Clinical trial NCT03726879
Conditions: Breast Cancer
Sponsor: Hoffmann-La Roche
Start date: 2019-01-11; Completion date: 2023-08-24
Enrollment: 454 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study (also known as IMpassion050) will evaluate the efficacy and safety of atezolizumab compared with placebo when given in combination with neoadjuvant dose-dense anthracycline (doxorubicin) + cyclophosphamide followed by paclitaxel + trastuzumab + pertuzumab (ddAC-PacHP) in patients with early HER2-positive breast cancer (T2-4, N1-3, M0).

Detailed description:

Arms: arm 1: Participants will receive atezolizumab (atezo) 840 mg IV Q2W for 4 cycles during neoadjuvant phase with ddAC (doxorubicin 60 mg/m2 \& cyclophosphamide 600 mg/m2 IV), followed by atezo 1200 mg IV Q3W for 4 cycles with paclitaxel 80 mg/m2 IV weekly for 12 continuous weeks, trastuzumab 6 mg/kg IV (with initial 8mg/kg IV loading dose) Q3W for 4 cycles, \& pertuzumab 420 mg IV (with initial 840-mg IV loading dose) Q3W for 4 cycles. During adjuvant phase, participants will continue to receive following study treatments Q3W to complete up to 1 year HER2-target therapy inclusive of therapy given both in neoadjuvant and adjuvant setting: atezo 1200 mg IV Q3W, trastuzumab 6 mg/kg IV (with initial 8-mg/kg IV loading dose) Q3W, \& pertuzumab 420 mg IV (with initial 840-mg IV loading dose) Q3W. Participants who do not achieve pCR have option of receiving blinded atezo+trastuzumab emtansine post surgery for 14 cycles. In response to USM DIL dated 3 Feb 2021 treatment with atezo must be discontinued. arm 2: Participants will receive placebo 840 mg IV Q2W for 4 cycles during neoadjuvant phase with ddAC (doxorubicin 60 mg/m2 \& cyclophosphamide 600 mg/m2 IV), followed by placebo 1200 mg IV Q3W for 4 cycles with paclitaxel 80 mg/m2 IV weekly for 12 continuous weeks, trastuzumab 6 mg/kg IV (with initial 8-mg/kg IV loading dose) Q3W for 4 cycles \& pertuzumab 420 mg IV (with initial 840-mg IV loading dose) Q3W for 4 cycles. During adjuvant phase, participants will continue to receive following study treatments Q3W to complete up to 1 year HER2-target therapy inclusive of therapy given both in neoadjuvant \& adjuvant setting: placebo 1200 mg IV Q3W, trastuzumab 6 mg/kg IV (with initial 8-mg/kg IV loading dose) Q3W, \& pertuzumab 420 mg IV (with initial 840-mg IV loading dose) Q3W. Participants who do not achieve pCR have option of receiving blinded atezolizumab + trastuzumab emtansine post surgery for 14 cycles. In response to USM DIL, dated 3 Feb 2021 treatment with placebo must be discontinued.
Interventions: intervention 1: Atezolizumab intervention 2: Placebo intervention 3: Doxorubicin intervention 4: Cyclophosphamide intervention 5: Paclitaxel intervention 6: Trastuzumab intervention 7: Pertuzumab intervention 8: Trastuzumab Emtansine
Intervention descriptions: intervention 1: Atezolizumab will be administered as per the schedule specified in the respective arm. intervention 2: Placebo matched to atezolizumab will be administered as per the schedule specified in the respective arm. intervention 3: Doxorubicin will be administered as per the schedule specified in the respective arm. intervention 4: Cyclophosphamide will be administered as per the schedule specified in the respective arm. intervention 5: Paclitaxel will be administered as per the schedule specified in the respective arm. intervention 6: Trastuzumab will be administered as per the schedule specified in the respective arm. intervention 7: Pertuzumab will be administered as per the schedule specified in the respective arm. intervention 8: Participants without pCR have the option of receiving adjuvant atezolizumab/placebo combined with Trastuzumab Emtansine 3.6 mg/kg IV Q3W.

Protocol documents:
Prot_002.pdf: 
 
Official Title: 
A Phase III, Randomized, Double-Blind, Placebo-Controlled Clinical 
Trial To Evaluate the Efficacy and Safety Of Atezolizumab or Placebo 
in Combination With Neoadjuvant Doxorubicin + Cyclophosphamide 
Followed By Paclitaxel + Trastuzumab + Pertuzumab In Early Her2-
Positive Breast Cancer 
NCT Number: 
NCT03726879 
Document Date: 
Protocol Version 6: 23-February-2023 
 
 


CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche's 
local affiliates, including Genentech, Inc. in the United States.  The information 
contained in this document, especially any unpublished data, is the property of 
F. Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in 
confidence as an investigator, potential investigator, or consultant, for review by you, 
your staff, and an applicable Ethics Committee or Institutional Review Board.  It is 
understood that this information will not be disclosed to others without written 
authorization from Roche except to the extent necessary to obtain informed consent 
from persons to whom the drug may be administered. 
 
Atezolizumab—F. Hoffmann-La Roche Ltd 
Protocol BO40747, Version 6 
PROTOCOL 
TITLE: 
A PHASE III, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED CLINICAL TRIAL TO EVALUATE 
THE EFFICACY AND SAFETY OF ATEZOLIZUMAB OR 
PLACEBO IN COMBINATION WITH NEOADJUVANT 
DOXORUBICIN  CYCLOPHOSPHAMIDE FOLLOWED BY 
PACLITAXEL  TRASTUZUMAB  PERTUZUMAB IN EARLY 
HER2-POSITIVE BREAST CANCER 
PROTOCOL NUMBER: BO40747 
VERSION NUMBER: 
6 
EUDRACT NUMBER: 
2018-001881-40 
NCT NUMBER: 
NCT03726879 
IND NUMBER: 
123277 
TEST PRODUCT: 
Atezolizumab (RO5541267), 
Pertuzumab (RO4368451), 
Trastuzumab (RO0452317), 
Trastuzumab emtansine (RO5304020) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
APPROVAL: 
See electronic signature and date stamp on the final 
page of this document. 


Atezolizumab—F. Hoffmann-La Roche Ltd 
2/Protocol BO40747, Version 6 
PROTOCOL HISTORY 
 
Protocol 
Version 
Date Final 
6 
See electronic date stamp on the final page of this document 
5 
12 February 2021 
4 
14 February 2020 
3 
4 June 2019 
2 
22 March 2019 
1 
9 July 2018 
 
 


Atezolizumab—F. Hoffmann-La Roche Ltd 
3/Protocol BO40747, Version 6 
PROTOCOL AMENDMENT, VERSION 6: 
RATIONALE 
Protocol BO40747 has been amended to update safety information and align with the 
Trastuzumab Emtansine Investigator’s Brochure, Version 16 and Atezolizumab 
Investigator’s Brochure, Version19.  
Additional changes to the protocol are summarized below: 
 
The synopsis has been simplified to align with European Union Clinical Trial 
Regulation (Reg. No. 536/2014) and other guidelines. 
 
The responsibilities of the investigator and the role of the Medical Monitor in 
determining patient eligibility and during study conduct have been clarified 
(Sections 4.1.1, 4.1.2, 4.4.2.2, 4.5.8, 4.5.9, 5.1.10, Appendix 11, and Appendix 12). 
 
The medical term “Wegener granulomatosis” has been replaced by the term 
“granulomatosis with polyangiitis” to align with the updated preferred term in 
MedDRA (Section 4.1.2 and Appendix 9). 
 
A new section of cautionary therapies has been added to indicate that certain 
therapies used to treat chemotherapy-induced thrombocytopenia should be avoided 
in patients in this study (e.g., thrombopoietin receptor agonists, recombinant 
thrombopoietins, recombinant interleukin) to align with the Trastuzumab Emtansine 
Investigator’s Brochure, Version 16 (Section 4.4.2.4). 
 
The email address for withdrawal from the Research Biosample Repository after site 
closure has been corrected (Section 4.5.14.6). 
 
In alignment with the Trastuzumab Emtansine Investigator’s Brochure, Version 16, 
human recombinant thrombopoeitin has been identified as a risk factor for 
prolonged thrombocytopenia in patients who are being treated with trastuzumab 
emtansine (Section 5.1.6.5). 
 
Personal identifiable information (i.e., name and telephone number) for the 
Medical Monitors has been removed from the protocol (front matter and 
Section 5.4.1).  Medical Monitor contact information has been replaced with a 
sentence indicating that this information will be provided separately to sites. 
 
Language has been added to permit the collection of infant health information if a 
female patient or a female partner of a male patient becomes pregnant to align with 
the Trastuzumab Emtansine Risk Management Plan (Sections 5.4.3.1 and 5.4.3.2). 
 
It has been clarified that there is no requirement to report special situations within 
24 hours unless there is a serious adverse event associated with the special 
situation, in which case the serious adverse event must be reported within 24 hours 
(Section 5.4.4). 
 
The Sponsor record retention policy has been clarified (Section 7.1). 
 
A description of the technical and organizational security measures taken to protect 
personal data has been added to align with Roche practices (Section 8.4). 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
4/Protocol BO40747, Version 6 
 
Due to certain local requirements and an alignment of Sponsor process, it has been 
clarified that summaries of clinical study results may be available in health authority 
databases for public access in addition to redacted Clinical Study Reports 
(Section 9.6). 
 
The medical term “primary biliary cirrhosis” has been replaced by the term “primary 
biliary cholangitis” to align with the updated preferred term in MedDRA (Appendix 9). 
 
To align with the Atezolizumab Investigator’s Brochure, Version 19 and Addenda 1 
and 2, the following updates have been made: 
– 
The list of identified risks for atezolizumab has been revised to include myelitis, 
facial paresis, and pericardial disorders (Section 5.1.1). 
– 
Hemophagocytic lymphohistiocytosis has been updated from a potential risk to 
an identified risk associated with atezolizumab and language has been revised 
accordingly (Section 5.1.1) 
– 
The list of adverse events of special interest has been revised to include 
myelitis and facial paresis (Section 5.2.3). 
– 
Appendix 9 has been revised to indicate that caution should be used when 
considering atezolizumab for patients who have previously experienced a 
pericardial disorder while receiving another immunostimulatory anti-cancer 
agent. 
– 
Appendix 9 has been revised to include autoimmune myelitis. 
– 
The adverse event management guidelines have been updated to align with the 
Addendum 1 and Addendum 2 to the Atezolizumab Investigator's Brochure, 
Version 19 (Appendix 9). 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 14 
PROTOCOL SYNOPSIS .................................................................................... 15 
1. 
BACKGROUND ............................................................................ 24 
1.1 
Background on HER2-Positive Breast cancer ......................... 24 
1.2 
Treatment of Early HER2-Positive Breast Cancer ................... 25 
1.3 
Background on Atezolizumab .................................................. 27 
1.3.1 
Clinical Experience with Atezolizumab in Triple-Negative 
Breast Cancer .......................................................................... 27 
1.3.2 
Clinical Experience with Atezolizumab in HER2-Positive 
Breast Cancer .......................................................................... 29 
1.4 
Study Rationale and BenefitRisk Assessment ....................... 31 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 35 
2.1 
Efficacy Objectives .................................................................. 35 
2.1.1 
Co-Primary Efficacy Objective ................................................. 35 
2.1.2 
Secondary Efficacy Objectives ................................................ 36 
2.1.3 
Exploratory Efficacy Objectives ............................................... 36 
2.2 
Safety Objective ....................................................................... 37 
2.3 
Pharmacokinetic Objective ...................................................... 37 
2.4 
Immunogenicity Objectives ...................................................... 37 
2.5 
Biomarker Objectives ............................................................... 38 
3. 
STUDY DESIGN ........................................................................... 38 
3.1 
Discontinuation of Experimental Treatment and Unblinding 
at Study Level .......................................................................... 38 
3.1.1 
Implications of Unblinding on Study Design and 
Assessments ........................................................................... 39 
3.2 
Description of the Study Prior to Stopping Blinded 
Treatment ................................................................................ 39 
3.2.1 
Overview of Study Design........................................................ 39 
3.2.2 
Independent Data Monitoring Committee ................................ 47 
3.3 
End of Study and Length of Study ........................................... 47 
3.4 
Rationale for Study Design ...................................................... 47 
3.4.1 
Rationale for Atezolizumab Dose and Schedule ...................... 47 


 
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3.4.2 
Rationale for Chemotherapy Choice and Schedule ................. 48 
3.4.3 
Rationale for Patient Population .............................................. 49 
3.4.4 
Rationale for Control Group and Combination with 
Atezolizumab ........................................................................... 49 
3.4.5 
Rationale for Trastuzumab Emtansine in Combination with 
Atezolizumab as Adjuvant Treatment Option ........................... 50 
3.4.6 
Rationale for Pathologic Complete Response as Primary 
Endpoint .................................................................................. 51 
3.4.7 
Rationale for Biomarker Assessments ..................................... 51 
3.4.8 
Rationale for Patient-Reported Outcome Assessments ........... 53 
4. 
MATERIALS AND METHODS ...................................................... 55 
4.1 
Patients .................................................................................... 55 
4.1.1 
Inclusion Criteria ...................................................................... 55 
4.1.2 
Exclusion Criteria ..................................................................... 58 
4.2 
Method of Treatment Assignment and Blinding ....................... 61 
4.2.1 
Treatment Assignment ............................................................. 61 
4.2.2 
Blinding .................................................................................... 62 
4.3 
Study Treatment and Other Treatments Relevant to the 
Study Design ........................................................................... 63 
4.3.1 
Study Treatment Formulation, Packaging, and Handling ......... 63 
4.3.1.1 
Atezolizumab and Placebo ...................................................... 63 
4.3.1.2 
Pertuzumab (Perjeta) ............................................................. 64 
4.3.1.3 
Trastuzumab (Herceptin) ....................................................... 64 
4.3.1.4 
Trastuzumab Emtansine (Kadcyla) ........................................ 64 
4.3.1.5 
Chemotherapy ......................................................................... 64 
4.3.2 
Study Treatment Dosage, Administration, and Compliance .... 64 
4.3.2.1 
Atezolizumab and Placebo ...................................................... 65 
4.3.2.2 
Pertuzumab (Perjeta) ............................................................. 66 
4.3.2.3 
Trastuzumab (Herceptin) ....................................................... 67 
4.3.2.4 
Trastuzumab Emtansine (Kadcyla) ........................................ 68 
4.3.2.5 
Chemotherapy ......................................................................... 69 
4.3.3 
Other Required Medication ...................................................... 70 
4.3.4 
Investigational Medicinal Product Accountability ..................... 70 


 
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4.3.5 
Continued Access to Atezolizumab, Pertuzumab, 
Trastuzumab, and Trastuzumab Emtansine ............................ 71 
4.4 
Concomitant Therapy .............................................................. 71 
4.4.1 
Permitted Therapy ................................................................... 71 
4.4.2 
Cautionary Therapy for Atezolizumab-Treated Patients .......... 74 
4.4.2.1 
Corticosteroids and TNF- Inhibitors ....................................... 74 
4.4.2.2 
Medications Given with Precaution due to Effects Related 
to Cytochrome P450 Enzymes ................................................ 74 
4.4.2.3 
Herbal Therapies ..................................................................... 75 
4.4.2.4 
Therapies Given for Thrombocytopenia Induced by 
Chemotherapy .......................................................................... 75 
4.4.3 
Prohibited Therapy .................................................................. 75 
4.5 
Study Assessments ................................................................. 76 
4.5.1 
Informed Consent Forms and Screening Log .......................... 76 
4.5.2 
Medical History, Concomitant Medication, and 
Demographic Data ................................................................... 76 
4.5.3 
Physical Examinations ............................................................. 76 
4.5.4 
Vital Signs ................................................................................ 77 
4.5.5 
Locoregional Tumor Status Assessments ............................... 77 
4.5.6 
Distant Sites Tumor Assessment ............................................. 78 
4.5.7 
Disease Follow-Up and Confirmation of Disease 
Progression or Recurrence ...................................................... 79 
4.5.8 
Surgical Specimen Pathology .................................................. 82 
4.5.9 
Laboratory, Biomarker, and Other Biological Samples ............ 82 
4.5.10 
Electrocardiograms .................................................................. 85 
4.5.11 
Echocardiograms or Multiple-Gated Acquisition Scans ........... 85 
4.5.12 
Patient-Reported Outcomes .................................................... 85 
4.5.12.1 
EORTC QLQ-C30 .................................................................... 86 
4.5.12.2 
FACT-G Single Item GP5 ........................................................ 86 
4.5.12.3 
EQ-5D-5L................................................................................. 87 
4.5.13 
Samples for Whole Genome Sequencing ................................ 87 
4.5.14 
Optional Samples for Research Biosample Repository ........... 88 
4.5.14.1 
Overview of the Research Biosample Repository .................... 88 
4.5.14.2 
Approval by the Institutional Review Board or Ethics 
Committee ............................................................................... 89 


 
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4.5.14.3 
Sample Collection .................................................................... 89 
4.5.14.4 
Confidentiality .......................................................................... 89 
4.5.14.5 
Consent to Participate in the Research Biosample 
Repository................................................................................ 90 
4.5.14.6 
Withdrawal from the Research Biosample Repository ............. 90 
4.5.14.7 
Monitoring and Oversight ......................................................... 91 
4.6 
Treatment, Patient, Study, and Site Discontinuation ................ 91 
4.6.1 
Study Treatment Discontinuation ............................................. 91 
4.6.2 
Patient Discontinuation from Study .......................................... 92 
4.6.3 
Partial Withdrawal from Study .................................................. 92 
4.6.4 
Study Discontinuation .............................................................. 93 
4.6.5 
Site Discontinuation ................................................................. 93 
5. 
ASSESSMENT OF SAFETY ......................................................... 93 
5.1 
Safety Plan .............................................................................. 93 
5.1.1 
Risks Associated with Atezolizumab ........................................ 94 
5.1.2 
Risks Associated with Doxorubicin .......................................... 94 
5.1.2.1 
Cardiomyopathy ....................................................................... 94 
5.1.3 
Risks Associated with Cyclophosphamide ............................... 95 
5.1.4 
Risks Associated with Paclitaxel .............................................. 95 
5.1.5 
Risks Associated with Pertuzumab, Trastuzumab, and 
Trastuzumab Emtansine .......................................................... 96 
5.1.5.1 
Cardiotoxicity ........................................................................... 97 
5.1.5.2 
EGFR-Related Toxicities ....................................................... 100 
5.1.6 
Risks Associated with Trastuzumab Emtansine .................... 100 
5.1.6.1 
Pulmonary Toxicity ................................................................ 100 
5.1.6.2 
Hepatotoxicity ........................................................................ 101 
5.1.6.3 
Left Ventricular Dysfunction ................................................... 101 
5.1.6.4 
Infusion-Related Reactions and Hypersensitivity Reactions .. 102 
5.1.6.5 
Hematologic Toxicity .............................................................. 102 
5.1.6.6 
Hemorrhage ........................................................................... 103 
5.1.6.7 
Neurotoxicity .......................................................................... 103 
5.1.6.8 
Extravasation ......................................................................... 103 
5.1.7 
Risks Associated with Combination Use of Pertuzumab 
with Trastuzumab and Paclitaxel ........................................... 104 


 
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5.1.8 
Risks Associated with Combination Use of Atezolizumab 
and Doxorubicin, Cyclophosphamide, Paclitaxel, 
Trastuzumab, Pertuzumab, or Trastuzumab Emtansine ........ 105 
5.1.9 
General Plan to Manage Safety Concerns ............................ 107 
5.1.10 
Dose Modifications ................................................................ 107 
5.1.10.1 
Dose Modifications of Trastuzumab Emtansine and 
Atezolizumab/Placebo ........................................................... 108 
5.2 
Safety Parameters and Definitions ........................................ 109 
5.2.1 
Adverse Events ...................................................................... 110 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) ................................................................................ 110 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................... 111 
5.2.4 
Selected Adverse Events ....................................................... 112 
5.2.4.1 
Cardiac, General .................................................................... 112 
5.2.4.2 
Asymptomatic Left Ventricular Systolic Dysfunction .............. 112 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................. 113 
5.3.1 
Adverse Event Reporting Period ............................................ 114 
5.3.2 
Eliciting Adverse Event Information ....................................... 114 
5.3.3 
Assessment of Severity of Adverse Events ........................... 114 
5.3.4 
Assessment of Causality of Adverse Events.......................... 115 
5.3.5 
Procedures for Recording Adverse Events ............................ 116 
5.3.5.1 
Infusion-Related Reactions and Cytokine Release 
Syndrome .............................................................................. 116 
5.3.5.2 
Diagnosis versus Signs and Symptoms ................................. 117 
5.3.5.3 
Adverse Events That Are Secondary to Other Events ........... 117 
5.3.5.4 
Persistent or Recurrent Adverse Events ................................ 117 
5.3.5.5 
Abnormal Laboratory Values ................................................. 118 
5.3.5.6 
Abnormal Vital Sign Values ................................................... 119 
5.3.5.7 
Abnormal Liver Function Tests .............................................. 119 
5.3.5.8 
Deaths ................................................................................... 120 
5.3.5.9 
Preexisting Medical Conditions .............................................. 120 
5.3.5.10 
Lack of Efficacy or Worsening of HER2-Positive Breast 
Cancer ................................................................................... 120 


 
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5.3.5.11 
Hospitalization or Prolonged Hospitalization .......................... 121 
5.3.5.12 
Patient-Reported Outcome Data ............................................ 121 
5.3.5.13 
Safety Biomarker Data ........................................................... 121 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................. 121 
5.4.1 
Emergency Medical Contacts ................................................ 122 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest ........................................ 122 
5.4.2.1 
Events That Occur prior to Study Treatment Initiation ........... 122 
5.4.2.2 
Events That Occur after Study Treatment Initiation ............... 122 
5.4.3 
Reporting Requirements for Pregnancies .............................. 123 
5.4.3.1 
Pregnancies in Female Patients ............................................ 123 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ................. 124 
5.4.3.3 
Abortions................................................................................ 124 
5.4.3.4 
Congenital Anomalies/Birth Defects ...................................... 124 
5.4.4 
Reporting Requirements for Cases of Accidental Overdose 
or Medication Error ................................................................ 125 
5.5 
Follow-Up of Patients after Adverse Events........................... 126 
5.5.1 
Investigator Follow-Up ........................................................... 126 
5.5.2 
Sponsor Follow-Up ................................................................ 126 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period .................................................................... 126 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............. 127 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....... 127 
6.1 
Analysis Populations .............................................................. 127 
6.2 
Determination of Sample Size ............................................... 128 
6.2.1 
Type I Error Control ............................................................... 128 
6.3 
Summaries of Conduct of Study ............................................ 128 
6.4 
Summaries of Demographic and Baseline Characteristics .... 129 
6.5 
Efficacy Analyses ................................................................... 129 
6.5.1 
Co-Primary Efficacy Endpoint ................................................ 129 
6.5.2 
Secondary Efficacy Endpoints ............................................... 130 
6.5.2.1 
pCR in the Subgroups ........................................................... 130 


 
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6.5.2.2 
Event-Free Survival ............................................................... 130 
6.5.2.3 
Disease-Free Survival ........................................................... 131 
6.5.2.4 
Overall Survival ...................................................................... 131 
6.5.2.5 
Patient-Reported Outcomes of Role and Physical Function 
and GHS/HRQoL:  EORTC Data ........................................... 132 
6.5.3 
Exploratory Efficacy Endpoints .............................................. 132 
6.5.3.1 
Patient-Reported Outcomes of 
Disease/TreatmentRelated Symptoms, and Emotional 
and Social Function:  EORTC Data ....................................... 132 
6.5.3.2 
Patient-Reported Outcome of Treatment Bother:  FACT-G, 
GP5 Single-Item Data ............................................................ 132 
6.5.3.3 
Health Economic EQ-5D-5L Data .......................................... 133 
6.6 
Safety Analyses ..................................................................... 133 
6.6.1 
Exposure of Study Medication ............................................... 133 
6.6.2 
Adverse Events ...................................................................... 133 
6.6.3 
Laboratory Data ..................................................................... 133 
6.6.4 
Vital Signs .............................................................................. 134 
6.7 
Pharmacokinetic Analyses ..................................................... 134 
6.8 
Immunogenicity Analyses ...................................................... 134 
6.9 
Biomarker Analyses ............................................................... 135 
6.10 
Interim Analyses .................................................................... 135 
6.10.1 
Planned Interim Analyses ...................................................... 135 
6.10.2 
Optional Interim Analyses ...................................................... 135 
7. 
DATA COLLECTION AND MANAGEMENT ............................... 136 
7.1 
Data Quality Assurance ......................................................... 136 
7.2 
Electronic Case Report Forms ............................................... 136 
7.3 
Source Data Documentation .................................................. 136 
7.4 
Use of Computerized Systems .............................................. 137 
7.5 
Retention of Records ............................................................. 137 
8. 
ETHICAL CONSIDERATIONS .................................................... 138 
8.1 
Compliance with Laws and Regulations ................................ 138 
8.2 
Informed Consent .................................................................. 138 
8.3 
Institutional Review Board or Ethics Committee .................... 139 
8.4 
Confidentiality ........................................................................ 140 


 
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8.5 
Financial Disclosure ............................................................... 140 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................... 141 
9.1 
Study Documentation ............................................................ 141 
9.2 
Protocol Deviations ................................................................ 141 
9.3 
Management of Study Quality ................................................ 141 
9.4 
Site Inspections ..................................................................... 141 
9.5 
Administrative Structure ......................................................... 141 
9.6 
Dissemination of Data and Protection of Trade Secrets ........ 142 
9.7 
Protocol Amendments ........................................................... 143 
10. 
REFERENCES............................................................................ 143 
 
 
LIST OF TABLES 
Table 1 
Administration of First and Subsequent Atezolizumab 
Infusions...................................................................................... 66 
Table 2 
Administration of First and Subsequent Infusions of 
Trastuzumab Emtansine ............................................................. 68 
Table 3 
Hormonal Therapy ...................................................................... 73 
Table 4 
Definitions of and Procedures for Confirming Disease 
Recurrence, Death, and Other Noteworthy Events on 
Follow-Up .................................................................................... 80 
Table 5 
Guidance for Managing Overlapping Toxicities ......................... 105 
Table 6 
Dose Modification Scheme for Trastuzumab Emtansine .......... 109 
Table 7 
Reporting Conventions for Left Ventricular Systolic 
Dysfunction/Congestive Heart Failure ....................................... 113 
Table 8 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 115 
Table 9 
Causal Attribution Guidance ..................................................... 116 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 41 
Figure 2 
Documenting Treatment Burden in Patients with Early Breast 
Cancer ........................................................................................ 54 
Figure 3 
Algorithm for Continuation and Discontinuation of Study 
Treatment on the Basis of LVEF Assessment............................. 99 
 


 
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LIST OF APPENDICES 
Appendix 1 Schedule of Activities ..................................................................... 152 
Appendix 2 
 Schedule of Pharmacokinetic and Immunogenicity Samples ... 161 
Appendix 3 
 Schedule of Blood and Tissue Samples for Biomarker 
Analysis..................................................................................... 164 
Appendix 4 
 European Organisation for Research and Treatment of 
Cancer Quality-of-Life QuestionnaireCore 30:  EORTC 
QLQ-C30................................................................................... 166 
Appendix 5 
 Functional Assessment of Cancer TherapyGeneral (FACT-
G) Single-Item GP5 ................................................................... 168 
Appendix 6 
 EuroQol 5-Dimension, 5-Level Questionnaire: EQ-5D-5L ........ 169 
Appendix 7 
 Ventana HER2 IHC Assay ....................................................... 172 
Appendix 8 
 Ventana HER2 ISH Assay ....................................................... 173 
Appendix 9 
 Preexisting Autoimmune Diseases and Immune Deficiencies . 174 
Appendix 10 
 Anaphylaxis Precautions .......................................................... 176 
Appendix 11 
 Overall Guidelines for Management of Patients Who 
Experience Adverse Events ...................................................... 177 
Appendix 12 
 Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab ............................................................................ 187 
Appendix 13 
 Eastern Cooperative Oncology Group Scale of Performance 
Status ........................................................................................ 221 
Appendix 14 
 Guidelines for Management of Adverse Events Associated 
with Trastuzumab Emtansine .................................................... 222 
Appendix 15 
 Guidelines for Management of Adverse Events that are 
Potential Overlapping Toxicities Associated with 
Trastuzumab Emtansine in Combination with Atezolizumab .... 227 
 
 


 
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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE III, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED CLINICAL TRIAL TO EVALUATE 
THE EFFICACY AND SAFETY OF ATEZOLIZUMAB OR 
PLACEBO IN COMBINATION WITH NEOADJUVANT 
DOXORUBICIN  CYCLOPHOSPHAMIDE FOLLOWED BY 
PACLITAXEL  TRASTUZUMAB  PERTUZUMAB IN EARLY 
HER2-POSITIVE BREAST CANCER 
PROTOCOL NUMBER: BO40747 
VERSION NUMBER: 
6 
EUDRACT NUMBER: 
2018-001881-40 
NCT NUMBER: 
NCT03726879 
IND NUMBER: 
123277 
TEST PRODUCT: 
Atezolizumab (RO5541267), 
Pertuzumab (RO4368451), 
Trastuzumab (RO0452317), 
Trastuzumab emtansine (RO5304020) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator's Name  (print) 
 
 
 
 
 
Principal Investigator's Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your local study monitor. 


 
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PROTOCOL SYNOPSIS 
TITLE: 
A PHASE III, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 
CLINICAL TRIAL TO EVALUATE THE EFFICACY AND SAFETY OF 
ATEZOLIZUMAB OR PLACEBO IN COMBINATION WITH NEOADJUVANT 
DOXORUBICIN  CYCLOPHOSPHAMIDE FOLLOWED BY 
PACLITAXEL  TRASTUZUMAB  PERTUZUMAB IN EARLY 
HER2-POSITIVE BREAST CANCER 
PROTOCOL NUMBER: 
BO40747 
VERSION NUMBER: 
6 
EUDRACT NUMBER: 
2018-001881-40 
NCT NUMBER: 
NCT03726879 
IND NUMBER: 
123277 
TEST PRODUCT: 
Atezolizumab (RO5541267), 
Pertuzumab (RO4368451), 
Trastuzumab (RO0452317), 
Trastuzumab emtansine (RO5304020) 
PHASE: 
Phase III 
INDICATION: 
Early HER2-positive breast cancer 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
STUDY RATIONALE 
This study (also known as IMpassion050) will evaluate the efficacy and safety of atezolizumab 
compared with placebo when given in combination with neoadjuvant dose-dense anthracycline 
(doxorubicin)  cyclophosphamide followed by paclitaxel  trastuzumab  pertuzumab 
(ddAC-PacHP) in patients with early human epidermal growth factor 2 (HER2)-positive breast 
cancer at high risk of recurrence (T24, N13, M0). 
OBJECTIVES AND ENDPOINTS 
Specific objectives and corresponding endpoints for the study are outlined below. 
EFFICACY OBJECTIVES 
CO-PRIMARY EFFICACY OBJECTIVE 
The co-primary efficacy objective for this study is to evaluate the efficacy of 
atezolizumab  ddAC-PacHP compared with placebo  ddAC-PacHP in the early breast cancer 
(EBC) setting in the PD-L1positive (IC 1/2/3) and the intent-to-treat (ITT) populations on the 
basis of the following endpoint: 
 
Pathological complete response (pCR), defined as the absence of residual invasive cancer 
on hematoxylin and eosin evaluation of the complete resected breast specimen and all 
sampled regional lymph nodes following completion of neoadjuvant systemic therapy 
(i.e., ypT0/is ypN0 in the current American Joint Committee on Cancer [AJCC] staging 
system, 8th edition) in the PD-L1positive and ITT populations 


 
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SECONDARY EFFICACY OBJECTIVES 
The secondary efficacy objectives for this study are as follows: 
 
To evaluate the efficacy of atezolizumab  ddAC-PacHP compared with 
placebo  ddAC-PacHP in the EBC setting on the basis of the following endpoints: 
- 
pCR (ypT0/is ypN0) based upon hormone receptor status (estrogen receptor 
[ER]/progesterone receptor [PgR] positive or ER/PgR negative) 
- 
pCR (ypT0/is ypN0) in the PD-L1negative (IC 0) population 
- 
Event-free survival (EFS), defined as the time from randomization to the first 
documented disease recurrence, unequivocal tumor progression determined by the 
treating investigator, or death from any cause, whichever occurs first, in all patients and 
based upon hormone receptor status (ER/PgR positive or ER/PgR negative) and PD-L1 
status (IC 0; IC 1/2/3) 
- 
Disease-free survival (DFS), defined as the time from surgery to the first documented 
disease recurrence or death from any cause, whichever occurs first, in all patients who 
undergo surgery and based upon hormone receptor status (ER/PgR positive or ER/PgR 
negative) and PD-L1 status (IC 0; IC 1/2/3) 
- 
Overall survival (OS), defined as the time from randomization to death from any cause 
in all patients and based upon hormone receptor status (ER/PgR positive or ER/PgR 
negative) and PD-L1 status (IC 0; IC 1/2/3) 
 
To evaluate patient-reported outcomes (PROs) of function (role, physical) and 
health-related quality of life (HRQoL) associated with atezolizumab  ddAC-PacHP 
compared with placebo  ddAC-PacHP, as measured by the European Organisation for 
Research and Treatment of Cancer (EORTC) Quality of Life QuestionnaireCore 30 
(QLQ-C30), on the basis of the following endpoint: 
- 
Mean and mean changes from baseline score in function (role, physical) and global 
health status (GHS)/HRQoL by assessment timepoint, and between treatment arms as 
assessed by the functional and GHS/HRQoL scales of the EORTC QLQ-C30 
 
SAFETY OBJECTIVE 
The safety objective for this study is to evaluate the safety of atezolizumab  ddAC-PacHP 
compared with placebo  ddAC-PacHP in the neoadjuvant setting and the safety of 
atezolizumab combined with trastuzumab  pertuzumab (or combined with trastuzumab 
emtansine) compared with placebo combined with trastuzumab  pertuzumab (or combined with 
trastuzumab emtansine) in the adjuvant EBC setting on the basis of the following endpoints: 
 
Incidence and severity of adverse events, with severity determined according to National 
Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 
(NCI CTCAE v5.0) 
 
Change from baseline in targeted vital signs 
 
Change from baseline in targeted clinical laboratory test results 
 
PHARMACOKINETIC OBJECTIVE 
The pharmacokinetic (PK) objective for this study is to characterize the PK profile of 
atezolizumab, pertuzumab, and trastuzumab when given in combination and of atezolizumab 
and trastuzumab emtansine when given in combination on the basis of the following endpoints: 
 
Peak and trough (maximum serum concentration observed [Cmax] and minimum serum 
concentration under steady-state conditions within a dosing interval [Cmin]) of atezolizumab 
concentrations in serum at specified timepoints 
 
Trough concentration for pertuzumab and trastuzumab in serum at specified timepoints 
 
Peak and trough concentration for trastuzumab emtansine in serum at specified timepoints 
 


 
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IMMUNOGENICITY OBJECTIVES 
The immunogenicity objective for this study is to evaluate the immune response to 
atezolizumab, trastuzumab, pertuzumab, and trastuzumab emtansine on the basis of the 
following endpoints: 
 
Incidence of treatment-emergent anti-drug antibodies (ADAs) to atezolizumab and its 
impact on pharmacokinetics, efficacy, and safety 
 
Incidence of treatment-emergent ADAs to trastuzumab, pertuzumab, and trastuzumab 
emtansine 
 
BIOMARKER OBJECTIVES 
The secondary biomarker objectives for this study are as follows: 
 
To evaluate pCR (ypT0/is ypN0), EFS, DFS, and OS based upon PIK3CA mutation status 
 
OVERALL DESIGN AND STUDY POPULATION 
DISCONTINUATION OF EXPERIMENTAL TREATMENT AND UNBLINDING AT 
STUDY LEVEL 
On 26 January 2021, the independent Data Monitoring Committee (iDMC) met and conducted a 
review of unblinded safety and efficacy data.  Following their review of the data, the iDMC 
recommended to stop randomized treatment assignment with atezolizumab or placebo.  Study 
treatment without atezolizumab/placebo should be continued through the completion of the 
adjuvant treatment phase.  On 3 February 2021, the Sponsor issued an “Urgent Safety Measure 
Dear Investigator Letter” (USM DIL) communicating the request to stop treatment with 
atezolizumab or placebo and informed about the unblinding of the study. 
The addition of atezolizumab did not result in an increase in the pCR rate compared with the 
control arm both in the ITT and the PD-L1positive population.  There were four Grade 5 
adverse events in the atezolizumab arm, which occurred in the neoadjuvant phase.  The iDMC 
commented that the difference in death between the two arms was not significant but in the 
margin of significance.  Considering that the majority of the patients had undergone surgery, 
their recommendation was to stop the atezolizumab/placebo treatment administration from an 
ethical perspective. 
IMPLICATIONS OF UNBLINDING ON STUDY DESIGN AND ASSESSMENTS 
Following the discontinuation of atezolizumab or placebo, patients should continue all other 
study drugs without atezolizumab or placebo and follow study assessments and follow-up 
assessments as described in the protocol.  Following the implementation of Protocol Version 5, 
the PK and ADA sample collection for atezolizumab, trastuzumab and pertuzumab (or 
trastuzumab emtansine) is only required at the treatment discontinuation visit. 
The study was unblinded on 5 February 2021 and the unblinding date will be used as the 
clinical cutoff date for the primary analysis.  As per Statistical Analysis Plan, patients with 
missing pCR assessment will be counted as not achieving pCR in the analysis; this includes 
patients who have not yet undergone surgery and pCR assessment due to the early unblinding 
of the study.  Patients who are still in the neoadjuvant phase of the study at the time of 
unblinding should continue their study treatment without atezolizumab or placebo and undergo 
surgery and pathological assessment as per study protocol followed by the adjuvant study 
phase with study treatment excluding atezolizumab or placebo. 
OVERVIEW OF STUDY DESIGN PRIOR TO STOPPING BLINDED TREATMENT 
This is a global Phase III, randomized, double-blind, placebo-controlled study designed to 
evaluate the efficacy, safety, and pharmacokinetics of atezolizumab compared with placebo 
when given in combination with neoadjuvant ddAC-PacHP in patients eligible for surgery with 
early HER2-positive breast cancer at high risk of recurrence (T24, N13, M0). 


 
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Several key aspects of the study design and study population are summarized below. 
Phase: 
Phase III 
Population Type: 
Adult patients 
Control Method: 
Placebo 
Population Diagnosis 
or Condition: 
Early HER2-positive 
breast cancer 
Interventional 
Model: 
Parallel group 
Population Age: 
 18 years of age 
Test Compounds: 
Atezolizumab 
(RO5541267), 
Pertuzumab 
(RO4368451), 
Trastuzumab 
(RO0452317), 
Trastuzumab 
emtansine 
(RO5304020) 
Site Distribution: 
Multi-site 
Active Comparator: 
Not applicable 
Study Intervention 
Assignment Method: 
Randomization and 
stratification 
Number of Arms: 
Two 
Number of 
Participants to Be 
Enrolled: 
Approximately 453 
 
STUDY TREATMENT 
The investigational medicinal products for this study are atezolizumab, trastuzumab, 
pertuzumab, trastuzumab emtansine, doxorubicin, cyclophosphamide, and paclitaxel. 
ATEZOLIZUMAB AND PLACEBO 
During the neoadjuvant phase, atezolizumab/placebo will be administered by IV infusion at a 
fixed dose of 840 mg on Day 1 of each 14-day cycle during Cycles 14, and 1200 mg on Day 1 
of each 21-day cycle during Cycles 58.  During the adjuvant phase (postoperatively), 
atezolizumab/placebo will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 
of each 21-day cycle (maximum of 22 cycles [neoadjuvant  adjuvant phases]).  
Atezolizumab/placebo should be administered as the first infusion. 
Treatment will continue as scheduled or until disease progression, recurrence of disease, or 
unmanageable toxicity. 
Administration of atezolizumab will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to manage 
potentially serious reactions.  For anaphylaxis precautions, see the protocol.  Atezolizumab 
infusions will be administered per the instructions outlined in the protocol. 
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 
Guidelines for medical management of infusion-related reactions (IRRs) are provided in the 
protocol. 
No dose modification for atezolizumab is allowed. 
PERTUZUMAB 
Pertuzumab is given as a fixed nonweight-based dose of 840-mg IV loading dose, then 
420 mg IV Q3W.  Pertuzumab will be administered on Day 1 of a 21-day cycle, to complete up 
to a total duration of 52 weeks (i.e., maximum of 18 cycles within 1 year) of HER2-targeted 
therapy, inclusive of therapy given both in the neoadjuvant and adjuvant setting.  
Atezolizumab/placebo should be administered prior to pertuzumab and trastuzumab.  The order 
of administration of pertuzumab and trastuzumab is according to investigator preference. 


