A Phase III, Multicenter, Randomised, Double-Blind, Placebo-Controlled Study of Atezolizumab (Anti-Pd-L1 Antibody) in Combination With Paclitaxel Compared With Placebo With Paclitaxel for Patients With Previously Untreated Inoperable Locally Advanced or Metastatic Triple Negative Breast Cancer
Phase: PHASE3
Conditions: Triple-Negative Breast Cancer
Sponsor: Hoffmann-La Roche

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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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 
1/Protocol MO39196 (IMpassion131), Version 6.0 
PROTOCOL 
TITLE: 
A PHASE III, MULTICENTER, RANDOMISED,  
DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF 
ATEZOLIZUMAB (ANTI–PD-L1 ANTIBODY) IN 
COMBINATION WITH PACLITAXEL COMPARED WITH 
PLACEBO WITH PACLITAXEL FOR PATIENTS WITH 
PREVIOUSLY UNTREATED INOPERABLE LOCALLY 
ADVANCED OR METASTATIC TRIPLE-NEGATIVE 
BREAST CANCER 
PROTOCOL NUMBER: MO39196 
VERSION NUMBER: 
6.0 
EUDRACT NUMBER: 
2016-004024-29  
IND NUMBER: 
123277 
NCT NUMBER: 
NCT03125902 
TEST PRODUCT: 
Atezolizumab (MPDL3280A)  
MEDICAL MONITOR: 
, MD 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 1.0:  14th February 2017 
DATE AMENDED: 
Version 2.0:  12th May 2017 
 
Version 3.0:  5th December 2017  
 
Version 4.0:  17th December 2018  
Version 5.0:  23rd May 2019 
Version 6.0:  See electronic date stamp below. 
 
11-Feb-2020 21:32:01
Title
Approver's Name
Company Signatory
Date and Time (UTC)

Atezolizumab—F. Hoffmann-La Roche Ltd 
3/Protocol MO39196 (IMpassion131), Version 6.0 
PROTOCOL AMENDMENT, VERSION 6.0: 
RATIONALE 
 
Protocol MO39196 (IMpassion131) has been amended to update risks and management 
guidelines for atezolizumab to align with the latest Atezolizumab Investigator's Brochure. 
Changes to the protocol, along with a rationale for each change, are summarized below: 
• 
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, 5.1.2, 5.1.4, 5.1.5.2.1, 5.1.5.3.2, 
and Appendix 11). 
• 
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 5.1.2) and the management 
guidelines for systemic immune activation have been replaced with management 
guidelines for hemophagocytic lymphohistiocytosis and macrophage activation 
syndrome (Section 5.1.4.1 has been deleted and subsequent sections have been 
renumbered; new guidelines are in Appendix 11). In addition, systemic immune 
activation has been removed from the list of adverse events of special interest 
(Section 5.2.3). 
• 
Serum pharmacokinetic/anti-drug antibody samples have been removed at Follow-
Up in Appendix 1 as the assessment was already discontinued as of 
Protocol MO39196, Version 3. 
• 
To address a request by the French ANSM, the atezolizumab adverse event 
management guidelines have been revised to add laboratory (e.g., B-type natriuretic 
peptide) and cardiac imaging abnormalities as signs or symptoms that are 
suggestive of myocarditis (Appendix 11). 
• 
The management guidelines for infusion-related reactions associated with 
atezolizumab have been updated to include guidelines for cytokine-release 
syndrome (CRS) to align with the definition, grading, and management of CRS 
reflected in a recent publication (Lee et al. 2019) (Appendix 11). 
 
 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
5/Protocol MO39196 (IMpassion131), Version 6.0 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 14 
PROTOCOL SYNOPSIS .................................................................................... 15 
1. 
BACKGROUND .......................................................................................... 36 
1.1 
Background on Breast cancer ............................................... 36 
1.1.1 
Triple-Negative Breast Cancer (TNBC) ................................. 37 
1.1.2 
Treatment of Metastatic Breast Cancer ................................. 37 
1.1.2.1 
Taxanes and Paclitaxel in Metastatic Breast 
Cancer ................................................................................... 38 
1.1.2.2 
PD-L1 Inhibitors in the Treatment of TNBC ........................... 38 
1.2 
Background on Atezolizumab ................................................ 39 
1.2.1 
Summary of Nonclinical Studies ............................................ 39 
1.2.2 
Summary of Clinical Studies in Patients with 
TNBC ..................................................................................... 40 
1.2.2.1 
Efficacy of Atezolizumab Monotherapy in 
Patients with TNBC ............................................................... 40 
1.2.2.2 
Safety of Atezolizumab Monotherapy .................................... 41 
1.2.2.3 
Efficacy of Atezolizumab Combined with 
Chemotherapy in Patients with TNBC ................................... 43 
1.2.2.4 
Safety of Atezolizumab Combined with 
Chemotherapy ....................................................................... 44 
1.2.2.5 
Clinical Pharmacokinetics and Immunogenicity of 
Atezolizumab ......................................................................... 45 
1.3 
Study Rationale and Benefit-Risk Assessment ...................... 46 
1.3.1 
Atezolizumab ......................................................................... 46 
1.3.2 
Paclitaxel and Combination Treatment with 
Atezolizumab ......................................................................... 47 
2. 
OBJECTIVES AND ENDPOINTS ............................................................... 48 
3. 
STUDY DESIGN ......................................................................................... 52 
3.1 
Description of the Study......................................................... 52 
3.1.1 
Overview of the Study Design ............................................... 52 
3.1.2 
Independent Data Monitoring Committee .............................. 54 
3.2 
End of Study and Length of Study ......................................... 54 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
6/Protocol MO39196 (IMpassion131), Version 6.0 
3.2.1 
Global Study .......................................................................... 54 
3.2.2 
China Population ................................................................... 54 
3.3 
Rationale for Study Design .................................................... 55 
3.3.1 
Rationale for the Atezolizumab Dose and 
Schedule ................................................................................ 55 
3.3.2 
Rationale for Patient Population and Analysis 
Groups ................................................................................... 55 
3.3.3 
Rationale for Concomitant Paclitaxel Treatment .................... 56 
3.3.4 
Rationale for the Placebo Control .......................................... 58 
3.3.5 
Rationale for Biomarker Assessments ................................... 58 
3.3.5.1 
Rationale for Pre-treatment Tumour Samples ....................... 58 
3.3.5.2 
Rationale for Biopsy Specimen Collection at the 
Time of Radiographic Progression ........................................ 59 
3.3.5.3 
Rationale for the Optional On-treatment Biopsy 
Specimen Collection .............................................................. 59 
3.3.5.4 
Rationale for Blood Sampling for Biomarkers ........................ 59 
3.3.6 
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 59 
3.3.7 
Rationale for the Adverse Event Reporting 
Period .................................................................................... 60 
4. 
MATERIALS AND METHODS .................................................................... 60 
4.1 
Patients .................................................................................. 60 
4.1.1 
Inclusion Criteria .................................................................... 60 
4.1.2 
Exclusion Criteria ................................................................... 63 
4.2 
Method of Treatment Assignment and Blinding ..................... 67 
4.2.1 
Unblinding .............................................................................. 68 
4.2.1.1 
Emergency Unblinding........................................................... 68 
4.2.1.2 
Unblinding upon Disease Progression ................................... 68 
4.2.1.3 
Unblinding at the Study Level ................................................ 69 
4.3 
Study Treatment .................................................................... 69 
4.3.1 
Formulation, Packaging, and Handling .................................. 69 
4.3.1.1 
Atezolizumab ......................................................................... 69 
4.3.1.2 
Placebo .................................................................................. 70 
4.3.1.3 
Paclitaxel ............................................................................... 70 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
7/Protocol MO39196 (IMpassion131), Version 6.0 
4.3.2 
Dosage, Administration, and Compliance .............................. 70 
4.3.2.1 
Atezolizumab/Placebo ........................................................... 70 
4.3.2.2 
Paclitaxel ............................................................................... 71 
4.3.3 
Investigational Medicinal Product Accountability ................... 72 
4.3.4 
Post-Trial Access to Atezolizumab ........................................ 73 
4.4 
Concomitant Therapy ............................................................ 73 
4.4.1 
Permitted Therapy ................................................................. 73 
4.4.1.1 
Premedication ........................................................................ 73 
4.4.1.2 
Treatment of Infusional Adverse Events ................................ 74 
4.4.1.3 
Other Permitted Therapy ....................................................... 74 
4.4.2 
Prohibited and Cautionary Therapy ....................................... 75 
4.4.3 
Additional Restrictions Related to Paclitaxel .......................... 76 
4.5 
Study Assessments ............................................................... 77 
4.5.1 
Informed Consent Forms and Screening Log ........................ 77 
4.5.2 
Medical History and Demographic Data ................................ 78 
4.5.3 
Physical Examinations ........................................................... 78 
4.5.4 
Vital Signs .............................................................................. 78 
4.5.5 
Tumour and Response Evaluations ....................................... 78 
4.5.5.1 
Screening/Baseline Tumour Evaluations ............................... 78 
4.5.5.2 
On-treatment Tumour and Response Evaluations ................. 79 
4.5.6 
Laboratory, Biomarker, and Other Biological 
Samples ................................................................................. 80 
4.5.6.1 
Local Laboratory Assessments .............................................. 80 
4.5.6.2 
Central Laboratory Assessments ........................................... 81 
4.5.6.3 
Use and Storage of Remaining Samples from 
Other Procedures .................................................................. 85 
4.5.7 
Electrocardiograms ................................................................ 85 
4.5.8 
Patient-Reported Outcomes .................................................. 86 
4.5.9 
Optional Samples for Research Biosample 
Repository ............................................................................. 87 
4.5.9.1 
Overview of the Research Biosample Repository .................. 87 
4.5.9.2 
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 87 
4.5.9.3 
Sample Collection .................................................................. 88 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
8/Protocol MO39196 (IMpassion131), Version 6.0 
4.5.9.4 
Confidentiality ........................................................................ 88 
4.5.9.5 
Consent to Participate in the Research 
Biosample Repository ............................................................ 88 
4.5.9.6 
Withdrawal from the Research Biosample 
Repository ............................................................................. 89 
4.5.9.7 
Monitoring and Oversight ....................................................... 89 
4.5.10 
Patient Engagement Application ............................................ 89 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation ...................................................................... 90 
4.6.1 
Patient Withdrawal ................................................................. 90 
4.6.2 
Study Drug Discontinuation ................................................... 90 
4.6.3 
Study and Site Discontinuation .............................................. 90 
5. 
ASSESSMENT OF SAFETY ....................................................................... 91 
5.1 
Safety Plan ............................................................................ 91 
5.1.1 
General Plan to Manage Safety Concerns ............................ 91 
5.1.2 
Risks Associated with Atezolizumab ..................................... 92 
5.1.3 
Risks Associated with Paclitaxel ............................................ 93 
5.1.4 
Management of Patients Who Experience 
Specific Adverse Events ........................................................ 94 
5.1.4.1 
Pulmonary events/Pneumonitis ............................................. 94 
5.1.4.2 
Infusion-Related Reactions .................................................... 95 
5.1.5 
Dose Modifications and Interruptions due to 
Adverse Events ..................................................................... 95 
5.1.5.1 
General Considerations ......................................................... 95 
5.1.5.2 
Events requiring Permanent Treatment 
Discontinuation ...................................................................... 96 
5.1.5.3 
Dose Modifications and Interruptions .................................... 97 
5.2 
Safety Parameters and Definitions ...................................... 100 
5.2.1 
Adverse Events ................................................................... 100 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) .................................................................... 101 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................. 101 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters .............................................. 102 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
9/Protocol MO39196 (IMpassion131), Version 6.0 
5.3.1 
Adverse Event Reporting Period ......................................... 103 
5.3.2 
Eliciting Adverse Event Information ..................................... 103 
5.3.3 
Assessment of Severity of Adverse Events ......................... 103 
5.3.4 
Assessment of Causality of Adverse Events ....................... 104 
5.3.5 
Procedures for Recording Adverse Events .......................... 104 
5.3.5.1 
Infusion-Related Reactions .................................................. 105 
5.3.5.2 
Diagnosis versus Signs and Symptoms............................... 105 
5.3.5.3 
Adverse Events That Are Secondary to Other 
Events.................................................................................. 105 
5.3.5.4 
Persistent or Recurrent Adverse Events .............................. 105 
5.3.5.5 
Abnormal Laboratory Values ............................................... 106 
5.3.5.6 
Abnormal Vital Sign Values ................................................. 107 
5.3.5.7 
Deaths ................................................................................. 107 
5.3.5.8 
Preexisting Medical Conditions ............................................ 108 
5.3.5.9 
Lack of Efficacy or Worsening of Breast Cancer ................. 108 
5.3.5.10 
Hospitalisation or Prolonged Hospitalisation ........................ 108 
5.3.5.11 
Adverse Events Associated with an Overdose or 
Error in Drug Administration ................................................ 109 
5.3.5.12 
Patient-Reported Outcome Data ......................................... 109 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor ........................................................ 110 
5.4.1 
Emergency Medical Contacts .............................................. 110 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest ................... 111 
5.4.2.1 
Events That Occur prior to Study Drug Initiation .................. 111 
5.4.2.2 
Events That Occur after Study Drug Initiation ...................... 111 
5.4.3 
Reporting Requirements for Pregnancies ............................ 111 
5.4.3.1 
Pregnancies in Female Patients .......................................... 111 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ............... 112 
5.4.3.3 
Abortions ............................................................................. 112 
5.4.3.4 
Congenital Anomalies/Birth Defects .................................... 112 
5.5 
Follow-Up of Patients after Adverse Events ........................ 113 
5.5.1 
Investigator Follow-Up ......................................................... 113 
5.5.2 
Sponsor Follow-Up .............................................................. 113 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
10/Protocol MO39196 (IMpassion131), Version 6.0 
5.6 
Adverse Events That Occur after the Adverse 
Event Reporting Period........................................................ 113 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ............................................................... 114 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ..................... 114 
6.1 
Determination of Sample Size ............................................. 115 
6.1.1 
Global Study ........................................................................ 115 
6.1.2 
Controlling for Type I Error .................................................. 118 
6.1.3 
China Population ................................................................. 119 
6.2 
Summaries of Conduct of Study .......................................... 119 
6.3 
Summaries of Treatment $rm Comparability ....................... 119 
6.4 
Efficacy Analyses ................................................................ 119 
6.4.1 
Primary Efficacy Endpoint .................................................... 119 
6.4.2 
Secondary Efficacy Endpoints ............................................. 120 
6.4.2.1 
Secondary Endpoint: Overall Survival ................................. 121 
6.4.2.2 
Time to deterioration in Global Health Status ...................... 121 
6.4.2.3 
Secondary Analyses of Progression-Free 
Survival ................................................................................ 121 
6.4.2.4 
Objective Response Rate .................................................... 121 
6.4.2.5 
Duration of Objective Response .......................................... 122 
6.4.2.6 
Clinical Benefit Rate ............................................................ 122 
6.4.3 
Exploratory Efficacy Endpoints ............................................ 122 
6.4.4 
Handling of Missing Data ..................................................... 123 
6.5 
Safety Analyses ................................................................... 123 
6.6 
Pharmacokinetic Analyses ................................................... 124 
6.7 
Patient-Reported Outcome Analyses .................................. 124 
6.7.1 
Analysis of Time to Deterioration in Global Heath 
Status .................................................................................. 124 
6.7.2 
Exploratory Patient-Reported Outcomes 
Analyses .............................................................................. 125 
6.7.2.1 
Changes from Baseline in Patient Function and 
Symptoms (EORTC QLQ C30 and QLQ BR23) .................. 125 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
11/Protocol MO39196 (IMpassion131), Version 6.0 
6.7.2.2 
Changes from Baseline in Overall Health and 
Quality of Life (EORTC QLQ C30, Items 29 
and 30) ................................................................................ 126 
6.7.2.3 
Health Economic Data ......................................................... 126 
6.7.2.4 
Burden of Treatment ............................................................ 126 
6.8 
Immunogenicity Analyses .................................................... 126 
6.9 
Biomarker Analyses ............................................................. 127 
6.9.1 
Exploratory Biomarker Analyses .......................................... 127 
6.10 
Subgroup Analyses ............................................................. 128 
6.11 
Interim Analysis ................................................................... 128 
6.11.1 
Planned Interim Analysis ..................................................... 128 
6.11.2 
Optional Interim Analysis ..................................................... 128 
6.12 
China Population Analyses .................................................. 129 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 129 
7.1 
Data Quality Assurance ....................................................... 129 
7.2 
Electronic Case Report Forms ............................................. 129 
7.3 
Electronic Patient-Reported Outcome Data ......................... 130 
7.4 
Source Data Documentation ................................................ 130 
7.5 
Use of ComputeriSed Systems ............................................ 131 
7.6 
Retention of Records ........................................................... 131 
8. 
ETHICAL CONSIDERATIONS .................................................................. 131 
8.1 
Compliance with Laws and Regulations .............................. 131 
8.2 
Informed Consent ................................................................ 131 
8.3 
Institutional Review Board or Ethics Committee .................. 133 
8.4 
Confidentiality ...................................................................... 133 
8.5 
Financial Disclosure ............................................................ 133 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 134 
9.1 
Study Documentation .......................................................... 134 
9.2 
Protocol Deviations .............................................................. 134 
9.3 
Site Inspections ................................................................... 134 
9.4 
Administrative Structure....................................................... 134 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
12/Protocol MO39196 (IMpassion131), Version 6.0 
9.5 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 135 
9.6 
Protocol Amendments ......................................................... 136 
10. REFERENCES ......................................................................................... 137 
 
 
LIST OF TABLES 
Table 1 
Study Objectives and Corresponding Endpoints ......................... 15 
Table 2 
Study Objectives and Corresponding Endpoints ......................... 48 
Table 3 
Administration of First and Subsequent Infusions 
of Atezolizumab/Placebo............................................................. 7 
Table 4 
Prohibited Medications and Treatments ...................................... 76 
Table 5 
Proposed Biomarkers for Exploratory Research ......................... 83 
Table 6 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 104 
Table 7 
Operating Characteristics for the Global Study ......................... 11 
Table 8 
Timing of the PFS and OS Analyses ......................................... 118 
Table 9 
Management Guidelines for Pulmonary Events, Including 
Pneumonitis .............................................................................. 179 
Table 10 
Management Guidelines for Hepatic Events ............................. 180 
Table 11 
Management Guidelines for Gastrointestinal Events 
(Diarrhoea or Colitis) ................................................................. 182 
Table 12 
Management Guidelines for Endocrine Events ......................... 184 
Table 13 
Management Guidelines for Ocular Events............................... 187 
Table 14 
Management Guidelines for Immune-Mediated Myocarditis ..... 189 
Table 15 
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome .................................................... 191 
Table 16 
Management Guidelines for Pancreatic Events, Including 
Pancreatitis ............................................................................... 195 
Table 17 
Management Guidelines for Dermatologic Events .................... 197 
Table 18 
Management Guidelines for Neurologic Disorders .................... 198 
Table 19 
Management Guidelines for Immune-Mediated 
Meningoencephalitis ................................................................. 199 
Table 20 
Management Guidelines for Immune-Mediated Renal Events .. 200 
Table 21 
Management Guidelines for Immune-Mediated Myositis .......... 201 
Table 22 
Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome ....... 204 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 21 
 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
13/Protocol MO39196 (IMpassion131), Version 6.0 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Activities ................................................................ 146 
Appendix 2 
Anti-Drug Antibody, Pharmacokinetic, Pharmacodynamic, 
and Exploratory Biomarker Sampling Schedule ........................ 151 
Appendix 3 
Response Evaluation Criteria in Solid Tumors:  Modified 
Excerpt from Original Publication .............................................. 153 
Appendix 4 
Patient-Reported Outcome Instruments .................................... 164 
Appendix 5 
Preexisting Autoimmune Diseases ........................................... 172 
Appendix 6 
Anaphylaxis Precautions ........................................................... 173 
Appendix 7 
Eastern Cooperative Oncology Group (ECOG) Performance 
Status Scale .............................................................................. 174 
Appendix 8 
Cockcroft-Gault formula ............................................................ 175 
Appendix 9 
Guide to Interpreting the AE Causality Question ....................... 176 
Appendix 10 Patient Engagement Application ............................................... 177 
Appendix 11 Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab ............................................................................ 178 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
14/Protocol MO39196 (IMpassion131), Version 6.0 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE III, MULTICENTER, RANDOMISED,  
DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF 
ATEZOLIZUMAB (ANTI-PD-L1 ANTIBODY) IN 
COMBINATION WITH PACLITAXEL COMPARED WITH 
PLACEBO WITH PACLITAXEL FOR PATIENTS WITH 
PREVIOUSLY UNTREATED INOPERABLE LOCALLY 
ADVANCED OR METASTATIC TRIPLE-NEGATIVE 
BREAST CANCER 
PROTOCOL NUMBER: 
MO39196 
VERSION NUMBER: 
6.0 
EUDRACT NUMBER: 
2016-004024-29 
IND NUMBER: 
123277 
NCT NUMBER: 
NCT03125902 
TEST PRODUCT: 
Atezolizumab (MPDL3280A) 
MEDICAL MONITOR: 
, MD 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
Please retain the signed original of this form for your study files.  Please return a copy as 
instructed by your local study monitor. 
 
 
 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
19/Protocol MO39196 (IMpassion131), Version 6.0 
tumour biopsy sample may be used. Of these additional options, the most recent sample should 
be used.  
Study Design 
Description of the Study 
This is a Phase III, global, multicentre, randomised, double-blind, two-arm, placebo-
controlled study designed to evaluate the efficacy and safety of atezolizumab 
(MPDL3280A, an anti-PD-L1 antibody) administered in combination with paclitaxel 
compared with placebo in combination with paclitaxel in patients with previously 
untreated, inoperable locally advanced or metastatic, centrally confirmed TNBC.  
Patients will be enrolled in the study globally (Global study), which may be followed by 
additional enrolment in China only:  
• 
Global study: Approximately 600 patients are planned to be randomised at 
approximately 200 sites globally (in select countries from Europe, Asia/Pacific, as 
well as North-, and South America). Patients will be randomised centrally, using an 
interactive voice or web response system (IxRS), in a 2:1 randomisation ratio to 
receive atezolizumab (840 mg) or placebo IV infusions on Days 1 and 15 of every 
28-day cycle, plus paclitaxel (90 mg/m2) administered via IV infusion on Days 1, 8, 
and 15 of every 28-day cycle.  Randomisation will be stratified by the following 
factors: tumour PD-L1 status (PD-L1 expression on tumour-infiltrating immune cells 
[ICs] assessed by immunohistochemistry [IHC]) (IC0 vs. IC1/2/3), prior taxane 
treatment (yes vs. no), presence of liver metastases (yes vs. no), and region (North 
America vs. Western Europe/Australia; vs. Eastern Europe/Asia Pacific vs. South 
America). Randomised patients will not be replaced. 
• 
Additional enrolment in China: After approximately 600 patients have been 
randomised in the Global study, global recruitment will be closed. Additional patients 
may be subsequently randomised in China only, following the same randomisation 
procedures and ratio (2:1), to ensure a total enrolment of approximately 130 patients 
in mainland China (including patients enrolled in the Global study), referred to as the 
China Population. The schedule of assessments and study treatments for these 
patients will be identical to those in the Global study. Analyses based on the China 
Population will be performed and summarised separately. 
In the absence of disease progression or unacceptable toxicity, study treatment will 
continue until the end of the study (EOS; defined as last patient last visit, or LPLV). In 
the absence of disease progression, paclitaxel and atezolizumab/placebo may be 
discontinued for toxicity independently of each other, with the other treatment being 
continued. The Sponsor, patients, and investigators will not be aware of the patient’s 
treatment assignment. 
In order to evaluate the mechanism of action of the drug combination in the tumour 
microenvironment, its dependency on PD-L1 expression, changes in blood- and tissue-
based biomarkers during treatment, as well as possible study treatment resistance 
mechanisms, paired tumour tissue biopsies will be collected close to the treatment start 
(mandatory sample), on-treatment (optional sample; collected pre-dose on Cycle 2, Day 
1, prior to steroid medication), and at first evidence of radiographic disease progression 
per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (optional sample; 
collected if clinically feasible from a new or progressing tumour lesion).  
Tumour assessments will be performed at screening/baseline, approximately every 
8 weeks (± 1 week) for the first 12 months after randomisation, and every 12 weeks 
thereafter until disease progression (PD), withdrawal of consent, death, or study 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
20/Protocol MO39196 (IMpassion131), Version 6.0 
termination by the Sponsor, whichever occurs first. Tumour assessments performed as 
part of standard of care prior to obtaining informed consent and within 28 days of Cycle 
1, Day 1 may be used as baseline assessments rather than repeating the tests. Tumour 
assessments will be performed on the specified schedule regardless of treatment 
delays, interruptions or discontinuations. Radiologic imaging performed during the 
screening period should consist of 1) computerized tomography (CT) and/or magnetic 
resonance imaging (MRI) of the chest/abdomen/pelvis, 2) bone scan or PET scan, 3) CT 
(with contrast) or MRI scan of the head must be performed at screening to evaluate CNS 
metastasis, and 4) any other imaging studies (CT neck, plain films, etc.) as clinically 
indicated/determined by the treating physician. 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. For each patient, the same radiographic procedures and technique must 
be used for disease evaluation throughout the study (e.g., the same contrast protocol for 
CT scans and/or MRI). Evaluation of tumour response (e.g., for estimation of PFS, PFS 
rate, ORR, DoR and CBR) will be completed per RECIST v1.1. All primary imaging data 
used for tumour assessment will be collected by the Sponsor to enable centralised, 
independent review of response endpoints by an Independent Review Committee (IRC) 
(e.g., to meet potential requests by a reviewing Health Authority).    
Patients randomised to either group must discontinue all study treatment upon 
determination of PD 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.  
All patients who discontinued study treatment before EOS (including due to PD) will be 
followed for survival approximately every 3 months until death, withdrawal of consent, 
loss to follow-up, or study termination by the Sponsor. Information regarding PFS2, 
PROs and the use of subsequent anti-cancer agents for metastatic TNBC will also be 
collected during the survival follow-up period. In addition, for patients who discontinue 
study treatment before EOS for reasons other than PD, tumour assessments will 
continue until PD, death, withdrawal of consent, loss to follow-up, or study termination by 
the Sponsor. 
The study Steering Committee (SC) will provide scientific oversight for the trial. Details 
on the composition and mandate of the SC will be provided in the SC Charter. In 
addition, an independent Data Monitoring Committee (iDMC) will be in place for periodic 
review of aggregate safety data. Details on the composition of the iDMC and safety 
review plan will be provided in the iDMC Charter. 
A schedule of activities is provided in Appendix 1. A study design schema is presented 
in Figure 1 below. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
22/Protocol MO39196 (IMpassion131), Version 6.0 
Number of Patients 
Approximately 600 patients will be randomised at approximately 200 sites globally 
(Global study). This total accounts for an estimated 10% drop-out rate during the study. 
Based on the results of the IMpassion130 study (Schmid et al. 2018), it is estimated 
that approximately 40% of the enrolled patients will have PD-L1-positive tumour status. 
As described above, after approximately 600 patients have been randomised, global 
recruitment will be closed. Additional patients may be subsequently randomised in 
mainland China only, following the same randomisation procedures and ratio (2:1), to 
for enrolment of approximately 130 patients in mainland China (including patients from 
China enrolled in the Global study). 
 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
1. Signed Informed Consent Form 
2. Women or men aged ≥18 years 
3. Patients with locally advanced or metastatic, histologically documented TNBC 
(absence of human epidermal growth factor 2 [HER2], oestrogen receptor [ER], and 
progesterone receptor [PR] expression), not amenable to surgical therapy. 
a. HER2 negativity is defined as either of the following: IHC 0, IHC 1+ or IHC2+/in 
situ hybridisation (ISH)- as per American Society of Clinical Oncology (ASCO)-
College of American Pathologists Guideline (CAP) guideline (ISH- is defined as 
a ratio of HER2 to CEP17 <2.0) (Wolff et al. 2018). 
b. ER and PR negativity are defined as <1% of cells expressing hormonal 
receptors via IHC analysis as per ASCO-CAP guideline (Hammond et al. 2010). 
4. Eligible for taxane monotherapy. 
5. No prior chemotherapy or targeted systemic therapy (including endocrine therapy) 
for inoperable locally advanced or metastatic TNBC.  
Prior radiation therapy for metastatic disease is permitted. There is no required 
minimum washout period for radiation therapy; however, patients should have 
recovered from the effects of radiation before randomisation. 
Previous chemotherapy for early breast cancer (eBC; neoadjuvant or adjuvant setting) 
is permitted if completed ≥12 months before randomisation.  
China Population only: Chinese traditional medicines with an approved indication for 
cancer treatment are permitted as long as the last administration occurred at least 2 
weeks prior to randomisation. 
6. Availability of formalin-fixed paraffin-embedded (FFPE) tumour block (preferred) or 
at least 17 unstained slides, collected ≤3 months prior to randomisation, with an 
associated pathology report, if available. If a tumour sample taken within 3 months 
before randomisation is not available, and a tumour biopsy is not clinically feasible, the 
primary surgical resection sample or the most recent FFPE tumour biopsy sample may 
be used. Of these additional options, the most recent sample should be used. 
a. The tumour tissue should be of good quality based on total and viable tumour 
content and must be evaluated centrally for PD-L1 expression prior to 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
23/Protocol MO39196 (IMpassion131), Version 6.0 
enrolment. Patients whose tumour tissue is not evaluable for prospective central 
testing are not eligible.  
b. If multiple tumour specimens are submitted, patients may be eligible if at least 
one specimen is evaluable for PD-L1 testing, and the score measured in the 
most recent sample prior to enrolment will be used as the PD-L1 score for 
patient stratification.  
i. 
Acceptable samples include core needle biopsies for deep tumour tissue 
(more than one core if clinically feasible) or excisional, incisional, punch, or 
forceps biopsies for cutaneous, subcutaneous, or mucosal lesions. 
ii. 
Fine needle aspiration, brushing, cell pellet from pleural effusion, bone 
metastases, and lavage samples are not acceptable.   
iii. 
Tumour tissue from bone metastases is not evaluable for PD-L1 
expression and is therefore not acceptable. 
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
8. Life expectancy ≥ 12 weeks 
9. Measurable disease, as defined by RECIST v1.1. (Note: Previously irradiated 
lesions can be considered as measurable disease only if disease progression has 
been unequivocally documented at that site since radiation.)  
10. Adequate haematologic and end-organ function, defined by the following laboratory 
results obtained within 2 weeks prior to the first study treatment (Cycle 1, Day 1): 
a. Absolute neutrophil count (ANC) ≥ 1500 cells/μL (without granulocyte colony 
stimulating factor [G-CSF] support within 2 weeks prior to Cycle 1, Day 1) 
b. Lymphocyte count ≥ 500/μL 
c. Platelet count ≥ 100,000/μL (without transfusion within 2 weeks prior to Cycle 1, 
Day 1) 
d. Haemoglobin ≥ 9.0 g/dL 
Patients may be transfused or receive erythropoietic treatment to meet this 
criterion. 
e. Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline 
phosphatase ≤ 2.5× the upper limit of normal (ULN), with the following 
exceptions: 
i. 
Patients with documented liver metastases:  AST and ALT ≤ 5× ULN 
ii. 
Patients with documented liver or bone metastases: alkaline phosphatase 
≤ 5× ULN 
f. Serum bilirubin ≤ 1.25× ULN 
Patients with known Gilbert’s disease who have serum bilirubin level ≤ 3× ULN 
may be enrolled. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
24/Protocol MO39196 (IMpassion131), Version 6.0 
g. International Normalized Ratio (INR) and activated partial thromboplastin time 
(aPTT) ≤ 1.5× ULN 
This applies only to patients who are not receiving an anticoagulant medicinal 
product; patients receiving an anticoagulant medicinal product should be on a 
stable dose and have an INR which is not above the target therapeutic range. 
h. Calculated creatinine clearance (CrCl) ≥30 mL/min (Cockcroft-Gault). 
11. Negative human immunodeficiency virus (HIV) test at screening. 
12. Negative hepatitis B surface antigen (HBsAg) test at screening. 
13. Negative total hepatitis B core antibody (HBcAb) test at screening, or positive 
HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening. 
The HBV DNA test will be performed only for patients who have a positive HBcAb test. 
14. Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV 
antibody test followed by a negative HCV RNA test at screening. 
The HCV RNA test will be performed only for patients who have a positive 
HCV antibody test. 
15. Women of child bearing potential must agree to either use a contraceptive method 
with a failure rate of ≤1% per year or to remain abstinent (refrain from heterosexual 
intercourse) during the treatment period and for at least 5 months after the last dose of 
atezolizumab/placebo, or for at least 6 months after the last dose of paclitaxel. 
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 sterilisation 
(removal of ovaries and/or uterus). 
Examples of contraceptive methods with a failure rate of ≤1% per year include bilateral 
tubal ligation, male sterilisation, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices. 
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal 
are not acceptable methods of contraception. 
16. Women of child bearing potential must have a negative serum pregnancy test result 
within 7 days prior to initiation of study drug. 
17. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm, as 
defined below: 
a. 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 paclitaxel. Men must refrain from donating 
sperm during this same period. 
b. 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 post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
25/Protocol MO39196 (IMpassion131), Version 6.0 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
Cancer-Specific Exclusion Criteria 
1. 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 at least 2 weeks prior to randomisation 
2. Known central nervous system (CNS) disease, except for treated asymptomatic 
CNS metastases, provided all of the following criteria are met: 
a. Measurable disease outside the CNS 
b. Metastases are limited solely to cerebellar and supratentorial lesions (i.e., no 
metastases to midbrain, pons, medulla, or spinal cord) 
c. No ongoing requirement for corticosteroids as therapy for CNS disease 
(anticonvulsants at a stable dose are allowed) 
d. No stereotactic radiation within 7 days or whole-brain radiation within 14 days 
prior to randomisation 
e. No evidence of progression or haemorrhage after completion of CNS directed 
therapy  
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 if all other 
criteria above are met. 
3. Leptomeningeal disease 
4. Uncontrolled pleural effusion, pericardial effusion, or ascites (Note: patients with 
indwelling catheters, such as PleurX® are allowed) 
5. Uncontrolled tumour-related pain  
a. Patients requiring narcotic pain medication must be on a stable regimen at 
study entry.  
b. Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to 
randomisation.  Patients should be recovered from the effects of radiation.  
There is no required minimum recovery period.  
c. 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 randomisation. 
6. Uncontrolled hypercalcemia (>1.5 mmol/L [>6 mg/dL] ionized calcium or serum 
calcium [uncorrected for albumin] >3 mmol/L [>12 mg/dL] or corrected serum calcium 
> ULN) or clinically significant (symptomatic) hypercalcemia.  
Patients who are receiving bisphosphonate therapy specifically to prevent skeletal 
events and who do not have a history of clinically significant (symptomatic) 
hypercalcemia are eligible. 
7. Malignancies other than TNBC within 5 years prior to randomisation, with the 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
26/Protocol MO39196 (IMpassion131), Version 6.0 
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, 
non-melanoma skin carcinoma, or Stage I uterine cancer).  
General Medical Exclusion Criteria 
8. Pregnant or lactating women, or intending to become pregnant during the study. 
9. 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). 
10. Significant cardiovascular disease, such as New York Heart Association (NYHA) 
cardiac disease (Class II or greater), myocardial infarction within 3 months prior to 
randomisation, unstable arrhythmias, or unstable angina. 
a. Patients with a known left ventricular ejection fraction (LVEF) < 40% will be 
excluded.  
b. 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 optimised in the opinion of the treating physician, in consultation 
with a cardiologist if appropriate. 
11. Presence of an abnormal electrocardiogram (ECG) that is clinically significant in the 
investigator’s opinion, including complete left bundle branch block, second- or third-
degree heart block, evidence of prior myocardial infarction, or QT interval corrected 
using Fridericia’s formula (QTcF) > 470 ms demonstrated by at least two consecutive 
ECGs.   
12. Serious infection requiring antibiotics within 2 weeks prior to randomisation, 
including but not limited to infections requiring hospitalisation or IV antibiotics, such as 
bacteraemia, or severe pneumonia. 
13. Major surgical procedure within 4 weeks prior to randomisation or anticipation of 
the need for a major surgical procedure during the course of the study other than for 
diagnosis. Note: Placement of central venous access catheter(s) (e.g., port or similar) 
is not considered a major surgical procedure and is therefore permitted. 
14. Treatment with investigational therapy within 30 days prior to initiation of study 
treatment. 
15. Inability to understand the local language(s) for which the Patient Reported 
Outcome (PRO) questionnaires are available. 
Exclusion Criteria Related to Atezolizumab 
16. History of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric or humanised antibodies or fusion proteins. 
17. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese 
hamster ovary (CHO) cells or any component of the atezolizumab formulation. 
18. History of autoimmune disease, including but not limited to myasthenia gravis, 
myositis, autoimmune hepatitis, systemic lupus erythematosus (SLE), rheumatoid 
arthritis (RA), inflammatory bowel disease, vascular thrombosis associated with 
antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-
Barré 
syndrome, 
multiple 
sclerosis 
(MS), 
vasculitis, 
or 
glomerulonephritis. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
27/Protocol MO39196 (IMpassion131), Version 6.0 
(Note: Patients with a history of autoimmune-related hypothyroidism on a stable dose 
of thyroid replacement hormone and patients with controlled Type 1 diabetes mellitus 
on a stable insulin regimen may be eligible for this study.) 
19. Prior allogeneic stem cell or solid organ transplantation 
20. History of idiopathic pulmonary fibrosis (IPF, including pneumonitis), drug-induced 
pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic 
organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan. 
(Note: History of radiation pneumonitis in the radiation field [fibrosis] is permitted.) 
21. Current treatment with anti-viral therapy for HBV. 
22. Active tuberculosis. 
23. Receipt of a live, attenuated vaccine within 4 weeks prior to randomisation or 
anticipation that such a live, attenuated vaccine will be required during the study. 
Note: Patients must agree not to receive live, attenuated influenza vaccine (e.g., 
FluMist®) within 28 days prior to randomisation, during treatment or within 5 months 
following the last dose of atezolizumab/placebo. 
24. Prior treatment with CD137 agonists, anti-PD-1, or anti-PD-L1 therapeutic antibody 
or immune checkpoint targeting agents. 
25. Treatment with systemic immunostimulatory agents (including but not limited to 
interferons or interleukin [IL]-2) within 4 weeks or five half-lives of the drug (whichever 
is longer) prior to randomisation. 
26. Treatment with systemic immunosuppressive medications (including but not limited 
to corticosteroids, cyclophosphamide, azathioprine, cyclosporine, methotrexate, 
thalidomide, and anti-tumour necrosis factor [TNF] agents) within 2 weeks prior to 
randomisation, 
or 
anticipated 
requirement 
for 
systemic 
immunosuppressive 
medications during the trial. 
a. Patients who have received acute, low-dose (≤ 10 mg oral prednisone or 
equivalent), systemic immunosuppressant medications may be enrolled in the 
study.  
b. Patients with a history of allergic reaction to IV contrast requiring steroid pre-
treatment should have baseline and subsequent tumour assessments 
performed using MRI. 
c. The use of corticosteroids (≤10 mg oral prednisone or equivalent) for chronic 
obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for 
patients 
with 
orthostatic 
hypotension, 
and 
low 
dose 
supplemental 
corticosteroids for adrenocortical insufficiency are allowed. 
d. Systemic corticosteroids are allowed as paclitaxel premedication during the trial 
at a dose ≤10 mg dexamethasone or equivalent in order to avoid severe 
hypersensitivity reactions. 
27. Poor peripheral venous access 
28. Illicit drug or alcohol abuse within 12 months prior to screening, in the investigator’s 
judgment 
29. Any other serious medical condition or abnormality in clinical laboratory tests that, 
in the investigator’s judgment, precludes the patient’s safe participation in and 
completion of the study. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
28/Protocol MO39196 (IMpassion131), Version 6.0 
Exclusion Criteria Related to Paclitaxel 
30. History of hypersensitivity reactions to paclitaxel or other drugs formulated in the 
same solvent as paclitaxel (polyoxyethylated castor oil). 
 
