 2) the tumor interstitial fluid (TIF) 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, 
pharmacokinetics, and immunogenicity data. Anti-tumor activity has been observed 
across doses from 1 mg/kg to 20 mg/kg. The maximum tolerated dose (MTD) of 
atezolizumab was not reached, and no DLTs have been observed at any dose in 
Study PCD4989g. Available preliminary PK data (0.0320 mg/kg) from 
Study PCD4989g suggest that for doses 1 mg/kg q3w, atezolizumab generally exhibits 
pharmacokinetics that are both linear and consistent with typical IgG1 antibodies. 
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changes in pharmacokinetics for some patients in the lower dose cohorts only (0.3, 1, 
and 3 mg/kg q3w). 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.  Available 
data suggest that the development of detectable ATAs does not appear to have a 
significant impact on the pharmacokinetics for doses from 10 to 20 mg/kg q3w in most 
patients. Correspondingly, patients dosed at the 10, 15, and 20 mg/kg q3w 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) would be sufficient to maintain Ctrough 6 g/mL and further 
safeguard against both interpatient variability and the 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 a fixed dose or a dose adjusted for weight.  On the basis of this 
analysis, a fixed dose of 1200 mg has been selected for when atezolizumab is 
administered q3w (equivalent to an average body weightbased dose of 15 mg/kg).  For 
the q2w dosing interval used in this study, the corresponding fixed dose is 800 mg.
Because atezolizumab is formulated at a concentration of 60 mg/mL, 800 mg 
corresponds to a volume of 13.33 mL. In the interest of simplifying administration, the 
exact dose used in this study will be 840 mg, corresponding to a volume of 14 mL, which 
can be accurately administered with a single syringe. The 840-mg dose is not expected 
to result in meaningfully different exposures compared with an 800-mg dose.
Refer to the Atezolizumab Investigator’s Brochure for details regarding nonclinical and 
clinical pharmacology of atezolizumab.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
1.3.1
Atezolizumab
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).
PD-L1 is an extracellular protein that downregulates immune responses primarily in 
peripheral tissues through binding to its two receptors: 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, 
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(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 downregulation of immune responses, 
including inhibition of T-cell activation and cytokine production (Butte et al. 2007; 
Yang et al. 2011).
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 and the PD-L1/B7.1 pathways represents an attractive 
strategy to reinvigorate tumor-specific T-cell immunity.
Targeting the PD-L1 pathway with atezolizumab has demonstrated activity in patients 
with advanced malignancies who have failed standard-of-care therapies, including 
patients with TNBC (see Section 1.2.3).
The observation that high CD8T-cell density in primary breast tumors is correlated with 
improved OS, and that metastatic TNBC tumors have fewer tumor-infiltrating 
lymphocytes than their matched primary tumors, suggests that the immune system is 
able to partially restrain human breast cancer but that immune suppression becomes 
more prevalent with increasing growth and metastasis (Cimino-Mathews et al. 2013; 
Adams et al. 2014; Loi 2014). The identification of immune-enriched subtypes of TNBC 
underscores the potential to harness preexisting host anti-tumor immunity in this disease 
(Lehmann et al. 2011).  In this setting, invigorating T-cell activity with atezolizumab may 
be an effective treatment strategy.
Atezolizumab has been generally well tolerated (see Sections 1.2.2.2 and 1.2.2.3); 
adverse events with potentially immune-mediated causes consistent with an 
immunotherapeutic agent, including rash, hypothyroidism, hepatitis/transaminitis, colitis, 
and myasthenia gravis, have been observed in ongoing studies of atezolizumab.  To 
date, the majority of these events have been manageable without requiring treatment 
discontinuation.
1.3.2
nab-Paclitaxel and Combination Treatment with Atezolizumab
Because of the opportunity to avoid immunosuppressive effects from steroids, 
nab-paclitaxel potentially represents a preferred chemotherapy for combination with 
immunomodulatory drugs such as atezolizumab. 
Preliminary safety data from Study GP28328 indicate that atezolizumab can be safely 
combined with chemotherapy (several combinations have been evaluated and 
determined to be well tolerated; refer to the Atezolizumab Investigator’s Brochure for 
details).  Specifically, atezolizumab was tested in combination with 
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combination with nab-paclitaxel in patients with TNBC. No exacerbation of 
chemotherapy-associated adverse events was reported.
The safety of single-agent nab-paclitaxel in patients with mBC has been demonstrated in 
several studies. Although a higher paclitaxel dose was achieved in the nab-paclitaxel 
arm in the Phase III study comparing sb-paclitaxel to nab-paclitaxel, the incidence of 
Grade 4 neutropenia was significantly lower in the nab-paclitaxel arm than in the 
sb-paclitaxel (control) arm (9% vs. 22%, respectively; Gradishar et al. 2005).
Grade 3 sensory neuropathy was more common with nab-paclitaxel than with 
sb-paclitaxel (10% vs. 2%, respectively), but was reported to be manageable and 
self-limiting with treatment interruption and dose reduction. 
There is increasing evidence that in addition to causing tumor cell death, certain 
conventional chemotherapies may have immunogenic effects (Zitvogel et al. 2008).  
Clinical evidence exists to suggest that T-cell and NK-cell functions are enhanced in 
patients with breast cancer (Stage II/III) treated with taxanes compared with patients 
who did not receive taxanes (Carson et al. 2004). In addition, tumor cell killing by 
cytotoxic chemotherapy can be expected to expose the immune system to high levels of 
tumor antigens, and invigorating tumor-specific T-cell immunity in this setting by 
inhibiting PD-L1/PD-1 signaling may result in deeper and more durable responses 
compared with standard chemotherapy alone.
Further rationale for the choice of nab-paclitaxel as the comparator and for the selected 
dose of nab-paclitaxel is provided in Sections 3.3.2 and 3.3.3.  
In summary, combination treatment with atezolizumab and nab-paclitaxel offers the 
potential for clinical benefit in patients with mBC. 
2.
OBJECTIVES
The following objectives will be assessed in patients with metastatic or locally advanced 
triple-negative adenocarcinoma of the breast who have not received prior systemic 
therapy for mBC.
2.1
EFFICACY OBJECTIVES
The following efficacy objectives will be evaluated in both the intent-to-treat (ITT) 
population (i.e., all randomized patients) and the subpopulation with PD-L1selected
tumor status.
2.1.1
Co-Primary Efficacy Objectives

To evaluate the efficacy of atezolizumabnab-paclitaxel compared with 
placebonab-paclitaxel as measured by PFS (per investigator assessment using 
RECIST v1.1) 


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
To evaluate the efficacy of atezolizumab nab-paclitaxel compared with 
placebo nab-paclitaxel as measured by overall survival (OS)
2.1.2
Secondary Efficacy Objectives

To evaluate the efficacy of atezolizumabnab-paclitaxel compared with 
placebonab-paclitaxel as measured by objective response rate (ORR; per 
investigator assessment using RECIST v1.1)

To evaluate the efficacy of atezolizumabnab-paclitaxel compared with 
placebonab-paclitaxel as measured by duration of objective response (DOR; per 
investigator using RECIST v1.1) among patients with an objective response

To evaluate patient-reported outcomes (PROs) of health status/health-related 
quality of life (HRQoL) associated with atezolizumabnab-paclitaxel compared with 
placebonab-paclitaxel, as measured by the time to deterioration (TTD) in 
Items 29 and 30 of the European Organisation for Research and Treatment of 
Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) 
2.2
SAFETY OBJECTIVES
The safety objectives for this study are as follows:

To evaluate the safety and tolerability of atezolizumabnab-paclitaxel compared 
with placebonab-paclitaxel

To evaluate the incidence of ATAs against atezolizumab and to explore the potential 
relationship of the immunogenicity response with pharmacokinetics, 
pharmacodynamics, safety, and efficacy
2.3
PHARMACOKINETIC OBJECTIVES
The PK objectives for this study are as follows:

To characterize the pharmacokinetics of atezolizumab when administered with
nab-paclitaxel

To characterize the pharmacokinetics of nab-paclitaxel when administered with 
atezolizumab
2.4
EXPLORATORY OBJECTIVES
The exploratory objectives for this study are as follows:

To evaluate PROs of function and disease/treatment-related symptoms associated 
with atezolizumabnab-paclitaxel compared with placebonab-paclitaxel, as 
measured by the EORTC QLQ-C30 and its breast cancer module (QLQ-BR23)

To evaluate health utility as measured by the EuroQoL 5 Dimension (EQ-5D-5L) 
questionnaire for health economic modeling of atezolizumabnab-paclitaxel 
compared with placebonab-paclitaxel

To assess predictive, prognostic, and pharmacodynamic (PD) exploratory 
biomarkers in archival and/or fresh tumor tissue and blood and their association with 
disease status and/or response to study treatment


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3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
This is a Phase III, global, multicenter, double-blind, two-arm, randomized, 
placebo-controlled study designed to evaluate the efficacy and safety of atezolizumab
administered with nab-paclitaxel compared with placebo in combination with 
nab-paclitaxel in patients with locally advanced or metastatic TNBC who have not 
received prior systemic therapy for mBC. 
Patients who have a known ER-positive, PR-positive, or HER2-positive status are not 
eligible to participate in the study. Patients who have an unknown ER, PR, or HER2 
status, and for whom determination of status is not possible, are also not eligible for this 
study. Figure 1 illustrates the study design.
Figure 1
Study Schema
ECOGEastern Cooperative Oncology Group; PSperformance status; q2wevery 2 weeks; 
RECIST v1.1Response Evaluation Criteria in Solid Tumors, version 1.1; TNBCtriple-negative 
breast cancer; wkweek.
A representative formalin-fixed paraffin-embedded (FFPE) tumor specimen with an 
associated pathology report documenting ER, PR, and HER2 negativity must be 
submitted prior to enrollment. Tumor tissue should be of good quality based on total and 
viable tumor content and must be prospectively evaluated for PD-L1 expression prior to 
enrollment. A tumor specimen obtained from relapsed metastatic or locally advanced 
disease must also be submitted, if clinically feasible.
Eligible, consented patients 
with locally advanced or 
metastatic TNBC
(n = up to 900)
Atezolizumab (q2w) +
nab-Paciltaxel
(3-wk-on/1-wk-off)
Placebo (q2w) +
nab-Paciltaxel
(3-wk-on/1-wk-off)
Survival Follow-Up
Randomization (1:1)
Disease Progression
(RECIST v1.1)


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Up to 900 patients will be enrolled at approximately 257 sites globally.  Patients will be 
randomized in a 1:1 ratio to receive atezolizumab (840 mg) or placebo IV infusions on 
Days 1 and 15 of every 28-day cycle plus nab-paclitaxel (100 mg/m2) administered via
IV infusion on Days 1, 8, and 15 of every 28-day cycle. Randomization will be stratified 
by the following three factors:

Presence of liver metastases (yes vs. no)

Prior taxane treatment (yes vs. no)

Tumor PD-L1 status (IC0 vs. IC1/2/3)
In the absence of disease progression or unacceptable toxicity, nab-paclitaxel will be 
administered for a target of at least 6 cycles, with no maximum.  nab-Paclitaxel and 
atezolizumab or placebo may be discontinued for toxicity independently of each other in 
the absence of disease progression.  The Sponsor, patients, and investigators will not be 
aware of each patient’s treatment assignment prior to unblinding (see Section 4.2).
Once treatment unblinding has occurred, investigators may request crossover to the 
atezolizumabnab-paclitaxel arm for patients who were randomized to the 
placebonab-paclitaxel arm, who have not yet experienced disease progression, and 
who have not started any other systemic anti-cancer agents beyond those offered in this
study. Patients must still meet the safety-related eligibility criteria for the study prior to 
initiating atezolizumab.
In order to interrogate the mechanism of action of the drug combination in the tumor 
microenvironment and possible resistance mechanisms, tumor tissue may be optionally 
collected pre-dose on Cycle 2, Day 1.
To test the mechanisms of resistance to the drug combination in the tumor 
microenvironment, all patients will undergo a mandatory tumor biopsy collection (if 
clinically feasible) at first evidence of radiographic disease progression per RECIST v1.1.  
DNA sequencing of cancer-related genes will be performed on these specimens by 
Foundation Medicine, Inc. (Cambridge, MA). The research report may be obtained by 
the Investigator, if desired, directly from Foundation Medicine, Inc. and will describe 
results from investigational tests that are not intended to be used to guide future 
treatment decisions.
Tumor assessments per RECIST v1.1 (see Appendix 3) will be performed approximately 
every 8 weeks (1 week) for the first 12 months after Cycle 1, Day 1 and every 12 weeks
(1 week) thereafter until disease progression or treatment discontinuation, whichever is 
later. Tumor assessments will be performed on the specified schedule regardless of 
treatment delays.
Treatment will be discontinued upon radiographic disease progression per RECIST v1.1. 
For equivocal findings of progression (e.g., very small or uncertain new lesions or lymph 
nodes; cystic changes or necrosis in existing lesions), treatment may continue until the 


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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.
For estimation of PFS, ORR, and DOR, tumor response will be based on RECIST v1.1 
(see Appendix 3). The imaging data used for tumor assessment will be collected by the 
Sponsor to enable centralized, independent review of response endpoints by an 
Independent Review Committee (IRC). 
All patients will be followed for survival approximately every 3 months after the treatment 
discontinuation visit until death, withdrawal of consent, loss to follow-up, or study 
termination by the Sponsor.  In addition, information regarding use of subsequent 
anti-cancer agents for metastatic TNBC during the survival follow-up period will be 
collected.
The pharmacokinetics of atezolizumab and nab-paclitaxel will be determined
(see Appendix 2).
Safety assessments will include the incidence, nature, and severity of adverse events 
and laboratory abnormalities graded per 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 pharmacokinetics and to detect 
the presence of antibodies to atezolizumab.  Patient samples, including tumor tissues, 
as well as serum and plasma and whole blood, will be collected for exploratory 
biomarker assessments.
A schedule of assessments is provided in Appendix 1.
3.1.1
Independent Data Monitoring Committee
An independent data monitoring committee (iDMC) will monitor safety and study conduct 
on a periodic basis.  Members of the iDMC will be external to the Sponsor and will follow 
a charter that outlines their roles and responsibilities.  The iDMC will meet approximately 
every 6 months from the point of first patient in (FPI) to review unblinded safety and 
study conduct data prepared by an independent Data Coordinating Center (iDCC). The 
safety data will include demographic data, adverse events, serious adverse events, and 
relevant laboratory data.  
Following each data review, the iDMC will provide recommendations to the Sponsor as 
to whether the study should continue or be amended, or whether the study should be 
stopped on the basis of safety (i.e., evidence of harm).  The Sponsor’s Data Review 
Board (DRB; a group consisting of employees of the Sponsor empowered to make 
critical decisions) will make a decision on the basis of the iDMC’s recommendations.  
The final decision will rest with the Sponsor. 


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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).
There are two interim analyses planned for the co-primary endpoint of OS.  No interim 
efficacy analysis is planned for the co-primary endpoint of PFS.  The final analysis of 
PFS will occur at the time of the first OS interim analysis.  The first interim analysis of 
OS together with the final analysis of PFS, and if necessary, the second interim analysis, 
will be carried out by the iDCC in a blinded fashion and provided to the iDMC.  The 
iDMC will review these data and will recommend or not recommend to release the trial 
results and to unblind the study to the sponsor.  The DRB of the sponsor will either 
accept or reject this recommendation.  Details are specified in the iDMC charter. 
3.2
END OF STUDY
The end of the study is expected to occur about 53 months after FPI when 
approximately the pre-planned number of deaths will have been observed (see
Section 6.1.3). 
OS events will be monitored throughout the course of the study, and study timelines 
might be updated as indicated.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Atezolizumab Dosage
The fixed dose of 840 mg q2w was selected on the basis of both nonclinical studies and 
available clinical data from Study PCD4989g (see Section 1.2.5).
3.3.2
Rationale for Use of nab-Paclitaxel Comparator
The taxane class of cytotoxic agents (paclitaxel, docetaxel, nab-paclitaxel) have 
significant antitumor activity in breast cancer. Although combinations of cytotoxic agents 
may be administered to patients with severe symptomatic disease or imminent visceral 
crisis, combination regimens are associated with increased toxicity and have not 
demonstrated an OS benefit compared with the sequential administration of single 
agents. The response rates and progression-free intervals observed with available 
agents vary depending on the extent and type of prior therapy and extent of metastatic 
disease, as well as the biology of disease.  In general, taxanes such as paclitaxel and 
docetaxel are believed to show the greatest activity and are now the most commonly 
used agents for patients with locally advanced or metastatic disease, particularly in the 
front-line setting (Greene and Hennessy 2014). 
nab-Paclitaxel is an albumin-bound formulation of paclitaxel that was developed to 
mitigate the significant toxicities associated with the vehicles that are necessary for 
parenteral administration of solvent-based (sb) paclitaxel (polyethylated castor oil and 
polysorbate 80).  In addition, it has an advantageous PK profile compared with


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sb-paclitaxel and achieves a 33% higher tumor uptake in preclinical models 
(Yardley et al. 2013). Steroids are routinely administered with sb-paclitaxel to lower the 
risk of hypersensitivity allergic reactions, but steroid premedication is not required with 
the use of nab-paclitaxel.
nab-Paclitaxel received a label from the U.S. Food and Drug Administration (FDA) for 
the treatment of mBC after failure of front-line combination chemotherapy for metastatic 
disease or relapse within 6 months of adjuvant chemotherapy, based on the pivotal 
Phase III study performed by Gradishar et al. (2005). However, in real-world practice, 
nab-paclitaxel is used throughout the continuum of care for patients with mBC. Both the 
NCCN and ESMO clinical practice guidelines include nab-paclitaxel as a standard of 
care that may be administered as a single agent to patients with newly diagnosed 
recurrent or metastatic breast cancer (Cardoso et al. 2014; NCCN 2014).
The recently reported randomized Phase III GeparSepto study compared the efficacy of 
nab-paclitaxel versus paclitaxel when the agents were administered to women with 
early-stage breast cancer as part of a neoadjuvant regimen (Untch et al. 2014).  Overall, 
38% of patients who received nab-paclitaxel achieved a pathologic complete response 
(pCR), compared with 29% of those who received conventional paclitaxel. Notably, the 
pCR rate among patients with TNBC who received nab-paclitaxel was twice that of 
women who received paclitaxel. The GeparSepto study was started with a weekly
nab-paclitaxel dose of 150 mg/m2, which was lowered to 125 mg/m2 after an interim 
safety analysis determined that the higher dose was not tolerated. Although these data 
are from the neoadjuvant setting, they support the position that nab-paclitaxel constitutes 
an appropriate standard of care for women with TNBC and a suitable comparator in the 
present study.
nab-Paclitaxel represents the preferred chemotherapy for combination with 
immunomodulatory drugs such as atezolizumab because of both 1) the opportunity to 
avoid immunosuppressive effects from the concurrent steroid use required with other 
taxanes, and 2) the high rate of tumor cell death achieved by nab-paclitaxel, which can 
be expected to expose the immune system to high levels of tumor antigens, thereby 
enhancing the degree and duration of cancer-specific T-cell immunity by inhibition of 
PD-L1-mediated immune suppression by atezolizumab.
3.3.3
Rationale for nab-Paclitaxel Dosage and Regimen
The q3w dose of nab-paclitaxel (260 mg/m2) in the FDA label established from the 
Phase III study comparing sb-paclitaxel with nab-paclitaxel (Gradishar et al. 2005) is not 
generally used in current clinical practice.  Instead, weekly dosing of nab-paclitaxel is the 
most commonly utilized schedule given the better tolerability and suggestions of 
increased efficacy of weekly dosing compared to q3w dosing.
The superiority of the weekly regimen of nab-paclitaxel was first demonstrated in a
randomized Phase II study conducted in patients with previously untreated mBC 


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(Gradishar et al 2009).  In the four arms of this study, the ORRs were 37% with q3w
nab-paclitaxel, 45% with weekly nab-paclitaxel 100 mg/m2 (3-weeks-on/1-week-off 
schedule), 49% with weekly nab-paclitaxel 150 mg/m2 (3-weeks-on/1-week-off schedule), 
and 35% with q3w docetaxel 100 mg/m2 (independent radiologist assessment), 
illustrating the anti-tumor advantages of the weekly dosing schedule.  PFS was 
11.0 months, 12.8 months, 12.9 months, and 7.5 months (independent radiologist 
assessment) for each of the four arms, respectively.  The difference in PFS and ORR 
between the 100 and 150 mg/m2 weekly dose levels of nab-paclitaxel was not 
statistically significant, but patients receiving the higher dose experienced a greater 
incidence of Grade 3 or 4 neutropenia (44% vs. 25%) and Grade 3 sensory neuropathy 
(14% vs. 8%). 
Subsequent clinical studies have not clearly demonstrated that weekly doses of 
nab-paclitaxel greater than 100 mg/m2 are more efficacious.  Furthermore, higher doses 
of nab-paclitaxel are associated with greater toxicities.  The CALGB 40502 Phase III 
study randomized patients with chemotherapy-naive, HER2-negative mBC to receive 
weekly paclitaxel, weekly nab-paclitaxel at a higher dose of 150 mg/m2, or ixabepilone, 
with all agents given in combination with bevacizumab, and on a 3-weeks-on/1-week-off
schedule (Rugo et al. 2012).  Nab-paclitaxel was not tolerable at this higher weekly dose 
and did not improve PFS in any subtype over standard dose paclitaxel, leading to the 
conclusion that 150 mg/m2 should not be utilized.  
To date, 100 mg/m2 of nab-paclitaxel weekly on a 3-weeks-on/1-week-off schedule is the 
best-studied and tolerated dose, with suggestions of improved efficacy and decreased 
toxicities in mBC compared with both higher weekly doses and the every 3-week dosing 
schedule of the same drug.  As a result, subjects on this study will receive nab-paclitaxel 
100 mg/m2 via IV infusion on Days 1, 8, and 15 of an every 28-day cycle.  In the 
absence of disease progression or unacceptable toxicity, nab-paclitaxel will be 
administered for a target of six cycles, with no maximum number of cycles mandated by 
the study.
3.3.4
Rationale for Collection of Archival and Pre-Treatment Tumor 
Specimens
A portion of archival and pre-treatment tumor specimens will be used for confirmation of 
ER, PR, and HER2 triple-negative status by a central testing laboratory.
Published results suggest that the expression of PD-L1 in tumors correlates with 
response to antiPD-1 therapy (Herbst et al. 2014). This correlation is also observed 
with atezolizumab in preliminary data from Phase Ia Study PCD4989g (see
Section 1.2.3).
To evaluate the potential predictive significance of PD-L1 expression in TNBC, 
representative tumor specimens in paraffin blocks (preferred) or at least 20 unstained 
slides (with an associated pathology report) must be submitted prior to 


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study randomization.  Patients will be stratified on the basis of tumor PD-L1 expression 
determined by IHC (IC0 vs. IC1/2/3).
To enable evaluation of the potential for prior therapies to alter expression of PD-L1, 
patients will also be required to submit tumor specimens obtained from relapsed 
metastatic or locally advanced disease if clinically feasible, in addition to archival tumor 
tissue.
In addition to the assessment of PD-L1 status, other exploratory markers such as 
potential predictive and prognostic markers related to the clinical benefit of atezolizumab
nab-paclitaxel, tumor immunobiology, mechanisms of resistance, or tumor type, may 
also be analyzed.
3.3.5
Rationale for the Collection of Biopsy at the Time of
Radiographic Progression
All patients will undergo a mandatory tumor biopsy collection (if clinically feasible) at the 
first evidence of radiographic disease progression. Analysis of biological material 
(including but not restricted to DNA and RNA) from these specimens will help elucidate 
molecular changes associated with resistance to or disease progression after treatment 
with nab-paclitaxel or nab-paclitaxelatezolizumab in patients with TNBC. DNA 
sequencing of cancer-related genes will be performed on these specimens by 
Foundation Medicine, Inc. (Cambridge, MA). The research report may be obtained by 
the Investigator, if desired, directly from Foundation Medicine, Inc. and will describe 
results from investigational tests that are not intended to be used to guide future 
treatment decisions.
3.3.6
Rationale for Optional Biopsies
Optional tumor tissue samples collected at Cycle 2, Day 1 will be analyzed for molecular 
changes occurring after treatment with nab-paclitaxelplacebo or 
nab-paclitaxelatezolizumab.  These analyses will help elucidate early mechanisms of 
action and resistance to study treatment.  The conclusions obtained from these studies 
will aid in the development of therapies to improve anti-tumor immune response in 
patients with TNBC. 
3.3.7
Rationale for Blood Sampling for Biomarkers
Changes in different blood biomarkers may provide evidence for biologic activity of 
atezolizumab in combination with nab-paclitaxel in humans and may allow for the 
development of a blood-based biomarker to help predict which patients may benefit from 
atezolizumabnab-paclitaxel.  An exploratory objective of this study is to evaluate 
changes in surrogate biomarkers in blood samples.
In addition, potential correlations of these PD markers with the dose, safety, and
anti-tumor activity of atezolizumab will be explored.


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3.3.8
Rationale for Patient-Reported Outcome Assessments
As mBC is not curable with currently approved and available therapies, the main goals of 
treatment are to prolong survival and maintain or improve quality-of-life 
(Cardoso et al. 2012).  PROs of global health status, function, and disease/treatment 
related symptoms will be assessed using the EORTC QLQ-C30 in conjunction with the 
QLQ-BR23 breast cancer module, as well as the EQ-5D-5L (see Section 5.3.5.13 and
Appendix 4).
The EORTC QLQ-C30 and its breast cancerspecific module, the QLQ-BR23, are 
validated and reliable self-report measures (Aaronson et al.1993; Sprangers et al. 1996; 
Osoba et al. 1997). The EQ-5D-5L is a validated, generalized HRQoL measure that 
assesses patient’s health status related to mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression (Herdman et al. 2011; Janssen et al. 2013).  
A utility measure is obtained that is used to inform pharmacoeconomic evaluations.
The EORTC QLQ-C30, QLQ-BR23, and EQ-5D-5L will be assessed at baseline (Cycle 1, 
Day 1); at Day 1 of each subsequent cycle; and at the treatment discontinuation visit.  In 
addition, all patients will complete the PRO questionnaires every 28 days for 1 year after 
treatment discontinuation, regardless of whether the patient is receiving subsequent 
anti-cancer therapy. Questionnaires will be completed after treatment discontinuation by 
the patient at home on an ePRO handheld device provisioned to the patient at the time 
of treatment discontinuation visit.  As the QLQ-BR23 was not developed or tested and
validated with men, male patients in this study will not complete the QLQ-BR23 measure.
3.4
OUTCOME MEASURES
3.4.1
Efficacy Outcome Measures
3.4.1.1
Co-Primary Efficacy Outcome Measures
The co-primary efficacy outcome measures to be assessed in the ITT population and in 
the PD-L1selected subpopulation are as follows:

PFS, defined as the time from randomization to the time of radiographic progression 
or death from any cause during the study, whichever occurs first

OS, defined as the time from the date of randomization to the date of death from 
any cause
Progression will be assessed by the investigator using RECIST v1.1.
3.4.1.2
Secondary Efficacy Outcome Measures
The secondary efficacy outcome measures to be assessed in the ITT population and in 
the PD-L1selected subpopulation are as follows:

ORR, defined as the proportion of patients with an objective tumor response (either 
partial response [PR] or complete response [CR] per investigator using
RECIST v1.1)


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
DOR, defined as the time from the first occurrence of a documented objective tumor 
response to the time of radiographic progression (per investigator using 
RECIST v1.1) or death from any cause on study, whichever occurs first

TTD in global health status/HRQoL, defined by a minimally important decrease of 
10 points on the global health status/HRQoL scale of the EORTC QLQ-C30
3.4.2
Safety Outcome Measures
The safety outcome measures are as follows:

Incidence, nature, and severity of adverse events graded according to 
NCI CTCAE v4.0

Changes in vital signs, physical findings, and clinical laboratory results

Incidence of ATA response to atezolizumab and potential correlation with PK, PD, 
safety, and efficacy parameters
3.4.3
Pharmacokinetic Outcome Measures
The PK outcome measures are as follows:

Atezolizumab maximum observed serum concentration (Cmax) and minimum
observed serum concentration (Cmin) within a dosing interval at specified timepoints 
during treatment and at treatment termination

Plasma concentration of nab-paclitaxel (reported as total paclitaxel) 
3.4.4
Exploratory Outcome Measures
The exploratory outcome measures are as follows:

Association of tumor immune-mediated or disease typerelated exploratory 
biomarkers in archival and/or freshly obtained tumor tissues with disease status 
and/or response to atezolizumabnab-paclitaxel

Association of exploratory biomarkers in plasma, whole blood, or serum (including 
but not limited to cytokines such as interleukin [IL]-6) collected before treatment,
during treatment with atezolizumabnab-paclitaxel, or at disease progression with 
disease status and/or response to atezolizumabnab-paclitaxel

TTD in the functional (physical, role, cognitive) subscales of the EORTC QLQ-C30

Assessment of mean changes in function and disease/treatment-related symptoms 
in all scales of the EORTC QLQ-C30 and QLQ-BR23 by treatment arm

Health utility assessment as measured by the EQ-5D-5L during the study for health 
economic evaluations
4.
MATERIALS AND METHODS
4.1
PATIENTS
Patients with metastatic or locally advanced TNBC who have not received prior systemic 
cytotoxic therapy for mBC may be eligible for this study. Locally advanced disease must 
not be amenable to resection with curative intent.  Patients may have received prior 


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chemotherapy in the neoadjuvant/adjuvant setting if treatment was completed 
12 months prior to randomization.  Patients must comply with all eligibility criteria to be 
enrolled.
4.1.1
Inclusion Criteria
Patients must meet all of the following criteria to be eligible for study entry:

Signed Informed Consent Form

Women or men aged 18 years

Metastatic or locally advanced, histologically documented TNBC (absence of HER2, 
ER, and PR expression)
HER2 negativity is defined as either of the following (Wolff et al. 2013) by local 
laboratory assessment:
In situ hybridization (ISH) non-amplified (ratio of HER2 to CEP17 2.0 or 
single probe average HER2 gene copy number 4 signals/cell), or
IHC 0 or IHC 1.  If more than one test result is available and not all results 
meet the inclusion criterion definition, all results should be discussed 
with the Medical Monitor to establish eligibility of the patient.
ER and PR negativity are defined as 1% of cells expressing hormonal 
receptors via IHC analysis.  