 
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The initial dose of pertuzumab will be administered over 60 ( 10) minutes, and patients will be 
observed for a further 60 minutes.  The infusion should be slowed or interrupted if the patient 
experiences infusion-related symptoms.  If the infusion is well tolerated, subsequent doses may 
be administered over 30 ( 10) minutes, and patients will be observed for a further 30 minutes 
for infusion-related symptoms such as fever or chills.  All infusion-related symptoms must have 
resolved before trastuzumab or chemotherapy is given or the patient is discharged.  Patients 
who experience infusion-related symptoms may be premedicated with analgesics and 
antihistamines for subsequent infusions. 
Guidelines for dosage modification and treatment interruption or discontinuation are provided in 
the protocol.  No dose reductions are allowed for pertuzumab.  If the patient misses a dose of 
pertuzumab for any cycle and the time between doses is  6 weeks, a reloading dose of 
pertuzumab (840 mg) should be given.  Subsequent maintenance pertuzumab (420 mg) will 
then be given Q3W, starting 3 weeks later. 
If the interval between the first dose of adjuvant pertuzumab and the last dose of neoadjuvant 
pertuzumab is 6 weeks or more, a reloading dose of 840 mg of pertuzumab is required. 
TRASTUZUMAB 
Trastuzumab is given as an 8-mg/kg IV loading dose and then 6 mg/kg IV Q3W.  Trastuzumab 
will be administered on Day 1 of a 21-day cycle, to complete up to a total duration of 52 weeks 
(i.e., maximum of 18 cycles within 1 year) of HER2-targeted therapy, inclusive of therapy given 
both in the neoadjuvant and adjuvant setting.  Atezolizumab/placebo should be administered 
prior to pertuzumab and trastuzumab.  The order of administration of pertuzumab and 
trastuzumab is according to investigator preference. 
Weight should be recorded during screening and on Day 1 of each cycle for all patients. The 
baseline weight for a patient will be that measured on Cycle 1, Day 1.  The amount of 
trastuzumab to be administered must be recalculated if the patient’s body weight has changed 
by  10% (increased or decreased) from the Cycle 1, Day 1 weight.  The amount of trastuzumab 
administered is calculated according to the patient’s actual body weight, with no upper limit. 
The initial dose of trastuzumab will be administered over 90 ( 10) minutes, and patients will be 
observed for at least 30 minutes from the end of the infusion for infusion-related symptoms such 
as fever or chills.  Interruption or slowing of the infusion may help control such symptoms and 
may be resumed when symptoms abate.  If the infusion is well tolerated, subsequent infusions 
may be administered over 30 ( 10) minutes, and patients will be observed for a further 
30 minutes.  All infusion-related symptoms must have resolved before pertuzumab or 
chemotherapy is given or the patient is discharged.  Patients who experience infusion-related 
symptoms may be premedicated with analgesics and antihistamines for subsequent infusions. 
Guidelines for dosage modification and treatment interruption or discontinuation are provided in 
the protocol.  No dose reductions are allowed for trastuzumab.  If the patient misses a dose of 
trastuzumab for any cycle and the time between doses is  6 weeks, a reloading dose of 
trastuzumab (8 mg/kg) should be given.  Subsequent maintenance trastuzumab (6 mg/kg) 
doses will then be given Q3W, starting 3 weeks later. 
If the interval between the first dose of adjuvant trastuzumab and the last dose of neoadjuvant 
trastuzumab is 6 weeks or more, a reloading dose of 8 mg/kg of trastuzumab is required. 
TRASTUZUMAB EMTANSINE 
Trastuzumab emtansine will be given at a dose of 3.6 mg/kg by IV infusion Q3W.  The dose of 
trastuzumab emtansine administered will be determined on the basis of the baseline weight of 
the patient.  Weight will be measured at each visit and the dose must be re-adjusted for weight 
changes  10% compared with the previous visit or baseline.  The investigator may choose to 
recalculate the dose at every cycle using actual weight at that time, in accordance to local 
practice.  Administration may be delayed to assess or treat adverse events.  Dose reduction will 
be allowed, following the dose reduction levels provided in the protocol.  Once a dose has been 
reduced for an adverse event(s), it must not be re-escalated. 
Trastuzumab emtansine should be administered in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to manage 
potentially serious reactions.  Trastuzumab emtansine will be administered after the infusion of 
atezolizumab or placebo. 


 
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CHEMOTHERAPY 
Chemotherapy will be administered in the neoadjuvant setting as follows: 
 
Doxorubicin 60 mg/m2 IV on Day 1 of a 14-day cycle for 4 cycles (Cycles 14); with  
 
Cyclophosphamide 600 mg/m2 IV on Day 1 of a 14-day cycle for 4 cycles (Cycles 14); 
followed by 
 
Paclitaxel 80 mg/m2 IV weekly for 12 continuous weeks (Cycles 58) 
 
The dose of chemotherapy is calculated according to the patient’s BSA.  The BSA and the 
amount of drug administered must be recalculated if the patient’s body weight has changed by 
 10% (increased or decreased) from baseline.  Recalculation of the amount of drug 
administered on the basis of smaller changes in body weight or BSA is at the investigators’ 
discretion. 
There is no mandatory delay between atezolizumab/placebo and ddAC chemotherapy, 
assuming the infusion is well tolerated. 
See the protocol for details on the dosage and administration of doxorubicin, 
cyclophosphamide, and paclitaxel. 
DURATION OF PARTICIPATION 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 54 months, assuming a recruitment period of approximately 
18 months, and follow-up for 36 months from the date of enrollment of the last patient in the 
study. 
COMMITTEES 
Independent Committees: Independent Data Monitoring Committee 
Other Committees: 
Not applicable 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADA 
anti-drug antibody, also called anti-therapeutic antibody 
AJCC 
American Joint Committee on Cancer 
ASCO 
American Society of Clinical Oncology 
AV 
atrioventricular 
BSA 
body surface area 
Cmax 
maximum serum concentration observed 
Cmin 
minimum serum concentration under steady-state 
conditions within a dosing interval 
COPD 
chronic obstructive pulmonary disease 
CSR 
Clinical Study Report 
CT 
computed tomography (scan) 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating-tumor DNA 
ddAC 
dose-dense anthracycline 
(doxorubicin  cyclophosphamide) 
ddAC-PacHP 
dose-dense anthracycline 
(doxorubicin  cyclophosphamide) followed by 
paclitaxel  trastuzumab  pertuzumab 
DFS 
disease-free survival 
DLT 
dose-limiting toxicity 
EBC 
early breast cancer 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
ECHO 
echocardiogram 
EDC 
electronic data capture 
EFS 
event-free survival 
EMA 
European Medicines Agency 
EORTC 
European Organisation for Research and Treatment of 
Cancer 
EQ-5D-5L 
EuroQol 5-Dimension, 5-Level (questionnaire) 
ER 
estrogen receptor 
ESMO 
European Society for Medical Oncology 
FACT-G 
Functional Assessment of Cancer TherapyGeneral 
FDA 
Food and Drug Administration 
FEC 
5-fluorouracil, epirubicin, and cyclophosphamide 
FFPE 
formalin-fixed, paraffin-embedded 
G-CSF 
granulocyte colonystimulating factor 


 
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Abbreviation 
Definition 
EGFR 
epidermal growth factor receptor 
GHS 
global health status 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HER2 
human epidermal growth factor 2 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
hazard ratio 
HRQoL 
health-related quality of life 
IC 
tumor-infiltrating immune cell 
ICH 
International Council for Harmonisation 
iDCC 
independent Data Coordinating Center 
iDMC 
independent Data Monitoring Committee 
IHC 
immunohistochemistry 
IL-2 
interleukin-2 
ILD 
interstitial lung disease 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
ISH 
in situ hybridization 
ITT 
intent-to-treat (population) 
IxRS 
interactive voice or web-based response system 
LDH 
lactate dehydrogenase 
NE 
not evaluable 
LN 
lymph node 
LVEF 
left ventricular ejection fraction 
LVSD 
left ventricular systolic dysfunction 
MRI 
magnetic resonance imaging 
MUGA 
multiple-gated acquisition (scan) 
NAST 
neoadjuvant systemic therapy 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria 
for Adverse Events 
NGS 
next-generation sequencing 


 
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Abbreviation 
Definition 
NRH 
nodular regenerative hyperplasia 
NSCLC 
nonsmall cell lung cancer 
NYHA 
New York Heart Association 
OS 
overall survival 
PacHP 
paclitaxel  trastuzumab  pertuzumab 
pCR 
pathological complete response 
PET 
positron emission tomography 
PFS 
progression-free survival 
PgR 
progesterone receptor 
PK 
pharmacokinetic 
PRO 
patient-reported outcome 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
QLQ-C30 
Quality-of-Life QuestionnaireCore 30 
RBR 
Research Biosample Repository 
SAP 
Statistical Analysis Plan 
SOC 
standard-of-care 
T3 
triiodothyronine 
TC 
tumor cell 
TIL 
tumor-infiltrating lymphocyte 
TNBC 
triple-negative breast cancer 
TNF- 
tumor necrosis factor- 
ULN 
upper limit of normal 
USM DIL 
Urgent Safety Measure Dear Investigator Letter 
WES 
whole exome sequencing 
WGS 
whole genome sequencing 
 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON HER2-POSITIVE BREAST CANCER 
Globally, breast cancer is the second most common invasive malignancy and the most 
common cause of cancer-related mortality in women.  An estimated 1.7 million new 
breast cancer cases were diagnosed in 2012 (25% of all cancers in women) and there 
were 521,900 deaths (DeSantis et al. 2015; Ferlay et al. 2015).  The majority of breast 
cancers in the Western world is diagnosed when the cancer is still confined to the 
breast, with or without locoregional lymph node spread (Sant et al. 2003; 
Jemal et al. 2011; Ferlay et al. 2013; Howlader et al. 2016).  At these early stages (IIII, 
early breast cancer [EBC]), the largely asymptomatic disease is usually operable and 
can be treated with curative intent. 
Approximately 1 in 5 women diagnosed with EBC will have human epidermal growth 
factor 2 (HER2)-positive disease (Wolff et al. 2013).  Breast cancers over-expressing 
HER2 are the most aggressive, and while current therapies have improved patient 
outcomes, up to 1 in 4 women with HER2-positive EBC will experience recurrence or 
death within 1011 years of diagnosis, despite treatment with adjuvant trastuzumab plus 
standard chemotherapy (Perez et al. 2014; Slamon et al. 2016; Cameron et al. 2017).  
In those patients treated with neoadjuvant trastuzumab and pertuzumab with standard 
chemotherapy, 5-year disease-free survival (DFS) rates sit at 84% (Gianni et al. 2016). 
Patients who relapse with metastatic or unresectable disease are generally incurable.  
Overall (i.e., all subtypes of breast cancer, including HER2-negative disease), patients 
with metastatic disease have a median survival of approximately 24 months and a 
5-year life expectancy of 18%26% in the United States and Europe (Sant et al. 2003; 
Howlader et al. 2016).  With the advent of pertuzumab, life expectancy for patients with 
metastatic HER2-positive breast cancer has greatly improved with an observed median 
overall survival (OS) of 56.5 months in the CLEOPATRA study.  Nevertheless, more 
than 50% of patients receiving first-line treatment with trastuzumab, pertuzumab, and a 
taxane for metastatic disease die within 5 years (Swain et al. 2015). 
New active agents are still required for patients with HER2-positive breast cancer, which 
is estimated to account for approximately 6,0008,000 deaths per year in the United 
States, 19,00026,000 deaths per year in Europe, and approximately 
78,000104,000 deaths per year globally (DeSantis et al. 2015; Ferlay et al. 2015; 
Howlader et al. 2016).  Since metastatic disease is currently incurable, improving the 
results of initial therapy, when the disease is still localized to the breast and regional 
lymph nodes but without distant metastases offers the best chance of cure.  For patients 
who are not cured, improved initial therapy may also produce meaningful delays in 
disease recurrence and death. 


 
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1.2 
TREATMENT OF EARLY HER2-POSITIVE BREAST CANCER 
The treatment and prognosis of patients with HER2-positive breast cancer have been 
transformed by the advent of HER2-targeted agents.  The humanized monoclonal 
antibody trastuzumab (Herceptin), which binds to the extracellular domain of HER2, is 
approved for use as a single agent or in combination with chemotherapy or hormonal 
therapy in the metastatic setting, and as (neo)adjuvant treatment for patients with 
early-stage HER2-positive breast cancer.  Globally, trastuzumab-based therapy is the 
recommended treatment for patients with HER2-positive early-stage breast cancer who 
do not have contraindications for its use (Herceptin Prescribing Information; 
European Society for Medical Oncology [ESMO] guidelines [Senkus et al. 2015]; 
National Comprehensive Cancer Network [NCCN] Guidelines, Version 1.2017 
[Gradishar et al. 2017]). 
An improvement to standard trastuzumab therapy for HER2-positive EBC comes with 
the addition of another HER2-targeted therapy, pertuzumab (Perjeta), approved in 
many countries for the treatment of HER2-positive metastatic breast cancer and for 
neoadjuvant use in patients with high-risk, HER2-positive EBC.  This combination has 
been adopted in global guidelines for use in these patients in the neoadjuvant setting 
(Perjeta Prescribing Information; ESMO guidelines [Senkus et al. 2015]; 
NCCN Guidelines, Version 1.2017 [Gradishar et al. 2017]).  Pertuzumab has also been 
recently approved in the United States, Europe, and other countries throughout the world 
for post-surgery (adjuvant) treatment of HER2-positive EBC at high risk of recurrence 
(Perjeta Prescribing Information; NCCN 2019; Hammond et al. 2010). 
In HER2-positive EBC, neoadjuvant pertuzumab  trastuzumab  docetaxel provides a 
statistically significant and clinically meaningful improvement in pathological complete 
response (pCR) rates over trastuzumab  docetaxel alone (45.8% vs. 29.0%; p  0.0141; 
Gianni et al. 2012).  Patients in this study went on to receive additional chemotherapy 
following surgery regardless of pCR status.  In a descriptive analysis, 5-year DFS rates 
were reported to be higher in those patients who received neoadjuvant 
pertuzumab  trastuzumab  docetaxel than those patients who received 
trastuzumab  docetaxel alone (hazard ratio [HR]  0.60; 0.281.27).  In a study in which 
neoadjuvant pertuzumab and trastuzumab were evaluated with either 
anthracycline-based chemotherapy or carboplatin-based chemotherapy, pCR rates 
(ypT0/is, ypN0 in the current American Joint Committee on Cancer [AJCC] staging 
system) for all regimens ranged from 57.3%66.2%, with the highest pCR rate being 
achieved in the docetaxel  carboplatin  trastuzumab  pertuzumab regimen 
(Schneeweiss et al. 2013).  Supporting these results, in the BERENICE study 
(Study WO29217), pCR (ypT0/is, ypN0) rates in two neoadjuvant regimens containing 
pertuzumab  trastuzumab  taxane and chemotherapy were high in both treatment arms 
(61.8% [Cohort A; dose-dense doxorubicin and cyclophosphamide (ddAC)-taxane]) and 
60.7% [Cohort B; 5-fluorouracil, epirubicin, and cyclophosphamide (FEC)-taxane]; 
Swain et al. 2018). 


 
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Neratinib (Nerlynx) is a HER2-targeted tyrosine kinase inhibitor that has recently been 
approved for use in the United States as additional adjuvant therapy in patients with 
early-stage HER2-positive breast cancer (Nerlynx Prescribing Information; 
Chan et al. 2016]). 
Trastuzumab emtansine is an approved treatment for patients with HER2-positive 
advanced breast cancer who have received therapy with trastuzumab and a taxane and 
who have received prior therapy for metastatic disease or developed disease recurrence 
during or within 6 months of completing adjuvant therapy (Verma et al 2012; 
NCCN 2019).  Study BO27938 (Katherine) was designed to investigate the effect of 
trastuzumab emtansine in patients with HER2-positive early breast cancer.  The study 
was a randomized, multicenter, open-label Phase III study to evaluate the efficacy and 
safety of trastuzumab emtansine compared with trastuzumab as adjuvant therapy for 
patients with HER2-positive early breast cancer who have residual tumor present in the 
breast or axillary lymph nodes following neoadjuvant therapy containing a taxane and 
trastuzumab.  Results showed that invasive DFS was significantly improved with 
trastuzumab emtansine compared with trastuzumab (HR  0.50; 95% CI: 0.39 to 0.64; 
p  0.001; von Minckwitz et al 2019).  The estimated percentage of patients free of 
invasive disease at 3 years from randomization was 88.3% with trastuzumab emtansine 
and 77.0% with trastuzumab.  A higher proportion of patients receiving trastuzumab 
emtansine compared with patients receiving trastuzumab experienced Grade  3 
adverse events (25.7% vs. 15.4%), serious adverse events (12.7% vs. 8.1%), and 
adverse events leading to discontinuation of study drug (18.0% vs. 2.1%).  The 
proportion of patients receiving adjuvant radiotherapy was 84.2% in the trastuzumab 
emtansine arm and 81.9% in the trastuzumab arm (Primary Clinical Study Report [CSR] 
Study BO27938, Report Number 1087528, January 2019).  Higher rates of pulmonary 
toxicities, including pneumonitis and radiation pneumonitis, were reported in the 
trastuzumab emtansine arm (21 patients; 2.8%) compared with the trastuzumab arm 
(6 patients; 0.8%).  In the trastuzumab emtansine arm, 1.5% of patients (n  11) 
experienced radiation pneumonitis, 1.1% of patients (n  8) experienced pneumonitis, 
0.1% of patients (n  1) experienced pulmonary fibrosis, and 0.1% of patients (n  1) 
experienced pulmonary radiation injury.  In the trastuzumab arm, 0.7% of patients (n  5) 
experienced radiation pneumonitis, 0.1% of patients (n  1) experienced pneumonitis; no 
patient experienced pulmonary fibrosis or pulmonary radiation injury.  In the trastuzumab 
emtansine arm, the majority of patients (18 of 21) experienced pulmonary toxicities of 
Grade 1 or 2.  Of the 11 patients in the trastuzumab emtansine arm who experienced 
radiation pneumonitis, the event was Grade 1 or 2 in 9 patients; 2 patients experienced 
Grade 3 events.  All events of radiation pneumonitis resolved and were reported in 
patients who received radiation concurrent with adjuvant trastuzumab emtansine.  Of the 
8 patients in the trastuzumab emtansine arm who experienced pneumonitis, the event 
was Grade 1 or 2 in 7 patients; 1 patient experienced a Grade 3 event of pneumonitis.  
Trastuzumab emtansine was withdrawn in all but one patient who experienced 
pneumonitis and all events resolved or resolved with sequelae 


 
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(Primary CSR Study BO27938, Report Number 1087528, January 2019).  Based on the 
results of the Katherine study, the U.S. Food and Drug Administration (FDA) and 
European Commission have approved trastuzumab emtansine in the adjuvant setting for 
patients with HER2-positive early breast cancer who have residual invasive disease after 
neoadjuvant taxane and trastuzumab-based treatment. 
1.3 
BACKGROUND ON ATEZOLIZUMAB 
Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD-L1 and inhibits 
the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), 
both of which function as inhibitory receptors expressed on T cells.  Therapeutic 
blockade of PD-L1 binding by atezolizumab has been shown to enhance the magnitude 
and quality of tumor-specific T-cell responses, resulting in improved anti-tumor activity 
(Fehrenbacher et al. 2016; Rosenberg et al. 2016).  Atezolizumab has minimal binding 
to Fc receptors, thus eliminating detectable Fc-effector function and associated 
antibody-mediated clearance of activated effector T cells. 
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients 
and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant 
therapy settings, as well as in combination with chemotherapy, targeted therapy, and 
cancer immunotherapy. 
Atezolizumab is approved for the treatment of urothelial carcinoma, nonsmall cell lung 
cancer (NSCLC), small cell lung cancer, hepatocellular carcinoma, melanoma, and 
triple-negative breast cancer (TNBC).  Refer to the atezolizumab Investigator’s Brochure 
for further details. 
1.3.1 
Clinical Experience with Atezolizumab in Triple-Negative 
Breast Cancer 
Atezolizumab is currently being tested in multiple Phase I, II, and III studies, both as 
monotherapy and in combination with several anti-cancer therapies in multiple 
indications.  See the Atezolizumab Investigator’s Brochure for full study descriptions and 
available data. 
The available safety and efficacy data in TNBC are primarily from three studies: 
 
Study PCD4989g is a Phase Ia, multicenter, first-in-human, open-label, 
dose-escalation trial evaluating the safety, tolerability, immunogenicity, 
pharmacokinetics, exploratory pharmacodynamics, and preliminary evidence of 
biologic activity of atezolizumab monotherapy in patients with locally advanced or 
metastatic solid malignancies or hematologic malignancies.  Data from the TNBC 
cohort have been reported and demonstrate promising safety and efficacy results 
regardless of line of therapy and PD-L1 expression (Schmid et al. 2017). 


 
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 
Study GP28328 is a Phase Ib multi-cohort trial of the safety and pharmacology of 
atezolizumab administered with bevacizumab and/or chemotherapy in patients with 
advanced solid tumors.  Arm F of the trial is evaluating atezolizumab administered in 
combination with weekly nab-paclitaxel in patients with TNBC.  Data from Arm F 
have been submitted for publication and support the use of atezolizumab in 
combination with chemotherapy in patients with TNBC.  Confirmed responses were 
seen in 53.8% (95% CI: 25.1% to 80.8%) of patients with first-line metastatic TNBC 
and 39.4% (95% CI: 22.9% to 57.98%) of all patients regardless of line of therapy 
and PD-L1 expression.  No new safety signals were seen (Adams et al. 2016).  
Results from Study GP28328 support the hypothesis that tumor-cell killing by 
cytotoxic chemotherapy may expose the immune system to high levels of tumor 
antigens.  Boosting tumor-specific T-cell immunity in this setting by blocking the 
PD-L1 pathway may result in deeper and more durable responses than those 
observed with standard chemotherapy alone, and these responses may reasonably 
occur in tumors regardless of PD-L1 expression (Merritt et al. 2003; 
Apetoh et al. 2007). 
 
Study WO29522 (IMpassion130) is a Phase III, global, multicenter, double-blind, 
two-arm, randomized, placebo-controlled study designed to evaluate the efficacy 
and safety of atezolizumab administered with nab-paclitaxel in patients with 
metastatic or unresectable locally advanced TNBC who have not received prior 
systemic therapy for metastatic breast cancer.  At the final analysis of 
progression-free survival (PFS) in the intent-to-treat (ITT) and the PD-L1positive 
patient population, a statistically significant benefit was observed with the addition of 
atezolizumab to nab-paclitaxel with a median PFS of 5.5 months in the control arm 
and 7.2 months in the experimental arm (HR  0.80; 95% CI, 0.690.92; p  0.002) in 
the ITT population and a median PFS of 5.0 months in the control arm and 
7.5 months in the experimental arm (HR  0.62; 95% CI: 0.49 to 0.78; p  0.001) in 
the PD-L1positive population (Schmid et al. 2018). 
An interim analysis of OS was performed.  The 16% reduction in the risk of death 
with atezolizumab  nab-paclitaxel compared with placebo  nab-paclitaxel did not 
cross the interim boundary for statistical significance (HR: 0.759, available 
  0.0065), with a stratified HR of 0.84; 95% CI: 0.69 to 1.02; p  0.0840.  
The Kaplan-Meier estimated median OS was nearly 4 months longer in the 
atezolizumab  nab-paclitaxel arm (21.3 months vs. 17.6 months in the 
placebo  nab-paclitaxel arm).  No formal testing of OS was performed in the 
PD-L1positive population because hierarchy of testing indicates formal testing can 
only occur if OS is statistically significant in the ITT population first.  However, OS 
results were unprecedented in the PD-L1positive population.  A clinically 
meaningful reduction in the risk of death of 38% was observed with 
atezolizumab  nab-paclitaxel compared with placebo  nab-paclitaxel (stratified 
HR  0.62; 95% CI: 0.45 to 0.86).  This was accompanied by a 10-month 
prolongation in the Kaplan-Meier estimated median OS in the 
atezolizumab  nab-paclitaxel arm (25.0 months vs. 15.5 months 
placebo  nab-paclitaxel). 


 
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 
Safety results from IMpassion130 are consistent with the known safety profile of 
atezolizumab monotherapy and atezolizumab in combination therapy, with no new 
safety concerns observed.  The overall safety profile of atezolizumab and 
nab-paclitaxel is concordant between the PD-L1positive and the overall 
safety-evaluable population. 
 
Ongoing studies exploring atezolizumab combinations in TNBC include the following: 
 
Study WO39392 (IMpassion031) is a Phase III, randomized, placebo-controlled 
study evaluating the safety and efficacy of neoadjuvant nab-paclitaxel followed by 
dose-dense doxorubicin and cyclophosphamide administered in combination with 
either atezolizumab or placebo in early TNBC. 
 
Study WO39391 (IMpassion030) is a Phase III, randomized study evaluating the 
safety and efficacy of adjuvant paclitaxel followed by dose-dense anthracycline and 
cyclophosphamide with or without atezolizumab in early TNBC. 
 
Study NSABP B-59/GBG 96-GeparDouze is a randomized, double-blind Phase III 
clinical trial of neoadjuvant chemotherapy with atezolizumab or placebo in patients 
with TNBC followed by adjuvant atezolizumab or placebo (Geyer et al. 2018). 
 
1.3.2 
Clinical Experience with Atezolizumab in HER2-Positive 
Breast Cancer 
Ongoing studies exploring atezolizumab combinations in HER2-positive patients include 
the following: 
 
Study GO29831 is a Phase Ib open-label, multi-cohort study.  This study includes 
cohorts that evaluate the safety and pharmacokinetics of atezolizumab in 
combination with trastuzumab and pertuzumab or atezolizumab in combination with 
trastuzumab emtansine in patients with HER2-positive breast cancer.  Enrollment in 
the study has been completed with a total of 73 patients with HER2-positive breast 
cancer (early or metastatic). 
– 
Cohort 1A has enrolled 6 patients with HER2-positive metastatic breast cancer 
who received atezolizumab in combination with trastuzumab and pertuzumab.  
After 6 patients in Cohort 1A were treated for at least 1 cycle, no patients 
experienced a dose-limiting toxicity (DLT). 
– 
Cohort 1F has enrolled a total of 6 patients with HER2-positive metastatic 
breast cancer who received atezolizumab in combination with docetaxel, 
trastuzumab, and pertuzumab.  There was 1 patient among the first 3 patients 
enrolled in Cohort 1F who experienced an event that met the protocol definition 
of a DLT.  However, stopping rules for enrollment to Cohort 1F as defined in the 
protocol were not met and enrollment of the remaining 3 patients was 
completed. 
– 
Cohort 2D has enrolled 1 patient with HER2-positive metastatic breast cancer 
who received atezolizumab in combination with trastuzumab and pertuzumab.  
This cohort was subsequently closed for resource alignment reasons unrelated 
to patient safety and efficacy. 


 
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– 
Cohort 2A has enrolled a total of 20 patients with HER2-positive EBC who 
received 2 cycles of atezolizumab in combination with trastuzumab and 
pertuzumab with sequential tumor biopsies for biomarkers, followed by 
standard-of-care (SOC) pre-operative docetaxel, carboplatin, trastuzumab, and 
pertuzumab and surgery.  Cohort 2B has enrolled 20 patients with 
HER2-positive EBC who received 2 cycles of atezolizumab in combination with 
trastuzumab emtansine with sequential tumor biopsies for biomarkers, followed 
by SOC pre-operative docetaxel, carboplatin, trastuzumab, and pertuzumab 
and surgery. 
– 
Additional cohorts with patients with HER2-positive metastatic breast cancer 
are Cohorts 1B (n  6; safety run-in cohort; atezolizumab  trastuzumab 
emtansine) and 2C (n  14; expansion cohort; atezolizumab  trastuzumab 
emtansine). 
With a data cut-off of 17 December 2018, there have been no new safety signals 
overall emerging in the HER2-positive cohorts of Study GO29831, and adverse 
events are in line with the known safety profile of the individual components of the 
regimens being evaluated. 
 
Study WO30085 (Kate2) is a Phase II randomized study of trastuzumab emtansine 
with or without atezolizumab in HER2-positive, locally advanced unresectable or 
metastatic breast cancer with prior exposure to a taxane and trastuzumab.  This 
study enrolled 202 patients. 
– 
On 22 November 2017, the independent Data Monitoring Committee (iDMC) 
met and conducted a pre-planned benefitrisk analysis.  Following this analysis, 
the iDMC recommended to the Sponsor that the study be unblinded with 
respect to treatment assignment to allow investigators and patients to have an 
open discussion of the potential benefits and risks of continuing the 
experimental therapy.  Unblinding was based upon the improbability of meeting 
the progression-free survival endpoint, numerically higher rates of serious 
adverse events that included one fatal event (hemophagocytic syndrome), and 
numerically higher adverse events leading to discontinuation of study drugs in 
the atezolizumab arm.  The Sponsor issued a "Dear Investigator Letter" on 
11 December 2017 communicating the unblinding of the study. 
– 
The clinical cutoff date for the primary efficacy analysis was 
11 December 2017, at which time 107 PFS events had occurred in the ITT 
population.  For the primary endpoint of PFS based on investigator 
assessment, the study did not demonstrate a meaningful PFS benefit from the 
addition of atezolizumab to trastuzumab emtansine in the ITT population.  The 
stratified hazard ratio was 0.82 (95% CI: 0.55 to 1.23; p  0.3332).  The median 
PFS for trastuzumab emtansine  placebo was 6.8 months (95% CI: 4.0 to 11.1) 
and for trastuzumab emtansine  atezolizumab 8.2 months 
(95% CI: 5.8 to 10.7).  The OS data were immature with a low event rate 
(11.6% in the trastuzumab emtansine  placebo arm vs. 9.8% in the 
trastuzumab emtansine  atezolizumab arm). 


 
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– 
The subgroup results of the PFS analysis suggested potential benefit of the 
trastuzumab emtansine  atezolizumab arm in the PD-L1selected subgroup 
(tumor-infiltrating immune cell [IC] 1/2/3), although the magnitude of the benefit 
is uncertain given the limited number of patients and the observed imbalances 
in confounding factors.  The stratified hazard ratio of PFS assessment in the 
PD-L1selected subgroup was lower (HR: 0.60; 95% CI: 0.32 to 1.11; 
p  0.0987) compared with the results of the PFS analysis in the ITT population.  
The median PFS in PD-L1selected patients for trastuzumab 
emtansine  placebo was 4.1 months (2.7; 11.1) versus 8.5 months (5.7; not 
evaluable [NE]) with trastuzumab emtansine  atezolizumab. 
– 
The safety profile of the combination was consistent with the known profiles of 
each study drug, and adverse events for the combination were manageable.  
Although the incidence of Grade  3 adverse events was similar between arms 
with 43.9% in the experimental arm and 41.2% in the control arm, 
thrombocytopenia, AST elevation, anemia, and pyrexia were numerically 
increased in the combination arm.  A higher incidence of serious adverse 
events, of adverse events leading to atezolizumab or placebo discontinuation, 
and of adverse events leading to dose reduction of trastuzumab emtansine was 
reported in the combination arm.  A total of 13 patients (19.1%) in the 
trastuzumab emtansine  placebo arm experienced at least one serious adverse 
event compared with 43 patients (32.6%) in the trastuzumab 
emtansine  atezolizumab arm.  The most common serious adverse event 
reported in the trastuzumab emtansine  atezolizumab arm was pyrexia 
(10 patients [7.6%]), which was mostly driven by hospitalization for Grade 1 or 2 
pyrexia (5.3%), 2 patients (1.5%) experienced Grade 3 pyrexia, and 1 patient 
(0.8%) experienced Grade 4 pyrexia; all 10 patients were reported to have 
recovered.  The most common serious adverse events in the trastuzumab 
emtansine  placebo arm were seizure (2 patients [2.9%]) and abdominal pain 
(2 patients [2.9%]).  One patient in the experimental arm experienced a fatal 
hemophagocytic syndrome.  For the trastuzumab emtansineselected adverse 
events, the incidence of thrombocytopenia, hepatotoxicity, peripheral 
neuropathy, and infusion-related reaction or hypersensitivity Type 1 were 
numerically increased in the trastuzumab emtansine  atezolizumab arm.  For 
the atezolizumab adverse events of special interest, the incidence of 
immune-mediated hypothyroidism, immune-mediated colitis, immune-mediated 
rash, and immune-mediated ocular inflammatory toxicity were numerically 
increased in the trastuzumab emtansine  atezolizumab arm compared with the 
trastuzumab emtansine  placebo arm. 
 
1.4 
STUDY RATIONALE AND BENEFITRISK ASSESSMENT 
Encouraging clinical data emerging in the field of tumor immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant survival benefit in patients with advanced malignancies 
(Hodi et al. 2010; Kantoff et al. 2010; Chen et al. 2012). 


 
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The PD-L1 pathway serves as an immune checkpoint to temporarily dampen immune 
responses in states of chronic antigen stimulation, such as chronic infection or cancer.  
PD-L1 is a transmembrane protein that downregulates immune responses through 
binding to its two receptors, PD-1 and B7-1.  PD-1 is an inhibitory receptor expressed on 
T cells following T-cell activation, and expression is sustained in states of chronic 
stimulation (Blank et al. 2005; Keir et al. 2008).  B7-1 is a molecule expressed on 
antigen-presenting cells and activated T cells.  Binding of PD-L1 to PD-1 and B7-1 
inhibits T-cell proliferation and activation, cytokine production, and cytolytic activity, 
leading to the functional inactivation or exhaustion of T cells (Butte et al. 2007; 
Yang et al. 2011).  Overexpression of PD-L1 on tumor cells has been reported to impede 
anti-tumor immunity, resulting in immune evasion (Blank and Mackensen 2007).  
Therefore, interruption of the PD-L1 pathway represents an attractive strategy for 
restoring tumor-specific T-cell immunity. 
Targeting the PD-L1 pathway with atezolizumab has demonstrated activity in patients 
with advanced malignancies who have failed SOC therapies.  Objective responses have 
been observed across a broad range of malignancies, including NSCLC, urothelial 
carcinoma, renal cell carcinoma, melanoma, colorectal cancer, head and neck cancer, 
gastric cancer, breast cancer, and sarcoma.  In particular, available data from the TNBC 
cohorts in Studies PCD4989g and GP28328 have demonstrated activity and durable 
responses in patients receiving atezolizumab as monotherapy or in combination with 
nab-paclitaxel (see the Atezolizumab Investigator's Brochure for detailed efficacy 
results).  More recently, clinically meaningful improvement of OS with 
atezolizumab  nab-paclitaxel compared with placebo  nab-paclitaxel was observed in 
the Phase III Study WO29522 (IMpassion130) in patients with PD-L1positive advanced 
TNBC (Schmid et al. 2018). 
While cancer immunotherapy has demonstrated impressive results in patients with 
advanced malignancies, emerging data suggest that responses to cancer 
immunotherapy may be better when agents are administered in early-stage cancers, 
where higher levels of tumor-infiltrating lymphocytes (TILs) may be present 
(Lee et al. 2017; Loi et al. 2017).  In particular, this may be more relevant in tumors 
where TILs are a prognostic factor, such as in early HER2-positive breast cancer. 
Cancer immunotherapy is a relatively new focus for breast cancer studies.  It is 
hypothesized that an important mechanism of action of therapeutic antibodies such as 
trastuzumab and pertuzumab (both humanized monoclonal IgG antibodies) is to induce 
cellular immunity via interactions with the Fc fragment of the molecule and/or destroy 
malignant cells, resulting in release of tumor antigens for uptake by antigen-presenting 
cells, which in turn upregulate immune effector cells.  With these mechanisms of action, 
the combination of trastuzumab and pertuzumab with an antiPD-L1 inhibitor such as 
atezolizumab might further enhance anti-tumor immune responses, thereby improving 
clinical outcomes for patients with minimal increases in clinically significant toxicities. 


 
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Nonclinical models provide support for this hypothesis.  It has been demonstrated that 
the addition of PD-1:PD-L1 blockade improves the therapeutic activity of a 
HER2-positive monoclonal antibody in murine experimental model of 
HER2-positive breast cancer (Stagg et al. 2011; data on file).  These findings suggest 
that antiPD-L1 immunostimulatory approaches may further capitalize on the 
immune-mediated effects of therapeutic antibodies.  With the potential for therapeutic 
synergy, combining atezolizumab (antiPD-L1 antibody) with trastuzumab and 
pertuzumab may further enhance the anti-tumor efficacy of these established anti-HER2 
treatments. 
The subtype of breast cancers over-expressing HER2 is the most aggressive.  While 
current therapies have significantly improved patient outcomes, up to 1 in 4 women with 
HER2-positive EBC will experience recurrence or death within 10 to 11 years of 
diagnosis, despite treatment with adjuvant trastuzumab plus standard chemotherapy 
(Perez et al. 2014; Slamon et al. 2016; Cameron et al. 2017).  Patients who received 
neoadjuvant trastuzumab and pertuzumab with standard chemotherapy, a patient group 
with tumor size  2 cm and who are considered at higher risk for recurrence, have 
demonstrated pCR rates ranging from 45%68% (Gianni et al. 2012; 
Schneeweiss et al. 2013; Untch et al. 2016; van Ramshorst et al. 2017; 
Swain et al. 2018).  Even with such rates, 5-year DFS rates in these patients are around 
84% and are expected to be lower in those who are node positive (Gianni et al. 2012).  
More recently, data from the APHINITY study have demonstrated high invasive DFS 
rates at 3 years (94.1%) and 4 years (92.3%) with adjuvant trastuzumab and 
pertuzumab plus chemotherapy (von Minckwitz et al. 2017).  However, in patients with 
node-positive disease, these values were numerically lower at both 3 years (92%) and 
4 years (89.9%).  As such, there is an opportunity to improve pCR rates and long-term 
outcomes for patients with high-risk, HER2-positive breast cancer. 
Atezolizumab has been generally well tolerated.  Adverse events with potentially 
immune-mediated causes consistent with an immunotherapeutic agent, including rash, 
influenza-like illness, endocrinopathies, hepatitis or transaminitis, pneumonitis, colitis, 
and myasthenia gravis, have been observed (see the Atezolizumab Investigator's 
Brochure for detailed safety results).  To date, these events have been manageable with 
treatment or interruption of atezolizumab treatment. 
Atezolizumab in combination with taxanes has been investigated or is currently being 
investigated as part of several studies including Studies GP28328, GO29436 
(IMpower150), GO29537 (IMpower130), GO30140, WO29522 (IMpassion130), 
WO39392 (IMpassion031), and WO39391 (IMpassion030).  Atezolizumab in 
combination with chemotherapeutic regimens including anthracyclines and 
cyclophosphamide is currently being investigated as part of Studies BO29563, 
GO29831, WO39392 (IMpassion031), and WO39391 (IMpassion030).  Thus far, 
reported adverse events observed were similar to those experienced with the individual 
components of the study treatment and have generally been manageable.  