End of Study 
The EOS is defined as the date when the last patient, last visit (LPLV) is completed.  
Global Study  
This is an event driven trial. The Global study will end after the required number of 
events for the final analysis of OS has been reached.  
In addition, the Sponsor may decide to terminate the study at any time. 
China Population  
For patients randomised during additional enrolment in China, the study will end when 
the pre-specified number of 36 PFS events has occurred in the China population with 
PD-L1-positive tumour status, or when the Global study ends, whichever is later. 
In case additional enrolment in China is not initiated, patients from China enrolled in 
the Global study will end the study as defined for all other patients in the Global study. 
 
Length of Study 
The length of the study and the time for final analysis will depend on the actual 
enrolment rate and the number of events that occur. Mortality events will be monitored 
throughout the course of the study, and study timelines might be updated.  
 
Investigational Medicinal Products 
Atezolizumab/placebo and paclitaxel are considered investigational medicinal products 
(IMPs) in this study. All IMPs will be supplied by the Sponsor. 
Atezolizumab (Investigational Drug) 
The atezolizumab drug product is provided in a single-use, 20cc USP/Ph. Eur. Type 1 
glass vials intended for IV administration. The vial contains ~20 mL (1200 mg) of 
atezolizumab solution (60 mg/mL). 
Placebo (Comparator)  
Placebo will consist of the vehicle without the antibody. Placebo will be supplied in a 
single-use, 20cc glass vials containing ~20 mL of solution.  
Patients will receive atezolizumab 840 mg (corresponding to 14 mL from drug product, 
in 250 mL 0.9% sodium chloride [NaCl]) or matching placebo by IV infusion 
administered on Day 1 and Day 15 (± 3 days) of every 28-day cycle. The first dose 
(Cycle 1, Day 1) will be administered over 60 (± 15) minutes. If the first infusion is well 
tolerated, all subsequent infusions may be delivered over 30 (± 10) minutes. 
For the first infusion of atezolizumab/placebo, no premedication will be administered. 
Should the patient experience infusion-related reaction(s) during any infusion, 
premedication with antihistamines may be administered for subsequent infusions at the 
discretion of the treating physician. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
29/Protocol MO39196 (IMpassion131), Version 6.0 
Administration of atezolizumab/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 
the current atezolizumab Investigator’s Brochure (IB). 
Paclitaxel (Background Chemotherapy) 
For information on the formulation, packaging, and handling of paclitaxel, refer to the 
local prescribing information for paclitaxel. 
Paclitaxel will be administered at the 90 mg/m2 dose via 1-hour IV infusion on Days 1, 
8, and 15 of every 28-day cycle. In the absence of unacceptable toxicity, paclitaxel will 
be administered until PD or until the end of the study, whichever occurs earlier.  
All patients should be premedicated prior to paclitaxel administration to prevent severe 
hypersensitivity reactions. Prior to receiving the first two study infusions of paclitaxel, 
all patients will receive corticosteroids (8-10 mg dexamethasone or equivalent) as part 
of either the institutional standard of care or the following premedication:  
• 
Dexamethasone 8-10 mg (or equivalent) administered orally approximately 12 and 
6 hours prior to the paclitaxel infusion 
Patients may be treated with dexamethasone ≤10 mg IV within 1 hour prior to the 
paclitaxel infusion if the patient did not take the oral dexamethasone. 
• 
Diphenhydramine 50 mg IV (or equivalent) 30-60 minutes prior to the 
paclitaxel infusion 
• 
Cimetidine 300 mg IV or ranitidine 50 mg IV (or equivalent) 30-60 minutes prior to 
paclitaxel infusion.  
Because the effects of corticosteroids on T-cell proliferation have the potential to ablate 
early atezolizumab-mediated anti-tumour immune activity, it is recommended that the 
dose of dexamethasone (or equivalent) is minimised to the extent that is clinically 
feasible. For example, if paclitaxel is well tolerated during the first two weekly infusions 
without apparent hypersensitivity reaction, a reduction in the dose of dexamethasone 
premedication (or equivalent) should be considered for subsequent cycles if permitted 
by institutional standard of care. This approach has been reported to be successful in 
the literature (Berger et al. 2012). 
Details on paclitaxel dose modifications due to toxicity are provided in Section 5.1.5.3.2. 
Sites should follow their institutional standard of care for determining the 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. 
Atezolizumab/placebo and paclitaxel may be discontinued for toxicity independently of 
each other in the absence of PD.  
Non-Investigational Medicinal Products 
Non-investigational medicinal products (NIMPs) used in the study include 
premedication, medications that may be administered to manage adverse events, and 
other permitted concomitant medications. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
30/Protocol MO39196 (IMpassion131), Version 6.0 
Statistical Methods 
Primary Analysis 
The primary efficacy objective for this study is to evaluate the efficacy of atezolizumab 
plus paclitaxel compared with placebo plus paclitaxel in patients with inoperable locally 
advanced or metastatic TNBC based on the following primary efficacy endpoint: 
• 
Progression-free survival (PFS), defined as the time from randomisation to the first 
occurrence of disease progression, as determined by the investigator using RECIST 
v1.1, or death from any cause during the study, whichever occurs first. 
PFS will be tested hierarchically in the following fixed order: 
• 
PFS in the PD-L1-positive subpopulation (defined as patients in the intent-to-treat 
[ITT] population whose PD-L1 status is IC1/2/3 at the time of randomisation). 
• 
PFS in the ITT population (defined as all randomised patients, whether or not the 
assigned study treatment was received). 
PFS will be compared between treatment arms based on the stratified log-rank test. 
The stratification factors will be three of the four predefined randomisation stratification 
factors: tumour PD-L1 status (IC0 vs. IC1/2/3), prior taxane treatment (yes vs. no) and 
presence of liver metastases (yes vs. no) and will be obtained from the interactive 
Web/phone response system (IxRS). The hazard ratio (HR) for disease progression or 
death will 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 unstratified 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 Brookmeyer-Crowley 
methodology will be used to construct the 95% CI for the median PFS for each 
treatment arm (Brookmeyer and Crowley 1982). 
Data for patients without disease progression or death will be censored at the last 
tumour assessment date.  Data for patients with a PFS event who missed two or more 
assessments scheduled immediately prior to the date of the PFS event will be censored 
at the last tumour assessment prior to the missed visits as a sensitivity analysis. If no 
tumour assessment was performed after randomisation, data will be censored at the 
date of randomisation + 1 day. 
The final analysis of the primary endpoint (PFS) in the China population will be 
conducted after approximately 36 PFS events have been documented in the China 
population with PD-L1-positive tumour status. Methods for analysing data from the 
China population will be provided in the Statistical Analysis Plan (SAP). Results from 
these analyses will be summarised in a separate report from the clinical study report 
(CSR) for the Global study. 
Further details will be provided in the SAP. 
Determination of Sample Size  
Global Study 
The purpose of this event-driven study is to evaluate the efficacy of atezolizumab plus 
paclitaxel compared to placebo plus paclitaxel as measured by PFS (either investigator-
assessed disease progression per RECIST v1.1 or death from any cause, whichever 
occurs first). PFS will be assessed hierarchically in the following fixed order: (1) PFS in 
the PD-L1-positive subpopulation; followed by (2) PFS in the ITT population.  

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
31/Protocol MO39196 (IMpassion131), Version 6.0 
The sample size for the Global study is determined based on the following assumptions: 
• 
Median PFS of 5.0 months in patients with PD-L1-positive tumour status 
randomised to the placebo plus paclitaxel group (as detected in patients with PD-L1-
positive TNBC in the placebo plus albumin-bound (nab-)paclitaxel control arm of the 
IMpassion130 study) (Schmid et al. 2018); 
• 
Treatment effect (between-group difference) of 2.5 months in the median PFS (HR 
0.62) in the PD-L1-positive subpopulation (as detected in the PD-L1-positive 
subpopulation of the IMpassion130 study) (Schmid et al. 2018); 
• 
Randomisation ratio of 2:1; 
• 
Approximately 40% of the enrolled patients are expected to have PD-L1-positive 
tumour status (as detected in the IMpassion130 study) (Schmid et al. 2018); 
• 
80% power and an overall 2-sided α of 0.05; 
• 
Drop-out rate of 10%.  
Based on these assumptions and parameters, approximately 213 evaluable patients 
with PD-L1-positive tumour status (approximately 142 in the atezolizumab plus 
paclitaxel group and approximately 71 in the placebo plus paclitaxel group) and a total 
of 155 PFS events are required to detect a between-group difference of 2.5 months in 
the final analysis of median PFS (HR 0.62). Assuming that approximately 40% of the 
enrolled patients will have PD-L1-positive tumour status, and to account for an 
estimated drop-out rate of 10%, approximately 600 patients will be randomised in the 
Global study (approximately 400 in the atezolizumab plus paclitaxel group and 
approximately 200 in the placebo plus paclitaxel group). Anticipating a global 
recruitment period of approximately 23 months (up to 40 patients per month), the 
clinical cut-off (CCO) date for the primary (final) PFS analysis in the subpopulation with 
PD-L1-positive tumour status is expected to occur approximately 29 months after the 
first patient was randomised (FPI) in the Global study. 
In addition, overall survival (OS) is a secondary analysis in this study. As for the primary 
analysis of PFS, OS will be analysed in the PD-L1-positive subpopulation and ITT 
population. Based on the previously noted assumptions, with an anticipated global 
recruitment period of approximately 23 months (up to 40 patients per month) and 
assuming that in the subpopulation with PD-L1-positive tumour status, median OS will 
be 15.5 months in the placebo plus paclitaxel group (based on the median OS in the 
PD-L1-positive subpopulation receiving nab-paclitaxel only in the IMpassion130 study 
(Schmid et al. 2018), the study will have approximately 70% power to detect a between-
group difference of 9.5 months in the median OS (HR 0.62). The final analysis of OS 
should occur after 122 mortality events have been observed in the subpopulation with 
PD-L1-positive tumour status, which is expected approximately 40 months after FPI. By 
this time-point, 305 mortality events are expected to have occurred in the ITT population. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
32/Protocol MO39196 (IMpassion131), Version 6.0 
All tests will be performed at two-sided alpha of 5% with testing for secondary endpoints 
conducted hierarchically, using a fixed sequence testing approach (Westfall and 
Krishen, 2001), where each subsequent hypothesis will be tested only if all previously 
tested hypotheses have been rejected, according to the following pre-specified and 
fixed order of endpoints: 
• 
Primary: [1] PFS by RECIST v1.1 in the PD-L1-positive subpopulation; [2] PFS 
by RECIST v1.1 in the ITT population;  
• 
Secondary: [3] overall survival (OS) in the PD-L1-positive subpopulation; [4] OS 
in the ITT population; [5] ORR by RECIST v1.1 in the PD-L1-positive, Response-
evaluable subpopulation; [6] ORR by RECIST v1.1 in the ITT population. 
Further details will be included in the SAP. 
China Population 
After approximately 600 patients have been randomised in the Global study, global 
recruitment will be closed. Additional patients may be subsequently enrolled in China 
only, following the same randomisation procedures and ratio (2:1), for a total of 
approximately 130 patients from mainland China (including patients enrolled in the 
Global study), referred to as the China Population.  
The objective of the China population analyses is to evaluate whether the efficacy of 
atezolizumab plus paclitaxel compared with placebo plus paclitaxel in the China 
population (enrolled in the Global study and during additional recruitment in China) is 
consistent with the efficacy observed in the Global population (Global study). 
Further details will be included in the SAP. 
Interim Analyses  
No interim analysis of PFS is planned. 
An interim analysis of OS will be performed (in the PD-L1-positive subpopulation and 
the ITT population) at the primary (final) analysis of PFS. A group sequential design 
(Lan-DeMets with O’Brien-Fleming stopping boundaries) will be used to control the 
overall type I error rate (Lan and DeMets, 1983). Testing on OS will be conducted 
hierarchically only if the null hypothesis for testing on PFS has been rejected.   
The iDMC will complete periodic reviews of safety data. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
33/Protocol MO39196 (IMpassion131), Version 6.0 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Definition 
ADA 
anti-drug antibody (also known as anti-therapeutic antibody, ATA) 
AE 
adverse event 
ALT 
alanine transaminase 
ANA 
anti-nuclear antibody 
ANC 
absolute neutrophil count  
ANCA 
anti-neutrophil cytoplasmic antibody  
anti-dsDNA 
anti-double-stranded deoxyribonucleic acid  
aPTT 
activated partial thromboplastin time  
ASCO 
American Society of Clinical Oncology  
AST 
aspartate transaminase 
ATA 
anti-therapeutic antibody  
BRCA 
breast cancer susceptibility gene  
BUN 
blood urea nitrogen 
c-ANCA 
circulating anti-neutrophil cytoplasmic antibody  
CAP 
College of American Pathologists 
CBR 
clinical benefit rate 
CCO 
clinical cut-off (date) 
CD 
cluster of differentiation 
C-DoR 
duration of response for confirmed responders 
CEP17 
centromeric probe for chromosome 17 
CNS 
central nervous system 
Cmax 
maximum observed serum concentration 
Cmin 
minimum observed serum concentration 
C-ORR 
confirmed objective response rate 
CrCL 
creatinine clearance 
CRO 
Contract Research Organisation 
CSR 
clinical study report 
CT 
computed tomography 
DEHP 
di-(2-ethylhexyl)phthalate  
DNA 
deoxyribonucleic acid 
DoR 
duration of objective response 
DRB 
Data Review Board 
eBC 
early breast cancer 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
34/Protocol MO39196 (IMpassion131), Version 6.0 
Abbreviation 
Definition 
eCRF 
electronic Case Report Form 
ECG 
Electrocardiogram 
EDC 
electronic data capture 
EORTC 
European Organization for Research and Treatment of Cancer 
EOS 
end of study 
ePRO 
electronic patient-reported outcome 
ER 
(o)estrogen receptor 
ESMO 
European Society for Medical Oncology 
EQ-5D-5L 
European Quality of Life 5 Dimension, 5-level version 
FFPE 
formalin-fixed paraffin-embedded 
FPI 
first patient in 
G-CSF 
granulocyte colony stimulating factor  
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HER2 
human epidermal growth factor 2 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
HRQoL 
health-related quality of life 
IB 
Investigators Brochure 
IC 
immune cell 
ICH 
International Conference on Harmonisation 
iDMC 
independent Data Monitoring Committee 
IHC 
Immunohistochemistry 
Ig 
Immunoglobulin 
IL 
Interleukin 
IMP 
investigational medicinal product 
IND 
Investigational New Drug application 
INR 
International Normalized Ratio 
IRC 
Independent Review Committee 
IRR 
infusion-related reaction 
ISH 
in situ hybridization 
ITT 
intent to treat 
IV 
Intravenous 
IxRS 
interactive voice/web response system 
LPI 
last patient in 
LPLV 
last patient last visit 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
35/Protocol MO39196 (IMpassion131), Version 6.0 
Abbreviation 
Definition 
LVEF 
left ventricular ejection fraction 
mBC 
metastatic breast cancer 
MRI 
magnetic resonance imaging 
TNBC 
triple-negative breast cancer 
NCI CTCAE v4.0 
National Cancer Institute Common Terminology Criteria for Adverse 
Events Version 4.0 
NSCLC 
non-small cell lung cancer  
NYHA 
New York Heart Association 
ORR 
objective response rate 
OS 
overall survival 
p-ANCA 
perinuclear anti-neutrophil cytoplasmic antibody  
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PD 
Progression of disease / disease progression 
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 
QLQ-BR23 
breast cancer module for QLQ-C30 
QLQ-C30 
Quality of Life Questionnaire Core 30 
RA 
rheumatoid arthritis  
RBC 
red blood cell 
RBR 
Research Biosample Repository 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
SAP 
Statistical Analysis Plan 
SD 
stable disease 
SLE 
systemic lupus erythematosus  
TNBC 
triple-negative breast cancer 
TNF 
tumour necrosis factor 
ULN 
upper limit of normal 
WBC 
white blood cell  
 
 
 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
36/Protocol MO39196 (IMpassion131), Version 6.0 
1. 
BACKGROUND 
1.1 
BACKGROUND ON BREAST CANCER  
Breast cancer is the second most common cancer in the world and, by far, the most 
frequent cancer among women both in more and less developed regions. There were an 
estimated 1.67 million new cancer cases diagnosed worldwide in 2012 (25% of all 
cancers) (Ferlay et al. 2013; Ferlay et al. 2015; Torre et al. 2015). Age-adjusted 
incidence rates (per 100,000 population) are highest in North America (91.6), followed 
by Europe (69.9), Latin America (47.2), and Eastern Asia (27.0) (Ferlay et al. 2013). In 
the United States of America (USA), it is projected that there will be 246,660 new 
diagnoses (not including about 61,000 cases of female breast carcinoma in situ) due to 
BC, and an estimated 3,560,570 women will be living with BC in 2016 (Siegel et al. 
2016; Miller et al. 2016). In Europe, BC accounts for 28.8% of female cancer and is 
estimated to affect more than one in 10 women (Lundqvist et al. 2016). In five Latin 
American countries, the estimated incidence rates for BC were between 27.2 and 74.0 
per 100,000 women in 2008 (Nigenda et al. 2016). The majority of patients are 
diagnosed with localised breast cancer, however, approximately 6% of patients present 
with de novo metastatic disease and between 10% and 40% of patients with localized 
breast cancer will relapse systemically (Zeichner et al. 2015a; Zeichner et al. 2015b).  
Breast cancer ranks as the fifth cause of death from cancer overall in the world (522,000 
deaths; 6.4% of all cancer-related deaths), the leading cause of cancer-related deaths in 
women (14.7% of all cases), and the second cause of cancer death in women in more 
developed regions (198,000 deaths, 15.4% of total) after lung cancer (Ferlay et al. 2013; 
Ferlay et al. 2015; Torre et al. 2015). Age-adjusted mortality rates (per 100,000 
population) are highest in Europe (16.1), followed by North America (14.8), Latin 
America (13.0), and Eastern Asia (6.1) (Ferlay et al. 2013). In the USA, it is projected 
that there will be 40,450 deaths due to BC in 2016 (Siegel et al. 2016; Miller et al. 2016). 
In five Latin American countries, the estimated mortality rates for BC were between 10.0 
and 20.1 per 100,000 women in 2008 (Nigenda et al. 2016).  
The above statistics include all subtypes of BC (Ferlay et al. 2013; Collignon et al. 2016). 
However, BC is a heterogeneous disease encompassing about 15 different types of 
carcinomas, which are for therapeutic reasons, further classified according to their 
oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth 
factor receptor 2 (HER2) status (Brouckaert et al. 2012). These subgroups have 
important implications for the choice of therapy, treatment outcomes, recurrence rate, 
and mortality risk. The lack of expression of oestrogen receptor (ER), progesterone 
receptor (PR), and human epidermal growth factor receptor 2 (HER2), is referred to as 
triple-negative BC (TNBC) (Trivers et al. 2009; Zeichner et al. 2016).  
The prognosis of patients with metastatic breast cancer (mBC) varies from several 
months to many years depending upon multiple factors, including, but not limited to, 
ER/PR status and HER2 status (Zeichner et al. 2015a; Zeichner et al. 2015b). Most new 
treatment options for mBC are only effective for ER/PR-positive or HER2-positive 
metastatic tumours (Zeichner et al. 2016). The 5-year survival rate following metastatic 
diagnosis is around 15% (Jemal et al. 2011; Ferlay et al. 2013). 

Atezolizumab—F. Hoffmann-La Roche Ltd
37/Protocol MO39196 (IMpassion131), Version 6.0
1.1.1
Triple-Negative Breast Cancer (TNBC)
The triple-negative subtype is a heterogeneous group of BCs, characterised by the lack 
of expression of hormonal receptors and the absence of HER2 overexpression 
(Collignon et al. 2016). According to the St. Gallen International Expert Consensus 
(Goldhirsch et al. 2009), and the recommendations of the American Society of Clinical 
Oncology and the American College of Pathology (Hammond et al. 2010), tumour 
specimens are ER or PR negative if less than 1% of tumour cells express the oestrogen 
and progesterone receptors via immunohistochemistry (IHC), and HER2-negative if
showing IHC 0 or 1+ or in situ hybridisation (ISH) negative using single-probe ISH or 
dual-probe ISH (Wolff et al. 2018). 
Approximately 15%-20% of all BCs belong to the triple-negative phenotype that has 
distinct risk factors, distinct molecular features, and a particular clinical presentation and 
outcome (Brouckaert et al. 2012; Lin et al. 2012; Penault-Llorca and Viale, 2012). The 
TNBC phenotype has been associated with Black race, younger age, and more 
advanced tumour stage at presentation (Millikan et al. 2008; Lund et al. 2009; Trivers et 
al. 2009; Lin et al. 2012; Danforth et al. 2013). TNBCs are more likely to have 
aggressive features, such as a high proliferative rate, and exhibit an invasive phenotype. 
Patients with metastatic TNBCs exhibit rapid progression and a poor clinical outcome 
(Mersin et al. 2008; Trivers et al. 2009; Wahba and El-Hadaad, 2015). TNBC is 
associated with a higher risk of brain or lung metastases, and worse breast cancer-
specific and overall survival (OS) (Lin et al. 2012); median OS is generally between 13
months (Kassam et al. 2009) and 17.5 months in patients treated with various 
chemotherapy agents (Roche data on file).
Large-scale comprehensive genomic analyses have characterised 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 (Hirshfield and Ganesan, 2014). Chemotherapy is 
the mainstay of treatment of TNBC, and current treatment strategies for triple-negative 
disease include anthracyclines, taxanes, ixabepilone, platinum agents, and bevacizumab 
(Hudis and Gianni, 2011). However, although TNBC may respond to chemotherapy, 
including taxanes, relatively few new agents have been approved for the subset of 
patients with metastatic TNBC (mTNBC) (Carey et al. 2012; O’Shaughnessy et al. 2014; 
Hirshfield and Ganesan, 2014; Zeichner et al. 2016) and there are no targeted therapies 
with widespread global approval available for patients with this specific subtype of breast 
cancer. Therefore, there is a pressing need for clinically active agents for mTNBC.
1.1.2
Treatment of Metastatic Breast Cancer 
The treatment algorithm for patients with mBC is based on several factors that include 
clinical, pathologic, and histologic characteristics such as the presence or absence of 
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 (Piccart-Gebhart et al. 2008). Treatment 
options for mBC include endocrine therapies, monoclonal antibodies, antibody-drug 
conjugates, targeted therapies and different types of chemotherapy (Hernandez-Aya and 
Ma, 2016). Several cytotoxic chemotherapy agents have shown activity in mBC, 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
38/Protocol MO39196 (IMpassion131), Version 6.0 
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, 2015).  
However, despite striking discoveries and a broad therapeutic armamentarium, mBC 
remains incurable. The goal of treatment of mBC is to prolong survival and to improve 
quality of life by mitigating cancer-related symptoms without increasing toxicity 
(Hernandez-Aya and Ma, 2016). 
1.1.2.1 
Taxanes and Paclitaxel in Metastatic Breast Cancer  
Taxane-based regimens are considered a standard of care option 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 BC is 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).  
Weekly paclitaxel (80–90mg/m2) is currently considered the most effective schedule for 
delivering paclitaxel (Swanton 2011), and was found to be associated with higher overall 
survival (OS) and lower incidence of serious adverse events, neutropoenia, 
neutropoenic fever, and peripheral neuropathy compared with the three-weekly taxane 
schedules in advanced breast cancer (Seidman et al. 2008; Mauri et al. 2010). In 
addition, a regimen consisting of weekly paclitaxel administrations for three weeks, 
followed by one-week break was reported to be associated with less neurotoxicity 
compared to continuous weekly administrations (Swanton 2011); refer to Section 3.3.3 
for further details. 
1.1.2.2 
PD-L1 Inhibitors in the Treatment of TNBC  
Recent investigations of targeted therapy for advanced TNBC includes immune 
checkpoint inhibitors targeting the programmed death receptor 1 (PD-1)/ programmed 
death ligand 1 (PD-L1; also called B7-H1 or cluster of differentiation [CD]274). PD-L1 is 
expressed on many cancer and immune cells (e.g., macrophages), and plays an 
important part in blocking the 'cancer immunity cycle' by binding and stimulating PD-1 
and B7.1 (CD80), both of which are negative regulators of T-lymphocyte activation. PD-1 
is an inhibitory receptor expressed on T cells following T-cell activation, which is 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
39/Protocol MO39196 (IMpassion131), Version 6.0 
sustained in states of chronic stimulation such as in chronic infection or cancer (Keir et al. 
2008; Herbst et al. 2014). B7.1 is a molecule expressed on antigen-presenting cells and 
activated T cells. Binding of PD-L1 to its receptors suppresses T-cell migration, 
proliferation and secretion of cytotoxic mediators, and restricts tumour cell killing, leading 
to the functional inactivation or exhaustion of T cells (Butte et al. 2007; Yang et al. 2011; 
Herbst et al. 2014). The PD-1/PD-L1 pathway has been implicated in tumours evading 
immune surveillance. Blockage of the PD-1/PD-L1 interaction enables the rapid 
restoration of the effector function of preexisting anticancer T cells (Chen and Mellman, 
2013; Saha and Nanda, 2016). Blocking PD-L1 should therefore enhance anticancer 
immunity (Herbst et al. 2014). 
Based on results of early clinical studies, blockade of the PD-1/PD-L1 axis with 
atezolizumab (Emens et al. 2018; Adams et al. 2018; Schmid et al. 2018), 
pembrolizumab (Nanda et al. 2016; Adams et al. 2019a; Adams et al. 2019b), or 
avelumab (Dirix et al. 2018) has demonstrated promising efficacy and durable responses 
in patients with advanced TNBC. 
 
1.2 
BACKGROUND ON ATEZOLIZUMAB  
Atezolizumab (TECENTRIQ™, formerly known as MPDL3280A) is a humanised 
immunoglobulin (Ig) G1 monoclonal antibody consisting of two heavy chains (448 amino 
acids) and two light chains (214 amino acids) and is produced in Chinese hamster ovary 
(CHO) 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 PD-L1 and inhibits its interaction with its receptors, PD-1 and B7.1 (CD80, 
B7-1). Both interactions are reported to provide inhibitory signals to T cells. 
Atezolizumab is being investigated as a potential therapy against solid tumours and 
haematologic malignancies in humans.  Atezolizumab has been approved in the USA for 
the treatment of locally advanced or metastatic urothelial carcinoma, metastatic non-
small cell lung cancer (NSCLC), and PD-L1-positive unresectable locally advanced or 
metastatic 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) behaviour, 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, PK, 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, PK, and 
toxicokinetics of atezolizumab. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
40/Protocol MO39196 (IMpassion131), Version 6.0 
Overall, the nonclinical PK 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 down-modulating the PD-L1/PD-1 pathway and 
supported entry into clinical trials in patients. 
Refer to the atezolizumab Investigator’s Brochure for details on the nonclinical studies.  
1.2.2 
Summary of Clinical Studies in Patients with TNBC 
Atezolizumab is being investigated in multiple Phase I, II, and III clinical studies, both as 
monotherapy and in combination with several anti-cancer therapies against solid 
tumours and haematologic malignancies (see the most recent version of the 
atezolizumab Investigator’s Brochure for study descriptions).  
Anti-tumour activity, as determined by Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1 responses, has been observed across multiple advanced tumour types 
for both atezolizumab monotherapy (Phase 1a study PCD4989g) as well as in 
combination with bevacizumab and/or chemotherapy (Phase 1b study GP28328). In 
patients with mTNBC, atezolizumab has shown activity as monotherapy (Emens et al. 
2018; Schmid et al. 2017), and in combination with nab-paclitaxel (Adams et al. 2018; 
Schmid et al. 2018). Combining atezolizumab with chemotherapy is hypothesised to 
enhance tumour-specific T-cell immunity by exposing the immune system to high levels 
of chemotherapy-induced tumour antigens and modulating T-cell and NK cell functions 
(Adams et al. 2016). 
1.2.2.1 
Efficacy of Atezolizumab Monotherapy in Patients with TNBC 
Atezolizumab monotherapy has been evaluated in a mTNBC expansion cohort as part of 
a multicentre Phase Ia study PCD4989g (clinicaltrials.gov identifier: NCT01375842). 
PCD4989g is a first-in-human, ongoing open-label, dose-escalation trial evaluating the 
safety, tolerability, immunogenicity, PK, exploratory pharmacodynamics, and preliminary 
evidence of biologic activity of atezolizumab administered as a single agent to patients 
with locally advanced or metastatic solid malignancies or haematologic malignancies. 
Atezolizumab is administered at 15 mg/kg, 20 mg/kg or 1200 mg flat dose IV every three 
weeks (Q3W). Among 115 objective response rate (ORR)-evaluable patients, 
investigator-assessed confirmed ORR was 10% (95% CI, 5-16) with 3 complete 
responses (CRs) and 8 partial responses (PRs).  Median duration of objective response 
(DoR) was 21 months (range 9.6 weeks to non-estimable [NE]) and all-patient median 
OS was 8.9 months (95% CI, 7.0-12.6), with a median follow-up duration of 25.3 months. 
Median progression-free survival (PFS) was 1.4 months (95% CI, 1.4–1.6). These data 
suggest a similarity to or advantage over standard of care (SOC) treatment. Higher PD-
L1 expression (IC2/3) compared to lower PD-L1 expression (IC0/1) was associated with 
better clinical outcomes, as evidenced by higher ORR (12% vs. 5% in the two subgroups, 
respectively), and longer median OS (10.5 months [95% CI, 7.1–14.7] vs 7.0 [95% CI, 
5.1–12.6], respectively). Greater treatment benefit was also observed in patients 
receiving first-line (1L) compared to subsequent lines (2L+) of atezolizumab treatment, 
as evidenced by higher ORR (24% among 1L patients vs. 6% among 2L+ patients), and 
longer median OS (17.6 months [95% CI, 10.1–NE], vs. 7.3 months [95% CI, 6.1–10.8], 
respectively). Median PFS was consistent (approximately 1.4 months) regardless of PD-

Atezolizumab—F. Hoffmann-La Roche Ltd
41/Protocol MO39196 (IMpassion131), Version 6.0
L1 expression or line of therapy (Atezolizumab Investigator’s Brochure, 2018). 
Atezolizumab increased intratumoural tumour infiltrating lymphocytes (TILs), CD8, 
macrophages and IC PD-L1 expression, but no response association was observed 
(Schmid et al. 2017).
1.2.2.2
Safety of Atezolizumab Monotherapy 
As of the all-indication data cut-off date of 31 December 2016, safety information was 
available for 658 safety-evaluable patients from all lines of therapy in the PCD4989g 
study, including 116 patients with TNBC. The median age of the 658 safety-evaluable 
patients was 61 years (range 20 to 89 years); 79% were White, and approximately half 
(53%) were male.  Approximately one-third (35%) of the patients received 1200 mg Q3W 
of atezolizumab (Roche Data on File).  
Adverse Events in the mTNBC Subpopulation of Study PCD4989g
Of the 116 safety-evaluable TNBC patients, 114 (98.3%) reported one or more adverse 
events (AEs). A total of 59 (50.9%) patients experienced Grade 3 - 4 AEs based on the 
National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 
(NCI CTCAE v4.0). Treatment-related Grade 3-4 events occurred in 13 (11.2%) of 
patients.  Serious adverse events (SAEs) were reported for 51 patients (44.0%). Grade 5 
AEs (not including deaths due to cancer progression) occurred in three patients (2.6%). 
Adverse events led to atezolizumab discontinuation in five (4.3%) patients (Roche Data 
on File).  
Long-term follow-up data from 115 safety-evaluable patients in study PCD4989g (data 
cut-off Mar 31, 2016) indicated that atezolizumab was generally well tolerated, with no 
new safety signals detected (Schmid et al. 2017).
Safety findings in the TNBC cohort of Study PCD4989g are consistent with those 
observed in the overall study population. Refer to the atezolizumab Investigator’s 
Brochure for further details.
Adverse Events in the Overall Population of Study PCD4989g
Almost all (98.6%) of the 658 safety-evaluable patients reported at least one AE. The 
most common AEs (occurring in ≥ 20% of patients) included fatigue (40.6%), nausea 
(29.0%), decreased appetite (26.6%), diarrhoea (22.5%), constipation (22.0%), pyrexia 
(21.9%), dyspnoea (21.7%), cough (20.7%), vomiting (20.5%), and anaemia (20.1%). 
Other AEs reported ≥10% of patients included back pain, headache, asthenia, arthralgia, 
pruritus, rash, abdominal pain, oedema peripheral, insomnia, dizziness, upper 
respiratory tract infection, chills, and urinary tract infection. Treatment-related AEs (per 
investigator’s assessment of causality) were reported in 444 patients (70.6%). 
Approximately half of the 658 patients (51.5%) experienced Grade 3-4 AEs, most 
commonly anaemia (5.6%), dyspnoea (4.6%), hyponatraemia (4.4%), fatigue (3.2%), 
dehydration (2.4%), asthenia (2.3%), and hyperglycaemia and abdominal pain (2.0% 
each). Treatment-related Grade 3-4 events were reported in 95 (14.4%) of patients, with 
AST increased, asthenia, and anaemia (1.2% each), dyspnoea (1.1%), and 
hyponatremia (0.9%) as the most frequently occurring.

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
42/Protocol MO39196 (IMpassion131), Version 6.0 
The rate of serious adverse events (SAEs) was 43.6%, with the most common (≥24 
patients or 3.6%) being dyspnoea (3.6%), pyrexia (3.0%), and UTI (2.0%). Ten patients 
(0.5%) experienced Grade 5 AEs (not including deaths due to cancer progression), 
including three events considered as related to atezolizumab: hepatic failure (in the 
NSCLC cohort), and death (not otherwise specified) and pulmonary hypertension (both 
in the TNBC cohort). Adverse events led to atezolizumab discontinuation in 30 (4.6%) 
patients; of these, hypoxia, pneumonitis, sepsis, and pyrexia were reported in two 
patients (0.3%) each; the remaining events were single occurrences (Roche Data on 
File). 
Immune-Mediated Adverse Events 
The safety data presented in this section is based on pooled data from 3075 patients 
with multiple tumour types and supporting data from the estimated cumulative exposure 
in >16,000 patients across all clinical trials.  
Given the mechanism of action of atezolizumab, events associated with inflammation 
and/or immune-mediated AEs have been closely monitored during the atezolizumab 
clinical program. Important identified risks associated with atezolizumab include the 
occurrence of the following immune-mediated AEs (listed with total frequencies of these 
events in pooled clinical trials of atezolizumab): immune-mediated pneumonitis (2.8% 
[86/3075]); immune-mediated hepatitis (2.0% [62/3075]); immune-mediated colitis 
(1.1% [34/3075]); immune-mediated pancreatitis (0.5% [16/3075]); immune-mediated 
endocrinopathies, including diabetes mellitus (0.3% [10/3075]), hypothyroidism (4.8% 
[149/3075]), hyperthyroidism (0.9% [28/3075]), and adrenal insufficiency (0.4% 
[12/3075]); immune-mediated myositis occurred in <0.2% (4/3075); immune-
mediated hypophysitis (<0.1% [1/3075]); immune-mediated neuropathies, including 
myasthenic syndrome/myasthenia gravis (<0.1% [4/3075]), and Guillain-Barré syndrome 
(0.2% [5/3075]); immune-mediated meningoencephalitis (0.4% [12/3075]);  immune-
mediated myocarditis (<0.1% [2/3075]), and immune-mediated nephritis (<0.1% 
[1/3075], representing one case of Henoch-Schoenlein purpura nephritis) (Atezolizumab 
Investigator’s Brochure, 2018). Overall, the nature and frequency of immune-mediated 
AEs has been consistent across multiple tumour types in clinical studies of atezolizumab. 
Excessive activation of the immune system is a potential risk associated with 
atezolizumab and has been observed when used in combination with other immune-
modulating agents. 
Treatment-emergent (treatment-induced plus treatment-enhanced) anti-drug antibodies 
(ADAs) were detected at one or more post dose time-points in 31.7% (139/439) patients 
in Study PCD4989g. The presence of ADAs did not appear to have a clinically significant 
impact on PK, safety, or efficacy.  
Refer to the atezolizumab Investigator’s Brochure for additional details regarding clinical 
safety. 