No prior chemotherapy or targeted systemic therapy for inoperable locally advanced 
or metastatic TNBC
Radiation therapy for metastatic disease is permitted. There is no required 
minimum washout period for radiation therapy. Patients should be recovered 
from the effects of radiation.
Prior chemotherapy (including taxanes) in the neoadjuvant or adjuvant setting is 
allowable if treatment was completed 12 months prior to randomization

Eligible for taxane monotherapy (i.e., absence of rapid clinical progression, 
life-threatening visceral metastases, or the need for rapid symptom and/or disease 
control)

Representative FFPE tumor specimen (either an archival specimen or fresh 
pre-treatment tissue from relapsed disease) in paraffin blocks (preferred) or at least
20 unstained slides, with an associated pathology report documenting ER, PR, and 
HER2 negativity (see Appendix 8 for detailed tissue requirements at screening)
Patients with fewer than 20 unstained slides available at baseline (but no fewer 
than 12) may be eligible upon discussion with the Medical Monitor.
Tumor tissue should be of good quality based on total and viable tumor content
and must be evaluated for PD-L1 expression prior to enrollment.  Patients 
whose tumor tissue is not evaluable for PD-L1 expression are not eligible.  
If multiple tumor specimens are submitted (e.g., an archival specimen and 
tissue from relapsed disease), patients may be eligible if at least one specimen 


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is evaluable for PD-L1. For the purpose of stratification, the PD-L1 score of the 
patient will be the maximum PD-L1 score among the samples.
A tumor specimen obtained from relapsed metastatic or locally advanced 
disease (if applicable) must be submitted, if clinically feasible.
Acceptable samples include core needle biopsies for deep tumor tissue 
(minimum three cores) or excisional, incisional, punch, or forceps biopsies 
for cutaneous, subcutaneous, or mucosal lesions.
FFPE tumor specimens in paraffin blocks are preferred.
Fine-needle aspiration, brushing, cell pellet from pleural effusion, bone 
metastases, and lavage samples are not acceptable.
Tumor tissue from bone metastases is not evaluable for PD-L1 expression 
and is therefore not acceptable.

ECOG performance status of 0 or 1 (see Appendix 7)

Life expectancy 12 weeks

Measurable disease, as defined by RECIST v1.1
Previously irradiated lesions can be considered as measurable disease only if 
disease progression has been unequivocally documented at that site since 
radiation.

Adequate hematologic and end-organ function, defined by the following laboratory 
results obtained within 14 days prior to the first study treatment (Cycle 1, Day 1):
ANC 1500 cells/L (without granulocyte colony-stimulating factor [G-CSF] 
support within 2 weeks prior to Cycle 1, Day 1)
Lymphocyte count 500/L
Platelet count 100,000/L (without transfusion within 2 weeks prior to Cycle 1, 
Day 1)
Hemoglobin 9.0 g/dL
Patients may be transfused or receive erythropoietic treatment to meet this 
criterion.
AST, ALT, and alkaline phosphatase 2.5the upper limit of normal (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 1.25ULN
Patients with known Gilbert disease who have serum bilirubin level
3ULN may be enrolled.
INR and aPTT 1.5ULN


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This applies only to patients who are not receiving therapeutic 
anticoagulation; patients receiving therapeutic anticoagulation should be 
on a stable dose.
Calculated creatinine clearance 30 mL/min

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 5 months after the last 
dose of atezolizumab/placebo or 1 month after the last dose of nab-paclitaxel, 
whichever is later.
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 
(IUDs), and copper IUDs.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical study 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 or pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and for at 
least 6 months after the last dose of nab-paclitaxel.  Men must refrain from 
donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical study 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.

Women who are not postmenopausal (12 months of nontherapy-induced 
amenorrhea) or surgically sterile must have a negative serum pregnancy test result 
within 14 days prior to initiation of study drug.
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry.
4.1.2.1
Cancer-Specific Exclusion Criteria

Spinal cord compression not definitively treated with surgery and/or radiation, or 
previously diagnosed and treated spinal cord compression without evidence that 
disease has been clinically stable for 2 weeks prior to randomization


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
Known CNS disease, except for treated asymptomatic CNS metastases, provided all
of the following criteria are met:
Only supratentorial and cerebellar metastases allowed (i.e., no metastases to 
midbrain, pons, medulla, or spinal cord)
No ongoing requirement for corticosteroids as therapy for CNS disease
No stereotactic radiation within 7 days or whole brain radiation within 14 days 
prior to randomization
No evidence of interim progression between the completion of CNS-directed 
therapy and the screening radiographic study
Note: 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, if all other criteria are 
met.

Leptomeningeal disease

Uncontrolled pleural effusion, pericardial effusion, or ascites 
Patients with indwelling catheters (e.g., PleurX) are allowed.

Uncontrolled tumor-related pain
Patients requiring narcotic pain medication must be on a stable regimen at 
study entry.
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to 
randomization. Patients should be recovered from the effects of radiation.  
There is no required minimum recovery period.
Asymptomatic metastatic lesions whose further growth would likely cause 
functional deficits or intractable pain (e.g., epidural metastasis that is not 
presently associated with spinal cord compression) should be considered for 
loco-regional therapy if appropriate prior to randomization.

Uncontrolled hypercalcemia (1.5 mmol/L ionized calcium or calcium 12 mg/dL or 
corrected serum calcium ULN) or symptomatic hypercalcemia requiring continued 
use of bisphosphonate therapy 
Patients who are receiving denosumab must discontinue denosumab use and 
replace it with a bisphosphonate instead while on study. There is no required 
minimum washout period for denosumab.
Patients who are receiving bisphosphonate therapy specifically to prevent 
skeletal events and who do not have a history of clinically significant 
hypercalcemia are eligible.


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
Malignancies other than TNBC within 5 years prior to randomization, with the 
exception of those with a negligible risk of metastasis or death and treated with 
expected curative outcome (such as adequately treated carcinoma in situ of the 
cervix or basal or squamous cell skin cancer)
4.1.2.2
General Medical Exclusion Criteria

Pregnancy or lactation

Evidence of significant uncontrolled concomitant disease that could affect 
compliance with the protocol or interpretation of results, including significant liver 
disease (such as cirrhosis, uncontrolled major seizure disorder, or superior vena 
cava syndrome)

Significant cardiovascular disease, such as New York Heart Association (NYHA) 
cardiac disease (Class II or greater), myocardial infarction within 3 months prior to 
randomization, unstable arrhythmias, or unstable angina
Patients with a known left ventricular ejection fraction (LVEF) 40% will be 
excluded.
Patients with known coronary artery disease, congestive heart failure not 
meeting the above criteria, or LVEF 50% must be on a stable medical regimen 
that is optimized in the opinion of the treating physician, in consultation with a 
cardiologist if appropriate.

Severe infection within 4 weeks prior to randomization, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia

Received 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.

Major surgical procedure within 28 days prior to randomization or anticipation of the 
need for a major surgical procedure during the course of the study other than for 
diagnosis
Placement of central venous access catheter(s) (e.g., port or similar) is not 
considered a major surgical procedure and is therefore permitted

Known hypersensitivity to nab-paclitaxel or to any of the excipients.
4.1.2.3
Exclusion Criteria Related to Atezolizumab

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, 


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multiple sclerosis, vasculitis, or glomerulonephritis (see Appendix 5 for a more 
comprehensive list of autoimmune diseases)
Patients with a history of autoimmune-mediated hypothyroidism on a stable 
dose of thyroid replacement hormone are eligible for this study.
Patients with controlled Type 1 diabetes mellitus on a stable insulin dosing 
regimen are eligible for this study.
Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with 
dermatologic manifestations only (e.g., no psoriatic arthritis) are permitted 
provided that they meet the following conditions:
Rash must cover less than 10% of body surface area (BSA).
Disease is well controlled at baseline and only requiring low potency topical 
steroids
No acute exacerbations of underlying condition within the last 12 months 
(not requiring PUVA [psoralen plus ultraviolet A radiation], 
methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, 
high potency or oral steroids)

Prior allogeneic stem cell or solid organ transplantation

History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced 
pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic 
organizing pneumonia), or evidence of active pneumonitis on screening chest CT 
scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Positive test for HIV

Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] 
test at screening) or hepatitis C 
Patients with past hepatitis B virus (HBV) infection or 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.
Patients positive for hepatitis C virus (HCV) antibody are eligible only if 
polymerase chain reaction (PCR) is negative for HCV RNA.

Active tuberculosis

Receipt of a live, attenuated vaccine within 4 weeks prior to randomization 
or anticipation that such a live, attenuated vaccine will be required during the study
Patients must agree not to receive live, attenuated vaccine (e.g., FluMist) 
within 28 days prior to randomization, during treatment, or within 5 months
following the last dose of atezolizumab/placebo.

Prior treatment with CD137 agonists or immune checkpoint blockade therapies,
including antiCTLA-4, antiPD-1, or antiPD-L1 therapeutic antibodies


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
Treatment with systemic immunostimulatory agents (including but not limited to 
interferons or IL-2) within 4 weeks or five half-lives of the drug (whichever is shorter)
prior to randomization

Treatment with systemic corticosteroids or other systemic immunosuppressive 
medications (including but not limited to prednisone, dexamethasone, 
cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis 
factor [TNF] agents) within 2 weeks prior to randomization, or anticipated 
requirement for systemic immunosuppressive medications during the study
Patients who have received acute, low-dose, systemic immunosuppressant 
medications (e.g., a one-time dose of dexamethasone for nausea) may be 
enrolled in the study 
Patients with a history of allergic reaction to IV contrast requiring steroid 
pre-treatment should have baseline and subsequent tumor assessments 
performed using MRI.
The use of inhaled corticosteroids for chronic obstructive pulmonary disease,
mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic 
hypotension, and low-dose supplemental corticosteroids for adrenocortical 
insufficiency are allowed.
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
After written informed consent has been obtained, all screening procedures and 
assessments have been completed, and eligibility has been established, the study site 
will obtain the patient’s identification number and treatment assignment from the 
interactive voice or Web response system (IxRS) for eligible patients.
Randomization will occur in a 1:1 ratio using a permuted-block randomization method. 
Patients will be randomized to one of two treatment arms: atezolizumabnab-paclitaxel 
or placebonab-paclitaxel.  The randomization scheme is designed to ensure that an 
approximately equal number of patients will be enrolled in each treatment arm within the 
baseline characteristics of the following stratification factors:

Presence of liver metastases (yes vs. no)

Prior taxane treatment (yes vs. no)

Tumor PD-L1 status (IC0 vs. IC1/2/3)
Patients should receive their first dose of study treatment on the day of randomization if 
possible.  If this is not possible, the first dose should occur no later than 3 days after 
randomization.
The Sponsor and its agents (with the exception of the IxRS service provider [the external 
independent statistical coordinating center responsible for verifying patient 
randomization and study treatment kit assignments], PK/PD laboratory personnel, and 
the iDMC members); the study site personnel, including the investigator; and the patient 
will be blinded to treatment assignment prior to unblinding (see Section 4.2.1).


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The Sponsor and its agents (with the exception of the PD-L1 assay provider and the 
iDMC members); the study site personnel, including the investigators; and the patients 
will be blinded to PD-L1 status prior to study unblinding of the treatment assignment at 
the study level.  
4.2.1
Unblinding
Unblinding of treatment assignment may occur under the following circumstances.
Emergency Unblinding
Per health authority reporting requirements, treatment assignment will be unblinded for 
serious, unexpected study drug-related toxicity (as part of the IND safety reporting 
process). In these instances, investigators will not be notified of individual patient’s
treatment assignment as a matter of course.   Emergency unblinding by the investigator 
should be a last resort performed only in cases when knowledge of treatment 
assignment will affect the management of a patient who experiences a 
treatment-emergent adverse event. Investigators are encouraged to consult with the 
Medical Monitor prior to performing emergency unblinding.  If unblinding is necessary for 
patient safety management, the investigator is credentialed to break the treatment code 
within the IxRS autonomously by means of a pin code which is issued to them at the 
start of the study. All such occurrences should be documented in the study file.
Unblinding should not result in the withdrawal of the patients from the study. Every effort 
should be made to retain unblinded patients and continue data collection as per 
protocol.
Unblinding at the Study Level
Treatment assignment will be unblinded prior to the primary analysis, after all data have 
been cleaned and verified and the database has been locked.
For the process related to the interim efficacy analyses, see Section 3.1.1.
4.3
STUDY TREATMENT
Atezolizumab/placebo and nab-paclitaxel are considered the investigational medicinal 
products (IMPs) in this study. 
4.3.1
Formulation, Packaging, and Handling 
4.3.1.1
Atezolizumab/Placebo
Atezolizumab will be supplied by the Sponsor as sterile liquid in 20-mL glass vials. For 
information on the formulation and handling of atezolizumab, refer to the Investigator's 
Brochure and Pharmacy Manual.  The vial contains 20 mL (1200 mg) of atezolizumab 
solution. Fourteen (14 mL) of atezolizumab solution will contain an 840-mg dose.
Placebo will consist of the vehicle without the antibody. Placebo will be supplied in a 
single-use, 20-cc USP/Ph. Eur. Type 1 glass vial as a colorless, sterile, preservative-free 
clear liquid solution intended for IV administration.  The vial contains approximately 


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20 mL of solution.  The formulation contains 20 mM histidine acetate, 120 mM sucrose, 
and 0.04% polysorbate 20, pH 5.8.
For further details on the storage and preparation of atezolizumab/placebo, see the 
Pharmacy Manual and the Investigator’s Brochure.
Atezolizumab/placebo will be supplied by the Sponsor.
4.3.1.2
nab-Paclitaxel
Refer to the nab-paclitaxel (Abraxane®) Package Insert for details on formulation and 
storage.
nab-Paclitaxel will be supplied by the Sponsor. 
4.3.2
Dosage, Administration, and Compliance
On days of scheduled infusions of atezolizumab or placebo and nab-paclitaxel (i.e., 
Day 1 and Day 15 of every cycle; nab-paclitaxel will be administered alone on Day 8 of 
every cycle), chemotherapy is to be administered after infusion of atezolizumab/placebo.
4.3.2.1
Atezolizumab or Placebo
Patients will receive atezolizumab 840 mg or placebo administered by IV infusion q2w 
(every 14 [3] days).
Administration of atezolizumab or placebo will be performed in a setting with emergency 
medical facilities and staff who are trained to monitor for and respond to medical 
emergencies.
Atezolizumab or placebo infusions will be administered per the instructions outlined in 
Table 1.


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Table 1
Administration of First and Subsequent Infusions of 
Atezolizumab/Placebo
Administration of First and Subsequent Infusions of Atezolizumab/Placebo
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 14 mL atezolizumab (840 mg) in 
250 mL NaCl) over 60 (15) minutes.

Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) during and after the infusion if 
clinically indicated

Patients will be informed about the possibility 
of delayed symptoms following infusion 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 at subsequent infusions
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 
administered over 30 (10) minutes.

If no reaction occurs, subsequent 
infusions may be administered over 
30 (10) minutes
Continue to record vital signs within 
60 minutes before starting infusion 
and during and after the infusion if 
clinically indicated.

If the patient had an infusion-related 
reaction during the previous infusion, the 
subsequent infusion must be administered 
over 60 (15) minutes.
Record patient’s vital signs (heart 
rate, respiratory rate, blood pressure, 
and temperature) during and after 
the infusion if clinically indicated.
Dose reduction of atezolizumab/placebo is not permitted. Guidelines for treatment 
interruption or discontinuation and the management of specific adverse events are 
provided in Sections 5.1.5 and 5.1.6, respectively.
Refer to the Atezolizumab Investigator’s Brochure and Pharmacy Manual for detailed 
instructions on drug preparation, storage, and administration.
4.3.2.2
nab-Paclitaxel
nab-Paclitaxel will be administered according to the local prescribing information. The 
starting dose level of nab-paclitaxel in this study will be 100 mg/m2 administered 
intravenously over 30 minutes on Days 1, 8, and 15 of each 28-day cycle 
(3-weeks-on/1-week-off schedule). Doses of nab-paclitaxel should not be administered 


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more frequently than every 7 days. Dose modifications should be performed according 
to Section 5.1.7.
Sites should follow their institutional standard of care for determining the nab-paclitaxel 
dose for patients who are obese and for dose adjustments in the event of patient weight 
changes. The infusion site should be closely monitored for possible infiltration during 
drug administration.
In the absence of disease progression or unacceptable toxicity, nab-paclitaxel will be
administered for a target of at least 6 cycles, with no maximum.
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (atezolizumab, placebo, and nab-paclitaxel) 
will be provided by the Sponsor where required by local health authority regulations.
The investigational site will acknowledge receipt of the IMPs using the IxRS to confirm 
the shipment condition and content.  Any damaged shipments will be replaced and must 
be reported immediately to the study monitor.
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
The Sponsor will offer continued access to Roche IMP (atezolizumab) free of charge to 
eligible patients in accordance with the Roche Global Policy on Continued Access to
Investigational Medicinal Product, as outlined below.
A patient will be eligible to receive Roche IMP (atezolizumab) after completing the study 
if all of the following conditions are met:

The patient has a life-threatening or severe medical condition and requires 
continued Roche IMP treatment for his or her well-being

There are no appropriate alternative treatments available to the patient

The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them


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A patient will not be eligible to receive Roche IMP (atezolizumab) after completing the 
study if any of the following conditions are met:

The Roche IMP is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient)

The Sponsor has discontinued development of the IMP or data suggest that the IMP 
is not effective for metastatic or unresectable locally advanced TNBC that has not 
received prior chemotherapy for metastatic disease

The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
metastatic or unresectable locally advanced TNBC that has not received prior 
chemotherapy for metastatic disease

Provision of the Roche IMP is not permitted under the laws and regulations of the 
patient's country
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
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 to the treatment discontinuation visit.  All such medications 
should be reported to the investigator and recorded on the Concomitant Medications
electronic Case Report Form (eCRF).
Premedication with antihistamines may be administered for any atezolizumab/placebo
infusions after Cycle 1, Day 1.
The following therapies are permitted on study:

Prophylactic or therapeutic anticoagulation therapy (such as lowmolecular weight 
heparin or warfarin at a stable dose level)

Palliative radiotherapy (e.g., treatment of known bone metastases) provided it does 
not interfere with assessment of tumor target lesions
It is not required to hold atezolizumab/placebo during palliative radiotherapy; 
nab-paclitaxel should be interrupted per institutional standard of care.

Inactivated vaccinations (including for influenza)

Megestrol administered as an appetite stimulant

Inhaled corticosteroids for chronic obstructive pulmonary disease

Mineralocorticoids (e.g., fludrocortisone)


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
Low-dose corticosteroids for patients with orthostatic hypotension or adrenocortical 
insufficiency

Bisphosphonates for the prevention of skeletal events
Patients who are receiving denosumab must be willing and able to receive a 
bisphosphonate instead while on study. There is no required minimum washout 
period for patients who discontinue denosumab. 
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated and 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 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 6).
4.4.2
Excluded and Cautionary Therapy
The following medications are excluded while the patient is receiving study treatment:

Other systemic anti-cancer therapy

RANKL inhibitor (denosumab): patients who are receiving denosumab prior to 
randomization must be willing and eligible to receive a bisphosphonate instead while 
on study.

Immunomodulatory agents, including but not limited to interferons or IL-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.

Use of steroids to premedicate patients for whom CT scans with contrast are 
contraindicated (i.e., patients with contrast allergy or impaired renal clearance); in 
such patients, MRIs of the chest, abdomen, and pelvis with a non-contrast CT scan
of the chest must be performed.

Any live, attenuated vaccine (e.g., FluMist®) within 28 days prior to randomization, 
treatment, or within 5 months following the last dose of atezolizumab/placebo.
Systemic corticosteroids and antiTNF-agents may also attenuate potential beneficial 
immunologic effects of treatment with atezolizumab but may be administered at the 
discretion of the treating physician.  If feasible, alternatives to these agents should be 
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In addition, patients should not receive other immunomodulatory agents for 10 weeks 
after atezolizumab discontinuation.
The concomitant use of herbal therapies is not recommended, as their pharmacokinetics, 
safety profiles, and potential drug-drug interactions are generally unknown. However, 
their use for patients in the study is allowed at the discretion of the investigator.
4.4.3
Concomitant Medications with nab-Paclitaxel
The metabolism of nab-paclitaxel is catalyzed by cytochrome P450 (CYP) isoenzymes 
CYP2C8 and CYP3A4. Caution should be exercised when nab-paclitaxel is 
concomitantly administered with known inhibitors (e.g., atazanavir, clarithromycin, 
indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and 
telithromycin) and inducers (e.g., rifampin and carbamazepine) of CYP3A4.
G-CSF treatment is permitted for patients receiving nab-paclitaxel. The primary 
prophylaxis should be administered per the American Society of Clinical Oncology 
(ASCO), EORTC, and ESMO guidelines; namely, in patients who are 60 years of age 
and/or with comorbidities (Smith et al. 2006; Crawford et al. 2009; Aapro et al. 2011).
Evidence supporting the use of long-acting (pegylated) forms of G-CSF in patients 
receiving weekly chemotherapy is limited, and investigators should consider giving 
preference to conventional formulations of G-CSF.
Anti-emetics, anti-allergic measures, and other treatments for concomitant nab-paclitaxel 
toxicities may be used at the discretion of the investigator, taking into account 
precautions from the Summary of Product Characteristics.
Refer to the Summary of Product Characteristics (package insert) for nab-paclitaxel for 
all boxed warnings and contraindications.
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.


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4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.
Informed Consent Forms for enrolled patients and for patients who are not subsequently 
enrolled will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before randomization.  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.
4.5.2
Description of Study Assessments
4.5.2.1
Medical History and Demographic Data
Medical history includes clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history, 
use of alcohol and drugs of abuse, 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 Cycle 1, Day 1 visit.
TNBC history will include prior cancer therapies, procedures, and an assessment of 
tumor mutational status.
Demographic data will include age and self-reported race/ethnicity.
4.5.2.2
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, genitourinary, and neurological systems.  Any abnormality identified at 
baseline should be recorded on the General Medical History and Baseline Conditions 
electronic Case Report Form (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.
4.5.2.3
Vital Signs
Vital signs will include measurements of respiratory rate, heart rate, systolic and diastolic 
blood pressures while the patient is in a seated position, and temperature.
At all clinic visits where study treatment is administered, vital signs should be determined 
within 60 minutes before the first infusion. Vital signs will also be determined during and 
after the infusions if clinically indicated (see Table 1).


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4.5.2.4
Tumor and Response Evaluations
All sites of measurable and non-measurable disease must be documented at screening 
and re-assessed at each subsequent tumor evaluation. Tumor assessments are to be 
performed at the timepoints specified in Appendix 1, regardless of drug delays or 
interruptions. Tumor assessments will continue until disease progression, withdrawal of 
consent, death, or study termination by the Sponsor, whichever occurs first.
Initial screening assessments must include CT scans (with oral/IV contrast unless 
contraindicated) or MRI of the chest, abdomen, and pelvis.  Bone scan or PET scan 
should also be performed to evaluate for bone metastases.  A spiral CT scan of the 
chest may be obtained but is not a requirement.  MRIs of the chest, abdomen, and pelvis 
with a noncontrast CT scan of the chest may be used in patients for whom CT scans 
with contrast are contraindicated (i.e., patients with contrast allergy or impaired renal 
clearance).
A CT (with contrast) or MRI scan of the head must be performed at screening to 
evaluate CNS metastasis in all patients. An MRI scan of the brain is required to confirm 
or refute a diagnosis of CNS metastasis at screening in the event of an equivocal scan. 
Patients with active or untreated CNS metastasis are not eligible for this study (see 
Section 4.1.2.1 for CNS-related exclusion criteria).
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.
CT scans of the neck should also be performed if clinically indicated during the 
screening period.  At the investigator’s discretion, other methods of assessment of 
measurable disease per RECIST v1.1 may be used.
After baseline tumor assessments, evaluation of tumor response per RECIST v1.1 (see 
Appendix 3) will be performed every 8 weeks for the first 12 months following 
randomization (1 week) and every 12 weeks thereafter (1 week), with additional scans 
performed as clinically indicated. The same radiographic procedures used to assess 
measurable disease sites at screening should be used throughout the study (e.g., the 
same contrast protocol for CT scans and/or MRI).  All known sites of disease must be
documented at screening and re-assessed at each subsequent tumor evaluation. 
Assessments should be performed by the same evaluator, if possible, to ensure internal 
consistency across visits.
At the investigator’s discretion, CT or other clinically appropriate scans may be repeated 
at any time if progressive disease is suspected.  If the initial screening bone scan or 
PET scan does not show evidence of bone metastases, then these procedures do not 
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All primary imaging data used for tumor assessment will be collected by the Sponsor to 
enable centralized, independent review of response endpoints, if needed.
If treatment is discontinued prior to disease progression per RECIST v1.1, tumor 
response assessment should continue to be performed per the schedule specified above.
4.5.2.5
Laboratory, Biomarker, and Other Biological Samples
Refer to the laboratory manual for additional details on laboratory assessments and 
sample handling.
Local Laboratory Assessments
Samples for the following laboratory tests will be sent to the study site’s local laboratory 
for analysis:

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, total protein, and albumin)
Levels of magnesium and phosphorus must be tested during screening.  During 
treatment, levels of magnesium and phosphorus should be tested as clinically 
indicated

Coagulation (aPTT and INR)

Serum pregnancy test for women of childbearing potential, including women who 
have had a tubal ligation; urine pregnancy tests will be performed at each cycle 
during treatment.  If a urine pregnancy test is positive, it must be confirmed by a 
serum pregnancy test.
Childbearing potential is defined as not having undergone surgical sterilization, 
hysterectomy, and/or bilateral oophorectomy or not being postmenopausal 
(12 months of amenorrhea).

Levels of magnesium and phosphorus must be tested during screening.  During 
treatment, levels of magnesium and phosphorus should be tested as clinically 
indicated

Thyroid function testing (thyroid-stimulating hormone [TSH], free T3, free T4)

HIV (tested prior to inclusion into the study)
HIVpositive patients will be excluded from study participation.

HBV serology (HBsAg, antibody to HBsAg [anti-HBs], anti-HBc)
HBV DNA testing is required on or before Cycle 1, Day 1 if the patient has 
negative serology for HBsAg and positive serology for anti-HBc. 

HCV serology (anti-HCV)


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Central Laboratory Assessments
The assessments listed below will be performed at a central laboratory or by the 
Sponsor.  Any residual material from samples collected to enable these central 
assessments may be used for additional atezolizumab-related safety assessments (e.g., 
ATA assay), exploratory biomarker profiling, identification, and PD assay development 
purposes.  Instruction manuals and supply kits will be provided for all central laboratory 
assessments.

C-reactive protein (CRP)

ATA assays
Serum samples will be assayed for the presence of ATAs to atezolizumab using
validated immunoassays.

PK assays
Serum samples will be assayed for atezolizumab concentration using a 
validated immunoassay.
Plasma samples will be assayed for nab-paclitaxel using validated methods.

Auto-antibody testing; baseline sample to be collected on Cycle 1, Day 1 prior to the
first dose of study drug. For patients who show evidence of immune-mediated
toxicity, additional samples may be collected and all samples will be analyzed 
centrally.
Antidouble-stranded DNA
Circulating anti-neutrophil cytoplasmic antibody
Perinuclear anti-neutrophil cytoplasmic antibody

Biomarker assays
Blood samples will be obtained for biomarker evaluation (including but not 
limited to biomarkers that are related to TNBC or tumor immune biology) from 
all eligible patients according to the schedule in Appendix 2.  Samples will be 
processed to obtain plasma and serum for the determination of changes in 
blood-based biomarkers. Whole blood samples may be processed to obtain 
peripheral blood mononuclear cells (PBMCs) and their derivatives (e.g., RNA
and DNA).

Archival or fresh tumor tissue samples for eligibility
Representative tumor specimens in paraffin blocks (preferred) or at least 
20 unstained slides, with an associated pathology report, must be submitted for 
determination of PD-L1 status prior to study enrollment. 
Patients with fewer than 20 unstained slides available at baseline (but no fewer 
than 12) may be eligible upon discussion with the medical monitor.
A portion of archival and pre-treatment tumor specimens will be used for 
confirmation of ER, PR, and HER2 triple-negative status by a central testing 
laboratory.


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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, and lavage samples are not acceptable.  For core needle 
biopsy specimens, at least three cores should be submitted for evaluation.
Patients having additional tissue samples from procedures performed at 
different times during the course of their breast tumor will be requested (but not 
required) to also submit these samples for central testing.  Tissue samples 
obtained at multiple times for individual patients will greatly contribute to an 
improved understanding of the dynamics of PD-L1 expression and relationship 
with intervening anticancer therapy.
The status of immune-mediated and tumor typerelated, and other exploratory 
biomarkers (including but not limited to T-cell markers) in archival and fresh 
tumor tissue samples of enrolled patients may be evaluated.
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.
If clinically feasible, the Sponsor also requests fresh pre-treatment biopsy 
specimens obtained from either relapsed metastatic or locally advanced 
disease.  Acceptable samples include core needle biopsies for deep tumor 
tissue or excisional, incisional, punch, or forceps biopsies for cutaneous, 
subcutaneous, or mucosal lesions.  For core needle biopsy specimens, at least 
three cores should be submitted for evaluation.
Tumor tissue from bone metastases is not evaluable for PD-L1 expression and 
is therefore not acceptable.

Biopsy at radiographic progression
All patients will undergo a mandatory tumor biopsy sample collection, if 
clinically feasible and if permitted by local guidelines and regulations, at the 
time of radiographic disease progression. 

Optional biopsy
Patients may agree to provide optional tumor tissue samples for biopsy by 
providing consent on the Consent for Optional Biopsy, which is separate from 
the main study Informed Consent Form. For patients who agree to optional 
biopsies, biopsy samples may be collected prior to dosing on Cycle 2, Day 1
(7 days) per investigator discretion
Acceptable samples include core needle biopsies for deep tumor tissue or lymph nodes 
or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or 
mucosal lesions. For core needle biopsy specimens, at least three cores should be 
submitted for evaluation.