 
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See Sections 1.3.1 and 1.3.2 and the Atezolizumab Investigator’s Brochure for additional 
details.  Atezolizumab in combination with pertuzumab and trastuzumab is currently 
being investigated as part of Study GO29831.  No new safety signals have been 
reported and the study is ongoing. 
The risk of overlapping toxicities between atezolizumab and doxorubicin, 
cyclophosphamide, paclitaxel, trastuzumab, pertuzumab, and trastuzumab emtansine is 
thought to be manageable based on the mechanism of action of each product.  In order 
to evaluate any potential risks associated with this combination regimen, a safety review 
of the first 12 patients enrolled (approximately 6 patients per arm) will be performed by 
the Sponsor and iDMC (without stopping accrual) after completion of 4 cycles of 
atezolizumab/placebo and doxorubicin  cyclophosphamide chemotherapy and 2 cycles 
of atezolizumab/placebo and paclitaxel  trastuzumab  pertuzumab chemotherapy.  
Furthermore, the first 26 patients of the study will be part of the safety cohort that will be 
closely monitored with additional cardiac monitoring (see Appendix 1).  To reduce the 
risk of cardiac dysfunction with the combination used in this study, patients with 
cardiopulmonary dysfunction will be excluded from the study.  Cardiac function will be 
closely monitored for all patients, including regular measurements of left ventricular 
ejection fraction (LVEF) throughout the study.  An iDMC will regularly review unblinded 
safety data (see Section 3.2.2). 
This trial will enroll patients with early (T24, N13, M0) HER2-positive breast cancer.  
HER2 status of the tumor will be centrally confirmed.  The study population will be such 
that the final population will contain no more than 50% of patients with 
hormone receptorpositive disease.  Given the rate of recurrence for these patients with 
very high-risk HER2-positive breast cancer, this population is considered appropriate for 
trials of novel therapeutic candidates.  On the basis of recent results from 
Study BO27938, trastuzumab emtansine has been added as a recommended treatment 
option in the adjuvant setting for patients who do not achieve pCR and will be given in 
combination with atezolizumab/placebo.  The anticipated benefitrisk ratio for 
atezolizumab in combination with trastuzumab, pertuzumab, chemotherapy, and 
trastuzumab emtansine is expected to be acceptable in this setting. 
In the setting of the COVID-19 pandemic, patients with comorbidities, including those 
with cancer, are considered a more vulnerable population, with the potential for more 
severe clinical outcomes from COVID-19.  However, it is unclear whether or how 
systemic cancer therapies such as chemotherapy, targeted therapy, or immunotherapy 
impact the incidence or severity of COVID-19. 
A possible consequence of inhibiting the PD-1/PD-L1 pathway may be the modulation of 
the host immune response to acute infection, which may result in immunopathology or 
dysregulated immune system defenses.  In nonclinical models, PD-1/PD-L1 blockade 
appears to be associated with serious exacerbation of inflammation in the setting of 
acute (as opposed to chronic) viral infection with lymphocytic choriomeningitis virus 


 
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(Clone 13; Frebel et al. 2012).  However, there are insufficient and inconsistent clinical 
data to assess if outcome from COVID-19 is altered by cancer immunotherapy. 
Severe COVID-19 appears to be associated with a cytokine release syndrome (CRS) 
involving the inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and interferon- 
(Merad and Martin 2020).  While it is not known, there may be a potential for an 
increased risk of an enhanced inflammatory response if a patient develops acute 
SARS-CoV-2 infection while receiving atezolizumab.  At this time, there is insufficient 
evidence for causal association between atezolizumab and an increased risk of severe 
outcomes from COVID-19. 
There may be potential synergy or overlap in clinical and radiologic features for 
immune-mediated pulmonary toxicity with atezolizumab and clinical and radiologic 
features for COVID-19related interstitial pneumonia.  Thus, investigators should use 
their clinical judgment when evaluating and managing patients with pulmonary 
symptoms. 
Neutropenia and lymphopenia associated with chemotherapy may increase the risk for 
developing an infection in patients receiving atezolizumab in combination with 
chemotherapy. 
2. 
OBJECTIVES AND ENDPOINTS 
This study (also known as IMpassion050) will evaluate the efficacy and safety of 
atezolizumab compared with placebo when given in combination with neoadjuvant 
dose-dense anthracycline (doxorubicin)  cyclophosphamide followed by 
paclitaxel  trastuzumab  pertuzumab (ddAC-PacHP) in patients with early 
HER2-positive breast cancer at high risk of recurrence (T24, N13, M0).  Specific 
objectives and corresponding endpoints for the study are outlined below. 
2.1 
EFFICACY OBJECTIVES 
2.1.1 
Co-Primary Efficacy Objective 
The co-primary efficacy objective for this study is to evaluate the efficacy of 
atezolizumab  ddAC-PacHP compared with placebo  ddAC-PacHP in the EBC setting 
in the PD-L1positive (IC 1/2/3) and the ITT population on the basis of the following 
endpoint: 
 
pCR, defined as the absence of residual invasive cancer on hematoxylin and eosin 
evaluation of the complete resected breast specimen and all sampled regional 
lymph nodes following completion of neoadjuvant systemic therapy (NAST; 
i.e., ypT0/is ypN0 in the current AJCC staging system, 8th edition) in the 
PD-L1positive and ITT populations 
 


 
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2.1.2 
Secondary Efficacy Objectives 
The secondary efficacy objectives for this study are as follows: 
 
To evaluate the efficacy of atezolizumab  ddAC-PacHP compared with 
placebo  ddAC-PacHP in the EBC setting on the basis of the following endpoints: 
– 
pCR (ypT0/is ypN0) based upon hormone receptor status (estrogen receptor 
[ER]/progesterone receptor [PgR] positive or ER/PgR negative) 
– 
pCR (ypT0/is ypN0) in the PD-L1negative (IC 0) population 
– 
Event-free survival (EFS), defined as the time from randomization to the 
first documented disease recurrence, unequivocal tumor progression 
determined by the treating investigator, or death from any cause, whichever 
occurs first, in all patients and based upon hormone receptor status (ER/PgR 
positive or ER/PgR negative) and PD-L1 status (IC 0; IC 1/2/3) 
– 
DFS, defined as the time from surgery to the first documented disease 
recurrence or death from any cause, whichever occurs first, in all patients who 
undergo surgery and based upon hormone receptor status (ER/PgR positive or 
ER/PgR negative) and PD-L1 status (IC 0; IC 1/2/3) 
– 
OS, defined as the time from randomization to death from any cause in all 
patients and based upon hormone receptor status (ER/PgR positive or ER/PgR 
negative) and PD-L1 status (IC 0; IC 1/2/3) 
 
To evaluate patient-reported outcomes (PROs) of function (role, physical) and 
health-related quality of life (HRQoL) associated with atezolizumab  ddAC-PacHP 
compared with placebo  ddAC-PacHP, as measured by the European Organisation 
for Research and Treatment of Cancer (EORTC) Quality of Life 
QuestionnaireCore 30 (QLQ-C30), on the basis of the following endpoint: 
– 
Mean and mean changes from baseline score in function (role, physical) and 
global health status (GHS)/HRQoL by assessment timepoint, and between 
treatment arms as assessed by the functional and GHS/HRQoL scales of the 
EORTC QLQ-C30 
 
2.1.3 
Exploratory Efficacy Objectives 
The exploratory efficacy objectives for this study are as follows: 
 
To evaluate PROs of disease/treatmentrelated symptoms and emotional, social 
function associated with atezolizumab  ddAC-PacHP by the EORTC QLQ-C30 on 
the basis of the following endpoint: 
– 
Mean and mean changes from baseline score in disease/treatmentrelated 
symptoms and emotional, social function by assessment timepoint and between 
treatment arms as assessed by all symptom items/scales and the emotional, 
social function scales of the EORTC QLQ-C30 
 
To evaluate any treatment burden patients may experience associated with the 
addition of atezolizumab to ddAC-PacHP compared with placebo  ddAC-PacHP, as 
measured by a single item (GP5:  “I am bothered by side effects of treatment”) from 
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TherapyGeneral (FACT-G) quality-of-life instrument on the basis of the following 
endpoint: 
– 
Proportion of patients reporting each response option at each assessment 
timepoint by treatment arm for item GP5 from the FACT-G 
 
To evaluate patient’s health utility as measured by the EuroQol 5 Dimension, 
5-Level (EQ-5D-5L) questionnaire to generate utility scores for use in economic 
models for reimbursement on the basis of the following endpoint: 
– 
Utility scores of the EQ-5D-5L questionnaire 
 
2.2 
SAFETY OBJECTIVE 
The safety objective for this study is to evaluate the safety of 
atezolizumab  ddAC-PacHP compared with placebo  ddAC-PacHP in the neoadjuvant 
setting and the safety of atezolizumab combined with trastuzumab  pertuzumab (or 
combined with trastuzumab emtansine) compared with placebo combined with 
trastuzumab  pertuzumab (or combined with trastuzumab emtansine) in the adjuvant 
EBC setting on the basis of the following endpoints: 
 
Incidence and severity of adverse events, with severity determined according to 
National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 5.0 (NCI CTCAE v5.0) 
 
Change from baseline in targeted vital signs 
 
Change from baseline in targeted clinical laboratory test results 
 
2.3 
PHARMACOKINETIC OBJECTIVE 
The pharmacokinetic (PK) objective for this study is to characterize the PK profile of 
atezolizumab, pertuzumab, and trastuzumab when given in combination and of 
atezolizumab and trastuzumab emtansine when given in combination on the basis of the 
following endpoints: 
 
Peak and trough (maximum serum concentration observed [Cmax] and minimum 
serum concentration under steady-state conditions within a dosing interval [Cmin]) of 
atezolizumab concentrations in serum at specified timepoints 
 
Trough concentration for pertuzumab and trastuzumab in serum at specified 
timepoints 
 
Peak and trough concentration for trastuzumab emtansine in serum at specified 
timepoints 
 
2.4 
IMMUNOGENICITY OBJECTIVES 
The immunogenicity objective for this study is to evaluate the immune response to 
atezolizumab, trastuzumab, pertuzumab, and trastuzumab emtansine on the basis of the 
following endpoints: 
 
Incidence of treatment-emergent anti-drug antibodies (ADAs) to atezolizumab and 
its impact on pharmacokinetics, efficacy, and safety 


 
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 
Incidence of treatment-emergent ADAs to trastuzumab, pertuzumab, and 
trastuzumab emtansine 
 
The exploratory immunogenicity objective for this study is to evaluate potential effects of 
ADAs on the basis of the following endpoint: 
 
Relationship between ADA status and efficacy, safety, or PK endpoints 
 
2.5 
BIOMARKER OBJECTIVES 
The secondary biomarker objectives for this study are as follows: 
 
To evaluate pCR (ypT0/is ypN0), EFS, DFS, and OS based upon PIK3CA mutation 
status 
 
The exploratory biomarker objectives for this study are as follows: 
 
To evaluate pCR (ypT0/is ypN0) based upon stromal TIL infiltration level 
 
To evaluate pCR (ypT0/is ypN0) based upon immune gene expression level 
 
To identify biomarkers and/or changes in biomarkers that are predictive of response 
to atezolizumab  ddAC-PacHP (i.e., predictive biomarkers), are early surrogates of 
efficacy, are associated with progression to a more severe disease state 
(i.e., prognostic biomarkers), are associated with acquired resistance to 
atezolizumab  ddAC-PacHP, are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation 
(i.e., safety biomarkers), can provide evidence of atezolizumab  ddAC-PacHP 
activity (i.e., pharmacodynamic biomarkers), or can increase the knowledge and 
understanding of disease biology and drug safety, on the basis of the following 
endpoint: 
- 
Relationship between biomarkers (or changes in biomarkers) in blood and 
tumor tissue and efficacy, safety, PK, immunogenicity, or other biomarker 
endpoints 
 
To evaluate biomarkers in association with EFS, DFS, and OS 
 
To evaluate post-surgical circulating-tumor DNA (ctDNA) with outcome 
 
To evaluate ctDNA on-treatment changes associated with 
atezolizumab  ddAC-PacHP compared with placebo  ddAC-PacHP and to evaluate 
its association with EFS, DFS, and OS 
 
3. 
STUDY DESIGN  
3.1 
DISCONTINUATION OF EXPERIMENTAL TREATMENT AND 
UNBLINDING AT STUDY LEVEL 
On 26 January 2021, the iDMC met and conducted a review of unblinded safety and 
efficacy data.  Following their review of the data, the iDMC recommended to stop 
randomized treatment assignment with atezolizumab or placebo.  Study treatment 
without atezolizumab/placebo should be continued through the completion of the 


 
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adjuvant treatment phase.  On 3 February 2021, the Sponsor issued an “Urgent Safety 
Measure Dear Investigator Letter” (USM DIL) communicating the request to stop 
treatment with atezolizumab or placebo and informed about the unblinding of the study. 
The addition of atezolizumab did not result in an increase in the pCR rate compared with 
the control arm both in the ITT and the PD-L1positive population.  There were 
four Grade 5 adverse events in the atezolizumab arm, which occurred in the 
neoadjuvant phase.  The iDMC commented that the difference in death between the 
two arms was not significant but in the margin of significance.  Considering that the 
majority of the patients had undergone surgery, their recommendation was to stop the 
atezolizumab/placebo treatment administration from an ethical perspective. 
3.1.1 
Implications of Unblinding on Study Design and Assessments 
Following the discontinuation of atezolizumab or placebo, patients should continue all 
other study drugs without atezolizumab or placebo and follow study assessments and 
follow-up assessments as described in Appendix 1.  Following the implementation of 
Protocol, Version 5, the PK and ADA sample collection for atezolizumab, trastuzumab, 
and pertuzumab (or trastuzumab emtansine) is only required at the treatment 
discontinuation visit (Appendix 2). 
The study was unblinded on 5 February 2021 and the unblinding date will be used as the 
clinical cutoff date for the primary analysis.  As per Statistical Analysis Plan (SAP), 
patients with missing pCR assessment will be counted as not achieving pCR in the 
analysis; this includes patients who have not yet undergone surgery and pCR 
assessment due to the early unblinding of the study.  Patients who are still in the 
neoadjuvant phase of the study at the time of unblinding should continue their study 
treatment without atezolizumab or placebo and undergo surgery and pathological 
assessment as per study protocol followed by the adjuvant study phase with study 
treatment excluding atezolizumab or placebo. 
3.2 
DESCRIPTION OF THE STUDY PRIOR TO STOPPING BLINDED 
TREATMENT 
3.2.1 
Overview of Study Design 
This is a global Phase III, randomized, double-blind, placebo-controlled study designed 
to evaluate the efficacy, safety, and pharmacokinetics of atezolizumab compared with 
placebo when given in combination with neoadjuvant ddAC-PacHP in patients eligible for 
surgery with early HER2-positive breast cancer at high risk of recurrence (T24, 
N13, M0). 
Patients who have histologically confirmed invasive HER2-positive breast cancer with a 
primary tumor size  2 cm by any radiologic measurement and who are node positive 
(node positivity pathologically confirmed by fine-needle aspiration or core-needle biopsy) 
are eligible.  Axillary surgery (including sentinel-node biopsy) prior to neoadjuvant 
treatment is prohibited.  HER2 positivity of the primary breast tumor will be confirmed by 


 
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a central laboratory (see Appendix 7 and Appendix 8).  Patients whose tumors are not 
centrally confirmed to be HER2-positive will not be eligible.  Patients whose tumor tissue 
is not evaluable for PD-L1 by central laboratory will not be eligible.  Patients who do not 
initially meet eligibility criteria may be re-screened once. 
Figure 1 presents an overview of the study design.  The schedules of activities are 
provided in Appendix 1, Appendix 2, and Appendix 3.


 
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Figure 1 Study Schema 
 
 


 
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Figure 1 Study Schema (cont.) 
 
Notes:  Following the receipt of the Urgent Safety Measure Dear Investigator Letter (USM DIL) dated 3 February 2021, patients will no longer 
receive atezolizumab or placebo. 
If trastuzumab emtansine is discontinued for toxicity not considered related to the trastuzumab component of the drug, treatment can be switched 
to trastuzumab and pertuzumab with atezolizumab/placebo to complete a total of 1 year of HER2-targeted therapy.  Patients discontinued from 
trastuzumab emtansine for pneumonitis may not switch study treatment to trastuzumab and pertuzumab and have to discontinue all study 
treatment. 


 
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Figure 1 Study Schema (cont.) 
 
ddAC-PacHP  dose-dense anthracycline (doxorubicin)  cyclophosphamide followed by paclitaxel  trastuzumab  pertuzumab; EBC  early breast 
cancer; ECHO  echocardiogram; ER  estrogen receptor; HER2  human epidermal growth factor 2; LN  lymph node; MUGA  multiple-gated 
acquisition (scan); pCR  pathologic complete response; PR  progesterone receptor; Rand  randomization. 
a LN determined through imaging and biopsy.  Ulcerating or inflammatory breast (e.g., erythema and/or dermal involvement, and/or pathologic 
detection of tumor cells in dermal lymphatics) cancer are excluded. 
b A real-time structured safety assessment of the first 12 patients enrolled (approximately 6 patients per arm) will be performed by the Sponsor 
and iDMC (without stopping accrual) after the first 12 patients have completed 4 cycles of atezolizumab/placebo  ddAC chemotherapy and 
2 cycles of atezolizumab/placebo  PacHP chemotherapy. 
c The first 26 patients enrolled (approximately 13 patients per arm) will undergo additional cardiac safety monitoring, including an additional ECHO 
or MUGA scan after the second dose of ddAC chemotherapy, as part of a cardiac safety cohort. 
 


 
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Patients who have consented and are eligible will be randomized in a 1:1 ratio to receive 
either atezolizumab or placebo administered IV in combination with the current standard 
neoadjuvant therapy for early HER2-positive breast cancer. 
Randomization will be stratified by the following factors: 
 
Stage at diagnosis (T2; T3 or 4) as determined by the AJCC staging system, 
8th edition (specifically according to the Anatomic Stage Group rules) 
 
Hormone receptor status (ER positive and/or PgR positive; ER negative and 
PgR negative) 
– 
Hormone receptorpositive status will be capped at 50%. 
 
PD-L1 status (IC 0; IC 1/2/3) 
 
Study treatment administration should begin within 7 days after randomization. 
During the neoadjuvant phase (i.e., prior to surgery; Cycles 18), all patients will receive: 
 
Atezolizumab or placebo 840 mg IV every 2 weeks (Q2W) for 4 cycles (Cycles 14) 
 
ddAC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 IV) given with 
granulocyte colonystimulating factor (G-CSF), granulocyte macrophage 
colonystimulating factor, or pegylated granulocyte colonystimulating factor 
support in accordance to local guidelines Q2W for 4 cycles (Cycles 14) 
 
Followed by: 
 
Atezolizumab or placebo 1200 mg IV every 3 weeks (Q3W) for 4 cycles 
(Cycles 58) 
 
Paclitaxel 80 mg/m2 IV every week (QW) for 4 cycles (Cycles 58) 
 
Trastuzumab 6 mg/kg IV (with an initial 8-mg/kg IV loading dose) Q3W for 4 cycles 
(Cycles 58) 
 
Pertuzumab 420 mg IV (with an initial 840-mg IV loading dose) Q3W for 4 cycles 
(Cycles 58) 
 
A cycle will be considered missed during the neoadjuvant phase if the subsequent cycle 
cannot be administered within 28 days of the last dose for Cycles 14 or within 42 days 
of the last dose for Cycles 58.  In this situation, make-up treatment of missed cycles of 
chemotherapies is permitted post-surgery (see Appendix 11) prior to the adjuvant phase 
(described below). 
During the adjuvant phase (i.e., post-surgery; Cycles 922), the following study 
treatments will be continued Q3W to complete up to a total duration of 52 weeks 
(i.e., maximum of 18 cycles within 1 year) of HER2-targeted therapy, inclusive of therapy 
given both in the neoadjuvant and adjuvant setting: 
 
Atezolizumab/placebo 1200 mg IV Q3W 
 
Trastuzumab 6 mg/kg IV (with an initial 8-mg/kg IV loading dose) Q3W 


 
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 
Pertuzumab 420 mg IV (with an initial 840-mg IV loading dose) Q3W 
 
Patients who do not achieve a pCR as defined in the protocol (i.e., ypT0/is ypN0 in the 
current AJCC staging system, 8th edition) have the option of receiving adjuvant 
treatment as outlined above or alternatively: 
 
Atezolizumab or placebo as per initial treatment assignment 1200 mg IV Q3W 
combined with trastuzumab emtansine 3.6 mg/kg IV Q3W 
 
Treatment assignment will not be unblinded following pCR evaluation.  The treatment 
decision for patients who do not achieve a pCR after neoadjuvant therapy is per 
investigator discretion. 
Atezolizumab/placebo  trastuzumab  pertuzumab will be given to complete 52 weeks of 
HER2-directed therapy (i.e., a maximum of 18 cycles of HER2-directed therapy).  
Adjuvant atezolizumab/placebo  trastuzumab emtansine will be given for 14 cycles.  
If trastuzumab emtansine is discontinued for toxicity not considered related to the 
trastuzumab component of the drug, treatment can be switched to trastuzumab and 
pertuzumab with atezolizumab/placebo to complete a total of 1 year of HER2-targeted 
therapy. 
Patients who discontinue neoadjuvant therapy early as a result of disease progression 
must be discontinued from all study treatment and will be managed as per local practice.  
Any patient who receives non-protocol therapy prior to surgery will be discontinued from 
study treatment and will be managed as per local practice; these patients will remain in 
the follow-up phase of the study.  For patients who do not achieve pCR, it is 
recommended to continue on study treatment with the option to receive 
atezolizumab/placebo  HP or atezolizumab/placebo  trastuzumab emtansine on the 
basis of a benefitrisk assessment for the individual patient.  Alternatively, as per 
investigator discretion, local clinical guidelines for management of non-pCR patients may 
be followed; the patient will remain in the follow-up phase of the study. 
Patients who discontinue one or more of the study treatment components due to toxicity 
should not be automatically withdrawn from all study treatments.  Guidelines for dosage 
modification and treatment interruption or discontinuation for patients who experience 
adverse events are provided in Table 2, Table 3, Table 4, Appendix 11, 
and Appendix 12. 
Patients who discontinue early from all components of the pre- or post-operative study 
treatment should remain in the follow-up phase of the study.  Patients who discontinue 
prematurely from the study will not be replaced. 
The primary efficacy endpoint (pCR; ypT0/is ypN0) will be established via local review 
following completion of neoadjuvant therapy and surgery.  In line with pCR guidance 
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study specimens in a blinded manner.  Pathologists must utilize the evaluations and 
assessments outlined in the study pathology manual.  Surgery should be performed at 
least 14 days after the last dose of neoadjuvant study treatment but no later than 
6 weeks after the last infusion.  Platelet counts should be checked prior to surgery and 
should be  75,000 cells/L.  Patients must undergo full axillary lymph node dissection at 
the time of definitive surgery.  Sentinel lymph node procedure alone is not permitted.  
If surgically feasible, it is recommended that at least 10 lymph nodes are removed for 
pathologic examination.  For sentinel nodes involving the internal mammary chain, refer 
to local, national, or international guidelines.  Level III axillary dissections should be 
performed for patients with gross disease in the Level II nodes.  The first dose of 
postoperative treatment should not start until 2 weeks after surgery but should be 
administered within 45 days of surgery.  Postoperative patient management for those in 
either treatment arm may include radiotherapy and hormonal therapy as clinically 
indicated and in accordance with standard local clinical practice (see Section 4.4.1). 
An iDMC will evaluate safety data and study conduct on a regular basis during the study 
until the analysis of the primary endpoint of pCR, after which iDMC review of the study 
data will be discontinued.  An administrative interim analysis of efficacy will also take 
place once 227 patients have been enrolled, completed neoadjuvant treatment, and 
undergone surgery.  Sponsor affiliates will be excluded from iDMC membership.  The 
iDMC will follow a charter that outlines the iDMC roles, responsibilities, and timing of 
iDMC meetings.  To assess the potential cardiac toxicity of the combination of 
anthracyclines and atezolizumab, the iDMC will review data from a cardiac safety cohort 
involving additional cardiac monitoring in the first 26 patients enrolled (approximately 
13 patients in the control arm and approximately 13 patients in the atezolizumab arm) 
after all 26 patients have completed or have discontinued the neoadjuvant portion of 
the study. 
A real-time safety assessment of the first 12 patients enrolled (approximately 6 patients 
in the control arm and approximately 6 patients in the atezolizumab arm) will be 
conducted without stopping accrual.  This safety evaluation by the Sponsor of blinded 
data and the iDMC of unblinded data will be conducted after the first 12 patients have 
completed 6 cycles of neoadjuvant therapy (4 cycles of atezolizumab/placebo  ddAC 
and 2 cycles of atezolizumab/placebo  PacHP). 
Following completion of study treatment and surgery, all patients will continue to be 
followed for efficacy, safety, and PRO objectives until the end of the study.  No interim 
efficacy analyses for early stopping are planned, although an administrative interim 
analysis of efficacy is planned (see Section 3.2.2).  Safety assessments will include the 
occurrence and severity of adverse events and laboratory abnormalities graded per 
NCI CTCAE v5.0.  Laboratory safety assessments will include the regular monitoring of 
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Tumor tissue will also be collected by biopsy, unless not clinically feasible as assessed 
and documented by the investigator, at the time of disease recurrence.  These samples 
will enable analysis of tumor tissue biomarkers related to resistance, disease 
progression, and clinical benefit of atezolizumab. 
3.2.2 
Independent Data Monitoring Committee 
An iDMC will evaluate safety data on a regular basis during the study.  Sponsor affiliates 
will be excluded from iDMC membership.  The iDMC will follow a charter that outlines 
the iDMC roles, responsibilities and timing of iDMC meetings. 
Unblinded safety data will be reviewed on a regular basis by the iDMC.  To assess the 
potential toxicity of the combination, the iDMC, including a cardiologist, will review data 
from a cardiac safety cohort in the first 26 patients enrolled (approximately 13 patients in 
the control arm and approximately 13 patients in the atezolizumab arm) after all 
26 patients have completed or have discontinued the neoadjuvant portion of the study.  
Subsequent safety reviews will occur periodically during the study, as defined in the 
iDMC Charter, until analysis of the primary endpoint (refer to the iDMC Charter). 
An administrative interim efficacy analysis is planned once 227 patients have been 
enrolled, completed neoadjuvant treatment and undergone surgery, with the results 
reviewed by the iDMC. 
All summaries and analyses for the iDMC review will be prepared by an independent 
Data Coordinating Center (iDCC). 
After reviewing the data, the iDMC will provide a recommendation to the Sponsor as 
described in the iDMC Charter.  Final decisions will rest with the Sponsor. 
3.3 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date when the last patient, last visit occurs.  The 
end of the study is expected to occur approximately 36 months after the last patient is 
enrolled in the global study.  The total length of the study, from screening of the first 
patient to the end of the study, is expected to be approximately 54 months, assuming a 
recruitment period of approximately 18 months, and follow-up for 36 months from the 
date of enrollment of the last patient in the study.  The Sponsor may decide to terminate 
the study at any time. 
3.4 
RATIONALE FOR STUDY DESIGN 
3.4.1 
Rationale for Atezolizumab Dose and Schedule 
Atezolizumab will be administered at a fixed dose of 840 mg Q2W by IV infusion in 
combination with ddAC chemotherapy to align with the chemotherapy schedule 
(Cycles 14).  The atezolizumab dosing regimen will be switched to 1200 mg Q3W for 
subsequent cycles. 


 
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The average atezolizumab exposure following the 840 mg Q2W dosage (approved by 
the FDA in March 2019) is expected to be similar to that of 1200 mg Q3W 
(Tecentriq U.S. Package Insert).  Anti-tumor activity has been observed across doses 
ranging from 1 mg/kg to 20 mg/kg Q3W.  In Study PCD4989g, the maximum tolerated 
dose of atezolizumab was not reached, and no dose-limiting toxicities were observed at 
any dose.  The fixed dose of 1200 mg Q3W (equivalent to an average 
body weightbased dose of 15 mg/kg Q3W) was selected on the basis of both 
nonclinical studies and available clinical PK, efficacy, and safety data (Deng et al.2016; 
refer to the to the Atezolizumab Investigator's Brochure for details). 
Based on the understanding of population-PK variability and atezolizumab 
concentrationtumor dynamic relationship, 840 mg Q2W and 1200 mg Q3W are 
expected to have comparable efficacy and safety profiles. 
3.4.2 
Rationale for Chemotherapy Choice and Schedule 
The backbone chemotherapy regimens (anthracycline followed by taxane) used with 
HER2-directed therapy in the neoadjuvant part of this study are based on published 
data, routine clinical usage, as well as established clinical practice guidelines 
(e.g., Senkus et al. 2013; Gradishar et al 2017; Curigliano et al. 2017) for patients with 
high-risk, HER2-positive EBC, in combination with pertuzumab and trastuzumab.  The 
doses of chemotherapy in this trial are all consistent with the prescribing information for 
each agent. 
NCCN-preferred neoadjuvant/adjuvant regimens for HER2-positive EBC are AC or ddAC 
followed by QW paclitaxel with trastuzumab given concurrently with paclitaxel.  As per 
NCCN guidelines, pertuzumab can be added to trastuzumab-containing regimens 
including AC-paclitaxel (various schedules) for patients with HER2-positive EBC and a 
tumor size  2 cm in diameter or node positive.  The St. Gallen Guidelines also 
recommended dual anti-HER2 therapy with pertuzumab and trastuzumab and 
chemotherapy in the neoadjuvant setting for high-risk, HER2-positive patients.  The 
recommended chemotherapy regimen is anthracycline followed by taxane with 
concurrent HER2 therapy (Curigliano et al. 2017). 
Citron et al. (2003) compared standard Q3W and accelerated Q2W schedules of 
concurrent doxorubicin and cyclophosphamide followed by paclitaxel, or sequential 
doxorubicin, paclitaxel, and cyclophosphamide.  There was a significant improvement in 
OS with dose-dense therapy (risk ratio  0.69, p  0.013), with 3-year OS of 92% in the 
dose-dense arms and 90% in the Q3W arms.  The SWOG S0221 study has shown that 
patients treated with weekly paclitaxel demonstrated equivalent efficacy to those treated 
with Q2W paclitaxel (Budd et al. 2017). 
Combining dose-dense AC followed by paclitaxel and HER2-targeted therapy appears to 
be safe from a cardiac point of view, and toxicity does not seem to be increased in 
relation to previous nondose-dense HER2 clinical trials (Dang et al. 2008; 


 
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Dang et al. 2010; Hudis et al. 2014).  The BERENICE study explored the regimen that is 
used in the current study, namely ddAC followed by paclitaxel QW; pertuzumab and 
trastuzumab were given concurrently with the taxane.  The regimen was active, with high 
tpCR rate.  Cardiac and general safety of this regimen was as expected and was 
consistent with the known pertuzumab, trastuzumab, and chemotherapy safety profiles 
(Swain et al. 2018). 
3.4.3 
Rationale for Patient Population 
This study will enroll patients with early HER2-positive breast cancer at high risk of 
recurrence (T24, N13).  Patients are required to have histologically confirmed invasive 
HER2-positive breast cancer with a primary tumor size  2 cm and node-positive disease 
(node positivity pathologically confirmed by fine-needle aspiration or core-needle 
biopsy).  HER2 status will be centrally confirmed.  Based on observations in 
Study WO30085 in patients with HER2-positive advanced breast cancer, the expected 
proportion of PD-L1positive (IC 1/2/3) patients in Study BO40747 is approximately 40% 
(using the Ventana antiPD-L1 SP142 immunohistochemistry assay; 
Emens et al. 2018). 
Breast cancers over-expressing HER2 are the most aggressive type of breast cancers.  
Although current therapies have significantly improved patient outcomes in these 
patients, there are still those who remain at high risk for recurrence and who have poor 
long-term outcomes.  These patients are largely identified using clinical parameters, 
including tumor size  2 cm and positive nodal status.  In NEOSPHERE, a study in which 
enrolled patients were required to have tumors  2 cm, the 5-year DFS rate in patients 
treated with neoadjuvant trastuzumab and pertuzumab with standard chemotherapy was 
84% (Gianni et al. 2016).  Data from the APHINITY study have demonstrated high 
invasive DFS rates at 3 years (94.1%) and 4 years (92.3%) with adjuvant trastuzumab 
and pertuzumab plus chemotherapy (von Minckwitz et al. 2017).  However, in patients 
with node-positive disease, these values were numerically lower at both 3 years (92%) 
and 4 years (89.9%).  Patients with node-positive disease fared worse compared with 
the ITT population when treated with adjuvant chemotherapy  trastuzumab and 
pertuzumab in the APHINITY clinical trial (invasive DFS HR 0.77 vs. 0.81). 
The patient population for this study was selected to target those patients who are at 
highest risk for recurrence and where the potential for cancer immunotherapy to improve 
long-term patient outcomes can have the greatest impact. 
3.4.4 
Rationale for Control Group and Combination with 
Atezolizumab 
The control group for this study is current SOC for high-risk patients with HER2-positive 
EBC.  The combination of chemotherapy with trastuzumab and pertuzumab is approved 
for use in the neoadjuvant setting and adjuvant continuation of this combination therapy 
is currently approved in the United States and European Union.  The NCCN guidelines 
recommend the usage of AC-taxane-HP as pre-operative/adjuvant therapy in patients 


 
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with  T2 or  N1 HER2-positive, early-stage breast cancer (Curigliano et al. 2017; 
Association of Gynecologic Oncology [AGO] Guidelines 2018; Denduluri et al. 2018; 
NCCN Guidelines Version 4.2017 [Gradishar et al. 2018]).  Although guidelines have yet 
to be updated with recent APHINITY data, the 2015 ESMO Breast Cancer Clinical 
Practice Guidelines also consider the usage of trastuzumab  pertuzumab combination 
with chemotherapy as an acceptable option as neoadjuvant therapy 
(Senkus et al. 2013). 
It is hypothesized that an important mechanism of action of therapeutic antibodies such 
as trastuzumab and pertuzumab is to induce cellular immunity via interactions with the 
Fc fragment of the molecule and/or destroy malignant cells resulting in release of tumor 
antigens for uptake by antigen-presenting cells, which in turn upregulate immune 
effector cells.  The combination of these agents with an antiPD-L1 inhibitor might help 
to further enhance anti-tumor immune responses. 
Nonclinical models provide support for this hypothesis.  It has been demonstrated that 
the addition of PD-1:PD-L1 blockade improves the therapeutic activity of an anti-HER2 
monoclonal antibody in a murine model of HER2-positive breast cancer 
(Stagg et al. 2011).  This is supported by additional nonclinical data in murine models 
that show the combination of atezolizumab with trastuzumab, pertuzumab, and 
chemotherapy results in increased tumor immune infiltrate compared with any of the 
agents alone or in combinations that do not include atezolizumab (data on file).  These 
findings suggest that antiPD-L1 immunostimulatory approaches may further capitalize 
upon the immune-mediated effects of therapeutic antibodies such as trastuzumab and 
pertuzumab. 
3.4.5 
Rationale for Trastuzumab Emtansine in Combination with 
Atezolizumab as Adjuvant Treatment Option 
Results from Study BO27938 (Katherine) demonstrated a significant reduction in the risk 
of recurrence of invasive breast cancer or death in patients with HER2-positive early 
breast cancer with residual invasive disease after completion of neoadjuvant therapy 
who were treated with adjuvant trastuzumab emtansine compared with those treated 
with adjuvant trastuzumab (HR  0.50; 95% CI, 0.390.64; p  0.001; 
von Minckwitz et al. 2019).  These data resulted in a recent update of the NCCN 
guidelines that recommend trastuzumab emtansine for patients with residual disease for 
14 cycles.  The guidelines further recommend to switch treatment to 
trastuzumab  pertuzumab in patients who have to discontinue trastuzumab emtansine 
for toxicity to complete 1 year of HER2-targeted therapy (NCCN 2019). 
At the discretion of the investigator, the adjuvant treatment options offered in the study 
(BO40747) for patients not achieving pCR are trastuzumab emtansine in combination 
with atezolizumab/placebo as assigned at randomization without unblinding of the 
treatment arms, or atezolizumab/placebo  trastuzumab  pertuzumab.  This study 
(BO40747) will explore trastuzumab emtansine in combination with atezolizumab in 


 
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patients with non-pCR with exposure in a limited number of patients.  Based on the 
assumption that 227 patients will be randomized to the experimental arm, an estimated 
drop-out rate of 10%, and an estimated pCR rate of 80% in the experimental arm, 
approximately 41 patients will be eligible to receive atezolizumab  trastuzumab 
emtansine based on their non-pCR status.  Similarly, 82 patients in the control arm are 
estimated to be eligible to receive placebo  trastuzumab emtansine based on their 
non-pCR status. 
3.4.6 
Rationale for Pathologic Complete Response as Primary 
Endpoint 
The co-primary objective of this study is to evaluate the efficacy of 
atezolizumab  ddAC-PacHP compared with placebo  ddAC-PacHP in patients with 
newly diagnosed HER2-positive breast cancer in the ITT and PD-L1positive patient 
populations.  Efficacy will be assessed using pCR. 
pCR was selected as the primary efficacy endpoint because it is a validated, meaningful 
measure of response to therapy, and on the basis of data from several analyses and 
clinical trials and meta-analyses, there is an association between the pCR status of a 
patient and long-term outcomes (Liedtke et al. 2008; von Minckwitz et al. 2012; 
Cortazar et al. 2014).  More recently, data from the I-SPY 2 trial have shown that 
achieving pCR is a strong predictor of EFS and distant recurrence-free survival, 
EFS HR 0.21 [95% CI: 0.05 to 0.85]; DDFS HR 0.22 [95% CI: 0.08 to 0.70] in patients 
with HER2-positive breast cancer (Tripathy et al. 2017). 
pCR will be defined as the absence of residual invasive cancer on hematoxylin and 
eosin evaluation of the complete resected breast specimen and all sampled regional 
lymph nodes following completion of NAST, in line with the FDA and European 
Medicines Agency (EMA) guidance for industry on pCR endpoints (i.e., ypT0/Tis ypN0 in 
the current AJCC staging system). 
3.4.7 
Rationale for Biomarker Assessments 
Published results from several studies suggest that the expression of PD-L1 in tumors 
correlates with response to antiPD-1 and antiPD-L1 monotherapy 
(Topalian et al. 2012; Herbst et al. 2014; Borghaei et al. 2015; Fehrenbacher et al. 2016; 
Herbst et al. 2016; Rosenberg et al. 2016; Schmid et al. 2018).  Therefore, given the 
mode of action of atezolizumab, PD-L1 is considered a potential candidate to predict 
response to treatment.  However, emerging data on the basis of studies targeting the 
PD-1/PD-L1 pathway showed that the results are complex and ambiguous.  Contributing 
factors are PD-L1 variability between different assays, status of the biopsy, and the 
dynamic expression of PD-L1.  Interestingly, in melanoma, the predictive nature of 
PD-L1 expression seems to depend on whether the disease is early stage or metastatic.  
In resected high-risk Stage III melanoma, significantly longer recurrence-free survival 
was observed with adjuvant pembrolizumab compared with placebo in the ITT 
population.  Pembrolizumab was similarly effective in patients with PD-L1positive and 


 
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PD-L1negative tumors suggesting that the benefit of antiPD-1 treatment is not 
dependent on PD-L1 expression in an early disease setting (Eggermont et al. 2018).  
In contrast, advanced melanoma patients treated with pembrolizumab in the metastatic 
setting experienced longer PFS and OS when their tumors were PD-L1positive 
compared with patients whose tumors were PD-L1negative suggesting a predictive role 
of PD-L1 in this setting (Daud AI et al. 2016).  On the basis of these findings, it is 
hypothesized that the predictive value of PD-L1 expression for atezolizumab may differ 
between early versus metastatic disease.  Given the current uncertainty as to whether 
cancer immunotherapy can provide benefits in unselected versus PD-L1selected early 
breast cancer, this study (BO40747) will enroll an all-comer population but will test 
efficacy in the ITT and PD-L1positive patient populations and stratify randomization on 
the basis of PD-L1 status. 
In the current study, baseline tumor specimens will be collected from patients and tested 
for PD-L1 expression by a central laboratory during the screening period.  
Randomization will be stratified by PD-L1 expression (IC 0 vs. IC 1/2/3) as assessed by 
immunohistochemistry (IHC). 
Other immune markers of interest are TILs.  In HER2-positive breast cancer, increased 
TIL concentrations have shown an association with increased frequency of response to 
neoadjuvant therapy and longer survival (Loi et al. 2014; Salgado et al. 2015a, 2015b; 
Denkert et al. 2018; Ignatiadis et al. 2018).  Not all data have shown consistent results 
(Bianchini et al. 2015).  A standardized methodology for evaluating TILs has been 
established and will be applied to tissue samples in this study to understand the role of 
TILs in clinical benefit of the combination of atezolizumab and ddAC-PacHP 
(Salgado et al. 2015a, 2015b).  In the PANACEA study in patients with HER2-positive 
metastatic breast cancer treated with trastuzumab and pembrolizumab, the subgroup of 
patients with PD-L1positive tumor status and having 5% or more of TILs present in the 
metastatic tumor achieved an objective response rate of 39%, while no objective 
responses were observed in the PD-L1negative cohort (Loi et al. 2016). 
Other exploratory biomarkers, such as potential predictive and prognostic biomarkers 
related to the clinical benefit of the combination of atezolizumab and ddAC-PacHP, 
long-term benefit, tumor immunobiology (e.g., TILs, CD8 expression), mechanisms of 
resistance, or tumor type, may be analyzed.  In addition, phosphatase and tensin 
homolog may be performed. 
Differences in pCR rates and in long-term outcomes between patients with 
HER2-positive breast cancer with hormone receptorpositive disease and hormone 
receptornegative disease have been reported in several Phase II/III studies, showing 
lower pCR rates for patients with hormone receptorpositive compared with hormone 
receptornegative disease with pCR rates varying from 15% to 30% (Gianni et al. 2012; 
Untch et al. 2016; Zhang and Hurvitz 2016; Swain et al. 2018). 


 
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In this study, baseline tumor specimens will be tested for ER and PgR status and 
randomization will be stratified based upon centrally confirmed hormone receptor status.  
Another biomarker of interest is PIK3CA mutation.  Lower pCR rates in patients carrying 
a PIK3CA mutation were observed in the neoadjuvant setting across several trials in 
HER2-positive breast cancer (Schneeweis et al. 2013; Majewski et al. 2015; 
Loibl et al. 2016).  Therefore, PIK3CA mutations will also be assessed retrospectively in 
this study. 
In addition to baseline tumor collection, tumor tissue will also be collected by biopsy at 
the time of disease recurrence if deemed clinically feasible by the investigator to enable 
analysis of tumor tissue biomarkers related to resistance, disease progression, clinical 
benefit of the combination of atezolizumab and ddAC-PacHP, and long-term efficacy. 
Blood samples will be collected at baseline and during the study to evaluate changes in 
biomarkers.  Changes in biomarkers such as cytokines associated with T-cell activation 
and lymphocyte subpopulations, and ctDNA may provide evidence of biologic activity of 
the combination of atezolizumab and ddAC-PacHP and of their association with 
long-term efficacy outcomes.  Correlations between these biomarkers and safety and 
efficacy endpoints will be explored to identify blood-based biomarkers that might predict 
which patients are more likely to benefit from the combination of atezolizumab and 
ddAC-PacHP.  Exploratory biomarkers will also be tested for association with long-term 
efficacy. 
Exploratory research on safety biomarkers may be conducted to support future drug 
development.  Research may include further characterization of a safety biomarker or 
identification of safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation.  
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this 
study.  In addition, safety biomarker data will not inform decisions on patient 
management. 
3.4.8 
Rationale for Patient-Reported Outcome Assessments 
EBC is largely asymptomatic, with the majority of newly diagnosed patients exhibiting no 
disease-specific, discernable symptoms (Barrett et al. 2009; Ryerson et al. 2015).  
Therefore, toxicities, the corresponding treatment-related symptoms, and their impact 
define the patient experience (i.e., how patients feel and function).  These are important 
aspects to consider helping inform the overall clinical benefit of a novel drug for this 
potentially curable indication.  Treatment-related symptoms associated with EBC 
regimens can have significant impact on patients’ lives, including their ability to conduct 
activities of daily living, on physical functioning, and on emotional and social aspects 
(Petersen et al. 2016).  Therefore, it is critical to document the burden associated with 
EBC treatment and understand the experience of treatment-related symptoms and their 


 
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impact directly from patients to further inform benefitrisk assessment and treatment 
decision making (Montazeri 2008; Au et al. 2010; FDA 2013, 2015; EMA 2016). 
A comprehensive assessment of treatment burden from the patient’s perspective in this 
study will be conducted and will include a global assessment of the impact of treatment 
on patients’ functioning (role, physical) and HRQoL as secondary endpoints, as well as 
the experience of treatment-related symptoms and their associated level of bother and 
the impact on emotional and social functioning as exploratory endpoints.  The 
GHS/HRQoL, functional, and disease/treatmentrelated symptom items and scales of 
the EORTC QLQ-C30 (see Appendix 4) and the treatment bother item GP5 from the 
FACT-G (see Appendix 5) quality-of-life instrument will all be used to assess patients’ 
treatment burden (see Figure 2). 
Figure 2 Documenting Treatment Burden in Patients with Early Breast 
Cancer 
 
EORTC  European Organisation for Research and Treatment of Cancer; FACT-G  Functional 
Assessment of Cancer TherapyGeneral; HRQoL  health-related quality of life; 
QLQ-C30  Quality of Life QuestionnaireCore 30. 
 