Atezolizumab—F. Hoffmann-La Roche Ltd
43/Protocol MO39196 (IMpassion131), Version 6.0
1.2.2.3
Efficacy of Atezolizumab Combined with Chemotherapy in Patients 
with TNBC
mTNBC Subpopulation of Study GP28328
Building on the promising results of atezolizumab as a single agent, an open-label 
Phase 1b trial (GP28328; clinicaltrials.gov identifier: NCT01633970) was initiated to 
evaluate atezolizumab in combination with chemotherapy and/or bevacizumab in locally 
advanced or metastatic solid tumours. One of the arms (Arm F) is evaluating 4-week 
cycles consisting of atezolizumab 800 mg Q2W (days 1 and 15) in combination with nab-
paclitaxel 125 mg/m2 Q1W (days 1, 8, and 15) in patients with mTNBC, treated with ≤2 
prior lines of therapy for metastatic disease. After nab-paclitaxel discontinuation, 
maintenance atezolizumab is allowed until loss of clinical benefit. Primary endpoints are 
safety and tolerability; secondary endpoints include clinical activity. Preliminary results 
are available for the 32 enrolled female patients aged 32 to 84 years (median 56 years). 
The majority of patients (87%) received prior taxane therapy (Adams et al. 2018). As of 
the data cut-off of 14 January 2016, the investigator-assessed ORR per RECIST v1.1 
was 37.5% (95% CI, 21.1, 56.3; confirmed responses only); these included one 
complete CR and 11 PRs. Clinical benefit was observed across all lines of therapy, with
ORRs being comparable between patients with one vs three or more previous lines of 
treatment (46.2% and 40.0%, respectively); refer to the atezolizumab Investigator's 
Brochure for further details. 
Results of Study WO29522 (IMpassion130)
Based on the tolerability and promising activity of atezolizumab in mTNBC, the 
combination of atezolizumab and nab-paclitaxel is currently being evaluated in a global, 
randomised, placebo-controlled phase III study (WO29522 / IMpassion130 study; 
ClinicalTrials.gov identifier: NCT02425891) in previously untreated unresectable locally 
advanced or metastatic TNBC patients (N=902). Eligible patients were randomised 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. Pre-specified co-primary efficacy endpoints include 
investigator-assessed PFS by RECIST v1.1 (in the ITT and PD-L1positive population), 
and OS (in the ITT and PD-L1positive population). 
A total of 902 patients were randomised in the study; 451 in each group. In the 
atezolizumab plus nab-paclitaxel and placebo plus nab-paclitaxel groups, respectively, 
median age was 55 and 56 years, respectively; 57% and 60%, respectively had ECOG 
performance status of 0 and 63% each received prior (neo)adjuvant treatment. The PD-
L1-positive population included 369 patients (185 and 184 patients in the two groups, 
respectively). Analysis of the co-primary efficacy endpoints (final for PFS, and first 
interim for OS) showed that after a median follow-up of 12.9 months, treatment with 
atezolizumab plus nab-paclitaxel compared to placebo plus nab-paclitaxel resulted in a 
statistically significant reduction in the risk of disease worsening or death in the ITT 
population (median PFS 7.2 vs. 5.5 months, respectively; hazard ratio [HR] 0.80, 95% CI 
0.69-0.92, p=0.0025). In the PD-L1-positive population, median PFS was 7.5 vs. 5.0 
months in the two groups, respectively; HR=0.62, 95% CI: 0.49-0.78, p<0.0001. At this 
first interim analysis of OS, there was a trend for prolonged OS in the ITT population 

Atezolizumab—F. Hoffmann-La Roche Ltd
44/Protocol MO39196 (IMpassion131), Version 6.0
(median OS 21.3 vs 17.6 months, respectively; HR=0.84, 95% CI: 0.69-1.02, p=0.0840), 
with a clinically meaningful 9.5-month OS improvement in the PD-L1-positive 
subpopulation (median OS 25.0 vs 15.5 months, respectively; HR=0.62, 95% CI: 0.45-
0.86). Due to the hierarchical statistical design, OS results were not formally tested in 
the PD-L1-positive subpopulation. In the ITT population, investigator-assessed ORR was 
56% in the atezolizumab plus nab-paclitaxel group compared to 46% in the placebo plus 
nab-paclitaxel group (treatment-difference 10%, p=0.0021). In the PD-L1-positive 
subpopulation, ORRs were 59% vs 43% in the two groups, respectively (treatment 
difference 16%, p=0.0016). Median DoR was 7.4 months vs 5.6 months in the two 
groups, respectively in the ITT population, and 8.5 months vs 5.5 months, respectively in 
the PD-L1-positive subpopulation (Schmid et al. 2018). The Impassion130 study 
demonstrated that the largest and most consistent improvements in PFS, ORR, and OS 
for the addition of atezolizumab to nab-paclitaxel occurs in metastatic TNBC patients 
whose tumours are PD-L1-positive.
1.2.2.4
Safety of Atezolizumab Combined with Chemotherapy 
Adverse Events in the mTNBC Subpopulation of Study GP28328
As of 30 April 2017, all 33 (100%) safety-evaluable mTNBC patients experienced at 
least one AE. Consistent with the known toxicity profiles of atezolizumab and nab-
paclitaxel, the most commonly occurring AEs (≥30%) were fatigue (66.7%), diarrhoea 
(51.5%), alopecia (42.4%), nausea, constipation, and cough (39.4% each), pyrexia, and 
neutrophil count decreased (36.4% each), neutropoenia (33.3%), and peripheral 
neuropathy (30.3%). All 33 (100%) safety-evaluable mTNBC patients experienced at 
least one treatment-related AE.
Over three-quarters of the patients with TNBC (84.4%) had a Grade 3-4 event. Of these, 
neutrophil count decreased (27.3%), neutropoenia (18.2%), anaemia and AST increased 
(9.1% each), and thrombocytopoenia, diarrhoea, pneumonia, sepsis, platelet count 
decreased, white blood cell count decreased, hyponatraemia, and arthralgia (6.1% each) 
occurred in more than 1 patient (>3%). Twenty-four patients (72.7%) experienced a 
related Grade 3-4 event; of these, only neutrophil count decreased (9.1%) and 
pneumonia and thrombocytopenia (6.1%) were reported for more than one patient (>3%).
Seventeen (51.5%) TNBC patients experienced a SAE; of these, the event was 
assessed as related to study treatment in seven patients (1821.2%): pneumonia, (6.1%), 
diarrhoea, pyrexia, anaemia, and pneumonia mycoplasmal (3.0% each). None of the 
patients with TNBC experienced a Grade 5 AE, and two patients (6.1%) with TNBC 
discontinued atezolizumab due to an AE.
Adverse Events in the Overall Population of Study GP28328
As of the data cut-off of 30 April 2017, there were 229 safety-evaluable patients enrolled 
across six treatment arms in Study GP28328. All 229 (100%) safety-evaluable patients 
reported at least one AE, 171 patients (74.7%) experienced a Grade 3-4 AE, 112 (48.9%) 
experienced an SAE, and 22 (9.6%) experienced an AE leading to discontinuation of 
atezolizumab. Grade 5 AEs occurred in two of the 76 patients in the NSCLC cohorts.  
The safety profile of atezolizumab was generally consistent across treatment arms. 
Atezolizumab in combination with cytotoxic chemotherapy has not been associated with 

Atezolizumab—F. Hoffmann-La Roche Ltd
45/Protocol MO39196 (IMpassion131), Version 6.0
exacerbation of known AEs associated with either agent individually. The AEs observed 
for atezolizumab in combination with chemotherapy are consistent with the known risks 
of each study treatment. Available data suggest that atezolizumab can be safely 
combined with standard chemotherapy treatments and/or bevacizumab.
Refer to the atezolizumab Investigator's Brochure for further details on clinical studies of 
atezolizumab.
Adverse Events in Study WO29522 (IMpassion130)
As of the data cut-off of 17 April 2018, AEs occurred in 99.3% vs 97.9% in the 
atezolizumab plus nab-paclitaxel compared to placebo plus nab-paclitaxel groups, 
respectively, and Grade 3-4 AEs occurred 48.7% vs 42.2% of patients in the two groups, 
respectively. Adverse events (all grades) that occurred at a ≥5% higher frequency in the 
atezolizumab plus nab-paclitaxel compared to placebo plus nab-paclitaxel group 
included nausea, cough, neutropenia, pyrexia and hypothyroidism. The only Grade 3-4 
AEs occurring in >5% of patients were neutropenia reported in 8.2% of patients in each 
group), and peripheral neuropathy (reported in 5.5% of patients in the atezolizumab plus 
nab-paclitaxel group compared to 2.7% of patients in the placebo plus nab-paclitaxel 
group). 
Three of the six fatal AEs in the atezolizumab plus nab-paclitaxel group (autoimmune 
hepatitis [considered related to blinded atezolizumab], septic shock [considered related 
to nab-paclitaxel], mucosal inflammation [considered related to nab-paclitaxel]) and one 
of three fatal AEs in placebo plus nab-paclitaxel group (hepatic failure [considered 
related to blinded atezolizumab and nab-paclitaxel]) were assessed as treatment-related. 
One patient in each group experienced a Grade 5 AESIs (autoimmune hepatitis in the 
atezolizumab plus nab-paclitaxel group and hepatic failure in the placebo plus nab-
paclitaxel group). Grade 3-4 AESIs occurred in 7.5% and 4.3% of patients in the two 
groups, respectively.
Overall, combination treatment with atezolizumab plus nab-paclitaxel was well tolerated 
in this study, with a safety profile consistent with that of each agent (WO29522 Clinical 
Study Report; Roche Data on File).
1.2.2.5
Clinical Pharmacokinetics and Immunogenicity of Atezolizumab 
Based on available PK data exposure to atezolizumab increased dose proportionally 
over the dose range of 1 mg/kg to 20 mg/kg, including the fixed dose of 1200 mg 
administered Q3W. Based on a population PK analysis that included 472 patients in the 
dose range of 1 mg/kg to 20 mg/kg, the typical population clearance (CL) was 0.20 L/day, 
the volume of distribution at steady state (Vss) was 6.9 L, and the terminal half-life (t1/2) 
was 27 days. The population PK analysis suggested that steady state was obtained after 
6 to 9 weeks (2 to 3 cycles) of repeated dosing.  The systemic accumulation in area 
under the concentration-time curve (AUC), maximum concentration (Cmax), and trough 
concentration (Cmin) was 1.91, 1.46, and 2.75-fold, respectively. Based on an analysis of 
exposure-safety, and exposure-efficacy data, the following factors had no clinically 
relevant effect:  age (21 to 89 years), body weight, gender, positive ATA status, albumin 
levels, tumour burden, region or ethnicity, renal impairment, mild hepatic impairment, 
level of PD-L1 expression, or Eastern Cooperative Oncology Group (ECOG) status. The 
effect of moderate or severe hepatic impairment (bilirubin > upper limit of normal [ULN] 
and AST > ULN or bilirubin ≥ 1.0 to 1.5 x ULN and any AST elevation) on the PK of 
atezolizumab is unknown.

Atezolizumab—F. Hoffmann-La Roche Ltd
46/Protocol MO39196 (IMpassion131), Version 6.0
The development of ADAs has been observed in patients at all dose levels. ADA 
positivity had no major effect on atezolizumab concentrations and PK although there 
was a trend for lower Cmin values in the ADA positive subgroup in Study PCD4989g. The
presence of ADAs did not appear to have a clinically significant impact on PK, safety, or 
efficacy of atezolizumab. A Phase I population PK analysis that included 472 patients 
from Studies PCD4989g and JO28944 found that positive ADA status against 
atezolizumab led to approximately 13% reduction in overall exposure (Atezolizumab 
Investigator’s Brochure, 2018).
In all safety-evaluable patients with available post-treatment ADA status in the 
atezolizumab safety database (n 2007), the incidence of hypersensitivity events and 
infusion-related reactions was low and numerically higher in ADA-positive than ADA -
negative patients.  Hypersensitivity events were reported in 24 patients (1.2%):  9 ADA-
negative (0.7%) and 15 ADA-positive (1.9%) patients. Infusion-related reactions 
occurred in 25 patients (1.2%):  14 ADA-negative (1.1%) and 11 ADA-positive (1.4%) 
patients. The incidences of all grade adverse events, Grade 5 AEs, AEs leading to 
treatment discontinuation, AEs leading to dose interruption, and AESIs were similar 
irrespective of post-baseline ADA status (negative or positive).  Numerical differences 
were observed in Grade 34 AEs (40.7% in ADA-negative vs. 47.0% in ADA-positive 
patients), but no individual preferred terms could be identified to explain this difference 
(Atezolizumab Investigator’s Brochure, 2018).
In the IMpassion130 study, the incidence of treatment-emergent ADAs among patients 
receiving atezolizumab plus nab-paclitaxel was 13.1% and 11.8% in the ITT and PD-L1-
positive populations, respectively. ADA positivity had no clinically relevant effect on PK, 
although, on average, Cmin at steady state was approximately 25% lower in ADA-positive 
vs ADA-negative patients. The overall safety profile was generally concordant between 
ADA-positive and ADA-negative patients based on the incidence of related AEs (93.0% 
vs 97.9%, respectively), related Grade 3-4 AEs (40.4% vs 40.6%, respectively), SAEs 
(28.1% vs 21.5%, respectively), AEs leading to study treatment discontinuation (17.5% 
vs 15.9%, respectively), and AESIs (52.6% vs 58.6%, respectively) (WO29522 Clinical 
Study Report; Roche Data on File).
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
1.3.1
Atezolizumab
Encouraging clinical data emerging in the field of tumour 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).
As detailed in Section 1.1.2.2, 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. PD-L1 is expressed on many cancer and immune cells, and 
overexpression of PD-L1 on tumour cells has been reported to impede anti-tumour
immunity (Blank and Mackensen 2007; Herbst et al. 2014). Binding of PD-L1 to its 
receptors suppresses T-cell migration, proliferation and secretion of cytotoxic mediators, 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
47/Protocol MO39196 (IMpassion131), Version 6.0 
and restricts tumour cell killing (Herbst et al. 2014). The PD-1/PD-L1 pathway has been 
implicated in tumours evading immune surveillance. Therefore, interruption of the PD-
L1/PD-1 and the PD-L1/B7.1 pathways represents an attractive strategy to reinvigorate 
tumour-specific T-cell immunity (Blank and Mackensen 2007; Chen and Mellman, 2013; 
Herbst et al. 2014; Saha and Nanda, 2016).  
The rationale for investigating PD-L1 inhibitors in TNBC stems from a number of key 
clinical observations. ER-negative breast cancers have a higher density of tumour 
infiltrating lymphocytes (TILs) than their ER-positive counterparts (Loi et al. 2014), and 
greater numbers of TILs have been associated with better clinical outcomes in patients 
with TNBC (Cancer Discov. 2015). PD-L1 expression is also more prevalent in TNBC 
than in other breast cancer subtypes (Mittendorf et al. 2014). TNBCs have a higher 
mutational burden compared with their ER-positive counterparts, and have been linked 
with increased immunogenicity (Wang et al. 2014). Gene expression profiling of TNBCs 
has identified an immunomodulatory subtype that is characterised by increased 
expression of genes involved in T-cell function (Lehmann et al. 2011; Saha and Nanda, 
2016). Due to the higher mutation rate and a higher number of TILs relative to other 
breast cancer subtypes, TNBC may be particularly susceptible to immunotherapy 
(Cancer Discov. 2015).  
Targeting the PD-L1 pathway with atezolizumab has demonstrated activity in patients 
with advanced malignancies, including patients with TNBC, who have failed standard-of-
care therapies. The observation that high CD8+ T-cell density in primary breast tumours 
is correlated with improved OS, and that mTNBC tumours have fewer TILs than their 
matched primary tumours, 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 pre-existing host anti-tumour immunity in this disease (Lehmann et 
al. 2011). In this setting, re-invigorating T-cell activity with atezolizumab may be an 
effective treatment strategy. 
Atezolizumab has been generally well tolerated in clinical trials (see Section 1.1.2.2 and 
Section 1.2.2.4); adverse events with potentially immune-mediated causes consistent 
with an immunotherapeutic agent, including rash, hypothyroidism, hepatitis/elevated 
transaminases, 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 
Paclitaxel and Combination Treatment with Atezolizumab 
The safety of single-agent paclitaxel in patients with mBC has been demonstrated in 
several studies; refer to Section 3.3.3.  
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 carboplatin + nab-
paclitaxel or paclitaxel in patients with previously untreated NSCLC and is being tested 
in combination with nab-paclitaxel in patients with TNBC. No exacerbation of 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
52/Protocol MO39196 (IMpassion131), Version 6.0 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
3.1.1 
Overview of the Study Design 
This is a Phase III, global, multicentre, randomised, double-blind, two-arm, placebo-
controlled study designed to evaluate the efficacy and safety of atezolizumab 
(MPDL3280A, an anti-PD-L1 antibody) administered in combination with paclitaxel 
compared with placebo in combination with paclitaxel in patients with previously 
untreated, inoperable locally advanced or metastatic, centrally confirmed TNBC.  
Patients will be enrolled in the study globally (Global study), which may be followed by 
additional enrolment in China only: 
• 
Global study: Approximately 600 patients will be randomised at approximately 
200 sites globally (in select countries from Europe, Asia/Pacific, as well as North-, 
and South America). Patients will be randomised centrally, using an interactive 
voice or web response system (IxRS), in a 2:1 randomisation ratio to receive 
atezolizumab (840 mg) or placebo IV infusions on Days 1 and 15 of every 28-day 
cycle, plus paclitaxel (90 mg/m2) administered via IV infusion on Days 1, 8, and 15 
of every 28-day cycle. Randomisation will be stratified by the following factors: 
tumour PD-L1 status (IC0 vs. IC1/2/3), prior taxane treatment (yes vs. no), presence 
of liver metastases (yes vs. no), and region (North America vs. Western 
Europe/Australia; vs. Eastern Europe/Asia Pacific vs. South America). Randomised 
patients will not be replaced. 
• 
Additional enrolment in China: After approximately 600 patients have been 
randomised in the Global study, global recruitment will be closed. Additional patients 
may be subsequently randomised in China only, following the same randomisation 
procedures and ratio (2:1), for a total enrolment of approximately 130 patients in 
mainland China (including patients enrolled in the Global study), referred to as the 
China Population. The schedule of assessments and study treatments for these 
patients will be identical to those in the Global study. Analyses based on the China 
Population will be performed and summarised separately. 
In the absence of disease progression or unacceptable toxicity, study treatment will 
continue until the end of the study (EOS; defined as last patient last visit, or LPLV). In 
the absence of disease progression, paclitaxel and atezolizumab/placebo may be 
discontinued for toxicity independently of each other, with the other treatment being 
continued. The Sponsor, patients, and investigators will not be aware of the patient’s 
treatment assignment. 
In order to evaluate the mechanism of action of the drug combination in the tumour 
microenvironment, its dependency on PD-L1 expression, changes in blood- and tissue-
based biomarkers during treatment, as well as possible resistance mechanisms, paired 
tumour tissue biopsies will be collected close to the treatment start (mandatory sample), 
on-treatment (optional sample; collected pre-dose on Cycle 2, Day 1, prior to steroid 
medication), and at first evidence of radiographic disease progression per RECIST v1.1 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
53/Protocol MO39196 (IMpassion131), Version 6.0 
(optional sample; collected if clinically feasible from a new or progressing tumour 
lesion).  
Tumour assessments will be performed at screening/baseline, approximately every 
8 weeks (± 1 week) for the first 12 months after randomisation, and every 12 weeks 
thereafter until disease progression (PD), withdrawal of consent, death, or study 
termination by the Sponsor, whichever occurs first. Tumour assessments performed as 
part of standard of care prior to obtaining informed consent and within 28 days of Cycle 
1, Day 1 may be used as baseline assessments rather than repeating the tests. Tumour 
assessments will be performed on the specified schedule regardless of treatment 
delays, interruptions or discontinuations. Radiologic imaging performed during the 
screening period should consist of 1) computerized tomography (CT) and/or magnetic 
resonance imaging (MRI) of the chest/abdomen/pelvis, 2) bone scan or PET scan, 3) 
CT (with contrast) or MRI scan of the head must be performed at screening to evaluate 
CNS metastasis, and 4) any other imaging studies (CT neck, plain films, etc.) as 
clinically indicated/determined by the treating physician. 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.  For each patient, the same radiographic procedures and technique 
must be used for disease evaluation throughout the study (e.g., the same contrast 
protocol for CT scans and/or MRI). Evaluation of tumour response (e.g., for estimation 
of PFS, PFS rate, ORR, DoR and CBR) will be completed per RECIST v1.1. All primary 
imaging data used for tumour assessment will be collected by the Sponsor to enable 
centralised, independent review of response endpoints by an Independent Review 
Committee (IRC) (e.g., to meet potential requests by a reviewing Health Authority).   
Patients randomised to either group must discontinue all study treatment upon 
determination of PD 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.  
All patients who discontinued study treatment before EOS (including due to PD) will be 
followed for survival approximately every 3 months until death, withdrawal of consent, 
loss to follow-up, or study termination by the Sponsor. Information regarding PFS2, 
PROs and the use of subsequent anti-cancer agents for metastatic TNBC will also be 
collected during the survival follow-up period. In addition, for patients who discontinue 
study treatment before EOS for reasons other than PD, tumour assessments will 
continue until PD, death, withdrawal of consent, loss to follow-up, or study termination 
by the Sponsor. 
The study Steering Committee (SC) will provide scientific oversight for the trial. Details 
on the composition and mandate of the SC will be provided in the SC Charter.  
A schedule of activities is provided in Appendix 1. A study design schema is presented 
in Figure 1. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
54/Protocol MO39196 (IMpassion131), Version 6.0 
3.1.2 
Independent Data Monitoring Committee 
An independent Data Monitoring Committee (iDMC) will monitor study conduct and 
review aggregate safety data by treatment arm on a periodic basis. Members of the 
iDMC will be independent of 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) until the last patient has completed study treatment, to review study 
conduct and unblinded safety data prepared by an independent Data Coordinating 
Center (iDCC). The safety data will include demographic, adverse event, serious 
adverse event, adverse events leading to treatment discontinuations and relevant 
laboratory data.   
Following each data review, the iDMC will provide recommendations to the Sponsor as 
to whether the study should continue as planned, or be amended, or whether the study 
should be stopped on safety grounds (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 based on the iDMC’s recommendations.  
The final decision will rest with the Sponsor.  
Any outcomes of the iDMC safety reviews that affect the study conduct will be 
communicated in a timely manner to the investigators for notification of their respective 
Institutional Review Boards/Ethics Committees (IRBs/ECs). 
Further details on the composition and responsibilities of the iDMC and the safety review 
plan will be provided in the iDMC Charter. 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The EOS is defined as the date when the last patient, last visit (LPLV) is completed.  
In addition, the Sponsor may decide to terminate the study at any time. 
3.2.1 
Global Study 
This is an event driven trial. The Global study will end after the required number of 
events for the final analysis of OS in the PD-L1-positive subpopulation has been reached. 
The clinical cut-off (CCO) date for the final OS analysis will be confirmed when the 
targeted number of mortality events (122 deaths) have occurred in the PD-L1-positive 
subpopulation globally, which is expected approximately 40 months after the first patient 
was randomised ("first patient in"; FPI) in the Global study.  
The actual length of the study and the time for final analysis will depend on the actual 
enrolment rate and the number of events that occur. Mortality events will be monitored 
throughout the course of the study, and study timelines might be updated. 
3.2.2 
China Population 
For patients randomised during additional enrolment in China, the study will end when 
the pre-specified number of 36 PFS events has occurred in the China population with 
PD-L1-positive tumour status, or when the Global study ends, whichever is later. 
 

Atezolizumab—F. Hoffmann-La Roche Ltd
55/Protocol MO39196 (IMpassion131), Version 6.0
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for the Atezolizumab Dose and Schedule
Atezolizumab will be administered IV at a flat dose of 840 mg every two weeks (Q2W) to 
align with the chemotherapy schedule.
The fixed dose of 840 mg administered Q2W was selected with the intent of selecting a 
dose that is the exposure equivalent of the fixed dose of 1200 mg Q3W (weight-based 
equivalent of 15 mg/kg), which has been approved for treating patients with metastatic
TNBC (in the USA), urothelial carcinoma and NSCLC (refer to the TECENTRIQTM
prescribing information).
Of note, the exact equivalent dose is 800 mg; however, 
because atezolizumab is formulated at a concentration of 60 mg/mL, 800 mg 
corresponds to a volume of 13.33 mL, and 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 exposure compared with the 800 mg dose.
In the Phase Ia Study PCD4989g, patients were treated with doses ranging from 0.1 to 
20 mg/kg. Anti-therapeutic antibodies (ADAs) to atezolizumab were associated with 
changes in PK for some patients in the lower dose cohorts (0.3, 1, and 3 mg/kg), but not 
for patients treated at 10, 15, and 20 mg/kg, including the approved dose of 1200 
mg.
To date, no relationship has been observed between the development of 
measurable ADAs and safety or efficacy.
3.3.2
Rationale for Patient Population and Analysis Groups
The target population will include patients with previously untreated inoperable locally 
advanced or metastatic TNBC. Patients will be either newly diagnosed or have disease 
progression after completing treatment for early breast cancer at least 12 months prior to 
randomisation.
As detailed in Section 1.1.1, TNBC is more likely to have aggressive features, such as a 
high proliferative rate, and exhibit an invasive phenotype. Patients with metastatic TNBC 
are characterised by a more aggressive course compared to other subtypes (Wahba and 
El-Hadaad, 2015) and a poor clinical outcome (Mersin et al. 2008; Trivers et al. 2009), 
including worse breast cancer-specific survival and OS (Lin et al. 2012), generally with 
rapid progression and a median OS generally between 13 months (Kassam et al. 2009) 
and 17.5 months in patients treated with various chemotherapy agents (Roche data on 
file). Although TNBC may respond to chemotherapy, including taxanes, there are no 
targeted therapies with widespread global approval available for patients with this
subtype of breast cancer, and relatively few new agents have been approved for 
mTNBC (Carey et al. 2012; O’Shaughnessy et al. 2014; Hirshfield and Ganesan, 2014; 
Zeichner et al. 2016). Therefore, there is a pressing need for clinically active targeted 
therapy for mTNBC.
Regarding its immunologic properties, TNBC is characterised by high DNA mutational 
rates (TCGAN, 2012) which have been postulated as a source of immunogenic tumour-
specific neoantigens. Consistent with this, a significant proportion of TNBC patients 
display CD8+ tumour infiltrating lymphocytes at diagnosis, which has been correlated 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
56/Protocol MO39196 (IMpassion131), Version 6.0 
with a better prognosis (Ali et al. 2014) and suggests that activation of the immune 
system in TNBC patients could be utilised to modify the course of the disease. 
Atezolizumab showed promising anti-tumour activity, as determined by RECIST v1.1 
responses, across multiple advanced tumour types (including TNBC) both as 
monotherapy (Phase 1a study PCD4989g) as well as in combination with bevacizumab 
and/or chemotherapy (Phase 1b study GP28328). In patients with mTNBC, 
atezolizumab has shown activity as monotherapy (Emens et al. 2018), and most notably 
in combination with nab-paclitaxel (Adams et al. 2018; Schmid et al. 2018). 
The rationale for performing the primary analysis of PFS in patients with PD-L1-positive 
tumour status is based on the results of the primary analysis of PFS in the global, 
randomised, double-blind, phase 3 IMpassion130 study, and specifically on the result in 
the PD-L1-positive subpopulation (Schmid et al. 2018). Analysis of the co-primary 
efficacy endpoints (final for PFS, and 1st interim for OS) in the PD-L1-positive population 
showed that after a median follow-up of 12.9 months, treatment with atezolizumab plus 
nab-paclitaxel compared to placebo plus nab-paclitaxel resulted in significantly 
prolonged PFS (median PFS 7.5 vs. 5.0 months, respectively; HR=0.62, 95% CI: 0.49-
0.78, p<0.0001), and longer OS (median OS 25.0 vs 15.5 months, respectively; 
HR=0.62, 95% CI: 0.45-0.86); due to the pre-specified hierarchical testing for OS first in 
the ITT and then in the PD-L1-positive population, the difference between the treatment 
arms for OS in the PD-L1-positive population was not formally tested. In addition, in the 
PD-L1-positive subpopulation, treatment with atezolizumab plus nab-paclitaxel 
compared to placebo plus nab-paclitaxel was associated with longer investigator-
assessed objective response rate (ORR; 59% vs 43%, respectively; treatment difference 
16%, p=0.0016), and median duration of response (8.5 months vs 5.5 months, 
respectively) (Schmid et al. 2018). 
Driven by the results of the interim analysis of the IMpassion130 study, the Sponsor, in 
consultation with the Steering Committee, has decided to amend the primary analysis of 
the MO39196 (IMpassion131) study to include PFS by RECIST v1.1 in the PD-L1-
positive subpopulation (analysed first), while retaining PFS by RECIST v1.1 in the intent-
to-treat (ITT) population (analysed second). In addition, stratified analyses of PFS will be 
completed according to predefined and clinically important randomisation stratification 
factors, including tumour PD-L1 status (PD-L1-negative subpopulation, defined as IC0 at 
the time of randomisation vs. PD-L1-positive subpopulation, defined as IC1/2/3 at the 
time of randomisation), prior taxane treatment (yes vs. no) and presence of liver 
metastases (yes vs. no). Analysis of the relationship between PD-L1 status by IHC in 
tumour tissues obtained prior to patient randomisation, and clinical efficacy and safety 
outcomes is a predefined biomarker objective of the study.  
3.3.3 
Rationale for Concomitant Paclitaxel Treatment 
The taxane class of cytotoxic agents (paclitaxel, docetaxel, nab-paclitaxel) have 
significant anti-tumour activity in breast cancer.  Despite the expansion of the 
therapeutic landscape for mBC over the last three decades, including the increasing 
availability of targeted therapies for various BC subtypes, cytotoxic taxane-based 
regimens remain standard of care in first-line therapy for patients with mBC, including 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
57/Protocol MO39196 (IMpassion131), Version 6.0 
TNBC (Cardoso et al. 2012; Greene and Hennessy 2015; Hernandez-Aya and Ma 2016; 
Fukada et al. 2016). 
Several studies and meta-analyses support the benefit of taxanes on clinical outcomes 
in mBC (Piccart-Gebhart et al. 2008; Qi et al. 2013; Ghersi et al. 2015), and these 
benefits were generally comparable to those of anthracyclines in randomised controlled 
clinical studies. However, in a recent meta-analysis of 28 studies (N= 6871 randomised 
women), the combined hazard ratio (HR) for OS and time to progression (TTP) favoured 
the taxane-containing compared to the anthracycline regimens (HR 0.93, 95% CI 0.88 to 
0.99, P = 0.002, deaths = 4477; and HR 0.92, 95% CI 0.87 to 0.97, P = 0.002, estimated 
5122 events, respectively). When the analyses were restricted to first-line treatments, 
this effect persisted for OS (HR 0.93, 95% CI 0.87 to 0.99, P = 0.03) but not for TTP. 
Tumour response rates were higher with taxane-containing chemotherapy in assessable 
women (RR 1.20, 95% CI 1.14 to 1.27, P < 0.00001). Taxanes were also associated with 
an increased risk of neurotoxicity but less nausea and vomiting compared to non-taxane-
containing regimens (Ghersi et al. 2015). 
Although combinations of cytotoxic agents may be administered to patients with severe 
symptomatic disease or imminent visceral crisis, these combination regimens are 
associated with increased toxicity (Piccart-Gebhart et al. 2008; Greene and Hennessy 
2015), which underscores the need for combination regimens in which adding a targeted 
therapy to a cytotoxic agent does not result in enhanced or cumulative toxicity.  
Paclitaxel, docetaxel, and nab-paclitaxel are approved drugs for the treatment of 
recurrent and metastatic BC in many countries. Paclitaxel is administered weekly (80 - 
90 mg/m2) (Swanton 2011) or every three weeks (175 mg/m2 dose recommended by the 
current Prescribing Information for Taxol® IV injection), with weekly paclitaxel (80–
90mg/m2) currently considered the most effective schedule for delivering paclitaxel 
(Swanton 2011). A meta-analysis of 11 randomised clinical trials (n=2,540 patients) 
comparing weekly- and three-weekly taxanes in patients with advanced BC found that 
weekly administration of paclitaxel resulted in higher OS compared to the three-weekly 
schedule (HR 0.78; 95% CI, 0.67–0.89 P=0.001); PFS was similar between the two 
schedules. The incidence of serious adverse events, neutropoenia, neutropoenic fever, 
and peripheral neuropathy were also significantly lower with the weekly compared to the 
three-weekly taxane schedules (Mauri et al. 2010). In addition, a regimen consisting of 
weekly paclitaxel administrations for three weeks, followed by one-week break was 
reported to be associated with less neurotoxicity compared to continuous weekly 
administrations (Swanton 2011). This finding is consistent with the lower neurotoxicity 
rate observed in the HER2-negative mBC population of the studies E2100 (Miller et al. 
2007) and MERIDIAN (Miles et al. 2017), both using a 90 mg/m2 3-week on/1-week off 
weekly paclitaxel schedule, compared to study CALGB9840 (Seidman et al. 2008) using 
continuous 80 mg/m2 weekly paclitaxel dosing without interruption. Taken together, 
these findings support the selected regimen for paclitaxel (90 mg/m2 on days 1, 8, and 
15 of every 28-day cycle) in the current study.  
The solvents used to enhance the solubility of taxanes have been associated with 
allergic reactions and peripheral neuropathy (ten Tije et al. 2003). Therefore, to reduce 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
58/Protocol MO39196 (IMpassion131), Version 6.0 
the risk of severe hypersensitivity reactions, study patients should be premedicated as 
described in Section 4.4.1.1. 
3.3.4 
Rationale for the Placebo Control  
Randomised, double-blind, placebo-controlled trials are the “gold standard” of assessing 
the effectiveness of a new therapeutic drug. The use of placebo control in cancer clinical 
trials is scientifically feasible; however, it is ethically justifiable only in certain 
circumstances, such as in trials with an “add-on” design, in which patients randomly 
assigned to one arm receive standard therapy plus the investigational drug, while those 
in the control arm receive standard therapy plus a placebo. In the current study, all 
randomised patients will receive paclitaxel, a standard treatment for mTNBC; refer to 
Section 3.3.3. 
Placebo-controlled trials may be necessary or desirable to meet regulatory standards for 
drug approval. Trials that used standard therapy as background treatment led to recent 
regulatory approval of several targeted agents in various advanced cancer types (Cohen 
et al. 2005; Summers et al. 2010; Larkins et al. 2015). 
3.3.5 
Rationale for Biomarker Assessments 
TNBC is a heterogeneous disease and the need for identification and characterisation of 
molecular biomarkers to predict response to therapy, in order to further improve 
treatment strategies including targeted therapies, is well recognised (Verma et al. 2011; 
Wahba and El-Hadaad, 2015). 
PD-L1 expression in triple-negative tumours has been shown to correlate with response 
to anti-PD-1 therapy (Herbst et al. 2014). This correlation was also observed with 
atezolizumab in the Phase Ia Study PCD4989g, most notably in urothelial and renal 
cancers and NSCLC (see Section 1.2.2.1). The correlation between PD-L1 expression 
and atezolizumab activity in TNBC is not well established yet. However, it is possible 
that not all patients may equally benefit from treatment with atezolizumab. Predictive 
biomarker samples collected prior to dosing will be assessed in an effort to identify those 
patients who are most likely to respond to atezolizumab.  As these biomarkers may also 
have prognostic value, their potential association with disease progression will also be 
explored. 
3.3.5.1 
Rationale for Pre-treatment Tumour Samples 
To evaluate the potential predictive significance of PD-L1 expression in mTNBC, 
representative tumour specimens obtained from metastatic or locally advanced TNBC 
will be collected within 3 months prior to randomisation. If a tumour sample taken within 
3 months before randomisation is not available and a tumour biopsy is not clinically 
feasible, the primary surgical resection sample or the most recent FFPE tumour biopsy 
sample may be used. Tumour specimens should be formalin-fixed paraffin-embedded 
(FFPE) (preferred; alternatively, at least 17 unstained slides are required to participate in 
this study. Slides must be of good quality (based on total and viable tumour content), 
with an associated pathology report. These tumour specimens will also be used for 
retrospective confirmation of HER2, ER, PR expression by a central testing laboratory. If 
multiple tumour specimens are submitted, at least one specimen must be evaluable for 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
59/Protocol MO39196 (IMpassion131), Version 6.0 
PD-L1, to allow for stratification based on tumour PD L1 expression as determined by 
IHC (IC0 vs. IC1/2/3) at randomisation. 
In addition to the assessment of PD-L1 status, exploratory markers such as potential 
predictive and prognostic markers related to the clinical benefit of atezolizumab plus 
paclitaxel, tumour immunobiology, mechanisms of resistance, or tumour type, may also 
be analysed. 
3.3.5.2 
Rationale for Biopsy Specimen Collection at the Time of 
Radiographic Progression 
To test the mechanisms of resistance to the drug combination, consenting patients will 
undergo a tumour biopsy collection (optional sample; collected if clinically feasible, 
preferably from new or progressing lesions) at first evidence of radiographic disease 
progression per RECIST v1.1. Analysis of biological material (including but not restricted 
to DNA and ribonucleic acid [RNA] sequencing) from these specimens will help elucidate 
molecular changes associated with resistance to or disease progression after treatment 
with paclitaxel plus atezolizumab or paclitaxel plus placebo in patients with TNBC.  
3.3.5.3 
Rationale for the Optional On-treatment Biopsy Specimen 
Collection  
One optional on-treatment tumour sample will be collected (if clinically feasible) pre-dose 
on Cycle 2, Day 1 (prior to steroid medication), from patients who have provided consent 
for paired biopsies. The samples will be analysed for molecular changes occurring after 
treatment with paclitaxel plus atezolizumab compared to paclitaxel plus placebo. These 
analyses will help elucidate changes in the immune tumour microenvironment under 
treatment and 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-tumour immune response in patients with TNBC. 
3.3.5.4 
Rationale for Blood Sampling for Biomarkers  
Changes in different blood biomarkers may provide evidence for biologic activity of 
atezolizumab in combination with paclitaxel in humans and may allow for the 
development of a blood-based biomarker to help predict which patients may benefit from 
atezolizumab plus paclitaxel. An exploratory objective of this study is to evaluate 
changes in surrogate biomarkers in blood samples. 
In addition, potential correlations of these pharmacodynamic markers with the safety and 
anti-tumour activity of atezolizumab will be explored. 
3.3.6 
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). Patient-reported outcomes (PROs) of global health status, function, and 
disease/treatment related symptoms will be assessed using the European Organization 
for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 
(QLQ-C30) in conjunction with its QLQ-BR23 breast cancer module, as well as the 
European Quality of Life 5 Dimension, 5-level version (EQ-5D-5L) questionnaire (see 
Section 4.5.8 for further details and Appendix 4 for a sample of each instrument). 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
60/Protocol MO39196 (IMpassion131), Version 6.0 
The EORTC QLQ-C30 and QLQ-BR23 instruments are validated and reliable self-report 
measures (Aaronson et al.1993; Sprangers et al. 1996; Osoba et al. 1997; Osoba et al. 
1998). The EQ-5D-5L is a validated, generalised HRQoL measure that assesses 
patient’s health status related to mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression (EuroQol Group 1990; Brooks 1996; Herdman et al. 2011; Janssen 
et al. 2013).  A utility measure is obtained that is used to inform pharmacoeconomic 
evaluations. 
As the QLQ BR23 was not developed or tested and validated in men, male patients in 
this study will not complete the QLQ-BR23 questionnaire. 
3.3.7 
Rationale for the Adverse Event Reporting Period 
The reporting period in this study is defined as 30 days after the last dose of 
atezolizumab/placebo for adverse events, and 90 days after the last dose of 
atezolizumab/placebo for serious adverse events (SAEs) or adverse events of special 
interest (AESI). The rationale for this reporting period (as opposed to five half-lives of 
atezolizumab, or five months) is based on a review of adverse events occurring >30 
days after the last dose of atezolizumab in Study PCD4989g, which revealed no long-
term safety concerns. Approximately 92 of 443 treated patients (21%) in Study 
PCD4989g reported adverse events between 31 and 90 days after last dose of 
atezolizumab; of these, 38 patients (9%) reported events related to disease progression. 
Adverse events reported by the remainder of patients were mainly single occurrences of 
a broad range of event terms with no pattern or trend for any System Organ Class 
(SOC) or type of event. These events were considered indicative of the patients’ 
underlying cancer and were not representative of delayed toxicity related to 
atezolizumab. Therefore, the Sponsor considers the collection of all adverse event data 
until 30 days after the last dose of the study drug, and for 90 days after the last dose for 
SAEs and adverse events of special interest to be sufficient for the on-going assessment 
and characterisation of the overall safety profile for atezolizumab. 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
The target population will include patients with previously untreated inoperable locally 
advanced or metastatic TNBC. Patients will be either newly diagnosed or have disease 
progression after completing treatment for early breast cancer at least 12 months prior to 
randomisation. The enrolment criteria will be identical for all patients (global and 
additional enrolment in China). 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
1. Signed Informed Consent Form 
2. Women or men aged ≥18 years 
3. Patients with locally advanced or metastatic, histologically documented TNBC 
(absence of human epidermal growth factor 2 [HER2], oestrogen receptor [ER], and 
progesterone receptor [PR] expression), not amenable to surgical therapy. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
61/Protocol MO39196 (IMpassion131), Version 6.0 
a) HER2 negativity is defined as either of the following: IHC 0, IHC 1+ or IHC2+/in 
situ hybridisation (ISH)- as per American Society of Clinical Oncology (ASCO)-
College of American Pathologists Guideline (CAP) guideline (ISH- is defined as 
a ratio of HER2 to CEP17 <2.0) (Wolff et al. 2018). 
b) ER and PR negativity are defined as <1% of cells expressing hormonal 
receptors via IHC analysis as per ASCO-CAP guideline (Hammond et al. 2010).   
4. Eligible for taxane monotherapy.  
5. No prior chemotherapy or targeted systemic therapy (including endocrine therapy) 
for inoperable locally advanced or metastatic TNBC.  
Prior radiation therapy for metastatic disease is permitted. There is no required 
minimum washout period for radiation therapy; however, patients should have 
recovered from the effects of radiation before randomisation. 
Previous chemotherapy for early breast cancer (eBC; neoadjuvant or adjuvant 
setting) is permitted if completed ≥12 months before randomisation.  
China population only: Chinese traditional medicines with an approved indication for 
cancer treatment are permitted as long as the last administration occurred at least 2 
weeks prior to randomisation. 
6. Availability of formalin-fixed paraffin-embedded (FFPE) tumour block (preferred) or 
at least 17 unstained slides, collected ≤3 months prior to randomisation, with an 
associated pathology report, if available. If a tumour sample taken within 3 months 
before randomisation is not available and a tumour biopsy is not clinically feasible, 
the primary surgical resection sample or the most recent FFPE tumour 
biopsy sample may be used. Of these additional options, the most recent sample 
should be used. 
a) The tumour tissue should be of good quality based on total and viable tumour 
content and must be evaluated centrally for PD-L1 expression prior to enrolment. 
Patients whose tumour tissue is not evaluable for prospective central testing are 
not eligible.  
b) If multiple tumour specimens are submitted, patients may be eligible if at least 
one specimen is evaluable for PD-L1 testing, and the score measured in the 
most recent sample prior to enrolment will be used as the PD-L1 score for patient 
stratification.  
i. Acceptable samples include core needle biopsies for deep tumour tissue 
(more than one core if clinically feasible) or excisional, incisional, punch, 
or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions. 
ii. Fine needle aspiration, brushing, cell pellet from pleural effusion, bone 
metastases, and lavage samples are not acceptable.   
iii. Tumour tissue from bone metastases is not evaluable for PD-L1 
expression and is therefore not acceptable. 
7. ECOG performance status of 0 or 1 
8. Life expectancy ≥ 12 weeks 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
62/Protocol MO39196 (IMpassion131), Version 6.0 
9. Measurable disease, as defined by RECIST v1.1. (Note: Previously irradiated 
lesions can be considered as measurable disease only if disease progression has 
been unequivocally documented at that site since radiation.)  
10. Adequate haematologic and end-organ function, defined by the following laboratory 
results obtained within 2 weeks prior to the first study treatment (Cycle 1, Day 1): 
a. Absolute neutrophil count (ANC) ≥ 1500 cells/μL (without granulocyte colony 
stimulating factor [G-CSF] support within 2 weeks prior to Cycle 1, Day 1) 
b. Lymphocyte count ≥ 500/μL 
c. Platelet count ≥ 100,000/μL (without transfusion within 2 weeks prior to Cycle 1, 
Day 1) 
d. Haemoglobin ≥ 9.0 g/dL 
Patients may be transfused or receive erythropoietic treatment to meet this 
criterion. 
e. Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline 
phosphatase ≤ 2.5× the upper limit of normal (ULN), with the following 
exceptions: 
i. Patients with documented liver metastases:  AST and ALT ≤ 5× ULN 
ii. Patients 
with 
documented 
liver 
or 
bone 
metastases: 
alkaline 
phosphatase ≤ 5× ULN 
f. Serum bilirubin ≤ 1.25× ULN 
Patients with known Gilbert’s disease who have serum bilirubin level ≤ 3× ULN 
may be enrolled. 
g. International Normalized Ratio (INR) and activated partial thromboplastin time 
(aPTT) ≤ 1.5× ULN 
This applies only to patients who are not receiving an anticoagulant medicinal 
product; patients receiving an anticoagulant medicinal product should be on a 
stable dose and have an INR which is not above the target therapeutic range.  
h. Calculated creatinine clearance (CrCl) ≥ 30 mL/min (Cockcroft-Gault). 
11. Negative human immunodeficiency virus (HIV) test at screening. 
12. Negative hepatitis B surface antigen (HBsAg) test at screening. 
13. Negative total hepatitis B core antibody (HBcAb) test at screening, or positive 
HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening. 
The HBV DNA test will be performed only for patients who have a positive HBcAb 
test. 
14. Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV 
antibody test followed by a negative HCV RNA test at screening. 
The HCV RNA test will be performed only for patients who have a positive 
HCV antibody test. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
63/Protocol MO39196 (IMpassion131), Version 6.0 
15. Women of child bearing potential must agree to either use a contraceptive method 
with a failure rate of ≤ 1% per year or to remain abstinent (refrain from heterosexual 
intercourse) during the treatment period and for at least 5 months after the last dose 
of atezolizumab/placebo, or for at least 6 months after the last dose of paclitaxel. 
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 
sterilisation (removal of ovaries and/or uterus). 
Examples of contraceptive methods with a failure rate of ≤ 1% per year include 
bilateral tubal ligation, male sterilisation, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) 
and withdrawal are not acceptable methods of contraception. 
16. Women of child bearing potential must have a negative serum pregnancy test result 
within 7 days prior to initiation of study drug. 
17. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures and agreement to refrain from donating sperm, as 
defined below: 
a. 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 paclitaxel.  Men must refrain from donating 
sperm during this same period. 
b. 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 post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
Cancer-Specific Exclusion Criteria 
1. 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 at least 2 weeks prior to randomisation. 
2. Known central nervous system (CNS) disease, except for treated asymptomatic 
CNS metastases, provided all of the following criteria are met: 
a. Measurable disease outside the CNS 
b. Metastases are limited solely to cerebellar and supratentorial lesions (i.e., no 
metastases to midbrain, pons, medulla, or spinal cord) 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
64/Protocol MO39196 (IMpassion131), Version 6.0 
c. No ongoing requirement for corticosteroids as therapy for CNS disease 
(anticonvulsants at a stable dose are allowed) 
d. No stereotactic radiation within 7 days or whole-brain radiation within 14 days 
prior to randomisation 
e. No evidence of progression or haemorrhage after completion of CNS directed 
therapy 
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, if all 
other criteria above are met.  
3. Leptomeningeal disease 
4. Uncontrolled pleural effusion, pericardial effusion, or ascites (Note: patients with 
indwelling catheters, such as PleurX® are allowed) 
5. Uncontrolled tumour-related pain  
a. Patients requiring narcotic pain medication must be on a stable regimen at 
study entry.  
b. Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to 
randomisation.  Patients should be recovered from the effects of radiation.  
There is no required minimum recovery period.  
c. 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 randomisation. 
6. Uncontrolled hypercalcemia (>1.5 mmol/L [>6 mg/dL] ionized calcium or serum 
calcium [uncorrected for albumin] >3 mmol/L [>12 mg/dL] or corrected serum 
calcium >ULN) or clinically significant (symptomatic) hypercalcemia  
Patients who are receiving bisphosphonate therapy specifically to prevent skeletal 
events and who do not have a history of clinically significant (symptomatic) 
hypercalcemia are eligible. 
7. Malignancies other than TNBC within 5 years prior to randomisation, 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, non-melanoma skin carcinoma, or Stage I uterine cancer).  
General Medical Exclusion Criteria 
8. Pregnant or lactating women, or intending to become pregnant during the study. 
9. 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 
65/Protocol MO39196 (IMpassion131), Version 6.0 
10. Significant cardiovascular disease, such as New York Heart Association (NYHA) 
cardiac disease (Class II or greater), myocardial infarction within 3 months prior to 
randomisation, unstable arrhythmias, or unstable angina. 
a. Patients with a known left ventricular ejection fraction (LVEF) < 40% will be 
excluded.  
b. 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. 
11. Presence of an abnormal electrocardiogram (ECG) that is clinically significant in the 
investigator’s opinion, including complete left bundle branch block, second- or third-
degree heart block, evidence of prior myocardial infarction, or QT interval corrected 
using Fridericia’s formula (QTcF) >470 ms demonstrated by at least two 
consecutive ECGs.  
12. Serious infection requiring antibiotics within 2 weeks prior to randomisation, 
including but not limited to infections requiring hospitalisation or IV antibiotics, such 
as bacteraemia, or severe pneumonia. 
13. Major surgical procedure within 4 weeks prior to randomisation or anticipation of 
the need for a major surgical procedure during the study other than for diagnosis. 
Note: Placement of central venous access catheter(s) (e.g., port or similar) is not 
considered a major surgical procedure and is therefore permitted. 
14. Treatment with investigational therapy within 30 days prior to initiation of study 
treatment. 
15. Inability to understand the local language(s) for which the Patient Reported 
Outcome (PRO) questionnaires are available. 
Exclusion Criteria Related to Atezolizumab 
16. History of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric or humanized antibodies or fusion proteins 
17. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese 
hamster ovary (CHO) cells or any component of the atezolizumab formulation 
18. History of autoimmune disease, including but not limited to myasthenia gravis, 
myositis, autoimmune hepatitis, systemic lupus erythematosus (SLE), rheumatoid 
arthritis (RA), inflammatory bowel disease, vascular thrombosis associated with 
antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, 
Guillain-Barré syndrome, multiple sclerosis (MS), vasculitis, or glomerulonephritis. 
(Note: Patients with a history of autoimmune-related hypothyroidism on a stable 
dose of thyroid replacement hormone and patients with controlled Type 1 diabetes 
mellitus on a stable insulin regimen may be eligible for this study.) 
19. Prior allogeneic stem cell or solid organ transplantation 
20. History of idiopathic pulmonary fibrosis (IPF, including pneumonitis), drug-induced 
pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
66/Protocol MO39196 (IMpassion131), Version 6.0 
organizing pneumonia), or evidence of active pneumonitis on screening chest CT 
scan. (Note: History of radiation pneumonitis in the radiation field [fibrosis] is 
permitted.) 
21. Current treatment with anti-viral therapy for HBV. 
22. Active tuberculosis 
23. Receipt of a live, attenuated vaccine within 4 weeks prior to randomisation 
or anticipation that such a live, attenuated vaccine will be required during the study. 
Note: Patients must agree not to receive live, attenuated influenza vaccine (e.g., 
FluMist®) within 28 days prior to randomisation, during treatment or within 5 months 
following the last dose of atezolizumab/placebo. 
24. Prior treatment with CD137 agonists, anti-PD-1, or anti-PD-L1 therapeutic antibody 
or immune checkpoint targeting agents 
25. Treatment with systemic immunostimulatory agents (including but not limited to 
interferons or interleukin [IL]-2) within 4 weeks or five half-lives of the drug 
(whichever is longer) prior to randomisation 
26. Treatment with systemic immunosuppressive medications (including but not limited 
to corticosteroids, cyclophosphamide, azathioprine, cyclosporine, methotrexate, 
thalidomide, and anti-tumour necrosis factor [TNF] agents) within 2 weeks prior to 
randomisation, or anticipated requirement for systemic immunosuppressive 
medications during the trial. 
a. Patients who have received acute, low-dose (≤ 10 mg oral prednisone or 
equivalent), systemic immunosuppressant medications may be enrolled in the 
study. 
b. Patients with a history of allergic reaction to IV contrast requiring steroid pre-
treatment should have baseline and subsequent tumour assessments 
performed using MRI. 
c. The use of corticosteroids (≤ 10 mg oral prednisone or equivalent) for chronic 
obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for 
patients 
with 
orthostatic 
hypotension, 
and 
low 
dose 
supplemental 
corticosteroids for adrenocortical insufficiency are allowed. 
d. Systemic corticosteroids are allowed as paclitaxel premedication during the trial 
at a dose ≤10 mg dexamethasone or equivalent in order to avoid severe 
hypersensitivity reactions. 
27. Poor peripheral venous access 
28. Illicit drug or alcohol abuse within 12 months prior to screening, in the investigator’s 
judgment 
29. Any other serious medical condition or abnormality in clinical laboratory tests that, in 
the investigator’s judgment, precludes the patient’s safe participation in and 
completion of the study. 
 