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Use and Storage of Remaining Samples from Study-Related Procedures
If a patient undergoes a medically indicated procedure (e.g., bronchoscopy, 
esophagogastroduodenoscopy, colonoscopy, etc.) 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 (body fluid samples or leftover tumor 
tissue) may be used for exploratory analysis. Patients must provide specific consent in 
order for discarded samples from routine care to be obtained.
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 in the RCR for future research 
(see Section 4.5.6), the samples will be destroyed no later than 15 years after the date 
of final closure of the clinical database.
4.5.3
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 study treatment (see 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.
4.5.4
Electrocardiograms and Cardiac Function Assessment
A twelve-lead ECG is required at screening and when clinically indicated.  ECGs for 
each patient should be obtained from the same machine wherever possible.  ECG 
recordings must be performed after the patient has been resting in a supine position for 
at least 10 minutes.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Any clinically significant morphologic waveform changes or other 
ECG abnormalities must be documented on the eCRF.
4.5.5
Patient-Reported Outcomes
The EORTC QLQ-C30, QLQ-BR23, and EQ-5D-5L questionnaires will be collected to 
more fully characterize the clinical profile of atezolizumabnab-paclitaxel and nab 
paclitaxel.
The EORTC QLQ-C30 and the QLQ-BR23 (see Appendix 4) are validated and reliable 
self-report measures (Aaronson et al. 1993; Sprangers et al. 1996; Osoba et al. 1997). 


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The EORTC QLQ-C30 (version 3) consists of thirty questions that assess global HRQoL, 
including five aspects of patient functioning (physical, emotional, role, cognitive, and 
social); three symptom scales (fatigue, nausea and vomiting, and pain); and 
six single-items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial 
difficulties) with a recall period of “the last week”. Scale scores can be obtained for the 
multi-item scales. The breast cancerspecific QLQ-BR23 module consists of 
23 additional items assessing disease/treatment symptoms (systemic therapy side 
effects, breast symptoms, arm symptoms, and hair loss) and aspects of patient 
functioning (body image, sexual functioning, and future perspective). Because the 
QLQ-BR23 was not developed or tested and validated with men, male patients in this 
study will not complete the QLQ-BR23 measure.
The EQ-5D-5L (see Appendix 4) is a generic, preference-based measure that assesses 
health status and is used to inform pharmacoeconomic evaluations.  The EQ-5D-5L
consists of two parts: the health state classification and the visual analogue scale 
(EQ VAS). The health state classification contains five dimensions of health:  mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression (Herdman et al. 2011; 
Janssen et al. 2013).  From these five items, a utility measure is obtained for each 
patient.  The EQ VAS records the respondent’s self-rated health on a scale from 0 (“the 
worst health you can imagine”) to 100 (“the best health you can imagine”).
The PRO instruments will be translated as required in the local language and completed 
in their entirety by the patient.  To ensure instrument validity and that data standards 
meet health authority requirements, PRO questionnaires scheduled for administration 
during a clinic visit must be completed by the patient at the investigational site at the 
start of the clinic visit prior to other study assessments and before administration of 
study treatment.  Interviewer assessment is allowed but can only be conducted by a 
member of the clinic staff if the patient is unable to complete the measure on their own.  
Study personnel should review all questionnaires for completeness before the patient 
leaves the investigational site.
An electronic PRO (ePRO) data collection modality will be employed.  To capture PRO 
data during study treatment, patients will complete the questionnaires on an ePRO tablet 
at the site.  The ePRO device and instructions for completing the PRO questionnaires 
electronically will be provided by the investigator staff. The data will be transmitted via a 
pre-specified transmission method (e.g., Web or wireless) automatically after entry to a 
centralized database at the ePRO vendor.  The data can be accessed securely by 
appropriate study personnel via the Internet.   
The PRO questionnaires (EORTC QLQ-C30, QLQ-BR23, and EQ-5D-5L) will be 
completed on the ePRO device at the site at baseline (Cycle 1, Day 1) and Day 1 of 
each subsequent cycle, and at the end of treatment/discontinuation visit. In addition, all 
patients will complete the PRO questionnaires every 28 days for 1 year after treatment 
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therapy.  Questionnaires will be completed after treatment discontinuation by the patient 
at home on an ePRO handheld device provisioned to the patient at the time of the 
treatment discontinuation visit.
4.5.6
Samples for Roche Clinical Repository
4.5.6.1
Overview of the Roche Clinical Repository
The RCR is a centrally administered group of facilities 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
4.5.6.2
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 Institutional Review Board or Ethics Committee (IRB/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 4.5.6) will not be 
applicable at that site.
4.5.6.3
Sample Collection
The following samples will be collected for the identification of dynamic (non-inherited) 
biomarkers for patients who have signed the RCR optional consent:

Remaining blood derivatives (serum, plasma, and PBMCs and their derivatives) after 
study-related tests have been performed

Remaining FFPE tissue (with the exception of archival FFPE blocks, which will be 
returned to sites) after study-related tests have been performed

Leftover tumor tissue samples (from clinically indicated procedures performed during 
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A blood sample for DNA isolation and genetic biomarker analysis will be collected from
patients who have consented to optional RCR sampling at baseline as shown in the 
schedule of assessments in Appendix 1.  If, however, the RCR genetic blood sample is 
not collected during the scheduled visit, it may be collected as soon as possible (after 
randomization) during the conduct of the clinical study.  Collection of whole blood may 
enable the evaluation of single nucleotide polymorphisms in genes associated with 
immune biology including but not restricted to the target and pathway associated genes 
such as PD-L1, PD-1, and B7.1.  The sample may be processed using techniques such 
as kinetic PCR and DNA sequencing.
For all samples, the 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 destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  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.
4.5.6.4
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.
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 


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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.
4.5.6.5
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 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.
4.5.6.6
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 using the RCR Patient Withdrawal Form and, if 
the study 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 study is closed.  A patient's withdrawal from 
Study WO29522 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 WO29522.
4.5.6.7
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 
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 


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Informed Consent Form.  Roche monitors (or their designees) 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, 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 noncompliance
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.
4.6.1.1
Discontinuation from Study Drug
Patients must discontinue study drug if they experience any of the following:

Intolerable toxicity related to study treatment

Any medical condition that may jeopardize the patient’s safety if he or she continues 
on study treatment

Use of another systemic anti-cancer therapy (see Section 4.4.2)

Pregnancy

Radiographic disease progression per RECIST v1.1
The primary reason for study drug discontinuation should be documented on the 
appropriate eCRF.
4.6.2
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


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The Sponsor will notify the investigator if the study is placed on hold or if the Sponsor 
decides to discontinue the study or the development program.
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

Noncompliance 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
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria (see Sections 4.1.1 and 
4.1.2) and close monitoring (as indicated below and in Section 4.5).  Section 5.3
(Methods and Timing for Capturing and Assessing Safety Parameters) provides 
complete details regarding safety reporting for this study.  An iDMC (see Section 3.1.1) 
has also been incorporated into the study design to periodically review aggregate safety
data.
Administration of study treatment will be performed in a setting with emergency medical 
facilities and staff who are trained to monitor for and respond to medical emergencies. 
All adverse events and serious adverse events will be recorded during the study and for 
up to 30 days after the last dose of study drug or until the initiation of another anti-cancer 
therapy, whichever occurs first. After this period, investigators should report serious 
adverse events and adverse events of special interest that are believed to be related to 
prior treatment with study drug.  The potential safety issues anticipated in this study, as 
well as measures intended to avoid or minimize such toxicities, are outlined in the 
following sections.
This is a double-blind study. Study treatment assignment may be unblinded for a 
serious, unexpected study drug-related toxicity (as part of the IND safety reporting 
process; see Section 4.2.1). Emergency unblinding should be a last resort only 
performed in cases where knowledge of treatment assignment will affect the ongoing
management of a patient who experiences a treatment-emergent adverse event.
5.1.1
Risks Associated with Atezolizumab
Atezolizumab has been associated with risks such as the following:  infusion-related 
reactions (IRRs) and immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, 


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diabetes mellitus, hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, 
Guillain-Barré syndrome, myasthenic syndrome/myasthenia gravis, meningoencephalitis, 
myocarditis, nephritis, and myositis.  Immune-mediated reactions may involve any 
organ system and may lead to hemophagocytic lymphohistiocytosis and macrophage 
activation syndrome (considered to be potential risks for atezolizumab).  Refer to 
Appendix 10 of the protocol for the AE management guidelines and Section 6 of the 
Atezolizumab Investigator’s Brochure for a detailed description of anticipated risks for 
atezolizumab.
5.1.2
Risks Associated with nab-Paclitaxel
In clinical studies and post-marketing experience, nab-paclitaxel has been associated 
with alopecia, myelosuppression (primarily neutropenia, anemia, thrombocytopenia), 
peripheral neuropathy, cranial nerve palsies, hypersensitivity reactions, pneumonitis, 
gastrointestinal events (i.e., nausea, vomiting, diarrhea), myalgia, arthralgia, 
cardiotoxicity (myocardial disorders, cardiac failure, angina, tachycardia, ventricular 
arrhythmia), cystoid macular edema, Stevens-Johnson syndrome/toxic epidermal 
necrolysis, sepsis, infusion site reactions/extravasation, hepatic toxicity (drug-induced 
liver injury), acute renal failure, hemolytic-uremic syndrome, drug-induced lupus 
erythematous, and tumor lysis syndrome.
Patients will be monitored for nab-paclitaxelrelated adverse events, including 
hematologic, gastrointestinal, hepatic toxicities, and peripheral neuropathy. 
For more details regarding the safety profile of nab-paclitaxel, refer to the local 
prescribing information. Other specific instructions can be found in Sections 4.4.3 and 
5.1.7 for nab-paclitaxel.
5.1.3
General Plan to Manage Safety Concerns
5.1.3.1
Eligibility Criteria
Eligibility criteria were selected to guard the safety of patients in this study.  Results from 
the nonclinical toxicology studies with atezolizumab, as well as the nonclinical/clinical 
data from other PD-L1/PD-1 inhibitors, 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 of randomization are excluded from the 
study (see Section 4.1 for additional details).
5.1.3.2
Monitoring
Safety will be evaluated in this study through the monitoring of all serious and 
non-serious adverse events defined and graded according to NCI CTCAE v4.0.  Patients 
will be assessed for safety (including laboratory values) according to the schedule in
Appendix 1.  Laboratory values must be reviewed prior to each infusion.


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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 adverse 
events, including signs or symptoms of autoimmune conditions and infection.
All serious adverse events and protocol-defined events of special interest will be 
reported in an expedited fashion (see Sections 5.2.2 and 5.2.3).
Patients will be followed for safety for 30 days following their last dose of study drug or 
until they receive another anti-cancer therapy, whichever comes first.
Patients who have an ongoing study drug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 
until it has been determined that study treatment or participation is not the cause of the 
adverse event.
5.1.4
Dose Modification
5.1.4.1
General Notes Regarding Dose Modification
Reasons for dose modifications or delays, the supportive measures taken, and the 
outcomes will be documented in the patient's chart and recorded on the eCRF.  
The severity of adverse events will be graded according to the NCI CTCAE v4.0 grading 
system.

Dose reduction of atezolizumab/placebo is not permitted.  

For any concomitant conditions already apparent at baseline, the dose modifications 
will apply according to the corresponding shift in toxicity grade, if the investigator 
feels it is appropriate.  For example, if a patient has Grade 1 asthenia at baseline 
that increases to Grade 2 during treatment, this will be considered a shift of 
one grade and treated as Grade 1 toxicity for dose-modification purposes.

When several toxicities with different grades of severity occur at the same time, 
the dose modifications should be according to the highest grade observed.

If, in the opinion of the investigator, a toxicity is considered to be due solely to 
one component of the study treatment (i.e., atezolizumab/placebo or nab-paclitaxel) 
and the dose of that component is delayed or modified in accordance with the 
guidelines below, the other component may be administered if there is no 
contraindication.

When treatment is temporarily interrupted because of toxicity caused by 
atezolizumab/placebo or nab-paclitaxel, the treatment cycles will be restarted such 
that the atezolizumab/placebo and nab-paclitaxel infusions remain synchronized.


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
If it is anticipated that nab-paclitaxel will be delayed by 2 weeks, then 
atezolizumab/placebo should be given without the chemotherapy if there is 
no contraindication.

In general, the start of a cycle may be delayed to allow recovery from toxicities, but 
there shall be no delay within cycles. Cycle length is fixed at 28 days, and dosing 
on Days 8 and 15 of a cycle may be skipped but shall not be delayed outside of the 
window specified in the Appendix 1 (i.e., 3 days).
The treating physician may use discretion in modifying or accelerating the 
dose modification guidelines described below depending on the severity of toxicity and
an assessment of the risk versus benefit for the patient, with the goal of maximizing 
patient compliance and access to supportive care.
5.1.5
Atezolizumab/Placebo Dose Modification
There will be no dose reduction for atezolizumab or placebo in this study.  Patients may 
temporarily suspend study treatment if they experience an adverse event that requires a 
dose to be held.  If atezolizumab or placebo is held because of adverse events for 
12 weeks after event onset, then the patient will be discontinued from atezolizumab or 
placebo treatment and will be followed for safety as specified in Section 5.5. If, in the 
judgment of the investigator, the patient is likely to derive clinical benefit from resuming 
atezolizumab after a hold 12 weeks, study drug may be restarted with the approval of
the Medical Monitor.
If a patient must be tapered off steroids used to treat adverse events, atezolizumab or 
placebo may be held for 12 weeks 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 investigator and the Medical 
Monitor will determine the acceptable length of treatment interruption.
5.1.6
Management of Atezolizumab/Placebo-Specific Adverse Events
For details on the management of infusion-related reactions and all other immune-
mediated adverse events, including but not limited to, gastrointestinal, dermatologic, 
endocrine, pulmonary toxicity, hepatotoxicity, pancreatic, or eye toxicity refer to the 
Appendix 10.
Refer to Section 5.1.7.5 and Table 6 for management of pulmonary events, including
pneumonitis, for atezolizumab/placebo and nab-paclitaxel. 


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5.1.7
nab-Paclitaxel Dose Modification and Management of Specific 
Adverse Events
5.1.7.1
Hematologic Toxicity
In general, ANC must be 1500/L and platelet count must be 100,000/L on Day 1 of 
each cycle. When nab-paclitaxel is administered on Day 1, it should not be administered 
on Days 8 or 15 of the cycle unless ANC 500 cells/L and platelets 50,000 cells/L.  
In certain situations (see Section 5.1.4.1) a cycle may begin with the administration of 
atezolizumab/placebo alone (without nab-paclitaxel on Day 1). If Day 1 of a cycle begins 
with only atezolizumab/placebo but without the administration of nab-paclitaxel due to 
low platelet or ANC levels, nab-paclitaxel should not be administered subsequently
within that cycle until ANC 1500/Land platelet count ≥100,000/L If the delay in 
re-starting nab-paclitaxel is 7 days (i.e., counts do not recover until Day 15) dosing 
should be resumed with applicable reductions according to the criteria in Table 2.
If the start of a cycle is delayed (i.e. both atezolizumab/placebo and nab-paclitaxel are 
held) for low counts, postpone Day 1 and resume dosing when counts recover with 
applicable reductions according to criteria in Table 2. 
If nab-paclitaxel cannot be administered on Day 8 of the cycle, it may be administered 
on Day 15 if counts have recovered to permissible levels with applicable dose reductions 
according to the criteria in Table 2.
If nab-paclitaxel cannot be administered on Day 15 of the cycle, the next dose of 
nab-paclitaxel should be administered on Day 1 of the following cycle when ANC and 
platelets counts have recovered to permissible levels.  When dosing resumes, the 
nab-paclitaxel doses should be permanently reduced as outlined in Table 2. 


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Table 2
nab-Paclitaxel Permanent Dose Reductions for Hematologic 
Toxicity
Hematologic Toxicity
Occurrence
Weekly 
nab-Paclitaxel 
Dose (mg/m2)
Neutropenic fever (nadir ANC 500/L
with fever 38°C)
or
Delay of first administration of nab-
paclitaxel in a cycle by 7 days for
nadir ANC 1500/L
or
Nadir ANC 500/L for 7 days
First
75
Second
50
Third
Discontinue 
treatment
Nadir platelet count 50,000/L
First
75
Second
Discontinue 
treatment
ANCabsolute neutrophil count; AUCarea under the concentration-time 
curve.
5.1.7.2
Gastrointestinal Toxicity
For Grade 3 or 4 gastrointestinal toxicities, treatment should be delayed until resolution 
to less than or equal to the patient’s baseline value. Dose reductions at the start of the 
subsequent cycle will be based on gastrointestinal toxicities from the dose administered 
in the preceding cycle. Table 3 provides the relevant dose adjustments for 
gastrointestinal toxicities.
Table 3
nab-Paclitaxel Dose Modification Based on Gastrointestinal 
Toxicities in the Preceding Cycle
Toxicity
Grade
Adjusted nab-Paclitaxel Dose as 
Percentage of Starting Dose
Diarrhea
Grade 4
Discontinue nab-paclitaxel
Oral mucositis/stomatitis
Grade 4
Discontinue nab-paclitaxel
Oral mucositis/stomatitis
Grade 3
1st occurrence: 75%
2nd occurrence: 50%
3rd occurrence: discontinue nab-paclitaxel
Diarrhea
Grade 3
Nausea/vomiting
Grade 3 or 4


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Nausea and/or vomiting should be controlled with adequate anti-emetics. If Grade 3 or 
4 nausea/vomiting occurs in spite of anti-emetics, the dose should be reduced by 25% 
for the next course.
5.1.7.3
Neurological Toxicity
Nab-paclitaxel should be withheld for Grade 34 peripheral neuropathy and may be 
resumed at reduced doses (see Table 4) when peripheral neuropathy recovers to 
Grade 1 or completely resolves. 
Table 4
nab-Paclitaxel Permanent Dose Reductions for Neurological 
Toxicity 
Neurological Toxicity
Occurrence
Weekly nab-Paclitaxel Dose 
Modification
Grade 3 or 4 peripheral 
neuropathy
First
Withhold treatment until resolves 
to Grade 1, then resume 
treatment at 75 mg/m2
Second
Withhold treatment until 
peripheral neuropathy resolves to 
Grade 1, then resume treatment 
at 50 mg/m2
Third
Discontinue treatment
5.1.7.4
Hepatic Toxicity
Nab-paclitaxel should be withheld for Grade 3 or 4 hepatic toxicity as specified in 
Table 5.


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Table 5
nab-Paclitaxel Dose Modification for Hepatic Toxicity
Hepatic Toxicity
Nab-Paclitaxel Dose Modification 
SGOT (AST) level 
10ULN
and
Bilirubin level ULN to 
1.5ULN
No dose modification;
proceed with 100 mg/m2
SGOT (AST) level
10ULN
and
Bilirubin level 
1.5 to 5ULN
Interrupt treatment until SGOT (AST) 
level 10ULN and bilirubin level 
1.5ULN, then reduce to 75 mg/m2 a
If toxicity does not resolve to above 
criteria within 3 weeks, discontinue 
treatment.
SGOT (AST) or SGPT 
(ALT) level 10ULN
or
Bilirubin level 
5ULN
Discontinue treatment
SGOTserum glutamic-oxaloacetic transaminase; SGPTserum 
glutamic pyruvic transaminase; ULNupper limit of normal.
a A dose increase to 100 mg/m
2 in subsequent courses should be 
considered if the patient tolerates the reduced dose for two cycles.
The investigator should make all efforts to exclude malignant disease progression as a 
cause of liver enzyme derangement.
5.1.7.5
Pulmonary events/Pneumonitis:  Atezolizumab/Placebo and 
nab-Paclitaxel
Atezolizumab
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been 
associated with the administration of atezolizumab.  Patients will be assessed for 
pulmonary signs and symptoms throughout the study and will also have CT scans of the 
chest performed at every tumor assessment.  
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension.  Management guidelines for pulmonary events are provided in the 
Atezolizumab Investigator’s Brochure.


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nab-Paclitaxel 
Interstitial pneumonitis has been observed in <1% of patients with nab-paclitaxel 
monotherapy and 4% with the use of nab-paclitaxel in combination with gemcitabine. 
Monitor patients closely for signs and symptoms of pneumonitis. 
nab-Paclitaxel should be permanently discontinued upon ruling out infectious etiology 
and making a diagnosis of pneumonitis. Promptly initiate appropriate treatment and 
supportive measures.
Infections should be ruled out with routine microbiological and/or immunologic methods.
After ruling out an infectious etiology, intravenous high-dose corticosteroid therapy 
should be instituted without delay, with appropriate premedication and secondary 
pathogen coverage. Patients with an added immunological component may also require 
immune modulation with azathioprine or cyclophosphamide.
Table 6
Management Guidelines for Pulmonary Events, including 
Pneumonitis:  Atezolizumab/Placebo and nab-Paclitaxel, or 
nab-Paclitaxel Alone
Event
Atezolizumab/Placebo
nab-Paclitaxel
Pulmonary 
event,
All Grades

Refer to Appendix 10

Permanently discontinue 
nab-paclitaxel.

After ruling out infection, start 
high-dose IV corticosteroids 
with appropriate premedication 
and secondary pathogen 
coverage.
IVintravenous.
5.1.7.6
Other Toxicities
For any Grade 3 or 4 toxicity not mentioned above, nab-paclitaxel should be withheld 
until the patient recovers completely or to Grade 1 toxicity. Nab-paclitaxel may be 
resumed at reduced doses (see Table 7) when toxicity recovers to Grade 1 or 
completely resolves. The treatment should then be resumed at 75% dose (permanent 
dose reduction) for Grade 3 toxicities and 50% of dose (permanent dose reduction) for 
Grade 4 toxicities. If recovery to Grade 1 toxicity does not occur within 3 weeks, the 
patient’s chemotherapy will be discontinued. For Grade 1 and 2 toxicities, no dose 
reduction should be made.


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Table 7
nab-Paclitaxel Permanent Dose Reductions for Non-Hematologic, 
Non-GI, Non-Neurologic, and Non-Hepatic, Toxicity
Adverse Reaction
Occurrence
Weekly nab-Paclitaxel 
Dose (mg/m2)
Grade 3 or 4 non-hematologic, 
non-GI, non-neurologic, 
non-hepatic toxicity 
First
75
Second
50
Third
Discontinue treatment
GIgastrointestinal.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording of adverse events (including 
serious adverse events and non-serious adverse events of special interest), performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.10

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)


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5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Fatal (i.e., the adverse event actually causes or leads to death)

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)

Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

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 
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 5.4.2 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 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
include the following conditions which may be suggestive of an autoimmune disorder:

Pneumonitis

Grade 3 hypoxia or dyspnea

Colitis

Endocrinopathies:  diabetes mellitus, pancreatitis, or adrenal insufficiency

Vasculitis

Hepatitis


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
Grade 2 transaminitis (AST or ALT 3ULN and bilirubin 2ULN or
AST/ALT 10ULN)

Systemic lupus erythematosus

Guillain-Barre Syndrome

Skin reactions:  vitiligo, pemphigoid
The following events also require immediate reporting:

Events suggestive of hypersensitivity, cytokine release, influenza-like illness, 
systemic inflammatory response syndrome (SIRS), 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, Abnormal Liver Function Tests)

Suspected transmission of an infectious agent by the study drug, as defined below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected
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, 5.5, and 5.6.
For each adverse event, 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) on the Adverse Event eCRF.
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; 
see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events, regardless of relationship to study 
drug, will be reported until 30 days after the last dose of study drug or until the initiation 
of another anti-cancer therapy, whichever occurs first.  After this period, investigators 


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should report any serious adverse events and adverse events of special interest that are 
believed to be related to prior treatment with study drug (see Section 5.6).
5.3.2
Eliciting Adverse Event Information
A consistent methodology of nondirective questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of nondirective 
questions include the following:
“How have you felt since your last clinic visit?”
“Have you had any new or changed health problems since you were last here?”
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE v4.0 will be used for 
assessing adverse event severity.  Table 8 will be used for assessing the severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 8
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the NCI CTCAE (Version 4.0), which can be found at:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d 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. Deaths that are attributed by the 
investigator solely to progression of mBC should be recorded only on the Study 
Discontinuation eCRF (see Section 5.3.5.8).


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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 related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration:

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
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; colloquialisms and abbreviations should be avoided.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Infusion-Related Reactions 
Adverse events that occur during or within 24 hours after study drug administration 
should be captured as individual signs and symptoms on the Adverse Event eCRF 
rather than an overall diagnosis (e.g., record dyspnea and hypotension as separate 
events rather than a diagnosis of infusion-related reaction).
5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events other than infusion-related reactions, 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 on the basis of
the single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis.


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5.3.5.3
Adverse Events Occurring Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe 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 or not the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF. The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.
If the event becomes serious, it should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning 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:

Accompanied by clinical symptoms


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
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

Clinically significant in the investigator’s judgment
Note:  For oncology studies, 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 if the test result is above or below the normal range (e.g., "elevated 
potassium," as opposed to "abnormal potassium").  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event.  For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens (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 5.3.5.2) 


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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 a non-serious 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:

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

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 if 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 not be repeatedly recorded on the Adverse Event eCRF (see Section 5.3.5.4), 
unless the etiology changes.  The initial severity of the event should be recorded, and 
the severity or seriousness should be updated any time the event worsens (see 
Section 5.3.5.4 for details on recording persistent adverse events).
5.3.5.8
Deaths
All deaths occurring during the protocol-specified adverse event reporting period (see 
Section 5.3.1) that are attributed by the investigator solely to progression of mBC should 
be recorded only on the Study Completion/Early Discontinuation eCRF.  All other deaths, 
regardless of relationship to study drug, must be recorded on the Adverse Event eCRF
and immediately reported to the Sponsor (see Section 5.4.2).
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 after 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 


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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 mBC should be recorded 
only on the Survival eCRF, while the date of death should be captured on the Study 
Discontinuation 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”).
5.3.5.10
Lack of Efficacy or Worsening of Breast Cancer
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. In rare 
cases, the determination of clinical progression will be based on symptomatic 
deterioration.  However, every effort should be made to document progression through 
use of objective criteria.  If there is any uncertainty as to whether an event is due to 
disease progression, it should be reported as an adverse event.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient hospitalization 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

Planned hospitalization required by the protocol (e.g., for study drug administration 
or to perform an efficacy measurement for the study)

Hospitalization for a preexisting condition, provided that both 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 
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The patient has not experienced an adverse event.

Hospitalization due solely to progression of the underlying cancer (including 
symptoms)
The following hospitalization scenario is not considered to be a serious adverse event
but should be reported as an adverse event 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
Study drug overdose is the accidental or intentional use of the drug(s) in an amount 
higher than the dose being studied.  An overdose or incorrect administration of study 
drug is not an adverse event but it may result in an adverse event.
Any study drug overdose or incorrect administration of study drug should be noted on 
the Study Drug Administration eCRF and reported as a protocol deviation.
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 5.4.2).
No safety data related to overdosing of atezolizumab are available.
5.3.5.13
Patient-Reported Outcome Data
PRO measures to be collected in the study are described in Section 3.3.8. The methods 
for collecting and analyzing PRO data are different from those for the ascertainment of 
observed or volunteered adverse events.  Because of these differences, PRO data will 
not be reported as adverse events; no attempt will be made to resolve any noticeable 
discrepancies between PRO data and observed or volunteered adverse events and no 
safety analyses will be performed using PRO data.  The PRO data will be presented in 
tables, figures, and data listings separate from the adverse event data, and will be 
included in the appropriate section of the final study report.
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 study.  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)


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
Non-serious 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 on the basis of 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 
Medical Monitor:
, M.D. (primary)
Telephone No.:
Mobile Telephone No.:
Medical Monitor:
, M.D. (secondary) 
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 
Non-Serious 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.  
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to investigators should be completed and submitted to Roche or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and emailing the form using the fax number or email address provided to 
investigators.


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5.4.2.2
Events that Occur After Study Drug Initiation
After initiation of study drug, serious adverse events and non-serious adverse events of 
special interest will be reported until 30 days after the last dose of study drug or until 
initiation of another anti-cancer therapy, whichever occurs first.  Investigators should 
record all case details that can be gathered immediately (i.e., within 24 hours after 
learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Roche 
Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the 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 using 
the fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.  
Instructions for reporting 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 5 months after the last 
dose of study drug.  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 
Roche Safety Risk Management.  Pregnancies 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 the conclusion of the pregnancy.  Any serious 
adverse events associated with the pregnancy (e.g., an event in the fetus, an event in 
the mother during or after the pregnancy, or a congenital anomaly/birth defect in the 
child) should be reported on the Adverse Event eCRF. In addition, the investigator will 
update the Pregnancy Report eCRF when updated information on the course and 
outcome of the pregnancy becomes available.  
In the event that the EDC system is unavailable, a Clinical Trial Pregnancy Reporting 
Form and Fax Coversheet should be completed and faxed to Roche Safety Risk 
Management or its designee immediately (i.e., no more than 24 hours after learning of 
the pregnancy), with use of the fax numbers provided to investigators (see "Protocol 
Administrative and Contact Information & List of Investigators").
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 


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6 months after the last dose of nab-paclitaxel.  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
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significants), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).
If a therapeutic or elective abortion was performed because of an underlying maternal 
or embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
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 or is assessed as stable by the investigator or until the patient is lost to 
follow-up or withdraws consent.  Every effort should be made to follow all serious adverse 


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events considered related to study drug or study-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 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, non-serious 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-TREATMENT ADVERSE EVENTS
At the treatment discontinuation visit, the investigator should instruct each patient to 
report to the investigator any subsequent adverse events that the patient’s personal 
physician believes could be related to prior study drug treatment or study procedures.
Investigators should notify the Sponsor of any serious adverse events and adverse 
events of special interest that are believed to be related to prior drug treatment or study 
procedures that occur at any time after a patient has discontinued treatment.  The 
Sponsor should also be notified if the investigator becomes aware of the development of 
cancer or a congenital anomaly/birth defect in a subsequently conceived offspring of a 
patient who participated in this study.
The investigator should report these events to Roche Safety Risk Management on the 
Adverse Event eCRF.  If the Adverse Event eCRF is no longer available, the investigator 
should report these events directly to the Sponsor or its designee, either by 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.
During survival follow-up, deaths attributed to progression of mBC should be recorded 
only on the Survival eCRF.