Given the duration of treatment and the potential for long-term treatment impact, all PRO 
measures will be assessed at specified timepoints while patients are on treatment and 
after treatment discontinuation as defined in the schedule of activities (see Appendix 1).  
All PRO data collected will be analyzed per published scoring manuals to support and 
inform the benefitrisk assessment of atezolizumab therapy (Cella 1997; 
Fayers et al. 2001). 


 
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4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
Approximately 453 patients with cT 24, cN13, cM0 HER2-positive breast cancer 
(tumor  2 cm and lymph node positive) will be enrolled in this study. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
Signed Informed Consent Form 
 
Age  18 years at time of signing Informed Consent Form 
 
Ability to comply with the study protocol, in the investigator's judgment 
 
Confirmed diagnosis of HER2-positive breast cancer, and hormonal and PD-L1 
status, as documented through central testing of a representative tumor tissue 
specimen, is required. 
– 
A formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin block 
(preferred) or at least 20 slides containing unstained, freshly cut, serial sections 
must be submitted prior to study enrollment.  Any deviation of the material 
requirements (see Appendix 3) are only allowed after Sponsor’s approval has 
been obtained. 
– 
HER2-positive status will be determined on the basis of pretreatment breast 
biopsy material and defined as an IHC score of 3  or positive by in situ 
hybridization (ISH; see Appendix 3 and Appendix 7) prospectively assessed by 
a central laboratory prior to study enrollment.  ISH positivity is defined as a ratio 
of  2 for the number of HER2 gene copies to the number of signals for 
chromosome 17 copies.  A central laboratory will perform both IHC and ISH 
assays; however, only one positive result is required for eligibility. 
– 
PD-L1 status through measurement of IHC will be used for stratification.  The 
maximum PD-L1 score assessed among samples submitted for eligibility will be 
used as the PD-L1 score for the patient. 
– 
ER/PgR status will be determined centrally based on pretreatment breast 
biopsy material according to the American Society of Clinical Oncology (ASCO) 
and the College of American Pathologists guidelines (Hammond et al. 2010). 
 
Primary breast tumor size of  2 cm by any radiographic measurement 
(see Section 4.5.5 for additional details) 
 
Stage at presentation:  T2T4, N1N3, M0 as determined by AJCC staging system, 
8th edition (specifically in accordance with Anatomic Stage group rules) 
 
Pathologic confirmation of nodal involvement with malignancy must be determined 
by fine-needle aspiration or core-needle biopsy.  Surgical excision of lymph nodes 
(e.g., sentinel lymph node biopsy and axillary lymph node biopsy) is not permitted. 
 
Patients with multifocal tumors (more than one mass confined to the same quadrant 
as the primary tumor) are eligible provided at least one focus is sampled and 


 
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centrally confirmed as HER2-positive (see Appendix 3 for tissue sample 
requirements). 
 
Patients with multicentric tumors (multiple tumors involving more than one quadrant) 
are eligible provided all discrete lesions are sampled and centrally confirmed as 
HER2 positive (see Appendix 3 for tissue sample requirements). 
– 
In patients with multifocal or multicentric breast cancer, the largest lesion 
should be measured to determine T stage. 
 
Patient agreement to undergo appropriate surgical management, including axillary 
lymph node surgery and partial or total mastectomy, after completion of neoadjuvant 
treatment 
 
Eastern Cooperative Oncology Group Performance Status of 0 or 1 
 
Baseline LVEF  55% measured by echocardiogram (ECHO) or multiple-gated 
acquisition (MUGA) scans 
 
Adequate hematologic and end-organ function, defined by the following laboratory 
test results, obtained within 14 days prior to initiation of study treatment: 
– 
ANC  1.5  109/L (1500 cells/L) without G-CSF support 
– 
Lymphocyte count  0.5  109/L (500 cells/L) 
– 
Platelet count  100  109/L (100,000 cells/L) without transfusion 
– 
Hemoglobin  90 g/L (9 g/dL) 
Patients may be transfused to meet this criterion. 
– 
AST, ALT, and ALP  2.5  upper limit of normal (ULN) 
– 
Serum bilirubin  1.5  ULN with the following exception: 
Patients with known Gilbert disease:  serum bilirubin level  3  ULN 
– 
Creatinine clearance  30 mL/min (calculated using the Cockcroft-Gault 
formula) 
– 
Serum albumin  25 g/L (2.5 g/dL) 
– 
For patients not receiving therapeutic anticoagulation:  INR or aPTT  1.5  ULN 
within 14 days prior to initiation of study treatment 
– 
For patients receiving therapeutic anticoagulation: 
INR or aPTT within therapeutic limits for at least 1 week immediately prior 
to initiation of study treatment 
Stable anticoagulant regimen and stable INR during the 14 days 
immediately preceding initiation of study treatment 
 
Negative HIV test at screening 
 
Negative hepatitis B surface antigen (HBsAg) test at screening 
 
Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total 
HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening 


 
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– 
The HBV DNA test will be performed only for patients who have a positive total 
HBcAb test. 
 
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. 
 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods, and agreement to refrain 
from donating eggs, as defined below: 
– 
Women must remain abstinent or use contraceptive methods with a failure rate 
of  1% per year during the treatment period and for 5 months after the final 
dose of atezolizumab/placebo, 6 months after the final dose of doxorubicin, 
12 months after the final dose of cyclophosphamide, 6 months after the final 
dose of paclitaxel, and 7 months after the final dose of trastuzumab. 
pertuzumab, or trastuzumab emtansine, whichever occurs last.  Women must 
refrain from donating eggs during this same period. 
– 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state ( 12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).  The 
definition of childbearing potential may be adapted for alignment with local 
guidelines or requirements. 
– 
Examples of contraceptive methods with a failure rate of  1% per year include 
bilateral tubal ligation, male sterilization, copper intrauterine devices, hormonal 
contraceptives that inhibit ovulation, and hormone-releasing intrauterine 
devices in women with hormone receptor-negative tumors only; the use of 
hormonal contraceptives and hormone releasing intrauterine devices are 
prohibited in women with hormone receptorpositive tumors. 
– 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm, as 
defined below: 
– 
With a female partner of childbearing potential who is not pregnant, men who 
are not surgically sterile must remain abstinent or use a condom plus an 
additional contraceptive method that together result in a failure rate of  1% per 
year during the treatment period and for 6 months after the final dose of 
doxorubicin and/or cyclophosphamide, 6 months after the final dose of 
paclitaxel, and 7 months after the final dose of trastuzumab, pertuzumab, or 
trastuzumab emtansine, whichever occurs last.  Men must refrain from donating 
sperm during this same period.  Male patients are encouraged to seek advice 


 
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regarding cryoconservation of sperm prior to commencing study treatment 
because of the possibility of infertility with chemotherapy. 
– 
With a pregnant female partner, men must remain abstinent or use a condom 
during the treatment period and for 6 months after the final dose of doxorubicin 
and/or cyclophosphamide, 6 months after the final dose of paclitaxel, and 
7 months after the final dose of trastuzumab, pertuzumab, or trastuzumab 
emtansine, whichever occurs last to avoid exposing the embryo. 
– 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
Prior history of invasive breast cancer 
 
Stage IV (metastatic) breast cancer 
– 
Baseline tumor staging determination should be performed in alignment with 
AJCC staging system, 8th edition (specifically in accordance with Anatomic 
Stage group rules). 
 
Patients with synchronous bilateral invasive breast cancer 
 
Patients with hormone receptorpositive disease (estrogen receptorpositive and/or 
progesterone receptorpositive) will be excluded once approximately 227 patients 
(50% of the total target sample size) with hormone receptorpositive disease have 
been enrolled. 
 
Prior systemic therapy for treatment of breast cancer 
 
Previous therapy with anthracyclines or taxanes for any malignancy 
 
Ulcerating or inflammatory breast cancer (e.g., erythema and/or dermal 
involvement, and/or pathologic detection of tumor cells in dermal lymphatics) 
 
Undergone incisional and/or excisional biopsy of primary tumor and/or axillary lymph 
nodes 
 
Sentinel lymph node procedure or axillary lymph node dissection prior to initiation of 
neoadjuvant therapy 
 
History of other malignancy within 5 years prior to screening, with the exception of 
those patients who have a negligible risk of metastasis or death (e.g., 5-year OS of 
 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma 
skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I 
uterine cancer 
 
Cardiopulmonary dysfunction as defined by any of the following prior to 
randomization: 
– 
History of congestive heart failure of any classification 


 
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– 
Angina pectoris requiring anti-anginal medication, serious cardiac arrhythmia 
not controlled by adequate medication, severe conduction abnormality, or 
clinically significant valvular disease  
– 
High-risk uncontrolled arrhythmias (i.e., atrial tachycardia with a heart rate 
 100/min at rest, significant ventricular arrhythmia [ventricular tachycardia], or 
higher-grade atrioventricular [AV]-block [second degree AV-block Type 2 
[Mobitz 2] or third degree AV-block])  
– 
Significant symptoms (Grade  2) relating to left ventricular dysfunction, cardiac 
arrhythmia, or cardiac ischemia  
– 
Myocardial infarction within 12 months prior to randomization  
– 
Uncontrolled hypertension (systolic blood pressure  180 mmHg and/or diastolic 
blood pressure  100 mmHg)  
– 
Evidence of transmural infarction on ECG 
– 
Requirement for oxygen therapy 
– 
Dyspnea at rest 
 
Active or history of autoimmune disease or immune deficiency, including but not 
limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid 
antibody syndrome, granulomatosis with polyangiitis, Sjögren syndrome, 
Guillain-Barré syndrome, or multiple sclerosis (see Appendix 9 for a more 
comprehensive list of autoimmune diseases and immune deficiencies), with the 
following exceptions: 
– 
Patients with a history of autoimmune-related hypothyroidism who are on a 
stable dose of thyroid-replacement hormone are eligible for the study. 
– 
Patients with controlled type 1 diabetes mellitus who are on a stable insulin 
regimen are eligible for the study. 
– 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are 
excluded) are eligible for the study provided all the following conditions are met: 
Rash must cover  10% of body surface area (BSA). 
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids. 
No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic 
agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids 
within the previous 12 months. 
 
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of 
active pneumonitis on screening chest computed tomography (CT) scan 
– 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 


 
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 
Active tuberculosis 
 
Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation 
of study treatment or anticipation of need for a major surgical procedure during the 
study 
 
Severe infection within 4 weeks prior to initiation of study treatment, including but 
not limited to hospitalization for complications of infection, bacteremia, or severe 
pneumonia 
 
Treatment with therapeutic antibiotics within 2 weeks (IV antibiotics) or 5 days (oral 
antibiotics) prior to initiation of study treatment 
– 
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract 
infection or chronic obstructive pulmonary disease [COPD] exacerbation) are 
eligible for the study. 
 
Prior allogeneic stem cell or solid organ transplantation 
 
Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that contraindicates the use of an investigational drug and may 
affect the interpretation of the results, or may render the patient at high risk from 
treatment complications 
 
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during atezolizumab/placebo 
treatment or within 5 months after the final dose of atezolizumab/placebo 
 
Treatment with investigational therapy within 28 days prior to initiation of study 
treatment 
 
Prior treatment with CD137 agonists or immune checkpoint blockade therapies, 
including anticytotoxic T lymphocyte-associated protein-4, antiPD-1, and 
antiPD-L1 therapeutic antibodies 
 
Treatment with systemic immunostimulatory agents (including but not limited to 
interferon and interleukin-2 [IL-2]) within 4 weeks or 5 half-lives of the drug 
(whichever is longer) prior to initiation of study treatment 
 
Treatment with systemic immunosuppressive medication (including but not limited to 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
antitumor necrosis factor- [TNF-] agents) within 2 weeks prior to initiation of 
study treatment, or anticipation of need for systemic immunosuppressive medication 
during study treatment, with the following exceptions: 
– 
Cyclophosphamide as part of the study treatment 
– 
Patients who received acute, low-dose systemic immunosuppressant 
medication or a one-time pulse dose of systemic immunosuppressant 
medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible 
for the study after Medical Monitor approval has been obtained. 
– 
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids 
for COPD or asthma, or low-dose corticosteroids for orthostatic hypotension or 
adrenal insufficiency are eligible for the study. 


 
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 
History of severe allergic anaphylactic reactions to chimeric or humanized 
antibodies or fusion proteins 
 
Known hypersensitivity to Chinese hamster ovary cell products or to any component 
of the atezolizumab formulation 
 
Known allergy or hypersensitivity to the components of the paclitaxel, 
cyclophosphamide, or doxorubicin formulations  
 
Known allergy or hypersensitivity to trastuzumab or pertuzumab formulations 
 
Pregnancy or breastfeeding, or intention of becoming pregnant during study 
treatment or within 5 months after the final dose of atezolizumab/placebo, 6 months 
after the final dose of doxorubicin, 12 months after the final dose of 
cyclophosphamide, 6 months after the final dose of paclitaxel, or 7 months after the 
final dose of trastuzumab, pertuzumab, or trastuzumab emtansine, whichever 
occurs last 
– 
Women of childbearing potential must have a negative serum pregnancy test 
result within 7 days prior to initiation of study treatment. 
 
Exclusions Related to Trastuzumab Emtansine in the Adjuvant Setting 
 
Patients who achieved pCR defined as the absence of residual invasive cancer on 
hematoxylin and eosin evaluation of the complete resected breast specimen and all 
sampled regional lymph nodes following completion of neoadjuvant systemic 
therapy (i.e., ypT0/is ypN0 in the current AJCC staging system, 8th edition) 
 
Evidence of clinically evident gross residual or recurrent disease following 
neoadjuvant therapy and surgery 
 
Unable to complete surgery with curative intent after conclusion of neoadjuvant 
systemic therapy 
 
Patient discontinued treatment with trastuzumab because of toxicity during the 
neoadjuvant phase of the study. 
 
Clinically significant history of liver disease, including cirrhosis, current alcohol 
abuse, autoimmune hepatic disorders, or sclerosis cholangitis 
 
Patients with current Grade  2 peripheral neuropathy 
 
Prior treatment with trastuzumab emtansine 
 
Serum AST, ALT, and alkaline phosphatase not within  1.5  ULN 
 
Serum total bilirubin not within normal range ( 1.0  ULN) 
– 
Except for patients with Gilbert’s syndrome, for whom direct bilirubin should be 
within the normal range. 
 
Serum creatinine not within  1.5  ULN 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
4.2.1 
Treatment Assignment 
After written informed consent has been obtained, all screening procedures and 
assessments have been completed, and eligibility has been established, the study site 


 
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will enter demographic and baseline characteristics in the interactive voice or web-based 
response system (IxRS).  For those patients who are eligible for enrollment, the study 
site will obtain the patient’s identification number and treatment assignment from the 
IxRS. 
Randomization will occur in a 1:1 ratio using a permuted-block randomization method.  
Patients will be randomized to one of two treatment arms:  atezolizumab  neoadjuvant 
ddAC-PacHP or placebo  neoadjuvant ddAC-PacHP.  The randomization scheme is 
designed to ensure that an approximately equal number of patients will be enrolled in 
each treatment arm within the categories defined for the following stratification factors at 
baseline: 
 
Stage at diagnosis (T2, T34) 
 
Hormone receptor status (ER positive and/or PgR positive; ER negative and 
PgR negative) 
– 
Enrollment of patients with hormone receptorpositive disease will be capped 
at 50%. 
 
PD-L1 status (IC 0; IC 1/2/3) 
 
Patients should receive their first dose of study treatment on the day of randomization if 
possible.  If treatment is not possible, the first dose should occur no later than 7 days 
after randomization. 
4.2.2 
Blinding 
Study site personnel and patients will be blinded to treatment assignment during the 
study.  The Sponsor and its agents will also be blinded to treatment assignment, with the 
exception of individuals who require access to patient treatment assignments to fulfill 
their job roles during a clinical trial (e.g., IxRS service provider and iDMC members). 
In general, unblinding of participants during the conduct of the clinical trial is not allowed.  
If unblinding is necessary for a medical emergency (e.g., in the case of a serious 
adverse event for which patient management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  The investigator is not required to contact the Medical Monitor prior 
to breaking the treatment code; however, investigators are encouraged to consult with 
the Medical Monitor prior to performing unblinding.  If knowledge of treatment 
assignment is required to help investigators decide whether patients should switch to or 
start an approved therapy, the investigator will be able to break the treatment code by 
contacting the IxRS.  Investigators are not allowed to break the treatment code to help 
decide if patients should switch to or start an unapproved therapy (including 
investigational treatments in other clinical trials) without prior approval by Medical 
Monitor. 


 
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If the investigator wishes to know the identity of the study drug for any reason other than 
a medical emergency, he or she should contact the Medical Monitor directly. 
On 26 January 2021, the iDMC met and conducted a review of unblinded safety and 
efficacy data.  Following their review of the data, the iDMC recommended to stop 
randomized treatment assignment with atezolizumab or placebo.  The Sponsor accepted 
the iDMC recommendation and on 3 February 2021, issued a USM DIL communicating 
the request to stop treatment with atezolizumab or placebo and the unblinding of the 
study.  The Sponsor unblinded the study on 5 February 2021 and subsequently informed 
sites about treatment assignment of their patients. 
As per health authority reporting requirements, the Sponsor's drug safety representative 
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 5.7) that are considered by the investigator or Sponsor to be related to 
study drug.  The patient may continue to receive treatment, and the investigator, patient, 
and Sponsor personnel, with the exception of the drug safety representative and 
personnel who must have access to patient treatment assignments to fulfill their roles 
(as defined above), will remain blinded to treatment assignment. 
While PK and ADA samples must be collected from patients assigned to the comparator 
arm to maintain the blinding of treatment assignment, PK and ADA assay results for 
these patients are generally not needed for the safe conduct or proper interpretation of 
this study.  Laboratories responsible for performing study drug PK and ADA assays will 
be unblinded to patients' treatment assignments to identify appropriate samples to be 
analyzed.  PK samples from patients assigned to the comparator arm will not be 
analyzed for study drug PK concentration except by request (e.g., to evaluate a possible 
error in dosing).  Baseline ADA samples will be analyzed for all patients.  Postbaseline 
ADA samples from patients assigned to the comparator arm will not be analyzed for 
ADAs except by request. 
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
The investigational medicinal products (IMPs) for this study are atezolizumab, 
trastuzumab, pertuzumab, trastuzumab emtansine, doxorubicin, cyclophosphamide, and 
paclitaxel.  The IMPs required for completion of this study will be provided by the 
Sponsor where required by local health authority regulations. 
4.3.1 
Study Treatment Formulation, Packaging, and Handling 
4.3.1.1 
Atezolizumab and Placebo 
On 3 February 2021, the Sponsor issued a USM DIL communicating the request to stop 
treatment with atezolizumab or placebo.  Therefore, atezolizumab and placebo will no 
longer be supplied by the Sponsor following this date.  The following information reflects 
the situation prior to the USM DIL. 


 
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The atezolizumab Drug Product and placebo will be supplied by the Sponsor as a sterile 
liquid in a single-use, 20-mL glass vial.  The vial contains approximately 20 mL 
(1200 mg) of atezolizumab solution; 14 mL of vial content contains approximately 
840 mg of atezolizumab. 
For information on the formulation and handling of atezolizumab, see the pharmacy 
manual and the Atezolizumab Investigator's Brochure. 
4.3.1.2 
Pertuzumab (Perjeta) 
Pertuzumab will be supplied by the Sponsor as a single-use formulation containing 
30 mg/mL pertuzumab formulated in 20 mM L-histidine (pH 6.0), 120 mM sucrose, and 
0.02% polysorbate-20.  Each 20-cc vial contains approximately 420 mg of pertuzumab 
(14.0 mL/vial).  For information on the formulation and handling of pertuzumab, see the 
pharmacy manual and the Pertuzumab Investigator's Brochure, or the local prescribing 
information for pertuzumab. 
4.3.1.3 
Trastuzumab (Herceptin) 
Trastuzumab will be supplied by the Sponsor in vials containing a freeze-dried 
preparation for parenteral administration.  The vial is reconstituted with Sterile Water for 
Injection and the reconstituted solution contains 21 mg/mL. 
For information on the formulation and handling of trastuzumab, see the pharmacy 
manual and the Trastuzumab Investigator's Brochure, or the local prescribing 
information for trastuzumab. 
4.3.1.4 
Trastuzumab Emtansine (Kadcyla) 
Trastuzumab emtansine will be supplied by the Sponsor in vials containing freeze-dried 
product.  The vial is reconstituted with Sterile Water for Injection and the reconstituted 
solution contains 20 mg/mL. 
For information on the formulation and handling of trastuzumab emtansine, see the 
pharmacy manual and the Trastuzumab Emtansine Investigator’s Brochure, or the local 
prescribing information for trastuzumab emtansine. 
4.3.1.5 
Chemotherapy 
Doxorubicin, cyclophosphamide, and paclitaxel are administered in accordance with 
local prescribing information.  These drugs will be obtained locally by the investigational 
sites or will be provided by the Sponsor as per country requirements. 
Refer to the respective local prescribing information or other appropriate local reference 
document for information on the formulation, preparation, administration, 
contraindications, and patient monitoring. 
4.3.2 
Study Treatment Dosage, Administration, and Compliance 
The treatment regimens are summarized in Section 3.2.1 and Figure 1. 


 
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All study therapy will be completed following 52 weeks of HER2-directed therapy 
(neoadjuvant and adjuvant; i.e., a maximum of 18 cycle of HER2-directed therapy).  
Surgery should be performed at least 14 days after the last dose of neoadjuvant therapy 
but no later than 6 weeks after the last infusion.  Platelet counts should be checked prior 
to surgery and should be  75,000 cells/L. 
The first dose of postoperative treatment should not start until 2 weeks after surgery but 
should be administered within 45 days of surgery. 
Treatment will continue as scheduled or until progression, recurrence of disease, or 
unmanageable toxicity. 
Any dose modification should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).  Cases of accidental overdose or medication error, along 
with any associated adverse events, should be reported as described in Section 5.4.4. 
Patients who discontinue one or more of the study treatment components due to toxicity 
should not be automatically withdrawn from all study treatments. 
Guidelines for dosage modification and treatment interruption or discontinuation for 
patients who experience adverse events and the timing of surgery are provided in 
Appendix 11 and Appendix 12. 
4.3.2.1 
Atezolizumab and Placebo 
On 3 February 2021, the Sponsor issued a USM DIL communicating the request to stop 
treatment with atezolizumab or placebo. 
During the neoadjuvant phase, atezolizumab/placebo will be administered by IV infusion 
at a fixed dose of 840 mg on Day 1 of each 14-day cycle during Cycles 14, and 
1200 mg on Day 1 of each 21-day cycle during Cycles 58.  During the adjuvant phase 
(post-operatively), atezolizumab/placebo will be administered by IV infusion at a fixed 
dose of 1200 mg on Day 1 of each 21-day cycle (maximum of 22 cycles 
[neoadjuvant  adjuvant phases]).  Atezolizumab/placebo should be administered as the 
first infusion. 
Treatment will continue as scheduled or until disease progression, recurrence of 
disease, or unmanageable toxicity. 
Administration of atezolizumab will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to 
manage potentially serious reactions.  For anaphylaxis precautions, see Appendix 10.  
Atezolizumab infusions will be administered per the instructions outlined in Table 1. 


 
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Table 1 
Administration of First and Subsequent Atezolizumab Infusions 
First Infusion 
Subsequent Infusions 
 
No premedication is permitted prior to the 
atezolizumab infusion. 
 
Vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) should 
be measured within 60 minutes prior to the 
infusion. 
 
Atezolizumab should be infused over 
60 ( 15) minutes. 
 
If clinically indicated, vital signs should be 
measured every 15 ( 5) minutes during the 
infusion and at 30 ( 10) minutes after the 
infusion. 
 
Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms. 
 
If the patient experienced an 
infusion-related reaction with any 
previous infusion, premedication with 
antihistamines, antipyretic medications, 
and/or analgesics may be administered 
for subsequent doses at the discretion of 
the investigator. 
 
Vital signs should be measured within 
60 minutes prior to the infusion. 
 
Atezolizumab should be infused over 
30 ( 10) minutes if the previous infusion 
was tolerated without an infusion-related 
reaction, or 60 ( 15) minutes if the 
patient experienced an infusion-related 
reaction with the previous infusion. 
 
If the patient experienced an 
infusion-related reaction with the previous 
infusion or if clinically indicated, vital 
signs should be measured during the 
infusion and at 30 ( 10) minutes after the 
infusion. 
 
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration.  Guidelines for medical management of infusion-related reactions (IRRs) 
are provided in Appendix 12. 
No dose modification for atezolizumab is allowed. 
4.3.2.2 
Pertuzumab (Perjeta) 
Pertuzumab is given as a fixed nonweight-based dose of 840-mg IV loading dose, then 
420 mg IV Q3W.  Pertuzumab will be administered on Day 1 of a 21-day cycle, to 
complete up to a total duration of 52 weeks (i.e., maximum of 18 cycles within 1 year) of 
HER2-targeted therapy, inclusive of therapy given both in the neoadjuvant and adjuvant 
setting (see Figure 1).  Atezolizumab/placebo should be administered prior to 
pertuzumab and trastuzumab.  The order of administration of pertuzumab and 
trastuzumab is according to investigator preference. 
The initial dose of pertuzumab will be administered over 60 ( 10) minutes, and patients 
will be observed for a further 60 minutes.  The infusion should be slowed or interrupted if 
the patient experiences infusion-related symptoms.  If the infusion is well tolerated, 
subsequent doses may be administered over 30 ( 10) minutes, and patients will be 
observed for a further 30 minutes for infusion-related symptoms such as fever or chills.  
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is given or the patient is discharged.  Patients who experience infusion-related 
symptoms may be premedicated with analgesics and antihistamines for subsequent 
infusions. 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.10 and Appendix 11.  No dose reductions are allowed for 
pertuzumab.  If the patient misses a dose of pertuzumab for any cycle and the time 
between doses is  6 weeks, a reloading dose of pertuzumab (840 mg) should be given.  
Subsequent maintenance pertuzumab (420 mg) will then be given Q3W, starting 
3 weeks later. 
If the interval between the first dose of adjuvant pertuzumab and the last dose of 
neoadjuvant pertuzumab is 6 weeks or more, a reloading dose of 840 mg of pertuzumab 
is required. 
4.3.2.3 
Trastuzumab (Herceptin) 
Trastuzumab is given as an 8-mg/kg IV loading dose and then 6 mg/kg IV Q3W.  
Trastuzumab will be administered on Day 1 of a 21-day cycle, to complete up to a total 
duration of 52 weeks (i.e., maximum of 18 cycles within 1 year) of HER2-targeted 
therapy, inclusive of therapy given both in the neoadjuvant and adjuvant setting 
(see Figure 1).  Atezolizumab/placebo should be administered prior to pertuzumab and 
trastuzumab.  The order of administration of pertuzumab and trastuzumab is according 
to investigator preference. 
Weight should be recorded during screening and on Day 1 of each cycle for all patients.  
The baseline weight for a patient will be that measured on Cycle 1, Day 1.  The amount 
of trastuzumab to be administered must be recalculated if the patient’s body weight has 
changed by  10% (increased or decreased) from the Cycle 1, Day 1 weight.  The 
amount of trastuzumab administered is calculated according to the patient’s actual body 
weight, with no upper limit. 
The initial dose of trastuzumab will be administered over 90 ( 10) minutes, and patients 
will be observed for at least 30 minutes from the end of the infusion for infusion-related 
symptoms such as fever or chills.  Interruption or slowing of the infusion may help control 
such symptoms and may be resumed when symptoms abate.  If the infusion is well 
tolerated, subsequent infusions may be administered over 30 ( 10) minutes, and 
patients will be observed for a further 30 minutes.  All infusion-related symptoms must 
have resolved before pertuzumab or chemotherapy is given or the patient is discharged. 
Patients who experience infusion-related symptoms may be premedicated with 
analgesics and antihistamines for subsequent infusions. 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.10 and Appendix 11.  No dose reductions are allowed for 
trastuzumab.  If the patient misses a dose of trastuzumab for any cycle and the time 


 
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between doses is  6 weeks, a reloading dose of trastuzumab (8 mg/kg) should be given.  
Subsequent maintenance trastuzumab (6 mg/kg) doses will then be given Q3W, starting 
3 weeks later. 
If the interval between the first dose of adjuvant trastuzumab and the last dose of 
neoadjuvant trastuzumab is 6 weeks or more, a reloading dose of 8 mg/kg of 
trastuzumab is required. 
4.3.2.4 
Trastuzumab Emtansine (Kadcyla) 
Trastuzumab emtansine will be given at a dose of 3.6 mg/kg by IV infusion Q3W.  The 
dose of trastuzumab emtansine administered will be determined on the basis of the 
baseline weight of the patient.  Weight will be measured at each visit and the dose must 
be re-adjusted for weight changes  10% compared with the previous visit or baseline.  
The investigator may choose to recalculate the dose at every cycle using actual weight 
at that time, in accordance with local practice.  Administration may be delayed to assess 
or treat adverse events.  Dose reduction will be allowed, following the dose reduction 
levels provided in Table 6.  Once a dose has been reduced for an adverse event(s), it 
must not be re-escalated. 
See Table 2 for guidelines for administration of first and subsequent infusions of 
trastuzumab emtansine. 
Table 2 
Administration of First and Subsequent Infusions of 
Trastuzumab Emtansine 
First Infusion 
Subsequent Infusions 
 
No premedication is administered. 
 
Vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) should 
be measured within 60 minutes prior to the 
infusion. 
 
Administer the initial dose as a 
90-minute IV infusion. 
 
Patients should be observed during the 
infusion and for at least 90 minutes 
following the initial dose for fever, chills, or 
other infusion-related reactions. 
 
The infusion rate should be slowed or 
interrupted if the patient develops 
infusion-related symptoms. 
 
The infusion site should be closely 
monitored for possible subcutaneous 
infiltration during drug administration. 
 
Vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) should 
be measured within 60 minutes prior to the 
infusion. 
 
If prior infusions were well tolerated, 
subsequent doses may be administered as 
30-minute infusions. 
 
Patients should be observed during the 
infusions and for at least 30 minutes after 
the infusion. 
 


 
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Trastuzumab emtansine should be administered in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to 
manage potentially serious reactions. 
Trastuzumab emtansine will be administered after the infusion of atezolizumab/placebo. 
4.3.2.5 
Chemotherapy 
Chemotherapy will be administered in the neoadjuvant setting as follows: 
 
Doxorubicin 60 mg/m2 IV on Day 1 of a 14-day cycle for 4 cycles (Cycles 14); with  
 
Cyclophosphamide 600 mg/m2 IV on Day 1 of a 14-day cycle for 4 cycles 
(Cycles 14); followed by 
 
Paclitaxel 80 mg/m2 IV weekly for 12 continuous weeks (Cycles 58) 
The dose of chemotherapy is calculated according to the patient’s BSA.  The BSA and 
the amount of drug administered must be recalculated if the patient’s body weight has 
changed by  10% (increased or decreased) from baseline.  Recalculation of the amount 
of drug administered on the basis of smaller changes in body weight or BSA is at the 
investigators’ discretion. 
There is no mandatory delay between atezolizumab/placebo and ddAC chemotherapy, 
assuming the infusion is well tolerated. 
Doxorubicin 
Doxorubicin will be given as an IV bolus over 35 minutes or as an infusion over 
1530 minutes, in accordance with local SOC.  Dose delays and reduction for toxicity 
are permitted, and patients should receive G-CSF support according to local practice 
guidelines. 
Refer to the local prescribing information for details regarding the preparation and 
administration of doxorubicin. 
Cyclophosphamide 
Cyclophosphamide will be given as an IV bolus over 35 minutes or as an IV infusion, in 
accordance with local SOC.  Patients with BSA of  2 m2 should have their dose capped 
at 1200 mg. 
Dose delays and dose reductions for toxicity are permitted, and patients should receive 
G-CSF support according to local practice guidelines.  Oral cyclophosphamide is not 
permitted.  Refer to the local prescribing information for details regarding the preparation 
and administration of cyclophosphamide. 
Paclitaxel 
Paclitaxel will be administered as an IV infusion over 60 ( 10) minutes or according to 
local SOC, after atezolizumab/placebo, pertuzumab and trastuzumab administration, at 


 
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a dose of 80 mg/m2.  See Appendix 11 for guidance on dose reductions.  Premedication, 
including corticosteroids, should be administered according to routine practice. 
Patients must be closely observed from the start of the infusion for hypersensitivity 
reactions, which may occur within minutes.  Severe hypotension, bronchospasm, or 
generalized rash/erythema requires immediate discontinuation of paclitaxel and 
appropriate treatment.  The infusion may be slowed for minor symptoms, such as 
flushing or local cutaneous reactions.  Patients experiencing severe hypersensitivity 
reactions should be discontinued from study treatment but maintained in the study 
unless consent is withdrawn.  Premedication consisting of a corticosteroid may be given 
according to institutional guidelines. 
Premedications/Supportive Care 
In general, chemotherapy supportive care should be administered per ASCO, EORTC, 
or ESMO guidelines or local SOC.  For further details regarding permitted therapies, 
see Section 4.4.1. 
Chemotherapy-induced nausea and vomiting prophylaxis and treatment should be 
administered as clinically indicated (see Section 4.4.2 for further guidance).  Because 
systemic corticosteroids may attenuate the potential beneficial immunologic effects of 
treatment with atezolizumab, alternative agents should be considered when clinically 
feasible, with the exception of guidance currently in the protocol. 
Prophylactic G-CSF or GM-CSF may be used to mitigate the risk of hematologic 
toxicities according to local policies.  Treatment of neutropenia with G-CSF or GM-CSF 
is permitted according to local policies.  In all cases, G-CSF or GM-CSF will not be 
considered as a study drug and will not be provided by the Sponsor. 
4.3.3 
Other Required Medication 
After surgery, patients with hormone receptorpositive disease should receive adjuvant 
hormone therapy according to guidelines provided in Section 4.4.1.  Postoperative 
radiotherapy is also indicated according to the guidelines provided in Section 4.4.1. 
4.3.4 
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study (atezolizumab, pertuzumab, trastuzumab, 
trastuzumab emtansine, doxorubicin, cyclophosphamide, and paclitaxel) will be provided 
by the Sponsor where required by local health authority regulations.  The study site will 
acknowledge receipt of IMPs supplied by the Sponsor, using the IxRS to confirm the 
shipment condition and content.  Any damaged shipments will be replaced. 
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor (if supplied by the Sponsor) 
with the appropriate documentation.  The site's method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor.  The site must obtain written authorization from 


 
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the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must 
be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 
4.3.5 
Continued Access to Atezolizumab, Pertuzumab, Trastuzumab, 
and Trastuzumab Emtansine 
Currently, the Sponsor does not have any plans to provide Roche IMPs (atezolizumab, 
pertuzumab, trastuzumab, and trastuzumab emtansine) or any other study treatments or 
interventions to patients who have completed the study.  The Sponsor may evaluate 
whether to continue providing pertuzumab, trastuzumab, and trastuzumab emtansine in 
accordance with the Roche Global Policy on Continued Access to Investigational 
Medicinal Product, available at the website below.  Following the discontinuation of 
atezolizumab based on the iDMC’s recommendation, continued access to atezolizumab 
will not be considered. 
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 in addition to protocol-mandated treatment from 30 days prior to initiation of study 
treatment (for the purposes of screening) until the treatment discontinuation visit.  
Medication used by the patient within 7 days prior to initiation of study treatment should 
be recorded.  All such medications should be reported to the investigator and recorded 
on the Concomitant Medications eCRF.  Record all prior anti-cancer therapies, as 
applicable. 
4.4.1 
Permitted Therapy 
Patients are permitted to use the following therapies during the study: 
 
Acceptable methods of contraception must be used when the female patient or male 
partner is not surgically sterilized or does not meet the study definition of 
postmenopausal ( 12 months of amenorrhea). 
 
Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin) 
– 
Patients on anti-coagulant treatment should have their platelet count monitored 
closely during treatment with trastuzumab emtansine. 
 
Inactivated influenza vaccinations 
 
Megestrol acetate administered as an appetite stimulant 
 
Mineralocorticoids (e.g., fludrocortisone) 
 
Corticosteroids administered for COPD or asthma 


 
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 
Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency 
 
Medication to treat diarrhea (e.g., loperamide) 
 
Colony-stimulating factors (e.g., G-CSF) 
 
Estrogen-receptor antagonists (e.g., tamoxifen), aromatase inhibitors 
(e.g., anastrazole, exemestane), and gonadotropin-releasing hormone agonists 
(e.g., buserelin, triptorelin) after surgery, as per local practice and guidelines;  
luteinizing hormonereleasing hormone agonist as part of an attempt at ovarian 
function preservation starting prior to chemotherapy 
 
Radiotherapy after chemotherapy and surgery, during adjuvant therapy 
 
Premedication with antihistamines, antipyretics, and/or analgesics may be administered 
for the second and subsequent atezolizumab infusions only, at the discretion of the 
investigator. 
In general, investigators should manage a patient's care (including preexisting 
conditions) with supportive therapies other than those defined as cautionary or 
prohibited therapies (see Section 4.4.2 and Section 4.4.3) as clinically indicated, per 
local standard practice.  Patients who experience infusion-associated symptoms may be 
treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or 
H2-receptor antagonists (e.g., famotidine, cimetidine), or equivalent medications per local 
standard practice.  Serious infusion-associated events manifested by dyspnea, 
hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or 
respiratory distress should be managed with supportive therapies as clinically indicated 
(e.g., supplemental oxygen and 2-adrenergic agonists; see Appendix 10). 
Radiotherapy 
Postoperative patient management may include radiotherapy as clinically indicated, and 
management of patients who do not achieve a pCR should follow current SOC 
guidelines.  Radiotherapy may be given concurrent with HER2 therapy and 
atezolizumab/placebo. 
Hormone Therapy 
Sites should prescribe hormonal therapy per standard local clinical practice.  Hormonal 
therapy is not considered study drug and will not be provided by the Sponsor.  
Aromatase inhibitors will be allowed as adjuvant hormone therapy for postmenopausal 
patients who are hormone receptorpositive, in countries where it has been registered 
for this indication.  Its use must be consistent with the registered label.  Hormone 
therapy is given after chemotherapy and surgery, during adjuvant therapy.  No other 
hormone therapy for primary breast cancer is allowed, unless approved for adjuvant 
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Female patients must be classified according to one of the following menopausal status 
definitions: 
 
Premenopausal: 
– 
 12 months since last menstrual period AND no prior bilateral ovariectomy 
AND 
Not receiving estrogen replacement 
 
Postmenopausal: 
– 
 12 months since last menstrual period with no prior hysterectomy 
OR 
Prior bilateral ovariectomy 
OR 
Biochemical evidence of postmenopausal status, according to local policies 
 
Female patients should be treated according to the recommendations in Table 3; 
however, investigators may follow local practice guidelines.  Male patients should be 
treated according to local policies. 
Table 3 
Hormonal Therapy 
Patient Status a 
Hormone Therapy 
Hormone receptor negative 
Not allowed 
Hormone receptorpositive 
and premenopausal 
Permitted: 
 Tamoxifen for 510 years with or without ovarian 
suppression, as per local policy 
 Aromatase inhibitor for 5 years and ovarian suppression or 
ablation, followed by tamoxifen to complete 10 years 
Hormone receptorpositive 
and postmenopausal 
The following regimens are permitted: 
 Aromatase inhibitor for 510 years 
 Aromatase inhibitor for 23 years, followed by tamoxifen to 
complete a total of 5 years 
 Tamoxifen for 23 years, followed by an aromatase 
inhibitor to complete a total of 5 years 
 Tamoxifen for 510 years, as per local policy 
 Tamoxifen for 5 years, followed by an aromatase inhibitor 
for 5 years 
a Hormone receptor positivity is defined as positive estrogen receptor or progesterone receptor 
or both.  The investigator may treat the patient with adjuvant hormone therapy according to 
local or central results of hormone receptor testing, but central results will be used in data 
analyses for the study. 
 