Atezolizumab—F. Hoffmann-La Roche Ltd
67/Protocol MO39196 (IMpassion131), Version 6.0
Exclusion Criteria Related to Paclitaxel
30. History of hypersensitivity reactions to paclitaxel or other drugs formulated in the 
same solvent as paclitaxel (polyoxyethylated castor oil).
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 IxRS 
(ALMAC Clinical Technologies) for eligible patients.
Randomisation to atezolizumab plus paclitaxel or placebo plus paclitaxel will occur in a 
2:1 ratio, using a permuted-block randomisation method.  The randomisation scheme is 
designed to ensure that an approximately equal number of patients will be enrolled in 
each treatment arm, and within the following baseline stratification factors:

Tumour PD-L1 status (IC0 vs. IC1/2/3)

Prior taxane treatment (yes vs. no), and 

Presence of liver metastases (yes vs. no)

Region (North America vs. Western Europe/Australia; vs. Eastern Europe/Asia 
Pacific vs. South America).
Patients should receive their first dose of study treatment on the day of randomisation, if 
possible.  If this is not possible, the first dose should occur no later than 3 days after 
randomisation.
With the exception of stratifying by region, the same randomisation method and ratio 
(2:1) will be implemented for the China only patients.
The Sponsor and its agents (with the exception of the IxRS service provider [the external 
independent 
statistical 
coordinating 
centre 
responsible 
for 
verifying 
patient 
randomisation and study treatment kit assignments], PK/pharmacodynamic testing 
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 of 
the treatment assignment at the study level; refer to Section 4.2.1. While PK samples 
must be collected from patients assigned to the comparator arm to maintain the blinding 
of treatment assignment, PK assay results for these patients are generally not needed 
for the safe conduct or proper interpretation of this trial. Therefore, Sponsor personnel 
responsible for performing PK assays will be unblinded to patients’ treatment 
assignments to identify appropriate PK samples to be analysed.  Samples from patients 
assigned to the comparator arm will not be analysed except by request (e.g., to evaluate 
a possible error in dosing).
The Sponsor and its agents (except for the PD-L1 assay provider and members of the 
iDCC and iDMC), the study site personnel, including the investigators, and the patients 
will be blinded to PD-L1 status prior to unblinding of the treatment assignment at the 
study level; refer to Section 4.2.1.

Atezolizumab—F. Hoffmann-La Roche Ltd
68/Protocol MO39196 (IMpassion131), Version 6.0
4.2.1
Unblinding
All occurrences of unblinding, including their date, time, and rationale, should be 
documented in the study file.
Unblinding of treatment assignment may only occur under the following circumstances.
4.2.1.1
Emergency Unblinding
Per health authority reporting requirements, treatment assignment will be unblinded for 
serious, unexpected study drug-related toxicity (e.g., as part of the Investigational New 
Drug [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 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 authorised to break the 
treatment code within the IxRS solely for the patient experiencing the treatment 
emergent adverse event by using a personal identification (PIN) code which is issued to 
them at the start of the study.  
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. 
4.2.1.2
Unblinding upon Disease Progression
Prior to disease progression, patients’ treatment allocation must remain blinded.
Upon radiographic disease progression per RECIST v1.1, and the resulting 
discontinuation of study treatment, the study drug assignment may be unblinded (for the 
patient with confirmed disease progression only), provided that the following conditions 
are met:

There is a plan to treat the patient with next line of approved treatment or enrolling 
her/him in a subsequent clinical trial; and 

There is documented evidence that the patient meets the eligibility criteria for the 
next-line of approved treatment or clinical trial, except for invasive/radiation-requiring 
procedures; and

The knowledge of treatment allocation (atezolizumab/placebo) in the current study is 
required to confirm eligibility for the next-line approved treatment or clinical trial; 

Data entry related to the documented progression is entered in the eCRF; and 

The Investigator obtains Sponsor approval for the potential unblinding.  
The study centre will be required to send all requests for unblinding, including 
documentation of radiographic disease progression, to the Sponsor for approval. Upon 
Sponsor approval, the IxRS system will provide the site with the study treatment 
assignment. Approval of the request and unblinding of study drug assignment under this 
scenario will occur only during business hours. The Sponsor will not be informed of the 
patient’s treatment allocation at the time of unblinding.

Atezolizumab—F. Hoffmann-La Roche Ltd
69/Protocol MO39196 (IMpassion131), Version 6.0
Crossover to atezolizumab for patients allocated to placebo is not allowed upon 
unblinding.
Continued treatment with atezolizumab, beyond radiographic evidence of disease 
progression per RECIST v1.1, in patients allocated to atezolizumab is not allowed upon 
unblinding.
4.2.1.3
Unblinding at the Study Level
Treatment assignment will be unblinded at the time of the primary endpoint analysis, 
after all data have been cleaned and verified and the database has been locked.
4.3
STUDY TREATMENT 
Atezolizumab/placebo and paclitaxel are considered investigational medicinal products 
(IMPs) in this study. Non-investigational medicinal products (NIMPs) used in the study 
include premedication (see Section 4.4.1.1), medications that may be administered to 
manage adverse events (see Section 4.4.1.2), and other permitted concomitant 
medications (see Section 4.4.1.3). 
The term "study drug" is used throughout this protocol to refer to atezolizumab/placebo.  
The 
term 
"study 
treatment" 
refers 
to 
all 
protocol-mandated 
treatment 
(atezolizumab/placebo and paclitaxel).  
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Atezolizumab
Atezolizumab/placebo will be supplied by the Sponsor.
The atezolizumab drug product is provided in a single-use, 20cc USP/Ph. Eur. Type 1 
glass vial as a colourless-to-slightly-yellow, sterile, preservative-free clear liquid solution 
intended for IV administration. The vial contains ~20 mL (1200 mg) of atezolizumab 
solution.  The atezolizumab drug product is formulated as 60 mg/mL atezolizumab in 20 
mM histidine acetate, 120 mM sucrose, 0.04% polysorbate 20, pH 5.8.
Atezolizumab will be administered in 250 mL 0.9% NaCl IV infusion bags and infusion 
lines equipped with 0.2 μm in-line filters. The IV bag may be constructed of 
polyvinylchloride (PVC) or polyolefin; the IV infusion line may be constructed of PVC or 
polyethylene; and the 0.2 μm in-line filter may be constructed of polyethersulfone. No 
incompatibilities have been observed between atezolizumab and these infusion 
materials (bags and infusion lines).
Atezolizumab vials must be refrigerated at 2°C-8°C (36°F-46°F) upon receipt until use.  
Vials should not be used beyond the expiration date provided by the manufacturer.  
Atezolizumab must be prepared/diluted under appropriate aseptic conditions as it does 
not contain antimicrobial preservatives. The solution for infusion should be used 
immediately to limit microbial growth in case of potential accidental contamination. Any 
unused portion of drug left in a vial should be discarded.  Vial contents should not be 
frozen or shaken and should be protected from direct sunlight.

Atezolizumab—F. Hoffmann-La Roche Ltd
70/Protocol MO39196 (IMpassion131), Version 6.0
Further details on the storage and preparation of atezolizumab are provided in the 
atezolizumab Investigator’s Brochure and the Pharmacy Manual.
4.3.1.2
Placebo
Matching placebo will be supplied by the Sponsor.
Placebo will consist of the vehicle without the antibody. Placebo will be supplied in a 
single-use, 20cc USP/Ph. Eur. Type 1 glass vial as a colourless, sterile, preservative-
free clear liquid solution intended for IV administration.  The vial contains ~20 mL of 
solution. The formulation contains 20 mM histidine acetate, 120 mM sucrose, and 0.04% 
polysorbate 20, pH 5.8.
Placebo will be stored, handled, and administered as described for atezolizumab. 
Further details are provided in the Pharmacy Manual.
4.3.1.3
Paclitaxel
Paclitaxel is considered standard of care in patients with TNBC. However, the paclitaxel 
dosing regimen used in this study (90 mg/m2 via IV infusion on Days 1, 8, and 15 of 
every 28-day cycle) is not approved in patients with TNBC. Therefore, paclitaxel will be 
considered an IMP in this study, and provided by the Sponsor. For information on the 
formulation, packaging, and handling of paclitaxel, refer to the local prescribing 
information for paclitaxel.
4.3.2
Dosage, Administration, and Compliance
4.3.2.1
Atezolizumab/Placebo
Patients will receive atezolizumab 840 mg (corresponding to 14 mL from drug product, in 
250 mL 0.9% sodium chloride [NaCl]) or matching placebo by IV infusion administered 
on Day 1 and Day 15 (± 3 days) of every 28-day cycle. The first dose (Cycle 1, Day 1) 
will be administered over 60 (± 15) minutes. If the first infusion is well tolerated, 
all subsequent infusions may be delivered over 30 (±10) minutes.
For the first infusion of atezolizumab/placebo, no premedication will be administered. 
However, should the patient experience infusion-related reaction(s) during any infusion, 
premedication with antihistamines will be administered for subsequent infusions at the 
discretion of the treating physician.
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/placebo infusions will be administered per the instructions 
outlined in Table 3.

Atezolizumab—F. Hoffmann-La Roche Ltd
71/Protocol MO39196 (IMpassion131), Version 6.0
Table 3
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 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.
Patients randomised to either group must discontinue all study treatment upon 
determination of PD 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. In the absence of disease progression or 
unacceptable toxicity, study treatment will continue until EOS.
Dose reduction of atezolizumab/placebo is not permitted. Atezolizumab/placebo and 
paclitaxel may be discontinued for toxicity independently of each other in the absence of 
PD. 
Guidelines 
for 
management 
of 
specific 
adverse 
events 
and 
for 
atezolizumab/placebo 
dosing 
interruption 
or 
discontinuation 
are 
provided 
in 
Section 5.1.4 and Section 5.1.5.3.1, respectively.
There is currently no information on overdose with atezolizumab. Any overdose or 
incorrect administration of study drug should be noted on the Study Drug Administration 
electronic Case Report Form (eCRF). Adverse events associated with an overdose or 
incorrect administration of study drug should be recorded on the Adverse Event eCRF.
4.3.2.2
Paclitaxel
Paclitaxel will be administered at the 90 mg/m2 dose via 1-hour IV infusion on Days 1, 8, 

Atezolizumab—F. Hoffmann-La Roche Ltd
72/Protocol MO39196 (IMpassion131), Version 6.0
and 15 of every 28-day cycle. On days of scheduled infusions of atezolizumab/placebo 
and paclitaxel (i.e., Day 1 and Day 15 of every cycle), paclitaxel is to be administered 
after infusion of atezolizumab/placebo. Doses of paclitaxel should not be administered 
more frequently than every 7 days.
In the absence of unacceptable toxicity, paclitaxel will be administered until PD or until 
the end of the study, whichever occurs earlier. Paclitaxel and atezolizumab/placebo may 
be discontinued for toxicity independently of each other in the absence of disease 
progression. 
To reduce the risk of severe hypersensitivity reactions, study patients will be 
premedicated as described in Section 4.4.1.1.
Sites should follow their institutional standard of care for determining the 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.
Guidelines 
for 
paclitaxel 
dosage 
modification 
and 
treatment 
interruption 
or 
discontinuation due to toxicity are provided in Section 5.1.5.3.2.
Any overdose or incorrect administration of paclitaxel should be noted on the Paclitaxel 
Administration eCRF. Adverse events associated with an overdose or incorrect 
administration of paclitaxel should be recorded on the Adverse Event eCRF.
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (atezolizumab/placebo and paclitaxel) will 
be provided by the Sponsor. The study site will acknowledge receipt of 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.
Unused 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 destruction of any unused IMP must 
be agreed to by the Sponsor. The site must obtain written authorisation from the 
Sponsor before any IMP is destroyed, and IMP destruction must be documented on the 
appropriate form.

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
73/Protocol MO39196 (IMpassion131), Version 6.0 
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-Trial Access to Atezolizumab  
The Sponsor will offer post-trial access to the study drug (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 atezolizumab after completing the study if all the 
following conditions are met: 
• 
The patient has a life-threatening or severe medical condition and requires 
continued atezolizumab treatment for his or her well-being  
• 
There are no appropriate alternative treatments available to the patient 
• 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
• 
The patient was assigned to atezolizumab treatment at study randomisation. 
A patient will not be eligible to receive atezolizumab after completing the study if any of 
the following conditions are met: 
• 
Atezolizumab 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 atezolizumab or data suggest that 
atezolizumab is not effective for mTNBC 
• 
The Sponsor has reasonable safety concerns regarding atezolizumab as treatment 
for mTNBC 
• 
The patient was assigned to placebo treatment at study randomisation. 
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 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, vaccines, 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 eCRF.  
Between the treatment discontinuation and the EOS visit, only new anti-cancer treatment 
will be recorded. 
4.4.1 
Permitted Therapy  
4.4.1.1 
Premedication 
For the first infusion of atezolizumab/placebo, no premedication will be administered. 
However, should the patient experience infusion-related reaction(s) during any infusion, 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
74/Protocol MO39196 (IMpassion131), Version 6.0 
premedication with antihistamines may be administered for subsequent infusions at the 
discretion of the treating physician. 
To reduce the risk of severe hypersensitivity reactions, all patients should be 
premedicated prior to paclitaxel administration. Prior to receiving the first two study 
infusions of paclitaxel, all patients will receive corticosteroids (8-10 mg dexamethasone 
or equivalent) as part of either the institutional standard of care or the following 
premedication:  
• 
Dexamethasone 8-10 mg (or equivalent) administered orally approximately 12 and 
6 hours prior to the paclitaxel infusion 
Patients may be treated with dexamethasone ≤10 mg IV within 1 hour prior to the 
paclitaxel infusion if the patient did not take the oral dexamethasone. 
• 
Diphenhydramine 50 mg IV (or equivalent) 30-60 minutes prior to the 
paclitaxel infusion 
• 
Cimetidine 300 mg IV or ranitidine 50 mg IV (or equivalent) 30-60 minutes prior to 
paclitaxel infusion.  
Because the effects of corticosteroids on T-cell proliferation have the potential to ablate 
early atezolizumab-mediated anti-tumour immune activity, it is recommended that the 
dose of dexamethasone (or equivalent) is minimised to the extent that is clinically 
feasible. For example, if paclitaxel is well tolerated during the first two weekly infusions 
without apparent hypersensitivity reaction, a reduction in the dose of dexamethasone 
premedication (or equivalent) should be considered for subsequent cycles if permitted by 
institutional standard of care. This approach has been reported to be successful in the 
literature (Berger et al. 2012). 
4.4.1.2 
Treatment of Infusional Adverse Events 
Patients who experience infusion-associated symptoms may be treated symptomatically 
with acetaminophen, ibuprofen, diphenhydramine (or equivalent substitutes, per local 
practice), and/or famotidine or another H2 receptor antagonist, per standard practice. 
Serious infusion-associated events manifested by dyspnoea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should 
be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen 
and β2-adrenergic agonists; see Appendix 6). 
4.4.1.3 
Other Permitted Therapy 
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 tumour target lesions. Candidate lesions for 
radiotherapy must be decided prior to study entry. 
Note: It is not required to hold atezolizumab/placebo during palliative radiotherapy; 
paclitaxel should be interrupted per institutional standard of care. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
75/Protocol MO39196 (IMpassion131), Version 6.0 
• 
Inactivated vaccinations (including for influenza)  
• 
Megestrol administered as an appetite stimulant 
• 
Inhaled corticosteroids for chronic obstructive pulmonary disease 
• 
Mineralocorticoids (e.g., fludrocortisone) 
• 
Low-dose corticosteroids (≤10 mg prednisone equivalent per day) for patients with 
orthostatic hypotension or adrenocortical insufficiency 
• 
Bisphosphonates for the prevention of skeletal events 
• 
Anticonvulsants at a stable dose are allowed, e.g., for patients with CNS metastases  
• 
Narcotic pain medication is permitted as long as the patient is on a stable regimen at 
study entry. 
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated and per local standards.   
Patients who use contraceptives should continue their use during the treatment period 
and for at least 5 months after the last dose of study treatment; refer to Section 4.1.1. 
4.4.2 
Prohibited and Cautionary Therapy 
Cytochrome P450 enzymes, as well as conjugation/glucuronidation reactions, are not 
involved in the metabolism of atezolizumab. No drug interaction studies have been 
conducted for atezolizumab, and there are no known PK interactions with other 
medicinal products. 
Excessive activation of the immune system is a potential risk associated with 
atezolizumab and has been observed when atezolizumab is used in combination with 
other immunomodulating agents. Therefore, the use of these agents is prohibited (i.e., 
immune checkpoint modulators) or limited (e.g. interferons or IL-2; prohibited within 28 
days or five half-lives of the drug prior to randomisation, whichever is longer) prior to 
randomisation, during study treatment, and for 10 weeks after atezolizumab 
discontinuation. 
Medications that are prohibited while the patient is receiving study treatment, and their 
respective washout periods prior to randomisation are listed in Table 4. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
76/Protocol MO39196 (IMpassion131), Version 6.0 
Table 4 
Prohibited Medications and Treatments 
 
Prohibited Medication/Class 
Minimum Washout Period 
Prior to Randomisation 
Any other systemic anti-cancer therapy 
28 days or five half-lives of the 
drug (whichever is longer) 
Any investigational therapy 
30 days 
Immunomodulatory agents, e.g., interferons or IL 2 [1] 
28 days or five half-lives of the 
drug (whichever is longer) 
Immunosuppressive medications, e.g., cyclophosphamide, 
azathioprine, cyclosporine, methotrexate, thalidomide [2] 
14 days 
Corticosteroids as therapy for CNS disease 
1 day 
Any live, attenuated vaccine (e.g., FluMist) [3] 
28 days 
Stereotactic radiation for CNS metastases 
Whole-brain radiation for CNS metastases 
7 days 
14 days 
[1] These agents could potentially increase the risk for autoimmune conditions when received in combination 
with atezolizumab. 
[2] These agents could potentially alter the activity and the safety of atezolizumab. 
[3] Any live, attenuated vaccine is prohibited within 28 days prior to randomisation, during treatment, and 
within 5 months following the last dose of atezolizumab/placebo. 
 
The above list of medications is not necessarily comprehensive.  Thus, the investigator 
should consult the prescribing information for any concomitant medication and/or contact 
the Medical Monitor if questions arise regarding medications not listed above. 
Systemic corticosteroids and TNF-α inhibitors may attenuate potential beneficial 
immunologic effects of treatment with atezolizumab. Therefore, in situations where 
systemic corticosteroids or TNF-α inhibitors would be routinely administered, alternatives, 
including antihistamines, should be considered first by the treating physician. If the 
alternatives are not feasible, systemic corticosteroids and TNF-α inhibitors may be 
administered at the discretion of the treating physician. 
Systemic corticosteroids are recommended, with caution at the discretion of the treating 
physician, for the treatment of specific adverse events when associated with 
atezolizumab therapy. Guidelines for the management of immune-mediated adverse 
events are described in Section 5.1.4. 
The concomitant use of herbal therapies is not recommended, as their PK, 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 
Additional Restrictions Related to Paclitaxel 
The metabolism of paclitaxel is catalysed by cytochrome P450 (CYP) isoenzymes 
CYP2C8 and CYP3A4. The PK of paclitaxel was shown to be altered in vivo as a result 
of interactions with compounds that are substrates, inducers, or inhibitors of CYP2C8 
and/or CYP3A4. Therefore, caution should be exercised when paclitaxel is 
concomitantly administered with known substrates (e.g., midazolam, buspirone, 
felodipine, lovastatin, eletriptan, sildenafil, simvastatin, and triazolam), inhibitors (e.g., 
atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
77/Protocol MO39196 (IMpassion131), Version 6.0 
ritonavir, saquinavir, and telithromycin), and inducers (e.g., rifampin and carbamazepine) 
of CYP3A4. Caution should also be exercised when paclitaxel is concomitantly 
administered with known substrates (e.g., repaglinide and rosiglitazone), inhibitors (e.g., 
gemfibrozil), and inducers (e.g., rifampin) of CYP2C8.  
Potential interactions between paclitaxel, a substrate of CYP3A4, and protease inhibitors 
(ritonavir, saquinavir, indinavir, and nelfinavir), which are substrates and/or inhibitors of 
CYP3A4, have not been evaluated in clinical trials. 
Granulocyte-colony stimulating factor (G-CSF) as haematopoietic support is permitted 
for patients receiving paclitaxel. The primary prophylaxis should be administered per the 
ASCO, EORTC, and European Society for Medical Oncology (ESMO) guidelines; 
namely, in patients who have an approximately 20% or higher risk for febrile 
neutropoenia based on patient-, disease- and treatment-related factors, such as age ≥ 
65 years, previous chemotherapy or radiation therapy, preexisting neutropoenia or bone 
marrow involvement, infection, comorbidities, etc. (Smith et al. 2015; Aapro et al. 2011; 
Crawford et al. 2009). 
Consistent with the latest ASCO recommendations (Smith et al. 2015), and results of 
meta-analyses of primary G-CSFs in adults undergoing chemotherapy for a solid tumour 
or lymphoma (Pinto et al. 2007; Cooper et al. 2011; Renner et al. 2012), both 
conventional (e.g., filgrastim) and long-acting, or pegylated (e.g., pegfilgrastim) G-CSFs 
may be used for the prevention of treatment-related febrile neutropoenia. The choice of 
agent will be at the discretion of the investigator, depending on the clinical situation and 
institutional standard of care practice. 
Anti-emetics, anti-allergic measures, and other treatments for concomitant paclitaxel 
toxicities may be used at the discretion of the investigator, taking into account 
precautions from the local prescribing information for paclitaxel.  
Refer to the local prescribing information (label) for paclitaxel for all boxed warnings and 
contraindications. 
 
4.5 
STUDY ASSESSMENTS  
Please see Appendix 1 for the schedule of activities to be performed during the study. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures or evaluations.  Informed Consent Forms for 
enrolled patients and for patients who are screening failures will be maintained at the 
study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before randomisation.  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. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
78/Protocol MO39196 (IMpassion131), Version 6.0 
4.5.2 
Medical History and Demographic Data 
General medical history includes clinically significant diseases, surgeries, reproductive 
status, smoking history, use of alcohol, and drugs of abuse. TNBC history will include 
prior cancer therapies, procedures, and an assessment of tumour mutational status 
(breast cancer susceptibility gene [BRCA] mutational status, where available). In 
addition, all medications (e.g., prescription drugs, over-the-counter drugs, vaccines, 
herbal or homeopathic remedies, nutritional supplements) used by the patient within 7 
days prior to screening will be recorded. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.3 
Physical Examinations 
A complete physical examination should be performed at screening.  Any abnormality 
identified at baseline should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed. Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF. 
4.5.4 
Vital Signs  
Vital signs will include measurements of respiratory rate, pulse rate, systolic and 
diastolic blood pressures while the patient is in a seated position, and 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 3). 
4.5.5 
Tumour and Response Evaluations 
Tumour assessments will be performed at screening/baseline, approximately every 
8 weeks (±1 week) for the first 12 months after randomisation, and every 12 weeks 
thereafter (see Appendix 1) until disease progression (PD), withdrawal of consent, death, 
or study termination by the Sponsor, whichever occurs first. All sites of measurable and 
non-measurable disease must be documented at screening/baseline and re-assessed at 
each subsequent tumour evaluation.  
4.5.5.1 
Screening/Baseline Tumour Evaluations 
Tumour assessments performed as part of standard of care prior to obtaining informed 
consent and within 28 days of Cycle 1, Day 1 may be used as baseline assessments 
rather than repeating the tests.  
Radiologic imaging performed during the screening period should consist of the 
following: 
1) Initial screening assessments must include computerized tomography (CT) scans 
(with oral/IV contrast unless contraindicated) and/or magnetic resonance imaging (MRI) 
of the chest/abdomen/pelvis. A spiral CT scan of the chest may be obtained but is not a 
requirement. MRIs of the chest, abdomen, and pelvis with a non-contrast CT scan of the 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
79/Protocol MO39196 (IMpassion131), Version 6.0 
chest may be used in patients for whom CT scans with contrast are contraindicated (i.e., 
patients with contrast allergy or impaired renal clearance). If a CT scan for tumour 
assessment is performed using a positron emission tomography (PET)/CT scanner, the 
CT acquisition must be consistent with the standards for a full contrast diagnostic CT 
scan. 
2) Bone scan or PET scan should be performed to evaluate for bone metastases; 
3) 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 for CNS-related exclusion criteria); 
4) CT scans of the neck should also be performed if clinically indicated during the 
screening period; 
5) At the investigator’s discretion, other methods of assessment of measurable disease 
per RECIST v1.1 may be used. 
4.5.5.2 
On-treatment Tumour and Response Evaluations 
After randomisation, tumour assessments evaluation of tumour response per RECIST 
v1.1 (see Appendix 3) will be performed according to the schedule specified in 
Appendix 1, regardless of treatment delays, interruptions or discontinuations. 
For each patient, the same radiographic procedures and technique used to assess 
disease sites at screening must be used throughout the study (e.g., the same contrast 
protocol for CT scans and/or magnetic resonance imaging [MRI]), and results must be 
reviewed by the investigator before dosing at the next cycle. All known sites of disease 
documented at screening/baseline should be re-assessed at each subsequent tumour 
evaluation. To the extent feasible, assessments should be performed by the same 
evaluator 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 need 
to be repeated unless clinically indicated or at the treating physician’s discretion. 
Evaluation of tumour response will be completed by the investigator based on physical 
examinations, computed tomography (CT) scans, and other modalities, per RECIST v1.1 
(see Appendix 3). All primary imaging data used for tumour assessment will be collected 
by the Sponsor to enable centralised, independent review of response endpoints by an 
Independent Review Committee (IRC) (e.g., to meet potential requests by a reviewing 
Health Authority).   
If treatment is discontinued prior to disease progression per RECIST v1.1 (e.g., due to 
study treatment-related toxicity), tumour response assessment should continue to be 
performed per the schedule specified in Appendix 1. During the post-treatment follow-up 
period, only patients with no PD will undergo tumour assessments. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
80/Protocol MO39196 (IMpassion131), Version 6.0 
4.5.6 
Laboratory, Biomarker, and Other Biological Samples  
An overview of the standard safety laboratory, biomarker, and other sampling 
requirements is provided below. For additional details on laboratory assessments and 
sample handling, refer to the laboratory manual. 
4.5.6.1 
Local Laboratory Assessments 
Samples for the following laboratory tests will be sent to the study site’s local laboratory 
for analysis: 
• 
Haematology: red blood cell (RBC) count, haemoglobin, haematocrit, white blood cell 
(WBC) count with differential (neutrophils, eosinophils, lymphocytes, monocytes, 
basophils, and other cells), if clinically indicated, and platelet count.  
• 
Serum chemistry: blood urea nitrogen (BUN) or urea, creatinine, sodium, potassium, 
magnesium, chloride, bicarbonate, calcium, phosphorus, glucose, total bilirubin, 
aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase, 
total protein, and albumin. Bicarbonates should only be tested at sites where this test 
is part of the standard safety laboratory panel. 
The Cockcroft-Gault formula (see Appendix 8) will be used to calculate creatinine 
clearance. Patients must have a CrCl ≥ 30 mL/min to be eligible for enrolment. 
Levels of magnesium and phosphorus must be tested during screening. During 
treatment, levels of magnesium and phosphorus should be tested as clinically 
indicated. 
• 
Coagulation panel: activated partial thromboplastin time (aPTT) and International 
Normalized Ratio (INR); performed at screening/baseline and at treatment 
discontinuation. 
• 
Serum pregnancy test for women of childbearing potential at screening/baseline 
(within 7 days prior to initiation of study drug); after randomisation, urine pregnancy 
tests will be performed at each cycle during treatment and at treatment 
discontinuation. If a urine pregnancy test is positive, it must be confirmed by a serum 
pregnancy test. 
A woman is 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 sterilisation (removal 
of ovaries and/or uterus).  
• 
Thyroid function testing: thyroid-stimulating hormone (TSH), free T3 (or total T3 for 
sites where free T3 is not performed), free T4; performed at screening, on Day 1 of 
Cycle 1, every second cycle thereafter, and at treatment discontinuation. 
• 
Urinalysis: specific gravity, pH, glucose, protein, ketones, and blood; performed at 
screening, and thereafter only if clinically indicated. 
In addition, all patients will be tested for HIV antibody, HBsAg, hepatitis B surface 
antibody (HBsAb), total hepatitis B core antibody (HBcAb), and hepatitis C virus antibody 
(HCVAb) locally during screening. HIV-positive patients will be excluded from the clinical 
trial. In patients with a negative HBsAg and positive HBcAb serology, HBV DNA must 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
81/Protocol MO39196 (IMpassion131), Version 6.0 
also be collected prior to randomisation. Patients positive for HCVAb require a negative 
PCR for HCV RNA to confirm eligibility.  
All laboratory tests results must be available for the Investigator’s review before 
treatment administration. 
4.5.6.2 
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., 
ADA assay), exploratory biomarker profiling, identification, and PD assay development 
purposes and development and/or improvement of diagnostic tests. Instruction manuals 
and supply kits will be provided by Covance Inc. for all central laboratory assessments. 
4.5.6.2.1 
C-reactive protein 
Samples for C-reactive protein (CRP) assessment will be obtained at screening/baseline, 
and on Day 1 of each treatment cycle. 
4.5.6.2.2 
Anti-Drug Antibody Testing 
Atezolizumab may elicit an immune response. Patients with signs of any potential 
immune response to atezolizumab will be closely monitored. Serum samples collected 
from patients enrolled in the Global Study will be assayed for the presence of ADAs to 
atezolizumab using validated immunoassays at multiple timepoints before, during, and 
after study treatment (see Appendix 2 for the sampling schedule). The immunogenicity 
evaluation will utilise a risk-based immunogenicity strategy (Rosenberg and Worobec 
2004; Koren et al. 2008) to characterise ADA responses to atezolizumab in support of 
the clinical development program. This tiered strategy will include an assessment of 
whether ADA responses correlate with relevant clinical endpoints, as described in 
Section 6.8.  Implementation of ADA characterisation assays will depend on the safety 
profile and clinical immunogenicity data. 
Patients enrolled in mainland China will not undergo ADA assessments. 
4.5.6.2.3 
Pharmacokinetic Testing 
Samples for atezolizumab PK will be collected from patients enrolled in the Global Study 
at 
specific 
timepoints 
(see 
Appendix 2) 
during 
the 
first 
four 
cycles 
of 
atezolizumab/placebo and at the Treatment discontinuation visit. Serum samples will be 
assayed for atezolizumab concentrations using a validated immunoassay.  
Samples for paclitaxel PK were collected from the first approximately 60 patients 
randomised in the Global Study (approximately 30 patients in each treatment arm). No 
further sampling for paclitaxel PK will occur in the study. Plasma samples will be 
assayed for paclitaxel concentrations using validated methods. 
Patients enrolled in mainland China will not undergo atezolizumab PK and paclitaxel PK 
assessments. 