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5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and non-serious 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 using the following reference documents:

Atezolizumab Investigator’s Brochure

EU Summary of Product Characteristics for nab-paclitaxel.
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
An iDMC will monitor the incidence of these expected events during the study.  An 
aggregate report of any clinically relevant imbalances that do not favor the test product 
will be submitted to health authorities.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
This is a randomized, Phase III, double-blind, placebo-controlled study designed to 
evaluate the safety and efficacy of atezolizumabnab-paclitaxel as compared with 
placebonab-paclitaxel. 
The 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 subpopulation is defined as patients in the ITT population 
whose PD-L1 status is IC1/2/3 at the time of randomization.

The ORR-evaluable population is defined as patients in the ITT population with 
measurable disease at baseline.

The DOR-evaluable population is defined as patients with an objective response.

The PRO-evaluable population is defined as patients in the ITT population with 
baseline PRO assessment.


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
The safety-evaluable population is defined as patients who received any amount of 
any study drug.
For all efficacy analyses, patients will be grouped according to the treatment assigned at 
randomization.
For safety analyses, patients will be grouped according to whether any amount of 
atezolizumab was received, including cases in which atezolizumab was received in error.
6.1
DETERMINATION OF SAMPLE SIZE
Up to 900 patients in total will be randomized into the study.
6.1.1
Type I Error Control
The Type I error () for this study is 0.05 (two-sided).  Type I error will be controlled for 
the following efficacy endpoints:

Co-primary efficacy endpoint of investigator-assessed PFS by RECIST v1.1 (as 
defined for United States registrational purposes; see Section 6.4.1; ITT and 
PD-L1selected subgroups) 

Co-primary efficacy endpoint of OS (ITT and PD-L1selected subgroups)

Secondary efficacy endpoint: Investigator-assessed ORR by RECIST v1.1 
(measurable disease population) 
Type I error will be controlled by comparing these endpoints between treatment arms 
according to the following testing procedure (Figure 2).
At the time of the analysis of PFS, the co-primary endpoints of PFS and OS and the 
secondary endpoint of ORR are tested in the ITT population and in the PD-L1selected 
subpopulation, as follows:
1.
(0.05) will be allocated between PFS (0.01) and OS (0.04).  The allocated 
type I error for PFS is further allocated to PFS in the ITT (0.005) and PFS in the 
PD-L1selected subgroup (0.005).
Testing of PFS and ORR
2.
Test the null hypothesis of no difference in PFS between the two arms using the 
stratified log-rank test in the ITT population and the PD-L1selected subgroup with 
the allocated type I error.
3.
If one or both of the null hypotheses from the step above is rejected, ORR will 
subsequently be compared between the two arms in the corresponding populations 
(one or both) using the stratified Cochran-Mantel-Haenszel test using a Type I error 
of 0.001 for each correspondingly.


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Testing of OS
4.
At the time of the analysis of PFS, an interim analysis of OS in the ITT (OS [ITT]) 
will be performed. The interim analysis of OS (ITT) will be performed regardless of 
the results of the analyses of PFS and ORR. The interim analysis boundary for 
statistical significance will be determined based on the Lan-DeMets implementation 
of the O’Brien-Fleming use function according to the Type I error allocated to the 
comparison of OS (ITT). Allocation of the type I error to the comparison of OS (ITT) 
will depend on the outcome of the testing of PFS and ORR outlined in the Steps 
13 above. Details for the different Type I error allocations to the OS (ITT) testing 
are provided in Appendix 9.
5.
If hypothesis of no difference in OS in the ITT population can be rejected, OS in the 
PD-L1selected subgroup will be compared by recycling the Type I error used for 
OS (ITT) testing.  
Figure 2
Overview of the Type I Error Control
ITTintent to treat; ORRoverall response rate; OSoverall survival; PFSprogression-free 
survival; PD-L1programmed death-ligand 1.
6.1.2
Co-Primary Endpoint: Progression-Free Survival 
The definitive analysis of the co-primary endpoint of PFS will take place when 
approximately 600 PFS events (67% of 900; see Section 6.4.1), have occurred in the 
ITT population on the basis of the following assumptions:

Two-sided, stratified log-rank test at the 0.005 significance level (two-sided) in the 
ITT population

Approximately 95% power for PFS in ITT population


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
Median PFS for of 6 months in the placebonab-paclitaxel arm and 10 months in the 
atezolizumabnab-paclitaxel arm (corresponding to an HR of 0.6) in the ITT 
population

2-month initial delay in the onset of the treatment effect

5% annual loss to follow-up for PFS

No interim analysis for PFS in the ITT population
Accrual is projected to occur over 26 months. On the basis of these assumptions, the 
required number of PFS events in the ITT population is projected to occur at Month 30. 
Also on the basis of these assumptions, it is projected that an observed HR of 0.72 or 
better will result in a statistically significant difference between the treatment arms (i.e., 
HR0.72 will be the minimally detectable difference for the analysis; this corresponds to 
an improvement of 2.3 months in median PFS from 6 months in the 
placebonab-paclitaxel arm to 8.3 months in the atezolizumabnab-paclitaxel arm).
At this timepoint, a definitive analysis of PFS in the PD-L1selected subgroup and an 
interim analysis on OS are conducted in addition (see Section 6.1.1). Assuming a 
PD-L1selected rate of 40% and assuming a median PFS of 6 months in the 
placebonab-paclitaxel arm and 12 months in the atezolizumabnab-paclitaxel arm 
(corresponding to a HR of 0.5) in the PD-L1selected subgroup, it is predicted that there 
will be about 215 PFS events (59.8% of 360 PFS events). This corresponds to a power 
of about 75% and a minimally detectable difference of HR0.57 (corresponding to an 
increase of about 4.5 months from 6 months to 10.5 months).
6.1.3
Co-Primary Endpoint: Overall Survival
The timing and the two interim analyses and the final analysis for OS depends on the 
results of the definitive analysis of the co-primary endpoint PFS as well as the secondary 
endpoint ORR as described in Appendix 9, where the pre-specified boundaries for the 
different scenarios are also presented.
The final analysis will take place around 53 months after FPI, when approximately the 
pre-planned number of deaths will have been observed (see Section 3.2 for details on 
the end of the study), based on the following assumptions:

Two-sided, stratified log-rank test at the 0.005 significance level (two-sided) in the 
ITT population

Approximately 88% power for OS in ITT population

Median OS of 16 months in the placebonab-paclitaxel arm and 20.5 months in the 
atezolizumabnab-paclitaxel arm (corresponding to an HR of 0.78) in the 
ITT population

Assumption of proportionality

5% annual loss to follow-up for OS


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
Two interim analyses, at approximately 50% and 80% of the information fraction 
(see Appendix 9 for details)
Accrual is projected to occur over 26 months. On the basis of these assumptions, the 
required number of OS events in the ITT population is projected to occur in 
Month 53 (0.05; Month 58 if 0.04).
If the null hypothesis of no difference of OS in the ITT population can be rejected, OS in 
the PD-L1selected subgroup will be tested with the same as OS in the ITT population. 
Again assuming a PD-L1selected rate of 40% and assuming a median OS of
16 months in the placebonab-paclitaxel arm and 22.5 months in the 
atezolizumabnab-paclitaxel arm (corresponding to a HR of 0.71) in the PD-L1selected
subgroup, it is predicted that there will be about 253 (0.05; 269 if 0.04) OS events 
in this subgroup. This corresponds to a power of about 76%.
6.2
SUMMARIES OF CONDUCT OF STUDY
Enrollment, major protocol violations including major deviations of inclusion/exclusion 
criteria, and discontinuation from the study will be summarized overall and by treatment 
arm for all randomized patients.  The reasons for study discontinuation will be tabulated.
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic variables such as age, sex, race/ethnicity, and baseline characteristics
(in particular, stratification variables) will be summarized by treatment arm for all 
randomized patients.  Continuous variables will be summarized with use of means, SDs, 
medians, and ranges.  Categorical variables will be summarized by proportions.
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
Efficacy analyses will be performed separately for the ITT population and the 
PD-L1selected subpopulation.
6.4.1
Co-Primary Efficacy Endpoints
6.4.1.1
Progression-Free Survival
PFS is defined as the time from randomization to the occurrence of disease progression, 
as determined by investigators from tumor assessments per RECIST v1.1 (see 
Appendix 3), or death from any cause, whichever occurs first.  PFS is simultaneously
assessed in the ITT and PD-L1selected subgroup (see Section 6.1.1).
For United States registration 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 


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prior to the PFS event will be censored at the last tumor assessment prior to the missed 
visits.  Type I error control (see Section 6.1.1) will be applied to this analysis of PFS.
The following analyses will be performed for both PFS endpoints described above.  PFS 
will be compared between treatment arms with use of the stratified log-rank test.  The 
HR for disease progression or death 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 metastases (yes 
vs. no), prior taxane treatment (yes vs. no), and tumor PD-L1 status (IC0 vs. IC1/2/3).  
Results from an unstratified analysis will also be provided.  Kaplan-Meier methodology 
will be used to estimate the median PFS 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 for each treatment arm (Brookmeyer and 
Crowley 1982).
6.4.1.2
Overall Survival
OS is defined as the time from the date of randomization to the date of death from any 
cause. Testing of OS is outlined in Section 6.1.1 and analysis of OS is performed
analogously to PFS.
OS will be analyzed in a similar manner as PFS.
6.4.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are:

ORR by investigator assessment (ORR-evaluable population; RECIST v1.1 [see 
Appendix 3]) 

DOR by investigator assessment (DOR-evaluable population; RECIST v1.1) 

TTD in Items 29 and 30 of the EORTC QLQ-C30 
6.4.2.1
Objective Response Rate
An objective response is defined for patients with measurable disease at baseline as 
either a partial response (PR) or a complete response (CR) using RECIST v1.1.  
Confirmation of PR or CR is not required. Patients not meeting this criterion, including 
patients without any post-baseline tumor assessment, will be considered as 
non-responders.  ORR is defined as the proportion of patients who have an objective 
response.
An estimate of ORR will be calculated for each treatment arm, and its 95% CI will be 
calculated using the Clopper-Pearson method.  
ORR will be compared between treatment arms using the stratified 
Cochran-Mantel-Haenszel test.  The stratification factors will be the same as those 
described for the analysis of the primary endpoint of PFS.  The difference in ORR 


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between treatment arms will be calculated, and its 95% CI will be calculated using the 
normal approximation to the binomial distribution.
6.4.2.2
Duration of Objective Response
DOR is defined for patients who had an objective response as the time from the first 
occurrence of a documented unconfirmed response (CR or PR) to the date of disease 
progression 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.  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.
The analysis of DOR is based on a non-randomized subset of patients (those who 
achieved an unconfirmed response); therefore, formal hypothesis testing will not be 
performed for this endpoint.  Comparisons between treatment arms will be made for 
descriptive purposes only.  The methodologies described for the analysis of PFS will be 
used for the analysis of DOR except that the analysis will not be stratified. 
6.4.2.3
Time to Deterioration in Global Health Status
See Section 6.7 for a description of the endpoint and corresponding analysis.
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 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. 
For objective response, patients without any post-baseline assessment will be 
considered non-responders.
6.5
SAFETY ANALYSES
Safety analyses will include all patients who received at least one dose of study 
treatment, with patients grouped according to the treatment actually received.
Safety will be assessed through summaries of adverse events, changes in laboratory 
test results, changes in vital signs, study treatment exposures, and immunogenicity as 
measured by ATA and will be presented by treatment arm.


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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 
study treatment and within 30 days prior to the last dose of study treatment) will be 
summarized by MedDRA term, appropriate MedDRA levels, and NCI CTCAE v4.0 grade, 
regardless of relationship to study drug as assessed by the investigator.  For each 
patient, if multiple incidences of the same adverse events occur, the maximum severity 
reported will be used in the summaries.  
The following treatment-emergent adverse events will be summarized separately:
adverse events leading to withdrawal of study drug, adverse events leading to dose 
reduction or interruption, Grade 3 adverse events, Grade 5 adverse events, serious 
adverse events, and adverse events of special interest.  
All deaths and causes of death will be summarized.
Relevant laboratory values will be summarized by time, with NCI CTCAE Grade 3 and 
Grade 4 values identified, where appropriate.  Changes in NCI CTCAE grade will be 
tabulated by treatment arm.  
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. Descriptive statistics will include means, medians, ranges, and SDs, as 
appropriate.
Plasma concentrations of nab-paclitaxel (reported as total paclitaxel) will be measured 
where applicable (see Appendix 2). The concentration data will be summarized with use 
of descriptive statistics as stated above.
Additional PK and PD analyses will be conducted as appropriate.
6.7
PATIENT-REPORTED OUTCOME ANALYSES 
6.7.1
Analysis of Time to Deterioration in Global Heath Status
The primary patient-reported endpoint is the TTD in Global Health Status/HRQoL.  
Deterioration in global health status/HRQoL (Items 29, 30 of the EORTC QLQ C30) is 
defined as a 10-point decrease from the baseline scale score. A 10-point change is 
defined as the minimally important difference (MID) (Osoba et al. 1998). Data for 
patients who do not achieve a 10-point decrease will be censored at the last time PRO 
data are available.  Only patients with baseline global health status/HRQoL scores will 
be included in the analysis.  Data for patients without at least one post-baseline 
assessment will be censored at the date of randomization 1 day.


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TTD in global health status/HRQoL will be compared between the treatment groups 
using the same method as the primary endpoint of PFS.  
6.7.2
Exploratory Patient-Reported Outcomes Analyses
Summary statistics (mean, standard deviation, median, and range) of absolute scores 
and mean changes from baseline will be calculated for all items and subscales of the 
EORTC QLQ-C30 and QLQ-BR23 at each assessment timepoint for each arm while on 
treatment. The mean (and 95% CI) and median of the absolute scores and the changes 
from baseline will be reported for interval and continuous variables. Previously 
published minimally important differences will be used to identify meaningful change 
from baseline within each treatment group on the functional and 
disease/treatment-related symptoms scales (Osoba et al. 1998; Cocks et al. 2011).  
A time-to-event analysis to investigate the time to clinically meaningful deterioration in 
the functional (physical, role, and cognitive) subscales of the EORTC QLQ-C30 will be 
conducted to assess the time from baseline to worsening in patient function.
Deterioration in function will be assessed using the published corresponding MIDs by 
Cocks et al. (2011). Patients who do not achieve an MID on the basis of published 
thresholds will be censored at the last time PRO data are available and only patients 
with baseline scores will be included. Patients without at least one post-baseline 
assessment will be censored at the date of randomization 1 day. A stratified log-rank 
test will be used to test the differences between treatment arms.
A longitudinal analysis will be conducted to estimate the effect difference on PRO 
repeated responses over a selected period of time and between the treatment arms, and 
mixed models on a set of covariates (baseline domain score, patient demographic, and 
clinical variables) will be conducted.  Change from baseline at subsequent cycles will be 
presented by treatment arm and will include least squares mean (LS Mean), difference 
in LS Mean between two treatment arms, and 95% confidence intervals for the 
differences.  The standard error (SE) will also be calculated for each LS Mean. 
The EORTC QLQ-C30 and QLQ-BR23 data will be scored according to the EORTC
scoring manual (Fayers et al. 2001).  In the event of incomplete data, for all 
questionnaire subscales, if more than 50% of the constituent items are completed, a 
pro-rated score will be computed consistent with the scoring manuals and validation 
papers.  For subscales with less than 50% of the items completed, the subscale will be 
considered as missing.  PRO completion, compliance rates, and reasons for missing 
data will be summarized at each timepoint by treatment arm. 
6.7.2.1
Health Economic Data
Health economic data, as assessed by the EQ-5D-5L, will be evaluated for patients with 
a baseline assessment and at least one post-baseline EQ-5D-5L assessment.  The 
results from the health economic data analysis will be reported separately from the 
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6.8
EXPLORATORY ANALYSES
6.8.1
Subgroup Analyses
To assess the consistency of study results in subgroups defined by demographic and 
baseline characteristics, PFS, OS, and ORR in these subgroups will be examined.
6.8.2
Exploratory Biomarker Analysis
Exploratory biomarker analyses (in tumor tissues and plasma, whole blood, or serum) 
will be performed in an effort to understand the association of these markers with study 
drug response, including efficacy and/or adverse events.  Results will be presented 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 three analyses of OS will be performed (two interim analyses and one final 
analysis).  The timing and the two interim analyses and the final analysis for OS 
depends on the results of the definitive analysis of the co-primary endpoint PFS as well 
as the secondary endpoint ORR as described in Appendix 9, where the pre-specified 
boundaries for OS of all different scenarios are also presented (see Section 6.1.3).
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 use 
function (DeMets and Lan 1994).
6.9.3
Safety Monitoring
The iDMC will convene to review interim safety analysis results.  See Section 3.1.1 for 
additional details regarding the iDMC.
6.9.4
Optional Interim Analysis
To adapt to information that may emerge during the course of this study, the Sponsor 
may choose to conduct one additional interim efficacy analysis for OS.  The 
specifications in place to ensure the study continues to meet the highest standards of 
integrity when an optional interim analysis is executed are outlined below.
The Sponsor will remain blinded. The interim analysis will be conducted by an external 
statistical group and reviewed by the independent Data Monitoring Committee (iDMC).  
Interactions between the iDMC and Sponsor will be carried out as specified in the iDMC 
charter. 
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 


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(SAP), and the SAP will be submitted to relevant health authorities at least 2 months 
prior to the conduct of the interim analysis.  The iDMC charter will document potential 
recommendations the iDMC can make to the Sponsor as a result of the analysis 
(e.g., stop the study for positive efficacy, stop the study for futility), and the iDMC charter 
will also be made available to relevant health authorities.
If there is a potential for the study to be stopped for positive efficacy as a result of the 
interim analysis, the type I error rate will be controlled to ensure statistical validity is 
maintained.  
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 using 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, using the Sponsor’s standard procedures 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 through use of 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.


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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, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical study.
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 study-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of
IMP, including eCRFs, ePRO data, Informed Consent Forms, laboratory test results, and 
medication inventory records, must be retained by the Principal Investigator for 15 years 
after completion or discontinuation of the study or for the length of time required by 


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relevant national or local health authorities, whichever is longer.  After that period of time 
the documents may be destroyed, subject to local regulations.
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final Clinical Study Report has been 
completed or for the length of time required by relevant national or local health 
authorities, whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
applicable regulations of the country in which the research is conducted, whichever 
affords the greater protection to the individual.  The study will comply with the 
requirements of the ICH E2A guideline (Clinical Safety Data Management: Definitions 
and Standards for Expedited Reporting).  Studies conducted in the United States or 
under a U.S. Investigational New Drug application (IND) will comply with FDA 
regulations and applicable local, state, and federal laws.  Studies conducted in the 
European Union (E.U.) or European Economic Area will comply with the E.U. Clinical 
Trial Directive (2001/20/EC) and applicable local, regional, and national laws.
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Caregiver’s Informed Consent Form, if applicable) will be provided to 
each site.  If applicable, it will be provided in a certified translation of the local language.  
The Sponsor or its designee must review and approve any proposed deviations from the 
Sponsor's sample Informed Consent Forms or any alternate consent forms proposed by 
the site (collectively, the “Consent Forms”) before IRB/EC submission.  The final 
IRB/EC-approved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements.
The Informed Consent Form will contain a separate section that addresses the collection 
of optional samples and the use of remaining mandatory samples (plasma, serum, whole 
blood, and tissue) 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 the collection of optional 
samples and to use any remaining specimens for exploratory research.  Patients who 
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The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act 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 


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or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician, or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
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 (i.e., last patient last visit 
[LPLV]).
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.


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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 study will be sponsored and managed by F. Hoffmann-La Roche Ltd.  
Approximately 257 sites globally will participate in the study and up to 900 patients will 
be randomized.
Randomization will occur through the IxRS.  Central facilities will be used for study 
assessments throughout the study (e.g., specified laboratory tests and PK analyses).  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected.
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a study, the Sponsor is dedicated to openly providing 
information on the study to healthcare professionals and to the public, both at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study, and redacted clinical study reports and 
other summary reports will be provided upon request (see Section 8.4 for more details), 
provided the requirements of Roche's global policy on data sharing have been met.  For
more information, refer to the Roche Global Policy on Sharing of Clinical Trials Data at 
the following website:
http://www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pd
The results of this study may be published or presented at scientific congresses.  For all 
clinical studies 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 study results within 6 months after the 
availability of the respective clinical study report.  In addition, for all clinical studies in 
patients involving an IMP for which a marketing authorization application has been filed 
f 


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or approved in any country, the Sponsor aims to publish results from analyses of 
additional endpoints and exploratory data that are clinically meaningful and statistically 
sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter studies 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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Atezolizumab—F. Hoffmann-La Roche Ltd
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Appendix 1
Schedule of Assessments
Assessment Window (Days)
Screening
All Cycles
Treatment 
Discontinuation d
Days – 28
to 1
1 b
8
(3) b,c
15
(3) b
30 Days after 
Last Dose
Follow-
Up
Signed Informed Consent Form(s) a
x
Review of eligibility criteria
x
Medical, surgical, and cancer histories, including demographic 
information e
x
HIV, HBV, HCV serology f
x
Concomitant medications g
x
x
x
x
x
Tumor assessment h
x
See footnote (h)
x
x
Head CT or MRI
x
Patient-reported outcomes i
x
x
xj
Complete physical examination k
x
x
Limited physical examination k
x l
ECOG performance status
x
x l
x
Vital signs m
x
x
x
x
x
12-lead electrocardiogram n
x
Perform as clinically indicated
Weight
x
x
x
Height
x
Hematology o
x
x l
x 
x
x


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
116/Protocol WO29522, Version 9
Assessment Window (Days)
Screening
All Cycles
Treatment 
Discontinuation d
Days – 28
to 1
1 b
8
(3) b,c
15
(3) b
30 Days after 
Last Dose
Follow-
Up
Serum chemistry p
x
x l
x
x
x
Coagulation panel (aPTT, INR)
x
x
C-reactive protein testing
x
x l
Urinalysis q,r
x
Perform as clinically indicated
Pregnancy test (women of childbearing potential only)
x s
x t
x t 
TSH, free T3, free T4
x
C1D1 & every 2nd cycle l
x
Auto-antibody testing u
x
Serum sample for ATA assessment v
x
x
x
Serum sample for atezolizumab PK sampling v
x
x
x
Plasma samples for nab-paclitaxel v
x
Blood samples for PD biomarkers v
x
x
Optional whole blood sample for RCR DNA w
x
Adverse events x
x
x
x
x
Atezolizumab/placebo infusion y
x
x
Nab-paclitaxel administration
x
x
x
Archival/fresh screening FFPE tumor tissue block or 20 unstained
slides z
x
Optional fresh biopsy
Cycle 2
aa
Mandatory FFPE tumor tissue specimen at disease progression bb
x
Survival and anti-cancer therapy follow-up cc
x


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
117/Protocol WO29522, Version 9
anti-HBcantibody to hepatitis B core antigen; anti-HBsantibody to hepatitis B surface antigen ATAanti-therapeutic antibody; 
CTcomputerized tomography; ECOGEastern Cooperative Oncology Group; EORTCEuropean Organisation for Research and Treatment of 
Cancer; ePROelectronic patient-reported outcome; EQ-5D (5L)European Quality of Life 5 Dimensions, 5 level; FFPEformalin fixed paraffin 
embedded; HBVhepatitis B virus; HCVhepatitis C virus; MRImagnetic resonance imaging; PD-L1programmed death-ligand 1; 
PKpharmacokinetic; q8wevery 8 weeks; QLQ-BR23Quality-of-life Questionnaire Breast Cancer Module; QLQ-C30Quality-of-life 
Questionnaire Core 30; RCRRoche Clinical Repository; RECISTResponse Evaluation Criteria in Solid Tumors; TSHthyroid-stimulating 
hormone; vversion.
Note:  Assessments scheduled on the days of study treatment infusions should be performed before the infusion unless otherwise noted.
a Written informed consent is required before performing any study-specific tests or procedures.  Signing of the Informed Consent Form can 
occur outside the 28-day screening period.  All screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before randomization.  Results of standard-of-care tests or examinations performed prior to obtaining informed consent and 
within 28 days prior to randomization (except where otherwise specified) may be used for screening assessments rather than repeating such 
tests.  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.  
b Assessment window of 3 days for Day 1 of Cycles 2.  Doses of nab-paclitaxel should not be administered more frequently than every 
7 days. If scheduled dosing is precluded because of a holiday, then dosing may be postponed to the soonest following date, with subsequent 
dosing continuing on the specified schedule.  After five cycles, one of three cycles may be delayed by 1 week to allow for vacations.  
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.  
c Day 8 visits are not required for patients who have discontinued nab-paclitaxel and are continuing treatment with atezolizumab/placebo 
alone.
d Patients will be asked to return to the clinic not more than 30 days after the decision to discontinue treatment for a treatment discontinuation 
visit.  The visit at which the decision is made to discontinue treatment (e.g., disease progression is determined or confirmed) may be used as 
the treatment discontinuation visit.
e Cancer history includes stage, date of diagnosis, and prior anti-tumor treatment.  Demographic information includes age and self-reported 
race/ethnicity.  Reproductive status and smoking history should also be captured.
f
All patients will be tested for HIV locally prior to the inclusion into the study; HIV-positive patients will be excluded from the clinical study.  
Hepatitis B surface antigen, anti-HBc, and anti-HBs should be collected during screening and tested locally.  HBV DNA must be collected 
prior to randomization in patients who have negative serology for hepatitis B surface antigen and positive serology for anti-HBc.


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
118/Protocol WO29522, Version 9
g Concomitant medications include any prescription medications or over-the-counter medications.  At screening, any medications the patient 
has used within the 7 days prior to 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
Tumor assessments performed as standard of care prior to obtaining informed consent and within 28 days of Cycle 1, Day 1 may be used 
rather than repeating tests.  All measurable and evaluable lesions should be assessed and documented at the screening visit. Radiologic 
imaging performed during the screening period should consist of 1) CT and/or MRI of the chest/abdomen/pelvis, 2) bone scan or PET scan, 
and 3) any other imaging studies (CT neck, plain films, etc.) as clinically indicated by the treating physician.  The same radiographic 
procedures and technique must be used throughout the study for each patient (e.g., if the patient had CT chest/abdomen/pelvis performed 
during screening, then she should subsequently undergo CT performed using the same radiologic protocol throughout the remainder of the 
study).  Results must be reviewed by the investigator before dosing at the next cycle.  Tumor assessments will be performed at baseline, 
every 8 weeks (1 week) for the first 12 months following randomization, and every 12 weeks (1 week) thereafter, with additional scans as 
clinically indicated.  All known sites of disease documented at screening should be re-assessed at each subsequent tumor evaluation.  
Tumor assessments performed after the screening period should consist of 1) CT and/or MRI of the chest/abdomen/pelvis, 2) bone scan or 
PET scan if there were osseous sites of disease identified on these studies during the screening period or if these studies are felt to be 
clinically indicated by the treating physician, and 3) any other imaging studies felt to be clinically indicated by the treating physician.  Tumor 
response will be evaluated using RECIST v1.1 (Appendix 3).  In the absence of disease progression, tumor assessments should continue 
regardless of whether patients discontinue study treatment, unless they withdraw consent or the study is terminated by the Sponsor, 
whichever occurs first.
i
The EORTC QLQ-C30, QLQ-BR23, and EQ-5D-5L questionnaires will be completed in order by the patient on an ePRO tablet at the site at 
baseline (Cycle 1, Day 1), and then Day 1 of each subsequent cycle thereafter, at the treatment discontinuation visit, and during survival 
follow-up.  All PRO questionnaires scheduled for administration during a clinic visit are required to be completed by the patient at the 
investigational site at the start of the clinic visit and before discussion of the patient’s health state, lab results, or health record, before 
administration of study treatment, and/or prior to any other study assessments that could bias patients’ responses to ensure that the validity 
of the instrument is not compromised and that data quality meets regulatory requirements. Interview assessment by a member of the clinical 
staff will be allowed if the patient is not able to complete the measure on their own.  Study personnel should review the ePRO device to 
ensure measures have been completed and saved before the patient leaves the investigational site.  All patients will also complete the three 
PRO questionnaires every 28 days for 1 year after treatment discontinuation, regardless of whether the patient is receiving subsequent anti-
cancer therapy.  Questionnaires will be completed after treatment discontinuation by the patient at home on an ePRO handheld device 
provisioned to the patient at the treatment discontinuation visit.  Male patients will not complete the QLQ-BR23, as this measure has not been 
validated in men.
j
Collect every 28 days (3 days) for 1 year during survival follow-up.


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
119/Protocol WO29522, Version 9
k Complete and limited physical examinations are defined in Section 4.5.2.2.
l
ECOG performance status, limited physical examination, local laboratory assessments, and C-reactive protein assessment may be obtained 
96 hours before Day 1 of each cycle.
m Vital signs include heart rate, respiratory rate, blood pressure, and temperature.  On days of study treatment administration (atezolizumab, 
placebo, or nab-paclitaxel), the patient’s vital signs should be determined up to 60 minutes before all infusions.  Vital signs will also be 
collected during and after every infusion of atezolizumab or placebo if clinically indicated.
n Patients should be resting and in a supine position for at least 10 minutes prior to each ECG collection.
o Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with differential (neutrophils, eosinophils, 
lymphocytes, monocytes, basophils, and other cells), and platelet count.  A manual differential can be done if clinically indicated.  Local 
laboratory assessment must be reviewed prior to every study treatment administration.  Refer to Section 4.1.1 for a list of laboratory results 
obtained within 14 days prior to the first study treatment.  
p Serum chemistry includes BUN or urea, creatinine, sodium, potassium, magnesium, chloride, bicarbonate, calcium, phosphorus, glucose, 
total bilirubin, ALT, AST, alkaline phosphatase, total protein, and albumin.  Magnesium and phosphorus must be tested during screening; 
during treatment, magnesium and phosphorus should be tested as clinically indicated. Local laboratory assessments must be reviewed prior 
to every study treatment administration.  Refer to Section 4.1.1 for a list of laboratory results obtained within 14 days prior to the first study 
treatment.
q Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood).
r
As clinically indicated during treatment.
s Serum pregnancy test within 14 days before Cycle 1, Day 1.
t
Urine pregnancy test; if a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.
u Baseline sample to be collected on Cycle 1, Day 1 prior to the first dose of study treatment.  For patients who show evidence of 
immune-mediated toxicity, additional samples will be collected, and all samples will be analyzed centrally.  Includes anti-nuclear antibody, 
antidouble-stranded DNA, circulating anti-neutrophil cytoplasmic antibody, and perinuclear anti-neutrophil cytoplasmic antibody. 
v See Appendix 2 for detailed schedule.
w Whole blood for DNA isolation will be collected from patients who have consented to optional RCR sampling at baseline.  If, however, the 
RCR genetic blood sample is not collected during the scheduled visit, it may be collected as soon as possible (after randomization) during the 
conduct of the clinical study.