 
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4.4.2 
Cautionary Therapy for Atezolizumab-Treated Patients 
4.4.2.1 
Corticosteroids and TNF- Inhibitors 
Systemic corticosteroids and TNF- inhibitors may attenuate potential beneficial 
immunologic effects of treatment with atezolizumab.  Therefore, with the exception of 
scenarios described elsewhere in the protocol (see Section 4.3.2.4), in situations in 
which systemic corticosteroids or TNF- inhibitors would be routinely administered, 
alternatives, including antihistamines, should be considered.  If the alternatives are not 
feasible, systemic corticosteroids and TNF- inhibitors may be administered at the 
discretion of the investigator. 
Systemic corticosteroids are recommended at the discretion of the investigator for the 
treatment of specific adverse events when associated with atezolizumab therapy 
(see Appendix 12 for details). 
4.4.2.2 
Medications Given with Precaution due to Effects Related to 
Cytochrome P450 Enzymes 
The chemotherapeutic agents used in this study are associated with potential drug 
interactions.  The metabolism of paclitaxel is catalyzed by CYP450 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.  Doxorubicin is a major substrate of CYP3A4 and CYP2D6 and 
P-glycoprotein.  Cyclophosphamide is a pro-drug that is activated by cytochrome P450s, 
including CYP2B6, 2C9, and 3A4. 
There is a moderate to high potential for drugdrug interactions with any medication that 
is metabolized by or strongly inhibits or induces these enzymes.  Therefore, such 
medications should be avoided when chemotherapy is being administered. 
Concomitant use of strong CYP3A4/5 inhibitors (such as ketoconazole and itraconazole) 
with trastuzumab emtansine should be avoided.  An alternate medication with no or 
minimal potential to inhibit CYP3A4/5 should be considered.  If a strong CYP3A4/5 
inhibitor is co-administered with trastuzumab emtansine, patients should be closely 
monitored for adverse reactions.  Excessive alcohol intake should be avoided 
(occasional to moderate use is permitted). 
The investigator should consult the prescribing information for any concomitant 
medication as well as the Internet references provided below when determining whether 
a certain medication is metabolized by or strongly inhibits or induces CYP enzymes.  In 
addition, the Medical Monitor is available to advise if questions arise regarding 
medications not listed above. 
 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/G
uidances/UCM292362.pdf 
 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
 


 
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4.4.2.3 
Herbal Therapies 
The concomitant use of herbal therapies is not recommended, as their 
pharmacokinetics, safety profiles, and potential drugdrug interactions are generally 
unknown.  However, their use for patients in the study is allowed at the discretion of the 
investigator as long as they are not intended to treat cancer. 
4.4.2.4 
Therapies Given for Thrombocytopenia Induced by 
Chemotherapy 
Concomitant use of therapies for prevention and treatment of thrombocytopenia induced 
by chemotherapy (e.g., thrombopoietin receptor agonists, recombinant thrombopoietins, 
recombinant interleukin-11) should be avoided.  Adherence to the relevant safety 
management guidelines to institute appropriate dose modifications of trastuzumab 
emtansine in case of thrombocytopenia is recommended (Appendix 14).  If any of those 
agents needs to be co-administered with trastuzumab emtansine in line with local 
standard clinical practice, patients should be closely monitored for adverse reactions 
and overlapping toxicities. 
4.4.3 
Prohibited Therapy 
Use of the following concomitant therapies is prohibited as described below: 
 
Concomitant therapy intended for the treatment of cancer (including but not limited 
to chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy), whether health authorityapproved or experimental, is prohibited for 
various time periods prior to starting study treatment, depending on the agent 
(see Section 4.1.2), and during study treatment, until the patient has discontinued 
study treatment, with the exception of previously listed hormone therapy, 
radiotherapy, and surgery under certain circumstances (see Section 4.4.1 for 
details). 
 
Investigational therapy is prohibited during study treatment. 
 
Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
initiation of study treatment, during study treatment, and for 5 months after the final 
dose of atezolizumab/placebo. 
 
Systemic immunostimulatory agents (including but not limited to interferons and 
IL-2) are prohibited within 4 weeks or 5 drug-elimination half-lives (whichever is 
longer) prior to initiation of study treatment and during study treatment with 
atezolizumab/placebo because these agents could potentially increase the risk for 
autoimmune conditions when given in combination with atezolizumab. 
 
Systemic immunosuppressive medications (including but not limited to azathioprine, 
methotrexate, and thalidomide) are prohibited during study treatment with 
atezolizumab/placebo because these agents could potentially alter the efficacy and 
safety of atezolizumab. 
 
Estrogen replacement therapy (hormone replacement therapy) 
 


 
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4.5 
STUDY ASSESSMENTS 
The schedules of activities to be performed during the study are provided in Appendix 1, 
Appendix 2, and Appendix 3.  All activities should be performed and documented for 
each patient. 
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  Leftover tumor tissue samples, local HER2 test 
information, baseline demographic, and disease-related characteristics data for all 
screened patients will be collected by the Sponsor, in order to support a potential 
registration of a companion diagnostic.  The investigator will maintain a detailed record 
of all patients screened and document eligibility or record reasons for screening failure, 
as applicable. 
4.5.2 
Medical History, Concomitant Medication, and Demographic 
Data 
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), cardiovascular history, menopausal 
status, and smoking history, will be recorded at baseline.  In addition, all medications 
(e.g., prescription drugs, over-the-counter drugs, vaccines) used by the patient within 
7 days prior to initiation of study treatment will be recorded.  At the time of each 
follow-up physical examination, an interval medical history should be obtained and any 
changes in medications and allergies should be recorded. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.3 
Physical Examinations 
A complete physical examination, performed at screening and other specified visits, 
should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurologic systems.  In the physical examination, particular care 
should be taken with regard to cardiovascular signs and symptoms (e.g., elevated 
jugular venous pressure, sinus tachycardia, tachypnea, the presence of an S3 heart 
sound, crackles on chest auscultation, etc.).  Bilateral breast examination, including 
evaluation of locoregional lymphatics, should be conducted (see Section 4.5.5).  Any 


 
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abnormality identified at baseline should be recorded on the General Medical History 
and Baseline Conditions eCRF. 
Limited, symptom-directed physical examinations should be performed at specified 
post-baseline visits and as clinically indicated.  Changes from baseline abnormalities 
should be recorded in patient notes.  New or worsened clinically significant abnormalities 
should be recorded as adverse events on the Adverse Event eCRF. 
4.5.4 
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, systolic and 
diastolic blood pressure, and temperature. 
Vital signs should be measured within 60 minutes prior to each study treatment infusion 
and, if clinically indicated, during or after the infusions.  In addition, vital signs should be 
measured at other specified timepoints as outlined in the schedule of activities 
(see Appendix 1).  The vital signs measured prior to the infusion of the first study drug at 
each cycle are required to be reported on the Vital Sign eCRF.  Other vital signs are not 
required to be entered into the eCRF unless abnormal and clinically significant, in which 
case they are to be reported as adverse events. 
4.5.5 
Locoregional Tumor Status Assessments 
Physical Examination 
Assessment of the primary tumor and regional lymph nodes must be done by physical 
examination during the baseline evaluation, within 3 days prior to each cycle of study 
treatment during the neoadjuvant phase, and within 14 days prior to surgery.  The tumor 
site must be marked with a radiopaque marker via radiographic guidance 
(e.g., ultrasound) prior to initiation of neoadjuvant therapy. 
Clinical assessment of tumor measurement in the breast and/or lymph nodes should be 
conducted in a consistent manner at each evaluation.  Clinical measurements of tumor 
in the breast should be performed, preferentially using calipers or a ruler/tape measure.  
If possible, these measurements should be conducted by the same assessor at baseline 
and throughout the neoadjuvant phase. 
Tumor measurements at baseline and within 14 days prior to surgery are to be recorded 
in the eCRF.  The main purpose of performing a physical examination prior to each cycle 
is for patient safety and to provide information that may help to rule out progressive 
disease that would lead to study treatment discontinuation. 
Mammogram 
Bilateral mammogram should be obtained within 28 days prior to randomization.  
To minimize unnecessary radiation exposure and provided that the clinical status of the 
patient has not changed, the screening mammogram can be performed up to 42 days 
prior to the start of study treatment.  Subsequent mammograms are optional during 


 
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neoadjuvant treatment and prior to surgery and should be performed per investigator’s 
discretion.  Bilateral mammogram should occur at the study completion/early termination 
visit and every 12 months ( 4 weeks) during the follow-up period.  Patients who have 
undergone mastectomy do not require mammograms on the side of mastectomy. 
Other Breast Imaging 
Eligibility with regards to the primary breast tumor size ( 2 cm) is to be confirmed 
through imaging (mammogram, positron emission tomography [PET] scan, CT scan, 
magnetic resonance imaging [MRI], ultrasound, or X-ray).  The tumor should be 
accurately measured in at least one dimension and the longest diameter recorded. 
Additional breast imaging throughout the study, such as MRI and ultrasound, are per 
investigator discretion.  MRI examination is not mandated by the protocol and should be 
per local practice.  If MRI is conducted, suggested timelines for MRI are within 28 days 
prior to protocol therapy, after Cycle 3, and 14 days prior to surgery. 
Surgical Treatment Plan 
A surgeon with experience in breast cancer surgery should evaluate patients.  The 
proposed surgical treatment plan at baseline should be documented and reported in the 
eCRF.  Patients should be reassessed after completion of neoadjuvant therapy and prior 
to surgery.  The surgeon should evaluate the patient and create a surgical treatment 
plan.  Then after completion of NAST, the surgeon should reassess the patient and 
modify the surgical treatment plan as needed.  These treatments should be documented 
and reported in the eCRF. 
4.5.6 
Distant Sites Tumor Assessment 
Baseline distant sites tumor staging procedures should be performed in alignment with 
NCCN or national guidelines, within 28 days prior to randomization. 
As a reference, as per NCCN guidelines, staging procedures are based on clinical stage: 
 
For Stage II and Stage IIIA:  Bone scan is to be performed in presence of bone pain 
and/or elevated ALP; abdominal/pelvic CT scan in case of elevated ALP, abnormal 
liver function tests, abdominal symptoms or abnormal physical examination; and 
chest CT scan. 
 
For Stage IIIB and Stage IIIC:  Bone scan and CT scan of chest, abdomen, and 
pelvis should be conducted for all patients. 
 
In addition, liver function tests, brain imaging, bone scans, chest X-ray/diagnostic 
CT scan, liver imaging, and/or other radiographic modalities may be considered when 
clinically indicated to exclude metastatic disease. 


 
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4.5.7 
Disease Follow-Up and Confirmation of Disease Progression or 
Recurrence 
During neoadjuvant treatment, diagnosis of disease progression or second primary 
breast cancer should be supported by clinical, laboratory, radiological, and/or histological 
findings.  Post-operatively, all patients must be followed to assess disease recurrence, 
second primary cancer, and survival.  The designation of disease recurrence, whether 
local, regional or distant, or a diagnosis of a second primary cancer can be made only 
when clinical, laboratory, radiological, and/or histological findings support the diagnosis. 
During the post-operative portion of this study, disease status should be clinically 
evaluated and documented every 3 months for 2 years and then every 6 months 
thereafter until the end of the study. 
The diagnosis of a breast cancer progression, recurrence, or second primary tumor 
should be confirmed histologically whenever clinically possible.  Differential diagnosis of 
clinical enlargement of an in-breast tumor during neoadjuvant therapy may include 
inflammatory response secondary to treatment-related tumor necrosis, infection/mastitis, 
or true tumor progression.  Additional diagnostic workup (e.g., biopsy for histologic 
confirmation of cancer versus immune-mediated inflammatory process), treatment, 
and/or multidisciplinary discussion should be considered to help elucidate whether 
disease progression is occurring and guide whether neoadjuvant treatment should be 
continued or not. 
Some patients may experience a suspicious recurrence that leads to death relatively 
quickly, without the possibility of confirming relapse of disease.  Efforts should be made 
to obtain an autopsy report in such cases. 
The earliest date of diagnosis of disease progression, recurrent disease, or a diagnosis 
of a second primary cancer should be used and recorded.  This date should be based on 
objective clinical, radiological, histological, or cytological evidence. 
Recurrent disease includes local, regional, or distant recurrence and contralateral breast 
cancer.  While ipsilateral or contralateral in situ disease and second primary non-breast 
cancers (including in situ carcinomas and non-melanoma skin cancers) will not be 
counted as progressive disease or recurrent disease, these events should be recorded.  
Patients who have a diagnosis of in situ breast disease or second (non-breast) 
malignancies should be maintained on a regular follow-up schedule whenever possible 
in order to fully capture any subsequent recurrent disease events. 
The definitions of and procedures for confirming disease recurrence, death, and other 
noteworthy events on follow-up are provided in Table 4. 


 
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Table 4 
Definitions of and Procedures for Confirming Disease 
Recurrence, Death, and Other Noteworthy Events on Follow-Up 
a) Local 
invasive 
recurrence 
Ipsilateral 
breast after 
previous 
lumpectomy 
 Defined as evidence of invasive tumor (except DCIS 
and LCIS) in the ipsilateral breast after lumpectomy.  
Patients who develop clinical evidence of tumor 
recurrence in the remainder of the ipsilateral breast 
should have a biopsy of the suspicious lesion to 
confirm the diagnosis. 
 Confirmed by positive histology or cytology 
Ipsilateral after 
previous 
mastectomy 
 Defined as evidence of invasive tumor in any soft 
tissue or skin of the ipsilateral chest wall.  This 
includes the area bounded by the midline of the 
sternum, extending superiorly to the clavicle and 
inferiorly to the costal margin.  Soft tissue 
recurrences in this area extending into the bony 
chest wall or across the midline will be considered as 
evidence of local recurrence. 
 Confirmed by positive histology or cytology 
b) Regional 
recurrence 
 Defined as the development of tumor in the ipsilateral internal 
mammary lymph nodes, ipsilateral axillary lymph nodes, or 
supraclavicular lymph nodes as well as extranodal soft tissue of the 
ipsilateral axilla.  Regional recurrence does not include tumor in the 
opposite breast. 
 Confirmed by positive histology or cytology, or radiologic evidence 
(especially in case of PET activity or visible internal mammary lymph 
nodes on CT scan or MRI if no biopsy was performed). 
CT  computed tomography (scan); DCIS  ductal carcinoma in situ; EFS  event-free survival; 
LCIS  lobular carcinoma in situ; MRI  magnetic resonance imaging; OS  overall survival; 
PET  positron emission tomography. 


 
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Table 4 
Definitions of and Procedures for Confirming Disease 
Recurrence, Death, and Other Noteworthy Events on Follow-Up 
(cont.) 
 
c) Distant 
recurrence 
 Defined as evidence of tumor in all areas, with the exception of those 
described in a) and b) above. 
 Confirmed by the following criteria: 
Skin, subcutaneous tissue, and lymph nodes (other than local or 
regional) 
Positive cytology, aspirate, or biopsy, OR  
Radiological (CT scan, MRI, PET scan, or ultrasound) evidence 
of metastatic disease 
Bone 
X-ray, CT scan, or MRI evidence of lytic or blastic lesions 
consistent with bone metastasis, OR 
Bone scan (requires additional radiological investigation, alone 
not acceptable in case of diagnostic doubt), OR 
Biopsy proof of bone metastases or cytology 
Bone marrow 
Positive cytology or histology or MRI 
Lung 
Radiologic (CT or PET scan) evidence of multiple pulmonary 
nodules consistent with pulmonary metastases 
Positive cytology or histology in case of diagnostic doubt 
(particularly for solitary lung lesions) if a biopsy is not performed.  
Serial scans should be obtained if possible to document stability 
or progression. 
Proof of neoplastic pleural effusions should be established by 
cytology or pleural biopsy. 
Liver 
Radiologic evidence consistent with liver metastases, OR 
Liver biopsy or fine-needle aspiration 
Note:  If radiological findings are not definitive (especially 
with solitary liver nodules), a liver biopsy is recommended; 
however, if a biopsy is not performed, serial scans should 
be obtained if possible to document stability or progression. 
Central nervous system 
Positive MRI or CT scan, usually in a patient with neurologic 
symptoms, OR 
Biopsy or cytology in case of inconclusive imaging (e.g., for a 
diagnosis of meningeal involvement) and, depending from the 
general status of the patient, additional investigations (including 
cytology of the cerebrospinal fluid) 
CT  computed tomography (scan); DCIS  ductal carcinoma in situ; EFS  event-free survival; 
LCIS  lobular carcinoma in situ; MRI  magnetic resonance imaging; OS  overall survival; 
PET  positron emission tomography. 


 
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Table 4 
Definitions of and Procedures for Confirming Disease 
Recurrence, Death, and Other Noteworthy Events on Follow-Up 
(cont.) 
 
d) Contralateral 
invasive 
breast cancer 
 Confirmed by positive cytology or histology 
e) Death from 
any cause 
 Any death occurring without prior breast cancer recurrence is 
considered an event for the following endpoints:  DFS, EFS, and OS. 
 Any death occurring during study (with or without prior breast cancer 
recurrence) is considered an event for the following endpoint:  OS. 
CT  computed tomography (scan); DCIS  ductal carcinoma in situ; EFS  event-free survival; 
LCIS  lobular carcinoma in situ; MRI  magnetic resonance imaging; OS  overall survival; 
PET  positron emission tomography. 
 
4.5.8 
Surgical Specimen Pathology 
Primary endpoint of the study (pCR) will be as identified by local pathology review using 
guidelines provided in the pathology manual.  A complete pathologic response is defined 
as the absence of invasive disease in the breast and axilla (tpCR; i.e., ypT0 or ypTis, 
ypN0) based on microscopic examination of the surgical specimen following neoadjuvant 
therapy.  Guidelines regarding pathology specimen preparation and labeling are outlined 
in the pathology manual.  The Sponsor will prospectively collect local pathology reports. 
If additional information on lymph nodes at surgery is present in other reports, these 
should also be submitted to the Sponsor. 
4.5.9 
Laboratory, Biomarker, and Other Biological Samples 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis as outlined in the schedule of activities (see Appendix 1) and as clinically 
indicated: 
 
Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, and 
other cells) 
 
Chemistry panel (serum or plasma):  bicarbonate or total carbon dioxide 
(if considered SOC for the region), sodium, potassium, magnesium, chloride, 
glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, 
total bilirubin, ALP, ALT, AST, and lactate dehydrogenase (LDH) 
 
Coagulation:  INR and aPTT 
 
Thyroid function testing:  thyroid-stimulating hormone, free triiodothyronine (T3) 
(or total T3 for sites where free T3 is not performed), and free thyroxine (also known 
as T4) 
 
HIV serology 


 
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 
HBV serology:  HBsAg, total HBcAb, and (if HBsAg test is negative and total HBcAb 
test is positive) HBV DNA 
– 
If a patient has a negative HBsAg test and a positive total HBcAb test at 
screening, an HBV DNA test must also be performed to determine if the patient 
has an HBV infection. 
 
HCV serology:  HCV antibody and (if HCV antibody test is positive) HCV RNA 
– 
If a patient has a positive HCV antibody test at screening, an HCV RNA test 
must also be performed to determine if the patient has an HCV infection. 
 
Pregnancy test 
– 
All women of childbearing potential will have a serum pregnancy test at 
screening, within 7 days prior to initiation of study treatment.  Urine pregnancy 
tests will be performed within 24 hours of Day 1 of every cycle until treatment 
discontinuation.  A pregnancy test must be done at the completion/early 
termination visit, and at 3 months and 7 months after the discontinuation of 
study treatment.  If a urine pregnancy test is positive, it must be confirmed by a 
serum pregnancy test. 
– 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state ( 12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus). 
 
Urinalysis (pH, specific gravity, glucose, protein, ketones, and blood); dipstick 
permitted. 
 
The following samples will be sent to one or several central laboratories or to the 
Sponsor or a designee for analysis: 
 
Serum sample for analysis of autoantibodies:  anti-nuclear antibody, 
antidouble-stranded DNA, circulating anti-neutrophil cytoplasmic antibody, and 
perinuclear anti-neutrophil cytoplasmic antibody 
 
Serum samples for atezolizumab, trastuzumab, pertuzumab, and trastuzumab 
emtansine PK analysis through use of validated assays 
 
Serum samples for assessment of ADAs to atezolizumab, trastuzumab, 
pertuzumab, and trastuzumab emtansine through use of validated assays 
 
Blood and plasma samples for exploratory research on biomarkers at baseline and 
during treatment (see Appendix 3) 
 
Tumor tissue sample obtained at baseline for determination of HER2 status and 
PD-L1 expression, ER, and PgR status and for biomarker research (including but 
not limited to PIK3CA mutation status, TILs, and CD8) 
– 
A representative FFPE tumor specimen in a paraffin block (preferred) or at least 
20 slides containing unstained, freshly cut, serial sections must be submitted.  
In case of any deviation in submission of tissue material, the patient may still be 
eligible for the study, after Medical Monitor approval has been obtained.   


 
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– 
Tumor tissue should be of good quality based on total and viable tumor content.  
Samples must contain a minimum of 50 viable tumor cells that preserve cellular 
context and tissue architecture regardless of needle gauge or retrieval method.  
Acceptable samples include those collected via core-needle biopsy (at least 
three cores, embedded in a single paraffin block).  Fine-needle aspiration 
(defined as samples that do not preserve tissue architecture and yield cell 
suspension and/or smears) is not acceptable. 
 
Tumor tissue sample obtained at time of surgery and at time of recurrence 
(if deemed clinically feasible) for exploratory biomarker research  
– 
A representative FFPE tumor specimen in a paraffin block (preferred) or at least 
15 slides containing unstained, freshly cut, serial sections must be submitted 
(see further details in Appendix 3). 
 
Leftover tumor tissue samples from all screened patients may be used for future 
development of diagnostic tests relating to HER2 and PD-L1. 
Biomarker analyses may include but will not be limited to analysis of genes or gene 
signatures associated with HER2 pathway, tumor immune biology, PD-L1, lymphocyte 
subpopulations, T-cell receptor repertoire, cytokines associated with T-cell activation, 
and ctDNA.  Analyses may involve extraction of DNA, ctDNA, or RNA, analysis of 
mutations, and genomic profiling through use of next-generation sequencing (NGS) of a 
comprehensive panel of genes.  Research will not be aimed at distinguishing germline 
mutations from somatic mutations.  NGS methods may include whole genome 
sequencing (WGS)/whole exome sequencing (WES) but only at participating sites 
(see Section 4.5.13). 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.14), biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exceptions: 
 
Serum samples collected for PK or immunogenicity analysis may be needed for 
additional immunogenicity characterization and for PK or immunogenicity assay 
development and validation; therefore, these samples will be destroyed no later than 
5 years after the final Clinical Study Report has been completed. 
 
Tissue samples collected for eligibility testing, at surgery, and at disease recurrence, 
and blood samples collected for biomarker research will be destroyed no later than 
5 years after the final Clinical Study Report has been completed or earlier 
depending on local regulations. 
 
For patients who are not enrolled, remaining tissue blocks will be returned to the site 
no later than 6 weeks after eligibility determination. 
 


 
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When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed, or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis, including data on mutations, will be subject to the 
confidentiality standards described in Section 8.4. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication. 
4.5.10 
Electrocardiograms 
A 12-lead ECG is required at screening and when clinically indicated (see Appendix 1).  
ECGs for each patient should be obtained from the same machine wherever possible.  
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Any morphologic waveform changes or other ECG abnormalities 
must be documented on the eCRF. 
4.5.11 
Echocardiograms or Multiple-Gated Acquisition Scans 
LVEF will be assessed by ECHO (preferably) or MUGA scan at specified timepoints, as 
outlined in the schedule of activities (see Appendix 1) and as clinically indicated.  
Patients should be reassessed with the same technique used for baseline cardiac 
evaluation throughout the study, unless clinically indicated. 
Investigators must be aware of local institutional regulations regarding the maximum 
allowable frequency of repeat MUGA scans.   The repeated administration of 
radioisotopes is limited in some nuclear medicine laboratories, and patients in this study 
require monitoring on more than four occasions within 1 year. 
4.5.12 
Patient-Reported Outcomes 
To more fully characterize the clinical profile of atezolizumab, PRO data will be 
obtained through use of the following instruments:  EORTC QLQ-C30; item GP5 of the 
FACT-G quality-of-life instrument; and the EQ-5D-5L. 
Official versions of the PRO instruments in booklet format, translated as required in the 
local language, will be distributed by the investigator staff and completed on paper in 
their entirety by the patient at the investigational site.  To ensure instrument validity and 


 
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that data standards meet health authority requirements, questionnaires must be 
completed by the patient at the start of the clinic visit before discussion of the patient’s 
health state, laboratory results, or health record; before administration of study 
treatment; and/or prior to the performance of any other study assessments that could 
bias the patient’s responses.  In scenarios where laboratory assessments (e.g., blood 
draws) are done in a different clinic than the one providing treatment or when they are 
done on a different day than study treatment administration, laboratory assessments can 
be completed before the completion of PROs as long as results have not been 
discussed with patients.  If the patient is unable to complete the measure on her or his 
own, interviewer assessment is allowed but may only be conducted by a member of the 
clinic staff who reads the questionnaire items to the patient verbatim; no interpretation, 
rephrasing, or rewording of the questions is allowed during interview-assisted 
completion. 
Study personnel should review all questionnaires for completeness before the patient 
leaves the investigational site, and the hard copy originals of the questionnaires must be 
maintained as part of the patient’s medical record at the site for source data verification. 
These originals should have the respondent’s initials, study patient number and date, 
and time of completion recorded in compliance with good clinical practice.  Sites will 
enter patient responses to the PRO questionnaires into the electronic data capture 
(EDC) system. 
All patients will begin completion of the questionnaires with the EORTC QLQ-C30, 
followed by the FACT-G single item GP5, and then the EQ-5D-5L at timepoints 
corresponding with in-clinic visits; both while receiving study treatment and after 
treatment discontinuation.  See Appendix 1 for the frequency and timing of PRO 
assessments. 
4.5.12.1 
EORTC QLQ-C30 
The EORTC QLQ-C30 is a validated, reliable self-report measure (Aaronson et al. 1993; 
Fitzsimmons et al. 1999; see Appendix 6).  It consists of 30 questions that assess 
5 aspects of patient functioning (physical, emotional, role, cognitive, and social), 
3 symptom scales (fatigue, nausea and vomiting, pain), global health/quality of life, and 
6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial 
difficulties) with a recall period of the previous week.  Scale scores can be obtained for 
the multi-item scales.  The EORTC QLQ-C30 module takes approximately 10 minutes to 
complete. 
4.5.12.2 
FACT-G Single Item GP5 
The FACT-G instrument Version 4 (see Appendix 5) is a validated and reliable 27-item 
questionnaire comprised of 4 subscales that measure physical (7 items), social/family 
(7 items), emotional (6 items), and functional well-being (7 items), and is considered 
appropriate for use with patients with any form of cancer (Cella et al. 1993; 
Webster et al. 1999).  In this study, the single-item GP5 (“I am bothered by side effects 


 
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of treatment”) from the physical well-being subscale of the FACT-G has been selected 
for individual item analysis to document the level of bother of symptoms on patients’ 
lives.  Patients will assess how true the statement “I am bothered by side effects of 
treatment” has been for them in the previous 7 days on a 5-point scale (0  not at all; 
1  a little bit; 2  somewhat; 3  quite a bit; 4  very much).  The single-item GP5 from the 
FACT-G takes less than 1 minute to complete. 
4.5.12.3 
EQ-5D-5L 
The EQ-5D-5L is a validated self-report health status questionnaire that is used to 
calculate a health status utility score for use in health economic analyses 
(EuroQol Group 1990; Brooks 1996; Herdman et al. 2011; Janssen et al. 2013; 
see Appendix 6).  There are two components to the EQ-5D-5L:  a five-item health state 
profile that assesses mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression, as well as a visual analog scale that measures health state.  
Published weighting systems allow for creation of a single composite score of the 
patient’s health utility.  Utility scores will be used in this study for informing 
pharmacoeconomic evaluations.  As such, the utility results will not be included in the 
Clinical Study Report.  The EQ-5D-5L takes approximately 3 minutes to complete. 
4.5.13 
Samples for Whole Genome Sequencing 
At participating sites, blood samples will be collected for DNA extraction to enable WGS 
to identify mutations that are predictive of response to study drug, are associated with 
progression to a more severe disease state, are associated with acquired resistance to 
study drug, are associated with susceptibility to developing adverse events, can lead to 
improved adverse event monitoring or investigation, or can increase the knowledge and 
understanding of disease biology and drug safety.  Research will aim to distinguish 
germline mutations from somatic mutations.  The samples may be sent to one or more 
laboratories for analysis. 
Collection and submission of WGS samples is contingent upon the review and approval 
of the exploratory research 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 WGS sampling, this section of the protocol (Section 4.5.13) 
will not be applicable at that site. 
Genomics is increasingly informing researchers’ understanding of disease pathobiology.  
WGS provides a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches or new methods for monitoring efficacy and safety or predicting which 
patients are more likely to respond to a drug or develop adverse events.  Data will be 
analyzed in the context of this study but will also be explored in aggregate with data from 
other studies.  The availability of a larger dataset will assist in identification and 
characterization of important biomarkers and pathways to support future drug 
development. 


 
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For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Blood samples collected for WGS are to be stored until they are no longer needed or 
until they are exhausted.  However, the storage period will be in accordance with the 
IRB/ECapproved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Patient medical information associated with WGS samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Given the complexity and exploratory nature of the WGS analyses, data derived from 
these analyses will generally not be provided to study investigators or patients unless 
required by law.  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication. 
4.5.14 
Optional Samples for Research Biosample Repository 
4.5.14.1 
Overview of the Research Biosample Repository 
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biological specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The 
collection, storage, and analysis of RBR samples will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future. 
Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be used to achieve the following 
objectives: 
 
To study the association of biomarkers with efficacy or disease recurrence 
 
To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation 
 
To increase knowledge and understanding of disease biology and drug safety 
 
To study drug response, including drug effects and the processes of drug absorption 
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 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.14.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not 
been granted approval for RBR sampling, this section of the protocol (Section 4.5.14) 
will not be applicable at that site. 
4.5.14.3 
Sample Collection 
The following samples will be stored in the RBR and used for research purposes, 
including but not limited to research on biomarkers related to atezolizumab, 
ddAC-PacHP, and diseases or drug safety: 
 
Biomarker blood samples collected at timepoints defined in the schedule of activities 
 
Leftover blood, serum, plasma, and tumor tissue samples and any derivatives 
thereof (e.g., DNA, RNA, proteins, peptides) 
 
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic mutations via WGS, WES, or other genomic analysis methods.  Genomics is 
increasingly informing researchers’ understanding of disease pathobiology.  WGS and 
WES provide a comprehensive characterization of the genome and exome, respectively, 
and, along with clinical data collected in this study, may increase the opportunity for 
developing new therapeutic approaches or new methods for monitoring efficacy and 
safety or predicting which patients are more likely to respond to a drug or develop 
adverse events. 
Data generated from RBR samples will be analyzed in the context of this study but will 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
RBR samples are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/ECapproved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
4.5.14.4 
Confidentiality 
RBR samples and associated data will be labeled with a unique patient identification 
number. 


 
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Patient medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication. 
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
4.5.14.5 
Consent to Participate in the Research Biosample Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR samples.  Patients 
who decline to participate will not provide a separate signature. 
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF. 
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research. 
 
4.5.14.6 
Withdrawal from the Research Biosample Repository 
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  However, if RBR samples have been tested prior to 
withdrawal of consent, results from those tests will remain as part of the overall research 
data.  If a patient wishes to withdraw consent to the testing of his or her RBR samples 
during the study, the investigator must inform the Medical Monitor in writing of the 
patient's wishes through use of the appropriate RBR Subject Withdrawal Form and must 
enter the date of withdrawal on the RBR Research Sample Withdrawal of Informed 
Consent eCRF.  If a patient wishes to withdraw consent to the testing of his or her RBR 


 
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samples after closure of the site, the investigator must inform the Sponsor by emailing 
the study number and patient number to the following email address: 
global.rcr-withdrawal@roche.com 
 
A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study. 
4.5.14.7 
Monitoring and Oversight 
RBR samples will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RBR for the purposes of verifying 
the data provided to the Sponsor.  The site will permit monitoring, audits, IRB/EC review, 
and health authority inspections by providing direct access to source data and 
documents related to the RBR samples. 
4.6 
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Study Treatment Discontinuation 
Patients must permanently discontinue study treatment if they experience any of the 
following: 
 
Intolerable toxicity related to study treatment, including development of an 
immune-mediated adverse event determined by the investigator to be unacceptable 
given the individual patient's potential response to therapy and severity of the event 
 
Any medical condition that may jeopardize the patient's safety if he or she continues 
study treatment 
 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient 
 
Use of another non-protocol anti-cancer therapy 
 
Pregnancy 
 
Confirmation of disease progression or disease recurrence 
 
Withdrawal by patient 
 
Following receipt of the USM DIL dated 3 February 2021, all patients currently 
receiving study treatment must discontinue treatment with atezolizumab or placebo. 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 


 
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Breast cancer surgery and pathological assessment will be performed and reported 
according to protocol requirements for patients who discontinue study treatment during 
the neoadjuvant phase (for any reason other than disease progression) and who 
proceed to surgery without receiving any other non-study anti-cancer therapy prior to 
surgery.  Patients who discontinue neoadjuvant study treatment due to disease 
progression contribute a non-pCR result and their disease progression must be reported. 
Patients who discontinue study treatment early for any reason, enter the follow-up phase 
of the study (Appendix 1). 
4.6.2 
Patient Discontinuation from Study 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include but are not limited to the following: 
 
Patient withdrawal of consent 
– 
From study treatment and/or procedures only (i.e., survival follow-up permitted) 
OR 
– 
From survival follow-up (patient does not want to be contacted) 
 
Study termination or site closure 
 
Investigator or Sponsor determines it is in the best interest of the patient. 
 
Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor 
 
The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator.  Patients 
who withdraw from the study will not be replaced. 
If a patient withdraws from the study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status where permitted by 
local law. 
4.6.3 
Partial Withdrawal from Study 
All of the above provisions regarding withdrawal from the entire study are applicable to 
partial withdrawal from the study, except that the patient agrees to be contacted for 
further information on recurrence as per the study secondary endpoint, survival status 
and anti-cancer therapy.  Whenever possible, information on recurrence should be 
documented through review of medical records as well as patient contact.  It should be 
documented in both the medical records and the eCRF that the patient agreed to be 
contacted for further information despite the patient’s withdrawal of informed consent. 


 
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4.6.4 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include but are not limited to the following: 
 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients 
 
Patient enrollment is unsatisfactory 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study. 
4.6.5 
Site Discontinuation 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include but are not limited to the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PLAN 
The safety plan for patients in this study is based on clinical experience with 
atezolizumab, ddAC-PacHP, and trastuzumab emtansine in completed and ongoing 
studies.  The anticipated important safety risks are outlined below 
(see Section 5.1.15.1.8). 
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria and close monitoring of 
patients during the study.  Administration of atezolizumab/placebo, ddAC-PacHP, and 
trastuzumab emtansine will be performed in a monitored setting in which there is 
immediate access to trained personnel and adequate equipment and medicine to 
manage potentially serious reactions.  Guidelines for managing patients who experience 
anticipated adverse events, including criteria for dosage modification and treatment 
interruption or discontinuation, are provided in Appendix 11, Appendix 12, Appendix 14, 
and Appendix 15.  See Section 5.1.105.6 for details on safety reporting (e.g., adverse 
events, pregnancies) for this study. 
In the setting of a pandemic or epidemic, screening for active infections (including 
SARS-CoV-2) during study participation should be considered according to local or 


 
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institutional guidelines or guidelines of applicable professional societies (e.g., American 
Society of Clinical Oncology or European Society for Medical Oncology). 
Severe COVID-19 appears to be associated with a CRS involving the inflammatory 
cytokines IL-6, IL-10, IL-2, and IFN- (Merad and Martin 2020).  If a patient develops 
suspected CRS during the study, a differential diagnosis should include COVID-19, 
which should be confirmed or refuted through assessment of exposure history, 
appropriate laboratory testing, and clinical or radiologic evaluations per investigator 
judgment.  If a diagnosis of COVID-19 is confirmed, the disease should be managed as 
per local or institutional guidelines. 
5.1.1 
Risks Associated with Atezolizumab 
Atezolizumab has been associated with risks such as the following:  IRRs and 
immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré 
syndrome, myasthenic syndrome or myasthenia gravis, facial paresis, myelitis, 
meningoencephalitis, myocarditis, pericardial disorders, nephritis, and myositis, and 
severe cutaneous adverse reactions.  In addition, immune-mediated reactions may 
involve any organ system and lead to hemophagocytic lymphohistiocytosis (HLH).  
Refer to Appendix 12 of the protocol and Section 6 of the Atezolizumab Investigator's 
Brochure for a detailed description of anticipated safety risks for atezolizumab. 
5.1.2 
Risks Associated with Doxorubicin 
Doxorubicin is known to cause serious cardiomyopathy; arrhythmias, including 
life-threatening arrhythmias; increased incidence of secondary acute myelogenous 
leukemia and myelodysplastic syndrome; extravasation and tissue necrosis; severe 
myelosuppression resulting in serious infection, septic shock, need for transfusions, 
hospitalization, and death; tumor lysis syndrome; radiation sensitization and radiation 
recall; embryofetal toxicity; infertility; alopecia; hyperuricemia; vomiting; nausea; and 
other gastrointestinal effects.  Hypersensitivity reactions, such as fever, urticaria and 
anaphylaxis have been occasionally reported. 
Refer to the local prescribing information for doxorubicin for more details regarding the 
full safety profile of doxorubicin, including boxed warnings and contraindications. 
Dose reduction and dose delays will be allowed as indicated in the relevant local 
prescribing information and Appendix 11 and will be managed as per local practice. 
5.1.2.1 
Cardiomyopathy 
Patients treated with doxorubicin are at risk of developing cumulative dose-related 
myocardial damage.  Significant cardiac events, including acute heart failure and LVEF 
of  40%, have been observed in clinical trials of doxorubicin.  Cardiomyopathy may 
develop during treatment or up to several years after completion of treatment.  There is 
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who have received radiotherapy to the mediastinum or concomitant therapy with other 
known cardiotoxic agents such as cyclophosphamide. 
Patients must meet specified LVEF requirements to be included in this study 
(see Section 4.1.1). 
Left ventricular function will be monitored by measurement of ejection fraction with the 
use of ECHO or MUGA scans as described in Section 4.5.11 and the schedule of 
activities (see Appendix 1).  For the algorithm for continuation and discontinuation of 
study treatment based on LVEF measurements see Figure 3. 
5.1.3 
Risks Associated with Cyclophosphamide 
Cyclophosphamide has been associated with myelosuppression sometimes leading to 
severe immunosuppression and infections that can be serious and sometimes fatal; 
hemorrhagic cystitis, pyelitis, ureteritis, and hematuria (with some fatal cases of 
urotoxicity); myocarditis, myopericarditis (which may be accompanied by pericardial 
effusion and cardiac tamponade, leading to severe cardiac heart failure), arrhythmias, 
and congestive heart failure; pulmonary toxicity including pneumonitis, pulmonary 
fibrosis, and pulmonary veno-occlusive disease leading to respiratory failure; secondary 
malignancies; veno-occlusive liver disease; embryo-fetal toxicity; infertility; impairment of 
wound-healing; hyponatremia; alopecia; nausea; vomiting; stomatitis and diarrhea; 
anaphylactic reactions including those with fatal outcomes; and cecitis. 
Refer to the local prescribing information for cyclophosphamide for more details 
regarding the full safety profile of cyclophosphamide, including boxed warnings and 
contraindications. 
Dose reduction and dose delays will be allowed as indicated in the relevant local 
prescribing information and Appendix 11, and managed as per local practice. 
5.1.4 
Risks Associated with Paclitaxel 
Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and 
hypotension requiring treatment, angioedema, and generalized urticaria have occurred.  
Fatal reactions have occurred in patients despite premedication.  Therefore, study 
patients must be premedicated according to local paclitaxel prescribing information and 
institutional SOC practice.  Such premedication may consist of a corticosteroid 
(dexamethasone 810 mg by mouth 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 re-challenged with the drug. 
Warnings related to paclitaxel use include myelosuppression (primarily neutropenia), 
which is dose-dependent and is the DLT during paclitaxel treatment; and increased risk 


 
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in patients with hepatic impairment.  Infectious episodes may occur and included sepsis, 
pneumonia, and peritonitis.  The use of supportive therapy, including G-CSF or 
GM-CSF, is recommended for patients who have experienced severe neutropenia. 
Other warnings for paclitaxel use include severe cardiac conduction abnormalities, which 
required pacemaker placement in some cases, peripheral neuropathy, 
pseudomembranous colitis, mucositis, interstitial pneumonitis.  When paclitaxel is used 
in combination with doxorubicin or trastuzumab, attention should be placed on the 
monitoring of cardiac function.  In addition, paclitaxel can cause fetal harm when 
administered to a pregnant woman. 
Hypotension, bradycardia, and hypertension have been observed during administration 
of paclitaxel.  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, and other 
serious neurologic events following paclitaxel administration have included grand mal 
seizures, syncope, ataxia, and neuroencephalopathy. 
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; see Section 4.4.2.1. 
Paclitaxel is contraindicated in patients with severe hepatic impairment. 
For more details regarding the safety profile of paclitaxel, refer to the local paclitaxel 
prescribing information. 
Dose reduction and dose delays will be allowed as indicated in the relevant local 
prescribing information and Appendix 11 and will be managed as per local practice. 
5.1.5 
Risks Associated with Pertuzumab, Trastuzumab, and 
Trastuzumab Emtansine 
The known risks associated with trastuzumab treatment include cardiac toxicity (as 
described below), infusion-related reactions, hypersensitivity and anaphylaxis, febrile 
neutropenia, diarrhea, pulmonary toxicity, as well as risk of oligohydramnios.  Refer to 


 
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the Trastuzumab Investigator’s Brochure for a full description of the trastuzumab safety 
profile, warnings, precautions, and guidance for investigators. 
For pertuzumab, infusion-related reactions, anaphylaxis and hypersensitivity, diarrhea, 
interstitial lung disease, left ventricular systolic dysfunction and symptomatic left 
ventricular systolic dysfunction/congestive heart failure, skin reactions/rash, leukopenia, 
and mucositis are adverse events of particular clinical relevance.  Refer to the 
Pertuzumab Investigator’s Brochure for a full description of the pertuzumab safety 
profile, warnings, precautions, and guidance for investigators. 
Identified risks with trastuzumab emtansine are interstitial lung disease and acute 
respiratory distress syndrome, hepatotoxicity, nodular regenerative hyperplasia of the 
liver, left ventricular dysfunction, infusion-related reactions, hypersensitivity reactions, 
hemorrhage, thrombocytopenia, and peripheral neuropathy.  Refer to the Trastuzumab 
Emtansine Investigator’s Brochure for a full description of the trastuzumab emtansine 
safety profile, warnings, precautions, and guidance for investigators. 
The administration of pertuzumab, trastuzumab, and trastuzumab emtansine should be 
performed in a setting with emergency equipment and staff who are trained to monitor 
medical situations and respond to medical emergencies.  Patients will be monitored 
during each infusion for adverse effects (see Section 4.3.2.2 and 4.3.2.3 for details).  
The management of infusion-associated symptoms is outlined in Appendix 11 
and Appendix 14. 
5.1.5.1 
Cardiotoxicity 
LVEF declines have been reported with drugs that block HER2 activity, including 
pertuzumab, trastuzumab, and trastuzumab emtansine. 
To enter this study, all patients must have a LVEF (by ECHO or MUGA scan) of  55% 
and regular monitoring of LVEF is required throughout the study according to the 
schedule of activities (see Appendix 1).  For the algorithm for continuation and 
discontinuation of study treatment based on LVEF measurements, see Figure 3. 
If severe symptomatic heart failure develops (New York Heart Association [NYHA] 
Class III or IV), the patient must discontinue anti-HER2 therapy.  If there is a significant 
LVEF decrease (LVEF decline  10 percentage points from baseline to an LVEF value 
 50%), anti-HER2 therapy should be withheld and a repeat LVEF assessment 
performed within approximately 3 weeks.  If LVEF has not improved or has declined 
further or if clinically significant heart failure develops, the patient must discontinue 
anti-HER2 therapy.  Patients who develop asymptomatic cardiac dysfunction may 
benefit from more frequent monitoring (e.g., every 68 weeks).  Heart failure or left 
ventricular dysfunction should be treated and monitored according to standard medical 
practice.  These patients should be evaluated by a certified cardiologist, and the results 
of this evaluation should be reported on the eCRF. 