Atezolizumab—F. Hoffmann-La Roche Ltd
82/Protocol MO39196 (IMpassion131), Version 6.0
4.5.6.2.4
Auto-antibody Testing
Auto-antibody testing will include anti-double-stranded DNA (anti-dsDNA), circulating 
anti-neutrophil cytoplasmic antibody (c-ANCA), and perinuclear anti-neutrophil 
cytoplasmic antibody (p-ANCA) assays. Baseline samples will 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 
analysed centrally.
4.5.6.2.5
Biomarker Assays
Blood samples will be obtained for biomarker evaluation (including but not limited to 
biomarkers that are related to TNBC or tumour immune biology) from all eligible patients 
according to the schedule in Appendix 2. Serially collected blood samples will be 
processed to obtain plasma for the determination of changes in blood-based biomarkers.  
Whole blood samples may be processed to assess peripheral blood mononuclear cells 
(PBMCs) and their derivatives (e.g., RNA and DNA).

Atezolizumab—F. Hoffmann-La Roche Ltd
83/Protocol MO39196 (IMpassion131), Version 6.0
Table 5
Proposed Biomarkers for Exploratory Research
Sample Type 
Timing
Proposed Biomarkers
Plasma
Pre-dose at day 1 of cycles 
1, 2 and 3, thereafter every 
3 months during treatment 
and at disease progression
●Immune- or tumour-related 
proteins 
Whole blood sample for 
germline DNA analysis 
(DNA extracted from 
blood)
Baseline 
●Germline DNA as a reference for 
analysis of somatic gene 
alterations
ctDNA isolated from 
plasma
Pre-dose at day 1 of cycles 
1, 2 and 3, thereafter every 
3 months during treatment 
and at disease progression
●ctDNA
Whole blood for 
exploratory biomarker 
analysis (Peripheral blood 
mononuclear cells) [1]
Pre-dose at day 1 of cycles 
1 and 2, and at disease 
progression
●Immune cell characterisation
Tumour tissue 
(mandatory)
Within 3 months before 
randomisation into the 
study or at baseline [2]
●PD-L1 (e.g. stratification factor), 
HER2, ER, PR (e.g. retrospective 
central confirmation of TNBC)
●TILs
●Immune-related proteins such as 
CD8, CD3, FoxP3, CD68 and 
others
Tumour tissue (optional)
On-treatment biopsy pre-
dose at day 1 of Cycle 2, 
prior to steroid medication 
(or within 14 days before 
the Cycle 2, Day 1 dose) 
(optional) and at time of 
radiographic progression 
(or within ±7 days) 
(optional; preferably from a 
new or progressing lesion) 
●TILs
●Immune-related proteins, such as 
CD8, CD3, FoxP3, CD68 and PD-
L1 and others
DNA extracted from 
tumour tissue
See timepoints for tumour 
tissue collection above
●Somatic gene alterations
RNA extracted from 
tumour tissue
See timepoints for tumour 
tissue collection above
●Gene expression signatures
ctDNA: circulating tumour deoxyribonucleic acid; DNA: deoxyribonucleic acid; FoxP3: Forkhead 
Box P3 protein (scurfin); PD-L1: programmed death ligand 1; RNA: ribonucleic acid; TILs: 
tumour-infiltrating-lymphocytes; TNBC: triple-negative breast cancer
[1] Whole blood samples for PBMC analysis have been collected from over 300 patients at 
baseline; for these patients, sample collection will continue as described in Appendix 2 (on 
Cycle 2, Day 1 and at PD). However, for newly enrolled patients, there will be no whole blood 
sampling for PBMC analysis at any time-point.
[2] If a tumour sample taken within 3 months before randomisation is not available and a tumour 
biopsy is not clinically feasible, the primary surgical resection sample or the most recent FFPE 
tumour biopsy sample may be used. Of these additional options, the most recent sample should 
be used.

Atezolizumab—F. Hoffmann-La Roche Ltd
84/Protocol MO39196 (IMpassion131), Version 6.0
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
4.5.6.2.6
Collection of Tumour Tissue Samples
Tumour tissue samples will be collected prior to randomisation for eligibility (mandatory), 
as well as on-treatment and at tumour progression (optional).
Paired tumour tissue biopsies are sought to be collected close to the time of treatment 
start (mandatory specimen obtained from relapsed metastatic or locally advanced 
tumour or, if clinically not feasible, from primary surgical resection sample or the most 
recent FFPE tumour biopsy sample or the most recent FFPE tumour biopsy sample) and 
on-treatment (optional sample; collected pre-dose on Cycle 2, Day 1, prior to steroid 
medication, or within 14 days before the Cycle 2, Day 1 dose) to assess changes in the 
immune tumour-microenvironment by exploratory immune-related biomarker analysis. 
Representative formalin-fixed paraffin-embedded (FFPE) tumour specimen blocks 
(preferred) or at least 17 unstained slides, with an associated pathology report, must be 
submitted for centralised determination of PD-L1 status prior to study enrolment, and 
retrospective confirmation of TNBC by HER2, ER and PR staining. If a tumour sample 
taken within 3 months before randomisation is not available and a tumour biopsy is not 
clinically feasible, the primary surgical resection sample or the most recent FFPE tumour 
biopsy sample may be used. Of these additional options, the most recent sample should 
be used. Acceptable tumour sample collection methods include core needle biopsies for 
deep tumour tissue (more than one core if clinically feasible), or excisional, incisional, 
punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions. Fine 
needle aspiration, brushing, cell pellet from pleural effusion, and lavage samples are not 
acceptable. Tumour tissue from bone metastases is not evaluable for PD-L1 expression 
and is therefore not acceptable. The tumour tissue should be of good quality based on 
total and viable tumour content.  
A diagnostic antihuman PD-L1 monoclonal antibody (VENTANA SP142) will be used to 
stain prospectively for PD-L1 expression on formalin-fixed paraffin-embedded tumour 
tissue by immunohistochemistry (IHC), as described in published literature (Herbst et al. 
2014; Powles et al. 2014). PD-L1 expression on tumour-infiltrating immune cells (IC) will 
be scored as IC0, 1, 2, or 3 if less than 1%, 1% to less than 5%, 5% to less than 10%, or 
10% or greater, respectively IC tumour area stain positive for PD-L1. All types of ICs, 
including macrophages, dendritic cells, and lymphocytes, will be counted together.
Patients will be stratified according to PD-L1 status (PD-L1 IC0 versus PD-L1 IC1/2/3).
Patients whose tumour tissue is not evaluable for prospective central testing are not 
eligible. If multiple tumour specimens are submitted, patients may be eligible if at least 
one specimen is evaluable for PD-L1 staining.
In the cadre of the exploratory biomarker objective, the status of immune-mediated and 
tumour type-related, and other exploratory biomarkers (including but not limited to 
immune cell markers, gene alterations and gene expression) in pre-treatment, on-
treatment and progressive disease tumour tissue samples of enrolled patients may be 
evaluated.

Atezolizumab—F. Hoffmann-La Roche Ltd
85/Protocol MO39196 (IMpassion131), Version 6.0
Tissue samples from patients who are not eligible to enrol into the study will be returned 
no later than 6 weeks after eligibility determination.
For patients who agree to provide optional tumour tissue samples for biopsy by signing 
the separate Consent for Optional Biopsies form, additional tumour samples may be 
collected prior to dosing on Cycle 2, Day 1 as per the investigator’s discretion. An 
optional tumour biopsy may also be collected (if clinically feasible and permitted by local 
guidelines and regulations; preferably from a new or progressing lesion) from consenting 
patients at first evidence of radiographic disease progression per RECIST v1.1. DNA 
and RNA sequencing will be performed on these specimens. Acceptable tumour sample 
collection methods for optional samples are identical to those for mandatory tumour 
biopsies at screening.
4.5.6.3
Use and Storage of Remaining Samples from Other Procedures
4.5.6.3.1
Remaining Samples from Study Procedures
Any remainder blood and tissue 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 RBR for 
future research (see Section 4.5.9), the samples will be stored until no longer needed or 
used up.
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analysed, unless the patient specifically requests that the 
samples be destroyed, or local laws require destruction of the samples.
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4.
4.5.6.3.2
Remaining Samples from Non-Study Procedures
If a patient undergoes a medically indicated procedure (e.g., bronchoscopy, 
esophagogastroduodenoscopy, colonoscopy, etc.) any time during the study that has the 
likelihood of yielding tumour tissue, any remaining samples or a portion of the sample 
not necessary for medical diagnosis (body fluid samples or leftover tumour tissue) may 
be used for exploratory analysis in the study. Patients must provide specific consent in 
order to obtain discarded samples from routine care.
4.5.7
Electrocardiograms
A 12-lead ECG recording will be obtained at screening, and may be obtained at 
unscheduled time-points during study treatment, as clinically indicated; see Appendix 1.  
ECGs should be performed prior to other procedures scheduled at that same time (e.g., 
blood draws). ECG recordings must be obtained 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.

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
86/Protocol MO39196 (IMpassion131), Version 6.0 
4.5.8 
Patient-Reported Outcomes 
PROs of global health status, function, and disease/treatment related symptoms will be 
assessed using the EORTC QLQ-C30, QLQ-BR23, EQ-5D-5L, and Functional 
Assessment of Cancer Therapy – General (FACT-G) questionnaires, to characterise the 
clinical profile of atezolizumab plus paclitaxel compared to placebo plus paclitaxel. A 
copy of the PRO instruments is provided in 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; Osoba et al. 1998). 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 (dyspnoea, insomnia, appetite loss, 
constipation, diarrhoea, 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).  
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. 
The EuroQol 5-Dimension Questionnaire, 5-level version (EQ-5D-5L), is a validated, 
generic, preference-based self-report health status questionnaire that consists of six 
questions used to calculate a health utility score for use in health economic analysis 
(EuroQol Group, 1990; Brooks 1996; Herdman et al. 2011; Janssen et al. 2013).  There 
are two components to the EuroQol EQ-5D: a health state profile that contains five 
dimensions of health:  mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression (Herdman et al. 2011; Janssen et al. 2013), and a visual analogue 
scale (VAS) that 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”). Published weighting 
systems allow for creation of a single summary score. Overall scores range from 0 to 1, 
with low scores representing a higher level of dysfunction. The EQ-5D will be utilised in 
this study for economic modelling. 
The Functional Assessment of Cancer Therapy – General (FACT-G) is a validated, 27-
item, general quality of life instrument comprised of four domains (physical, social/family, 
emotional, and functional well-being) (Cella et al. 1993). Each item is scored on a five-
point scale from 0 (not at all) to 4 (very much). In this study, the burden of treatment 
associated with the addition of atezolizumab to paclitaxel will be measured by the GP5 
item ("I am bothered by side effects of treatment") from the physical wellbeing subscale 
of the FACT-G instrument. Since item GP5 specifically assesses patients being bothered 
by the side-effects of treatment, this item will not be administered to patients at baseline. 
The PRO instruments (EORTC QLQ-C30, QLQ-BR23, EQ-5D-5L and VAS, and FACT-
G) will be completed by the patient on an electronic PRO (ePRO) device at baseline 
(Cycle 1, Day 1), on Day 1 of each subsequent cycle, and at the treatment 
discontinuation visit (30 ± 5 days after the last dose of study drug). In addition, all 
patients will be asked to complete the PRO questionnaires every 3 months for 1 year 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
87/Protocol MO39196 (IMpassion131), Version 6.0 
after treatment discontinuation, regardless of whether the patient is receiving 
subsequent anti-cancer therapy. To ensure instrument validity and that data standards 
meet health authority requirements, PRO questionnaires must be completed by the 
patient on the day of the clinic visit either at their home or at the site at the start of the 
visit, and 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 the ePRO device and ensure that all measures have been completed and 
saved before the patient leaves the investigational site. 
The electronic device will be provided by the sponsor together with instructions for 
completing the questionnaires electronically, which patients will be trained on by the 
investigator staff. The data will be transmitted to a centralised database maintained by 
the electronic device vendor. The data will be available for access by appropriate study 
personnel. 
4.5.9 
Optional Samples for Research Biosample Repository 
4.5.9.1 
Overview of the Research Biosample Repository 
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides). The collection, 
storage, and analysis of RBR specimens will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualised drug therapy for patients in the future. 
Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research. RBR specimens will be used to achieve the 
following objectives: 
• 
To study the association of biomarkers with efficacy, or disease progression 
• 
To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation. 
• 
To increase knowledge and understanding of disease biology 
• 
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. 
4.5.9.2 
Approval by the Institutional Review Board or Ethics Committee 
Collection and submission of biological samples to the RBR is contingent upon the 
review and approval of the exploratory research and the RBR portion of the Informed 
Consent Form by each site's Institutional Review Board or Ethics Committee (IRB/EC) 
and, if applicable, an appropriate regulatory body. If a site has not been granted 
approval for RBR sampling, this section of the protocol (Section 4.5.9) will not be 
applicable at that site. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
88/Protocol MO39196 (IMpassion131), Version 6.0 
4.5.9.3 
Sample Collection 
The following samples will be stored optionally in the RBR and used for research 
purposes, including, but not limited to, research on biomarkers related to atezolizumab 
and locally advanced or metastatic TNBC: leftover FFPE tissue and plasma, whole blood 
samples and derivatives thereof (e.g. RNA, DNA). 
Samples may be sent to one or more laboratories to enable analysis of germline 
mutations, somatic mutations via whole genome sequencing (WGS), next-generation 
sequencing (NGS), or other genomic analysis methods, such as RNA expression 
analysis.  
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS provides a comprehensive characterisation of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches. Data will be analysed in the context of this study but will also be explored in 
aggregate with data from other studies. The availability of a larger dataset will assist in 
identification of important pathways, guiding the development of new targeted agents. 
For sampling procedures, storage conditions, and shipment instructions, refer to the 
Laboratory manual.  
RBR specimens are to be stored until they are no longer needed or until they are 
exhausted. However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
4.5.9.4 
Confidentiality 
Specimens and associated data will be labelled with a unique patient identification 
number. 
Patient medical information associated with RBR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorisation for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Given the complexity and exploratory nature of the analyses, data derived from RBR 
specimens will generally not be provided to study investigators or patients unless 
required by law. The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication. 
Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
4.5.9.5 
Consent to Participate in the Research Biosample Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR. The investigator or authorised designee will explain to each patient the 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
89/Protocol MO39196 (IMpassion131), Version 6.0 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their 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 RBR specimens.  
Patients who decline to participate will not provide a separate signature. 
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF. 
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research. 
4.5.9.6 
Withdrawal from the Research Biosample Repository 
Patients who give consent to provide RBR specimens have the right to withdraw their 
specimens from the RBR 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 through use of the appropriate RBR Subject 
Withdrawal Form and, if the trial is ongoing, must enter the date of withdrawal on the 
RBR Research Sample Withdrawal of Informed Consent eCRF.  
If a patient wishes to withdraw consent to the testing of his or her RBR samples after 
closure of the site, the investigator must inform the Sponsor by emailing the study 
number and patient number to the following email address: 
global_rcr-withdrawal@roche.com 
The patient will be provided with instructions on how to withdraw consent after the trial is 
closed. A patient's withdrawal from Study MO39196 does not, by itself, constitute 
withdrawal of specimens from the RBR. Likewise, a patient's withdrawal from the RBR 
does not constitute withdrawal from Study MO39196. 
4.5.9.7 
Monitoring and Oversight 
RBR 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 authorised use of specimens as specified in this protocol and in the 
Informed Consent Form. Sponsor monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RBR for the purposes 
of verifying the data provided to the Sponsor. The site will permit monitoring, audits, 
IRB/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RBR samples. 
4.5.10 
Patient Engagement Application 
The Patient Engagement Application, a smartphone app, is an optional service that 
subjects can opt-in to use in the MO39196 study. The App supports study activities like 
when to take medication and attend site visits, helping patient compliance. It also 
provides study specific information on procedures, and can help patients track their own 
goals too. Available for both iOS and Android devices, the study coordinator will guide 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
90/Protocol MO39196 (IMpassion131), Version 6.0 
interested participants on using this supporting technology. Additional details are found 
in Appendix 10. 
 
4.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Withdrawal 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following: 
• 
Patient withdrawal of consent at any time 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
• 
Patient non-compliance. 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced. 
4.6.2 
Study Drug Discontinuation 
Patients must discontinue the study drug if they experience any of the following: 
• 
Intolerable toxicity related to the study drug, including development of an 
immune-mediated adverse event determined by the investigator to be unacceptable 
given the individual patient's potential response to therapy and severity of the event 
• 
Any medical condition that may jeopardize the patient’s safety if he or she continues 
receiving study drug 
• 
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. Patients who discontinue study treatment prematurely will not be 
replaced. 
4.6.3 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time. Reasons for terminating 
the study may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
• 
Patient enrolment is unsatisfactory. 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
91/Protocol MO39196 (IMpassion131), Version 6.0 
The Sponsor has the right to close a site at any time. Reasons for closing a site may 
include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice 
• 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled). 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
5.1.1 
General Plan to Manage Safety Concerns 
Atezolizumab (TECENTRIQTM) obtained accelerated approval in the USA in May 2016, 
for the treatment of patients with locally advanced or metastatic urothelial carcinoma 
who have disease progression (1) during or following platinum-containing chemotherapy 
and/or (2) within 12 months of neoadjuvant or adjuvant treatment with platinum-
containing chemotherapy. In October 2016, atezolizumab was approved in the USA for 
the treatment of patients with metastatic NSCLC whose disease progressed during or 
following platinum-containing chemotherapy. Approval for the same indications was 
subsequently obtained in Europe. Based on results of the primary analysis of the 
IMpassion130 (WO29522) study (Schmid et al. 2018), atezolizumab in combination with 
nab-paclitaxel received accelerated approval by the US FDA in March 2019 for the 
treatment of adult patients with unresectable locally advanced or metastatic TNBC 
whose tumours express PD-L1. The clinical development of atezolizumab in other 
advanced or metastatic cancer types is ongoing.   
The safety plan for patients in this study is based on clinical experience with 
atezolizumab in completed and ongoing studies. The anticipated important safety risks 
for atezolizumab are outlined in Section 5.1.2 below. Please refer to the atezolizumab 
Investigator's Brochure for a complete summary of safety information.  
Several measures will be taken to ensure the safety of patients participating in this study.  
These include stringent eligibility criteria (see Sections 4.1.1 and 4.1.2), designed to 
exclude patients at higher risk for toxicities, administration of the study drug in a 
controlled setting, and close safety monitoring of patients during the study (see Section 
4.5), including assessment of the nature, frequency, and severity of adverse events (see 
Section 5.3.3). 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.   
General safety assessments will consist of monitoring and recording adverse events, 
including serious adverse events and adverse events of special interest, performing 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
92/Protocol MO39196 (IMpassion131), Version 6.0 
protocol specified physical examinations, ECGs and safety laboratory assessments 
(including serum chemistries and blood counts), measuring protocol-specified vital signs, 
and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study; see Appendix 1 for the list and timing of study assessments. 
Laboratory values must be reviewed prior to each infusion. During the study, patients will 
be closely monitored for the development of any adverse events, including signs or 
symptoms of autoimmune conditions and infection. 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 atezolizumab/placebo or until initiation of new systemic anti-cancer 
therapy, whichever occurs first. Serious adverse events and adverse events of special 
interest will continue to be reported until 90 days after the last dose of 
atezolizumab/placebo or until initiation of new systemic 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; refer to Section 5.3.1 for further details. Adverse events will be defined and 
graded according to National Cancer Institute Common Terminology Criteria for Adverse 
Events Version 4.0 (NCI CTCAE v4.0). 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, respectively). 
Guidelines for management of specific adverse events and for atezolizumab/placebo 
dosing interruption or discontinuation are provided in Sections 5.1.4 and 5.1.5.3.1, 
respectively. Guidelines for paclitaxel dosage modification and treatment interruption or 
discontinuation due to toxicity are provided in Section 5.1.4.2.2. In addition, an iDMC has 
also been incorporated into the study design to periodically review aggregate safety data 
(for further details, refer to Section 3.1.2 and the iDMC Charter).  
This is a double-blind study. Emergency unblinding by the investigator should be 
performed only in cases when knowledge of treatment assignment will affect the 
management of a patient who experiences a treatment emergent adverse event; refer to 
Section 4.2.1 for details.  
The potential safety issues anticipated in this study, as well as measures intended to 
avoid or minimise such toxicities, are outlined in the following sections. 
5.1.2 
Risks Associated with Atezolizumab 
The PD-L1/PD-1 pathway is involved in peripheral tolerance; therefore, such therapy 
may increase the risk of immune-mediated adverse events, specifically the induction or 
enhancement of autoimmune conditions. The risks associated with atezolizumab include 
infusion-related reactions (IRRs) and immune-mediated hepatitis, pneumonitis, colitis, 
pancreatitis, diabetes mellitus, hypothyroidism, hyperthyroidism, adrenal insufficiency, 
Guillain-Barré syndrome, hypophysitis, myasthenic syndrome/myasthenia gravis, 
meningoencephalitis, myocarditis, nephritis, and myositis; refer to Section 5.2.3. 
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). Additional details regarding 
clinical safety are provided in the atezolizumab Investigator’s Brochure. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
93/Protocol MO39196 (IMpassion131), Version 6.0 
Although most immune-mediated adverse events observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognised early and 
treated promptly to avoid potential major complications (Di Giacomo et al. 2010). 
Suggested workup and management of procedures for suspected immune-mediated 
adverse events are provided in Section 6 (Guidance for the Investigator) of the 
Atezolizumab Investigator’s Brochure. 
5.1.3 
Risks Associated with Paclitaxel 
Anaphylaxis and severe hypersensitivity reactions characterised by dyspnoea and 
hypotension requiring treatment, angioedema, and generalised urticaria have occurred 
in 2 to 4% of patients receiving paclitaxel in clinical trials. Fatal reactions have occurred 
in patients despite premedication. Therefore, study patients may be premedicated 
according to local paclitaxel prescribing information and institutional standard of care 
practice. Such premedication may consist of a corticosteroid (dexamethasone 8 - 10 mg 
PO administered approximately 12 and 6 hours before paclitaxel), diphenhydramine (or 
its equivalent) 50 mg IV 30 to 60 minutes prior to paclitaxel, and a H2 antagonist 
(cimetidine 300 mg or ranitidine 50 mg IV 30 to 60 minutes before paclitaxel). Patients 
who experience severe hypersensitivity reactions to paclitaxel despite premedication 
must not be rechallenged with the drug. 
Warnings related to paclitaxel use include bone marrow suppression (primarily 
neutropoenia), which is dose-dependent and is the dose-limiting toxicity during paclitaxel 
treatment, with neutrophil nadirs occurring at a median of 11 days. Infectious episodes 
occurred in 30% of all patients exposed to paclitaxel in clinical trials; these episodes 
were fatal in 1% of all patients, and included sepsis, pneumonia and peritonitis. The use 
of supportive therapy, including G-CSF, is recommended for patients who have 
experienced severe neutropoenia. Thrombocytopenia (platelet count below 100,000 
cells/mm3 at least once while on treatment) was reported in 20% of the patients, with 
bleeding episodes in 14% of all patients receiving paclitaxel in clinical trials. Anaemia 
(haemoglobin <11 g/dL) was observed in 78% of all patients and was severe 
(haemoglobin <8 g/dL) in 16% of the cases, with no consistent relationship between 
dose or schedule and the frequency of anaemia. 
Other warnings for paclitaxel use include severe cardiac conduction abnormalities 
(documented in <1% of patients), which required pacemaker placement in some cases. 
In addition, paclitaxel can cause foetal harm when administered to a pregnant woman. 
Hypotension, bradycardia, and hypertension have been observed during administration 
of paclitaxel (in 12%, 3%, and 1% of patients, respectively), but generally do not require 
treatment. Occasionally paclitaxel infusions must be interrupted or discontinued because 
of initial or recurrent hypertension. Other significant cardiovascular events possibly 
related to single-agent paclitaxel occurred in approximately 1% of all patients, and 
included syncope, rhythm abnormalities, and venous thrombosis. 
Paclitaxel treatment is frequently associated with peripheral neuropathy; however, the 
development of severe symptomatology is unusual and requires a dose reduction of 
20% for all subsequent courses of the drug. Other serious neurologic events following 
paclitaxel administration have been rare (<1%) and have included grand mal seizures, 
syncope, ataxia, and neuroencephalopathy. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
94/Protocol MO39196 (IMpassion131), Version 6.0 
Injection site reactions, including reactions secondary to extravasation, were usually mild 
and consisted of erythema, tenderness, skin discoloration, or swelling at the injection 
site; more severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, 
and fibrosis have also been reported, with onset during or up to 10 days after paclitaxel 
infusions. 
Caution should be exercised when paclitaxel is concomitantly administered with known 
substrates, inhibitors, and inducers of CYP3A4 or CYP2C8; refer to Section 4.4.3. 
For more details regarding the safety profile of paclitaxel, refer to the local paclitaxel 
prescribing information.   
Patients will be monitored for paclitaxel-related adverse events throughout the study.  
5.1.4 
Management of Patients Who Experience Specific Adverse 
Events 
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic aetiology. 
Although most immune-mediated adverse events observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognised 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. 
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 
Appendix 11 of the protocol, and the current atezolizumab Investigator’s Brochure. 
5.1.4.1 
Pulmonary events/Pneumonitis  
5.1.4.1.1 
Atezolizumab 
Management guidelines for pulmonary events are provided in the current atezolizumab 
Investigator’s Brochure and in Appendix 11. 
5.1.4.1.2 
Paclitaxel 
Pneumonia, interstitial pneumonia, pleural effusion, lung fibrosis, pulmonary embolism, 
and respiratory failure are rare adverse effects, occurring in ≥1/10,000 and <1/1,000 of 
patients, and dyspnoea is a common adverse effect, occurring in ≥1/100 and <1/10 of 
patients treated with paclitaxel. Paclitaxel, particularly in combination with radiation of 
the lung, irrespective of their chronological order, may contribute to the development of 
interstitial or radiation pneumonitis. Fatal cases of pneumonia have also been reported. 
Paclitaxel should be permanently discontinued upon ruling out infectious aetiology (using 
routine microbiological and/or immunologic methods) and making a diagnosis of 
pneumonitis. After infectious aetiology is ruled out, IV high-dose corticosteroid therapy 
should be instituted without delay, with appropriate premedication and secondary 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
95/Protocol MO39196 (IMpassion131), Version 6.0 
pathogen coverage.  Patients with an added immunological component may also require 
immune modulation with azathioprine or cyclophosphamide. 
Refer to the local paclitaxel prescribing information for further details. 
5.1.4.2 
Infusion-Related Reactions  
5.1.4.2.1 
Atezolizumab 
No premedication is indicated for the administration of atezolizumab in Cycle 1.  
However, patients who experience an infusion-related reaction with atezolizumab in 
Cycle 1 may receive premedication with antihistamines or antipyretics/analgesics (e.g., 
acetaminophen) for subsequent infusions. 
Guidelines for medical management of infusion-related reactions or cytokine-release 
syndrome are provided in Table 15 and Appendix 11.  
5.1.4.2.2 
Paclitaxel 
Paclitaxel infusion should be discontinued immediately in case of severe hypersensitivity 
reactions, such as hypotension requiring treatment, dyspnoea requiring bronchodilators, 
angioedema, or generalised urticaria; these events should be treated with aggressive 
symptomatic therapy; refer to Section 5.1.5.2.2. 
5.1.5 
Dose Modifications and Interruptions due to Adverse Events 
5.1.5.1 
General Considerations 
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.  
When several toxicities with different grades of severity occur at the same time, the dose 
interruptions or 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 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 paclitaxel, the treatment cycles will be restarted such that the 
atezolizumab/placebo and paclitaxel infusions remain synchronised. 
If it is anticipated that paclitaxel will be delayed by ≥2 weeks, then atezolizumab/placebo 
should be given without the chemotherapy, as long as there is no contraindication. 
In general, the start of a cycle may be delayed to allow recovery from toxicities, but there 
should be no delays within cycles. Cycle length is fixed at 28 days, and dosing on Days 
8 and 15 of a cycle may be skipped but should not be delayed outside of the +3 days 
window.  
The treating physician may use discretion in accelerating the dose modification 
guidelines described below depending on the severity of toxicity and an assessment of 
the risk versus benefit for the patient. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
96/Protocol MO39196 (IMpassion131), Version 6.0 
5.1.5.2 
Events requiring Permanent Treatment Discontinuation  
5.1.5.2.1 
Atezolizumab/Placebo  
Atezolizumab/placebo should be discontinued in case of the following events: 
• 
Recurrent pneumonitis (any grade), Grade 2 pulmonary event that has not resolved 
to Grade ≤1 within 12 weeks, recurrent Grade 2 pulmonary event, or any Grade 3 or 
4 pulmonary event; 
• 
Grade 2 hepatic event that has not resolved to Grade ≤1 within 12 weeks, or any 
Grade 3 or 4 hepatic event; 
• 
Grade 2 or 3 diarrhoea or colitis that has not resolved to Grade ≤1 within 12 weeks, 
or any Grade 4 diarrhoea or colitis; 
• 
Life-threatening immune-mediated hyperthyroidism; 
• 
Grade 2 to 4 symptomatic adrenal insufficiency that has not resolved to Grade ≤1 or 
patient is not stable on replacement therapy within 12 weeks; 
• 
Grade 2 ocular event that has not resolved to Grade ≤1 within 12 weeks, or any 
Grade 3 or 4 ocular event; 
• 
Grade 3 dermatologic event that has not resolved to Grade ≤1 within 12 weeks, or 
any Grade 4 dermatologic event; 
• 
Any Grade 3 or 4 infusion-related reaction; 
• 
Immune-mediated meningoencephalitis (any grade); 
• 
Grade 3 or 4 amylase and/or lipase elevation or Grade 2 or 3 immune-mediated 
pancreatitis that has not resolved to Grade ≤1 within 12 weeks; or Grade 4 immune-
mediated pancreatitis; 
• 
Grade 2 immune-mediated neuropathy that has not resolved to Grade ≤1 within 12 
weeks; any Grade 3 or 4 immune-mediated neuropathy; myasthenia gravis or 
Guillain-Barre syndrome (any grade); 
• 
Grade 2 myocarditis that has not resolved to Grade ≤1 within 12 weeks, or any 
Grade 3 or 4 myocarditis; 
• 
Grade 2 or 3 hypophysitis that has not resolved to Grade ≤1 within 12 weeks, 
recurrent or any Grade 4 hypophysitis; 
• 
Grade 2 renal event/nephritis that has not resolved to Grade ≤1 within 12 weeks, or 
any Grade 3 or 4 renal event/nephritis; 
• 
Grade 2 or 3 immune-mediated myositis that has not resolved to Grade ≤1 within 
12 weeks, recurrent Grade 3 myositis. 
In all the above listed cases, resumption of atezolizumab may be considered for patients 
who are deriving benefit and have fully recovered from the immune-mediated event. 
Patients can be rechallenged with atezolizumab only after approval has been 
documented by both the investigator (or an appropriate delegate) and the Medical 
Monitor. In case of patients receiving steroids for management of immune-mediated 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
97/Protocol MO39196 (IMpassion131), Version 6.0 
adverse events, atezolizumab may be withheld for a period of time beyond 12 weeks to 
allow for corticosteroids to be reduced/tapered 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. For further details, including complete 
management guidelines for the above listed immune-mediated events, refer to the 
current atezolizumab Investigator’s Brochure and Appendix 11. 
5.1.5.2.2 
Paclitaxel  
Paclitaxel infusion should be discontinued immediately in case of severe hypersensitivity 
reactions, such as hypotension requiring treatment, dyspnoea requiring bronchodilators, 
angioedema, or generalised urticaria; these events should be treated with aggressive 
symptomatic therapy. Patients who have developed severe hypersensitivity reactions 
should not be rechallenged with paclitaxel. 
In addition, paclitaxel should be permanently discontinued upon ruling out infectious 
aetiology (using routine microbiological and/or immunologic methods) and making a 
diagnosis of pneumonitis. Consideration may be given to performing pulse oximetry and 
pulmonary function tests to confirm respiratory and ventilation compromise in patients 
with suspected pneumonitis. 
Other events that required discontinuation of paclitaxel in clinical trials include cases of 
severe neurotoxicity, such as peripheral neuropathies (1% of all patients). Occasionally 
paclitaxel infusions must be interrupted or discontinued because of initial or recurrent 
hypertension. Frequent vital sign monitoring, particularly during the first hour of paclitaxel 
infusion, is recommended. 
Refer to the local paclitaxel prescribing information for further details. 
5.1.5.3 
Dose Modifications and Interruptions 
5.1.5.3.1 
Atezolizumab/Placebo  
Dose reduction of atezolizumab/placebo is not permitted in this study.   
Atezolizumab/placebo infusions may be temporarily suspended in case of an adverse 
event that requires a dose to be held. If atezolizumab/placebo is held because of 
adverse events for >12 weeks beyond the last dose, then the patient will be discontinued 
from atezolizumab/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 of >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/placebo may be held for up to 12 weeks until steroids are discontinued or 
reduced to prednisone dose (or dose equivalent) of ≤10 mg/day. The acceptable length 
of interruption will depend on agreement between the investigator and the Medical 
Monitor. 
Dose interruptions for reason(s) other than adverse events, such as surgical procedures, 
may be allowed with Medical Monitor approval.  The acceptable length of interruption will 
depend on agreement between the investigator and the Medical Monitor. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
98/Protocol MO39196 (IMpassion131), Version 6.0 
5.1.5.3.2 
Paclitaxel  
Haematologic Toxicities 
Absolute neutrophil count (ANC) must be ≥1500/µL (≥1500 cells/mm3) and platelet count 
must be ≥100,000/µL (≥100,000 cells/mm3) for the patient to receive paclitaxel on any 
treatment day (Day 1, 8, 15 of any 28-day cycle).  
Dose modifications should be made according to the following table: 
ANC 
 
Platelets 
Paclitaxel dose 
≥1,500/µL  
(≥1,500 cells/mm3) 
and 
≥100,000/µL  
(≥100,000 cells/mm3) 
90 mg/m2 
1,000-1,499/µL  
(1,000-1,499 cells/mm3) 
or 
75,000-99,999/µL  
(75,000-99,999 cells/mm3) 
65 mg/m2 
<1,000/µL  
(<1,000 cells/mm3) 
or 
<75,000/µL  
(<75,000 cells/mm3) 
Hold [1] 
[1] If treatment is held, the CBC should be repeated until ANC ≥1500/µL (≥1500 cells/mm3) and 
platelets ≥100,000/µL (≥100,000 cells/mm3). If paclitaxel therapy must be held for > 3 weeks to 
allow for resolution of haematologic toxicity, the patient will discontinue paclitaxel treatment but 
may continue receiving atezolizumab/placebo. 
For any patient experiencing any of the following haematologic toxicities, the paclitaxel 
dose should be reduced to 65 mg/m² for all subsequent cycles: 
• 
Fever (>38.5°C) associated with ANC <1,000/µL (<1,000 cells/mm3) 
• 
Absolute granulocyte count <500/µL (<500 cells/mm3) for > 5 days 
• 
Significant bleeding associated with a platelet count <40,000/µL (<40,000 cells/mm3) 
• 
Any platelet count <20,000/µL (<20,000 cells/mm3). 
If these severe haematologic toxicities recur in subsequent cycles despite dose 
reduction, paclitaxel should be discontinued, however the patient may continue receiving 
atezolizumab/placebo. 
If the start of a cycle is delayed (i.e. both atezolizumab/placebo and paclitaxel are held) 
for low counts, Day 1 will be postponed, and dosing resumed when ANC recovers to 
≥1500/µl (≥1500 cells/mm3) and platelet count returns to ≥100,000/µl (≥100,000 
cells/mm3).  
In certain situations, (see Section 5.1.5.1) a cycle may begin with the administration of 
atezolizumab/placebo alone (without paclitaxel on Day 1). If paclitaxel cannot be 
administered on Day 8 of the cycle, it may be administered on Day 15 if counts have 
recovered to permissible levels. If paclitaxel cannot be administered on Day 15 of the 
cycle, the next dose of paclitaxel should be administered on Day 1 of the following cycle 
when ANC and platelets counts have recovered to permissible levels.  