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
120/Protocol WO29522, Version 9
x After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 30 days after the last dose of study 
treatment or until initiation of another anti-cancer therapy, whichever occurs first.  After this period, investigators should report any serious 
adverse events and adverse events of special interest that are believed to be related to prior treatment with study drug.  The investigator 
should follow each adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by the investigator, 
the patient is lost to follow-up, or the patient withdraws consent.  Every effort should be made to follow all serious adverse events considered 
to be related to study drug or study-related procedures until a final outcome can be reported.
y Patients should receive their first dose of study drug on the day of randomization if possible.  If this is not possible, the first dose should occur 
no later than 3 days after randomization.  For atezolizumab/placebo, the initial dose will be administered over 60 (10) minutes.  If the first 
infusion is well tolerated, all subsequent infusions may be administered over 30 (10) minutes.  For nab-paclitaxel, study drug will be 
administered according to the local prescribing information.
z 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).  An FFPE block or at least 20 unstained slides should be provided.  Fine-needle aspiration, 
brushing, cell pellets from pleural effusion, and lavage samples are not acceptable.  For core needle biopsy specimens, at least three cores 
should be submitted for evaluation.  Retrieval of archival tumor sample can occur outside the 28-day screening period.
aa For patients who have provided consent on the Consent for Optional Biopsy; optional tumor biopsy samples may be collected by core needle 
or excisional/punch biopsy at Cycle 2 Day 1 per investigator discretion.
bb Preferably, samples collected at the time of radiographic progression should be collected from growing lesions.
cc Survival follow-up information will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months 
after the treatment discontinuation visit (21 days) until death, loss to follow-up, or until study termination by the Sponsor.  All patients will be 
followed for survival and new anti-cancer therapy (including targeted therapy and immunotherapy) information unless the patient requests to 
be withdrawn from follow-up; this request must be documented in the source documents and signed by the investigator.  If the patient 
withdraws from study, the study staff may use a public information source (e.g., county records) to obtain information about survival status 
only.


Atezolizumab—F. Hoffmann-La Roche Ltd
121/Protocol WO29522, Version 9
Appendix 2
Anti-Therapeutic Antibody, Pharmacodynamic, 
and Pharmacokinetic Sampling Schedule
Study Visit
Timepoint
Sample
Cycle 1, Day 1
Predose
ATA
Atezolizumab PK
Nab-paclitaxel PK
Pharmacodynamics b
30 (10) minutes after end 
of atezolizumab infusion
Atezolizumab PK
Cycle 2, Day 1 
Predose
ATA
Atezolizumab PK a
Pharmacodynamics b
Cycle 3, Day 1
Predose
ATA
Atezolizumab PK a
Nab-paclitaxel PK a
510 minutes before the end 
of nab-paclitaxel infusion
Nab-paclitaxel PK a
1 hour after the end of 
nab-paclitaxel infusion
Nab-paclitaxel PK a
Cycle 4, Day 1
Predose 
ATA
Atezolizumab PK a
Cycles 8 and 16 and every 
eight cycles thereafter, Day 1
Predose
ATA
Atezolizumab PK a
At time of radiographic 
progression
Pharmacodynamics c
Treatment discontinuation visit
At visit
ATA
Atezolizumab PK a
120 (30) days after last dose of 
atezolizumab/placebo
At visit
ATA
Atezolizumab PK a
ATAanti-therapeutic antibody; PKpharmacokinetic.
a Sample collection for both atezolizumab and nab-paclitaxel PK is required as long as 
patients are receiving both atezolizumab or placebo and nab-paclitaxel.  For patients who 
discontinue atezolizumab or placebo and continue on nab-paclitaxel alone, the scheduled 
collection for atezolizumab PK at the treatment discontinuation visit and 120 (30) days after 
the last dose of atezolizumab or placebo is still required.  
b Whole blood, serum, plasma.
c Plasma.


Atezolizumab—F. Hoffmann-La Roche Ltd
122/Protocol WO29522, Version 9
Appendix 3
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication
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 Nontarget 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 
masses/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques.
                                           
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.


Appendix 3
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
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123/Protocol WO29522, Version 9
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 to measure bone lesions.  However, these 
techniques can be used to confirm the presence or disappearance of bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as
CT or MRI can be considered measurable lesions if the soft tissue component meets
the definition of measurability described above.

Blastic bone lesions are non-measurable.
Cystic lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts.

Cystic lesions thought to represent cystic metastases can be considered measurable 
lesions if they meet the definition of measurability described above.  However, if 
noncystic 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.
TARGET LESIONS:  SPECIFICATIONS BY METHODS OF MEASUREMENTS 
Measurement of Lesions
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment.
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.


Appendix 3
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
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Clinical Lesions.  Clinical lesions will only be considered measurable when they are 
superficial and 10 mm in diameter as assessed using calipers (e.g., skin nodules).  
For the case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is suggested.
Chest X-Ray.  Chest CT is preferred over chest X-ray, particularly when progression is 
an important endpoint, since CT is more sensitive than X-ray, particularly in identifying 
new lesions.  However, lesions on chest X-ray may be considered measurable if they 
are clearly defined and surrounded by aerated lung.
CT, 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 due to allergy or renal insufficiency, the decision as to 
whether a noncontrast 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 noncontrast CT or MRI (enhanced or nonenhanced) 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 nontarget disease or new lesions since the same lesion may appear 
to have a different size using a new modality.
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.


Appendix 3
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
125/Protocol WO29522, Version 9
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 NONTARGET 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 since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of 15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  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 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 nontarget lesions.  Nodes that have a short axis 
10 mm are considered nonpathological and should not be recorded or followed.


Appendix 3
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
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A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of diameters.  If lymph 
nodes are to be included in the sum, then, as noted above, only the short axis is added 
into the sum.  The baseline sum of diameters will be used as a reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as nontarget lesions and should also be recorded at baseline.  Measurements 
are not required and these lesions should be followed as “present,” “absent,” or in rare 
cases “unequivocal progression.”
In addition, it is possible to record multiple nontarget 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”).
RESPONSE CRITERIA
Evaluation of Target Lesions
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions.

Complete response (CR):  disappearance of all target lesions
Any pathological lymph nodes (whether target or nontarget) must have 
reduction in short axis to 10 mm.

Partial response (PR):  at least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum of diameters

Progressive disease (PD):  at least a 20% increase in the sum of diameters 
of target lesions, taking as reference the smallest sum on study (nadir), 
including baseline
In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm.
The appearance of one or more new lesions is also considered progression.

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 


Appendix 3
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
127/Protocol WO29522, Version 9
even if CR criteria are met since a normal lymph node is defined as having a short axis 
10 mm.
Target Lesions That Become Too Small to Measure.  While on 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 since they 
usually have a definable size when normal and are frequently surrounded by fat such 
as in the retroperitoneum; however, if a lymph node is believed to be present and 
is faintly seen but too small to measure, a default value of 5 mm should be assigned
in this circumstance as well and 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.
Evaluation of Nontarget Lesions
This section provides the definitions of the criteria used to determine the tumor response 
for the group of nontarget lesions.  While some nontarget 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 nontarget lesions and (if applicable) normalization of tumor 
marker level)
All lymph nodes must be non-pathological in size (10 mm short axis).


Appendix 3
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
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
Non-CR/Non-PD:  persistence of one or more nontarget lesion(s) and/or (if 
applicable) maintenance of tumor marker level above the normal limits

PD:  unequivocal progression of existing nontarget lesions
The appearance of one or more new lesions is also considered progression.
Special Notes on Assessment of Progression of Nontarget Disease
When the Patient Also Has Measurable Disease.  In this setting, to achieve 
unequivocal progression on the basis of the nontarget disease, there must be an overall 
level of substantial worsening in nontarget 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 nontarget lesions is usually not sufficient to qualify for unequivocal progression 
status.  The designation of overall progression solely on the basis of change in nontarget 
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 studies 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 nontarget 
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 to have had overall PD at that 
point.  While it would be ideal to have objective criteria to apply to non-measurable 
disease, the very nature of that disease makes it impossible to do so; therefore, the
increase must be substantial.
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, 


Appendix 3
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
129/Protocol WO29522, Version 9
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.
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.
When patients have non-measurable (therefore nontarget) disease only, Table 2 is to be 
used.


Appendix 3
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
130/Protocol WO29522, Version 9
Table 1
Timepoint Response:  Patients with Target Lesions
(with or without Nontarget Lesions)
Target Lesions
Nontarget 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 Nontarget Lesions Only
Nontarget 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 nontarget
disease since stable disease is increasingly used as an endpoint for 
assessment of efficacy in some studies; 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 
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 


Appendix 3
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
131/Protocol WO29522, Version 9
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” since the patient is not 
evaluable.  Similarly, if one or more nontarget lesions are not assessed, the response for 
nontarget 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 
nontarget 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.


Appendix 3
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
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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 
(since 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 


Appendix 3
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
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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 nontarget disease as shown in Table 1, Table 2, and 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 nontarget 
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 nontarget lesion.


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Appendix 4
Patient-Reported Outcome Instruments


Appendix 4
Patient-Reported Outcome Instruments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
135/Protocol WO29522, Version 9


Appendix 4
Patient-Reported Outcome Instruments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
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ENGLISH
© Copyright 1994 EORTC Quality of Life Group  All rights reserved Version 1 0
During the past week:  
Not at
A 
Quite
Very
 
 
All
Little
a Bit
Much
47
Did you have any pain in your arm or shoulder?  
1
2
3
4
48
Did you have a swollen arm or hand?
1 
2
3
4 
49
Was it difficult to raise your arm or to move
 
it sideways?
1 
2
3
4 
50
Have you had any pain in the area of your
 
affected breast?
1 
2
3
4 
51
Was the area of your affected breast swollen?
1 
2
3
4 
52
Was the area of your affected breast oversensitive?
1
2
3
4
53
Have you had skin problems on or in the area of
 
your affected breast (e g , itchy, dry, flaky)?
1 
2 
3
4






Appendix 4
Patient-Reported Outcome Instruments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
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Appendix 5
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-mediated
hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for this 
study.  In addition, transient autoimmune manifestations of an acute infectious disease 
that resolved upon treatment of the infectious agent are not excluded (e.g., acute Lyme 
arthritis).  Please 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
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 6
Anaphylaxis Precautions
EQUIPMENT NEEDED

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:
6.
Stop the study drug infusion.
7.
Maintain an adequate airway.
8.
Administer antihistamines, epinephrine, or other medications as required by patient
status and directed by the physician in charge.
9.
Continue to observe the patient and document observations.


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Appendix 7
Eastern Cooperative Oncology Group (ECOG)
Performance Status Scale
Grade
Description
0
Fully active, able to carry on all predisease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature; e.g., light housework or office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about 50% of waking hours
3
Capable of only limited self-care, confined to a bed or chair 50% of 
waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to 
bed or chair
5
Dead


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Appendix 8
Patient Eligibility per Archival and Fresh Tumor Tissue Quantity 
and Histology
Archival Sample
Fresh Sample
Eligible?
Reason
Status
Quantity
Status
Quantity a
TNBC b
Adequate c
TNBC
Any
Yes
TNBC b
Adequate
Unknown/
not analyzed d
Any
Yes
TNBC b
Adequate
Not clinically feasible
Yes
TNBC b
Adequate
TNBC
Adequate
No
TNBC specimen amount 
inadequate
TNBC b
Adequate
Unknown/
not analyzed d
Any
No
TNBC specimen amount 
inadequate
TNBC b
Adequate
Not clinically feasible
No
TNBC specimen amount 
inadequate
Non-TNBC
Any
TNBC
Adequate
No
TNBC specimen amount 
inadequate
Non-TNBC
Any
Unknown/
not analyzed d
Any
No
No specimen 
demonstrating TNBC
Any
Any
2 specimens: 
1 TNBC/
1 non-TNBC
Adequate
No
Recurrent disease status 
uncertain
Any
Any
non-TNBC
Any
No
Most recent specimen is 
not TNBC
Any
Any
TNBC
Adequate
Yes
ASCOAmerican Society of Clinical Oncology; CAPCollege of American Pathologists; 
TNBCtriple negative breast cancer.
a A minimum of three cores is strongly recommended for the fresh specimen.  However, if an 
adequate archival specimen has also been submitted, any number of cores will be accepted.  
On the other hand, if an archival specimen demonstrating TNBC status is not available, fresh 
tissue in the amount of at least 20 unstained slides (or a paraffin block) will have to be 
submitted. 
b Triple-negative status will be determined by ASCO/CAP criteria (Wolff et al. 2013).
c ‘Adequate’ is defined as a block or 20 unstained slides.  Patients with fewer than 
20 unstained slides available at baseline (but no fewer than 12) may be eligible upon 
discussion with the Medical Monitor.
d ASCO/CAP guidelines recommend that the status of recurrent disease is confirmed.  Under 
some conditions (e.g., fine-needle aspirate having been used initially to confirm recurrence), 
core needle or other specimens obtained subsequently may be submitted without an 
associated pathology report.


Atezolizumab—F. Hoffmann-La Roche Ltd
144/Protocol WO29522, Version 9
Appendix 9
Interim and Final Analyses for Overall Survival
Different Scenarios of PFS 
and ORR Testing
Alpha 
Level
Analysis 
Timing
Time from 1st 
Patient Enrolled 
(months)
Information 
Fraction
No. of Events
Stopping Boundary 
in HR
Stopping Boundary 
in p-Value
Both PFS and ORR are 
statistically significant in 
both IC1/2/3 and ITT
0.05
First 
interim
30
53%
IC1/2/3: 134
AC:
345
IC1/2/3:
HR0.609
AC:
HR0.734
p-value0.0042
Second 
interim
41
80%
IC1/2/3: 202
AC:
520
IC1/2/3:
HR0.726
AC:
HR0.819
p-value0.0231
Final
53
100%
IC1/2/3: 253
AC:
650
IC1/2/3:
HR0.775
AC:
HR0.853
p-value0.0425
PFS is statistically 
significant in both IC1/2/3 
and ITT; ORR is statistically
significant in either IC1/2/3 
or ITT, but not both
0.049
First 
interim
30
53%
IC1/2/3: 134
AC:
346
IC1/2/3:
HR0.609
AC:
HR0.734
p-value0.004
Second 
interim
41
80%
IC1/2/3: 204
AC:
523
IC1/2/3:
HR0.726
AC:
HR0.819
p-value0.0226
Final
53
100%
IC1/2/3: 254
AC:
654
IC1/2/3:
HR0.775
AC:
HR0.853
p-value0.0417
PFS is statistically 
significant in both IC1/2/3 
and ITT; ORR is not 
statistically significant in 
either IC1/2/3 or ITT
0.048
First 
interim
30
53%
IC1/2/3: 135
AC:
348
IC1/2/3:
HR0.609
AC:
HR0.734
p-value0.0039
Second 
interim
41
80%
IC1/2/3: 205
AC:
526
IC1/2/3:
HR0.726
AC:
HR0.819
p-value0.022
Final
54
100%
IC1/2/3: 256
AC:
657
IC1/2/3:
HR0.774
AC:
HR0.853
p-value0.0409
PFS is statistically
significant in either IC1/2/3 
or ITT, but not both, and the 
subsequent ORR is 
statistically significant 
0.045
First 
interim
30
52%
IC1/2/3: 135
AC:
347
IC1/2/3:
HR0.602
AC:
HR0.728
p-value0.0031
Second 
interim
42
80%
IC1/2/3: 209
AC:
534
IC1/2/3:
HR0.725
AC:
HR0.818
p-value0.0205
Final
55
100%
IC1/2/3: 260
AC:
668
IC1/2/3:
HR0.774
AC:
HR0.852
p-value0.0384


Atezolizumab—F. Hoffmann-La Roche Ltd
145/Protocol WO29522, Version 9
Appendix 9
Interim and Final Analyses for Overall Survival (cont.)
Different Scenarios of PFS 
and ORR Testing
Alpha 
Level
Analysis 
Timing
Time from 1st 
Patient Enrolled 
(months)
Information 
Fraction
No. of Events
Stopping Boundary 
in HR
Stopping Boundary 
in p-Value
PFS is statistically 
significant in either IC1/2/3 
or ITT, but not both ; ORR is 
not statistically significant
0.044
First 
interim
30
52%
IC1/2/3: 136
AC:
349
IC1/2/3:
HR0.602
AC:
HR0.728
p-value0.003
Second 
interim
42
80%
IC1/2/3: 210
AC:
538
IC1/2/3:
HR0.725
AC:
HR0.818
p-value0.0199
Final
56
100%
IC1/2/3: 262
AC:
672
IC1/2/3:
HR0.774
AC:
HR0.852
p-value0.0376
PFS is not statistically 
significant in either IC1/2/3 
or ITT
0.04
First 
interim
30
50%
IC1/2/3: 134
AC:
344
IC1/2/3:
HR0.587
AC:
HR0.717
p-value0.002
Second 
interim
42
78%
IC1/2/3: 210
AC:
536
IC1/2/3:
HR0.717
AC:
HR0.813
p-value0.0162
Final
58
100%
IC1/2/3: 269
AC:
688
IC1/2/3:
HR0.773
AC:
HR0.851
p-value0.0348


Atezolizumab—F. Hoffmann-La Roche Ltd
146/Protocol WO29522, Version 9
Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology.
Although most immune-mediated adverse events observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications.  Discontinuation of atezolizumab 
may not have an immediate therapeutic effect, and in severe cases, immune-mediated
toxicities may require acute management with topical corticosteroids, systemic 
corticosteroids, or other immunosuppressive agents. 
The investigator should consider the benefitrisk balance a given patient may be 
experiencing prior to further administration of atezolizumab.  In patients who have met 
the criteria for permanent discontinuation, resumption of atezolizumab may be 
considered if the patient is deriving benefit and has fully recovered from the 
immune-mediated event.  Patients can be re-challenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and 
the Medical Monitor. 
Pulmonary Events
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been 
associated with the administration of atezolizumab.  Patients will be assessed for 
pulmonary signs and symptoms throughout the study and will also have computed 
tomography (CT) scans of the chest performed at every tumor assessment.  
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension.  Management guidelines for pulmonary events are provided in Table 1.


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
147/Protocol WO29522, Version 9
Table 1:  Management Guidelines for Pulmonary Events,
Including Pneumonitis
Event
Management
Pulmonary 
event, Grade 1 

Continue atezolizumab and monitor closely.

Re-evaluate on serial imaging.

Consider patient referral to pulmonary specialist.
Pulmonary 
event, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL.

Initiate treatment with 12 mg/kg/day oral prednisone or equivalent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c

For recurrent events, treat as a Grade 3 or 4 event.
Pulmonary 
event, Grade 3 
or 4

Permanently discontinue atezolizumab and contact Medical Monitor. c

Bronchoscopy or BAL is recommended.

Initiate treatment with 12 mg/kg/day oral prednisone or equivalent.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
BALbronchoscopic alveolar lavage.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone 
or equivalent.  The acceptable length of the extended period of time must be agreed upon 
by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
148/Protocol WO29522, Version 9
HEPATIC EVENTS
Immune-mediated hepatitis has been associated with the administration of atezolizumab.  
Eligible patients must have adequate liver function, as manifested by measurements of 
total bilirubin and hepatic transaminases, and liver function will be monitored throughout 
study treatment.  Management guidelines for hepatic events are provided in Table 2.
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or 
vomiting should have liver function tests (LFTs) performed immediately and reviewed 
before administration of the next dose of study drug.
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate.


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
149/Protocol WO29522, Version 9
Table 2:  Management Guidelines for Hepatic Events
Event
Management
Hepatic event, 
Grade 1

Continue atezolizumab.

Monitor LFTs until values resolve to within normal limits. 
Hepatic event, 
Grade 2
All events:

Monitor LFTs more frequently until return to baseline values. 
Events of 5 days’ duration:

Withhold atezolizumab for up to 12 weeks after event onset. a

Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Hepatic event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Consider patient referral to gastrointestinal specialist for 
evaluation and liver biopsy to establish etiology of hepatic 
injury. 

Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
LFTliver function tests.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day 
oral prednisone or equivalent.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor.
GASTROINTESTINAL EVENTS
Immune-mediated colitis has been associated with the administration of atezolizumab.  
Management guidelines for diarrhea or colitis are provided in Table 3.


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
150/Protocol WO29522, Version 9
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies.  For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute-phase reactants (e.g., increased C-reactive protein, 
platelet count, or bandemia):  Perform sigmoidoscopy (or colonoscopy, if appropriate) 
with colonic biopsy, with three to five specimens for standard paraffin block to check for 
inflammation and lymphocytic infiltrates to confirm colitis diagnosis. 


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
151/Protocol WO29522, Version 9
Table 3:  Management Guidelines for Gastrointestinal Events
(Diarrhea or Colitis)
Event
Management
Diarrhea or 
colitis, Grade 1

Continue atezolizumab.

Initiate symptomatic treatment.

Endoscopy is recommended if symptoms persist for 7 days.

Monitor closely.
Diarrhea or 
colitis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Initiate symptomatic treatment.

Patient referral to GI specialist is recommended.

For recurrent events or events that persist 5 days, initiate 
treatment with 12 mg/kg/day oral prednisone or equivalent. 

If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Diarrhea or 
colitis, Grade 3

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to GI specialist for evaluation and confirmatory 
biopsy.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Diarrhea or 
colitis, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to GI specialist for evaluation and confirmation 
biopsy.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
152/Protocol WO29522, Version 9
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone 
or equivalent.  The acceptable length of the extended period of time must be agreed upon 
by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.
ENDOCRINE EVENTS
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have 
been associated with the administration of atezolizumab.  Management guidelines for 
endocrine events are provided in Table 4.
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of thyroid, 
pituitary, or adrenal endocrinopathies.  The patient should be referred to an 
endocrinologist if an endocrinopathy is suspected.  Thyroid-stimulating hormone (TSH) 
and free triiodothyronine and thyroxine levels should be measured to determine whether 
thyroid abnormalities are present.  Pituitary hormone levels and function tests (e.g., TSH, 
growth hormone, luteinizing hormone, follicle-stimulating hormone, testosterone, 
prolactin, adrenocorticotropic hormone [ACTH] levels, and ACTH stimulation test) and 
magnetic resonance imaging (MRI) of the brain (with detailed pituitary sections) may 
help to differentiate primary pituitary insufficiency from primary adrenal insufficiency.


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
153/Protocol WO29522, Version 9
Table 4:  Management Guidelines for Endocrine Events
Event
Management
Asymptomatic 
hypothyroidism

Continue atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH weekly.
Symptomatic 
hypothyroidism

Withhold atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH weekly.

Consider patient referral to endocrinologist.

Resume atezolizumab when symptoms are controlled and 
thyroid function is improving.
Asymptomatic 
hyperthyroidism
TSH 0.1 mU/L and 0.5 mU/L:

Continue atezolizumab.

Monitor TSH every 4 weeks.
TSH 0.1 mU/L:

Follow guidelines for symptomatic hyperthyroidism.
Symptomatic 
hyperthyroidism

Withhold atezolizumab.

Initiate treatment with anti-thyroid drug such as methimazole 
or carbimazole as needed.

Consider patient referral to endocrinologist.

Resume atezolizumab when symptoms are controlled and 
thyroid function is  improving.

Permanently discontinue atezolizumab and contact Medical 
Monitor for life-threatening immune-mediated hyperthyroidism.
c
Symptomatic adrenal 
insufficiency, 
Grade 24 

Withhold atezolizumab for up to 12 weeks after event onset.a

Refer patient to endocrinologist.

Perform appropriate imaging.

Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab. b 
If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
154/Protocol WO29522, Version 9
Table 4:  Management Guidelines for Endocrine Events (cont.)
Event
Management
Hyperglycemia,  
Grade 1 or 2

Continue atezolizumab.

Initiate treatment with insulin if needed.

Monitor for glucose control.
Hyperglycemia, 
Grade 3 or 4

Withhold atezolizumab.

Initiate treatment with insulin.

Monitor for glucose control.

Resume atezolizumab when symptoms resolve and glucose 
levels are stable.
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

Initiate hormone replacement if clinically indicated.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c

For recurrent hypophysitis, treat as a Grade 4 event.
Hypophysitis 
(pan-hypopituitarism), 
Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

Initiate hormone replacement if clinically indicated.


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
155/Protocol WO29522, Version 9
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone. 
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator (or 
an appropriate delegate) and the Medical Monitor.


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
156/Protocol WO29522, Version 9
OCULAR EVENTS
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 5.
Table 5:  Management Guidelines for Ocular Events
Event
Management
Ocular event, 
Grade 1 

Continue atezolizumab.

Patient referral to ophthalmologist is strongly recommended.

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.

If symptoms persist, treat as a Grade 2 event.
Ocular event, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Patient referral to ophthalmologist is strongly recommended.

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Ocular event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to ophthalmologist.

Initiate treatment with 12 mg/kg/day oral prednisone or equivalent.  

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator (or
an appropriate delegate) and the Medical Monitor.


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
157/Protocol WO29522, Version 9
IMMUNE-MEDIATED MYOCARDITIS
Immune-mediated myocarditis has been associated with the administration of 
atezolizumab.  Immune-mediated myocarditis should be suspected in any patient 
presenting with signs or symptoms suggestive of myocarditis, including, but not limited to, 
laboratory (e.g., B-type natriuretic peptide) or cardiac imaging abnormalities, dyspnea, 
chest pain, palpitations, fatigue, decreased exercise tolerance, or syncope.  
Immune-mediated myocarditis needs to be distinguished from myocarditis resulting from 
infection (commonly viral, e.g., in a patient who reports a recent history of 
gastrointestinal illness), ischemic events, underlying arrhythmias, exacerbation of 
preexisting cardiac conditions, or progression of malignancy.  
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  An 
endomyocardial biopsy may be considered to enable a definitive diagnosis and 
appropriate treatment, if clinically indicated.
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 6.


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
158/Protocol WO29522, Version 9
Table 6:  Management Guidelines for Immune-Mediated Myocarditis
Event
Management
Immune-
mediated
myocarditis, 
Grade 1

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines.
Immune-
mediated
myocarditis, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset a and 
contact Medical Monitor.

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate.

Consider treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Immune-
mediated
myocarditis, 
Grade 3-4

Permanently discontinue atezolizumab and contact Medical Monitor. c

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
ECMOextracorporeal membrane oxygenation; VADventricular assist device.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone 
or equivalent.  The acceptable length of the extended period of time must be agreed upon 
by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
159/Protocol WO29522, Version 9
INFUSION-RELATED REACTIONS
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) with Cycle 1 of 
atezolizumab may receive premedication with antihistamines or antipyretics/analgesics 
(e.g., acetaminophen) for subsequent infusions.  Metamizole (dipyrone) is prohibited in 
treating atezolizumab-associated IRRs because of its potential for causing 
agranulocytosis.
Guidelines for medical management of IRRs during Cycle 1 are provided in Table 7.  For 
subsequent cycles, IRRs should be managed according to institutional guidelines.
Table 7:  Management Guidelines for Infusion-Related Reactions
Event
Management
IRR, Grade 1

Reduce infusion rate to half the rate being given at the time of 
event onset.

After the event has resolved, the investigator should wait for 
30 minutes while delivering the infusion at the reduced rate.

If the infusion is tolerated at the reduced rate for 30 minutes after 
symptoms have resolved, the infusion rate may be increased to 
the original rate.
IRR, Grade 2

Interrupt atezolizumab infusion.

Administer aggressive symptomatic treatment (e.g., oral or 
IV antihistamine, anti-pyretic medication, glucocorticoids, 
epinephrine, bronchodilators, oxygen).

After symptoms have resolved to baseline, resume infusion at half 
the rate being given at the time of event onset.

For subsequent infusions, consider administration of oral 
premedication with antihistamines, anti-pyretics, and/or 
analgesics and monitor closely for IRRs.
IRR, Grade 3 or 4

Stop infusion.

Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, anti-pyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen).

Permanently discontinue atezolizumab and contact Medical 
Monitor.a
IRRinfusion-related reaction; IVintravenous.
a Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
160/Protocol WO29522, Version 9
PANCREATIC EVENTS
Symptoms of abdominal pain associated with elevations of amylase and lipase, 
suggestive of pancreatitis, have been associated with the administration of atezolizumab.  
The differential diagnosis of acute abdominal pain should include pancreatitis.  
Appropriate work-up should include an evaluation for ductal obstruction, as well as 
serum amylase and lipase tests.  Management guidelines for pancreatic events, 
including pancreatitis, are provided in Table 8.
Table 8:  Management Guidelines for Pancreatic Events, Including Pancreatitis
Event
Management
Amylase and/or lipase 
elevation, Grade 2

Continue atezolizumab.

Monitor amylase and lipase weekly.

For prolonged elevation (e.g., 3 weeks), consider treatment 
with 10 mg/day oral prednisone or equivalent.
Amylase and/or lipase 
elevation, Grade 3 or 4

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to GI specialist.

Monitor amylase and lipase every other day.

If no improvement, consider treatment with 12 mg/kg/day 
oral prednisone or equivalent.

If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c

For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c
Immune-mediated
pancreatitis, Grade 2 or 3

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to GI specialist.

Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.

If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c

For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
161/Protocol WO29522, Version 9
Table 8:  Management Guidelines for Pancreatic Events, Including Pancreatitis 
(cont.)
Event
Management
Immune-mediated
pancreatitis, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to GI specialist.

Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be agreed upon by 
the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 
DERMATOLOGIC EVENTS
Treatment-emergent rash has been associated with atezolizumab.  The majority of 
cases of rash were mild in severity and self limited, with or without pruritus.  A 
dermatologist should evaluate persistent and/or severe rash or pruritus.  A biopsy should 
be considered unless contraindicated.  Management guidelines for dermatologic events 
are provided in Table 9.


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
162/Protocol WO29522, Version 9
Table 9:  Management Guidelines for Dermatologic Events
Event
Management
Dermatologic 
event, Grade 1 

Continue atezolizumab.

Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines).
Dermatologic 
event, Grade 2 

Continue atezolizumab.

Consider patient referral to dermatologist.

Initiate treatment with topical corticosteroids.

Consider treatment with higher-potency topical corticosteroids if 
event does not improve.
Dermatologic 
event, Grade 3 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to dermatologist.

Initiate treatment with 10 mg/day oral prednisone or equivalent, 
increasing dose to 12 mg/kg/day if event does not improve 
within 4872 hours.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Dermatologic 
event, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor.c
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day 
oral prednisone or equivalent.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor.
NEUROLOGIC DISORDERS
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab.  Patients may present with signs and symptoms of sensory and/or motor 
neuropathy.  Diagnostic work-up is essential for an accurate characterization to 
differentiate between alternative etiologies.  Management guidelines for neurologic 
disorders are provided in Table 10.


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
163/Protocol WO29522, Version 9
Table 10:  Management Guidelines for Neurologic Disorders 
Event
Management
Immune-
mediated
neuropathy, 
Grade 1

Continue atezolizumab.

Investigate etiology.
Immune-
mediated
neuropathy, 
Grade 2 

Withhold atezolizumab for up to 12 weeks after event onset. a

Investigate etiology.

Initiate treatment as per institutional guidelines.

If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Immune-
mediated
neuropathy, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c 

Initiate treatment as per institutional guidelines.
Myasthenia 
gravis and 
Guillain-Barré 
syndrome (any 
grade)

Permanently discontinue atezolizumab and contact Medical 
Monitor.c

Refer patient to neurologist.

Initiate treatment as per institutional guidelines.

Consider initiation of 12 mg/kg/day oral or IV prednisone or 
equivalent.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Medical Monitor. 
IMMUNE-MEDIATED MENINGOENCEPHALITIS
Immune-mediated meningoencephalitis is an identified risk associated with the 
administration of atezolizumab.  Immune-mediated meningoencephalitis should be 
suspected in any patient presenting with signs or symptoms suggestive of meningitis or 
encephalitis, including, but not limited to, headache, neck pain, confusion, seizure, motor 
or sensory dysfunction, and altered or depressed level of consciousness.  


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
164/Protocol WO29522, Version 9
Encephalopathy from metabolic or electrolyte imbalances needs to be distinguished from 
potential meningoencephalitis resulting from infection (bacterial, viral, or fungal) or 
progression of malignancy, or secondary to a paraneoplastic process.  
All patients being considered for meningoencephalitis should be urgently evaluated with 
a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or 
edema.  If deemed safe by the treating physician, a lumbar puncture should be 
performed and a neurologist should be consulted.
Patients with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in Table 11.
Table 11:  Management Guidelines for Immune-Mediated Meningoencephalitis
Event
Management
Immune-mediated
meningoencephalitis, 
all grades

Permanently discontinue atezolizumab and contact Medical Monitor. a

Refer patient to neurologist.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.
RENAL EVENTS
Immune-mediated nephritis has been associated with the administration of atezolizumab.  
Eligible patients must have adequate renal function.  Renal function, including serum 
creatinine, should be monitored throughout study treatment.  Patients with abnormal 
renal function should be evaluated and treated for other more common etiologies 
(including prerenal and postrenal causes, and concomitant medications such as 
non-steroidal anti-inflammatory drugs).  Refer the patient to a renal specialist if clinically 
indicated.  A renal biopsy may be required to enable a definitive diagnosis and 
appropriate treatment.


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
165/Protocol WO29522, Version 9
Patients with signs and symptoms of nephritis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 12.
Table 12:  Management Guidelines for Renal Events
Event
Management
Renal event, 
Grade 1

Continue atezolizumab.

Monitor kidney function, including creatinine, closely until 
values resolve to within normal limits or to baseline values. 
Renal event, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to renal specialist.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Renal event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. 

Refer patient to renal specialist and consider renal biopsy.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of 10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor.


Atezolizumab—F. Hoffmann-La Roche Ltd
166/Protocol WO29522, Version 9
IMMUNE-MEDIATED MYOSITIS
Immune-mediated myositis has been associated with the administration of 
atezolizumab.  Myositis or inflammatory myopathies are a group of disorders 
sharing the common feature of inflammatory muscle injury; dermatomyositis 
and polymyositis are among the most common disorders.  Initial diagnosis is 
based on clinical (muscle weakness, muscle pain, skin rash in dermatomyositis), 
biochemical (serum creatine kinase increase), and imaging 
(electromyography/MRI) features, and is confirmed with a muscle biopsy.
Patients with signs and symptoms of myositis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 13.
Table 13 Management Guidelines for Immune-Mediated Myositis
Event
Management
Immune-
mediated 
myositis, 
Grade 1

Continue atezolizumab.

Refer patient to rheumatologist or neurologist. 

Initiate treatment as per institutional guidelines.
Immune-
mediated 
myositis, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset
a and contact Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Consider treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If corticosteroids are initiated and event does not improve 
within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent.

If event resolves to Grade 1 or better, resume atezolizumab.
b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks 
after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of 10 mg/day oral prednisone.  The acceptable length of the 
extended period of time must be agreed upon by the investigator and the 
Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
the equivalent of 10 mg/day oral prednisone before atezolizumab can be 
resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-mediated event.  Patients 
can be re-challenged with atezolizumab only after approval has been 
documented by both the investigator (or an appropriate delegate) and the 
Medical Monitor. 


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
167/Protocol WO29522, Version 9
Table 13 Management Guidelines for Immune-Mediated Myositis 
(cont.)
Immune-
mediated 
myositis, 
Grade 3

Withhold atezolizumab for up to 12 weeks after event onset a
and contact Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Respiratory support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone, or higher-dose bolus 
if patient is severely compromised (e.g., cardiac or 
respiratory symptoms, dysphagia, or weakness that severely 
limits mobility); convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c

For recurrent events, treat as a Grade 4 event.
Immune-
mediated 
myositis, 
Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Respiratory support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone, or higher-dose bolus 
if patient is severely compromised (e.g., cardiac or 
respiratory symptoms, dysphagia, or weakness that severely 
limits mobility); convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
168/Protocol WO29522, Version 9
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of 10 mg/day oral prednisone.  The acceptable length of the 
extended period of time must be agreed upon by the investigator and the 
Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
the equivalent of 10 mg/day oral prednisone before atezolizumab can be 
resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-mediated event.  Patients 
can be re-challenged with atezolizumab only after approval has been 
documented by both the investigator (or an appropriate delegate) and the 
Medical Monitor. 
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND 
MACROPHAGE ACTIVATION SYNDROME
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation 
syndrome (MAS).  
Patients with suspected HLH should be diagnosed according to published 
criteria by McClain and Eckstein (2014).  A patient should be classified as 
having HLH if five of the following eight criteria are met:

Fever 38.5°C

Splenomegaly

Peripheral blood cytopenia consisting of at least two of the following:
–
Hemoglobin 90 g/L (9 g/dL) (100 g/L [10 g/dL] for infants 4 weeks 
old)
–
Platelet count 100109/L (100,000/L)
–
ANC 1.010 9/L (1000/L)

Fasting triglycerides 2.992 mmol/L (265 mg/dL) and/or fibrinogen 
1.5 g/L (150 mg/dL)

Hemophagocytosis in bone marrow, spleen, lymph node, or liver

Low or absent natural killer cell activity

Ferritin 500 mg/L (500 ng/mL)


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
169/Protocol WO29522, Version 9

Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated 2 standard 
deviations above age-adjusted laboratory-specific norms
Patients with suspected MAS should be diagnosed according to published 
criteria for systemic juvenile idiopathic arthritis by Ravelli et al. (2016).  A 
febrile patient should be classified as having MAS if the following criteria are 
met:

Ferritin 684 mg/L (684 ng/mL)

At least two of the following:
–
Platelet count 181109/L (181,000/L)
–
AST 48 U/L
–
Triglycerides 1.761 mmol/L (156 mg/dL)
–
Fibrinogen 3.6 g/L (360 mg/dL)
Patients with suspected HLH or MAS should be treated according to the 
guidelines in Table 14.
Table 14 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome
Event
Management
Suspected 
HLH or MAS

Permanently discontinue atezolizumab and contact Medical 
Monitor.

Consider patient referral to hematologist.

Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines.

Consider initiation of IV corticosteroids and/or an 
immunosuppressive agent.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
HLHhemophagocytic lymphohistiocytosis; MASmacrophage activation syndrome.
REFERENCES
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resource on the Internet]. 2014 [updated 
29 October 2018; cited: 17 May 2019]. Available from: 


Appendix 10
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
170/Protocol WO29522, Version 9
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-
hemophagocytic-lymphohistiocytosis.
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage 
activation syndrome complicating systemic juvenile idiopathic arthritis: a 
European League Against Rheumatism/American College of 
Rheumatology/Paediatric Rheumatology International Trials Organisation 
Collaborative Initiative. Ann Rheum Dis 2016;75:4819.

SAP_001.pdf: 
 
Official Title: A Phase III, Multicenter, Randomized, Placebo-Controlled Study of 
Atezolizumab (Anti-PD-L1 Antibody) in Combination With Nab-
Paclitaxel Compared With Placebo With Nab-Paclitaxel for Patients 
With Previously Untreated Metastatic Triple-Negative Breast Cancer 
NCT Number: NCT02425891 
Document Date: SAP Version 1: 26-May-2017 
 
 


STATISTICAL ANALYSIS PLAN APPROVAL 
 
CONFIDENTIAL 
 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
 
Atezolizumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WO29522 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A PHASE III, MULTICENTER, RANDOMIZED, 
PLACEBO-CONTROLLED STUDY OF 
ATEZOLIZUMAB (ANTIPD-L1 ANTIBODY) IN 
COMBINATION WITH NAB-PACLITAXEL 
COMPARED WITH PLACEBO WITH 
NAB-PACLITAXEL FOR PATIENTS WITH 
PREVIOUSLY UNTREATED METASTATIC 
TRIPLE-NEGATIVE BREAST CANCER 
PROTOCOL NUMBER: 
WO29522 
STUDY DRUG: 
Atezolizumab (MPDL3280A, RO5541267) 
VERSION NUMBER: 
1 
IND NUMBER: 
123,277 
EUDRACT NUMBER: 
2014-005490-37 
SPONSOR: 
F. Hoffmann-La Roche Ltd  
PLAN PREPARED BY: 
 
DATE FINAL: 
See electronic date stamp below. 
Name
Reason for Signing
Date and Time
(UTC)
26-May-2017 12:26:16
Company Signatory (Clinical)


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TABLE OF CONTENTS 
1. 
BACKGROUND ............................................................................................ 4 
2. 
STUDY DESIGN ........................................................................................... 4 
2.1 
Protocol Synopsis .................................................................... 4 
2.2 
Outcome Measures ................................................................. 4 
2.3 
Determination of Sample Size ................................................. 4 
2.3.1 
Type I Error Control ................................................................. 4 
2.3.2 
Co-Primary Endpoint:  Progression-Free Survival ................... 7 
2.3.3 
Co-Primary Endpoint:  Overall Survival ................................... 7 
3. 
STUDY CONDUCT ....................................................................................... 8 
3.1 
Randomization Issues ............................................................. 8 
3.2 
Independent Review Committee .............................................. 8 
3.3 
Data Monitoring ....................................................................... 9 
4. 
STATISTICAL METHODS .......................................................................... 10 
4.1 
Analysis Populations ............................................................. 10 
4.2 
Analysis of Study Conduct ..................................................... 10 
4.3 
Analysis of Treatment Group Comparability .......................... 10 
4.4 
Efficacy Analysis .................................................................... 11 
4.4.1 
Co-Primary Efficacy Endpoints .............................................. 11 
4.4.1.1 
Progression-Free Survival ..................................................... 11 
4.4.1.2 
Overall Survival (OS) ............................................................. 12 
4.4.2 
Secondary Efficacy Endpoints ............................................... 12 
4.4.2.1 
Objective Response Rate ...................................................... 12 
4.4.2.2 
Duration of Objective Response ............................................ 12 
4.4.2.3 
Time to Deterioration in Global Heath 
Status/Health-Related Quality of Life ..................................... 13 
4.4.3 
Exploratory Efficacy Endpoints .............................................. 13 
4.4.3.1 
EORTC Data ......................................................................... 13 
4.4.3.2 
Health Economic Data ........................................................... 14 
4.4.3.3 
Biomarker Analysis ................................................................ 14 
4.4.4 
Sensitivity Analyses ............................................................... 14 
4.4.4.1 
Sensitivity Analyses of Progression-Free Survival ................. 14 


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4.4.4.2 
Sensitivity Analyses of Overall Survival ................................. 15 
4.4.4.3 
Sensitivity Analyses of Objective Response Rate ................. 16 
4.4.4.4 
Sensitivity Analyses of Duration of Response ....................... 16 
4.4.5 
Subgroup Analyses ............................................................... 16 
4.5 
Pharmacokinetic Analysis ...................................................... 16 
4.6 
Safety Analyses ..................................................................... 17 
4.6.1 
Exposure of Study Medication ............................................... 17 
4.6.2 
Adverse Events ..................................................................... 17 
4.6.3 
Laboratory Data ..................................................................... 18 
4.6.4 
Anti-Therapeutic Antibody ..................................................... 19 
4.6.5 
Vital Signs and ECOG Performance Status ........................... 19 
4.6.6 
Electrocardiograms ................................................................ 19 
4.7 
Interim Analyses .................................................................... 19 
4.7.1 
Progression-Free Survival ..................................................... 19 
4.7.2 
Overall Survival ..................................................................... 19 
4.7.3 
Safety Monitoring ................................................................... 19 
4.7.4 
Optional Interim Analysis ....................................................... 19 
5. 
REFERENCES ........................................................................................... 21 
 
 
LIST OF FIGURES 
Figure 1 
Overview of the Type I Error Control ............................................. 6 
 
 
LIST OF APPENDICES 
Appendix 1 
 Protocol Synopsis ...................................................................... 22 
Appendix 2 
 Schedule of Assessments .......................................................... 32 
Appendix 3 
Anti-Therapeutic Antibody, TBNK, Pharmacodynamic, 
and Pharmacokinetic Sampling Schedule ................................... 38 
Appendix 4 
 Interim and Final Analyses for Overall Survival .......................... 39 


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1. 
BACKGROUND 
This Statistical Analysis Plan (SAP) describes the analyses that are planned to be 
performed for the Clinical Study Report of Study WO29522 (IMpassion130). 
2. 
STUDY DESIGN 
2.1 
PROTOCOL SYNOPSIS 
The Protocol Synopsis is in Appendix 1.  For additional details, see the Schedule of 
Assessments in Appendix 2 and Appendix 3. 
2.2 
OUTCOME MEASURES 
See the protocol synopsis in Appendix 1 for a description of the outcome measures. 
 
2.3 
DETERMINATION OF SAMPLE SIZE 
Up to 900 patients in total will be randomized into the study. 
2.3.1 
Type I Error Control 
The type I error () for this study is 0.05 (two-sided).  Type I error will be controlled for 
the following efficacy endpoints:  
 
Co-primary efficacy endpoint of investigator-assessed progression-free survival 
(PFS) by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (intent to 
treat [ITT] and programmed death-ligand 1 [PD-L1]selected subgroups). 
 
Co-primary efficacy endpoint of overall survival (OS) (ITT and PD-L1selected 
subgroups). 
 
Secondary efficacy endpoint: Investigator-assessed objective response rate (ORR) 
by RECIST v1.1 (measurable disease population). 
 
Type I error will be controlled by comparing these endpoints between treatment arms 
according to the following testing procedure (Figure 1). 
At the time of the analysis of PFS, the co-primary endpoints of PFS and OS and the 
secondary endpoint of ORR are tested in the ITT population and in the PD-L1selected 
subpopulation, as follows: 
1. 
 (0.05) will be allocated between PFS (0.01) and OS (0.04) .  The allocated 
type I error for PFS is further allocated to PFS in the ITT (0.005) and PFS in the 
PD-L1selected subgroup (0.005). 
 
Testing of PFS and ORR 
2. 
Test the null hypothesis of no difference in PFS between the two arms using the 
stratified log-rank test in the ITT population and the PD-L1selected subgroup with 
the allocated type I error. 


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5/Statistical Analysis Plan WO29522 
3. 
If one or both of the null hypotheses from the step above is rejected, ORR will 
subsequently be compared between the two arms in the corresponding populations 
(one or both) using the stratified Cochran-Mantel-Haenszel test using a Type I error 
of 0.001 for each correspondingly. 
 
Testing of OS 
4. 
At the time of the analysis of PFS, an interim analysis of OS in the ITT (OS [ITT]) 
will be performed.  The interim analysis of OS (ITT) will be performed regardless of 
the results of the analyses of PFS and ORR.  The interim analysis boundary for 
statistical significance will be determined based on the Lan-DeMets implementation 
of the O’Brien-Fleming use function according to the type I error allocated to the 
comparison of OS (ITT).  Allocation of the type I error to the comparison of OS (ITT) 
will depend on the outcome of the testing of PFS and ORR outlined in the Steps 13 
above.  Details for the different type I error allocations to the OS (ITT) testing are 
provided in Appendix 4. 
5. 
If hypothesis of no difference in OS in the ITT population can be rejected, OS in the 
PD-L1selected subgroup will be compared by subsequently using the same type I 
error used for OS (ITT) testing.


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Figure 1 Overview of the Type I Error Control 
 
ITT  intent to treat; ORR  objective response rate; OS  overall survival; PFS  progression-free survival; PD-L1  programmed 
death-ligand 1. 


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2.3.2 
Co-Primary Endpoint:  Progression-Free Survival  
The definitive analysis of the co-primary endpoint of PFS will take place when 
approximately 600 PFS events (67% of 900; see Section 4.4.1.1), have occurred in the 
ITT population on the basis of the following assumptions: 
 
Two-sided, stratified log-rank test at the 0.005 significance level (two-sided) in the 
ITT population. 
 
Approximately 95% power for PFS in ITT population. 
 
Median PFS of 6 months in the placebo  nab-paclitaxel arm and 10 months in the 
atezolizumab  nab-paclitaxel arm (corresponding to a hazard ratio [HR] of 0.6) in 
the ITT population. 
 
Two-months initial delay in the onset of the treatment effect. 
 
Five percent annual loss to follow-up for PFS. 
 
No interim analysis for PFS in the ITT population. 
 
Accrual is projected to occur over 26 months.  On the basis of these assumptions, the 
required number of PFS events in the ITT population is projected to occur at Month 30.  
Also on the basis of these assumptions, it is projected that an observed HR of 0.72 or 
better will result in a statistically significant difference between the treatment arms (i.e., 
HR  0.72 will be the minimally detectable difference for the analysis; this corresponds to 
an improvement of 2.3 months in median PFS from 6 months in the 
placebo  nab-paclitaxel arm to 8.3 months in the atezolizumab  nab-paclitaxel arm). 
At this time point, a definitive analysis of PFS and an interim analysis on OS are 
additionally conducted in the PD-L1selected subgroup.  Assuming a PD-L1selected 
rate of 40% in the enrolled population and assuming a median PFS of 6 months in the 
placebo  nab-paclitaxel arm and 12 months in the atezolizumab  nab-paclitaxel arm 
(corresponding to a HR of 0.5) in the PD-L1selected subgroup, it is predicted that there 
will be about 215 PFS events (59.8% of 360).  This corresponds to a power of about 75% 
and a minimally detectable difference of HR  0.57 (corresponding to an increase of 
about 4.5 months from 6 months to 10.5 months). 
2.3.3 
Co-Primary Endpoint:  Overall Survival 
The timing and the two interim analyses and the final analysis for OS depends on the 
results of the definitive analysis of the co-primary endpoint PFS as well as the secondary 
endpoint ORR as described in Appendix 4, where the pre-specified boundaries for the 
different scenarios are also presented. 


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The final analysis will take place around 56 months after first patient in (FPI), when 
approximately the pre-planned number of deaths will have been observed based on the 
following assumptions:  
 
Two-sided, stratified log-rank test at the 0.05 significance level (two-sided) in the ITT 
population. 
 
Approximately 88% power for OS in ITT population. 
 
Median OS of 16 months in the placebo  nab-paclitaxel arm and 20.5 months in the 
atezolizumab  nab-paclitaxel arm (corresponding to an HR of 0.78) in the ITT 
population. 
 
Assumption of proportionality. 
 
5% annual loss to follow-up for OS. 
 
Two interim analyses, at approximately 50% and 80% of the information fraction 
(see Appendix 4 for details). 
 
Accrual is projected to occur over 26 months.  On the basis of these assumptions, the 
required number of OS events in the ITT population is projected to occur in 
Month 56 (  0.05; Month 62 if   0.04).  
If the null hypothesis of no difference of OS in the ITT population can be rejected, OS in 
the PD-L1selected subgroup will be tested with the same  as OS in the ITT population.  
Again assuming a PD-L1selected rate of 40% and assuming a median OS of 
16 months in the placebo  nab-paclitaxel arm and 22.5 months in the 
atezolizumab  nab-paclitaxel arm (corresponding to a HR of 0.71) in the 
PD-L1selected subgroup, it is predicted that there will be about 251 (  0.05; 268 if 
  0.04) OS events in this subgroup.  This corresponds to a power of about 76%. 
3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION ISSUES 
Randomization occurs in a 1:1 ratio using a permuted-block randomization method.  
Patients are randomized to one of two treatment arms:  Atezolizumab  nab-paclitaxel or 
placebo  nab-paclitaxel.  The randomization scheme is designed to ensure that an 
approximately equal number of patients will be enrolled in each treatment arm within the 
baseline characteristics of the following stratification factors: 
 
Presence of liver metastases (yes vs. no). 
 
Prior taxane treatment (yes vs. no). 
 
Tumor PD-L1 status (tumor-infiltrating immune cell score [IC] 0 vs. IC 1/2/3). 
 
3.2 
INDEPENDENT REVIEW COMMITTEE 
The imaging data used for tumor assessment will be collected by the Sponsor to enable 
centralized, independent review of response endpoints by an Independent Review 


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Committee (IRC). An independent imaging group will be used to evaluate tumor 
assessments for determination of progression and response rate according to RECIST 
v1.1 for the primary analysis.  Imaging studies (computed tomography [CT]/magnetic 
resonance imaging [MRI]/bone scans) will be acquired according to a standard protocol 
and will be forwarded to the independent reviewers.  In addition, relevant clinical data 
(randomization and treatment start date, radiological treatment information) will be 
forwarded, if available, to the independent reviewers to aid with assessment of 
progressive disease and response.  Investigator tumor assessments will not be 
reconciled with the IRC tumor assessments.  Further details will be included in the IRC 
Charter.  Details of imaging handling procedures are also described in a separate 
laboratory manual.  
3.3 
DATA MONITORING 
An independent Data Monitoring Committee (iDMC) will monitor safety and study 
conduct on a periodic basis.  Members of the iDMC will be external to the Sponsor and 
will follow a charter that outlines their roles and responsibilities.  The iDMC will meet 
approximately every 6 months from the point of FPI to review unblinded safety and study 
conduct data prepared by an independent Data Coordinating Center (iDCC).  The safety 
data will include demographic data, adverse events, serious adverse events, and 
relevant laboratory data. 
Following each data review, the iDMC will provide recommendations to the Sponsor as 
to whether the study should continue or be amended, or whether the study should be 
stopped on the basis of safety (i.e., evidence of harm).  The Sponsor’s Data Review 
Board (DRB; a group consisting of employees of the Sponsor empowered to make 
critical decisions) will make a decision on the basis of the iDMC’s recommendations.  
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). 
There are two interim analyses planned for the co-primary endpoint OS.  No interim 
efficacy analysis is planned for the co-primary endpoint of PFS.  The final analysis of 
PFS will occur at the time of the first OS interim analysis.  The first interim analysis of 
OS together with the final analysis of PFS, and if necessary, the second interim analysis, 
will be carried out by the iDCC in a blinded fashion and provided to the iDMC.  The 
iDMC will review these data and will recommend or not recommend to release the trial 
results and to unblind the study to the sponsor.  The DRB of the sponsor will either 
accept or reject this recommendation.  Details are specified in the iDMC charter. 


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4. 
STATISTICAL METHODS 
The analyses outlined in this SAP supersede those specified in the protocol for the 
purpose of a regulatory filing. 
4.1 
ANALYSIS POPULATIONS 
The 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 subpopulation is defined as patients in the ITT population 
whose PD-L1 status is IC1/2/3 at the time of randomization. 
 
The ORR-evaluable population is defined as patients in the ITT population with 
measurable disease at baseline. 
 
The PD-L1ORR-evaluable population is defined as patients in the PD-L1selected 
subpopulation with measurable disease at baseline. 
 
The duration of response (DOR)-evaluable population is defined as patients with an 
objective response. 
 
The patient-reported outcome (PRO)-evaluable population is defined as patients in 
the ITT population with a baseline and ≥1 post-baseline PRO assessment. 
 
The safety-evaluable population is defined as patients who received any amount of 
any study drug. 
 
The pharmacokinetic (PK)-evaluable population is defined as all patients who 
received any dose of study medication and who have at least one post-baseline PK 
sample available. 
 
For all efficacy analyses, patients will be grouped according to the treatment assigned at 
randomization. 
For safety analyses, patients will be grouped according to whether any amount of 
atezolizumab was received, including cases in which atezolizumab was received in error. 
4.2 
ANALYSIS OF STUDY CONDUCT 
Study enrollment, patient disposition, reasons for discontinuation from the study 
treatment and reason for study termination will be summarized for all patients in the ITT 
population. 
Protocol deviations, including violations of inclusion/exclusion criteria and deviations 
during study conduct will be reported and summarized. 
4.3 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
Demographics, baseline disease characteristics and breast cancer history will be 
compared between both treatment arms for the ITT population.  Descriptive baseline 


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summaries of continuous data will present the group mean, standard deviation, median, 
ranges and inter-quartile ranges.  Descriptive baseline summaries of discrete data will 
present the category counts as frequencies and percentages. 
The baseline value of any efficacy variable will be defined as the last available value 
recorded prior to randomization. 
The baseline value of any non-efficacy variable will be defined as the last available value 
recorded prior to the first administration of study medication. 
Previous and concomitant cancer therapy will also be summarized, including 
radiotherapy and surgery, as well as subsequent anti-cancer therapy.  Previous and 
concurrent diseases and medications will also be summarized. 
4.4 
EFFICACY ANALYSIS 
4.4.1 
Co-Primary Efficacy Endpoints 
4.4.1.1 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the time from randomization to the 
occurrence of disease progression, as determined by investigators from tumor 
assessments, per RECIST v1.1, or death from any cause, whichever occurs first.  
Patients who have not experienced disease progression or death at the time of analysis 
will be censored at the time of the last tumor assessment.  Patients with no post-
baseline tumor assessment will be censored on the date of randomization. 
For U.S. registrational purposes, 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.  
Progression-free survival will be analyzed simultaneously in the ITT and PD-L1selected 
subgroup (see Section 2.3.1). The following analyses will be performed for both PFS 
endpoints described above: 
 
Treatment comparisons will be based on the stratified log-rank test. The 
stratification factors will be those used for randomization (see Section 3.1) and will 
be obtained from the interactive Web/phone response system IxRS.  Results from 
an un-stratified analysis and a stratified analysis with stratification factors based on 
the eCRF will also be provided. 
 
The HRwill be estimated using a stratified Cox regression model with the same 
stratification variables used for the stratified log-rank test, and the 95% CI for the HR 
will be provided.  Results from an un-stratified analysis will also be provided. 
 
Kaplan-Meier methodology will be used to estimate median PFS for each treatment 
arm and to construct survival curves for each treatment arm.  The 


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Brookmeyer-Crowley methodology will be used to construct the 95% CI for the 
median PFS for each treatment arm (Brookmeyer and Crowley 1982). 
4.4.1.2 
Overall Survival (OS) 
Overall survival is defined as the time from the date of randomization to the date of 
death due to any cause.  Patients who are not reported as having died at the time 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.  
Testing of OS is outlined in Section 2.3.1 and analysis of OS is performed analogously 
to PFS. OS is hierarchically tested in the ITT and PD-L1selected subgroup (see 
Section 2.3.1). 
4.4.2 
Secondary Efficacy Endpoints 
4.4.2.1 
Objective Response Rate 
An objective response is defined for patients with measurable disease at baseline who 
achieved a documented unconfirmed response [i.e., either a partial response (PR) or a 
complete response (CR)] on the basis of investigator assessment using RECIST v1.1.  
Patients not meeting this criterion, including patients without any post-baseline tumor 
assessment, will be considered as non-responders.  Objective response rate is defined 
as the proportion of patients with measurable disease at baseline who have an objective 
response.  
Objective response rate will be compared between treatment arms using the stratified 
Cochran-Mantel-Haenszel test.  The stratification factors will be the same as those 
described for the analysis of the primary endpoint of PFS.  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.  An estimate of ORR will be calculated 
for each treatment arm, and its 95% CI will be calculated using the Clopper-Pearson 
method.  ORR is simultaneously assessed in the ITT and PD-L1selected subgroup with 
measurable disease at baseline (see Section 2.3.1). 
The remaining secondary endpoints (duration of objective response and time to 
deterioration (TTD) in Global Heath Status [GHS]/Health-Related Quality of Life 
[HRQoL]) will not be adjusted for multiple testing and are based on a non-randomized 
subset of patients. 
4.4.2.2 
Duration of Objective Response 
Duration of response is defined for patients who had an objective response as the time 
from the first occurrence of a documented unconfirmed response (CR or PR) to the date 
of disease progression on the basis of investigator assessment using 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.  If no tumor assessments were performed after the date of the first occurrence of 
the objective response (CR or PR), patient will be censored at the date of the first 
occurrence of the objective response. 