 
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Patients who discontinue pertuzumab, trastuzumab, or trastuzumab emtansine for heart 
failure or LVEF decline should continue to undergo LVEF assessments according to the 
schedule of activities (see Appendix 1)irrespective of the initiation of alternative 
systemic anti-cancer therapyuntil resolution, improvement to baseline status, no 
further improvement can be expected, or death.  Additional LVEF assessments may be 
required for these patients (beyond those specified in the schedule of activities), 
according to the investigator’s clinical judgment.  The results of these assessments 
should be reported.


 
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Figure 3 Algorithm for Continuation and Discontinuation of Study Treatment on the Basis of LVEF Assessment 
 
HER2  human epidermal growth factor 2; LVEF  left ventricular ejection fraction.  
a Three intermittent holds of study treatment will lead to discontinuation. 
 


 
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5.1.5.2 
EGFR-Related Toxicities 
Although pertuzumab targets the HER2 receptor, it inhibits heterodimerization with other 
members of the HER family (e.g., epidermal growth factor receptor [EGFR; HER1]).  
Accordingly, it may cause toxicities associated with the use of EGFR inhibitors such as 
diarrhea, rash, and other dermatologic toxicities (e.g., dry skin, pruritus, nail disorders, or 
mucositis). 
To prevent dehydration, early treatment of diarrhea with anti-diarrheal medication should 
be considered, and patients should be treated with fluids and electrolyte replacement, as 
clinically indicated. 
Treatment recommendations for EGFR-associated rash include topical or oral antibiotics 
and topical steroids or systemic steroids (for severe reactions). 
These agents may be used in patients experiencing pertuzumab-related rash, as 
clinically indicated, although they have not been studied in this context. 
Mucositis is generally not considered preventable; although for some cytotoxic agents, 
mucositis may be reduced by cooling the mouth using ice chips before and during the 
infusion. 
5.1.6 
Risks Associated with Trastuzumab Emtansine 
5.1.6.1 
Pulmonary Toxicity 
Cases of interstitial lung disease (ILD), including pneumonitis, some leading to acute 
respiratory distress syndrome or fatal outcome have been reported in clinical trials with 
trastuzumab emtansine.  Signs and symptoms include dyspnea, cough, fatigue, and 
pulmonary infiltrates.  These events may or may not occur as sequelae of infusion 
reactions. 
Permanently discontinue treatment with trastuzumab emtansine in patients diagnosed 
with ILD or pneumonitis, except for radiation pneumonitis in the adjuvant setting, where 
trastuzumab emtansine should be permanently discontinued for Grade  3, or for 
Grade 2 not responding to standard treatment.  In comparison with drug-induced 
pneumonitis, radiation pneumonitis is often focal and limited to the area exposed to 
radiation. 
Patients with dyspnea at rest due to complications of advanced malignancy, 
co-morbidities, and receiving concurrent pulmonary radiation therapy may be at 
increased risk of pulmonary toxicity. 
Guidelines for management of trastuzumab emtansine in patients who develop ILD or 
pneumonitis are provided in Appendix 14. 


 
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5.1.6.2 
Hepatotoxicity 
The following events have been reported with administration of trastuzumab emtansine: 
 
Serious hepatobiliary disorders 
– 
Serious hepatobiliary disorders, including nodular regenerative hyperplasia 
(NRH) of the liver and hepatobiliary disorders with a fatal outcome due to 
drug-induced liver injury, have been observed in patients treated with 
trastuzumab emtansine.  Some of the observed cases may have been 
confounded by concomitant medications with known hepatotoxic potential. 
 
Increased serum transaminases 
– 
Asymptomatic increases in serum transaminase concentration (transaminitis) 
have been observed.  Grade 1 and 2 events have been observed frequently; 
Grade 3 and 4 events have been observed less commonly.  The incidence of 
increased AST was substantially higher than that for increased ALT.  Increases 
in AST and ALT were commonly observed by Day 8 of each cycle and 
generally improved or returned to baseline by Day 21.  A cumulative effect of 
trastuzumab emtansine, that is, an increase in the proportion of patients with 
Grade 1 or 2 elevations in transaminases with successive cycles has been 
observed; however, there was no increase in the proportion of patients with 
Grade 3 abnormalities over time. 
 
NRH 
– 
Cases of NRH have been identified from liver biopsies in patients treated with 
trastuzumab emtansine who presented with signs and symptoms of portal 
hypertension.  NRH is a rare liver condition characterized by widespread benign 
transformation of hepatic parenchyma into small regenerative nodules.  NRH 
may lead to non-cirrhotic portal hypertension.  Diagnosis of NRH can only be 
confirmed by histopathology.  Biopsy-confirmed NRH leading to fatal hepatic 
failure has been reported. 
– 
NRH should be considered in all patients with clinical symptoms of portal 
hypertension, even with normal transaminases, and no other manifestations of 
cirrhosis; in patients with a cirrhosis-like pattern seen on a CT scan of the liver; 
and/or in patients with liver failure following long-term treatment with 
trastuzumab emtansine. 
 
Guidelines for management of trastuzumab emtansine in patients who develop 
increased serum transaminases, increased serum bilirubin, or NRH are provided in 
Appendix 14. 
5.1.6.3 
Left Ventricular Dysfunction 
Patients treated with trastuzumab emtansine are at risk of developing left ventricular 
dysfunction.  To date, significant cardiac events, including LVEF of  40%, have been 
observed (infrequently) in clinical trials of trastuzumab emtansine; therefore, 
symptomatic CHF is a potential risk. 


 
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Guidelines for patient monitoring and management of trastuzumab emtansine in patients 
who develop left ventricular dysfunction are provided in Section 5.1.5.1 and 
Appendix 14. 
5.1.6.4 
Infusion-Related Reactions and Hypersensitivity Reactions 
IRRs and hypersensitivity reactions have been reported with administration of 
trastuzumab emtansine.  Despite the different pathophysiology of IRRs (reactions 
involving cytokine release) and hypersensitivity (allergic) reactions, the clinical 
manifestations are the same.  In general, IRRs are expected to be more frequent and 
severe with the first infusion and to decrease in number and severity over time.  The 
severity of true hypersensitivity reactions would be expected to increase with 
subsequent infusions. 
IRRs, characterized by one or more of the following symptomsflushing, chills, pyrexia, 
dyspnea, hypotension, wheezing, bronchospasm, and tachycardiahave been reported 
in clinical trials of trastuzumab emtansine.  In general, these symptoms were not severe.  
In most patients, these reactions resolved over the course of several hours to a day after 
the infusion was terminated. 
Hypersensitivity reactions, including serious anaphylactic-like reactions, have been 
observed in clinical trials of trastuzumab emtansine.  Patients with a history of 
intolerance to trastuzumab are excluded from this study (see Section 4.1.2). 
Administration of trastuzumab emtansine will be performed in a setting with access to 
emergency facilities and staff who are trained to monitor and respond to medical 
emergencies.  Patients should be closely monitored for IRRs during and after each 
infusion of trastuzumab emtansine. 
Guidelines for management of patients who experience IRRs or hypersensitivity 
reactions are provided in Appendix 14. 
5.1.6.5 
Hematologic Toxicity 
Thrombocytopenia has been reported in patients in clinical trials of trastuzumab 
emtansine.  The majority of these patients had Grade 1 or 2 events (platelet count 
 50,000/L), with the nadir occurring by Day 8 and generally improving to Grade 0 or 1 
(platelet count  75,000/L) by the next scheduled dose (i.e., within 3 weeks).  
Evaluation of this safety parameter across various clinical studies has shown a higher 
incidence and severity of thrombocytopenia in Asian patients. 
Patients with thrombocytopenia ( 100,000/mm3) and patients on anticoagulant 
treatment should be monitored closely during treatment with trastuzumab emtansine.  
It is required that platelet counts are monitored prior to each trastuzumab emtansine 
dose.  Rare cases of severe prolonged thrombocytopenia defined as persisting ( Grade 3 
thrombocytopenia events lasting for more than 90 days) have been reported with 


 
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trastuzumab emtansine on the basis of cumulative data review.  In most of these cases, 
patients received concomitant recombinant human thrombopoietin.  Trastuzumab 
emtansine has not been studied in patients with platelet counts  100,000/mm3 prior to 
initiation of treatment.  In the event of decreased platelet count to Grade  3 
( 50,000/mm3), do not administer trastuzumab emtansine until platelet counts recover to 
Grade 1 ( 75,000/mm3). 
Declines in other hematopoietic lineages (e.g., leukopenia, neutropenia, and anemia) 
were less frequent than that observed for platelets. 
Guidelines for management of trastuzumab emtansine in patients who develop 
hematologic toxicity are provided in Appendix 14. 
5.1.6.6 
Hemorrhage 
Cases of hemorrhagic events, including central nervous system, respiratory, and 
gastrointestinal hemorrhage, have been reported with trastuzumab emtansine.  Some of 
these bleeding events resulted in fatal outcomes.  In some of the observed cases, the 
patients were also receiving anticoagulation therapy, anti-platelet therapy, or had 
thrombocytopenia; in others, there were no known additional risk factors.  Caution 
should be used with these agents, and additional monitoring should be considered when 
concomitant use during treatment with trastuzumab emtansine is medically necessary. 
5.1.6.7 
Neurotoxicity 
Peripheral neuropathy, mainly Grade 1 and predominantly sensory, has been reported in 
clinical trials of trastuzumab emtansine. 
Patients with Grade  3 peripheral neuropathy should not be considered for treatment 
with trastuzumab emtansine. 
Guidelines for management of trastuzumab emtansine in patients who develop 
peripheral neuropathy are provided in Appendix 14. 
5.1.6.8 
Extravasation 
In trastuzumab emtansine clinical studies, reactions secondary to extravasation have 
been observed.  These reactions were usually mild and consisted of erythema, 
tenderness, skin irritation, pain, or swelling at the infusion site.  These reactions have 
been observed more frequently within 24 hours of the infusion. 
Closely monitor the infusion site for possible subcutaneous infiltration during drug 
administration.  Specific treatment for trastuzumab emtansine extravasation is unknown 
at this time.  Patients should be managed symptomatically per local institutional 
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5.1.7 
Risks Associated with Combination Use of Pertuzumab with 
Trastuzumab and Paclitaxel 
Pertuzumab was well tolerated in combination with trastuzumab (Study WO20697), with 
an increase in the incidence but not severity of the common adverse events seen with 
single-agent pertuzumab (notably, diarrhea, rash, and fatigue). 
Study WO29217 (BERENICE) is an open-label, nonrandomized, multicenter, 
multinational Phase II study to evaluate pertuzumab in combination with trastuzumab 
and standard neoadjuvant anthracycline-based chemotherapy in patients with 
HER2-positive, locally advanced, inflammatory, or EBC.  Eligible patients were allocated, 
by the investigator, to receive one of the two treatment regimens:  ddAC given Q2W for 
4 cycles, followed by weekly paclitaxel for 12 weeks, with pertuzumab and trastuzumab 
given Q3W from the start of paclitaxel; or FEC given Q3W for 4 cycles, followed by 
docetaxel given Q3W for 4 cycles, with pertuzumab and trastuzumab given Q3W from 
the start of docetaxel (FEC→docetaxel  pertuzumab and trastuzumab). 
 
There were no unexpected safety signals in Study WO29217. 
 
During the overall treatment period, the most frequently reported adverse events 
( 10% of patients) considered to be related to pertuzumab or trastuzumab included 
diarrhea, IRR, fatigue, ejection fraction decreased, epistaxis, arthralgia, myalgia, 
asthenia, anemia, and mucosal inflammation.  Grade  3 adverse events during 
overall treatment were reported by approximately half of the patients, and the most 
commonly reported terms were febrile neutropenia, neutropenia, diarrhea, and 
stomatitis.  The serious adverse events during the overall treatment period reported 
by  2% of patients in either cohort included febrile neutropenia, diarrhea, 
neutropenic sepsis, device-related infection, ejection fraction decreased, and 
pyrexia.  The adverse event profile observed in Study WO29217 is consistent with 
the established safety profile of pertuzumab and trastuzumab in combination with 
chemotherapy. 
 
The most common laboratory post-baseline abnormalities for the overall study 
period were hematological.  The highest incidence of Grade 3 or 4 abnormalities 
was reported for lymphocytopenia, absolute neutrophil count, and low white blood 
cell count. 
 
For those patients who received ddAC followed by paclitaxel with pertuzumab and 
trastuzumab:  The cardiac safety observed during the overall study period in 
patients with normal cardiac function at baseline remained in line with that observed 
in previous clinical studies with dual HER2-containing treatment regimens and the 
known clinical profile of pertuzumab and trastuzumab.  The incidence of NYHA 
Class III or IV heart failure occurring during the overall study period was low.  Based 
on the known cardiac safety profile of pertuzumab and trastuzumab from studies 
with dual HER2-containing treatment regimens, there were no unexpected findings. 
 


 
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5.1.8 
Risks Associated with Combination Use of Atezolizumab and 
Doxorubicin, Cyclophosphamide, Paclitaxel, Trastuzumab, 
Pertuzumab, or Trastuzumab Emtansine 
The following adverse events are important potential overlapping toxicities associated 
with combination use of atezolizumab and doxorubicin, cyclophosphamide, paclitaxel, 
trastuzumab, or pertuzumab:  cardiotoxic and gastrointestinal (diarrhea, colitis) events.  
Additional potential overlapping toxicities include respiratory disorders, skin rash, 
hypersensitivity and IRRs.  Myelosuppression (neutropenia, anemia, or 
thrombocytopenia) is an important potential overlapping toxicity of chemotherapy 
(doxorubicin, cyclophosphamide, paclitaxel) and HER2 targeted therapy (trastuzumab, 
pertuzumab).  The risk of overlapping toxicities is thought to be manageable based on 
the mechanism of action of each product.  
When there is a possibility of overlapping toxicities, the attribution of an adverse event to 
particular drug(s) will be based on the investigator’s clinical judgment.  See Table 5 
below for sources in the protocol that provide guidance for managing overlapping 
toxicities. 
Table 5 
Guidance for Managing Overlapping Toxicities 
Event 
Source in Protocol for Guidance 
Cardiotoxicity 
Doxorubicin 
 Section 5.1.2.1 and Appendix 11 (Doxorubicin and 
Cyclophosphamide, Cardiotoxicity) 
Cyclophosphamide 
 Appendix 11 (Doxorubicin and Cyclophosphamide, Cardiotoxicity) 
Pertuzumab 
 Section 5.1.5.1 and Appendix 11 (Pertuzumab and Trastuzumab, 
Cardiotoxicity) 
Trastuzumab 
 Section 5.1.5.1 and Appendix 11 (Pertuzumab and Trastuzumab, 
Cardiotoxicity) 
Atezolizumab 
 Appendix 12 (Immune-Mediated Myocarditis, including Table 6) 
Paclitaxel 
 Section 5.1.4 and local prescribing information for paclitaxel 
Diarrhea or colitis 
Pertuzumab 
 Section 5.1.5.2 and Appendix 11 (Pertuzumab and Trastuzumab, 
EGFR-Related Toxicities) 
Paclitaxel 
 Appendix 11 and local prescribing information for paclitaxel 
Atezolizumab 
 Appendix 12 (Gastrointestinal Events, including Table 3) 
 
 
 


 
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Table 5 
Guidance for Managing Overlapping Toxicities (cont.)  
Event 
Source in Protocol for Guidance 
Respiratory disorders 
Atezolizumab 
 Appendix 12 (Pulmonary Events, including Table 1), Appendix 15, 
and the Atezolizumab Investigator’s Brochure 
Pertuzumab 
 Pertuzumab Investigator’s Brochure 
Trastuzumab 
 Trastuzumab Investigator’s Brochure 
Cyclophosphamide 
 Local prescribing information for cyclophosphamide 
Paclitaxel 
 Appendix 11 (Pulmonary Events/Pneumonitis) and local prescribing 
information for paclitaxel 
Trastuzumab 
emtansine 
 Appendix 15 and the Trastuzumab Emtansine Investigator’s 
Brochure 
Skin rash 
Pertuzumab 
 Section 5.1.5.2 and Appendix 11 (Pertuzumab and Trastuzumab, 
EGFR-Related Toxicities) 
Atezolizumab 
 Appendix 12 (Dermatologic Events, including Table 9) 
Paclitaxel 
 Local prescribing information for paclitaxel 
Hypersensitivity and infusion-related reactions 
Atezolizumab 
 Section 4.3.2.1 and Appendix 12 (Infusion-Related Reactions, 
including Table 7) 
Pertuzumab 
 Section 4.3.2.2 and Appendix 11 (Pertuzumab and Trastuzumab, 
Infusion-Associated Symptoms) 
Trastuzumab 
 Section 4.3.2.3 and Appendix 11 (Pertuzumab and Trastuzumab, 
Infusion-Associated Symptoms) 
Paclitaxel 
 Sections 4.3.2.4 (Paclitaxel) and 5.1.4, and the local prescribing 
information for paclitaxel 
Myelosuppression 
Paclitaxel 
 Section 5.1.4, Appendix 11, and the local prescribing information for 
paclitaxel 
Doxorubicin 
 Local prescribing information for doxorubicin 
Cyclophosphamide 
 Local prescribing information for cyclophosphamide 
Pertuzumab 
 Pertuzumab Investigator’s Brochure 
Trastuzumab 
 Trastuzumab Investigator’s Brochure 


 
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Table 5 
Guidance for Managing Overlapping Toxicities (cont.)  
Event 
Source in Protocol for Guidance 
Hepatotoxicity 
Atezolizumab 
 Appendix 15 and the Atezolizumab Investigator’s Brochure 
Trastuzumab 
emtansine 
 Appendix 15 and the Trastuzumab Emtansine Investigator’s 
Brochure 
 
For additional information, dose reductions and management, see Section 5.1.1 5.1.6 
in conjunction with Appendix 11, Appendix 12, Appendix 14, and Appendix 15 as well as 
the local prescribing information for doxorubicin, cyclophosphamide, and paclitaxel, and 
the Trastuzumab, Pertuzumab, Atezolizumab, and Trastuzumab Emtansine 
Investigator’s Brochures. 
5.1.9 
General Plan to Manage Safety Concerns 
Safety will be evaluated in this study through the monitoring of all serious and 
non-serious adverse events defined and graded according to NCI CTCAE v5.0.  Patients 
will be assessed for safety (including laboratory test values) according to the schedule of 
activities in Appendix 1 and Appendix 2.  Laboratory test values must be reviewed prior 
to each infusion. 
General safety assessments will include serial interval histories, physical examinations, 
and specific laboratory studies, including serum chemistry and blood counts 
(see Section 4.5 and Appendix 1 and Appendix 2 for the list and timing of study 
assessments). 
Cardiac monitoring (ECHO or MUGA scan) will be performed on all patients enrolled in 
the study and will be obtained at baseline and at regular intervals throughout the study. 
See Appendix 1 for further details. 
During the study, patients will be closely monitored for the development of any signs or 
symptoms of autoimmune conditions and infection. 
All serious adverse events and protocol-defined events of special interest 
(see  Section 5.2.2 and 5.2.3) will be reported in an expedited fashion 
(see Section 5.4.2). 
5.1.10 
Dose Modifications 
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. 


 
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The severity of adverse events will be graded according to the NCI CTCAE v5.0. 
 
For any concomitant conditions reported at baseline, the dose modifications will 
apply according to the corresponding shift in toxicity grade, if the investigator 
determines that it is appropriate.  For example, if a patient has Grade 1 asthenia at 
baseline that increases to Grade 2 during treatment, this will be considered a shift of 
one grade and treated as Grade 1 toxicity for dose-modification purposes. 
 
When several toxicities with different grades of severity occur at the same time, the 
dose modifications should be according to the highest grade observed. 
 
If, in the opinion of the investigator, a toxicity is considered to be attributable solely 
to one component of the study treatment 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. 
 
See Appendix 11 and Appendix 12 for dose modification guidelines. 
5.1.10.1 
Dose Modifications of Trastuzumab Emtansine and 
Atezolizumab/Placebo 
Treatment management guidelines reflect the guidance prior to the issuance of the 
USM DIL dated 3 February 2021.  Following the mandated discontinuation of blinded 
study treatment with atezolizumab or placebo, these guidelines still apply; however, 
these guidelines apply without treatment with atezolizumab/placebo. 
If trastuzumab emtansine is held for toxicity, then atezolizumab/placebo must also be 
held.  If trastuzumab emtansine is discontinued for toxicity, atezolizumab/placebo must 
not be continued as single agent and must either be discontinued also or may be 
continued in combination with trastuzumab and pertuzumab to complete a total of 1 year 
of HER2-targeted therapy if the investigator considers the toxicity to be related to 
trastuzumab emtansine without compromising the continued use of trastuzumab.  
If treatment with atezolizumab/placebo had been discontinued prior to the 
discontinuation of trastuzumab emtansine or if both treatments are discontinued 
concurrently, it is at the investigator’s discretion to switch treatment to trastuzumab and 
pertuzumab if the toxicity is not considered related to the trastuzumab component of 
trastuzumab emtansine. 
If study treatment is temporarily interrupted because of toxicity caused by trastuzumab 
emtansine or atezolizumab/placebo, the treatment cycles will be restarted such that the 
atezolizumab/placebo and trastuzumab emtansine infusions remain synchronized.  
If significant trastuzumab emtansinerelated toxicities have not recovered to Grade 1 or 
baseline, the next scheduled dose may be delayed for up to 42 days after the last dose 
was received.  “Significant” and “related” will be based on the judgment of the 
investigator (in consultation with the Sponsor’s Medical Monitor or designee when 
appropriate).  For example, alopecia even if considered related to trastuzumab 
emtansine would most likely not be considered to be significant.  In general, when the 
significant related toxicity (or any other toxicity that the investigator chooses to delay 


 
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dosing for) resolves to Grade 1 or baseline, the patient may resume trastuzumab 
emtansine if the delay is not  42 days from the last dose received.  Patients should be 
re-evaluated weekly during the delay, whenever possible.  If dosing resumes, the patient 
may receive trastuzumab emtansine either at the same dose level as before or at one 
lower dose level (see Table 6), at the discretion of the investigator.  Subsequent cycles 
should remain Q3W.  If a patient requires a dose reduction, dosing will be reduced by 
one dose level as per Table 6.  A maximum of two dose reductions is allowed for 
trastuzumab emtansine.  No dose re-escalation is permitted.  A patient treated with 
2.4 mg/kg of trastuzumab emtansine who develops an adverse event requiring a dose 
reduction must discontinue trastuzumab emtansine.  For patients who experience 
Grade 3 or 4 hematologic events, other than thrombocytopenia, treatment should be 
interrupted and the patient should be checked at least weekly for recovery.  If values do 
not recover to baseline or Grade  1 within 42 days from the last dose received, the 
patient will be discontinued from trastuzumab emtansine.  For thrombocytopenia, 
see Appendix 14.  No dose modification is allowed for atezolizumab. 
If dosing with trastuzumab emtansine has been delayed for more than 42 days from the 
last dose, and the investigator wishes to re-start treatment with trastuzumab emtansine 
based on a positive benefitrisk assessment for the individual patient, the Medical 
Monitor is available for consultation. 
Table 6 
Dose Modification Scheme for Trastuzumab Emtansine 
Dose Reduction Schedule 
Dose Level (mg/kg, Q3W) 
Starting dose 
3.6 
First dose reduction 
3.0 
Second dose reduction 
2.4 
Requirement for further dose reduction 
Discontinue treatment 
Q3W  every 3 weeks. 
Note:  The dose of trastuzumab emtansine, once reduced, may not be re-escalated.  
A maximum of two dose reductions is allowed; patients with any further requirement for 
dose reduction will discontinue treatment with trastuzumab emtansine and 
atezolizumab/placebo. 
 
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. 


 
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5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition; see Section 5.3.5.9 
and Section 5.3.5.10 for more information) 
 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study treatment 
 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
 
Is fatal (i.e., the adverse event actually causes or leads to death) 
 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
– 
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death. 
 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.11) 
 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions) 
 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study treatment 
 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 


 
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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 are as follows: 
 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.7) 
 
Suspected transmission of an infectious agent by the study treatment, as defined 
below: 
– 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of study treatment is suspected. 
 
Pneumonitis 
 
Colitis 
 
Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency, 
hyperthyroidism, and hypophysitis 
 
Hepatitis, including AST or ALT  10  ULN 
 
Systemic lupus erythematosus 
 
Neurological disorders:  Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis 
 
Events suggestive of hypersensitivity, IRRs, cytokine release syndrome, 
influenza-like illness, HLH, and MAS 
 
Nephritis 
 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
 
Myositis 


 
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 
Myopathies, including rhabdomyolysis 
 
Grade  2 cardiac disorders 
 
Asymptomatic decline in LVEF requiring treatment or leading to discontinuation of 
trastuzumab, pertuzumab, or trastuzumab emtansine 
 
Vasculitis 
 
Autoimmune hemolytic anemia 
 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis) 
 
Myelitis 
 
Facial paresis 
 
5.2.4 
Selected Adverse Events 
Additional data will be collected for the following selected adverse events. 
5.2.4.1 
Cardiac, General 
Symptomatic left ventricular systolic dysfunction (referred to as heart failure) should be 
reported as a serious adverse event.  If the diagnosis is heart failure, it should be 
reported as such and not in terms of the individual signs and symptoms (i.e., report heart 
failure rather than dyspnea on exertion, bilateral ankle edema, and tachycardia; 
see Section 5.3.5.2).  A cardiac consultation is recommended for patients who develop 
symptomatic left ventricular systolic dysfunction (heart failure).  Heart failure should be 
graded according to the NCI CTCAE v5.0 for “heart failure” (Grade 2, 3, 4, or 5) and in 
addition according to the NYHA classification. 
Heart failure occurring at any point during the study (including the follow-up period), 
even beyond the 90 days after the final dose of study treatment (see Section 5.6) must 
be reported, irrespective of causal relationship, and followed until one of the following 
occurs:  resolution or improvement to baseline status, no further improvement can be 
expected, or death. 
5.2.4.2 
Asymptomatic Left Ventricular Systolic Dysfunction 
Asymptomatic declines in LVEF should generally not be reported as adverse events 
because LVEF data are collected separately in the eCRF.  Exceptions to this rule are as 
follows: 
 
An asymptomatic decline in LVEF  10 percentage points from baseline to an 
LVEF  50% must be reported as an adverse event with the term "ejection fraction 
decreased" as per NCI CTCAE v5.0, and, in addition, a comment in the adverse 
events comments field should confirm that this event was asymptomatic. 
 
An asymptomatic decline in LVEF requiring treatment or leading to discontinuation 
of trastuzumab, pertuzumab, or trastuzumab emtansine must be reported as an 
adverse event of special interest (see Section 5.2.3); a comment in the adverse 
event comments field should confirm that this event was asymptomatic. 


 
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Table 7 summarizes the reporting conventions for left ventricular systolic dysfunction 
and heart failure. 
Table 7 
Reporting Conventions for Left Ventricular Systolic 
Dysfunction/Congestive Heart Failure 
Observation 
How to Report 
Term to be 
Reported 
Grading 
Asymptomatic decline in 
LVEF of  10 percentage 
points from baseline or to an 
LVEF of  50% 
No additional reporting 
required; LVEF results to 
be reported on eCRF. 
NA 
NA 
Asymptomatic decline in 
LVEF of  10 percentage 
points from baseline to an 
LVEF of  50% 
AE a (eCRF AE eForm) 
Ejection fraction 
decreased a 
NCI CTCAE for 
"ejection fraction 
decreased" 
Asymptomatic decline in 
LVEF requiring treatment or 
leading to discontinuation of 
trastuzumab, pertuzumab, 
or trastuzumab emtansine 
AE (eCRF AE eForm) 
and reported as a 
non-serious AESI on an 
SAE form 
Ejection fraction 
decreased a 
NCI CTCAE for 
"ejection fraction 
decreased" 
Heart failure/CHF 
(symptomatic LVSD) b 
AE (eCRF AE eForm) and 
SAE (SAE form) 
"Heart failure" 
NCI CTCAE for 
"heart failure" and 
NYHA class 
AE  adverse event; AESI  adverse event of special interest; CHF  congestive heart failure; 
eCRF  electronic case report form; e-Form  electronic form; LVEF  left ventricular ejection 
fraction; LVSD  left ventricular systolic dysfunction; NA  not applicable; NCI CTCAE  National 
Cancer Institute Common Terminology Criteria for Adverse Events; NYHA  New York Heart 
Association; SAE  serious adverse event. 
a Report the status as asymptomatic and provide the LVEF value in the comments field as 
appropriate. 
b Any symptomatic LVSD event must be reported as "heart failure." 
 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4).   


 
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5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study treatment, all adverse events will be reported until 30 days after 
the final dose of study treatment or until initiation of new systemic anti-cancer therapy, 
whichever occurs first, and serious adverse events and adverse events of special 
interest will continue to be reported until 90 days after the final dose of study treatment 
or until initiation of new systemic anti-cancer therapy, whichever occurs first. 
For reporting of heart failure, see Section 5.2.4.1 and 5.6. 
Study drugrelated serious adverse events will be reported indefinitely (even if the study 
has been closed).  Instructions for reporting adverse events that occur after the adverse 
event reporting period are provided in Section 5.6. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
 
"How have you felt since your last clinic visit?" 
 
"Have you had any new or changed health problems since you were last here?" 
 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity.  Table 8 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 


 
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Table 8 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to study treatment, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see 
also Table 9): 
 
Temporal relationship of event onset to the initiation of study treatment 
 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study treatment, or reintroduction of study treatment (as 
applicable) 
 
Known association of the event with study treatment or with similar treatments 
 
Known association of the event with the disease under study 
 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 


 
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Table 9 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by study treatment on the basis of facts, 
evidence, science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of study treatment, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to study treatment; and/or the 
adverse event abates or resolves upon discontinuation of study treatment or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.   
Evidence exists that the adverse event has an etiology other than study treatment 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of study treatment (e.g., cancer diagnosed 2 days after 
first dose of study treatment). 
 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Infusion-Related Reactions and Cytokine Release Syndrome 
There may be significant overlap in signs and symptoms of IRRs and cytokine release 
syndrome.  While IRRs occur during or within 24 hours after treatment administration, 
time to onset of CRS may vary.  Differential diagnosis should be applied, particularly for 
late-onset CRS (occurring more than 24 hours after treatment administration), to rule out 
other etiologies such as delayed hypersensitivity reactions, sepsis or infections, HLH, 
tumor lysis syndrome, early disease progression, or other manifestations of systemic 
inflammation. 
Adverse events that occur during or within 24 hours after study treatment administration 
and are judged to be related to study treatment infusion should be captured as a 
diagnosis (e.g., "infusion-related reaction" or "cytokine release syndrome") on the 
Adverse Event eCRF.  If possible, avoid ambiguous terms such as "systemic reaction."  
Cases of late-onset CRS should be reported as "cytokine release syndrome" on the 
Adverse Event eCRF.  Associated signs and symptoms should be recorded on the 
dedicated Infusion-Related Reaction eCRF. 


 
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If a patient experiences both a local and systemic reaction to the same dose of study 
treatment, each reaction should be recorded separately on the Adverse Event eCRF, 
with signs and symptoms also recorded separately on the dedicated Infusion-Related 
Reaction eCRF. 
In recognition of the challenges in clinically distinguishing between IRRs and CRS, 
consolidated guidelines for medical management of IRRs and CRS are provided 
in Appendix 12. 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 


 
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Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; 
see Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be 
updated by changing the event from "non-serious" to "serious," providing the date that 
the event became serious, and completing all data fields related to serious adverse 
events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment  
– 
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events. 
 
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5  ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 


 
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Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal 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 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( 3  ULN) in combination with either an elevated 
total bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
 
Treatment-emergent ALT or AST  3  ULN in combination with total bilirubin 
 2  ULN 
 
Treatment-emergent ALT or AST  3  ULN in combination with clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2). 


 
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5.3.5.8 
Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.3.1) that are attributed 
by the investigator solely to progression of HER2-positive breast cancer should be 
recorded on the Death Attributed to Progressive Disease eCRF.  All other deaths that 
occur during the adverse event reporting period, regardless of relationship to study 
treatment, must be recorded on the Adverse Event eCRF and immediately reported to 
the Sponsor (see Section 5.4.2).  An 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.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
5.3.5.9 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.10 
Lack of Efficacy or Worsening of HER2-Positive 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.  Instances of disease recurrence will be 
verified by pathologic confirmation in accordance to the pathology manual.  In rare 
cases, the determination of clinical progression will be based on symptomatic 
deterioration.  However, every effort should be made to document progression through 
use of objective criteria.  If there is any uncertainty as to whether an event is due to 
disease progression, it should be reported as an adverse event. 


 
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5.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below. 
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
 
Hospitalization for respite care 
 
Planned hospitalization required by the protocol (e.g., for study treatment 
administration or performance of an efficacy measurement for the study) 
 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
– 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease. 
– 
The patient has not experienced an adverse event. 
 
Hospitalization due solely to progression of the underlying cancer 
 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead: 
 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.12 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  Sites are not expected to review the 
PRO data for adverse events. 
5.3.5.13 
Safety Biomarker Data 
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this 
study.  In addition, safety biomarker data will not inform decisions on patient 
management. 
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 


 
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of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study treatment: 
 
Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements) 
 
Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements) 
 
Pregnancies (see Section 5.4.3 for details on reporting requirements) 
 
Accidental overdoses or medication errors (see Section 5.4.4 for details on reporting 
requirements) 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following: 
 
New signs or symptoms or a change in the diagnosis 
 
Significant new diagnostic test results 
 
Change in causality based on new information 
 
Change in the event's outcome, including recovery 
 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
To ensure the safety of study patients access to Medical Monitors is available 24 hours 
per day, 7 days per week.  Details will be provided separately. 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Treatment Initiation 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Adverse Event/Special Situations Form provided to investigators 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the event), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators. 
5.4.2.2 
Events That Occur after Study Treatment Initiation 
After initiation of study treatment, serious adverse events and adverse events of special 
interest will be reported until 90 days after the final dose of study treatment or until 
initiation of new systemic anti-cancer therapy, whichever occurs first.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 


 
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EDC system.  A report will be generated and sent to Roche Safety Risk Management by 
the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Adverse Event/ 
Special Situations Form provided to investigators should be completed and submitted to 
the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.  Once the EDC system is available, all 
information will need to be entered and submitted via the EDC system. 
Instructions for reporting serious adverse events that occur after the reporting period are 
provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 5 months after the final 
dose of atezolizumab/placebo, 6 months after the final dose of doxorubicin, 12 months 
after the final dose of cyclophosphamide, 6 months after the final dose of paclitaxel, and 
7 months after the final dose of trastuzumab, pertuzumab, or trastuzumab emtansine 
(whichever is longer).  A paper Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study treatment and counsel the patient, discussing the risks of the 
pregnancy and the possible effects on the fetus.  Monitoring of the patient should 
continue until conclusion of the pregnancy.  Any serious adverse events associated with 
the pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available. 
Attempts should be made to collect and report infant health information.  When 
permitted by the site, an Authorization for the Use and Disclosure of Infant Health 
Information would need to be signed by one or both parents (as per local regulations) to 
allow for follow-up on the infant.  If the authorization has been signed, the infant's 
health status at birth should be recorded on the Clinical Trial Pregnancy Reporting 
Form.  In addition, the Sponsor may collect follow-up information on the infant's 
health status at 3, 6, and 12 months after birth. 


 
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5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
6 months after the final dose of doxorubicin and/or cyclophosphamide, 6 months after 
the final dose of paclitaxel, and 7 months after the final dose of trastuzumab, 
pertuzumab, or trastuzumab emtansine (whichever is longer).  A paper Clinical Trial 
Pregnancy Reporting Form should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Attempts should be made to collect and report details 
of the course and outcome of any pregnancy in the partner of a male patient exposed to 
study treatment.  When permitted by the site, the pregnant partner would need to sign an 
Authorization for Use and Disclosure of Pregnancy Health Information to allow for follow-
up on her pregnancy.  If the authorization has been signed, the investigator should 
submit a Clinical Trial Pregnancy Reporting Form when updated information on the 
course and outcome of the pregnancy becomes available.  An investigator who is 
contacted by the male patient or his pregnant partner may provide information on the 
risks of the pregnancy and the possible effects on the fetus, to support an informed 
decision in cooperation with the treating physician and/or obstetrician. 
Attempts should be made to collect and report infant health information.  When 
permitted by the site, an Authorization for the Use and Disclosure of Infant Health 
Information would need to be signed by one or both parents (as per local regulations) to 
allow for follow-up on the infant.  If the authorization has been signed, the infant's 
health status at birth should be recorded on the Clinical Trial Pregnancy Reporting 
Form.  In addition, the Sponsor may collect follow-up information on the infant's 
health status at 3, 6, and 12 months after birth. 
5.4.3.3 
Abortions 
Any 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). 
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
treatment or the female partner of a male patient exposed to study treatment should be 
classified as a serious adverse event, recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2). 


 
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5.4.4 
Reporting Requirements for Cases of Accidental Overdose or 
Medication Error 
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows: 
 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
 
Medication error:  accidental deviation in the administration of a drug  
– 
In some cases, a medication error may be intercepted prior to administration of 
the drug. 
 
Special situations are not in themselves adverse events but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  For 
atezolizumab/placebo, trastuzumab, pertuzumab, and trastuzumab emtansine, adverse 
events associated with special situations should be recorded as described below for 
each situation: 
 
Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes. 
 
Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes. 
 
In addition, all special situations associated with atezolizumab/placebo, trastuzumab, 
pertuzumab, and trastuzumab emtansine, regardless of whether they result in an 
adverse event, should be recorded on the Adverse Event eCRF.  In the instance where 
this results in a serious adverse event, the event must be reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event).  Special situations 
should be recorded as described below: 
 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 
 
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details. 