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
99/Protocol MO39196 (IMpassion131), Version 6.0 
Hepatic Toxicities 
In case of hepatic toxicities, dose modifications should be made according to the 
following table: 
AST 
 
Bilirubin 
Paclitaxel dose 
≤ 5 x ULN 
And 
≤ 1.5 mg/dL (≤ 25.65 μmol/L) 
90 mg/m2 
> 5 but ≤ 10 x ULN 
Or 
1.6 - 2.5 mg/dL (27.36 - 42.75 μmol/L) 
65 mg/m2 
> 10 x ULN 
Or 
≥ 2.6 mg/dL (≥ 44.46 μmol/L) 
Hold [1] 
AST: aspartate aminotransferase; ULN: upper limit of normal 
[1] Hold therapy until AST < 10 x ULN and bilirubin < 2.5 mg/dL. If paclitaxel must be held for > 3 
weeks to allow for resolution of hepatic toxicity, the patient will discontinue paclitaxel treatment 
but may continue receiving atezolizumab/placebo.  
Patients requiring a delay in paclitaxel therapy due to hepatic toxicity should be 
evaluated for possible progressive hepatic metastases. 
Peripheral Neuropathy 
If grade 3 toxicity develops, paclitaxel treatment should be withheld until the neuropathy 
recovers to < grade 1 (atezolizumab/placebo treatment should continue as scheduled), 
unless the neuropathy is thought to be immune mediated [refer to Appendix 11, Table 
18, Management Guidelines for Neurologic Disorders]). When treatment is resumed, the 
paclitaxel dose should be reduced permanently to 65 mg/m². If grade 3 neuropathy 
persists for > 3 weeks or recurs after dose reduction, the patient will discontinue 
paclitaxel treatment but may continue receiving atezolizumab/placebo.  
Gastrointestinal Toxicity 
Nausea and/or vomiting should be controlled with standard antiemetics and will not 
result in dose modification. 
Anaphylaxis/Hypersensitivity 
• 
Mild symptoms (e.g., mild flushing, rash pruritus): No treatment needed. Supervise at 
bedside and complete paclitaxel infusion. 
• 
Moderate symptoms (moderate flushing, rash, mild dyspnoea, chest discomfort): 
Stop paclitaxel infusion. Administer diphenhydramine 25 mg (or equivalent) and 
dexamethasone 10 mg IV (or equivalent). After recovery of symptoms, resume 
infusion at half the previous rate for 15 minutes. If no further symptoms occur, 
complete the infusion at the full dose rate. If symptoms recur, the reaction should be 
reported as an adverse event and the patient will discontinue paclitaxel treatment but 
may continue atezolizumab/placebo. 
• 
Severe life-threatening symptoms (e.g., hypotension requiring pressor therapy, 
angioedema, respiratory distress requiring bronchodilators, generalised urticaria): 
Stop the infusion and administer diphenhydramine 25 mg (or equivalent) and 
dexamethasone 10 mg IV (or equivalent). Add epinephrine or bronchodilators if 
needed. The reaction should be reported as an adverse event and the patient will 
discontinue paclitaxel treatment but may continue atezolizumab/placebo. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
100/Protocol MO39196 (IMpassion131), Version 6.0 
Gastrointestinal Toxicity 
If the patient develops any other grade 3 or 4 toxicity considered related to paclitaxel, 
paclitaxel 
should 
be 
held 
until 
symptoms 
resolve 
to 
grade 
1 
or 
less 
(atezolizumab/placebo treatment should continue as scheduled). When treatment is 
resumed, the paclitaxel dose should be reduced permanently to 65 mg/m². If grade 3 
toxicity persists for >3 weeks or recurs after dose reduction, the patient will discontinue 
paclitaxel treatment but may continue atezolizumab/placebo. 
Refer to the local paclitaxel prescribing information for further details. 
 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution. An adverse event can therefore 
be any of the following: 
• 
Any unfavourable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product; 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.9; 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline; 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug; 
• 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies). 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
101/Protocol MO39196 (IMpassion131), Version 6.0 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Is fatal (i.e., the adverse event actually causes or leads to death); 
• 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death); 
Note: 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 hospitalisation (see Section 5.3.5.10); 
• 
Results in persistent or significant disability/incapacity (i.e., the adverse event results 
in substantial disruption of the patient’s ability to conduct normal life functions); 
• 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug; 
• 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above). 
 
The terms "severe" and "serious" are not synonymous. Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE 
v4.0; 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 
• 
Colitis 
• 
Endocrinopathies: 
diabetes 
mellitus, 
pancreatitis, 
adrenal 
insufficiency, 
hypothyroidism, hyperthyroidism, and hypophysitis 
• 
Hepatitis, including AST or ALT >10 x ULN 
• 
Systemic lupus erythematosus 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
102/Protocol MO39196 (IMpassion131), Version 6.0 
• 
Neurological disorders: Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis 
• 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine release 
syndrome, influenza-like illness, and systemic inflammatory response syndrome 
• 
Nephritis 
• 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
• 
Myositis 
• 
Myopathies, including rhabdomyolysis 
• 
Grade ≥2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
• 
Vasculitis 
• 
Autoimmune haemolytic anaemia 
• 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis). 
The following events also require immediate reporting: 
• 
Cases of potential drug-induced liver injury that include elevated ALT or AST levels 
in combination with either elevated bilirubin levels or clinical jaundice, as defined by 
Hy’s law (see Section 5.3.5.5.1); 
• 
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 Section 5.4 (immediate 
reporting), Section 5.5 (follow-up), and Section 5.6 (events occurring after the reporting 
period). 
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.   

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
103/Protocol MO39196 (IMpassion131), Version 6.0 
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 (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study drug, all adverse events (regardless of relationship to study 
drug) will be reported until 30 days after the last dose of atezolizumab/placebo or until 
initiation of new systemic anti-cancer therapy, whichever occurs first. Serious adverse 
events and adverse events of special interest will continue to be reported until 90 days 
after the last dose of atezolizumab/placebo or until initiation of new systemic anti-cancer 
therapy, whichever occurs first. 
Instructions for reporting adverse events that occur after the adverse event reporting 
period (defined as 90 days after the last dose of atezolizumab/placebo) are provided in 
Section 5.6. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity. Table 6 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
104/Protocol MO39196 (IMpassion131), Version 6.0 
Table 6 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or 
intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; or limiting self-care activities of 
daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note: 
 
Based 
on 
the 
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 5.3.5.7). 
 
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, and answer "yes" or "no" to the 
question: “Do you consider that there is a reasonable possibility that the event may have 
been caused by the study drug?”  
A guide to the interpretation of this causality question is found in Appendix 9. 
Causality will be assessed individually for each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF. Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
105/Protocol MO39196 (IMpassion131), Version 6.0 
5.3.5.1 
Infusion-Related Reactions  
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug infusion should be captured as a diagnosis (e.g., 
"infusion-related reaction" or "anaphylactic reaction") on the Adverse Event eCRF. If 
possible, ambiguous terms such as "systemic reaction" should be avoided. If a patient 
experienced both a local and systemic reaction to the same dose of study drug, each 
reaction should be recorded separately on the Adverse Event eCRF. 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
For adverse events other than infusion-related reactions (see Section 5.3.5.1), 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 characterised as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF. If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, except for 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 haemorrhage 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 neutropoenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints. Such events should only be recorded once on the Adverse 
Event eCRF. The initial severity (intensity or grade) of the event will be recorded at the 
time the event is first reported.  If a persistent adverse event becomes more severe, the 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
106/Protocol MO39196 (IMpassion131), Version 6.0 
most extreme severity should also be recorded on the Adverse Event eCRF. If the event 
becomes serious, it should be reported to the Sponsor immediately (i.e., no more than 
24 hours after learning that the event became serious; see Section 5.4.2 for reporting 
instructions). The Adverse Event eCRF should be updated by changing the event from 
"non-serious" to "serious," providing the date that the event became serious, and 
completing all data fields related to serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs. Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event. A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms; 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation); 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalaemia) 
or a change in concomitant therapy; 
• 
Is clinically significant in the investigator’s judgment. 
Note: For oncology trials, certain abnormal values may not qualify as adverse 
events. 
It is the investigator’s responsibility to review all laboratory findings. Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., 
alkaline phosphatase and bilirubin 5 x ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range (e.g., 
"elevated potassium," as opposed to "abnormal potassium"). If the laboratory 
abnormality can be characterised 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 "hyperkalaemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the aetiology 
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). 
5.3.5.5.1 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (>3 x ULN) in combination with either an elevated 
total bilirubin (>2 x ULN) or clinical jaundice in the absence of cholestasis or other 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
107/Protocol MO39196 (IMpassion131), Version 6.0 
causes of hyperbilirubinemia is considered 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 x ULN or >3 x baseline value in combination 
with total bilirubin >2 x ULN (of which ≥35% is direct bilirubin) 
• 
Treatment-emergent ALT or AST >3 x ULN or >3 x baseline value in combination 
with clinical jaundice. 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2). 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event. A vital sign result must be 
reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  
 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g., 
high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on the 
Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.7 
Deaths 
For this protocol, mortality is an efficacy endpoint. All deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.3.1) that are attributed 
by the investigator solely to progression of mTNBC should be recorded on the Death 
Attributed to Progressive Disease eCRF. All other on-study 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). An independent monitoring 
committee will monitor the frequency of deaths from all causes. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF. Generally, only one such event should be reported. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
108/Protocol MO39196 (IMpassion131), Version 6.0 
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 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 mTNBC should be 
recorded only on the Survival eCRF, while the date of death should be captured on the 
Study Discontinuation eCRF. After the end of the adverse event-reporting period 
(defined as 90 days after the last dose of the study drug), during survival follow-up, all 
deaths, regardless of cause, should be reported through use of the Long-Term Survival 
Follow-Up eCRF.  
Reporting of deaths that occur after the adverse event reporting period is described in 
Section 5.6. 
5.3.5.8 
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"). 
5.3.5.9 
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. 
5.3.5.10 
Hospitalisation or Prolonged Hospitalisation 
Any adverse event that results in hospitalisation (i.e., inpatient admission to a hospital) 
or prolonged hospitalisation 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 hospitalisation scenarios are not considered to be adverse events: 
• 
Hospitalisation for respite care 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
109/Protocol MO39196 (IMpassion131), Version 6.0 
• 
Planned hospitalisation required by the protocol (e.g., for study drug administration 
or insertion of access device for study drug administration) 
• 
Hospitalisation for a preexisting condition, provided that all of the following criteria 
are met: 
o The hospitalisation was planned prior to the study or was scheduled 
during the study when elective surgery became necessary because of the 
expected normal progression of the disease 
o The patient has not experienced an adverse event 
• 
Hospitalisation due solely to progression of the underlying cancer (including 
symptoms). 
The following hospitalisation scenario is not considered to be a serious adverse event, 
and should be reported as an adverse event instead: 
• 
Hospitalisation for outpatient care outside of normal outpatient clinic operating hours 
that is required per protocol or per local standard of care. 
5.3.5.11 
Adverse Events Associated with an Overdose or Error in Drug 
Administration 
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied. An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  
No safety data related to overdosing of atezolizumab are available. 
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. Any overdose 
or incorrect administration of paclitaxel should be noted on the Paclitaxel Administration 
eCRF and reported as a protocol deviation. 
All adverse events associated with an overdose or incorrect administration of the study 
treatment (atezolizumab/placebo or paclitaxel) should be recorded on the Adverse Event 
eCRF. If the associated adverse event fulfils 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). 
5.3.5.12 
Patient-Reported Outcome Data 
PRO measures to be collected in the study are described in Section 4.5.8. The methods 
for collecting and analysing PRO data are different from those for the ascertainment of 
observed or volunteered adverse events. Because of these differences, adverse event 
reports will not be derived from PRO data by the Sponsor, and no attempt will be made 
to resolve any noticeable discrepancies between PRO data and observed or volunteered 
adverse events. However, if any PRO responses suggestive of a possible adverse event 
are identified during site review of the PRO data, the investigator should determine 
whether the criteria for an adverse event have been met and, if so, will report the event 
on the Adverse Event eCRF. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
110/Protocol MO39196 (IMpassion131), Version 6.0 
Safety analyses will not be performed using PRO data. 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 trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
• 
Serious adverse events (see Section 5.4.2 for further details) 
• 
Adverse events of special interest (see Section 5.4.2 for further details) 
• 
Pregnancies (see Section 5.4.3 for further details) 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
Medical Monitor Contact Information  
Medical Monitor: 
, MD (Primary) 
Mobile Telephone No.: 
 
 
Medical Monitor: 
, MD (Secondary)  
Telephone No.: 
 
 
Mobile Telephone No.: 
  
 
To ensure the safety of study patients, an Emergency Medical Call Centre Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
111/Protocol MO39196 (IMpassion131), Version 6.0 
calls. The Emergency Medical Call Centre Help Desk will be available 24 hours per day, 
7 days per week. Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators.  
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study 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 (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported. 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. 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 90 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 serious adverse events and adverse events of special interest 
that occur after the adverse event reporting period (defined as 90 days after the last 
dose of atezolizumab/placebo) are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 6 months after the last 
dose of study drug. A Clinical Trial Pregnancy Reporting Form should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators. 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 foetus.  Monitoring of the patient should continue until the conclusion of the 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
112/Protocol MO39196 (IMpassion131), Version 6.0 
pregnancy.  Any serious adverse events associated with the pregnancy (e.g., an event in 
the foetus, 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 Clinical Trial Pregnancy Reporting Form when 
updated information on the course and outcome of the pregnancy becomes available.  
5.4.3.2 
Pregnancies in Female Partners of Male Patients  
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
6 months after the last dose of paclitaxel. A Clinical Trial Pregnancy Reporting Form 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the pregnancy), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators. 
Attempts should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male patient exposed to study 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 authorisation has been 
signed, the investigator will update the Clinical Trial Pregnancy Reporting Form 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 foetus 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 significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).  
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofoetal 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 
embryofoetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the 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). 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
113/Protocol MO39196 (IMpassion131), Version 6.0 
 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow-up, or the patient withdraws consent. Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification. If, after follow-up, return to baseline status or stabilisation 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, 
by following the reporting instructions provided in Section 5.4.3.1. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case. 
 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
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. 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event or adverse events of special interest that occurs after the end of the 
adverse event reporting period (defined as 90 days after the last dose of the study drug), 
if the event is believed to be related to prior treatment with atezolizumab. 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 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 using the fax number 
or email address provided to investigators.  
After the end of the adverse event-reporting period (defined as 90 days after the last 
dose of the study drug), during survival follow-up, all deaths, regardless of cause, should 
be reported through use of the Long-Term Survival Follow-Up eCRF. 
 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
114/Protocol MO39196 (IMpassion131), Version 6.0 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs/ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents: 
• 
Atezolizumab Investigator's Brochure 
• 
Summary of Product Characteristics Accord UK Ltd for 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 the above-listed anticipated events during the 
study. An aggregate report of any clinically relevant imbalances that do not favour the 
test product will be submitted to health authorities. 
 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
This is a Phase III, global, multicentre, randomised, double-blind, two-arm, placebo-
controlled study designed to evaluate the efficacy, safety, and PK of atezolizumab plus 
paclitaxel compared with placebo plus paclitaxel in patients with previously untreated, 
inoperable locally advanced or metastatic TNBC.  
The analysis populations for the Global study are defined as follows: 
• 
ITT population: all randomised patients, whether or not the assigned study 
treatment was received. 
• 
PD-L1-positive subpopulation: patients in the ITT population whose PD-L1 status 
is IC 1/2/3 at the time of randomisation. 
• 
PD-L1-negative subpopulation: patients in the ITT population whose PD-L1 
status is IC0 at the time of randomisation. 
• 
Response-evaluable population: patients in the ITT population with measurable 
disease at baseline. 
• 
Duration of response (DoR)-evaluable population: patients in the ITT population 
with measurable disease at baseline and an objective response. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
115/Protocol MO39196 (IMpassion131), Version 6.0 
• 
Patient reported outcome (PRO)-evaluable population: patients in the ITT 
population with baseline PRO assessment and at least one post-baseline PRO 
assessment. 
• 
Safety-evaluable population: patients who received any amount of any study 
drug. 
For all efficacy analyses, patients will be grouped according to the treatment assigned at 
randomisation. For all safety analyses, patients will be grouped according to the 
treatment actually received, including cases in which atezolizumab was received in error.  
Hypothesis tests will be two-sided unless otherwise indicated. The type I error (α) for this 
study is 0.05 (two-sided).  
Further details of the analyses will be provided in the SAP. 
If additional enrolment in China is initiated, data from this phase will not be included in 
the primary analysis of global study. A separate analysis will be performed for China 
population (i.e. patients enrolled from China in both Global study and additional China 
enrolment phase). 
Details for the analyses based on the China population will be included in the SAP for 
the Global study. 
 
6.1 
DETERMINATION OF SAMPLE SIZE 
6.1.1 
Global Study 
The purpose of this event-driven study is to evaluate the efficacy of atezolizumab plus 
paclitaxel compared to placebo plus paclitaxel as measured by PFS (either investigator-
assessed disease progression per RECIST v1.1 or death from any cause, whichever 
occurs first). 
PFS will be assessed hierarchically in the following fixed order: (1) PFS in the PD-L1-
positive subpopulation; followed by (2) PFS in the ITT population.  
The sample size for the Global study is determined based on the following assumptions: 
• 
Median PFS of 5.0 months in patients with PD-L1-positive tumour status 
randomised to the placebo plus paclitaxel group (as detected in patients with PD-
L1-positive TNBC in the placebo plus albumin-bound (nab-)paclitaxel control arm 
of the IMpassion130 study) (Schmid et al. 2018); 
• 
Treatment effect (between-group difference) of 2.5 months in the median PFS 
(HR 0.62) in the PD-L1-positive subpopulation (as detected in the PD-L1-positive 
subpopulation of the IMpassion130 study) (Schmid et al. 2018); 
• 
Randomisation ratio of 2:1; 
• 
Approximately 40% of the enrolled patients are expected to have PD-L1-positive 
tumour status (as detected in the IMpassion130 study) (Schmid et al. 2018); 

Atezolizumab—F. Hoffmann-La Roche Ltd
116/Protocol MO39196 (IMpassion131), Version 6.0

80% power and an overall 2-sided α of 0.05;

Drop-out rate of 10%. 
Based on these assumptions and parameters, approximately 213 evaluable patients with 
PD-L1-positive tumour status (approximately 142 in the atezolizumab plus paclitaxel 
group and approximately 71 in the placebo plus paclitaxel group) and a total of 155 PFS 
events are required to detect a between-group difference of 2.5 months in the final 
analysis of median PFS (HR 0.62). Assuming that approximately 40% of the enrolled 
patients will have PD-L1-positive tumour status, and to account for an estimated drop-
out rate of 10%, approximately 600 patients will be randomised in the Global study 
(approximately 400 in the atezolizumab plus paclitaxel group and approximately 200 in 
the placebo plus paclitaxel group). Anticipating a global recruitment period of 
approximately 23 months (up to 40 patients per month), the clinical cut-off (CCO) date 
for the primary (final) PFS analysis in the subpopulation with PD-L1-positive tumour 
status is expected to occur approximately 29 months after the first patient was 
randomised (FPI) in the Global study.
In addition, overall survival (OS) is a secondary analysis in this study. As for the primary 
analysis of PFS, OS will be analysed in the PD-L1-positive subpopulation and ITT 
population. Based on the previously noted assumptions, with an anticipated global 
recruitment period of approximately 23 months (up to 40 patients per month) and 
assuming that in the subpopulation with PD-L1-positive tumour status, median OS will 
be 15.5 months in the placebo plus paclitaxel group (based on the median OS in the PD-
L1-positive subpopulation receiving nab-paclitaxel only in the IMpassion130 study 
(Schmid et al. 2018), the study will have approximately 70% power to detect a between-
group difference of 9.5 months in the median OS (HR 0.62). The final analysis of OS 
should occur after 122 mortality events have been observed in the subpopulation with 
PD-L1-positive tumour status, which is expected approximately 40 months after FPI. By 
this time-point, 305 mortality events are expected to have occurred in the ITT population.
Operating characteristics (power and expected total number of events) for HR values for
median PFS and median OS in the PD-L1-positive subpopulation are provided in 
Table 7. 

Atezolizumab—F. Hoffmann-La Roche Ltd
117/Protocol MO39196 (IMpassion131), Version 6.0
Table 7
Operating Characteristics for the Global Study
Total
ATZ+PAC
PL+PAC
Treatm. Δ
HR
Power
Duration 
of Study
mPFS, PD-L1-positive 
Subpopulation  (Primary)
-
7.5 mo
5.0 mo
2.5 mo
0.62
80%
29 mo
Total events
155
-
-
Evaluable Pts
~213
~142
~71
mPFS, ITT Population 
(Primary)  
-
-
-
-
-
-
-
Total events
~395
Evaluable Pts
~540
~360
~180
Total Pts
~600
~400
~200
mOS, PD-L1-positive 
Subpopulation  (Secondary)
-
25.0 mo
15.5 mo
9.5 mo
0.62
≈70%
40 mo
Total events
122
-
-
-
-
-
-
ATZ=atezolizumab; HR=hazard ratio; m=median; mo=months; PAC=paclitaxel; PFS=progression-free 
survival; PL=placebo; OS=overall survival
Note: Operating characteristics are based on the following assumptions: event times are exponentially 
distributed; mPFS in the control arm is 5.0 months, and patients are recruited over approximately 23 months 
(up to 40 patients per month); 2:1 randomisation; overall two-sided α = 0.05.

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
118/Protocol MO39196 (IMpassion131), Version 6.0 
6.1.2 
Controlling for Type I Error 
All tests will be performed at two-sided alpha of 5% with testing for secondary endpoints 
conducted hierarchically, using a fixed sequence testing approach (Westfall and Krishen, 
2001), where each subsequent hypothesis will be tested only if all previously tested 
hypotheses have been rejected, according to the following pre-specified and fixed order 
of endpoints:  
1. PFS by RECIST v1.1 (PD-L1-positive subpopulation) 
2. PFS by RECIST v1.1 (ITT population) 
3. OS (PD-L1-positive subpopulation) 
4. OS (ITT population) 
5. Objective response rate (ORR) by RECIST v1.1 (PD-L1-positive Response-
evaluable population). 
6. ORR by RECIST v1.1 (Response-evaluable population). 
The remaining secondary endpoints (12-month and 18-month OS rates, TTD, PFS rate 
at 12 months, DoR, CBR, as well as C-ORR and C-DoR [added as per FDA request]) 
will not be adjusted for multiple testing. 
OS will also be analysed (in the PD-L1-positive subpopulation and the ITT population) at 
the primary (final) analyses of PFS, as well as after 122 deaths are observed in the PD-
L1-positive subpopulation.  
A group sequential design (Lan-DeMets with O’Brien-Fleming stopping boundaries) will 
be used to control the overall type I error rate (Lan and DeMets, 1983). Testing on OS 
will be conducted hierarchically only if testing on PFS has been rejected. 
The information fraction at the time of each analysis will be re-calculated using the actual 
number of events included in the analysis, and the nominal alpha level re-calculated 
accordingly. 
Table 8 
Timing of the PFS and OS Analyses 
 
 
Analysis 
Timing of 
Analysis 
Percent 
Information 
Nominal Two-
Sided Alpha 
Level 
Cumulative 
Two-Sided 
Alpha Level 
Power 
(%) 
PFS Primary 
Analysis  
155 PFS 
events* 
100% 
- 
0.05 
80% 
OS Interim 
Analysis 
~83 OS 
events* 
67% 
0.012 
0.012 
- 
OS Final Analysis 
122 OS 
events* 
100% 
0.046 
0.05 
~70% 
* Number of outcome events in the PD-L1-positive subpopulation 
 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
119/Protocol MO39196 (IMpassion131), Version 6.0 
6.1.3 
China Population 
After approximately 600 patients have been randomised in the Global study, global 
recruitment will be closed. Additional patients may be subsequently enrolled in China 
only, following the same randomisation procedures and ratio (2:1), for a total of 
approximately 130 patients from mainland China. Assuming that 40% of patients will 
have PD-L1 positive tumour status, it is estimated that approximately 52 of the 130 
Chinese patients will be PD-L1-positive.  
Based on the same assumptions as in the Global population with PD-L1-positive tumour 
status, the China population analysis is planned to be conducted when approximately 36 
PFS events have occurred in China population with PD-L1-postive tumour status. This 
will provide an approximately 77% probability of maintaining ≥ 50% of PFS risk reduction 
to be observed from the global primary analysis. The recruitment period in China is 
expected to be approximately 19 months, and the CCO date for China population 
analysis is expected to occur approximately 23 months after the first Chinese patient is 
randomised. 
Refer to Section 6.12 and the SAP for further details. 
 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Enrolment, major protocol violations including major deviations of inclusion/exclusion 
criteria, and discontinuation from the study will be summarised overall and by treatment 
arm for all randomised patients. The reasons for study discontinuation will be tabulated. 
 
6.3 
SUMMARIES OF TREATMENT ARM COMPARABILITY 
Demographic variables such as age, sex, race/ethnicity, stratification variables and other 
relevant baseline characteristics will be summarised using means, standard deviations 
(SDs), medians, and ranges for continuous variables and proportions for categorical 
variables, as appropriate. Summaries will be presented overall and by treatment arm. 
The baseline value of any efficacy variable will be defined as the last available value 
recorded prior to randomisation. The baseline value of any non-efficacy variable will be 
defined as the last available value recorded on or prior to the first administration of any 
study medication. 
 
6.4 
EFFICACY ANALYSES 
Efficacy analyses will be performed separately for the PD-L1-positive subpopulation and 
the ITT population. 
6.4.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint for this study, PFS, is defined as the time from 
randomisation to the first occurrence of disease progression, as determined by the 
investigator from tumour assessments using RECIST v1.1 (see Appendix 3), or death 
from any cause during the study, whichever occurs first. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
120/Protocol MO39196 (IMpassion131), Version 6.0 
PFS will be assessed hierarchically in the following fixed order:  
(1) PFS in the PD-L1-positive subpopulation (defined as patients in the ITT population 
whose PD-L1 status is IC1/2/3 at the time of randomisation), followed by  
(2) PFS in the ITT population,  
with patients grouped according to their treatment assigned at randomisation. 
PFS will be compared between treatment arms based on the stratified log-rank test. The 
stratification factors will be three of the four predefined randomisation stratification 
factors: tumour PD-L1 status (IC0 vs. IC1/2/3), prior taxane treatment (yes vs. no) and 
presence of liver metastases (yes vs. no) and will be obtained from the interactive 
Web/phone response system (IxRS). The hazard ratio (HR) for disease progression or 
death will 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 unstratified 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 Brookmeyer-Crowley methodology 
will be used to construct the 95% CI for the median PFS for each treatment arm 
(Brookmeyer and Crowley 1982). 
Data for patients without disease progression or death will be censored at the last 
tumour assessment date. Data for patients with a PFS event who missed two or more 
assessments scheduled immediately prior to the date of the PFS event will be censored 
at the last tumour assessment prior to the missed visits as a sensitivity analysis. If no 
tumour assessment was performed after randomisation, data will be censored at the 
date of randomisation +1 day. 
The CCO date for the primary (final) analysis of PFS will take place when the required 
number of 155 PFS events have been observed in the PD-L1-positive population. This is 
projected to occur approximately 29 months after FPI. 
Further details will be included in the SAP. 
6.4.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints in this study are: 
• 
OS, assessed in the:  
o PD-L1-positive subpopulation;  
o ITT population; 
• 
ORR, by investigator assessment using RECIST v1.1 (see Appendix 3), assessed in 
the: 
o PD-L1-positive Response-evaluable subpopulation;  
o ITT Response-evaluable population; 
• 
12-month and 18-month OS rates in the ITT population; 
• 
Time to deterioration (TTD) in Global Health Status/HRQoL (items 29 and 30 of the 
EORTC QLQ-C30), in the PRO-evaluable population; 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
121/Protocol MO39196 (IMpassion131), Version 6.0 
• 
PFS rate at 12 months in the ITT population; 
• 
DoR, by investigator assessment using RECIST v1.1 (see Appendix 3), in the DoR-
evaluable population; 
• 
CBR, by investigator assessment using RECIST v1.1 (see Appendix 3), in the 
Response-evaluable population. 
In addition, as per FDA request, C-ORR and C-DoR will be analysed. Further details will 
be provided in the SAP. 
6.4.2.1 
Secondary Endpoint: Overall Survival 
Overall survival (OS), defined as the time from randomisation to death from any cause, 
is a secondary endpoint for the study. OS will be assessed hierarchically in the PD-L1-
positive subpopulation and in the ITT population, in a similar manner as PFS. 
An interim analysis of OS will be performed at the time of the primary (final) analysis of 
PFS. The final analysis of OS will take place when the required number of 122 mortality 
events have been observed in the PD-L1-positive subpopulation. This is projected to 
occur approximately 40 months after FPI. By this time-point, 305 mortality events are 
expected to have occurred in the ITT population. A group sequential design (Lan-
DeMets with O’Brien-Fleming stopping boundaries) will be used to control the overall 
type I error rate for the OS analyses (Lan and DeMets, 1983).  
In addition, the 12-month and 18-month OS rates will be compared between the 
treatment arms. 
Further details will be specified in the SAP. 
6.4.2.2 
Time to deterioration in Global Health Status 
Time to deterioration (TTD) in Global Health Status/HRQoL will be analysed based on 
the PRO-evaluable population. Deterioration in Global Health Status/HRQoL is defined 
as a minimally important decrease of ≥ 10 points on the Global Health Status /HRQoL 
scale (items 29 and 30) of the European Organization for the Research and Treatment 
of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) 
Refer to Section 6.7 for a detailed description of the PRO endpoints and corresponding 
analyses. 
6.4.2.3 
Secondary Analyses of Progression-Free Survival 
PFS rate at 12 months: all patients alive with known progression status at 12 months 
post-randomisation will be included in the analysis, and the percentages of survivors 
without a progression event along with the corresponding 95% confidence intervals will 
be reported by treatment arm. 
Further details will be provided in the SAP. 
6.4.2.4 
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. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
122/Protocol MO39196 (IMpassion131), Version 6.0 
Patients not meeting this criterion, including patients without any post-baseline tumour 
assessment, will be considered as non-responders.  
Objective response rate (ORR) is defined as the proportion of patients who have an 
objective response. ORR will be analysed using the Response-evaluable population. 
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 between treatment arms 
will be calculated, and its 95% CI will be calculated using the normal approximation to 
the binomial distribution.  
Confirmation of response was not required during the conduct of the study. Confirmed 
ORR will be derived as per details provided in the SAP. 
6.4.2.5 
Duration of Objective Response 
DoR is defined as the time from the first occurrence of a documented unconfirmed 
response (CR or PR) until the date of PD per RECIST v1.1 or death from any cause, 
whichever occurs first. DoR is evaluated in the subset of patients with measurable 
disease at baseline, who have achieved an objective response (DoR-evaluable 
population).  
Data for patients who have not experienced disease progression or death will be 
censored at the last tumour assessment date. If no tumour 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-randomised 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. 
Confirmation of response was not required during the conduct of the study. Confirmed 
DoR will be derived as per details provided in the SAP. 
6.4.2.6 
Clinical Benefit Rate 
Clinical benefit rate (CBR) is defined as the percentage of patients who have achieved 
either unconfirmed CR, or unconfirmed PR, or stable disease (SD) that lasts at least 6 
months. CBR will be displayed by treatment arm. 
6.4.3 
Exploratory Efficacy Endpoints 
The following exploratory efficacy endpoints will be analysed by cycle, and between the 
treatment arms using descriptive statistics: 
• 
Second-line PFS (PFS2): PFS2 is defined as time from randomisation to tumour 
progression or death from any cause on next line of treatment, whichever occurs first. 
Patients who are alive and who have not experienced disease progression on next 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
123/Protocol MO39196 (IMpassion131), Version 6.0 
line of treatment at the time of CCO date will be censored at the last date known to 
be alive. PFS2 will be compared between treatment arms in the subset of patients 
receiving second-line treatment using similar method as the primary endpoint of PFS; 
refer to Section 6.4.1; 
• 
Changes from baseline score in patient function (physical, role, social, emotional, 
cognitive) and disease/treatment-related symptoms, as assessed by all function 
scales and symptom items/scales of the EORTC QLQ-C30 and its breast cancer 
module (QLQ-BR23); 
• 
Changes from baseline score in overall health and quality of life, as assessed by the 
Global Health Status/HRQoL scale (items 29 and 30) of the EORTC QLQ-C30; 
• 
Health Economic data: Health utility scores derived from the EQ-5D-5L and EQ-VAS 
questionnaires;  
• 
Burden of treatment: Proportion of patients reporting each response option at each 
assessment timepoint by treatment arm for item GP5 from the FACT-G. 
Further details on the analysis of exploratory PRO endpoints are provided in 
Section 6.7.2 and in the SAP.  
6.4.4 
Handling of Missing Data 
For PFS analyses, patients without a date of disease progression will be analysed as 
censored observations at the last tumour assessment date. Data for patients with a PFS 
event who missed two or more scheduled assessments immediately prior to the date of 
the PFS event will be censored at the last tumour assessment prior to the missed visits 
as a sensitivity analysis. If no post-baseline tumour assessment is available, data will be 
censored at the date of randomisation +1 day (see Section 6.4.1). 
For OS, patients who are not reported as having died will be analysed 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 randomisation +1 day. 
For objective response, patients without any post-baseline assessment will be 
considered non-responders. 
Handling of missing PRO data is described in Section 6.7. 
 
6.5 
SAFETY ANALYSES 
Safety analyses will include all randomised patients who received at least one dose of 
study treatment (atezolizumab/placebo or paclitaxel), 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 will be presented by 
treatment arm. 
Verbatim descriptions of adverse events will be mapped to MedDRA terms. 
Treatment-emergent events (defined as events occurring on or after the first dose of 
study treatment and within 30 days prior to the last dose of study treatment) will be 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
124/Protocol MO39196 (IMpassion131), Version 6.0 
summarised by MedDRA term, appropriate MedDRA levels (for example, system organ 
class [SOC] and preferred term [PT]), 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 also be summarised:  
• 
Adverse events assessed as related to the study drug; 
• 
Adverse events leading to permanent discontinuation of study drug (with or without 
withdrawal from the study);  
• 
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 deaths will be summarised. 
Relevant laboratory values will be summarised 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.  
For details on immunogenicity analyses, as measured by ADA, refer to Section 6.8.  
 
6.6 
PHARMACOKINETIC ANALYSES 
The PK analyses will include patients who received at least one dose of study treatment 
and provided at least one evaluable post-dose PK.  
Atezolizumab serum concentration data (Cmin and Cmax) will be measured at specific 
timepoints (see Appendix 2), tabulated and summarised. Descriptive statistics will 
include means, medians, ranges, and SDs, as appropriate. 
Plasma concentrations of paclitaxel (reported as total paclitaxel) will be measured at 
specific timepoints (see Appendix 2), tabulated and summarised. The concentration data 
will be summarised with use of descriptive statistics as stated above. 
Additional PK analyses will be conducted as appropriate. 
 
6.7 
PATIENT-REPORTED OUTCOME ANALYSES  
Analyses of PRO measures will be completed on the PRO-evaluable population, defined 
as patients in the ITT population with baseline PRO assessment. 
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 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
125/Protocol MO39196 (IMpassion131), Version 6.0 
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 randomisation + 1 day. 
TTD in global health status/HRQoL will be compared between the treatment arms using 
the same method as the primary endpoint of PFS.  
6.7.2 
Exploratory Patient-Reported Outcomes Analyses 
6.7.2.1 
Changes from Baseline in Patient Function and Symptoms (EORTC 
QLQ C30 and QLQ BR23) 
Changes from baseline in patient function (physical, role, social, emotional, cognitive) 
and disease/treatment-related symptoms, using the EORTC QLQ-C30 questionnaire 
and its breast cancer module (QLQ-BR23), will also be assessed.  
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 treatment 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 MIDs will be used to identify meaningful change from baseline within each 
treatment arm 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 
(Cocks et al. 2011). Only patients with baseline scores will be included in the analysis. 
Patients who do not achieve an MID based on published thresholds will be censored at 
the last time PRO data are available. Patients without at least one post-baseline 
assessment will be censored at the date of randomisation +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 time-period 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 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 published validation reports. 
For subscales with less than 50% of the items completed, the subscale will be 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
126/Protocol MO39196 (IMpassion131), Version 6.0 
considered as missing. PRO completion, compliance rates, and reasons for missing data 
will be summarised at each timepoint by treatment arm.  
6.7.2.2 
Changes from Baseline in Overall Health and Quality of Life 
(EORTC QLQ C30, Items 29 and 30)  
Changes from baseline score for overall health and quality of life (items 29 and 30, 
respectively of the EORTC QLQ-C30) will be evaluated for patients with a baseline and 
at least one post-baseline assessment. For both items, scores will be derived from a 
seven-point scale (from 1 = very poor to 7 = excellent). Summary statistics (mean, 
standard deviation, median, and range) of absolute scores and mean changes from 
baseline will be calculated for both items at each assessment timepoint for both 
treatment arms while on treatment, as described in Section 6.7.2.1. 
6.7.2.3 
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 (CSR). 
6.7.2.4 
Burden of Treatment 
In this study, the burden of treatment associated with the addition of atezolizumab to 
paclitaxel will be measured by the GP5 item ("I am bothered by side effects of treatment") 
from the physical wellbeing subscale of the FACT-G quality of life instrument (Cella et al. 
1993). GP5 item scores will be derived from a five-point scale from 0 (not at all) to 4 
(very much). Item GP5 from version 4 of the FACT-G questionnaire will be scored 
according to the FACIT scoring manual (Cella 1997). A descriptive analysis of absolute 
scores and the proportion of patients selecting each response option at each 
assessment timepoint by treatment arm will be reported for item GP5 (“I am bothered by 
side effects of treatment”) from the FACT-G physical well-being subscale (see 
Appendix 4).   
 