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The analysis of DOR based on a non-randomized subset of patients (those who 
achieved an unconfirmed response); therefore, no formal hypothesis testing will be 
performed.  Comparisons between treatment arms will be made for descriptive purposes 
only.  The methodologies described for the analysis of PFS will be used for the analysis 
of DOR except that the analysis will not be stratified.  
4.4.2.3 
Time to Deterioration in Global Heath Status/Health-Related 
Quality of Life 
The primary patient-reported endpoint is the TTD in GHS/ HRQoL.  Deterioration in 
GHS/HRQoL (Items 29, 30 of the EORTC QLQ C30) is defined by the following two 
criteria:  
1. 
The time from randomization to the first time the patient’s GHS/HRQoL scale score 
shows a  10-point decrease from the baseline scale score.  A 10-point change is 
defined as the minimally important difference (MID) (Osoba et al. 1998). 
2. 
The score decrease of  10-points from baseline must be held for at least two 
consecutive cycles, or an initial score decrease of  10-points is followed by death 
or treatment discontinuation within 3 weeks from the last assessment.  
Only patients with baseline and  1 post-baseline GHS/HRQoL scores will be included in 
the analysis.  Patient-reported outcome (PRO) completion rates will be summarized at 
each timepoint by treatment arm.  Time to deterioration in GHS/HRQoL will be compared 
between the treatment groups using the same method as the primary endpoint of PFS. 
Patients who have not deteriorated before the last PRO assessment is completed will be 
censored at this time-point.  
In addition, the impact of non-protocol therapy (NPT) on the PRO endpoint of TTD in 
GHS/HRQoL will be evaluated in patients that completed the PRO assessments.  A 
sensitivity analysis will be performed in which data for patients who received NPT will be 
censored at the last PRO assessment date before receiving NPT. 
4.4.3 
Exploratory Efficacy Endpoints 
4.4.3.1 
EORTC Data 
Summary statistics (mean, standard deviation, median, and range) and mean change 
from baseline of linearly transformed absolute scores will be calculated for all items and 
scales of the EORTC QLQ-C30 and QLQ-BR23 at each assessment timepoint for each 
arm.  The mean change from baseline (and 95% CI) will be assessed on patients with at 
least one post-baseline measurement to further inform TTD in HRQoL and of patients’ 
treatment experience.  Previously published minimally important differences will be used 
to identify meaningful change from baseline within each treatment group on the 
functional and disease/treatment-related symptoms scales (Osoba et al. 1998; Cocks et 
al. 2011). 
A time-to-event analysis to investigate the time to clinically meaningful deterioration in 
the functional (physical, role, and cognitive) subscales of the EORTC QLQ-C30 will be 


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conducted.  Deterioration in function will be assessed using the published corresponding 
MIDs by Cocks et al. (2011).  Patients who do not achieve an MID on the basis of 
published thresholds will be censored at the last time PRO data are available and only 
patients with baseline scores will be included.  Patients without at least one 
post-baseline assessment will be censored at the date of randomization.  A stratified 
log-rank test will be used to test the differences between treatment arms. 
A longitudinal analysis will be conducted to estimate the effect difference on PRO 
repeated responses over a selected period of time and between the treatment arms, and 
mixed models on a set of covariates (baseline domain score, patient demographic, and 
clinical variables) will be conducted.  Change from baseline at subsequent cycles will be 
presented by treatment arm and will include least squares mean (LS Mean), difference 
in LS Mean between two treatment arms, and 95% confidence intervals for the 
differences.  The standard error (SE) will also be calculated for each LS Mean.  
The EORTC QLQ-C30 and QLQ-BR23 data will be scored according to the EORTC 
scoring manual (Fayers et al. 2001).  Missing data will be assessed and reported by 
cycle.  In the event of incomplete data, for all questionnaire subscales, if more than 50% 
of the constituent items are completed, a pro-rated score will be computed consistent 
with the scoring manuals and validation papers.  For subscales with less than 50% of the 
items completed, the subscale will be considered as missing.  PRO completion, 
compliance rates, and reasons for missing data will be summarized at each timepoint by 
treatment arm. 
4.4.3.2 
Health Economic Data 
Health economic data, as assessed by the EQ-5D-5L, will be evaluated for patients with 
a baseline assessment and at least one post-baseline EQ-5D-5L assessment.  The 
results from the health economic data analysis will be reported separately from the 
clinical study report. 
4.4.3.3 
Biomarker Analysis 
Exploratory biomarker analyses (in tumor tissues and plasma, whole blood, or serum) 
will be performed in an effort to understand the association of these markers with study 
drug response, including efficacy and/or adverse events.  Results will be presented in a 
separate report. 
4.4.4 
Sensitivity Analyses 
4.4.4.1 
Sensitivity Analyses of Progression-Free Survival 
 
Censoring for non-protocol therapy 
Non-protocol therapy is defined as any anti-cancer therapy other than study treatment 
that typically is the subsequent line of therapy.  The impact of NPT on the co-primary 
endpoint of investigator-assessed PFS by RECIST v1.1 will be evaluated.  A sensitivity 
analysis will be performed in which data for patients who received NPT will be censored 
at the last tumor assessment date before the patient received NPT. 


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PFS by IRC 
An analysis of PFS on the basis of the IRC assessments will be performed using the 
same methodology as specified for PFS on the basis of investigator assessment. 
Additional sensitivity analyses may be considered if appropriate. 
4.4.4.2 
Sensitivity Analyses of Overall Survival 
Accounting for second-line immunotherapy use 
Quickly evolving development of checkpoint inhibitors may lead to increased PD-1/PD-
L1 treatment options for patients in the second-line triple-negative breast cancer, either 
via trial participation or newly approved medicines in this class.  Second-line usage of 
such inhibitors by patients progressing on this first-line trial could result in biased 
estimate of the treatment effect on OS.  To account for this possibility of bias the 
following sensitivity analyses will be conducted. 
Censoring for treatment switching 
Treatment switching is defined as any checkpoint inhibitor therapy other than study 
treatment as subsequent line of therapy.  Censoring for treatment switching will be 
applied to OS, analogue to censoring for NPT for PFS, see above. 
Rank-preserving structural failure time (RPSFT) method 
The rank-preserving structural failure time (RPSFT) method was introduced by Robins 
and Tsiatis (1991).  It provides an estimate of the overall survival time for the placebo 
arm had treatment switching not occurred.  It estimates overall survival measured from 
the time of treatment switching by applying an estimate of the benefit of the 
atezolizumab treatment (derived iteratively and referred to as the inverse of the 
acceleration factor).  The adjusted OS time (sum of time to switching and the estimated 
survival time after switching) will then be analyzed together with the OS times of the 
patients who did not switch by using the same methodology as for the primary analysis 
of OS. 
Inverse Probability of Censoring Weighting method 
The inverse probability of censoring weighting (IPCW) method is discussed by Robins 
and Finkelstein (2000).  Inverse probability of censoring weighting (IPCW), like the 
censoring at treatment switch method, does not use any data collected after treatment 
switching.  Assuming only control patients switch treatment, the method censors patients 
at switch and uses the control arm patients to create weights that represent how similar 
a patient who didn’t switch is to a patient who did switch.  This weighted data then 
creates a pseudo population that would have been observed if censoring at treatment 
switching had not occurred (also known as a counterfactual population) by giving 
increased weight to non-censored patients with similar characteristics to censored 
patients.  These time varying weights are then included into the analysis (e.g., in a Cox 
model or log-rank test) so that the final analysis is corrected for the effect of treatment 
switching. 


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This approach includes a time-dependent indicator of treatment switching, with time-
dependent propensity-score weighting based on modeling the time-to- treatment-
switching via Cox models utilizing baseline and time-dependent covariates.   
The following baseline and time-dependent covariates will be included in the time-to- 
treatment-switching Cox model.  Baseline covariates include age and the stratification 
factors presence of liver metastases (yes vs. no), and prior taxane treatment (yes vs. no).  
Time-dependent covariates include treatment discontinuation (  1 after treatment 
discontinuation and 0 otherwise) and tumor PD-L1 status (tumor-infiltrating immune cell 
score [IC] 0 vs. IC 1/2/3) (measured at baseline and progression).  If less than 15% of 
patients in the atezolizumab + nab-paclitaxel arm receive a second line of another 
immunotherapy, the stabilized weights are set to one for all 
atezolizumab + nab-paclitaxel patients for stabilization of the analysis. 
4.4.4.3 
Sensitivity Analyses of Objective Response Rate  
 
ORR by IRC 
An analysis of ORR on the basis of the IRC assessments will be performed using the 
same methodology as specified for ORR on the basis of investigator assessment. 
Measurable disease at baseline is according to the assessment by the IRC. 
4.4.4.4 
Sensitivity Analyses of Duration of Response 
 
DOR by IRC 
An analysis of DOR on the basis of the IRC assessments will be performed using the 
same methodology as specified for DOR on the basis of investigator assessment. 
Objective response is according to the assessment by the IRC. 
4.4.5 
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.  Objective response rate will be summarized 
for each level of the categorical variables. 
4.5 
PHARMACOKINETIC ANALYSIS 
Atezolizumab serum concentration data (Cmin and Cmax) will be tabulated and 
summarized.  Descriptive statistics will include means, medians, ranges, SDs, and %CV, 
as appropriate. 
Plasma concentrations of nab-paclitaxel (reported as total paclitaxel) will be measured 
where applicable (see Appendix 3).  The concentration data will be summarized with use 
of descriptive statistics as stated above. 


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Additional PK analyses may be conducted if deemed appropriate. 
4.6 
SAFETY ANALYSES 
All safety analyses will be performed on the Safety Population, i.e. all patients who 
receive any dose of study medication (see Section 4.1).  Non-overlapping visit windows 
will be assigned to post-baseline assessments, e.g., assessments falling between Days 
22 and 32 will be reported under Week 4. 
4.6.1 
Exposure of Study Medication 
Study treatment (atezolizumab, placebo and nab-paclitaxel) exposure, including 
treatment duration, dose intensity, number of cycles and total cumulative dose will be 
summarized with descriptive statistics.  The number of missed doses will also be 
displayed. Reasons for discontinuation from study treatment will be summarized. 
4.6.2 
Adverse Events 
Verbatim description of adverse events (AEs) will be mapped to Medical Dictionary for 
Regulatory Activities (MedDRA) thesaurus terms and graded according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI 
CTCAE v4.0).  Adverse events  will be summarized by mapped term, appropriate 
thesaurus level and NCI CTCAE grade. 
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, all AEs, regardless of relationship to study drug, will be 
reported until 30 days after the last dose of study drug or until the initiation of non-
protocol anti-cancer therapy after the last administration of study drug, whichever occurs 
first.  After this period, investigators should report any serious adverse events (SAEs) 
and adverse events of special interest (AESI) that are believed to be related to prior 
treatment with study drug. 
Summary tables of the following will be provided: 
 
SAEs 
 
AEs leading to study treatment discontinuation  
 
AEs leading to dose reduction or interruption 
 
Treatment-related AEs 
 
Severe adverse events (Grade 3 or higher) 
 
AEs leading to death 
 
AEs by highest NCI CTCAE Grade 
 
Sponsor-defined AESI 


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A summary table of common AEs, i.e., those occurring in at least 10% of patients, will be 
provided. 
Adverse events of special interest for this study, as defined in the study protocol, include 
the following conditions which may be suggestive of an autoimmune disorder: 
 
Pneumonitis 
 
Grade  3 hypoxia or dyspnea 
 
Colitis 
 
Endocrinopathies:  diabetes mellitus, pancreatitis, or adrenal insufficiency 
 
Vasculitis 
 
Hepatitis 
 
Grade  2 transaminitis (AST or ALT   3  ULN and bilirubin  2  ULN or 
AST/ALT  10  ULN) 
 
Systemic lupus erythematosus 
 
Guillain-Barre Syndrome 
 
Skin reactions: vitiligo, pemphigoid 
Other AESI for this study, as defined in the study protocol, include: 
 
Events suggestive of hypersensitivity, cytokine release, influenza-like illness, 
systemic inflammatory response syndrome (SIRS), 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, Abnormal Liver Function Tests). 
 
Suspected transmission of an infectious agent by the study drug, as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
Multiple occurrences of the same event will be counted once at the maximum severity.  
All listings of AEs will include all AEs with onset on or after the first study drug treatment 
up to the data cutoff date. 
All deaths and causes of death will be summarized. 
4.6.3 
Laboratory Data 
Laboratory data will be classified according to NCI CTCAE 4.0 and will be summarized 
descriptively over time including change from baseline.  Highest NCI CTCAE grade 
post-baseline will also be reported and shift tables from baseline to worst value during 
the study post-baseline will be presented.  


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A Hy’s law analysis will be provided.  The potential Hy’s law quadrant is defined as ALT 
or AST increases above 3-fold the upper limit of normal (ULN) with concomitant total 
bilirubin increases above 2-fold the ULN.  
4.6.4 
Anti-Therapeutic Antibody 
Incidence of anti-therapeutic antibodies (ATAs) against atezolizumab will be summarized. 
The analyses of pharmacokinetics, key efficacy, and safety by ATA status may be 
conducted to explore the potential impact of immunogenicity. 
4.6.5 
Vital Signs and ECOG Performance Status 
Vital signs will be summarized descriptively over time including change from baseline. 
ECOG performance status will also be summarized over time. 
4.6.6 
Electrocardiograms 
The baseline ECG of the patients will be summarized and results of on-study ECGs will 
be listed. 
4.7 
INTERIM ANALYSES 
4.7.1 
Progression-Free Survival 
There are no planned interim analyses of the co-primary endpoint of PFS. 
4.7.2 
Overall Survival 
A total of three analyses of OS will be performed (two interim analyses and one final 
analysis).  The timing of the two interim analyses and the final analysis for OS depends 
on the results of the definitive analysis of the co-primary endpoint PFS as well as the 
secondary endpoint ORR as described in Appendix 4, where the pre-specified 
boundaries for OS of all different scenarios are also presented (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 use 
function (DeMets and Lan 1994). 
4.7.3 
Safety Monitoring 
The iDMC will convene to review interim safety analysis results.  See Section 3.3 for 
additional details regarding the iDMC. 
4.7.4 
Optional Interim Analysis 
To adapt to information that may emerge during the course of this study, the Sponsor 
may choose to conduct one additional interim efficacy analysis for OS.  The 
specifications in place to ensure the study continues to meet the highest standards of 
integrity when an optional interim analysis is executed are outlined below. 


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The Sponsor will remain blinded.  The interim analysis will be conducted by an external 
statistical group and reviewed by the iDMC.  Interactions between the iDMC and 
Sponsor will be carried out as specified in the iDMC charter.  
The decision to conduct the optional interim analysis, along with the rationale, timing, 
and statistical details for the analysis, will be documented in the SAP, and the SAP will 
be submitted to relevant health authorities at least 2 months prior to the conduct of the 
interim analysis.  The iDMC charter will document potential recommendations the iDMC 
can make to the Sponsor as a result of the analysis (e.g., stop the study for positive 
efficacy, stop the study for futility), and the iDMC charter will also be made available to 
relevant health authorities. 
If there is a potential for the study to be stopped for positive efficacy as a result of the 
interim analysis, the type I error rate will be controlled to ensure statistical validity is 
maintained. 


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5. 
REFERENCES 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982;38:2941. 
Cocks K. King MT, Velikova G, et al. Evidence-based guidelines for determination of 
sample size and interpretation of the European Organization for the Research and 
Treatment of Cancer Quality of Life Questionnaire Core 30. J Clin Oncol 
2011;29:8996. 
DeMets DL, Lan KK. Interim analysis: the alpha spending function approach. Stat Med 
1994;13:1341 52; discussion 1353-6. 
Fayers PM, Aaronson NK, Bjordal K, et al. on behalf of the EORTC Quality of Life Group. 
The EORTC QLQ-C30 scoring manual (3rd Edition). Published by: European 
Organisation for Research and Treatment of Cancer, Brussels 2001. 
Robins JM, Tsiatis AA. Correcting for non-compliance in randomized trials using rank 
preserving structural failure time models. Communications in Statistics-Theory and 
Methods 1991;20(8):2609-31. 
Robins JM, Finkelstein DM. Correcting for noncompliance and dependent censoring in 
an AIDS clinical trial with Inverse Probability of Censoring Weighted (IPCW) log-
rank tests. Biometrics. 2000;56:779-88. 
Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in health-
related quality of life score. J Clin Oncol 1998;16:13944. 
 


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Appendix 1  
Protocol Synopsis 
 
TITLE: 
A PHASE III, MULTICENTER, RANDOMIZED, PLACEBO-
CONTROLLED STUDY OF ATEZOLIZUMAB (ANTIPD-L1 
ANTIBODY) IN COMBINATION WITH NAB-PACLITAXEL 
COMPARED WITH PLACEBO WITH NAB-PACLITAXEL FOR 
PATIENTS WITH PREVIOUSLY UNTREATED METASTATIC 
TRIPLE-NEGATIVE BREAST CANCER 
PROTOCOL NUMBER: 
WO29522 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
2014-005490-37 
IND NUMBER: 
123,277 
TEST PRODUCT: 
Atezolizumab 
PHASE: 
III 
INDICATION: 
Triple-negative breast cancer (TNBC) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives and Endpoints 
This study will evaluate the efficacy, safety, and pharmacokinetics of atezolizumab with 
nab-paclitaxel compared with placebo with nab-paclitaxel in patients with metastatic or locally 
advanced triple-negative adenocarcinoma of the breast who have not received prior systemic 
therapy for metastatic breast cancer (mBC).  Specific objectives and corresponding endpoints 
for the study are outlined below. 
Efficacy Objectives 
The following efficacy objectives will be evaluated in both the intent-to-treat (ITT) population (i.e., 
all randomized patients) and the subpopulation with programmed deathligand 1 
(PD-L1)selected tumor status. 
The co-primary efficacy objectives for this study are as follows: 
 
To evaluate the efficacy of atezolizumab  nab-paclitaxel compared with 
placebo   nab-paclitaxel as measured by PFS  
 
To evaluate the efficacy of atezolizumab  nab-paclitaxel compared with 
placebo  nab-paclitaxel as measured by overall survival (OS) 
 
The secondary efficacy objectives for this study are as follows: 
 
To evaluate the efficacy of atezolizumab  nab-paclitaxel compared with 
placebo  nab-paclitaxel as measured by objective response rate (ORR; per investigator 
assessment using RECIST v1.1) 
 
To evaluate the efficacy of atezolizumab  nab-paclitaxel compared with 
placebo  nab-paclitaxel as measured by duration of objective response (DOR; per 
investigator using RECIST v1.1) among patients with an objective response 
 


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Appendix 1  
Protocol Synopsis (cont.)  
 
To evaluate patient-reported outcomes (PROs) of health status/health-related quality of life 
(HRQoL) associated with atezolizumab  nab-paclitaxel compared with 
placebo  nab-paclitaxel, as measured by the time to deterioration (TTD) in Items 29 and 
30 of the European Organisation for Research and Treatment of Cancer (EORTC) Quality 
of Life Questionnaire Core 30 (QLQ-C30) 
 
Safety Objectives 
The safety objectives for this study are as follows: 
 
To evaluate the safety and tolerability of atezolizumab  nab-paclitaxel compared with 
placebo  nab-paclitaxel 
 
To evaluate the incidence of anti-therapeutic antibodies (ATAs) against atezolizumab and to 
explore the potential relationship of the immunogenicity response with pharmacokinetics, 
pharmacodynamics, safety, and efficacy 
 
Pharmacokinetic Objectives 
The pharmacokinetic (PK) objectives for this study are as follows: 
 
To characterize the pharmacokinetics of atezolizumab when administered with 
nab-paclitaxel 
 
To characterize the pharmacokinetics of nab-paclitaxel when administered with 
atezolizumab 
 
Exploratory Objectives  
The exploratory objectives for this study are as follows: 
 
To evaluate PROs of function and disease/treatment-related symptoms associated with 
atezolizumab  nab-paclitaxel compared with placebo  nab-paclitaxel, as measured by the 
EORTC QLQ-C30 and its breast cancer module (QLQ-BR23) 
 
To evaluate health utility as measured by the EuroQoL 5 Dimension (EQ-5D-5L) 
questionnaire for health economic modeling of atezolizumab  nab-paclitaxel compared with 
placebo  nab-paclitaxel  
 
To assess predictive, prognostic, and pharmacodynamic (PD) exploratory biomarkers in 
archival and/or fresh tumor tissue and blood and their association with disease status 
and/or response to study treatment 
 
Study Design 
Description of Study 
This is a Phase III, global, multicenter, double-blind, two-arm, randomized, placebo-controlled 
study designed to evaluate the efficacy and safety of atezolizumab administered with 
nab-paclitaxel compared with placebo in combination with nab-paclitaxel in patients with locally 
advanced or metastatic TNBC who have not received prior systemic therapy for mBC.  
Eligible patients will be randomized in a 1:1 ratio to receive atezolizumab (840 mg) or placebo 
IV infusions on Days 1 and 15 of every 28-day cycle plus nab-paclitaxel (100 mg/m2) 
administered via IV infusion on Days 1, 8, and 15 of every 28-day cycle.  Randomization will be 
stratified by the following three factors:  presence of liver metastases (yes vs. no); prior taxane 
treatment (yes vs. no); and tumor PD-L1 status (IC0 vs. IC1/2/3). 
In the absence of disease progression or unacceptable toxicity, nab-paclitaxel will be 
administered for a target of at least 6 cycles, with no maximum.  nab-Paclitaxel and 
atezolizumab or placebo may be discontinued for toxicity independently of each other in the 
absence of disease progression.  The Sponsor, patients, and investigators will not be aware of 
each patient’s treatment assignment prior to unblinding. 
 


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Appendix 1  
Protocol Synopsis (cont.)  
In order to interrogate the mechanism of action of the drug combination in the tumor 
microenvironment and possible resistance mechanisms, tumor tissue may be optionally 
collected before dosing on Cycle 2, Day 1.   
To test the mechanisms of resistance to the drug combination in the tumor microenvironment, 
all patients will undergo a mandatory tumor biopsy collection (if clinically feasible) at first 
evidence of radiographic disease progression per RECIST v1.1.  DNA sequencing of cancer-
related genes will be performed on these specimens by Foundation Medicine, Inc. (Cambridge, 
MA).  The research report may be obtained by the Investigator, if desired, directly from 
Foundation Medicine, Inc. and will describe results from investigational tests that are not 
intended to be used to guide future treatment decisions. 
Tumor assessments per RECIST v1.1 will be performed approximately every 8 weeks ( 1 week) 
for the first 12 months after Cycle 1, Day 1 and every 12 weeks ( 1 week) thereafter until 
disease progression or treatment discontinuation, whichever is later.  Tumor assessments will 
be performed on the specified schedule regardless of treatment delays. 
Treatment will be discontinued upon radiographic disease progression per RECIST v1.1.  For 
equivocal findings of progression (e.g., very small or uncertain new lesions or lymph nodes; 
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.  
For estimation of PFS, ORR, and DOR, tumor response will be based on RECIST v1.1.  The 
imaging data used for tumor assessment will be collected by the Sponsor to enable centralized, 
independent review of response endpoints by an Independent Review Committee (IRC) in the 
future, if necessary. 
All patients will be followed for survival approximately every 3 months after the treatment 
discontinuation visit until death, withdrawal of consent, loss to follow-up, or study termination 
by the Sponsor.  In addition, information regarding use of subsequent anti-cancer agents for 
metastatic TNBC during the survival follow-up period will be collected. 
The pharmacokinetics of atezolizumab and nab-paclitaxel will be determined. 
Safety assessments will include the incidence, nature, and severity of adverse events and 
laboratory abnormalities graded per 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 pharmacokinetics and to detect the presence of antibodies to 
atezolizumab.  Patient samples, including tumor tissues, as well as serum and plasma and 
whole blood, will be collected for exploratory biomarker assessments. 
Number of Patients 
Up to 900 patients will be enrolled at approximately 257 sites globally. 
Target Population 
Patients with metastatic or locally advanced TNBC who have not received prior systemic 
cytotoxic therapy for mBC may be eligible for this study.  Locally advanced disease must not be 
amenable to resection with curative intent.  Patients may have received prior chemotherapy in 
the neoadjuvant/adjuvant setting if treatment was completed  12 months prior to randomization.  
Patients must comply with all eligibility criteria to be enrolled. 
Inclusion Criteria 
Patients must meet all of the following criteria to be eligible for study entry: 
 
Signed Informed Consent Form 
 
Women or men aged  18 years 
 
Metastatic or locally advanced, histologically documented TNBC (absence of HER2, ER, 
and PR expression) 
HER2 negativity is defined as either of the following by local laboratory assessment: 
 


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Appendix 1  
Protocol Synopsis (cont.)  
In situ hybridization (ISH) non-amplified (ratio of HER2 to CEP17  2.0 or single 
probe average HER2 gene copy number  4 signals/cell), or  
IHC 0 or IHC 1+ (if more than one test result is available and not all results meet 
the inclusion criterion definition, all results should be discussed with the Medical 
Monitor to establish eligibility of the patient) 
ER and PR negativity are defined as  1% of cells expressing hormonal receptors via 
IHC analysis. 
 
No prior chemotherapy or targeted systemic therapy for inoperable locally advanced or 
metastatic TNBC  
Radiation therapy for metastatic disease is permitted.  There is no required 
minimum washout period for radiation therapy.  Patients should be recovered from 
the effects of radiation. 
Prior chemotherapy (including taxanes) in the neoadjuvant or adjuvant setting is 
allowable if treatment was completed  12 months prior to randomization. 
 
Eligible for taxane monotherapy (i.e., absence of rapid clinical progression, life-threatening 
visceral metastases, or the need for rapid symptom and/or disease control)  
 
Representative FFPE tumor specimens (either an archival specimen or fresh pre-treatment 
tissue from relapsed disease) in paraffin blocks (preferred) or at least 15 unstained slides, 
with an associated pathology report documenting ER, PR, and HER2 negativity  
Patients with fewer than 20 unstained slides available at baseline (but no fewer 
than 12) may be eligible upon discussion with the Medical Monitor. 
Tumor tissue should be of good quality based on total and viable tumor content 
and must be evaluated for PD-L1 expression prior to enrollment.  Patients whose 
tumor tissue is not evaluable for PD-L1 expression are not eligible.   
If multiple tumor specimens are submitted (e.g., an archival specimen and tissue 
from relapsed disease), patients may be eligible if at least one specimen is 
evaluable for PD-L1.  For the purpose of stratification, the PD-L1 score of the 
patient will be the maximum PD-L1 score among the samples. 
A tumor specimen obtained from relapsed metastatic or locally advanced disease 
(if applicable) must also be submitted, if clinically feasible.  
Acceptable samples include core needle biopsies for deep tumor tissue (minimum 
three cores) or excisional, incisional, punch, or forceps biopsies for cutaneous, 
subcutaneous, or mucosal lesions. 
FFPE tumor specimens in paraffin blocks are preferred 
Fine-needle aspiration, brushing, cell pellet from pleural effusion, bone metastases, 
and lavage samples are not acceptable.   
Tumor tissue from bone metastases is not evaluable for PD-L1 expression and is 
therefore not acceptable. 
 
ECOG performance status of 0 or 1 
 
Life expectancy  12 weeks 
 
Measurable disease, as defined by RECIST v1.1 
Previously irradiated lesions can be considered as measurable disease only if 
disease progression has been unequivocally documented at that site since 
radiation.  
 
Adequate hematologic and end-organ function, defined by the following laboratory results 
obtained within 14 days prior to the first study treatment (Cycle 1, Day 1): 
ANC  1500 cells/L (without granulocyte colony-stimulating factor [G-CSF] support 
within 2 weeks prior to Cycle 1, Day 1) 
Lymphocyte count  500/L 


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Appendix 1  
Protocol Synopsis (cont.)  
Platelet count  100,000/L (without transfusion within 2 weeks prior to Cycle 1, Day 1) 
Hemoglobin  9.0 g/dL 
Patients may be transfused or receive erythropoietic treatment to meet this 
criterion. 
AST, ALT, and alkaline phosphatase  2.5  the upper limit of normal (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  1.25  ULN 
Patients with known Gilbert disease who have serum bilirubin level  3  ULN may 
be enrolled. 
INR and aPTT  1.5  ULN 
This applies only to patients who are not receiving therapeutic anticoagulation; 
patients receiving therapeutic anticoagulation should be on a stable dose. 
Calculated creatinine clearance  30 mL/min 
 
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 5 months after the last dose of 
atezolizumab/placebo or 1 month after the last dose of nab-paclitaxel, whichever is later. 
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 (IUDs), and copper IUDs. 
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical study 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 or pregnant female partners, men must 
remain abstinent or use a condom during the treatment period and for at least 6 months 
after the last dose of nab-paclitaxel.  Men must refrain from donating sperm during this 
same period. 
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical study 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. 
 
Women who are not postmenopausal ( 12 months of nontherapy-induced amenorrhea) or 
surgically sterile must have a negative serum pregnancy test result within 14 days prior to 
initiation of study drug 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
Cancer-Specific Exclusion Criteria 
 


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Appendix 1  
Protocol Synopsis (cont.)  
 
Spinal cord compression not definitively treated with surgery and/or radiation, or previously 
diagnosed and treated spinal cord compression without evidence that disease has been 
clinically stable for  2 weeks prior to randomization 
 
Known CNS disease, except for treated asymptomatic CNS metastases, provided all of the 
following criteria are met: 
Only supratentorial and cerebellar metastases allowed (i.e., no metastases to midbrain, 
pons, medulla, or spinal cord) 
No ongoing requirement for corticosteroids as therapy for CNS disease  
No stereotactic radiation within 7 days or whole brain radiation within 14 days prior 
to randomization 
No evidence of interim progression between the completion of CNS-directed therapy 
and the screening radiographic study 
Note:  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, if all other criteria are met. 
 
Leptomeningeal disease 
 
Uncontrolled pleural effusion, pericardial effusion, or ascites  
Patients with indwelling catheters (e.g., PleurX) are allowed. 
 