 
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 
Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details. 
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose 
and one to report the headache.  The "Accidental overdose" and "Medication error" 
boxes would need to be checked on both eCRF pages. 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study treatment or trial-related 
procedures until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
After the end of the reporting period for serious adverse events and adverse events of 
special interest (defined as 90 days after the final dose of study treatment or until 
initiation of new systemic anti-cancer therapy, whichever occurs first), deaths either 
attributed by the investigator solely to progression of HER2-positive breast cancer or due 
to an adverse event considered by the investigator unrelated to prior exposure to study 
treatment, should be reported through use of the Long-Term Survival Follow-Up eCRF. 
Heart failure occurring at any point during the study, even beyond the 90 days after the 
final dose of study treatment, must be reported, irrespective of causal relationship, and 
followed until one of the following occurs:  resolution or improvement to baseline status, 
no further improvement can be expected, or death.  Heart failure, irrespective of causal 


 
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relationship, that that occurs after study closure should be reported to Roche as a 
spontaneous report to be included in the Roche Global Safety Database. 
In addition, if the investigator becomes aware of a serious adverse event that is believed 
to be related to prior exposure to study treatment, the event should be reported through 
use of the Adverse Event eCRF.  However, if the EDC system is not available 
(e.g., completion of the study), the investigator should report these events directly to the 
Sponsor or its designee, either by faxing or by scanning and emailing the paper Clinical 
Trial Adverse Event/Special Situations Form using the fax number or email address 
provided to investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents: 
 
Atezolizumab Investigator's Brochure 
 
Pertuzumab Investigator's Brochure 
 
Trastuzumab Investigator's Brochure 
 
Trastuzumab Emtansine Investigator’s Brochure 
 
European Summary of Product Characteristics (EU-SmPC) for doxorubicin, 
cyclophosphamide, and 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. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
6.1 
ANALYSIS POPULATIONS 
The analysis populations are defined as follows: 
 
The ITT population is defined as all randomized patients, whether or not the 
assigned study treatment was received. 
 
The PD-L1positive population is defined as patients in the ITT population whose 
PD-L1 status is IC 1/2/3 at the time of randomization. 


 
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 
The PRO-evaluable population is defined as patients in the ITT population with a 
baseline and  1 postbaseline PRO assessment. 
 
The safety-evaluable population is defined as patients who received any amount of 
any study drug. 
 
For all efficacy analyses, patients will be assigned to the treatment group to which they 
were randomized. 
For safety analyses, patients will be assigned to treatment groups as treated, and all 
patients who received any dose of atezolizumab will be included in the atezolizumab 
treatment arm. 
6.2 
DETERMINATION OF SAMPLE SIZE 
The global study will randomize approximately 453 patients in total.  Assuming a 
prevalence of 40% of PD-L1positive patients (defined as tumors with a PD-L1 
expression level of IC 1/2/3), the PD-L1positive population is estimated to comprise 
approximately 181 patients. 
6.2.1 
Type I Error Control 
The Type I error () for this study is 0.05 (two-sided).  The Type I error will be controlled 
for the following efficacy endpoints: 
 
Co-primary efficacy endpoint of pCR, as defined in Section 2.1.1, in the 
PD-L1positive population with an allocated  of 0.048 
 
Co-primary efficacy endpoint of pCR, as defined in Section 2.1.1, in the 
ITT population with an allocated  of 0.002 
 
In the PD-L1positive population, this sample size will allow for 80% power to detect an 
improvement in pCR proportion from 70% in the placebo  ddAC-PacHP to 90% ( 20%) 
in the atezolizumab  ddAC-PacHP group at the 4.8% level of significance (two-sided) 
assuming a dropout of 7% of the patients (i.e., patients without pCR assessment will be 
regarded as not achieving pCR resulting in an improvement in pCR proportion from 
65% to 83%;  18%). 
In the ITT population, this sample size will allow for 82.8% power to detect an 
improvement in pCR proportion from 60% in the placebo  ddAC-PacHP to 80% ( 20%) 
in the atezolizumab  ddAC-PacHP group at the 0.2% level of significance (two-sided), 
assuming a dropout of 10% of the patients (i.e., patients without pCR assessment will be 
regarded as not achieving pCR resulting in an improvement in pCR proportion from 
54% to 72%;  18%). 
6.3 
SUMMARIES OF CONDUCT OF STUDY 
For all randomized patients (i.e., ITT population), a participant flowchart for depicting the 
progress of participants through the phases of the trial will be provided by treatment arm, 


 
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including a complete description of patient disposition specifying the number of 
randomized, completed, and discontinued patients from trial treatment and study with 
reasons for premature discontinuation.  Documented major protocol deviations including 
major deviations with regard to the inclusion and exclusion criteria, conduct of the study, 
patient management, or patient assessment will be also tabulated by treatment arm. 
6.4 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Demographic variables such as age, sex, race/ethnicity, and baseline characteristics 
(in particular, stratification variables) will be summarized by treatment arm for the ITT 
population.  Only descriptive analyses are planned; no formal statistical tests will be 
applied.  Continuous variables will be reported and summarized by use of standard 
measures of central tendency and dispersion (mean, standard deviation, median, and 
range including minimum and maximum), and categorical (i.e., discrete) data will be 
reported and summarized by frequencies and percentages.  The baseline value of any 
variable will be defined as the last available value prior to the first administration of study 
treatment. 
6.5 
EFFICACY ANALYSES 
Details of the analyses, including methods for handling missing data, are specified in the 
SAP. 
6.5.1 
Co-Primary Efficacy Endpoint 
The co-primary efficacy objective for this study is to evaluate the efficacy of 
atezolizumab compared with placebo when given in combination with neoadjuvant 
ddAC-PacHP in patients eligible for surgery with early HER2-positive breast cancer at 
high risk of recurrence (T24, N13) as measured by pCR in the ITT and in the 
PD-L1positive populations.  pCR is established following completion of neoadjuvant 
therapy and surgery. 
pCR is defined as the absence of residual invasive cancer on hematoxylin and eosin 
evaluation of the complete resected breast specimen and all sampled regional lymph 
nodes following completion of NAST (i.e., ypT0/is ypN0 in the current AJCC staging 
system). 
Patients with missing pCR assessment will be counted as not achieving a pCR.  
Treatment comparison of pCR will be made using Cochran-Mantel-Haenszel test 
stratified by disease stage (T2 vs. T3 or 4), hormone receptor status (positive vs. 
negative) and PD-L1 status (IC 0 vs. IC 1/2/3), if applicable.  The 2-sided significance 
level in the PD-L1positive population is 4.8% and in the ITT population 0.2%.  The 
stratification factors will be based on data collected by the IxRS at the time of 
randomization.  Confidence intervals for the difference in pCR rate between the 
two arms will be determined using the normal approximation to the binomial distribution. 


 
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A summary table that presents the number and proportion of pCR in each treatment 
arm, together with the 2-sided 95% CI with use of the Clopper-Pearson method will be 
produced (Clopper and Pearson 1934). 
6.5.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are the following: 
 
pCR (ypT0/is ypN0) based upon hormone receptor status (ER/PgR positive or 
ER/PgR negative) in all patients (ITT population) and based upon PD-L1 status 
(IC 0; IC 1/2/3) 
 
pCR (ypT0/is ypN0) in the PD-L1negative (IC 0) population 
 
EFS, defined as the time from randomization until documented disease recurrence, 
unequivocal tumor progression determined by the treating investigator, or death 
from any cause in all patients (ITT population) and based upon hormone receptor 
status (ER/PgR positive or ER/PgR negative) and PD-L1 status (IC 0; IC 1/2/3) 
 
DFS, defined as the time from surgery until documented disease recurrence or 
death from any cause in all patients (ITT population) who undergo surgery and 
based upon hormone receptor status (ER/PgR positive or ER/PgR negative) and 
PD-L1 status (IC 0; IC 1/2/3) 
 
OS, defined as the time from randomization to the date of death from any cause in 
all patients (ITT population) and based upon hormone receptor status (ER/PgR 
positive or ER/PgR negative) and PD-L1 status (IC 0; IC 1/2/3) 
 
PROs of function (role, physical) and HRQoL in PRO-evaluable population 
 
6.5.2.1 
pCR in the Subgroups 
pCR is defined in analogous manner to the primary endpoint and will be analyzed with 
the same methodology in the subgroups.  The stratification factors in the subgroup 
analysis will be as defined below: 
 
pCR by hormone receptor status:  The stratification factors will be disease stage 
and PD-L1 status. 
 
pCR by PD-L1 status:  The stratification factors will be disease stage and hormone 
receptor status. 
 
6.5.2.2 
Event-Free Survival 
EFS is defined as the time from randomization to the first documented disease 
recurrence, unequivocal tumor progression determined by the treating investigator, or 
death from any cause, whichever occurs first. 
Patients without an event at the time of the analysis will be censored on the date on 
which they are last known to be alive and event free, on or before the clinical data cutoff 
date of the respective analysis.  Patients with no postbaseline information will be 
censored at the date of randomization. 


 
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EFS will be compared between treatment arms with the use of the log-rank test stratified 
by the randomization stratification factors collected by the IxRS at the time of 
randomization and by the adjuvant treatment regimen.  The HR for EFS will be 
estimated using a Cox proportional hazards model.  The 95% CI for the HR will be 
provided.  Kaplan-Meier methodology will be used to estimate the median EFS 
(if reached) for each treatment arm, and Kaplan-Meier curves will be produced.  
Brookmeyer-Crowley methodology will be used to construct the 95% CI for the median 
EFS for each treatment arm (Brookmeyer and Crowley 1982).  The Kaplan-Meier 
approach will be also used to estimate landmark EFS rates, including 3-year EFS rates, 
and corresponding 95% CIs for each treatment arm.  Results from an unstratified 
analysis will also be provided. 
The EFS analysis will be performed approximately 36 months after the randomization of 
the last patient during the global enrollment phase. 
Exploratory subgroup analyses of EFS in pre-defined subgroups of interest will be 
performed, including adjuvant treatment regimen.  Full details will be provided in 
the SAP. 
6.5.2.3 
Disease-Free Survival 
DFS is defined as the time from surgery (i.e., the first date of no disease) to the first 
documented disease recurrence or death from any cause, whichever occurs first.  
Patients who do not undergo surgery at the end of neoadjuvant treatment will be 
excluded from the analysis of DFS. 
Patients without a DFS event at the time of analysis will be censored at the date when 
they were last known to be alive and event free.  Patients who do not have information 
after surgery will be censored at the date of surgery. 
DFS will be analyzed with the use of the same methodology as specified for EFS.  The 
DFS analysis will be performed approximately 36 months after the randomization of the 
last patient during the global enrollment phase. 
Exploratory subgroup analyses of DFS in pre-defined subgroups of interest will be 
performed, including adjuvant treatment regimen.  Full details will be provided in 
the SAP. 
6.5.2.4 
Overall Survival 
OS is defined as the time from randomization to death from any cause.  Patients who 
are not reported as having died at the time of analyses will be censored at the date when 
they were last known to be alive.  Patients who do not have information after baseline 
will be censored at the date of randomization.  OS will be analyzed with the use of the 
same methodology as specified for EFS.  The OS analysis will be performed 


 
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approximately 36 months after the randomization of the last patient during the global 
enrollment phase. 
Exploratory subgroup analyses of OS in pre-defined subgroups of interest will be 
performed, including adjuvant treatment regimen.  Full details will be provided in the 
SAP. 
6.5.2.5 
Patient-Reported Outcomes of Role and Physical Function and 
GHS/HRQoL:  EORTC Data 
The primary PRO endpoints are mean and mean changes from baseline score in 
function (role, physical) and GHS/HRQoL.  Summary statistics (mean, standard 
deviation, median, and range) of linearly transformed absolute scores and mean 
changes from baseline (with 95% CI) will be calculated for the functional (role [Question 
{Q} 6, Q7], physical [Q1Q5]), and the GHS/HRQoL (Q29, Q30) scales of the 
EORTC QLQ-C30 at each assessment timepoint for each arm.  The mean (and 95% CI) 
and median of the absolute scores and the changes from baseline will be reported for 
interval and continuous variables.  Previously published minimally important differences 
will be used to identify meaningful change from baseline within each treatment group on 
the functional and GHS/HRQoL scales (Osoba et al. 1998; Cocks et al. 2011). 
The EORTC QLQ-C30 (Version 3) data will be scored according to the EORTC scoring 
manual (Fayers et al. 2001).  PRO completion, compliance rates, and reasons for 
missing data will be summarized at each timepoint by treatment arm.  Details of the 
analysis, including methods for handling missing data, will be specified in the SAP. 
6.5.3 
Exploratory Efficacy Endpoints 
6.5.3.1 
Patient-Reported Outcomes of Disease/TreatmentRelated 
Symptoms, and Emotional and Social Function:  EORTC Data 
Summary statistics (mean, standard deviation, median, and range) of linearly 
transformed absolute scores and mean changes from baseline (with 95% CI) will be 
calculated for all disease/treatmentrelated symptom items and scales, and the 
emotional and social function scales of the EORTC QLQ-C30 (see Appendix 4) at each 
assessment timepoint for each arm. 
6.5.3.2 
Patient-Reported Outcome of Treatment Bother:  FACT-G, GP5 
Single-Item Data 
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 5).  Item GP5 from Version 4 of the FACT-G 
Questionnaire will be scored according to the Functional Assessment of Chronic Illness 
Therapy scoring manual (Cella 1997). 


 
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6.5.3.3 
Health Economic EQ-5D-5L Data 
Health utility data from the EQ-5D-5L (see Appendix 6) will be evaluated in 
pharmacoeconomic models.  The results from the health economic data analyses will be 
reported separately from the clinical study report. 
6.6 
SAFETY ANALYSES 
Safety analyses will be performed on the safety population defined as all patients who 
received any dose of study medication. 
Safety will be assessed through summaries of study treatment exposures, adverse 
events, changes in targeted laboratory and diagnostic test results, changes in vital signs, 
and immunogenicity as measured by ADAs and will be presented by treatment arm.  
Selected safety data will also be presented separately according to adjuvant treatment 
regimen. 
6.6.1 
Exposure of Study Medication 
Study drug exposure, including but not limited to treatment duration, number of cycles, 
and dose intensity, will be summarized with descriptive statistics for each study 
treatment on each treatment arm if deemed appropriate. 
6.6.2 
Adverse Events 
Verbatim descriptions of adverse events will be mapped to MedDRA thesaurus terms 
and graded according to NCI CTCAE v5.0. 
Treatment-emergent adverse events, defined as events occurring on or after the first 
dose of study treatment, will be summarized by MedDRA term, appropriate MedDRA 
levels, and NCI CTCAE v5.0 grade, regardless of relationship to study drug as assessed 
by the investigator.  For each patient, if multiple incidences of the same adverse events 
occur, the maximum severity reported will be used in the summaries. 
The following treatment-emergent adverse events will be summarized separately: 
 
Adverse events leading to withdrawal of study drug 
 
Adverse events leading to dose reduction or interruption 
 
Grade  3 adverse events, Grade 5 adverse events, serious adverse events 
 
Adverse events of special interest 
 
Selected adverse events on the basis of the safety profile of the study drug 
 
All deaths and causes of death will be summarized. 
6.6.3 
Laboratory Data 
Laboratory data with values outside of the normal ranges will be identified.  Relevant 
laboratory values will be summarized by treatment arm over time, with NCI CTCAE v5.0 
Grade 3 and Grade 4 values identified, where appropriate.  Changes from baseline in 


 
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NCI CTCAE v5.0 grade (i.e., shift tables) will be also provided by treatment arm.  
Of note, abnormal laboratory data that are clinically significant will be reported as 
adverse events and summarized in the adverse event tables. 
A Hy’s Law analysis will be provided:  the finding of an elevated ALT or AST 
(3  baseline value) in combination with either an elevated total bilirubin (2  ULN) or 
clinical jaundice in the absence of cholestasis or other causes of hyperbilirubinemia is 
considered to be an indicator of severe liver injury (as defined by Hy's Law). 
6.6.4 
Vital Signs 
Changes in selected vital signs will be summarized by change from baseline by 
treatment arm. 
6.7 
PHARMACOKINETIC ANALYSES 
Atezolizumab serum concentration data (Cmin and Cmax) will be tabulated and 
summarized.  Descriptive statistics will include means, medians, ranges, standard 
deviations, coefficient of variation (%CV), and others as appropriate. 
The pertuzumab, trastuzumab, and trastuzumab emtansine concentrations in serum will 
also be tabulated and summarized.  Additional PK and PD analyses may be conducted 
as appropriate. 
6.8 
IMMUNOGENICITY ANALYSES 
The immunogenicity analyses will include all patients with at least one ADA result, with 
patients grouped according to treatment received. 
The numbers and proportions of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) and after baseline (post-baseline incidence) will be 
summarized by treatment group.  When determining post-baseline incidence, patients 
are considered to be ADA-positive if they are ADA-negative or have missing data at 
baseline but develop an ADA response following study drug exposure 
(treatment-induced ADA response), or if they are ADA-positive at baseline and the titer 
of one or more post-baseline samples is at least 0.60 titer unit greater than the titer of 
the baseline sample (treatment-enhanced ADA response).  Patients are considered to 
be ADA-negative if they are ADA-negative or are missing data at baseline and all 
post-baseline samples are negative, or if they are ADA-positive at baseline but do not 
have any post-baseline samples with a titer that is at least 0.60 titer unit greater than the 
titer of the baseline sample (treatment unaffected). 
The relationship between ADA status and safety, efficacy, and pharmacokinetics may be 
investigated. 


 
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6.9 
BIOMARKER ANALYSES 
Biomarker analyses will be performed as follows: 
 
Analysis of pCR by stromal TIL infiltration levels will be stratified by disease stage, 
hormone receptor status, and PD-L1 status.  Cutoffs for stromal TIL infiltration levels 
will be specified in the SAP. 
 
Analysis of pCR by immune gene expression levels will be stratified by disease 
stage, hormone receptor status and PD-L1 status.  Cutoffs for immune gene 
expression levels will be specified in the SAP. 
 
Analysis of pCR, EFS, DFS, and OS by PIK3CA mutation status will be stratified by 
disease stage, hormone receptor status, and PD-L1 status. 
 
Descriptive statistics will be utilized for the analysis and reporting of other exploratory 
biomarker objectives outlined in Section 2.5.  This may include appropriate multivariate 
analyses.  Further details will be specified in the SAP. 
6.10 
INTERIM ANALYSES 
6.10.1 
Planned Interim Analyses 
In order to extract information from data accumulated thus far for reasons external to the 
study (administrative objective, to inform the initiation of a possible subsequent trial), an 
administrative interim efficacy analysis of pCR is planned to take place once 
227 patients have been enrolled, completed neoadjuvant treatment, and undergone 
surgery.  The administrative interim analysis is performed without any intention to stop 
the trial.  However, a minimum alpha of 0.0001 will be spent to protect the overall 
type I error.  The interim analysis will be performed by the iDCC, an external statistical 
group, to ensure the Sponsor study team personnel remain blinded.  The results will be 
reviewed by the iDMC.  Interactions between the iDMC and the Sponsor will be carried 
out as specified in the iDMC Charter. 
The rationale and methods, including those to be used for the assessment and 
protection of the overall type I error, will be documented in the SAP.  Details will also be 
included in the iDMC Charter. 
6.10.2 
Optional Interim Analyses 
The Sponsor may choose to conduct interim efficacy analyses after the primary analysis 
for pCR and before the final analysis for EFS and OS, if needed (e.g., for regulatory or 
publication purposes).  The decision to conduct an optional interim analysis, along with 
the rationale, timing, and statistical details for the analysis will be documented in the 
Sponsor’s trial master file prior to the conduct of the interim analysis.  The interim 
analysis will be performed and interpreted by Sponsor study team personnel who will 
have full access to unblinded data.  Access to treatment assignment information will 
follow the Sponsor’s standard procedures. 


 
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7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data and any other 
externally generated electronic study data will be sent directly to the Sponsor, using the 
Sponsor's standard procedures to handle and process the electronic transfer of these 
data. 
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures. 
PRO data will be collected on paper questionnaires at the site.  The data from the 
questionnaires will be entered into the EDC system by site staff. 
The Sponsor 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. 
7.2 
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 


 
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Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include but are not limited to hospital records, 
clinical and office charts, laboratory notes, memoranda, PRO questionnaires, evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies of transcriptions that are certified after verification as being accurate and 
complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, name of the 
person making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, paper PRO data, Informed Consent Forms, laboratory test 
results, and medication inventory records, must be retained by the Principal Investigator 
for 15 years after completion or discontinuation of the study or for the length of time 
required by relevant national or local health authorities, whichever is longer.  After that 
period of time, the documents may be destroyed, subject to local regulations. 
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 


 
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Roche will retain study data for 25 years after the final Clinical Study Report has been 
completed or for the length of time required by relevant national or local health 
authorities, whichever is longer. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trials Directive (2001/20/EC) 
or Clinical Trials Regulation (536/2014) and applicable local, regional, and national 
laws. 
8.2 
INFORMED CONSENT 
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child's Informed Assent Form or Mobile Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission.  The final IRB/ECapproved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 


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


 
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8.4 
CONFIDENTIALITY 
Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect such 
data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access.  In the event of a data security breach, appropriate mitigation measures will be 
implemented. 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.6). 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
Study data, which may include data on mutations, may be submitted to government or 
other health research databases or shared with researchers, government agencies, 
companies, or other groups that are not participating in this study.  These data may be 
combined with or linked to other data and used for research purposes, to advance 
science and public health, or for analysis, development, and commercialization of 
products to treat and diagnose disease.  In addition, redacted clinical study reports and 
other summary reports will be provided upon request. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.3). 


 
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9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
9.3 
MANAGEMENT OF STUDY QUALITY 
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  The 
Sponsor will identify potential risks associated with critical trial processes and data and 
will implement plans for evaluating and controlling these risks.  Risk evaluation and 
control will include the selection of risk-based parameters (e.g., adverse event rate, 
protocol deviation rate) and the establishment of quality tolerance limits for these 
parameters.  Detection of deviations from quality tolerance limits will trigger an 
evaluation to determine if action is needed.  Details on the establishment and monitoring 
of quality tolerance limits will be provided in a Quality Tolerance Limit Management Plan. 
9.4 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.5 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring. 


 
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Up to 120 sites globally will participate to randomize approximately 453 patients.  
Screening and enrollment will occur through an IxRS. 
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker analyses, and PK analyses), as specified in 
Section 4.5.9.  Accredited local laboratories will be used for routine monitoring; local 
laboratory ranges will be collected. 
An iDMC will be employed to monitor and evaluate patient safety throughout the study. 
9.6 
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries of the U.S. National Institutes of Health and the 
EMA, and in peer-reviewed journals.  The Sponsor will comply with all requirements for 
publication of study results.  Study data may be shared with others who are not 
participating in this study, and redacted clinical study reports and/or other summaries of 
clinical study results may be available in health authority databases for public access, 
as required by local regulation, and will be provided upon request (see Section 8.4 for 
more details).  For more information, refer to the Roche Global Policy on Sharing of 
Clinical Study Information at the following website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/ 
 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 


 
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Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.7 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 
10. 
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Appendix 1 
Schedule of Activities 
 
Screening/ 
Baseline a 
Treatment Cycles  
Treatment 
Discontinuation/Early 
Termination Visit d 
Follow- 
Up e 
Neoadjuvant Phase 
Cycles14: 14-Day Cycles 
Cycles 58: 21-Day Cycles 
Pre-
Surgery 
Visit/ 
Surgery b 
Adjuvant Phase c  
(Cycles 922)  
21-Day Cycles 
Days –28 
to –1  
Days –14 
to –1 
Day 1 of Each Cycle ( 3 days) 
Day 1 of Each 
Cycle ( 3 days) 
 30 Days after 
Final Dose 
1 
2 
3 
4 
5 
6 
7 
8 
Informed consent f 
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline tumor tissue sample g 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and baseline 
conditions 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease status assessment h 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
Tumor staging i 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bilateral mammogram j 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Surgical treatment plan k 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
 
Pathologic response 
assessment l 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
Vital signs m 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
 
Weight 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
 
Height 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
examination n  
x 
 
 
 
 
 
 
 
 
x 
 
 
x 
 
Limited physical examination o 
 
 
x 
x 
x 
x 
x 
x 
x 
 
 
x 
 
 


Appendix 1: Schedule of Activities 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
153/Protocol BO40747, Version 6 
 
Screening/ 
Baseline a 
Treatment Cycles  
Treatment 
Discontinuation/Early 
Termination Visit d 
Follow- 
Up e 
Neoadjuvant Phase 
Cycles14: 14-Day Cycles 
Cycles 58: 21-Day Cycles 
Pre-
Surgery 
Visit/ 
Surgery b 
Adjuvant Phase c  
(Cycles 922)  
21-Day Cycles 
Days –28 
to –1  
Days –14 
to –1 
Day 1 of Each Cycle ( 3 days) 
Day 1 of Each 
Cycle ( 3 days) 
 30 Days after 
Final Dose 
1 
2 
3 
4 
5 
6 
7 
8 
ECOG Performance Status p 
x 
 
x 
 
 
 
x 
 
 
x 
 
x 
x 
 
ECHO/MUGA scan q 
x 
 
See footnote "q" 
x 
x 
ECG (12-lead) r 
x 
 
As clinically indicated 
Hematology s 
 
x t 
x  
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
 
Chemistry u 
 
x t 
x  
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
 
Pregnancy test v 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
Coagulation (INR, aPTT) 
 
x t 
 
 
 
 
 
 
 
x 
 
 
x 
 
TSH, free T3 (or total T3), 
free T4 w 
x t 
 
x  
 
 
 
x  
 
 
 
 
x  
x 
 
HIV, HBV, and HCV serologies 
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis x 
x  
 
As clinically indicated 
EORTC QLQ-C30, EQ-5D-5Ly 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x  
FACT-G, single-item GP5 y, z 
 
 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x  
Serum autoantibody sample aa 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK samples and ADA samples 
See Appendix 2 for detailed schedule. 
Blood and plasma sample for 
biomarkers 
See Appendix 3 for detailed schedule. 


Appendix 1: Schedule of Activities 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
154/Protocol BO40747, Version 6 
 
Screening/ 
Baseline a 
Treatment Cycles  
Treatment 
Discontinuation/Early 
Termination Visit d 
Follow- 
Up e 
Neoadjuvant Phase 
Cycles14: 14-Day Cycles 
Cycles 58: 21-Day Cycles 
Pre-
Surgery 
Visit/ 
Surgery b 
Adjuvant Phase c  
(Cycles 922)  
21-Day Cycles 
Days –28 
to –1  
Days –14 
to –1 
Day 1 of Each Cycle ( 3 days) 
Day 1 of Each 
Cycle ( 3 days) 
 30 Days after 
Final Dose 
1 
2 
3 
4 
5 
6 
7 
8 
Blood sample for WGS or WES  
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
Whole blood sample types for 
RBR (optional)  
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
Tumor tissue (fresh sample 
preferred) at screening, 
on-study, and at time of 
disease progression or 
recurrence 
See Appendix 3 for detailed schedule. 
Concomitant medications bb 
 
x  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events cc 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Atezolizumab/placebo 
administration dd 
Stopped with protocol version 5 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
 
Dose-dense doxorubicin 
administration ee 
 
 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
Dose-dense cyclophosphamide 
administration ff 
 
 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
Pertuzumab administration gg 
 
 
 
 
 
 
x 
x 
x 
x 
 
x 
 
 
Trastuzumab administration hh 
 
 
 
 
 
 
x 
x 
x 
x 
 
x 
 
 


Appendix 1: Schedule of Activities 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
155/Protocol BO40747, Version 6 
 
Screening/ 
Baseline a 
Treatment Cycles  
Treatment 
Discontinuation/Early 
Termination Visit d 
Follow- 
Up e 
Neoadjuvant Phase 
Cycles14: 14-Day Cycles 
Cycles 58: 21-Day Cycles 
Pre-
Surgery 
Visit/ 
Surgery b 
Adjuvant Phase c  
(Cycles 922)  
21-Day Cycles 
Days –28 
to –1  
Days –14 
to –1 
Day 1 of Each Cycle ( 3 days) 
Day 1 of Each 
Cycle ( 3 days) 
 30 Days after 
Final Dose 
1 
2 
3 
4 
5 
6 
7 
8 
Paclitaxel administration ii 
 
 
 
 
 
 
x 
x 
x 
x 
 
 
 
 
Trastuzumab emtansine 
administration kk 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Survival follow-up and 
anti-cancer treatment jj 
 
 
 
 
 
 
 
 
 
 
 
 
 
x  
ADA  anti-drug antibody; AJCC  American Joint Committee on Cancer; CT  computed tomography (scan); ddAC  dose-dense anthracycline 
(doxorubicin)  cyclophosphamide; ECHO  echocardiogram; eCRF  electronic Case Report Form; EORTC  European Organisation for Research 
and Treatment of Cancer; EQ-5D-5L  EuroQol 5-Dimension, 5-Level (questionnaire); FACT-G  Functional Assessment of Cancer 
TherapyGeneral; FFPE  formalin-fixed, paraffin-embedded; HBV  hepatitis B virus; HCV  hepatitis C virus; MUGA  multiple-gated acquisition 
(scan); NAST  neoadjuvant systemic therapy; pCRpathological complete response; PK  pharmacokinetic; PRO  patient-reported outcome; 
Q3W  every 3 weeks; QLQ-C30  Quality of Life QuestionnaireCore 30; RBR  Research Biosample Repository; SOC  standard of care; 
T3  triiodothyronine; T4  thyroxine; TSH  thyroid-stimulating hormone; WES  whole exome sequencing; WGS  whole genome sequencing. 
Notes:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified. 
a Results of SOC tests or examinations performed prior to obtaining informed consent and within 28 days prior to Cycle 1, Day 1 may be used; 
such tests do not need to be repeated for screening.  
b Pre-surgical visit and associated assessments should occur within 14 days of surgery.  Surgery should be conducted no earlier than 14 days and 
no later than 6 weeks after last dose of neoadjuvant therapy.  Platelet counts should be checked prior to surgery and should be 
 75,000 cells/L. 
c All study therapy will be completed when the patient has received up to a total duration of 52 weeks of HER2-targeted study therapy 
(neoadjuvant  adjuvant [i.e., a maximum of 18 cycles of HER2-targeted treatment]). 
d Patients who discontinue study treatment will return to the clinic for a treatment discontinuation visit no more than 30 days after their final dose of 
study treatment or no more than 30 days from the date the decision was made to permanently discontinue study treatment. 


Appendix 1: Schedule of Activities 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
156/Protocol BO40747, Version 6 
e The survival follow-up period begins from the date of treatment completion/early termination visit with a duration of 36 months from the date of 
the enrollment of the last patient.  Follow-up visits have a window of  28 days. 
f Informed consent must be documented before any study-specific screening procedure is performed, and may be obtained more than 28 days 
before initiation of study treatment. 
g After signing of the Informed Consent Form, retrieval and submission of tumor tissue sample can occur outside the 28-day screening period.  
Tumor tissue should be of good quality based on total and viable tumor content (sites will be informed if the quality of the submitted specimen is 
inadequate to determine tumor PD-L1 status).  An FFPE block (preferred) or at least 20 slides containing unstained, freshly cut, serial sections 
should be provided.  Fine-needle aspiration is not acceptable.  For core-needle biopsy specimens, at least three cores should be submitted for 
evaluation.  See Section 4.5.9 for additional details. 
h Assessment of primary tumor and regional lymph nodes should be done by physical examination at baseline and prior to administration at each 
cycle of study treatment during neoadjuvant therapy and within 14 days prior to surgery.  During the postoperative portion of this study, disease 
status should be clinically evaluated and documented every 3 months for 2 years, and then every 6 months thereafter until the end of the study.  
In addition, liver function tests, brain imaging, bone scans, chest X-ray/diagnostic CT scan, liver imaging, and/or other radiographic modalities 
may be considered when clinically indicated to exclude metastatic disease; these assessments should be performed within a timeline as per 
current local SOC practice.  Whenever possible, disease recurrence should be confirmed pathologically.  If disease progression or disease 
recurrence is diagnosed at any time during the study, patients will discontinue study treatment and enter the follow-up phase of the study.  
Disease status assessments and imaging (mammogram) can be done as per local standard of care for patients with confirmed disease 
progression or recurrence.  All other follow-up assessments apply to patients with disease progression or recurrence as per Schedule of 
Assessments. 
i Baseline tumor staging procedures should be performed in alignment with AJCC, 8th edition (specifically in accordance with Anatomic Stage 
group rules) at diagnosis, within 28 days of randomization.  Tumor size is to be determined via radiologic measurement and node positivity 
pathologically confirmed by fine needle aspiration or core needle biopsy.  See Section 4.5.6 for requirements related to baseline distant sites 
tumor staging procedures.  
j Bilateral mammogram should be obtained within 28 days prior to randomization.  Alternatively, provided that the clinical status of the patients has 
not changed, the screening mammogram can be performed up to 42 days prior to the start of study treatment.  Subsequent mammograms are 
optional during neoadjuvant treatment and prior to surgery and should be performed per investigator’s discretion.  Bilateral mammogram should 
occur at the treatment completion/early termination visit and every 12 months ( 4 weeks) during the follow-up period.  Patients who have 
undergone mastectomy do not require mammograms on side of mastectomy.  Patients with confirmed disease progression or recurrence can 
undergo imaging procedures as per local standard of care. 
k The patient should be evaluated by a surgeon prior to initiation of neoadjuvant therapy as well as after completion of neoadjuvant therapy/prior to 
surgery.  At baseline, the surgeon should evaluate the patient and create a surgical treatment plan.  Then, after completion of NAST, the 
surgeon should reassess the patient and modify the surgical treatment plan as needed. 


Appendix 1: Schedule of Activities 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
157/Protocol BO40747, Version 6 
l Pathological response assessment to be performed using the resected specimen by the local pathologist on the basis of guidelines provided in 
the pathology manual.  Breast cancer surgery and pathological assessment will be performed and reported according to protocol requirements 
for patients who discontinue study treatment during the neoadjuvant phase (for any reason other than disease progression) and who proceed to 
surgery without receiving any other non-study anti-cancer therapy prior to surgery.  Patients who discontinue neoadjuvant study treatment due to 
disease progression contribute a non-pCR result and their disease progression must be reported. 
m Includes respiratory rate, pulse rate, systolic and diastolic blood pressure, and temperature.  Record abnormalities observed at baseline on the 
General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on the 
Adverse Event eCRF.  For the first infusion, vital signs should be measured within 60 minutes prior to each infusion and, if clinically indicated, 
every 15 ( 5) minutes during the infusion and at 30 ( 10) minutes after the infusion.  For subsequent infusions, vital signs should be measured 
within 60 minutes prior to each infusion and, if clinically indicated or if symptoms occurred during the previous infusion, during the infusion and at 
30 ( 10) minutes after the infusion.  The vital signs measured prior to the infusion of the first study drug at each cycle are required to be reported 
on the Vital Sign eCRF.  Other vital signs are not required to be entered into the eCRF unless abnormal and clinically significant, in which case 
they are to be reported as adverse events. 
n Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurologic systems.  See Section 4.5.3 for additional details.  Record abnormalities observed at baseline on 
the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on 
the Adverse Event eCRF. 
o Perform a limited, symptom-directed physical examination at specified timepoints and as clinically indicated.  Record new or worsened clinically 
significant abnormalities on the Adverse Event eCRF. 
p See Appendix 13. 
q Cardiac monitoring (ECHO or MUGA scan) will be performed on all patients enrolled in the study.  ECHO/MUGA results need to be reviewed 
and acted upon as soon as they are available, but study interventions may continue while ECHO/MUGA results are being read assuming that the 
subject is asymptomatic from a cardiac standpoint.  ECHO is the preferred method.  The same method used for a given patient at screening 
should be used throughout the study, unless clinically indicated.  ECHO or MUGA scan should be obtained at baseline, after the second dose of 
ddAC for the cardiac safety cohort (first 26 patients enrolled), after the fourth dose of ddAC (and prior to Cycle 5, Day 1), and then every 
3 months ( 2 weeks) during study treatment.  ECHO or MUGA scan should be obtained at the early termination visit if not performed within the 
previous 6 weeks. During the survival follow-up period, ECHO or MUGA scan should be obtained every 6 months for the first 2 years and then 
annually until the end of study.  Patients who discontinue study drug(s) for heart failure or LVEF decline should continue to undergo LVEF 
assessments according to this schedule of activitiesirrespective of the initiation of alternative systemic anti-cancer therapyuntil resolution, 
improvement to baseline status, and no further improvement can be expected, or death.  Additional ECHO or MUGA scans should be obtained if 
clinically indicated. 


Appendix 1: Schedule of Activities 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
158/Protocol BO40747, Version 6 
r ECG recordings will be obtained during screening and as clinically indicated at other timepoints.  ECGs for each patient should be obtained from 
the same machine wherever possible.  Patients should be resting in a supine position for at least 10 minutes prior to ECG recording. 
s Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, and other cells).  Local laboratory assessment can be performed up to 3 days prior to study treatment administration 
with the option of repeating on the day of study treatment, including the weekly administration of paclitaxel during Cycles 58.  Local assessment 
must be reviewed prior to every study treatment administration. 
t If screening laboratory assessments were performed within 3 days prior to Day 1 of Cycle 1, they do not have to be repeated. 
u Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if considered SOC for the region), sodium, potassium, 
magnesium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, ALP, ALT, AST, and LDH.  
Local laboratory assessments can be performed up to 3 days prior to study treatment administration with the option of repeating on the day of 
study treatment, including the weekly administration of paclitaxel during Cycles 58.  Local assessments must be reviewed prior to every study 
treatment administration.  
v All women of childbearing potential (as defined in Section 4.1.1) will have a serum pregnancy test at screening, within 7 days prior to initiation of 
study treatment.  Urine pregnancy tests will be performed within 24 hours of Day 1 of every cycle until treatment discontinuation.  A pregnancy 
test must be done at the treatment completion/early termination visit, and at 3 months and 7 months after the discontinuation of study treatment.  
If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
w TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed on Day 1 of Cycle 1 and every fourth cycle 
thereafter. 
x Includes pH, specific gravity, glucose, protein, ketones, and blood; dipstick permitted. 
y The PRO assessments (EORTC QLQ-C30, followed by the FACT-G single item GP5, and then the EQ-5D-5L questionnaire) will be completed 
by the patient at the start of the clinic visit before discussion of the patient’s health state, laboratory results, or health record; before 
administration of study treatment; and/or prior to the performance of any other study assessments that could bias the patient’s responses.  In 
scenarios where laboratory assessments (e.g., blood draws) are done in a different clinic than the one providing treatment or when they are 
done on a different day than study treatment administration, laboratory assessments can be completed before the completion of PROs as long 
as results have not been discussed with patients.  Study personnel should review all questionnaires for completeness before the patient leaves 
the investigational site.  EORTC QLQ-C30 and EQ-5D-5L questionnaires will be completed by patients at baseline (Cycle 1, Day 1); on Day 1 of 
every cycle thereafter until Cycle 8; on Cycle 9, Day 1; on Day 1 of every other cycle thereafter until Cycle 22; and at the treatment 
discontinuation/early termination visit.  If cycles are missed or delayed as permitted by the protocol, the PRO questionnaires should be 
completed on the day that the patient receives treatment for that cycle, before administration of study treatment.  Patients who discontinue study 
treatment for any reason will continue to complete the EORTC QLQ-C30, FACT-G single item GP5, and EQ-5D-5L questionnaires in clinic 


Appendix 1: Schedule of Activities 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
159/Protocol BO40747, Version 6 
during the follow-up period at the following timepoints:  every 3 months ( 28 days) for the first year and then every 6 months ( 28 days) 
thereafter until the end of the study. 
z While on study treatment, all patients will complete the FACT-G, single item GP5 beginning on Cycle 2, Day 1; on Day 1 of every cycle thereafter 
until Cycle 8; on Cycle 9, Day 1; on Day 1 of every other cycle thereafter until Cycle 22; and at the treatment discontinuation/early termination 
visit. 
aa Auto-antibody testing includes anti-nuclear antibody, antidouble-stranded DNA, and circulating anti-neutrophil cytoplasmic antibody, and 
perinuclear anti-neutrophil cytoplasmic antibody.  The baseline sample will be obtained pre-treatment Cycle 1, Day 1, before the first dose of 
study drug and stored.  For patients who show evidence of immune mediated toxicity, additional samples may be collected and assessed 
(including the baseline sample) at that time point.  All samples will be analyzed centrally. 
bb Includes any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) 
used by a patient in addition to protocol-mandated study treatment from 30 days prior to initiation of study treatment (for the purposes of 
screening) until the treatment discontinuation visit.  Medication used by the patient within 7 days prior to initiation of study treatment should be 
recorded.  Record all prior anti-cancer therapies, regardless of when they were received. 
cc After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study treatment, all adverse events will be reported until 30 days after the last dose of study 
treatment or until initiation of new systemic anti-cancer therapy, whichever occurs first, and serious adverse events and adverse events of 
special interest will continue to be reported until 90 days after the last dose of study treatment or until initiation of new systemic anti-cancer 
therapy, whichever occurs first.  After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event 
that is believed to be related to prior exposure to study treatment (see Section 5.6).  For reporting instructions for deaths, please 
see Section 5.3.5.8. 
dd During the neoadjuvant phase, atezolizumab/placebo will be administered by IV infusion at a fixed dose of 840 mg on Day 1 of each 
14-day cycle during Cycles 14, and 1200 mg on Day 1 of each 21-day cycle during Cycles 58.  During the adjuvant phase (post-operatively), 
atezolizumab/placebo will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each 21-day cycle (maximum of 22 cycles 
[neoadjuvant  adjuvant phases]).  Atezolizumab/placebo should be administered as the first infusion.  The initial dose of atezolizumab/placebo 
will be delivered over 60 ( 15) minutes.  Subsequent infusions will be delivered over 30 ( 10) minutes if the previous infusion was tolerated 
without infusion-associated adverse events, or 60 ( 15) minutes if the patient experienced an infusion-associated adverse event with the 
previous infusion.  See Section 4.3.2.1 for additional details.  Following the distribution of the USM DIL dated 3 February 2021, blinded 
atezolizumab/placebo will no longer be administered to patients. 
ee Doxorubicin 60 mg/m2 IV on Day 1 of a 14-day cycle for 4 cycles (Cycles 14) according to local practice guidelines.  See Section 4.3.2.4 for 
additional details. 