6.8 
IMMUNOGENICITY ANALYSES 
The immunogenicity analyses will include patients with at least one pre-dose and one 
post-dose ADA assessment, with patients grouped according to treatment received. 
Patients will be classified as ADA positive if they were ADA negative at baseline but 
developed an ADA response following study drug administration (treatment-induced 
ADA response), or if they are ADA positive at baseline and the titre of one or more post-
baseline samples is at least 4-fold greater (i.e., ≥0.60 titre units) than the titre of the 
baseline sample (treatment-enhanced ADA response). Patients will be classified as ADA 
negative if they were ADA negative at baseline and all post-baseline samples are 
negative, or if they were ADA positive at baseline but do not have any post-baseline 
samples with a titre that is at least 4-fold greater than the titre of the baseline sample 
(treatment unaffected). 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
127/Protocol MO39196 (IMpassion131), Version 6.0 
The numbers and proportions of ADA-positive patients and ADA-negative patients 
during both the treatment and follow-up periods will be summarised by treatment arm 
and listed by patient and cycle.  
Exploratory immunogenicity endpoints will be analysed and reported descriptively.  
 
6.9 
BIOMARKER ANALYSES  
To evaluate the dependency of the action of the drug combination (atezolizumab plus 
paclitaxel) according to prospectively determined PD-L1 expression, analyses of the 
relationship between PD-L1 status by immunohistochemistry (PD-L1-negative: IC0 vs 
PD-L1-positive: IC 1/2/3) in tumour tissues obtained prior to randomisation, and clinical 
efficacy and safety outcomes will be undertaken.  
6.9.1 
Exploratory Biomarker Analyses  
Exploratory biomarker analyses (in tumour tissues, plasma, and whole blood) will be 
performed to evaluate the association of these markers with study drug response, 
including efficacy and/or adverse events.   
To assess biomarkers that are predictive of response to atezolizumab (i.e., predictive 
biomarkers), are associated with outcomes independent of treatment (i.e., prognostic 
biomarkers), as well as pharmacodynamic exploratory biomarkers in tumour tissues 
(obtained at baseline/prior to randomisation, on-treatment, and at disease progression) 
and blood and their association with disease status and/or response to study drug, the 
following will be analysed: 
• 
Relationship between tumour immune-related or disease type-related biomarkers 
(including but not limited to TILs and CD8) by immunohistochemistry in tumour 
tissues, and clinical outcomes.  
• 
Relationship between PD-L1 status measured by various immunohistochemistry 
assays, and clinical outcomes. 
• 
Relationship between certain molecular subgroups and pre-defined gene signatures 
by RNA expression analysis in tumour tissues, and clinical outcomes. 
• 
Relationship between DNA mutations and mutational burden by NGS genotyping in 
tumour tissues. 
• 
Relationship between exploratory biomarkers (including but not limited to circulating 
cell-free DNA, proteins and cytokines) in plasma collected before treatment, during 
treatment and at disease progression, and clinical outcomes. 
• 
Changes in blood- and tissue- based biomarkers under paclitaxel +/- atezolizumab 
treatment. 
• 
In addition, correlation of immune biomarker findings in blood and tissue samples 
from this study to findings from other studies in TNBC and other tumour types will be 
evaluated. 
Results of biomarker analyses will be presented in a separate report. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
128/Protocol MO39196 (IMpassion131), Version 6.0 
 
6.10 
SUBGROUP ANALYSES 
To assess the consistency of treatment benefit study results in subgroups defined by 
demographic and relevant baseline characteristics (including geographical region), PFS 
and OS in these subgroups will be evaluated. 
Consistency of treatment benefit across geographical regions and other relevant 
demographic and baseline characteristics will be assessed using stratified Cox 
Proportional hazards models, and hazard ratios with 95% confidence intervals will be 
estimated. Forest plots will be used to summarise the results. As indicated by the data, 
random effects models might be used to further explore potential region/centre effects. 
Further details will be specified in the SAP. 
 
6.11 
INTERIM ANALYSIS 
The iDMC will review safety data periodically during the study. All summaries/analyses 
by treatment arm for iDMC review will be prepared by an iDCC. See Section 3.1.2 for 
additional details regarding the iDMC. 
6.11.1 
Planned Interim Analysis  
There will be one interim analysis of OS (in the PD-L1-positive subpopulation and the 
ITT population) at the primary (final) analysis of PFS. The final analysis of OS will be 
performed after 122 deaths are observed in the PD-L1-positive subpopulation.  
A group sequential design (Lan-DeMets with O’Brien-Fleming stopping boundaries) will 
be used to control the overall type I error rate (Lan and DeMets, 1983). Testing on OS 
will be conducted hierarchically only if the null hypothesis for testing on PFS has been 
rejected. 
The information fraction at the time of each analysis will be re-calculated using the actual 
number of events included in the analysis, and the nominal alpha level re-calculated 
accordingly. 
6.11.2 
Optional Interim Analysis  
To adapt to information that may emerge during the study, the Sponsor may also choose 
to conduct an interim efficacy analysis, based on a recommendation from the iDMC and 
in consultation with the Steering Committee. If such an interim analysis is conducted, the 
Sponsor will remain blinded. Provisions will be in place to ensure the study continues to 
meet the highest standards of integrity when an optional interim analysis is executed. 
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, which will be 
submitted to relevant health authorities at least 2 months prior to the conduct of the 
interim analysis. In addition, the iDMC charter will be updated to document potential 
recommendations the iDMC can make to the Sponsor based on the results of the 
analysis, and the iDMC charter will also be made available to relevant health authorities. 
 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
129/Protocol MO39196 (IMpassion131), Version 6.0 
6.12 
CHINA POPULATION ANALYSES 
The objective of the China population analyses is to evaluate whether the efficacy of 
atezolizumab plus paclitaxel compared with placebo plus paclitaxel in the China 
population (enrolled in the Global study and during additional recruitment in China) is 
consistent with the efficacy observed in the Global population (Global study). 
Analyses of study conduct and treatment group comparability (including demographic 
and baseline disease characteristics) will be performed similarly as described in 
Sections 6.2 and 6.3. 
Analysis of the efficacy endpoints will be performed for the China population in a similar 
way as done for the Global population described in Section 6.4.1 and 6.4.2 when 
appropriate, except that unstratified instead of stratified analysis will be performed. This 
is due to the consideration of the limited sample size of the China population, and small 
strata cell representation.  
Safety and PK data for the China population will be analysed using the same methods 
as described in Sections 6.5 and 6.6, respectively. 
The results of the China population analyses will be summarised in a separate CSR. 
Further details will be provided in the SAP. 
 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC 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 global Contract Research Organisation (CRO) will produce eCRF Specifications for 
the study based on Sponsor’s templates including 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. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
130/Protocol MO39196 (IMpassion131), Version 6.0 
All eCRFs should be completed by designated, trained site staff. eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records. 
Acknowledgement of receipt of the compact disc is required. 
 
7.3 
ELECTRONIC PATIENT-REPORTED OUTCOME DATA  
Patients will use an electronic device to capture PRO data. The data will be transmitted 
via web automatically after entry to a centralised database maintained by the Sponsor. 
Once the study is complete, the data, audit trail, and trial and system documentation will 
be archived. The investigator will receive patient data for the site in both human- and 
machine-readable formats on an archival-quality compact disc that must be kept with the 
study records as source data. Acknowledgement of receipt of the compact disc is 
required.  In addition, the Sponsor will receive all data in a machine-readable format on a 
compact disc. 
 
7.4 
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 authorised 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, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan. This includes any protocol data to be entered 
directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review. The study site must also allow 
inspection by applicable health authorities. 
 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
131/Protocol MO39196 (IMpassion131), Version 6.0 
7.5 
USE OF COMPUTERISED SYSTEMS 
When clinical observations are entered directly into a study site’s computerised 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 computerised systems used in clinical research. An 
acceptable computerised 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. 
 
7.6 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, PRO data, Informed Consent Forms, laboratory test results, and 
medication inventory records, must be retained by the Principal Investigator for 15 years 
after completion or discontinuation of the study or for the length of time required by 
relevant national or local health authorities, whichever is longer. After that period of time, 
the documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor. Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer. 
 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual. The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting). Studies conducted in the USA or under a U.S. Investigational New 
Drug (IND) application will comply with U.S. FDA regulations and applicable local, state, 
and federal laws. Studies conducted in the European Union or European Economic Area 
will comply with the E.U. Clinical Trial Directive (2001/20/EC) and applicable local, 
regional, and national laws. 
 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Mobile Nursing Informed Consent 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
132/Protocol MO39196 (IMpassion131), Version 6.0 
Form, if applicable) will be provided to each site. If applicable, it will be provided in a 
certified translation of the local language. The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission. The final IRB/EC-approved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures. The investigator or authorised designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason. A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorised 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 participating in the study must be re-consented to the most current version of 
the Consent Forms, or to a significant new information/findings addendum, according to 
the applicable local law and IRB/EC policy. For any updated or revised Consent Forms, 
the case history or clinical records for each patient shall document the informed consent 
process, and that written informed consent was obtained using the updated/revised 
Consent Forms, as required by local laws and IRB/EC policy for continued participation 
in the study.  
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorised 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 USA, each Consent Form may also include patient authorisation to allow 
use and disclosure of personal health information in compliance with the U.S. Health 
Insurance Portability and Accountability Act (HIPAA) of 1996. If the site utilises a 
separate Authorization Form for patient authorisation 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. 
 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
133/Protocol MO39196 (IMpassion131), Version 6.0 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC. Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC. Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor. Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.  
 
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number. This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorisation for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Given the complexity and exploratory nature of the analyses, data derived from 
exploratory biomarker specimens will generally not be provided to study investigators or 
patients unless required by law. The aggregate results of any conducted research will be 
available in accordance with the effective Roche policy on study data publication (see 
Section 9.5). 
Data generated by this study must be available for inspection upon request by 
representatives 
of 
national 
and 
local 
health 
authorities, 
Sponsor 
monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
 
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.  

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
134/Protocol MO39196 (IMpassion131), Version 6.0 
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., 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. 
 
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 authorised representative for 
inspection of study data, subjects’ 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 600 patients will be randomised at approximately 200 sites globally (in 
select countries from Europe, Asia/Pacific, as well as North-, and South America) over 
approximately 23 months. This total accounts for an estimated 10% drop-out rate during 
the study. Patients will be randomised centrally, using an IxRS (ALMAC Clinical 
Technologies).  
Total recruitment in China (to randomise approximately 130 patients in the Global study 
and during additional enrolment in China combined) will be approximately 19 months.  
Clinical operations, data management, day-to-day clinical science monitoring, and 
statistical programming responsibilities will be outsourced. The global CRO will be 
Chiltern International.  
Central testing laboratories will be responsible for the following: 
• 
Prospective testing of PD-L1 and retrospective confirmation of ER, PR, and HER2 
triple negative status  

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
135/Protocol MO39196 (IMpassion131), Version 6.0 
• 
Biomarker assays (blood-based and tumour sample-based) 
• 
PK assays 
• 
ADA assays 
• 
Auto-antibody testing  
• 
CRP testing. 
Supply kits for all central laboratory assessments will be provided by Covance Inc. 
Biomarker analyses, including PD-L1, ER, PR, and HER2 testing will be completed by 
HistoGeneX. 
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected. 
Clinical data will be captured using standard eCRFs, the design of which will be 
consistent with the eCRFs of other atezolizumab clinical trials. 
There will be one SAP for the Global study and for the China population. However, 
separate CSRs will be prepared for the Global study, and for the China population. 
Responsibilities of the study Steering Committee (SC) and the independent Data 
Monitoring Committee (iDMC) will be provided in the SC Charter and iDMC Charter, 
respectively. 
 
9.5 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results. For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site: 
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.pdf 
The results of this study may be published or presented at scientific congresses. For all 
clinical trials in patients involving an IMP for which a marketing authorisation application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective CSR. In addition, for all clinical trials in patients involving an IMP for which 
a marketing authorisation application has been filed or approved in any country, the 
Sponsor aims to publish results from analyses of additional endpoints and exploratory 
data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation. This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicentre trials only in their entirety and not as individual centre 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
136/Protocol MO39196 (IMpassion131), Version 6.0 
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). 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
137/Protocol MO39196 (IMpassion131), Version 6.0 
10. 
REFERENCES 
Aapro MS, Bohlius J, Cameron DA, et al; European Organisation for Research and 
Treatment of Cancer. 2010 update of EORTC guidelines for the use of 
granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-
induced febrile neutropenia in adult patients with lymphoproliferative disorders and 
solid tumours. Eur J Cancer. 2011 Jan;47(1):8-32. doi: 10.1016/j.ejca.2010.10.013. 
Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research 
and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in 
international clinical trials in oncology. J Natl Cancer Inst 1993;85:365-76. 
Adams S, Diamond J, Hamilton E, et al. Atezolizumab Plus nab-Paclitaxel in the 
Treatment of Metastatic Triple-Negative Breast Cancer With 2-Year Survival 
Follow-up: A Phase 1b Clinical Trial. JAMA Oncol. 2018 Oct 19. doi: 
10.1001/jamaoncol.2018.5152. 
Adams S, Diamond J, Hamilton E, et al. Phase Ib trial of atezolizumab in combination 
with nab-paclitaxel in patients with metastatic triple-negative breast cancer 
(mTNBC). J Clin Oncol 34, 2016 (suppl; abstr 1009). 
Adams S, Gray R, Demaria S, et al. Prognostic value of tumor-infiltrating lymphocytes in 
triple-negative breast cancers from two phase III randomized adjuvant breast 
cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol 2014;32:2959−66. 
Adams S, Loi S, Toppmeyer D et al. Pembrolizumab monotherapy for previously 
untreated, PD-L1-positive, metastatic triple-negative breast cancer: cohort B of the 
phase II KEYNOTE-086 study. Ann Oncol. 2019a Mar 1;30(3):405-411. doi: 
10.1093/annonc/mdy518. 
Adams S, Schmid P, Rugo HS et al. Pembrolizumab monotherapy for previously treated 
metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 
study. Ann Oncol. 2019b Mar 1;30(3):397-404. doi: 10.1093/annonc/mdy517. 
Ali HR, Provenzano E, Dawson SJ, et al. Association between CD8+ T-cell infiltration 
and breast cancer survival in 12,439 patients. Ann Oncol. 2014 Aug;25(8):1536-43. 
doi: 10.1093/annonc/mdu191. 
Atezolizumab (TECENTRIQ; RO5541267) Investigator’s Brochure. F. Hoffmann-La 
Roche Ltd. Version 14, October 2018 (Cut-off date for safety data: 17 May 2018). 
Berger MJ, et al.  Feasibility of stopping paclitaxel premedication after two doses in 
patients not experiencing a previous infusion hypersensitivity reaction. Support 
Care Cancer. 2012 Sep; 20(9): 1991–1997.  Published online 2011 Nov 17. doi:  
10.1007/s00520-011-1303-9 
Blank C, Mackensen A. Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an 
update on implications for chronic infections and tumor evasion. Cancer Immunol 
Immunother 2007;56:739−45. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
138/Protocol MO39196 (IMpassion131), Version 6.0 
Brookmeyer R, Crowley J. A K-sample median test for censored data. Journal of the 
American Statistical Association. 1982;77:433–440. 
Brooks R. EuroQol: the current state of play. Health Policy 1996;37:53-72. 
Brouckaert O, Wildiers H, Floris G, Neven P. Update on triple-negative breast cancer: 
prognosis and management strategies. Int J Womens Health. 2012;4:511-20. doi: 
10.2147/IJWH.S18541. 
Butte MJ, Keir ME, Phamduy TB, et al. Programmed death-1 ligand 1 interacts 
specifically with the B7-1 costimulatory molecule to inhibit T cell responses. 
Immunity 2007;27:111−22. 
Cardoso F, Harbeck N, Fallowfield L, et al. Locally recurrent or metastatic breast cancer: 
ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals 
of Oncology 2012;23 (Supplement 7):vii11−vii19. 
Carey LA, Rugo HS, Marcom PK et al. TBCRC 001: randomized phase II study of 
cetuximab in combination with carboplatin in stage IV triple-negative breast cancer. 
J Clin Oncol. 2012;30:2615-23. 
Carson WE 3rd, Shapiro CL, Crespin TR, et al. Cellular immunity in breast cancer 
patients completing taxane treatment. Clin Cancer Res 2004;10:3401−9. 
Cella D. The Functional Assessment of Cancer Therapy-Anemia (FAXCT-An) Scale: a 
new tool for the assessment of outcomes in cancer anemia and fatigue. Semin 
Hematol. 1997 Jul;34(3 Suppl 2):13-9. 
Cella DF, Tulsky DS, Gray G, et al. The Functional Assessment of Cancer Therapy 
Scale: development and validation of the general measure. J Clin Oncol 1993; 
11:570-79. 
Chen DS, Irving BA, Hodi FS, et al. Molecular pathways: next-generation 
immunotherapy⎯inhibiting programmed death−ligand 1 and programmed death-1. 
Clin Cancer Res 2012;18:6580−7. 
Chen D and Mellman I. Oncology meets immunology: the cancer-immunity cycle. 
Immunity 2013;39:1-10. 
Cimino-Mathews A, Ye X, Meeker A, et al. Metastatic triple-negative breast cancers at 
first relapse have fewer tumor-infiltrating lymphocytes than their matched primary 
breast tumors: a pilot study. Hum Pathol 2013;44:2055−63.  
Cocks K, King MT, Velikova G, et al. Evidence-based guidelines for determination of 
sample size and interpretation of the European Organisation for the Research and 
Treatment of Cancer Quality of Life Questionnaire Core 30. J Clin Oncol. 2011 Jan 
1;29(1):89-96. doi: 10.1200/JCO.2010.28.0107. 
Cohen MH, Johnson JR, Chen YF, Sridhara R, Pazdur R. FDA drug approval summary: 
erlotinib (Tarceva) tablets. Oncologist. 2005 Aug;10(7):461-6. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
139/Protocol MO39196 (IMpassion131), Version 6.0 
Collingnon J, Lousberg L, Schroeder H, et al. Triple-negative breast cancer: treatment 
challenges and solutions. Breast Cancer (Dove Med Press). 2016 May 20;8:93-
107. doi: 10.2147/BCTT.S69488. 
Cooper KL, Madan J, Whyte S, et al: Granulocyte colony-stimulating factors for febrile 
neutropenia prophylaxis following chemotherapy: Systematic review and meta-
analysis. BMC Cancer. 2011 Sep 23;11:404. doi: 10.1186/1471-2407-11-404  
Crawford J, Caserta C, Roila F; ESMO Guidelines Working Group. Hematopoietic 
growth factors: ESMO Clinical Practice Guidelines for the applications. Ann Oncol. 
2010 May;21 Suppl 5:v248-51. doi: 10.1093/annonc/mdq195.  
Danforth DN Jr. Disparities in breast cancer outcomes between Caucasian and African 
American women: a model for describing the relationship of biological and 
nonbiological factors [serial online]. Breast Cancer Res. 2013;15:208. 
DeMets DL, Lan KK. Interim analysis: the alpha spending function approach. Stat Med. 
1994 Jul 15-30;13(13-14):1341-52; discussion 1353-6. 
Di Giacomo AM, Biagioli M, Maio M. The emerging toxicity profiles of anti-CTLA-4 
antibodies across clinical indications. Semin Oncol 2010;37:499-507. 
Dirix L, Takacs I, Nikolinakos P, et al. Avelumab, an anti-PD-L1 antibody, in patients with 
locally advanced or metastatic breast cancer: a phase 1b JAVELIN Solid Tumor 
study. Breast Cancer Res Treat. 2018 Feb;167(3):671-686. doi: 10.1007/s10549-
017-4537-5. 
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. 
Emens LA, Cruz C, Eder JP, et al. Long-term Clinical Outcomes and Biomarker 
Analyses of Atezolizumab Therapy for Patients With Metastatic Triple-Negative 
Breast Cancer: A Phase 1 Study. JAMA Oncol. 2019 Jan 1;5(1):74-82. doi: 
10.1001/jamaoncol.2018.4224. 
EuroQol Group. EuroQol: a new facility for the measurement of health-related quality of 
life. Health Policy 1990;16:199-208. 
Fayers PM. Interpreting quality of life data: population-based reference data for the 
EORTC QLQ-C30. Eur J Cancer. 2001 Jul;37(11):1331-4. 
Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and 
Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: 
International 
Agency 
for 
Research 
on 
Cancer; 
2013. 
Available 
from: 
http://globocan.iarc.fr, accessed on 09/09/2016.  
Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: 
sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015 
Mar 1;136(5):E359-86. doi: 10.1002/ijc.29210.  
Fukada I, Araki K, Kobayashi K, et al. Therapeutic effect of taxanes on metastatic breast 
cancer of various immunohistochemical subtypes. Oncol Lett. 2016 Jul;12(1):663-
669. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
140/Protocol MO39196 (IMpassion131), Version 6.0 
Ghersi D, Willson ML, Chan MM, et al. Taxane-containing regimens for metastatic breast 
cancer. Cochrane Database Syst Rev. 2015 Jun 10;(6):CD003366. doi: 
10.1002/14651858.CD003366.pub3. 
Goldhirsch A, Ingle JN, Gelber RD, Coates AS, Thürlimann B, Senn HJ. Thresholds for 
therapies: highlights of the St Gallen International Expert Consensus on the 
primary therapy of early breast cancer 2009. Ann Oncol. 2009;20(8):1319–1329. 
Gradishar WJ, Krasnojon D, Cheporov S, et al. Significantly longer progression-free 
survival with nab-paclitaxel compared with docetaxel as first-line therapy for 
metastatic breast cancer. J Clin Oncol 2009;27:3611−9. 
Greene J, Hennessey B. The role of anthracyclines in the treatment of early breast 
cancer. 
J 
Oncol 
Pharm 
Pract. 
2015 
Jun;21(3):201-12. 
doi: 
10.1177/1078155214531513. 
Hammond ME, Hayes DF, Wolff AC, et al. American Society of Clinical 
Oncology/College of American Pathologists guideline recommendations for 
immunohistochemical testing of estrogen and progesterone receptors in breast 
cancer. J Oncol Pract. 2010 Jul;6(4):195-7. doi: 10.1200/JOP.777003. 
Hejblum G, Lambotte O, Galicier L, et al. A web-based Delphi study for eliciting helpful 
criteria in the positive diagnosis of hemophagocytic syndrome in adult patients. 
PLoS ONE 2014;9(4):e94024. doi: 10.1371/journal.pone.0094024. 
Herbst RS, Soria JC, Kowanetz M. Predictive correlates of response to the anti-PD-L1 
antibody MPDL3280A in cancer patients. Nature. 2014 Nov 27;515(7528):563-7. 
doi: 10.1038/nature14011. 
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new 
five-level version of EQ-5D (EQ 5D-5L). Qual Life Res 2011;20:1727-36. 
Hernandez-Aya LF, Ma CX. Chemotherapy principles of managing stage IV breast 
cancer in the United States. Chin Clin Oncol. 2016 Jun;5(3):42. doi: 
10.21037/cco.2016.04.01.  
Hirshfield KM, Ganesan S. Triple-negative breast cancer: molecular subtypes and 
targeted therapy. Curr Opin Obstet Gynecol. 2014 Feb;26(1):34-40. doi: 
10.1097/GCO.0000000000000038.  
Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients 
with metastatic melanoma. 201 Sep 23;363(13):1290. 
Hudis CA, Gianni L. Triple-negative breast cancer: an unmet medical need. Oncologist. 
2011;16 Suppl 1:1-11. doi: 10.1634/theoncologist.2011-S1-01.  
Janssen MF, Pickard AS, Golicki D, et al. Measurement properties of the EQ-5D-5L 
compared to the EQ 5D 3L across eight patient groups: a multi-country study. Qual 
Life Res 2013;22:1717-27. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
141/Protocol MO39196 (IMpassion131), Version 6.0 
Jemal A, Bray F, Center MM, et al. Global cancer statistics. Cancer J Clin 
2011;61:69−90.  
Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-
resitant prostate cancer. N Engl J Med. 2010 Jul 29;363(5):411-22. doi: 
10.1056NEJMoa1001294. 
Kassam F, Enright K, Dent R, et al. Survival outcomes for patients with metastatic triple-
negative breast cancer: implications for clinical practice and trial design. Clin 
Breast Cancer. 2009 Feb;9(1):29-33. doi: 10.3816/CBC.2009.n.005. 
Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. 
Annual Rev Immunol 2008;26:677−704. 
Koren E, Smith HW, Shores E, et al. Recommendations on risk-based strategies for 
detection and characterization of antibodies against biotechnology products. J 
Immuno Methods 2008;333:1-9. 
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika. 
1983;70:659–663. 
Larkins E, Scepura B, Blumenthal GM, Bloomquist E, Tang S, Biable M, Kluetz P, 
Keegan P, Pazdur R. U.S. Food and Drug Administration Approval Summary: 
Ramucirumab for the Treatment of Metastatic Non-Small Cell Lung Cancer 
Following Disease Progression On or After Platinum-Based Chemotherapy. 
Oncologist. 2015 Nov;20(11):1320-5. doi: 10.1634/theoncologist.2015-0221. 
Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine 
release syndrome and neurologic toxicity associated with immune effector 
cells. Biol Blood Marrow Transplant 2019;25:625−38. 
Lehmann B, Bauer J, Chen X, et al. Identification of human triple-negative breast cancer 
subtypes and preclinical models for selection of targeted therapies. J Clin Invest 
2011;121:2750-67.  
Lin NU, Vanderplas A, Hughes ME, et al. Clinico-pathologic features, patterns of 
recurrence, and survival among women with triple-negative breast cancer in the 
National Comprehensive Cancer Network. Cancer. 2012;118:5463.  
Loi S. Host antitumor immunity plays a role in the survival of patients with newly 
diagnosed triple-negative breast cancer. J Clin Oncol 2014;32:2935−7. 
Loi S, Michiels S, Salgado R, et al. Tumor infiltrating lymphocytes are prognostic in triple 
negative breast cancer and predictive for trastuzumab benefit in early breast 
cancer: results from the FinHER trial. Ann Oncol 2014;25:1544-50.  
Lund MJ, Trivers KF, Porter PL, et al. Race and triple negative threats to breast cancer 
survival: a population-based study in Atlanta, GA. Breast Cancer Res Treat 2009, 
113:357-370.  

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
142/Protocol MO39196 (IMpassion131), Version 6.0 
Lundqvist A, Andersson E, Ahlberg I, et al. Socioeconomic inequalities in breast cancer 
incidence and mortality in Europe-a systematic review and meta-analysis. Eur J 
Public Health. 2016 May 23. pii: ckw070. [Epub ahead of print] 
Mauri D, Kamposioras K, Tsali L, et al. Overall survival benefit for weekly vs. three-
weekly taxanes regimens in advanced breast cancer: A meta-analysis. Cancer 
Treat Rev. 2010 Feb;36(1):69-74. doi: 10.1016/j.ctrv.2009.10.006.  
Mersin H, Yildirim E, Berberoglu U, Gülben K. The prognostic importance of triple 
negative breast carcinoma. Breast. 2008;17(4):341–346.  
Miles D, Cameron D, Bondarenko I, et al. Bevacizumab plus paclitaxel versus placebo 
plus paclitaxel as first-line therapy for HER2-negative metastatic breast cancer 
(MERiDiAN): A double-blind placebo-controlled randomised phase III trial with 
prospective biomarker evaluation. Eur J Cancer. 2017 Jan;70:146-155. doi: 
10.1016/j.ejca.2016.09.024. 
Miller KD, Siegel RL, Lin CC, et al. Cancer treatment and survivorship statistics, 2016. 
CA Cancer J Clin. 2016 Jul;66(4):271-89. doi: 10.3322/caac.21349.   
Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone 
for metastatic breast cancer. N Engl J Med. 2007 Dec 27;357(26):2666-76. 
Millikan RC, Newman B, Tse CK, et al. Epidemiology of basal-like breast cancer. Breast 
Cancer Res Treat. 2008;109:123–139.  
Mittendorf EA, Philips AV, Meric-Bernstam F, et al. PD-L1 expression in triple-negative 
breast cancer. Cancer Immunol Res. 2014;2(4):361-370. doi: 10.1158/2326-
6066.CIR-13-0127. 
Nabholtz JM, Gelmon K, Bontenbal M, et al. Multicenter, randomized comparative study 
of two doses of paclitaxel in patients with metastatic breast cancer. J Clin Oncol 
1996;14:1858−67. 
Nanda R, Chow L, Dees E, et al. Pembrolizumab in patients with advanced triple-
negative breast cancer: phase Ib Keynote-012 Study. J Clin Oncol 2016 Jul 
20;34(21):2460-7. doi: 10.1200/JCO.2015.64.8931.  
Nigenda G, Gonzalez-Robledo MC, Gonzalez-Robledo LM, Bejarano-Arias RM. Breast 
cancer policy in Latin America: account of achievements and challenges in five 
countries. Global Health. 2016 Jul 12;12(1):39. doi: 10.1186/s12992-016-0177-5. 
[No authors listed]. Immunotherapy Slows TNBC Progression. Cancer Discov. 2015 
Jun;5(6):570. doi: 10.1158/2159-8290.CD-NB2015-059.  
O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 
1979;35:549-56. 
O'Shaughnessy J, Schwartzberg L, Danso MA, et al. Phase III study of iniparib plus 
gemcitabine and carboplatin versus gemcitabine and carboplatin in patients with 
metastatic triple-negative breast cancer. J Clin Oncol. 2014 Dec 1;32(34):3840-7. 
doi: 10.1200/JCO.2014.55.2984. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
143/Protocol MO39196 (IMpassion131), Version 6.0 
Osoba D, Aaronson N, Zee B, et al. Modification of the EORTC QLQ-C30 (version 2.0) 
based on content validity and reliability testing in large samples of patients with 
cancer. The Study Group on Quality of Life of the EORTC and the Symptom 
Control and Quality of Life Committees of the NCI of Canada Clinical Trials Group. 
Qual Life Res 1997;6:103-8. 
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. 
Penault-Llorca F, Viale G. Pathological and molecular diagnosis of triple-negative breast 
cancer: a clinical perspective. Ann Oncol. 2012 Aug;23 Suppl 6:vi19-22. 
Piccart-Gebhart MJ, Burzykowski T, Buyse M, et al. Taxanes alone or in combination 
with anthracyclines as first-line therapy of patients with metastatic breast cancer. J 
Clin Oncol. 2008 Apr 20;26(12):1980-6. doi: 10.1200/JCO.2007.10.8399.  
Pinto L, Liu Z, Doan Q, et al. Comparison of pegfilgrastim with filgrastim on febrile 
neutropenia, grade IV neutropenia and bone pain: a meta-analysis of randomized 
controlled trials. Curr Med Res Opin 2007;23:2283–95. 
Powles T, Eder JP, Fine GD, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical 
activity in metastatic bladder cancer. Nature 2014;515:558-62. 
Qi WX, Shen Z, Lin F, et al. Paclitaxel-based versus docetaxel-based regimens in 
metastatic breast cancer: a systematic review and meta-analysis of randomized 
controlled 
trials. 
Curr 
Med 
Res 
Opin. 
2013 
Feb;29(2):117-25. 
doi: 
10.1185/03007995.2012.756393. Epub 2012 Dec 26.  
Renner P, Milazzo S, Liu JP, Zwahlen M, Birkmann J, Horneber M. Primary prophylactic 
colony-stimulating factors for the prevention of chemotherapy-induced febrile 
neutropenia in breast cancer patients. Cochrane Database Syst Rev. 2012 Oct 
17;10:CD007913. doi: 10.1002/14651858.CD007913.pub2.  
Rosenberg AS, Worobec AS. A risk-based approach to immunogenicity concerns of 
therapeutic protein products. BioPharm Intl 2004;17:34-42. 
Saha P, Nanda R. Concepts and targets in triple-negative breast cancer: recent results 
and clinical implications. Ther Adv Med Oncol. 2016 Sep;8(5):351-9. doi: 
10.1177/1758834016657071.  
Schmid P, Adams S, Rugo HS, et al; IMpassion130 Trial Investigators. Atezolizumab 
and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N Engl J Med. 
2018 Nov 29;379(22):2108-2121. doi: 10.1056/NEJMoa1809615. 
Schmid P, Cruz C, Braiteh FS, et al. Atezolizumab in metastatic triple-negative breast 
cancer: long-term clinical outcomes and biomarker analyses. Abstract presented 
at: AACR Annual Meeting 2017; April 1-5, 2017; Washington DC. Abstract 2986. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
144/Protocol MO39196 (IMpassion131), Version 6.0 
Seidman AD, Berry D, Cirrincione C, et al. Randomized phase III trial of weekly 
compared with every-3-weeks paclitaxel for metastatic breast cancer, with 
trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab 
or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B 
protocol 
9840. 
J 
Clin 
Oncol. 
2008 
Apr 
1;26(10):1642-9. 
doi: 
10.1200/JCO.2007.11.6699. 
Seidman AD, Tiersten A, Hudis C, et al. Phase II trial of paclitaxel by 3-hour infusion as 
initial and salvage chemotherapy for metastatic breast cancer. J Clin Oncol 
1995;13:2575−81.  
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016; 66(1):7–
30.  
Smith TJ, Bohlke K, Lyman GH, et al; American Society of Clinical Oncology. 
Recommendations for the Use of WBC Growth Factors: American Society of 
Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2015 Oct 
1;33(28):3199-212. doi: 10.1200/JCO.2015.62.3488.  
Sprangers MA, Groenvold M, Arraras JI, et al. The European Organization for Research 
and Treatment of Cancer breast cancer-specific quality-of-life questionnaire 
module: first results from a three-country field study. J Clin Oncol 1996;14:2756-68. 
Summers J, Cohen MH, Keegan P, Pazdur R. FDA drug approval summary: 
bevacizumab plus interferon for advanced renal cell carcinoma. Oncologist. 
2010;15(1):104-11. doi: 10.1634/theoncologist.2009-0250. 
Swanton C. Chemotherapy and metastatic breast cancer. In: Handbook of Metastatic 
Breast Cancer, Second Edition; edited by Charles Swanton, Stephen R. D. 
Johnston. CRC Press, Nov 14, 2011; pp 67 – 92. 
ten Tije AJ, Verweij J, Loos WJ, et al. Pharmacological effects of formulation vehicles: 
implications for cancer chemotherapy. Clin Pharmacokinet 2003;42:665-85.  
The Cancer Genome Atlas Network (TCGAN). Comprehensive molecular portraits of 
human 
breast 
tumours. 
Nature 
04 
October 
2012;490:61–70.  
doi:10.1038/nature11412 
Available 
at: 
http://www.nature.com/nature/journal/v490/n7418/full/nature11412.html. Accessed 
on November 23, 2016. 
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 
2012. CA Cancer J Clin. 2015;65(2):87–108.  
Trivers KF, Lund MJ, Porter PL, et al. The epidemiology of triple-negative breast cancer, 
including 
race. 
Cancer 
Causes 
Control. 
2009 
Sep;20(7):1071-82. 
doi: 
10.1007/s10552-009-9331-1. 
Verma S, Provencher L, Dent R. Emerging trends in the treatment of triple-negative 
breast cancer in Canada: a survey. Curr Oncol. 2011 Aug;18(4):180-90. 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
145/Protocol MO39196 (IMpassion131), Version 6.0 
Wahba HA, El-Hadaad HA. Current approaches in treatment of triple-negative breast 
cancer. Cancer Biol Med. 2015 Jun;12(2):106-16. doi: 10.7497/j.issn.2095-
3941.2015.0030. 
Wang Y, Waters J, Leung M, et al. Clonal evolution in breast cancer revealed by single 
nucleus genome sequencing. Nature 2014;512:155-60. 
Westfall PH, Krishen A. Optimally weighted, fixed sequence and gatekeeper multiple 
testing procedures. Journal of Statistical Planning and Inference 2001; 99:25–41. 
Wilson WH, Berg SL, Bryant G, et al. Paclitaxel in doxorubicin-refractory or 
mitoxantrone-refractory breast cancer: a phase I/II trial of 96-hour infusion. J Clin 
Oncol 1994;12:1621−9. 
Wolff AC, Hammond MEH, Allison KH, et al. Human Epidermal Growth Factor Receptor 
2 Testing in Breast Cancer: American Society of Clinical Oncology/College of 
American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol. 
2018 Jul 10;36(20):2105-2122. doi: 10.1200/JCO.2018.77.8738. 
Yang J, Riella LV, Chock S. The novel costimulatory programmed death ligand 1/B7.1 
pathway is functional in inhibiting alloimmune responses in vivo. J Immunol 
2011;187:1113−9.  
Zeichner SB, Ambros T, Zaravinos J, et al. Defining the survival benchmark for breast 
cancer patients with systemic relapse. Breast Cancer (Auckl). 2015a;9:9–17.  
Zeichner SB, Herna S, Mani A, et al. Survival of patients with de-novo metastatic breast 
cancer: analysis of data from a large breast cancer-specific private practice, a 
university-based cancer center and review of the literature. Breast Cancer Res 
Treat. 2015b;153(3):617–624.  
Zeichner SB, Terawaki H, Gogineni K. A Review of Systemic Treatment in Metastatic 
Triple-Negative Breast Cancer. Breast Cancer (Auckl). 2016 Mar 22;10:25-36. doi: 
10.4137/BCBCR.S32783.  
Zitvogel L, Apetoh L, Ghiringhelli F et al. The anticancer immune response: 
indispensable for therapeutic success? J Clin Invest 2008;118:1991−2001. 
 