Uncontrolled tumor-related pain 
Patients requiring narcotic pain medication must be on a stable regimen at study entry. 
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to 
randomization.  Patients should be recovered from the effects of radiation.  There is no 
required minimum recovery period. 
Asymptomatic metastatic lesions whose further growth would likely cause functional 
deficits or intractable pain (e.g., epidural metastasis that is not presently associated 
with spinal cord compression) should be considered for loco-regional therapy if 
appropriate prior to randomization. 
 
Uncontrolled hypercalcemia ( 1.5 mmol/L ionized calcium or calcium  12 mg/dL or 
corrected serum calcium  ULN) or symptomatic hypercalcemia requiring continued use of 
bisphosphonate therapy  
Patients who are receiving denosumab must discontinue denosumab use and replace 
it with a bisphosphonate instead while on study.  There is no required minimum 
washout period for denosumab.  
Patients who are receiving bisphosphonate therapy specifically to prevent skeletal 
events and who do not have a history of clinically significant hypercalcemia are eligible. 
 
Malignancies other than TNBC within 5 years prior to randomization, with the exception of 
those with a negligible risk of metastasis or death and treated with expected curative 
outcome (such as adequately treated carcinoma in situ of the cervix or basal or squamous 
cell skin cancer) 
 
General Medical Exclusion Criteria 
 
Pregnancy or lactation 
 
Evidence of significant uncontrolled concomitant disease that could affect compliance with 
the protocol or interpretation of results, including significant liver disease (such as cirrhosis, 
uncontrolled major seizure disorder, or superior vena cava syndrome) 


Atezolizumab—F. Hoffmann-La Roche Ltd 
28/Statistical Analysis Plan WO29522 
Appendix 1  
Protocol Synopsis (cont.)  
 
Significant cardiovascular disease, such as New York Heart Association (NYHA) cardiac 
disease (Class II or greater), myocardial infarction within 3 months prior to randomization, 
unstable arrhythmias, or unstable angina 
Patients with a known left ventricular ejection fraction (LVEF)  40% will be excluded.  
Patients with known coronary artery disease, congestive heart failure not meeting the 
above criteria, or LVEF  50% must be on a stable medical regimen that is optimized 
in the opinion of the treating physician, in consultation with a cardiologist if appropriate. 
 
Severe infection within 4 weeks prior to randomization, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia 
 
Received 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. 
 
Major surgical procedure within 28 days prior to randomization or anticipation of the 
need for a major surgical procedure during the course of the study other than for diagnosis 
Placement of central venous access catheter(s) (e.g., port or similar) is not considered 
a major surgical procedure and is therefore permitted 
 
Known hypersensitivity to nab-paclitaxel or to any of the excipients. 
 
Exclusion Criteria Related to Atezolizumab 
 
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 
Patients with a history of autoimmune-mediated hypothyroidism on a stable dose of 
thyroid replacement hormone are eligible for this study. 
Patients with controlled Type 1 diabetes mellitus on a stable insulin dosing regimen 
are eligible for this study. 
Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with 
dermatologic manifestations only (e.g., no psoriatic arthritis) are permitted provided 
that they meet the following conditions: 
Rash must cover less than 10% of body surface area (BSA) 
Disease is well controlled at baseline and only requiring low potency topical 
steroids 
No acute exacerbations of underlying condition within the last 12 months (not 
requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids, 
biologic agents, oral calcineurin inhibitors, high potency or oral steroids) 
 
Prior allogeneic stem cell or solid organ transplantation 
 
History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, 
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or 
evidence of active pneumonitis on screening chest CT scan 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
 
Positive test for HIV 
 
Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test at 
screening) or hepatitis C  


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29/Statistical Analysis Plan WO29522 
Appendix 1  
Protocol Synopsis (cont.)  
Patients with past hepatitis B virus (HBV) infection or 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. 
Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase 
chain reaction (PCR) is negative for HCV RNA. 
 
Active tuberculosis 
 
Receipt of a live, attenuated vaccine within 4 weeks prior to randomization or anticipation 
that such a live, attenuated vaccine will be required during the study 
Patients must agree not to receive live, attenuated vaccine (e.g., FluMist) within 28 
days prior to randomization, during treatment, or within 5 months following the last 
dose of atezolizumab/placebo. 
 
Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including 
antiCTLA-4, antiPD-1, or antiPD-L1 therapeutic antibodies 
 
Treatment with systemic immunostimulatory agents (including but not limited to interferons 
or IL-2) within 4 weeks or five half-lives of the drug (whichever is shorter) prior to 
randomization 
 
Treatment with systemic corticosteroids or other systemic immunosuppressive medications 
(including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, 
methotrexate, thalidomide, and antitumor necrosis factor [TNF] agents) within 2 weeks 
prior to randomization, or anticipated requirement for systemic immunosuppressive 
medications during the study 
Patients who have received acute, low-dose, systemic immunosuppressant medications 
(e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study  
Patients with a history of allergic reaction to IV contrast requiring steroid pre-treatment 
should have baseline and subsequent tumor assessments performed using MRI. 
The use of inhaled corticosteroids for chronic obstructive pulmonary disease, 
mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and 
low-dose supplemental corticosteroids for adrenocortical insufficiency are allowed. 
 
End of Study 
The end of the study is expected to occur about 53 months after FPI when approximately the 
pre-planned number of deaths will have been observed.  
OS events will be monitored throughout the course of the study, and study timelines might be 
updated as indicated. 
Length of Study 
The end of the study is expected to occur about 53 months after FPI. 
Investigational Medicinal Products 
Test Products 
 
Atezolizumab 840-mg flat dose or placebo administered via IV infusion on Day 1 and 
Day 15 of every 28-day cycle 
 
nab-Paclitaxel 100 mg/m2 administered via IV infusion on Days 1, 8, and 15 of every 28-day 
cycle.  Doses of nab-paclitaxel should not be administered more frequently than every 
7 days. 
 
Statistical Methods 
Primary Analysis 
Efficacy analyses will be performed separately for the ITT population and the PD-L1selected 
subpopulation. 


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30/Statistical Analysis Plan WO29522 
Appendix 1  
Protocol Synopsis (cont.)  
Progression-Free Survival 
PFS is defined as the time from randomization to the occurrence of disease progression, as 
determined by investigators from tumor assessments per RECIST v1.1 or death from any cause, 
whichever occurs first.  PFS is simultaneously assessed in the ITT and PD-L1selected 
subgroup. 
For United States registration 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.  Type I error control will 
be applied to this analysis of PFS.  The following analyses will be performed for both PFS 
endpoints described above.  PFS will be compared between treatment arms with use of the 
stratified log-rank test.  The HR for disease progression or death 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 metastases (yes vs. no), prior taxane treatment (yes vs. no), and tumor PD-L1 status (IC0 
vs. IC1/2/3).  Results from an unstratified analysis will also be provided.  Kaplan-Meier 
methodology will be used to estimate the median PFS 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 for each treatment arm. 
Overall Survival 
OS is defined as the time from the date of randomization to the date of death from any cause.  
Testing of OS is outlined in the protocol and analysis of OS is performed analogously to PFS. 
OS will be analyzed in a similar manner as PFS. 
Determination of Sample Size 
Up to 900 patients in total will be randomized into the study. 
Type I Error Control 
The type I error () for this study is 0.05 (two-sided).  Type I error will be controlled for the 
following efficacy endpoints:  
 
Co-primary efficacy endpoint of investigator-assessed PFS by RECIST v1.1 (as defined for 
United States registrational purposes; ITT and PD-L1selected subgroups)  
 
Co-primary efficacy endpoint of OS (ITT and PD-L1selected subgroups) 
 
Secondary efficacy endpoint: Investigator-assessed ORR by RECIST v1.1 (measurable 
disease population)  
 
Type I error will be controlled by comparing these endpoints between treatment arms according 
to the following testing procedure. 
At the time of the analysis of PFS, the co-primary endpoints of PFS and OS and the secondary 
endpoint of ORR are tested in the ITT population and in the PD-L1selected subpopulation, as 
follows: 
1. 
 (0.05) will be allocated between PFS (0.01) and OS (0.04).  The allocated type I error for 
PFS is further allocated to PFS in the ITT (0.005) and PFS in the PD-L1selected subgroup 
(0.005). 
 
Testing of PFS and ORR 
2. 
Test the null hypothesis of no difference in PFS between the two arms using the stratified 
log-rank test in the ITT population and the PD-L1selected subgroup with the allocated type 
I error. 
3. 
If one or both of the null hypotheses from the step above is rejected, ORR will subsequently 
be compared between the two arms in the corresponding populations (one or both) using the 
stratified Cochran-Mantel-Haenszel test using a Type I error of 0.001 for each 
correspondingly. 


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31/Statistical Analysis Plan WO29522 
Appendix 1  
Protocol Synopsis (cont.)  
Testing of OS 
4. 
At the time of the analysis of PFS, an interim analysis of OS in the ITT (OS [ITT]) will be 
performed.  The interim analysis of OS (ITT) will be performed regardless of the results of 
the analyses of PFS and ORR.  The interim analysis boundary for statistical significance will 
be determined based on the Lan-DeMets implementation of the O’Brien-Fleming use 
function according to the type I error allocated to the comparison of OS (ITT).  Allocation of 
the type I error to the comparison of OS (ITT) will depend on the outcome of the testing of 
PFS and ORR outlined in the Steps 13 above.  Details for the different type I error 
allocations to the OS (ITT) testing are provided in the protocol. 
5. 
If hypothesis of no difference in OS in the ITT population can be rejected, OS in the 
PD-L1selected subgroup will be compared by recycling the type I error used for OS (ITT) 
testing. 
 
Interim Analyses 
There are no planned interim analyses of the co-primary endpoint of PFS. 
Overall Survival 
A total of three analyses of OS will be performed (two interim analyses and one final analysis).  
The timing and the two interim analyses and the final analysis for OS depends on the results of 
the definitive analysis of the co-primary endpoint PFS as well as the secondary endpoint ORR 
as described in the protocol, where the pre-specified boundaries for OS of all different scenarios 
are also presented. 
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 use function..


 
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32/Statistical Analysis Plan WO29522 
Appendix 2  
Schedule of Assessments 
Assessment Window (Days) 
Screening 
All Cycles 
Treatment 
Discontinuation d 
 
Days – 28
to -1 
1 b 
8( 3) 
b,c 
 
15 
( 3)
b 
 30 Days after 
Last Dose 
Follow-
Up 
Signed Informed Consent Form(s) a 
x 
 
 
 
 
 
Review of eligibility criteria 
x 
 
 
 
 
 
Medical, surgical, and cancer histories, including demographic 
information e 
x 
 
 
 
 
 
HIV, HBV, HCV serology f 
x 
 
 
 
 
 
Concomitant medications g 
x 
x 
x 
x 
x 
 
Tumor assessment h 
x 
See footnote (h) 
x 
x 
Head CT or MRI 
x 
 
 
 
 
 
Patient-reported outcomes i 
 
x  
 
 
x 
xj 
Complete physical examination k 
x 
 
 
 
x 
 
Limited physical examination k 
 
x l 
 
 
 
 
ECOG performance status 
x 
x l 
 
 
x 
 
Vital signs m 
x 
x 
x 
x 
x 
 
12-lead electrocardiogram n 
x  
Perform as clinically indicated 
 
Weight 
x  
x 
 
 
x 
 


 
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Appendix 2  
Schedule of Assessments (cont.) 
 
Assessment Window (Days) 
Screening 
All Cycles 
Treatment 
Discontinuation d 
 
Days – 28
to -1 
1 b 
8( 3) 
b,c 
 
15 
( 3)
b 
 
Days – 
28 
to -1 
Height 
x 
 
 
 
 
 
Hematology o 
x 
x l 
x  
x 
x 
 
 
 
 
 
 
 
 
Serum chemistry p 
x 
x l 
x 
x 
x 
 
Coagulation panel (aPTT, INR) 
x 
 
 
 
x 
 
C-reactive protein testing 
x 
x l 
 
 
 
 
Urinalysis q,r 
x 
Perform as clinically indicated 
 
Pregnancy test (women of childbearing potential only) 
x s 
x t 
 
 
x t  
 
TSH, free T3, free T4 
x 
C1D1 & every 2nd cycle 
l 
x 
 
Auto-antibody testing u 
 
x  
 
 
 
 
Serum sample for ATA assessment v 
 
x  
 
 
x 
x 
Serum sample for atezolizumab PK sampling v 
 
x  
 
 
x 
x 
Plasma samples for nab-paclitaxel v 
 
x 
 
 
 
 
Blood samples for PD biomarkers v 
 
x  
 
 
x 
 
Optional whole blood sample for RCR DNA w 
 
x 
 
 
 
 
Adverse events x 
 
x 
x 
x 
x 
 


 
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Appendix 2  
Schedule of Assessments (cont.) 
 
Assessment Window (Days) 
Screening 
All Cycles 
Treatment 
Discontinuation d 
 
Days – 28
to -1 
1 b 
8( 3) 
b,c 
 
15 
( 3)
b 
 
Days – 
28 
to -1 
Atezolizumab/placebo infusion y
  
 
x  
 
x  
 
 
Nab-paclitaxel administration  
 
x 
x 
x 
 
 
Archival/fresh screening FFPE tumor tissue block or 20 unstained 
slides z 
x 
 
 
 
 
 
Optional fresh biopsy 
 
Cycle 2 aa 
 
 
 
 
Mandatory FFPE tumor tissue specimen at disease progression bb 
 
 
 
 
x 
 
Survival and anti-cancer therapy follow-up cc 
 
 
 
 
 
x 
anti-HBc  antibody to hepatitis B core antigen; anti-HBs  antibody to hepatitis B surface antigen ATA  anti-therapeutic antibody; 
CT  computerized tomography; ECOG  Eastern Cooperative Oncology Group; EORTC  European Organization for Research and Treatment 
of Cancer; ePRO  electronic patient-reported outcome; EQ-5D (5L)  European Quality of Life 5 Dimensions, 5 level; FFPE  formalin fixed 
paraffin embedded; HBV  hepatitis B virus; HCV  hepatitis C virus; MRI  magnetic resonance imaging; PD-L1  programmed death-ligand 1; 
PK  pharmacokinetic; q8w  every 8 weeks; QLQ-BR23  Quality-of-life Questionnaire Breast Cancer Module; QLQ-C30  Quality-of-life 
Questionnaire Core 30; RCR  Roche Clinical Repository; RECIST  Response Evaluation Criteria in Solid Tumors; TSH  thyroid-stimulating 
hormone; v  version. 
Note:  Assessments scheduled on the days of study treatment infusions should be performed before the infusion unless otherwise noted. 
a 
Written informed consent is required before performing any study-specific tests or procedures.  Signing of the Informed Consent Form can 
occur outside the 28-day screening period.  All screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before randomization.  Results of standard-of-care tests or examinations performed prior to obtaining informed consent and 
within 28 days prior to randomization (except where otherwise specified) may be used for screening assessments rather than repeating such 
tests.  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.   
b 
Assessment window of ± 3 days for Day 1 of Cycles  2.  Doses of nab-paclitaxel should not be administered more frequently than every 
7 days.  If scheduled dosing is precluded because of a holiday, then dosing may be postponed to the soonest following date, with subsequent  


 
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Appendix 2
Schedule of Assessments (cont.) 
 
dosing continuing on the specified schedule.  After five cycles, one of three cycles may be delayed by 1 week to allow for vacations.  
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.   
c 
Day 8 visits are not required for patients who have discontinued nab-paclitaxel and are continuing treatment with atezolizumab/placebo 
alone. 
d 
Patients will be asked to return to the clinic not more than 30 days after the decision to discontinue treatment for a treatment 
discontinuation visit.  The visit at which the decision is made to discontinue treatment (e.g., disease progression is determined or confirmed) 
may be used as the treatment discontinuation visit. 
e 
Cancer history includes stage, date of diagnosis, and prior anti-tumor treatment.  Demographic information includes age and self-reported 
race/ethnicity.  Reproductive status and smoking history should also be captured. 
f 
All patients will be tested for HIV locally prior to the inclusion into the study; HIV-positive patients will be excluded from the clinical study.   
Hepatitis B surface antigen, anti-HBc, and anti-HBs should be collected during screening and tested locally.  HBV DNA must be collected prior 
to randomization in patients who have negative serology for hepatitis B surface antigen and positive serology for anti-HBc. 
g 
Concomitant medications include any prescription medications or over-the-counter medications.  At screening, any medications the patient 
has used within the 7 days prior to 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 
Tumor assessments performed as standard of care prior to obtaining informed consent and within 28 days of Cycle 1, Day 1 may be used 
rather than repeating tests.  All measurable and evaluable lesions should be assessed and documented at the screening visit.  Radiologic 
imaging performed during the screening period should consist of 1) CT and/or MRI of the chest/abdomen/pelvis, 2) bone scan or PET scan, and 
3) any other imaging studies (CT neck, plain films, etc.) as clinically indicated by the treating physician.  The same radiographic procedures and 
technique must be used throughout the study for each patient (e.g., if the patient had CT chest/abdomen/pelvis performed during screening, 
then she should subsequently undergo CT performed using the same radiologic protocol throughout the remainder of the study).  Results must 
be reviewed by the investigator before dosing at the next cycle.  Tumor assessments will be performed at baseline, every 8 weeks ( 1 week) 
for the first 12 months following randomization, and every 12 weeks ( 1 week) thereafter, with additional scans as clinically indicated.  All 
known sites of disease documented at screening should be re-assessed at each subsequent tumor evaluation.  Tumor assessments performed 
after the screening period should consist of 1) CT and/or MRI of the chest/abdomen/pelvis, 2) bone scan or PET scan if there were osseous 
sites of disease identified on these studies during the screening period or if these studies are felt to be clinically indicated by the treating 
physician, and 3) any other imaging studies felt to be clinically indicated by the treating physician.  Tumor response will be evaluated using 
RECIST v1.1.  In the absence of disease progression, tumor assessments should continue regardless of whether patients discontinue study 
treatment, unless they withdraw consent or the study is terminated by the Sponsor, whichever occurs first. 
i 
The EORTC QLQ-C30, QLQ-BR23, and EQ-5D-5L questionnaires will be completed in order by the patient on an ePRO tablet at the site at 


 
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Appendix 2
Schedule of Assessments (cont.) 
 
baseline (Cycle 1, Day 1), and then Day 1 of each subsequent cycle thereafter, at the treatment discontinuation visit, and during survival 
follow-up.  All PRO questionnaires scheduled for administration during a clinic visit are required to be completed by the patient at the 
investigational site at the start of the clinic visit and before discussion of the patient’s health state, lab results, or health record, before 
administration of study treatment, and/or prior to any other study assessments that could bias patients’ responses to ensure that the validity of 
the instrument is not compromised and that data quality meets regulatory requirements.  Interview assessment by a member of the clinical staff 
will be allowed if the patient is not able to complete the measure on their own.  Study personnel should review the ePRO device to  
ensure measures have been completed and saved before the patient leaves the investigational site.  All patients will also complete the three 
PRO questionnaires every 28 days for 1 year after treatment discontinuation, regardless of whether the patient is receiving subsequent anti-
cancer therapy.  Questionnaires will be completed after treatment discontinuation by the patient at home on an ePRO handheld device 
provisioned to the patient at the treatment discontinuation visit.  Male patients will not complete the QLQ-BR23, as this measure has not been 
validated in men. 
j 
Collect every 28 days (± 3 days) for 1 year during survival follow-up. 
k 
Complete and limited physical examinations are defined in Protocol Section 4.5.2.2. 
l 
ECOG performance status, limited physical examination, local laboratory assessments, and C-reactive protein assessment may be 
obtained  96 hours before Day 1 of each cycle. 
m 
Vital signs include heart rate, respiratory rate, blood pressure, and temperature.  On days of study treatment administration (atezolizumab, 
placebo, or nab-paclitaxel), the patient’s vital signs should be determined up to 60 minutes before all infusions.  Vital signs will also be collected 
during and after every infusion of atezolizumab or placebo if clinically indicated. 
n 
Patients should be resting and in a supine position for at least 10 minutes prior to each ECG collection. 
o 
Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with differential (neutrophils, eosinophils, 
lymphocytes, monocytes, basophils, and other cells), and platelet count.  A manual differential can be done if clinically indicated.  Local 
laboratory assessment must be reviewed prior to every study treatment administration.  Refer to Protocol Section 4.1.1 for a list of laboratory 
results obtained within 14 days prior to the first study treatment.   
p 
Serum chemistry includes BUN or urea, creatinine, sodium, potassium, magnesium, chloride, bicarbonate, calcium, phosphorus, glucose, 
total bilirubin, ALT, AST, alkaline phosphatase, total protein, and albumin.  Magnesium and phosphorus must be tested during screening; 
during treatment, magnesium and phosphorus should be tested as clinically indicated.  Local laboratory assessments must be reviewed prior 
to every study treatment administration.  Refer to Protocol Section 4.1.1 for a list of laboratory results obtained within 14 days prior to the first 
study treatment. 
q 
Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood).  
r 
As clinically indicated during treatment. 
s 
Serum pregnancy test within 14 days before Cycle 1, Day 1. 


 
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Appendix 2
Schedule of Assessments (cont.) 
 
t 
Urine pregnancy test; if a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
u 
Baseline sample to be collected on Cycle 1, Day 1 prior to the first dose of study treatment.  For patients who show evidence of 
immune-mediated toxicity, additional samples will be collected, and all samples will be analyzed centrally.  Includes anti-nuclear antibody, 
antidouble-stranded DNA, circulating anti-neutrophil cytoplasmic antibody, and perinuclear anti-neutrophil cytoplasmic antibody.  
v 
See Appendix 3 for detailed schedule. 
w 
Whole blood for DNA isolation will be collected from patients who have consented to optional RCR sampling at baseline.  If, however, the 
RCR genetic blood sample is not collected during the scheduled visit, it may be collected as soon as possible (after randomization) during the 
conduct of the clinical study. 
x 
After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 30 days after the last dose of study 
treatment or until initiation of another anti-cancer therapy, whichever occurs first.  After this period, investigators should report any serious  
adverse events and adverse events of special interest that are believed to be related to prior treatment with study drug.  The investigator should 
follow each adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by the investigator, the 
patient is lost to follow-up, or the patient withdraws consent.  Every effort should be made to follow all serious adverse events considered to be 
related to study drug or study-related procedures until a final outcome can be reported. 
y 
Patients should receive their first dose of study drug on the day of randomization if possible.  If this is not possible, the first dose should 
occur no later than 3 days after randomization.  For atezolizumab/placebo, the initial dose will be administered over 60 ( 10) minutes.  If the 
first infusion is well tolerated, all subsequent infusions may be administered over 30 ( 10) minutes.  For nab-paclitaxel, study drug will be 
administered according to the local prescribing information. 
z 
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).  An FFPE block or at least 20 unstained slides should be provided.  Fine-needle 
aspiration, brushing, cell pellets from pleural effusion, and lavage samples are not acceptable.  For core needle biopsy specimens, at least 
three cores should be submitted for evaluation.  Retrieval of archival tumor sample can occur outside the 28-day screening period. 
aa 
For patients who have provided consent on the Consent for Optional Biopsy; optional tumor biopsy samples may be collected by core 
needle or excisional/punch biopsy at Cycle 2 Day 1 per investigator discretion. 
bb 
Preferably, samples collected at the time of radiographic progression should be collected from growing lesions. 
cc 
Survival follow-up information will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 
months after the treatment discontinuation visit ( 21 days) until death, loss to follow-up, or until study termination by the Sponsor.  All 
patients will be followed for survival and new anti-cancer therapy (including targeted therapy and immunotherapy) information unless the patient 
requests to be withdrawn from follow-up; this request must be documented in the source documents and signed by the investigator.  If the 
patient withdraws from study, the study staff may use a public information source (e.g., county records) to obtain information about survival  
status only. 


 
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38/Statistical Analysis Plan WO29522 
Appendix 3 Anti-Therapeutic Antibody, TBNK, 
Pharmacodynamic, and Pharmacokinetic Sampling Schedule 
Study Visit 
Timepoint 
Sample 
Cycle 1, Day 1 
Predose 
ATA 
Atezolizumab PK 
Nab-paclitaxel PK 
Pharmacodynamics b 
30 ( 10) minutes after end 
of atezolizumab infusion 
Atezolizumab PK 
Cycle 2, Day 1  
Predose 
ATA 
Atezolizumab PK a 
Pharmacodynamics b 
Cycle 3, Day 1 
Predose 
ATA 
Atezolizumab PK a 
Nab-paclitaxel PK a 
510 minutes before the end 
of nab-paclitaxel infusion 
Nab-paclitaxel PK a 
1 hour after the end of 
nab-paclitaxel infusion 
Nab-paclitaxel PK a 
Cycle 4, Day 1 
Predose  
ATA 
Atezolizumab PK a 
Cycles 8 and 16 and every eight 
cycles thereafter, Day 1 
Predose 
ATA 
Atezolizumab PK a 
At time of radiographic 
progression  
 
Pharmacodynamics c 
Treatment discontinuation visit 
At visit 
ATA  
Atezolizumab PK a 
120 ( 30) days after last dose of 
atezolizumab/placebo d  
At visit 
ATA  
Atezolizumab PK a 
ATA  Anti-therapeutic Antibody, PK  Pharmacokinetic  
a Sample collection for both atezolizumab and nab-paclitaxel PK is required as long as 
patients are receiving both atezolizumab or placebo and nab-paclitaxel.  For patients who 
discontinue atezolizumab or placebo and continue on nab-paclitaxel alone, the scheduled 
collection for atezolizumab PK at the treatment discontinuation visit and 120 ( 30) days after 
the last dose of atezolizumab or placebo is still required.   
b Whole blood, serum, plasma. 
c Plasma. 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
39/Statistical Analysis Plan WO29522 
Appendix 4  
Interim and Final Analyses for Overall Survival 
Different Scenarios of PFS 
and ORR Testing 
Alpha 
Level 
Analysis 
Timing 
Time from 1st 
Patient Enrolled 
(months) 
Information 
Fraction 
No. of Events 
Stopping Boundary 
in HR 
Stopping Boundary 
in p-Value 
Both PFS and ORR are 
statistically significant in 
both IC1/2/3 and ITT 
0.05 
First 
interim 
30 
53% 
IC1/2/3: 133
AC: 
347 
IC1/2/3: HR  0.608
AC: 
HR  0.735
p-value  0.0041 
Second 
interim 
41 
80% 
IC1/2/3: 201
AC: 
524 
IC1/2/3: HR  0.726
AC: 
HR  0.820
p-value  0.0231 
Final 
56 
100% 
IC1/2/3: 251
AC: 
655 
IC1/2/3: HR  0.774
AC: 
HR  0.853
p-value  0.0425 
PFS is statistically 
significant in both IC1/2/3 
and ITT; ORR is statistically 
significant in either IC1/2/3 
or ITT, but not both 
0.049 
First 
interim 
30 
53% 
IC1/2/3: 134
AC: 
349 
IC1/2/3: HR  0.608
AC: 
HR  0.735
p-value  0.004 
Second 
interim 
41 
80% 
IC1/2/3: 202
AC: 
526 
IC1/2/3: HR  0.725
AC: 
HR  0.820
p-value  0.0225 
Final 
56 
100% 
IC1/2/3: 253
AC: 
658 
IC1/2/3: HR  0.774
AC: 
HR  0.853
p-value  0.0417 
PFS is statistically 
significant in both IC1/2/3 
and ITT; ORR is not 
statistically significant in 
either IC1/2/3 or ITT 
0.048 
First 
interim 
30 
53% 
IC1/2/3: 135
AC: 
351 
IC1/2/3: HR  0.609
AC: 
HR  0.735
p-value  0.0039 
Second 
interim 
42 
80% 
IC1/2/3: 203
AC: 
530 
IC1/2/3: HR  0.725
AC: 
HR  0.820
p-value  0.0210 
Final 
57 
100% 
IC1/2/3: 254
AC: 
662 
IC1/2/3: HR  0.774
AC: 
HR  0.853
p-value  0.0408 
PFS is statistically 
significant in either IC1/2/3 
or ITT, but not both, and the 
subsequent ORR is 
statistically significant  
0.045 
First 
interim 
30 
52% 
IC1/2/3: 135
AC: 
350 
IC1/2/3: HR  0.602
AC: 
HR  0.729
p-value  0.0031 
Second 
interim 
42 
80% 
IC1/2/3: 207
AC: 
538 
IC1/2/3: HR  0.724
AC: 
HR  0.819
p-value  0.0204 
Final 
59 
100% 
IC1/2/3: 259
AC: 
673 
IC1/2/3: HR  0.773
AC: 
HR  0.852
p-value  0.0384 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
40/Statistical Analysis Plan WO29522 
Appendix 4  
Interim and Final Analyses for Overall Survival (cont.)  
Different Scenarios of PFS 
and ORR Testing 
Alpha 
Level 
Analysis 
Timing 
Time from 1st 
Patient Enrolled 
(months) 
Information 
Fraction 
No. of Events
Stopping Boundary 
in HR 
Stopping Boundary 
in p-Value 
PFS is statistically 
significant in either IC1/2/3 
or ITT, but not both ; ORR 
is not statistically significant 
0.044 
First 
interim 
30 
52% 
IC1/2/3: 136
AC: 
352 
IC1/2/3: HR  0.601
AC: 
HR  0.729
p-value  0.003 
Second 
interim 
43 
80% 
IC1/2/3: 209
AC: 
542 
IC1/2/3: HR  0.725
AC: 
HR  0.819
p-value  0.0200 
Final 
59 
100% 
IC1/2/3: 261
AC: 
677 
IC1/2/3: HR  0.773
AC: 
HR  0.852
p-value  0.0376 
PFS is not statistically 
significant in either IC1/2/3 
or ITT 
0.04 
First 
interim 
30 
50% 
IC1/2/3: 134
AC: 
347 
IC1/2/3: HR  0.586
AC: 
HR  0.718
p-value  0.002 
Second 
interim 
44 
80% 
IC1/2/3: 214
AC: 
554 
IC1/2/3: HR  0.723
AC: 
HR  0.818
p-value  0.0179 
Final 
62 
100% 
IC1/2/3:268
AC: 
693 
IC1/2/3: HR  0.772
AC: 
HR  0.851
p-value  0.0344 
HR  Hazard ratio, IC  tumor-infiltrating immune cell, ITT  intent to treat, ORR  objective response rate, PFS  progression-free survival,