Appendix 1  
Schedule of Activities (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
148/Protocol MO39196 (IMpassion131), Version 6.0 
ADA = anti-drug 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; HBcAb = antibody to hepatitis B core antigen; HBsAb = antibody to hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; 
MRI = magnetic resonance imaging; PDL1 = programmed death ligand 1; PK = pharmacokinetic; q8w = every 8 weeks; QLQBR23 = Quality-of-life Questionnaire 
Breast Cancer Module; QLQC30 = Quality-of-life Questionnaire Core 30; PD=disease progression; RBR = Research Biosample Repository; RECIST = Response 
Evaluation Criteria in Solid Tumors; TSH = thyroid-stimulating hormone; v = version; WOCP = women of child-bearing potential 
[a1] If a scheduled treatment visit cannot be completed due to a holiday, dosing may be postponed to the earliest next date; subsequent dosing should 
continue according to the original schedule. However, paclitaxel should not be administered more frequently than every 7 days. After five cycles, one of 
three cycles may be delayed by one week to allow for vacations. 
[a2] 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. An assessment day window of ±3 days for Day1 of cycle ≥2 will be permitted in the study. 
[a3] Paclitaxel will be administered at the 90 mg/m2 dose via 1-hour IV infusion on Days 1, 8, and 15 of every 28-day cycle. Paclitaxel should not be 
administered more frequently than every 7 days. The Day 8 visits are not required for patients who have discontinued paclitaxel and are continuing 
treatment with atezolizumab/placebo only.  
[b] 
 Patients will be asked to return to the clinic within 30 days after their last study drug dose for a treatment discontinuation visit. The visit at which the 
decision is made to discontinue treatment (e.g., due to PD) may be used as the treatment discontinuation visit. 
[c] 
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 
randomisation. Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to randomisation 
(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. 
[d] 
Demographic information includes age, gender, and self-reported race/ethnicity. Reproductive status and smoking history should also be captured. 
Cancer history includes stage, date of diagnosis, and prior anti-tumour treatment.   
[e] 
All patients will be tested for HIV antibody, HBsAg, HBcAb, HBsAb, and hepatitis C virus antibody (HCVAb) locally, prior to the inclusion into the study. 
HIV-positive patients will be excluded from the clinical trial. In patients with a negative HBsAg and positive HBcAb serology, HBV DNA must also be 
collected prior to randomisation. Patients positive for HCVAb require a negative PCR for HCV RNA to confirm eligibility. 
[f] 
Includes all prescription or over-the-counter medications taken from 7 days prior to screening to EOS.   
[g] 
Tumour assessments will be performed every 8 weeks for the first 12 months following randomisation, and every 12 weeks thereafter, until PD, death, 
withdrawal of consent, or study termination by the Sponsor (whichever occurs first). All measurable and evaluable lesions should be assessed and 
documented at screening/baseline. 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, 3) CT (with contrast) or MRI scan of the head must be performed at screening to evaluate CNS 
metastasis, and 4) any other imaging studies (CT neck, plain films, etc.) as clinically indicated/determined by the treating physician. 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. For each patient, the same radiographic 
procedures and technique must be used throughout the study, and results must be reviewed by the investigator before dosing at the next cycle. Tumour 

Appendix 1  
Schedule of Activities (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
149/Protocol MO39196 (IMpassion131), Version 6.0 
response will be evaluated using RECIST v1.1 (Appendix 3).  During the post-treatment Follow-up period, only patients with no PD will undergo tumour 
assessments. For patients who discontinue study treatment before EOS for reasons other than PD, tumour assessments will continue until PD, death, 
withdrawal of consent, loss to follow-up, or study termination by the Sponsor. 
[h1] The EORTC QLQ-C30, QLQ-BR23, and EQ-5D-5L questionnaires and item GP5 of the FACT-G questionnaire will be completed by the patient on an 
electronic (ePRO) device either at their home or at the site at baseline (Cycle 1, Day 1, with the exception of item GP5 of the FACT-G; see comment [h2]), 
on Day 1 of each subsequent cycle, and at the treatment discontinuation visit.  In addition, all patients will be asked to complete the PRO questionnaires 
every 3 months for 1 year after treatment discontinuation, regardless of whether the patient is receiving subsequent anti-cancer therapy. At each visit, PRO 
questionnaires should be completed 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 and ensure measures have been completed and saved before the patient leaves 
the investigational site. 
[h2] Since item GP5 specifically assesses patients being bothered by the side-effects of treatment, this item will not be administered to patients at baseline 
(Cycle 1, Day 1). While on study treatment, all patients will complete the FACT-G, single item GP5 beginning on Cycle 2, Day 1 and at Day 1 of every cycle 
thereafter. 
[i] 
Complete physical examination at Screening, and EOT, and symptom-driven physical examinations within 96 hours before Day 1 of each cycle, and 
as clinically indicated. Physical examinations will include a review of the main body organs and systems, with special attention to cardiovascular (e.g. 
abnormally low or irregular pulse, chest pain, tachycardia, swollen legs), respiratory (e.g. shortness of breath, crackling), gastrointestinal (e.g. abdominal 
pain, digestive disorders) systems, and a neurological exam focusing on signs and symptoms potentially indicative of disorders such as myasthenia gravis, 
motor and sensory neuropathy, meningitis, and encephalitis. 
[j] 
ECOG performance status and local laboratory assessments may be obtained within 96 hours before Day 1 of each cycle. 
[k] 
Vital signs will include measurements of respiratory rate, pulse 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. 
[l] 
Standard 12-lead ECG, taken after resting in a supine position for at least 10 minutes. Additional cardiovascular monitoring (such as ECG and/or 
echocardiography) may be considered during the patient’s study participation, if clinically indicated by the appearance of symptoms or findings at regular 
vital sign checks or medical examinations suggestive of cardiovascular disease (e.g. abnormally low or irregular pulse, chest pain, tachycardia, swollen 
legs, shortness of breath, crackling) especially if these cannot be explained by thyroid or electrolyte abnormalities. 
[m] Haematology consists of RBC count, haemoglobin, haematocrit, WBC count with differential (if clinically indicated), and platelet count. Serum 
chemistry includes BUN, creatinine, sodium, potassium, chloride, bicarbonate, calcium, glucose, total bilirubin, ALT, AST, alkaline phosphatase, total 
protein, and albumin. Bicarbonates should only be tested at sites where this test is part of the standard safety laboratory panel. Magnesium and 
phosphorus should be collected at screening, and thereafter only if clinically indicated. Lipase and amylase levels should be determined if clinically 
indicated by the presence of abdominal symptoms suggestive of pancreatitis.    
[n] 
Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood) will be performed at screening, and thereafter only if clinically indicated.  

Appendix 1  
Schedule of Activities (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
150/Protocol MO39196 (IMpassion131), Version 6.0 
[o] 
Serum pregnancy test within 7 days before Cycle 1, Day 1. 
[p] 
Urine pregnancy test; if a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
[q] 
TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed within 96 hours before Day 1 of Cycle 1, within 96 
hours before Day 1 of every second cycle thereafter, and at treatment discontinuation. 
[r] 
Includes antinuclear antibody, anti-double stranded DNA, circulating anti-neutrophil cytoplasmic antibody, and perinuclear anti-neutrophil cytoplasmic 
antibody. 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. All samples will be analysed centrally.   
[s] 
See Appendix 2 for a detailed schedule. 
[t] 
Mandatory whole blood for germline DNA isolation will be collected during the Baseline visit. If this sample has not been collected during the Baseline 
visit, it can be collected at any of the following cycles. 
[u] 
After informed consent has been obtained but prior to initiation of study drug, only SAEs caused by a protocol-mandated intervention should be 
reported.  After initiation of study drug, all AEs will be reported until 30 days after the last dose of study treatment or until initiation of another anti-cancer 
therapy, whichever occurs first.  Serious adverse events and adverse events of special interest will continue to be reported until 90 days after the last dose 
of atezolizumab/placebo or until initiation of new systemic anti-cancer therapy, whichever occurs first. After this period, investigators should report any 
deaths, SAEs, or other AEs of concern that are considered related to prior treatment with the study drug. The investigator should follow each SAE and 
Grade ≥3 AE until the event has resolved to baseline grade, assessed as stable by the investigator, or until the patient withdraws consent or is lost to 
follow-up.  
[v] 
Patients should receive their first dose of study drug on the day of randomisation (no later than 3 days after randomisation).  The first dose of 
atezolizumab/placebo will be delivered over 60 ± 15 minutes; if well tolerated, all subsequent infusions may be delivered over 30 ± 10 minutes.   
[w] Mandatory tumour tissue biopsy collected within 3 months prior to study enrolment. If a tumour sample taken within 3 months before randomisation is 
not available and a tumour biopsy is not clinically feasible, the primary surgical resection sample or the most recent FFPE tumour biopsy sample may be 
used. Of these additional options, the most recent sample should be used. Samples may be collected by core needle or excisional/punch biopsy per 
investigator discretion. Tumour tissue should be of good quality based on total and viable tumour content.  Fine-needle aspiration, brushing, cell pellets 
from pleural effusion, and lavage samples are not acceptable. For core needle biopsy specimens, more than one core (if clinically feasible) should be 
submitted for evaluation. Retrieval of already available tumour sample can occur outside the 28-day screening period. 
[x] 
Optional on-treatment tumour tissue sample collected before the Cycle 2, Day 1 dose (or within 14 days before the Cycle 2, Day 1 dose) from patients 
who have provided consent for optional biopsies. Samples may be collected by core needle or excisional/punch biopsy per investigator discretion.   
[y] 
Optional sample, collected (if clinically feasible) at the time (or within ±7 days) of radiographic progression (per RECIST v1.1), preferably from growing 
lesions. 
[z] 
All patients will be followed for survival and new anti-cancer therapy (including targeted therapy and immunotherapy) information until death, 
withdrawal of consent, loss to follow-up, or until study termination by the Sponsor. Survival follow-up information will be collected via telephone calls, 
patient medical records, and/or clinic visits approximately every 3 months ± 21 days.  Public information sources (e.g., county records) may also be used to 
obtain information about survival status only in case the patient withdrew from the study. Information regarding PFS2 and PROs will also be collected 
during the survival follow-up period.  

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
151/Protocol MO39196 (IMpassion131), Version 6.0 
Appendix 2  
Anti-Drug Antibody, Pharmacokinetic, Pharmacodynamic, and 
Exploratory Biomarker Sampling Schedule  
Study Visit 
Timepoint 
Sample 
Screening 
Days -28 to -1 
Mandatory FFPE tumour tissue 
sample [c] 
 
 
 
 
 
 
 
 
Cycle 1, Day 1 
 
 
 
 
Prior to first dose of any study 
treatment  
Atezolizumab PK and ADA [a] 
Plasma sample for biomarker 
analysis 
Whole blood sample for germline 
DNA analysis [d] 
Whole blood sample for exploratory 
biomarker analysis [f] 
30±10 minutes after end of 
atezolizumab infusion 
Atezolizumab PK [a] 
5-10 minutes before the end of 
paclitaxel infusion 
Paclitaxel PK [b]  
1 hour after the end of paclitaxel 
infusion 
Paclitaxel PK [b]  
 
 
 
 
Cycle 2, Day 1 
 
 
 
Prior to first dose of any study 
treatment  
Atezolizumab PK and ADA [a] 
Optional FFPE tumour tissue 
sample [e] 
Plasma sample for biomarker 
analysis 
Whole blood sample for exploratory 
biomarker analysis [f] 
 
 
 
 
Cycle 3, Day 1 
 
Prior to first dose of any study 
treatment  
Atezolizumab PK and ADA [a] 
Plasma sample for biomarker 
analysis 
5-10 minutes before the end of 
paclitaxel infusion 
Paclitaxel PK [b]  
1 hour after the end of paclitaxel 
infusion 
Paclitaxel PK [b]  
Cycle 4, Day 1 
Prior to first dose of any study 
treatment  
Atezolizumab PK and ADA [a] 

Appendix 2  
Anti-Drug Antibody, Pharmacokinetic, Pharmacodynamic, and 
Exploratory Biomarker Sampling Schedule (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
152/Protocol MO39196 (IMpassion131), Version 6.0 
ADA=anti-drug antibody; PD=pharmacodynamic; PK=pharmacokinetics  
[a] Samples for atezolizumab PK and ADA will be collected from patients enrolled in the Global Study during 
the first four cycles of atezolizumab/placebo and at the Treatment discontinuation visit.  For patients who 
discontinue atezolizumab/placebo and continue on paclitaxel alone, the scheduled collection for 
atezolizumab PK at the treatment discontinuation visit is still required. Patients enrolled in mainland China 
will not undergo atezolizumab PK and ADA assessments. 
[b] Samples for paclitaxel PK were collected from the first approximately 60 patients randomised in the Global 
Study (Arm A and Arm B). No further sampling for paclitaxel PK will occur in the study. Patients enrolled in 
mainland China will not undergo paclitaxel PK assessments.  
[c]  Results of PD-L1 testing of this mandatory baseline tumour sample must be obtained from the designated 
central laboratory prior to enrolment. The screening sample must have been collected ≤ 3 months from 
randomisation. If a tumour sample taken within 3 months before randomisation is not available and a tumour 
biopsy is not clinically feasible, the primary surgical resection sample or the most recent FFPE tumour 
biopsy sample may be used. Of these additional options, the most recent sample should be used.  
[d] Mandatory whole blood for germline DNA isolation will be collected during the Baseline visit. If this sample 
has not been collected during the Baseline visit, it can be collected at any of the following cycles. 
[e] On-treatment tumour samples for biomarker analyses are optional. They must be collected within 14 days 
prior to treatment on Day 1 of Cycle 2 and at disease progression (±7 days) only if deemed clinically feasible 
by the Investigator. 
[f] Whole blood samples collected at Day 1 of Cycle 1, Day 1 of Cycle 2 and at disease progression are to 
assess peripheral blood mononuclear cells (PBMCs). Whole blood samples for PBMC analysis have been 
collected from over 300 patients at baseline; for these patients, sample collection will continue as described 
in the above table (on C2D1 and at PD). However, for newly enrolled patients, there will be no whole blood 
sampling for PBMC analysis at any time-point. Patients enrolled in China will not undergo this biomarker 
assessment. 
 
Study Visit 
Timepoint 
Sample 
Cycles 6, 9 and every 
three cycles thereafter, 
Day 1 
Prior to first dose of any study 
treatment  
Plasma sample for biomarker 
analysis 
 
 
 
At the time of radiographic 
progression 
 
 
 
NA 
Optional FFPE tumour tissue 
sample [e] 
Plasma sample for biomarker 
analysis 
Whole blood sample for exploratory 
biomarker analysis [f] 
Treatment discontinuation 
visit 
At visit 
Atezolizumab PK and ADA [a] 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
153/Protocol MO39196 (IMpassion131), Version 6.0 
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 (Eisenhauer et al. 2009) are presented below, with slight modifications and 
the addition of explanatory text as needed for clarity.1 
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. 
Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
                                            
1 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.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
154/Protocol MO39196 (IMpassion131), Version 6.0 
 
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. 
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).   

 
 
 
Appendix 3 
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
155/Protocol MO39196 (IMpassion131), Version 6.0 
 
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 enrolment 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 tumour 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 tumour 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. 
 
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. 

 
 
 
Appendix 3 
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
156/Protocol MO39196 (IMpassion131), Version 6.0 
 
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. 
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.” 
 

 
 
 
Appendix 3 
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
157/Protocol MO39196 (IMpassion131), Version 6.0 
 
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 
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 

 
 
 
Appendix 3 
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
158/Protocol MO39196 (IMpassion131), Version 6.0 
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). 
• 
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 

 
 
 
Appendix 3 
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
159/Protocol MO39196 (IMpassion131), Version 6.0 
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, 
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. 

 
 
 
Appendix 3 
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
160/Protocol MO39196 (IMpassion131), Version 6.0 
 
EVALUATION OF RESPONSE 
Timepoint Response (Overall Response) 
It is assumed that at each protocol-specified timepoint, a response assessment occurs.   
Table A 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 B is to be 
used. 
Table A 
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. 
 

 
 
 
Appendix 3 
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
161/Protocol MO39196 (IMpassion131), Version 6.0 
 
Table B 
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 
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 
162/Protocol MO39196 (IMpassion131), Version 6.0 
 
Table C 
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 

 
 
 
Appendix 3 
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
163/Protocol MO39196 (IMpassion131), Version 6.0 
“symptomatic deterioration.”  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and nontarget disease as shown in Table A, Table B, and Table C. 
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. 
 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
164/Protocol MO39196 (IMpassion131), Version 6.0 
Appendix 4  
Patient-Reported Outcome Instruments 
 
 

 
 
Appendix 4  
Patient-Reported Outcome Instruments (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
165/Protocol MO39196 (IMpassion131), Version 6.0 
 
 
 

 
 
Appendix 4  
Patient-Reported Outcome Instruments (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
166/Protocol MO39196 (IMpassion131), Version 6.0 

 
 
Appendix 4  
Patient-Reported Outcome Instruments (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
167/Protocol MO39196 (IMpassion131), Version 6.0 
 

 
 
Appendix 4  
Patient-Reported Outcome Instruments (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
168/Protocol MO39196 (IMpassion131), Version 6.0 

 
 
Appendix 4  
Patient-Reported Outcome Instruments (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
169/Protocol MO39196 (IMpassion131), Version 6.0 

 
 
Appendix 4  
Patient-Reported Outcome Instruments (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
170/Protocol MO39196 (IMpassion131), Version 6.0 
 

 
 
Appendix 4  
Patient-Reported Outcome Instruments (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
171/Protocol MO39196 (IMpassion131), Version 6.0 
 
 
 
Notes:  
Only item GP5 of the Physical Well-being domain of the FACT-4 instrument will be used 
in the current study.  
The remaining three domains of the FACT-G are not shown above. 
 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
172/Protocol MO39196 (IMpassion131), Version 6.0 
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 anaemia 
Autoimmune haemolytic 
anaemia 
Autoimmune hepatitis 
Autoimmune 
hypoparathyroidism 
Autoimmune hypophysitis 
Autoimmune myocarditis 
Autoimmune oophoritis 
Autoimmune orchitis 
Autoimmune 
thrombocytopenic 
purpura 
Behcet’s disease 
Bullous pemphigoid 
Chronic inflammatory 
demyelinating polyneuropathy 
Churg-Strauss syndrome 
Crohn’s disease  
Dermatomyositis 
Dysautonomia
Epidermolysis bullosa 
acquisita
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 anaemia 
Polyarteritis nodosa 
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
 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
173/Protocol MO39196 (IMpassion131), Version 6.0 
Appendix 6  
Anaphylaxis Precautions 
These guidelines are intended as a reference and should not supersede pertinent local 
or institutional standard operating procedures. 
Required Equipment and Medication: 
• 
Monitoring devices: ECG monitor, blood pressure monitor, oxygen saturation monitor, 
and thermometer 
• 
Oxygen 
• 
Epinephrine for intramuscular, subcutaneous, intravenous, and/or endotracheal 
administration in accordance with institutional guidelines  
• 
Antihistamines 
• 
Corticosteroids 
• 
Intravenous infusion solutions, tubing, catheters, and tape 
 
Procedures 
In the event of a suspected anaphylactic reaction during study drug infusion, 
the following procedures should be performed: 
1. Stop the study drug infusion. 
2. Call for additional medical assistance. 
3. Maintain an adequate airway. 
4. Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring if possible. 
5. Administer antihistamines, epinephrine, or other medications and IV fluids as 
required by patient status and as directed by the physician in charge. 
6. Continue to observe the patient and document observations. 
 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
174/Protocol MO39196 (IMpassion131), Version 6.0 
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 
 
 
 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
175/Protocol MO39196 (IMpassion131), Version 6.0 
Appendix 8  
Cockcroft-Gault formula 
 
Creatinine clearance will be calculated using the Cockcroft-Gault formula: 
For females: 
CrCl = 0.85 x ((140 - Age) / (Serum Creatinine)) x (Weight / 72) 
For males: 
CrCl = ((140 - Age) / (Serum Creatinine)) x (Weight / 72) 
 
Where the units are: 
CCr (creatinine clearance): mL/minute 
age: years 
Weight: kg 
SCr (serum creatinine): mg/dL 
 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
176/Protocol MO39196 (IMpassion131), Version 6.0 
Appendix 9  
Guide to Interpreting the AE Causality Question 
 
The following factors should be considered when deciding if there is a “reasonable 
possibility” that an AE may have been caused by the drug. 
• 
Time course. Exposure to suspect drug. Has the subject actually received the 
suspect drug? Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug? 
• 
Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? OR could the AE be anticipated from its pharmacological 
properties? 
• 
Dechallenge experience. Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug? 
• 
No alternative cause. The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors. 
• 
Rechallenge experience. Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? Sponsor would not normally recommend or support a 
rechallenge. 
• 
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship? 
A “reasonable possibility” could be considered to exist for an AE where one or more of 
these factors exist. 
In contrast, there would not be a “reasonable possibility” of causality if none of the above 
criteria apply or where there is evidence of exposure and a reasonable time course but 
any dechallenge or rechallenge (if performed) is negative or ambiguous or there is 
another more likely cause of the AE. 
In difficult cases, other factors could be considered such as: 
• 
Is this a recognised feature of overdose of the drug? 
• 
Is there a known mechanism? 
Ambiguous cases should be considered as being a “reasonable possibility” of a causal 
relationship unless further evidence becomes available to refute this. Causal relationship 
in cases where the disease under study has deteriorated due to lack of effect should be 
classified. 
 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
177/Protocol MO39196 (IMpassion131), Version 6.0 
Appendix 10  
Patient Engagement Application 
 
The Patient Engagement Application, a smartphone app, referred to as an “app” that can 
be used by a subject or the legally authorised representative of a subject in the 
MO39196 study.  
 
The App is an optional service that subjects can opt-in to use to remind them of 
activities/tasks relevant to study compliances like when to take their study medication, 
attend site visit, track goals. The App also provides supportive guides to help subjects be 
aware of visit procedures, study information and instructions. 
 
The App’s interactive features are intended to be a companion to the user during the 
course of a trial and include the following modules: 
 
• 
Study Information: targeted study information throughout the duration of the study 
• 
Visit Schedule: site visit reminder based on the predefined Schedule of Assessments 
and treatment groups 
• 
Medications: drug information, dosage, instructions and reminders 
• 
Goals:  ability to track personal goals (e.g. weight, exercise, sleep, etc.) 
• 
Reminders: reminders for activities/tasks relevant to study compliances   
• 
Site Information: module where patients can enter their site contacts details 
 
The App is available for download to smartphone devices that support iOS and Android. 
The app will contain study-specific information only once activated by a subject. The 
study coordinator will provide the subject with a secure activation code, which they can 
use to activate the app upon their first use. 
 
The App does not collect any subject identified information or clinical data. This app is 
intended for informational purposes only. It is not a substitute for professional medical 
advice.  Subjects should contact the study site investigator or coordinator with any 
medical questions or concerns. 
 

 
Atezolizumab—F. Hoffmann-La Roche Ltd 
178/Protocol MO39196 (IMpassion131), Version 6.0 
Appendix 11  
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 aetiology, 
when clinically indicated. 
Although most immune-mediated adverse events observed with atezolizumab have 
been mild and self-limiting, such events should be recognised 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 for a given patient 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 
Dyspnoea, 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 tumour assessment.   
All pulmonary events should be thoroughly evaluated for other commonly reported 
aetiologies 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 9. 

 
 
Appendix 11 
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
179/Protocol MO39196 (IMpassion131), Version 6.0 
Table 9 
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 11 
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
180/Protocol MO39196 (IMpassion131), Version 6.0 
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 10. 
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 aetiologies should be considered and addressed, as appropriate. 
Table 10 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 
LFT = liver function test. 
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 11 
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
181/Protocol MO39196 (IMpassion131), Version 6.0 
Table 10 
Management Guidelines for Hepatic Events (cont.)  
Event 
Management 
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 aetiology 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 test. 
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 diarrhoea or colitis are provided in Table 11. 
All events of diarrhoea or colitis should be thoroughly evaluated for other more common 
aetiologies.  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 11 
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
182/Protocol MO39196 (IMpassion131), Version 6.0 
Table 11 Management Guidelines for Gastrointestinal Events 
(Diarrhoea or Colitis) 
 
Event 
Management 
Diarrhoea or 
colitis, Grade 1 
• Continue atezolizumab. 
• Initiate symptomatic treatment. 
• Endoscopy is recommended if symptoms persist for > 7 days. 
• Monitor closely. 
Diarrhoea 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 
Diarrhoea or 
colitis, Grade 3 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to GI specialist for evaluation and confirmatory biopsy. 
• Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1−2 mg/kg/day oral prednisone or equivalent 
upon improvement. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c 
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.  
 
 

 
 
Appendix 11 
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
183/Protocol MO39196 (IMpassion131), Version 6.0 
Table 11 Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis) 
(cont.) 
Event 
Management 
Diarrhoea or 
colitis, Grade 4 
• Permanently discontinue atezolizumab and contact Medical Monitor. c 
• Refer patient to GI specialist for evaluation and confirmation biopsy. 
• Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1−2 mg/kg/day oral prednisone or equivalent 
upon improvement. 
• If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
GI = gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent.  The 
acceptable length of the extended period of time must be agreed upon by the investigator and the 
Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  Patients can be re-challenged with atezolizumab only 
after approval has been documented by both the investigator (or an appropriate delegate) and the 
Medical Monitor.  
 
ENDOCRINE EVENTS 
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have 
been associated with the administration of atezolizumab.  Management guidelines for 
endocrine events are provided in Table 12. 
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 11 
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
184/Protocol MO39196 (IMpassion131), Version 6.0 
Table 12 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 

 
 
Appendix 11 
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
185/Protocol MO39196 (IMpassion131), Version 6.0 
Table 12 
Management Guidelines for Endocrine Events (cont.)  
Event 
Management 
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 
Hyperglycaemia, 
Grade 1 or 2  
• Continue atezolizumab. 
• Initiate treatment with insulin if needed. 
• Monitor for glucose control. 
Hyperglycaemia, 
Grade 3 or 4 
• Withhold atezolizumab. 
• Initiate treatment with insulin. 
• Monitor for glucose control. 
• Resume atezolizumab when symptoms resolve and glucose levels 
are stable. 

 
 
Appendix 11 
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
186/Protocol MO39196 (IMpassion131), Version 6.0 
Table 12 
Management Guidelines for Endocrine Events (cont.)  
Event 
Management 
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3  
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to endocrinologist. 
• Perform brain MRI (pituitary protocol). 
• Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• Initiate hormone replacement if clinically indicated. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c 
• For recurrent hypophysitis, treat as a Grade 4 event. 
Hypophysitis 
(pan-hypopituitarism), 
Grade 4  
• Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
• Refer patient to endocrinologist. 
• Perform brain MRI (pituitary protocol). 
• Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• Initiate hormone replacement if clinically indicated. 
MRI = magnetic resonance imaging; TSH = thyroid-stimulating hormone. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent.  The acceptable 
length of the extended period of time must be agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  Patients can be re-challenged with atezolizumab only 
after approval has been documented by both the investigator (or an appropriate delegate) and the 
Medical Monitor.  

 
 
Appendix 11 
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
187/Protocol MO39196 (IMpassion131), Version 6.0 
OCULAR EVENTS 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 13. 
Table 13 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 11 
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
188/Protocol MO39196 (IMpassion131), Version 6.0 
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, 
dyspnoea, 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 aetiology, should be treated according to the guidelines in Table 14. 

 
 
Appendix 11 
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
189/Protocol MO39196 (IMpassion131), Version 6.0 
Table 14 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.a 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c 
Immune-mediated 
myocarditis, Grade 3−4 
• 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. a,b 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids 
over ≥ 1 month. 
ECMO = extracorporeal membrane oxygenation; VAD = ventricular assist device. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent.  The acceptable 
length of the extended period of time must be agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  Patients can be re-challenged with atezolizumab only 
after approval has been documented by both the investigator (or an appropriate delegate) and the 
Medical Monitor. 
 

 
 
Appendix 11 
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
190/Protocol MO39196 (IMpassion131), Version 6.0 
INFUSION-RELATED REACTIONS AND CYTOKINE-RELEASE SYNDROME 
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) or cytokine-
release syndrome (CRS) with atezolizumab may receive premedication with 
antihistamines, anti-pyretics, and/or analgesics (e.g., acetaminophen) for subsequent 
infusions.  Metamizole (dipyrone) is prohibited in treating atezolizumab-associated IRRs 
because of its potential for causing agranulocytosis. 
IRRs are known to occur with the administration of monoclonal antibodies and 
have been reported with atezolizumab.  These reactions, which are thought to be 
due to release of cytokines and/or other chemical mediators, occur within 24 
hours of atezolizumab administration and are generally mild to moderate in 
severity. 
CRS is defined as a supraphysiologic response following administration of any 
immune therapy that results in activation or engagement of endogenous or 
infused T cells and/or other immune effector cells.  Symptoms can be progressive, 
always include fever at the onset, and may include hypotension, capillary leak 
(hypoxia), and end-organ dysfunction (Lee et al. 2019).  CRS has been well 
documented with chimeric antigen receptor T-cell therapies and bispecific T-cell 
engager antibody therapies but has also been reported with immunotherapies 
that target PD-1 or PD-L1 (Rotz et al. 2017; Adashek and Feldman 2019), 
including atezolizumab. 
There may be significant overlap in signs and symptoms of IRRs and CRS, and 
in recognition of the challenges in clinically distinguishing between the two, 
consolidated guidelines for medical management of IRRs and CRS are provided in 
Table 15. 

 
 
Appendix 11 
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
191/Protocol MO39196 (IMpassion131), Version 6.0 
Table 15 
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome 
 
Event 
Management 
Grade 1 a 
Fever b with or 
without 
constitutional 
symptoms  
• Immediately interrupt infusion. 
• Upon symptom resolution, wait for 30 minutes and then 
restart infusion at half the rate being given at the time of 
event onset. 
• If the infusion is tolerated at the reduced rate for 30 minutes, the 
infusion rate may be increased to the original rate. 
• If symptoms recur, discontinue infusion of this dose. 
• Administer symptomatic treatment, c including 
maintenance of IV fluids for hydration. 
• In case of rapid decline or prolonged CRS (> 2 days) or in 
patients with significant symptoms and/or comorbidities, 
consider managing as per Grade 2. 
• For subsequent infusions, consider administration of oral 
premedication with antihistamines, anti-pyretics, and/or 
analgesics, and monitor closely for IRRs and/or CRS. 
 

 
 
Appendix 11 
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
192/Protocol MO39196 (IMpassion131), Version 6.0 
Table 15 
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.) 
Grade 2 a 
Fever b with 
hypotension not 
requiring 
vasopressors 
and/or 
Hypoxia 
requiring low-
flow oxygen d by 
nasal cannula or 
blow-by 
• Immediately interrupt infusion. 
• Upon symptom resolution, wait for 30 minutes and then restart 
infusion at half the rate being given at the time of event onset. 
• If symptoms recur, discontinue infusion of this dose. 
• Administer symptomatic treatment. c 
• For hypotension, administer IV fluid bolus as needed. 
• Monitor cardiopulmonary and other organ function closely (in 
the ICU, if appropriate).  Administer IV fluids as clinically 
indicated, and manage constitutional symptoms and organ 
toxicities as per institutional practice. 
• Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate 
workup and assess for signs and symptoms of HLH or MAS as 
described in this appendix. 
• Consider IV corticosteroids (e.g., methylprednisolone 
2 mg/kg/day or dexamethasone 10 mg every 6 hours). 
• Consider anti-cytokine therapy. e 
• Consider hospitalization until complete resolution of 
symptoms.  If no improvement within 24 hours, manage as per 
Grade 3, that is, hospitalize patient (monitoring in the ICU is 
recommended), permanently discontinue atezolizumab, and 
contact Medical Monitor. 
• If symptoms resolve to Grade 1 or better for 3 consecutive days, 
the next dose of atezolizumab may be administered.   
• For subsequent infusions, consider administration of oral premedication 
with antihistamines, anti-pyretics, and/or analgesics and monitor closely 
for IRRs and/or CRS. 
• If symptoms do not resolve to Grade 1 or better for 
3 consecutive days, contact Medical Monitor. 

 
 
Appendix 11 
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
193/Protocol MO39196 (IMpassion131), Version 6.0 
Table 15 
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.) 
Grade 3 a 
Fever b with 
hypotension 
requiring a 
vasopressor (with 
or without 
vasopressin) 
and/or 
Hypoxia 
requiring high-
flow oxygen d by 
nasal cannula, 
face mask, 
non-rebreather 
mask, or Venturi 
mask 
• Permanently discontinue atezolizumab and contact Medical Monitor. f 
• Administer symptomatic treatment. c 
• For hypotension, administer IV fluid bolus and vasopressor as 
needed. 
• Monitor cardiopulmonary and other organ function closely; 
monitoring in the ICU is recommended.  Administer IV fluids as 
clinically indicated, and manage constitutional symptoms and 
organ toxicities as per institutional practice. 
• Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate 
workup and assess for signs and symptoms of HLH or MAS as 
described in this appendix. 
• Administer IV corticosteroids (e.g., methylprednisolone 
2 mg/kg/day or dexamethasone 10 mg every 6 hours). 
• Consider anti-cytokine therapy. e 
• Hospitalize patient until complete resolution of symptoms.  If 
no improvement within 24 hours, manage as per Grade 4, that 
is, admit patient to ICU and initiate hemodynamic monitoring, 
mechanical ventilation, and/or IV fluids and vasopressors as 
needed; for patients who are refractory to anti-cytokine 
therapy, experimental treatments may be considered at the 
discretion of the investigator and in consultation with the 
Medical Monitor. 
Grade 4 a 
Fever b with 
hypotension 
requiring 
multiple 
vasopressors 
(excluding 
vasopressin) 
and/or 
Hypoxia 
requiring oxygen 
by positive 
pressure (e.g., 
CPAP, BiPAP, 
intubation and 
mechanical 
ventilation) 
• Permanently discontinue atezolizumab and contact Medical 
Monitor. f 
• Administer symptomatic treatment. c 
• Admit patient to ICU and initiate hemodynamic monitoring, 
mechanical ventilation, and/or IV fluids and vasopressors as 
needed.  Monitor other organ function closely.  Manage 
constitutional symptoms and organ toxicities as per 
institutional practice. 
• Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate 
workup and assess for signs and symptoms of HLH or MAS as 
described in this appendix. 
• Administer IV corticosteroids (e.g., methylprednisolone 
2 mg/kg/day or dexamethasone 10 mg every 6 hours). 
• Consider anti-cytokine therapy. e  For patients who are 
refractory to anti-cytokine therapy, experimental treatments g 
may be considered at the discretion of the investigator and in 
consultation with the Medical Monitor. 
• Hospitalize patient until complete resolution of symptoms. 

 
 
Appendix 11 
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
194/Protocol MO39196 (IMpassion131), Version 6.0 
Table 15 
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.) 
ASTCT = American Society for Transplantation and Cellular Therapy; BiPAP = bi-level 
positive airway pressure; CAR = chimeric antigen receptor; CPAP = continuous positive 
airway pressure; CRS = cytokine-release syndrome; CTCAE = Common Terminology 
Criteria for Adverse Events; eCRF = electronic Case Report Form; 
HLH = hemophagocytic lymphohistiocytosis; ICU = intensive care unit; IRR = infusion-
related reaction; MAS = macrophage activation syndrome; NCCN = National Cancer 
Comprehensive Network; NCI = National Cancer Institute. 
Note:  The management guidelines have been adapted from NCCN guidelines for 
management of CAR T-cell−related toxicities (Version 2.2019). 
a Grading system for management guidelines is based on ASTCT consensus grading for 
CRS.  NCI CTCAE v4.0 should be used when reporting severity of IRRs, CRS, or 
organ toxicities associated with CRS on the Adverse Event eCRF.  Organ toxicities 
associated with CRS should not influence overall CRS grading. 
b Fever is defined as temperature ≥ 38°C not attributable to any other cause.  In 
patients who develop CRS and then receive anti-pyretic, anti-cytokine, or 
corticosteroid therapy, fever is no longer required when subsequently determining 
event severity (grade).  In this case, the grade is driven by the presence of 
hypotension and/or hypoxia. 
c Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, 
analgesics, bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or 
dyspnea, additional treatment may be administered as per institutional practice. 
d Low flow is defined as oxygen delivered at ≤ 6 L/min, and high flow is defined as 
oxygen delivered at > 6 L/min. 
e There are case reports where anti-cytokine therapy has been used for treatment of 
CRS with immune checkpoint inhibitors (Rotz et al. 2017; Adashek and Feldman 
2019), but data are limited, and the role of such treatment in the setting of 
antibody-associated CRS has not been established. 
f Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the event.  Patients can be re-challenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the 
Medical Monitor.  For subsequent infusions, administer oral premedication with 
antihistamines, anti-pyretics, and/or analgesics, and monitor closely for IRRs 
and/or CRS.  Premedication with corticosteroids and extending the infusion time 
may also be considered after consulting the Medical Monitor and considering the 
benefit−risk ratio. 
g Refer to Riegler et al. (2019) for information on experimental treatments for CRS. 
 

 
 
Appendix 11 
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
195/Protocol MO39196 (IMpassion131), Version 6.0 
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 16. 
Table 16 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 
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.  
 
 

 
 
Appendix 11 
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
196/Protocol MO39196 (IMpassion131), Version 6.0 
Table 16 
Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.) 
Event 
Management 
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  
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.  
 

 
 
Appendix 11 
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
197/Protocol MO39196 (IMpassion131), Version 6.0 
DERMATOLOGIC EVENTS 
Treatment-emergent rash has been associated with atezolizumab.  The majority of 
cases of rash were mild in severity and self-limiting, 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 17. 
Table 17 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.  
 

 
 
Appendix 11 
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
198/Protocol MO39196 (IMpassion131), Version 6.0 
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 characterisation to 
differentiate between alternative aetiologies. Management guidelines for neurologic 
disorders are provided in Table 18. 
Table 18 Management Guidelines for Neurologic Disorders 
 
Event 
Management 
Immune-mediated 
neuropathy,  
Grade 1 
• Continue atezolizumab. 
• Investigate aetiology. 
Immune-mediated 
neuropathy,  
Grade 2  
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Investigate aetiology. 
• 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.  
 

 
 
Appendix 11 
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
199/Protocol MO39196 (IMpassion131), Version 6.0 
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.  
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 
oedema. 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 aetiology, should be treated according to the guidelines in Table 19. 
Table 19 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. 
 
IMMUNE-MEDIATED NEPHRITIS 
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 
aetiologies (including prerenal and postrenal causes, and concomitant medications such 

 
 
Appendix 11 
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
200/Protocol MO39196 (IMpassion131), Version 6.0 
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.  If no alternative cause of acute kidney injury is identified, patients 
with signs and symptoms of acute kidney injury, in the absence of an identified alternate 
aetiology, should be treated according to the management guidelines for immune-
mediated renal events in Table 20 below. 
Table 20 Management Guidelines for Immune-Mediated 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. 
Note:  Management guidelines are presented by adverse event severity based on NCI CTCAE 
and are applicable to both CTCAE Version 4.0 and CTCAE Version 5.0. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be 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 11 
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
201/Protocol MO39196 (IMpassion131), Version 6.0 
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 
aetiology, should be treated according to the guidelines in Table 21 below. 
Table 21 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 11 
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
202/Protocol MO39196 (IMpassion131), Version 6.0 
Table 21 
Management Guidelines for Immune-Mediated Myositis (cont.) 
Event 
Management 
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, 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 11 
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
203/Protocol MO39196 (IMpassion131), Version 6.0 
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), which are considered to be potential risks for atezolizumab.   
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/µL) 
– 
ANC < 1.0 × 109/L (1000/µL) 
• 
Fasting triglycerides > 2.992 mmol/L (265 mg/dL) and/or fibrinogen < 1.5 g/L 
(150 mg/dL) 
• 
Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
• 
Low or absent natural killer cell activity 
• 
Ferritin > 500 mg/L (500 ng/mL) 
• 
Soluble 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/µL) 
– 
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 22. 

 
 
Appendix 11 
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
204/Protocol MO39196 (IMpassion131), Version 6.0 
Table 22 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 
Adashek ML, Feldman M. Cytokine release syndrome resulting from 
anti−programmed death-1 antibody: raising awareness among community 
oncologist. J Oncol Practice 2019;15:502−4. 
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resource on the Internet]. 2014 [updated 
29 October 2018; cited: 17 May 2019]. Available from: 
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-
hemophagocytic-lymphohistiocytosis. 
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage 
activation syndrome complicating systemic juvenile idiopathic arthritis: a 
European League Against Rheumatism/American College of 
Rheumatology/Paediatric Rheumatology International Trials 
Organisation Collaborative Initiative. Ann Rheum Dis 2016;75:481−9. 
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and 
management of cytokine release syndrome after chimeric antigen receptor 
T-cell therapy. Ther Clin Risk Manag 2019;15:323−35. 
Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient 
receiving PD-1-directed therapy. Pediatr Blood Cancer 2017;64:e26642.