Appendix 1: Schedule of Activities 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
160/Protocol BO40747, Version 6 
ff Cyclophosphamide 600 mg/m2 IV on Day 1 of a 14-day cycle for 4 cycles (Cycles 14) according to local practice guidelines.  
See Section 4.3.2.4 for additional details. 
gg Pertuzumab is given as a fixed nonweight-based dose of 840-mg IV loading dose, then 420 mg IV Q3W.  Pertuzumab will be administered on 
Day 1 of a 21-day cycle, to complete up to a total duration of 52 weeks (i.e., maximum of 18 cycles within 1 year) of HER2-targeted therapy, 
inclusive of therapy given both in the neoadjuvant and adjuvant setting.  Day 1 dose administrations are to be performed within a 
 3-day window, unless treatment is delayed or on hold to manage toxicity.  If the scheduled dose administration coincides with a holiday that 
precludes administration, administration should be performed within 7 days following the scheduled date.  See Section 4.3.2.2 for additional 
details. 
hh Trastuzumab is given as an 8-mg/kg IV loading dose and then 6 mg/kg IV Q3W.  Trastuzumab will be administered on Day 1 of a 21-day cycle, 
to complete up to a total duration of 52 weeks (i.e., maximum of 18 cycles within 1 year) of HER2-targeted therapy, inclusive of therapy given 
both in the neoadjuvant and adjuvant setting.  Day 1 dose administrations are to be performed within a  3-day window, unless treatment is 
delayed or on hold to manage toxicity.  If the scheduled dose administration coincides with a holiday that precludes administration, administration 
should be performed within 7 days following the scheduled date.  See Section 4.3.2.3 for additional details. 
ii Paclitaxel is given 80 mg/m2 IV weekly for 12 continuous weeks (Cycles 58) according to local practice guidelines.  Chemotherapy should be 
given after pertuzumab and trastuzumab.  See Section 4.3.2.4 for additional details. 
jj After treatment discontinuation, information on survival follow-up and new anti-cancer therapy (including targeted therapy and immunotherapy) 
will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months for 1 year, then every 6 months 
until the end of the study (unless the patient withdraws consent or the Sponsor terminates the study).  If a patient requests to be withdrawn from 
follow-up, this request must be documented in the source documents and signed by the investigator.  If the patient withdraws from study, the 
study staff shall use a public information source (e.g., county records) to obtain information about survival status only, where allowable by local 
regulation. 
kk Trastuzumab emtansine will be an option for patients who did not achieve pCR after completion of neoadjuvant treatment.  Trastuzumab 
emtansine will be given as 3.6 mg/kg IV infusion on Day 1 of a 21-day cycle for a maximum of 14 cycles in the adjuvant setting.  Day 1 dose 
administrations are to be performed within a  3-day window, unless treatment is delayed or on hold to manage toxicity.  If the scheduled dose 
administration coincides with a holiday that precludes administration, administration should be performed within 7 days following the scheduled 
date.  See Section 4.3.2.4 for additional details. 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
161/Protocol BO40747, Version 6 
Appendix 2  
Schedule of Pharmacokinetic and Immunogenicity Samples 
Visit 
Timepoint 
Treatment Arms 
Atezolizumab with ddAC-PacHP 
Placebo with ddAC-PacHP 
Day 1 of 
Cycle 1 
Prior to the first 
infusion of 
atezolizumab/ 
placebo, 
pertuzumab, and 
trasuzumab 
 Atezolizumab PK (serum) 
 Atezolizumab ADA (serum) 
 Pertuzumab PK (serum) 
 Pertuzumab ADA (serum) 
 Trastuzumab PK (serum) 
 Trastuzumab ADA (serum) 
 Atezolizumab PK 
(serum) 
 Atezolizumab ADA 
(serum) 
 Pertuzumab PK (serum) 
 Pertuzumab ADA 
(serum) 
 Trastuzumab PK 
(serum)  
 Trastuzumab ADA 
(serum) 
30 ( 10) min after 
end of the 
atezolizumab/ 
placebo infusion 
 Atezolizumab PK (serum) 
 Atezolizumab PK 
(serum) 
Day 1 of 
Cycles 2, 
3, 4, 8, 12, 
and 16 
Prior (within 
3 days) to the 
atezolizumab/ 
placebo, 
pertuzumab, and 
trasuzumab 
infusions 
 Atezolizumab PK (serum) b 
 Atezolizumab ADA (serum) b 
 Pertuzumab PK (serum) 
(Cycles 8 and 12 only) a,b 
 Pertuzumab ADA (serum) 
(Cycles 8 and 12 only) a,b 
 Trastuzumab PK (serum) 
(Cycles 8 and 12 only) a,b 
 Trastuzumab ADA (serum) 
(Cycles 8 and 12 only) a,b 
 Atezolizumab PK 
(serum) b 
 Atezolizumab ADA 
(serum) b 
 Pertuzumab PK (serum) 
(Cycles 8 and 12 only) 
a,b 
 Pertuzumab ADA 
(serum) (Cycles 8 and 
12 only) a,b 
 Trastuzumab PK 
(serum) (Cycles 8 and 
12 only) a,b 
 Trastuzumab ADA 
(serum) (Cycles 8 and 
12 only) a,b 


Appendix 2: Schedule of Pharmacokinetic and Immunogenicity Samples 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
162/Protocol BO40747, Version 6 
Visit 
Timepoint 
Treatment Arms 
Atezolizumab with ddAC-PacHP 
Placebo with ddAC-PacHP 
Day 1 of 
Cycle 9 
Prior (within 
3 days) to the first 
infusion of 
trastuzumab 
emtansine 
 Trastuzumab emtansine and 
total trastuzumab PK (serum) b 
 DM1 PK (plasma) b 
 Trastuzumab emtansine ADA 
(serum)b 
 Trastuzumab emtansine 
and total trastuzumab 
PK (serum)b 
 DM1 PK (plasma) b 
 Trastuzumab emtansine 
ADA (serum)b 
30 ( 10) min after 
the end of the 
trastuzumab 
emtansine 
infusion 
 Trastuzumab emtansine and 
total trastuzumab PK (serum) b 
 DM1 PK (plasma) b 
 Trastuzumab emtansine 
and total trastuzumab 
PK (serum) b 
 DM1 PK (plasma) b 
Day 1 of 
Cycle 12 
Prior (within 
3 days) to the 
trastuzumab 
emtansine 
infusion 
 Trastuzumab emtansine and 
total trastuzumab PK (serum) b 
 Trastuzumab emtansine ADA 
(serum) b 
 Trastuzumab emtansine 
and total trastuzumab 
PK (serum) b 
 Trastuzumab emtansine 
ADA (serum) b 
30 ( 10) min after 
the end of the 
trastuzumab 
emtansine 
infusion 
 Trastuzumab emtansine and 
total trastuzumab PK (serum) b 
 DM1 PK (plasma) b 
 Trastuzumab emtansine 
and total trastuzumab 
PK (serum) b 
 DM1 PK (plasma) b 
Treatment 
discont. 
visit 
( 30 days 
after final 
dose) 
At visit 
 Atezolizumab PK (serum) 
 Atezolizumab ADA (serum) 
 Pertuzumab PK (serum) 
 Pertuzumab ADA (serum) 
 Trastuzumab PK (serum) 
 Trastuzumab ADA (serum) 
 Trastuzumab emtansine and 
total trastuzumab PK (serum) 
 DM1 PK (plasma) 
 Trastuzumab emtansine ADA 
(serum) 
 Pertuzumab PK (serum) 
 Pertuzumab ADA 
(serum) 
 Trastuzumab PK 
(serum) 
 Trastuzumab ADA 
(serum) 
 Trastuzumab emtansine 
and total trastuzumab 
PK (serum) 
 DM1 PK (plasma) 
 Trastuzumab emtansine 
ADA (serum) 
 
 


Appendix 2: Schedule of Pharmacokinetic and Immunogenicity Samples 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
163/Protocol BO40747, Version 6 
ADA  anti-drug antibody; ddAC-PacHP  dose-dense anthracycline 
(doxorubicin)  cyclophosphamide followed by paclitaxel  trastuzumab  pertuzumab; 
discont.  discontinuation; DM1  derivative of maytansine; pCR  pathological complete response; 
PK  pharmacokinetic. 
Notes:  PK and ADA samples for atezolizumab, pertuzumab, and trastuzumab will be collected for 
all patients.  PK and ADA samples for trastuzumab emtansine will be collected for only those 
patients receiving trastuzumab emtansine.  In an event where a dose is withheld, predose PK and 
ADA samples should be collected regardless if possible on the day of the planned dose.  If more 
than one dose is withheld, the PK and ADA samples will be handled on a case-by-case basis. 
a Patients who do not achieve pCR and switch treatment to atezolizumab/placebo with 
trastuzumab emtansine in the adjuvant phase of the study are not required to provide PK and 
ADA samples for trastuzumab and pertuzumab at Cycle 12. 
b Following the discontinuation of atezolizumab or placebo, this sample collection is no longer 
required.  The PK and ADA sample collection for atezolizumab, trastuzumab and pertuzumab 
(or trastuzumab emtansine) is only required at the treatment discontinuation visit following the 
implementation of Protocol Version 5. 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
164/Protocol BO40747, Version 6 
Appendix 3  
Schedule of Blood and Tissue Samples for Biomarker Analysis 
Blood Samples 
Visit 
Timepoint 
Sample Type 
Cycle 1, Day 1 
Pretreatment 
Plasma sample for biomarkers 
Blood sample for WGS/WES a, b 
Whole blood sample for RBR b, c 
Cycle 2, Day 1 
Pretreatment 
Plasma sample for biomarkers 
Surgery 
Pre-surgery 
Plasma sample for biomarkers 
Cycle 9, Day 1 
Pretreatment 
Plasma sample for biomarkers 
Cycle 13, Day 1 
Pretreatment 
Plasma sample for biomarkers 
Cycle 17, Day 1 
Pretreatment 
Plasma sample for biomarkers 
Treatment discontinuation 
( 30 days after final dose) d 
At any time during visit 
Plasma sample for biomarkers 
Disease recurrence 
At any time during visit 
Plasma sample for biomarkers 
RBR  Research Biosamle Repository; WES  whole exome sequencing; WGS  whole 
genome sequencing. 
a Not applicable for a site that has not been granted approval for WGS/WES. 
b If missed on Day 1, this blood sample can be collected at any point in the study. 
c Not applicable for a site that has not been granted approval for RBR sampling and 
performed only for patients at participating sites who have provided written optional RBR 
consent to participate. 
d If treatment is discontinued due to disease recurrence, the treatment discontinuation 
sample does not apply and only the disease recurrence sample needs to be collected. 
 
 
 


Appendix 3: Blood and Tissue Samples for Biomarker Analysis 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
165/Protocol BO40747, Version 6 
Tissue Samples 
Visit 
Timepoint 
Requirement 
Sample Type 
Screening a Pre-treatment 
Mandatory 
A representative FFPE tumor specimen in a paraffin 
block (preferred) or at least 20 slides containing 
unstained, freshly cut, serial sections must be 
submitted. 
Tumor sample must contain a minimum of 50 viable 
tumor cells. 
Samples are to be collected via core-needle biopsy 
(at least three cores, embedded in a single paraffin 
block).  Fine-needle aspiration is not acceptable. 
For patients with multifocal tumors, at least one focus 
must be sampled and centrally confirmed as 
HER2-positive.  A representative FFPE tumor 
specimen in a paraffin block is preferred or at least 
20 slides. 
Patients with multicentric tumors are eligible provided 
all discrete lesions are sampled and centrally 
confirmed as HER2-positive.  A representative FFPE 
tumor specimen in a paraffin block of all lesions is 
preferred or at least 11 slides are required from each 
lesion.  In addition to this requirement, a total of 
9 slides is required for the remaining biomarker tests.  
Preferably, these additional 9 slides are derived from 
one lesion. 
Surgery 
 
Mandatory 
A representative FFPE tumor specimen in a paraffin 
block (preferred) or at least 15 slides containing 
unstained, freshly cut, serial sections must be 
submitted. 
Disease 
recurrence b 
 
Mandatory, 
if clinically 
feasible 
A representative FFPE tumor specimen in a paraffin 
block (preferred) or at least 15 slides containing 
unstained, freshly cut, serial sections must be 
submitted. 
FFPE  formalin-fixed, paraffin-embedded; HER2  human epidermal growth factor 2. 
a A pretreatment tumor biopsy is required for central eligibility testing.  A new pretreatment tumor 
biopsy may be performed if tissue test results do not meet eligibility criteria.  Submission of a 
tumor sample can occur outside the 28-day screening period.  Patients with multicentric 
tumors are eligible provided all discrete lesions are sampled and centrally confirmed as 
HER2-positive. 
b If deemed clinically feasible by the investigator and within 40 days after recurrence or prior to 
the next anti-cancer therapy, whichever is sooner. 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
166/Protocol BO40747, Version 6 
Appendix 4  
European Organisation for Research and Treatment of Cancer 
Quality-of-Life QuestionnaireCore 30:  EORTC QLQ-C30 
 


Appendix 4: European Organisation for Research and Treatment of Cancer Quality-of-Life 
QuestionnaireCore 30:  EORTC QLQ-C30 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
167/Protocol BO40747, Version 6 
 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
168/Protocol BO40747, Version 6 
Appendix 5  
Functional Assessment of Cancer TherapyGeneral (FACT-G) 
Single-Item GP5 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
169/Protocol BO40747, Version 6 
Appendix 6  
EuroQol 5-Dimension, 5-Level Questionnaire: EQ-5D-5L 
 


Appendix 6: EuroQol 5-Dimension, 5-Level Questionnaire: EQ-5D-5L 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
170/Protocol BO40747, Version 6 
 


Appendix 6: EuroQol 5-Dimension, 5-Level Questionnaire: EQ-5D-5L 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
171/Protocol BO40747, Version 6 
 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
172/Protocol BO40747, Version 6 
Appendix 7  
Ventana HER2 IHC Assay 
The PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody 
(PATHWAYHER2 [4B5]) is a rabbit monoclonal antibody intended for laboratory use for 
the semi-quantitative detection of human epidermal growth factor 2 (HER2) antigen in 
sections of formalin-fixed, paraffin-embedded breast cancer tissue to determine tumor 
HER2 immunohistochemistry (IHC) status and to select HER2-positive patients for 
enrollment in Study BO40747. 
The PATHWAY HER2 (4B5) IHC assay is an automated immunohistochemical staining 
assay system comprising a pre-dilute, ready-to-use, rabbit monoclonal primary antibody 
(clone 4B5) directed against the internal domain of HER2, the BenchMark ULTRA 
automated slide staining platform, and ultraView universal DAB detection kit.  The 
reagents and the IHC procedure are optimized for use on the BenchMark ULTRA 
automated slide stainer, utilizing VSS software (Ventana System Software).  Details of 
the staining protocol and scoring criteria can be found in instruction for use and 
interpretation guide published by Ventana. 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
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Appendix 8  
Ventana HER2 ISH Assay  
Probe Cocktail is intended to determine the ratio of the human epidermal growth factor 2 
(HER2) gene to chromosome 17 using two-color chromogenic in situ hybridization (ISH) 
in formalin-fixed, paraffin-embedded (FFPE) human breast cancer tissue to determine 
tumor HER2 gene status and select HER2-positive patients for enrollment in 
Study BO40747. 
The Ventana INFORM HER2 Dual ISH assay consists of a dinitrophenyl (DNP)-labeled 
double stranded probe that targets the HER2 gene region of chromosome 17 and a 
digoxigenin (DIG)-labeled double stranded probe that hybridizes to repetitive sequences 
in the centromeric region of chromosome 17 (INFORM Chromosome 17 probe).  The 
probes are packaged as a mixture and require the use of Ventana’s ultraView™ 
SISHDNP Detection Kit, ultraView Red DIG Detection Kit, and other accessory reagents 
to stain routinely processed, FFPE tissue sections on Ventana automated slide stainer 
instruments. 
 


 
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Appendix 9  
Preexisting Autoimmune Diseases and Immune Deficiencies 
Patients should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease.  Patients with any history of immune 
deficiencies or autoimmune disease listed in the table below are excluded from 
participating in the study.  Possible exceptions to this exclusion could be patients with a 
medical history of such entities as atopic disease or childhood arthralgias where the 
clinical suspicion of autoimmune disease is low.  Patients with a history of 
autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone 
may be eligible for this study.  In addition, transient autoimmune manifestations of an 
acute infectious disease that resolved upon treatment of the infectious agent are not 
excluded (e.g., acute Lyme arthritis).  Caution should be used when considering 
atezolizumab for patients who have previously experienced a severe or life-threatening 
skin adverse reaction or pericardial disorder while receiving another immunostimulatory 
anti-cancer agent.  The Medical Monitor is available to advise on any uncertainty over 
autoimmune exclusions. 


 
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Autoimmune Diseases and Immune Deficiencies 
 Acute disseminated 
encephalomyelitis 
 Addison disease 
 Ankylosing spondylitis 
 Antiphospholipid antibody 
syndrome 
 Aplastic anemia 
 Autoimmune hemolytic 
anemia 
 Autoimmune hepatitis 
 Autoimmune 
hypoparathyroidism 
 Autoimmune hypophysitis 
 Autoimmune myelitis 
 Autoimmune myocarditis 
 Autoimmune oophoritis 
 Autoimmune orchitis 
 Autoimmune 
thrombocytopenic purpura 
 Behçet disease 
 Bullous pemphigoid 
 Chronic fatigue syndrome 
 Chronic inflammatory 
demyelinating 
polyneuropathy 
 Churg-Strauss syndrome 
 Crohn disease  
 Dermatomyositis 
 Diabetes mellitus type 1 
 Dysautonomia 
 Epidermolysis bullosa 
acquisita 
 Gestational pemphigoid 
 Giant cell arteritis 
 Goodpasture syndrome 
 Granulomatosis with 
polyangiitis 
 Graves disease 
 Guillain-Barré syndrome 
 Hashimoto disease 
 IgA nephropathy 
 Inflammatory bowel disease 
 Interstitial cystitis 
 Kawasaki disease 
 Lambert-Eaton myasthenia 
syndrome 
 Lupus erythematosus 
 Lyme disease, chronic 
 Meniere syndrome 
 Mooren ulcer 
 Morphea 
 Multiple sclerosis  
 Myasthenia gravis 
 Neuromyotonia 
 Opsoclonus myoclonus 
syndrome 
 Optic neuritis 
 Ord thyroiditis 
 Pemphigus 
 Pernicious anemia 
 Polyarteritis nodosa 
 Polyarthritis 
 Polyglandular autoimmune 
syndrome 
 Primary biliary cholangitis 
 Psoriasis 
 Reiter syndrome 
 Rheumatoid arthritis 
 Sarcoidosis 
 Scleroderma 
 Sjögren syndrome 
 Stiff-Person syndrome 
 Takayasu arteritis 
 Ulcerative colitis 
 Vitiligo 
 Vogt-Koyanagi-Harada 
disease 
 


 
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Appendix 10  
Anaphylaxis Precautions 
These guidelines are intended as a reference and should not supersede pertinent local 
or institutional standard operating procedures. 
REQUIRED EQUIPMENT AND MEDICATION 
The following equipment and medication are needed in the event of a suspected 
anaphylactic reaction during study treatment infusion. 
 
Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer 
 
Oxygen 
 
Epinephrine for subcutaneous, intravenous, and/or endotracheal administration in 
accordance with institutional guidelines 
 
Antihistamines 
 
Corticosteroids 
 
Intravenous infusion solutions, tubing, catheters, and tape 
 
PROCEDURES 
In the event of a suspected anaphylactic reaction during study treatment infusion, 
the following procedures should be performed: 
1. 
Stop the study treatment infusion. 
2. 
Call for additional medical assistance. 
3. 
Maintain an adequate airway. 
4. 
Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring if possible. 
5. 
Administer antihistamines, epinephrine, or other medications and IV fluids as 
required by patient status and as directed by the physician in charge. 
6. 
Continue to observe the patient and document observations. 
 


 
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Appendix 11  
Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
DOSE MODIFICATIONS, TREATMENT INTERRUPTION, AND 
MANAGEMENT GUIDELINES 
When there is a possibility of overlapping toxicities, the attribution of an adverse event to 
particular drug(s) will be based on the investigator’s clinical judgment.  See Section 5.1.7 
and 5.1.8 for guidance on potential overlapping toxicities. 
ATEZOLIZUMAB 
On 3 February 2021, the Sponsor issued a USM DIL communicating the request to stop 
treatment with atezolizumab or placebo. 
There will be no dose reduction for atezolizumab in this study. 
See Appendix 12 for management of adverse events, which are deemed by the 
investigator, to be due to atezolizumab. 
Atezolizumab treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment.  If corticosteroids are initiated for treatment 
of the toxicity, they must be tapered over  1 month to  10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed.  If atezolizumab is withheld for 
 12 weeks after event onset, the patient will be discontinued from atezolizumab.  
However, atezolizumab may be withheld for  12 weeks to allow for patients to taper off 
corticosteroids prior to resuming treatment.  Atezolizumab can be resumed after being 
withheld for  12 weeks if the patient is likely to derive clinical benefit.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator’s 
benefitrisk assessment and documented by the investigator.  The Medical Monitor is 
available to advise as needed.  Atezolizumab treatment may be suspended for reasons 
other than toxicity (e.g., surgical procedures).  The acceptable length of treatment 
interruption must be based on the investigator's benefitrisk assessment and in 
alignment with the protocol requirements for the duration of treatment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
DOXORUBICIN AND CYCLOPHOSPHAMIDE 
Dose reduction and dose delays will be allowed as indicated in the relevant local 
prescribing information for doxorubicin and cyclophosphamide, and should be managed 
as per local practice. 
Cardiotoxicity 
If severe symptomatic heart failure develops (New York Heart Association [NYHA] 
Class III or IV) or there is a significant left ventricular ejection fraction (LVEF) decrease 
(LVEF decline  10 percentage points from baseline to an LVEF value  50%), the 


Appendix 11: Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
  
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patient must discontinue atezolizumab  doxorubicin  cyclophosphamide and not 
proceed with anti-HER2 therapy.  Heart failure or left ventricular dysfunction should be 
treated and monitored according to standard medical practice.  These patients should be 
evaluated by a certified cardiologist and the results of this evaluation should be reported 
on the eCRF. 
Patients who discontinue atezolizumab  doxorubicin  cyclophosphamide for heart 
failure or LVEF decline should continue to undergo LVEF assessments according to the 
schedule of activities (see Appendix 1)irrespective of the initiation of alternative 
systemic anti-cancer therapyuntil resolution, improvement to baseline status, no 
further improvement can be expected, or death.  Additional LVEF assessments may be 
required for these patients (beyond those specified in the schedule of activities), 
according to the investigator’s clinical judgment.  The results of these assessments 
should be reported. 
Liver Function 
The major route of elimination of doxorubicin is the hepatobiliary system.  Serum total 
bilirubin should be evaluated before and during treatment with doxorubicin.  Patients with 
elevated bilirubin may experience slower clearance of the drug with an increase in 
overall toxicity.  Lower doses are recommended in these patients.  Patients with severe 
hepatic impairment should not receive doxorubicin. 
PACLITAXEL 
Dose reduction and dose delays will be allowed as indicated in the relevant local 
prescribing information for paclitaxel, and managed as per local practice. 
Pulmonary Events/Pneumonitis 
Paclitaxel should be permanently discontinued upon ruling out infectious etiology (using 
routine microbiological and/or immunologic methods) and making a diagnosis of 
pneumonitis.  After infectious etiology is ruled out, IV high-dose corticosteroid therapy 
should be instituted without delay, with appropriate premedication and secondary 
pathogen coverage.  The patient will discontinue paclitaxel treatment but may continue 
receiving other study drugs as per Table 2 below.  Also refer to Appendix 12 for 
atezolizumab-associated pulmonary events. 
Refer to the local prescribing information for paclitaxel for further details. 
Pertuzumab and Trastuzumab 
Pertuzumab and trastuzumab administration may be delayed up to 42 days from the last 
administered dose to allow resolution of adverse events.  If dosing with trastuzumab and 


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pertuzumab has been delayed for more than 42 days from the last dose and the 
investigator wishes to restart treatment with trastuzumab and pertuzumab based on a 
positive benefitrisk assessment for the individual patient, the Medical Monitor is 
available for consultation.  For guidance on drug administration requirements related to 
delayed or missed doses, please see Table 1 below.  No dose reduction is permitted for 
either pertuzumab or trastuzumab.  Note that if trastuzumab is permanently 
discontinued, the patient will not receive adjuvant treatment on study but will enter the 
study follow-up period. 
Table 1 
Pertuzumab and Trastuzumab Administration Guidance 
Regarding Delayed or Missed Doses 
Time Between Two 
Sequential Doses 
Pertuzumab 
Trastuzumab 
 6 weeks 
The 420-mg dose of pertuzumab IV 
should be administered as soon as 
possible.  Do not wait until the next 
planned dose. 
The 6 mg/kg dose of trastuzumab 
IV should be administered as soon 
as possible.  Do not wait until the 
next planned dose. 
 6 weeks 
The loading dose of 840 mg 
pertuzumab IV should be 
re-administered as a 60-minute 
infusion, followed by a maintenance 
dose of 420 mg IV administered over 
a period of 30 to 60 minutes every 
3 weeks thereafter. 
The loading dose of 8 mg/kg of 
trastuzumab IV should be 
re-administered over approximately 
90 minutes, followed by a 
maintenance dose of 6 mg/kg 
IV administered over a period of 
30 or 90 minutes every 3 weeks 
thereafter. 
 
Infusion-Associated Symptoms 
If infusion-associated symptoms occur, patients should be monitored until complete 
resolution of signs and symptoms.  Patients who experience infusion-associated 
symptoms may be managed by slowing or interrupting the infusion and by providing 
supportive care with oxygen and medications (e.g., -agonists, antihistamines, 
antipyretics, or corticosteroids), as determined by the investigator to be clinically 
appropriate.  Patients who experience infusion-associated symptoms may subsequently 
be premedicated with analgesia and antihistamines.  If the infusion is well tolerated, 
patients will be observed for 30 minutes following subsequent infusions.  The infusion of 
pertuzumab or trastuzumab should be stopped in patients who develop dyspnea or 
clinically significant hypotension (defined as per investigator discretion).  Patients who 
experience an NCI CTCAE Grade 3 or 4 allergic reaction or acute respiratory distress 
syndrome should be discontinued from treatment. 


Appendix 11: Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
  
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Cardiotoxicity 
If severe symptomatic heart failure develops (NYHA Class III or IV), the patient must 
discontinue anti-HER2 therapy.  If there is a significant LVEF decrease (LVEF decline 
 10 percentage points from baseline to an LVEF value  50%) anti-HER2 therapy 
should be withheld and a repeat LVEF assessment performed within approximately 
3 weeks.  If LVEF has not improved, or has declined further or if clinically significant 
heart failure develops, the patient must discontinue anti-HER2 therapy.  Patients who 
develop asymptomatic cardiac dysfunction may benefit from more frequent monitoring 
(e.g., every 68 weeks).  Heart failure or left ventricular dysfunction should be treated 
and monitored according to standard medical practice.  These patients should be 
evaluated by a certified cardiologist and the results of this evaluation should be reported 
on the eCRF. 
Patients who discontinue anti-HER2 therapy for heart failure or LVEF decline should 
continue to undergo LVEF assessments according to the schedule of activities 
(Appendix 1)irrespective of the initiation of alternative systemic anti-cancer 
therapyuntil resolution, improvement to baseline status, no further improvement can 
be expected, or death.  Additional LVEF assessments may be required for these patients 
(beyond those specified in the schedule of activities), according to the investigator’s 
clinical judgment.  The results of these assessments should be reported. 
Pulmonary Toxicity 
Severe pulmonary events have been reported with the use of the trastuzumab IV 
formulation in the postmarketing setting.  These events have occasionally been fatal.  
They may occur as part of an IRR or with delayed onset.  In addition, cases of interstitial 
lung disease, including lung infiltrates, acute respiratory distress syndrome (ARDS), 
pneumonia, pneumonitis, pleural effusion, respiratory distress, acute pulmonary edema, 
and respiratory insufficiency have been reported with trastuzumab IV.  These events 
have been most common with the first infusion, and their severity has decreased with 
subsequent infusions.  Serious reactions have been treated successfully with supportive 
therapy, such as oxygen, -agonists, and corticosteroids.  ARDS has been reported with 
a fatal outcome. 
Refer to the Trastuzumab Investigator’s Brochure and Pertuzumab Investigator’s 
Brochure for the most recent data related to the associated risks. 
Epidermal Growth Factor Receptor (EGFR)Related Toxicities 
To prevent dehydration, early treatment of diarrhea with anti-diarrheal medication should 
be considered, and patients should be treated with fluids and electrolyte replacement, as 
clinically indicated. 


Appendix 11: Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
  
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Treatment recommendations for EGFR-associated rash include topical or oral 
antibiotics, and topical steroids or systemic steroids (for severe reactions). 
These agents may be used in patients experiencing pertuzumab-related rash, as 
clinically indicated, although they have not been studied in this context. 
Mucositis is generally not considered preventable; although for some cytotoxic agents, 
mucositis may be reduced by cooling the mouth using ice chips before and during the 
infusion. 
MODIFICATIONS OF STUDY TREATMENT REGIMEN IF AGENT(S) CANNOT 
BE ADMINISTERED (IN THE EVENT OF TOXICITY) 
Investigators may consult with the Medical Monitor before discontinuing all components 
of study treatment.  See Table 2, Table 3, and Table 4 for modifications of study 
treatment regimen in the event that agent(s) cannot be administered (e.g., due to 
toxicity). 
 
 


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Table 2 
Neoadjuvant Cycles 14:  Atezolizumab/Placebo and Dose-Dense 
(dd) Doxorubicin (A)  Cyclophosphamide (C) 
Regimen 
Unable to Administer within 
14 Days of Scheduled Dosing 
(i.e., Cycle X, D1  14 Days) 
Action 
Atezolizumab/ 
Placebo  ddAC 
Either A or C  
Do not continue with only one component of 
the chemotherapy backbone. 
Move to 4 cycles of 
atezolizumab/placebo  PacHP. 
Per investigator discretion:  Option to make up 
missed chemotherapy cycles post-surgery 
and prior to adjuvant therapy with 
atezolizumab/placebo  HP. 
Note:  Due to increased risk of cardiotoxicity, 
ddAC is NOT to be given within 21 days of 
prior H and/or P. b  ddAC is NOT to be given 
concurrently with H and/or P. 
ddAC  
Move to 4 cycles 
atezolizumab/placebo  PacHP. 
Per investigator discretion:  Option to make up 
missed chemotherapy cycles post-surgery 
and prior to adjuvant therapy with 
atezolizumab/placebo   HP. 
Note:  Due to increased risk of cardiotoxicity, 
ddAC is NOT to be given within 21 days of 
prior H and/or P.b  ddAC is NOT to be given 
concurrently with H and/or P. 
Atezolizumab/placebo 
Continue ddAC then switch to PacHP followed 
by surgery followed by  HP adjuvant therapy. 
Atezolizumab/placebo may be reintroduced 
with subsequent cycles of therapy a if criteria 
for restarting are met.  (See above in 
Appendix 11 and also Appendix 12, Risks 
Associated with Atezolizumab and Guidelines 
for Management of Adverse Events 
Associated with Atezolizumab.) 
A  doxorubicin; C  cyclophosphamide; D1  Day 1; dd  dose-dense; ddAC  dose-dense anthracycline 
(doxorubicin)  cyclophosphamide; H  trastuzumab; P  pertuzumab; 
PacHP  paclitaxel  trastuzumab  pertuzumab. 
a When atezolizumab is restarted, the infusions should remain synchronized and aligned with the 
chemotherapy schedule. 
b The only exception is the period between Cycle 4 and Cycle 5 during which the Cycle 4 ddAC 
administration will be given 14 days prior to the Cycle 5 administration of HP. 
 


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Adverse Events 
  
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Table 3 
Neoadjuvant Cycles 58:  Atezolizumab/Placebo and 
Paclitaxel  Trastuzumab  Pertuzumab (PacHP) 
Regimen 
Unable to Administer 
Action 
Impact on Adjuvant 
(Post-Operative) 
Treatment 
If 1 agent in the regimen cannot be administered (i.e., due to toxicity) within 21 days of 
scheduled dosing (i.e., Cycle X, D1   21 days) 
Atezolizumab/ 
Placebo   
PacHP 
Atezolizumab/placebo  
 
Continue PacHP. 
Atezolizumab/placebo 
may be reintroduced with 
subsequent cycles of 
therapy a if criteria for 
restarting are met.  
(See above in 
Appendix 11 and also 
Section 5, Assessment of 
Safety, and Appendix 12, 
Risks Associated with 
Atezolizumab and 
Guidelines for 
Management of Adverse 
Events Associated with 
Atezolizumab.) 
HP adjuvant treatment. 
Atezolizumab/placebo 
may be reintroduced 
with subsequent cycles 
of therapy a if criteria for 
restarting are met.  
(See above in 
Appendix 11 and also 
Section 5, Assessment 
of Safety, and 
Appendix 12, Risks 
Associated with 
Atezolizumab and 
Guidelines for 
Management of Adverse 
Events Associated with 
Atezolizumab.) 
Pertuzumab (P)  
Continue atezolizumab/ 
placebo  PacH. 
Pertuzumab may be 
reintroduced with 
subsequent cycles of 
therapy a if criteria for 
restarting are met. 
(See above in 
Appendix 11 and also 
Section 5, Assessment of 
Safety.) 
Pertuzumab may be 
reintroduced with 
subsequent cycles of 
therapy a if criteria for 
restarting are met.  
(See above in 
Appendix 11 and also 
Section 5, Assessment 
of Safety.) 
Trastuzumab (H)  
Continue Atezolizumab/ 
Placebo  PacP. 
Trastuzumab may be 
reintroduced with 
subsequent cycles of 
therapy a if criteria for 
restarting are met.  
(See above in 
Appendix 11 and also 
Section 5, Assessment of 
Safety.) 
If H is permanently 
discontinued, no further 
adjuvant treatment (no 
H, P or atezolizumab/ 
placebo).  Patient enters 
study follow-up. 


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Adverse Events 
  
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Table 3 
Neoadjuvant Cycles 58:  Atezolizumab/Placebo and 
Paclitaxel  Trastuzumab  Pertuzumab (PacHP) (cont.) 
Regimen 
Unable to Administer 
Action 
Impact on Adjuvant 
(Post-Operative) 
Treatment 
Paclitaxel (Pac) b  
 
Per investigator 
discretion, either: 
(1) Proceed to surgery. 
(2) Continue 
atezolizumab/ 
placebo  HP. 
Paclitaxel (Pac) may be 
reintroduced with 
subsequent cycles of 
therapy a if criteria for 
restarting are met. (See 
above in Appendix 11 and 
also Section 5, 
Assessment of Safety.) 
Per investigator 
discretion: 
Option to make up 
missing chemotherapy 
cycle(s) post-surgery 
followed by 
atezolizumab/ 
placebo  HP adjuvant 
treatment. 
(Per investigator 
discretion:  HP and 
atezolizumab/placebo 
may be added to 
post-surgery 
chemotherapy.) 
If 2 agents in the regimen cannot be administered (i.e., due to toxicity) within 21 days of 
scheduled dosing (i.e., Cycle X, D1   21 days) 
Atezolizumab/ 
Placebo  
PacHP 
Pac  H  
Proceed to surgery. 
Postoperatively, per investigator discretion option to 
make up missing Pac  H  P  atezolizumab/placebo, 
followed by adjuvant H  P  atezolizumab/placebo if 
criteria for restarting agent(s) are met.  (See above in 
Appendix 11 and also Section 5, Assessment of 
Safety, and Appendix 12, Risks Associated with 
Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab.) 
If two or more of Pac, H, or P have been permanently 
discontinued then the patient stops all study therapies 
and enters follow up. 
Pac   P  
H   P  
D1  Day 1; H  trastuzumab; P  pertuzumab; Pac  paclitaxel; 
PacHP  paclitaxel  trastuzumab  pertuzumab. 
a When agent is restarted, the infusions should remain synchronized and aligned with the 
treatment schedule. 
b Patients may continue atezolizumab/placebo  HP during periods of chemotherapy-induced 
myelosuppression (e.g., chemotherapy may be delayed but H/P/atezolizumab/placebo are 
given while blood counts are waiting to recover) but should be carefully monitored for 
complications of neutropenia. 
 


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Adverse Events 
  
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Table 4 
Adjuvant Cycles 922:  Atezolizumab/Placebo and 
Trastuzumab  Pertuzumab (HP) or Atezolizumab/Placebo and 
Trastuzumab Emtansine 
Regimen 
Unable to Administer within 
21 Days of Scheduled Dosing 
(i.e., Cycle X D1  21 Days) 
Action 
Atezolizumab/ 
Placebo   HP 
Atezolizumab/placebo   
Continue HP. 
Atezolizumab/placebo may be 
reintroduced with subsequent cycles of 
therapy if criteria for restarting are met. 
(See above in Appendix 11 and also 
Section 5, Assessment of Safety, and 
Appendix 12, Risks Associated with 
Atezolizumab and Guidelines for 
Management of Adverse Events 
Associated with Atezolizumab.) 
Pertuzumab (P)  
Continue atezolizumab/placebo  H. 
Pertuzumab may be reintroduced with 
subsequent cycles of therapy if criteria 
for restarting are met.  (See above in 
Appendix 11 and also Section 5, 
Assessment of Safety.) 
Trastuzumab (H)  
Per investigator discretion, may either: 
(1) Hold all agents. 
(2) Continue atezolizumab  P. 
Trastuzumab may be reintroduced with 
subsequent cycles of therapy if criteria 
for restarting are met.  (See above in 
Appendix 11 and also Section 5, 
Assessment of Safety.) 
If/when trastuzumab is permanently 
discontinued, then discontinue all 
components of the regimen and move to 
follow up. 
 


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Table 4 
Adjuvant Cycles 922:  Atezolizumab/Placebo and 
Trastuzumab  Pertuzumab (HP) or Atezolizumab/Placebo and 
Trastuzumab Emtansine (cont.) 
Regimen 
Unable to Administer within 
21 Days of Scheduled Dosing 
(i.e., Cycle X, D1   21 Days) 
Action 
Atezolizumab/ 
Placebo + 
Trastuzumab 
Emtansine 
Atezolizumab/placebo 
Continue trastuzumab emtansine. 
Atezolizumab/placebo may be 
reintroduced with subsequent cycles of 
therapy if criteria for restarting are met. 
Trastuzumab emtansine 
Hold all agents. 
Trastuzumab emtansine (with 
atezolizumab/placebo) may be 
reintroduced with subsequent cycles of 
therapy if criteria for re-starting are met.  
(See Section 5.1.6, Section 5.1.10.1, 
Appendix 14, and Appendix 15) 
If trastuzumab emtansine is 
permanently discontinued for toxicity not 
considered related to the trastuzumab 
component of the drug, treatment can 
be switched to trastuzumab and 
pertuzumab with atezolizumab/placebo 
to complete a total of 1 year of 
HER2-targeted therapy. 
D1  Day 1; H  trastuzumab; P  pertuzumab. 
Notes:  All study therapy will be completed following 52 weeks of HER2-targeted therapy 
(neoadjuvant  adjuvant), regardless of the number of cycles administered. 
Following the distribution of the USM DIL dated 3 February 2021, patients will no longer receive 
atezolizumab or placebo. 
 


 
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Appendix 12  
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab  
When there is a possibility of overlapping toxicities, the attribution of an adverse event to 
particular drug(s) will be based on the investigator’s clinical judgment.  See Section 5.1.7 
and 5.1.8, and Appendix 11 for guidance on potential overlapping toxicities. 
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology. 
Although most immune-mediated adverse events observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications.  Discontinuation of atezolizumab 
may not have an immediate therapeutic effect, and in severe cases, immune-mediated 
toxicities may require acute management with topical corticosteroids, systemic 
corticosteroids, or other immunosuppressive agents.  
The following are general recommendations for management of any other adverse events 
that may occur and are not specifically listed in the following subsections.  
 
Patients and family caregivers should receive timely and up-to-date information 
about immunotherapies, their mechanism of action, and the clinical profile of 
possible immune-related adverse events prior to initiating therapy and throughout 
treatment and survival follow-up.  There should be a high level of suspicion that 
new symptoms are treatment related. 
 
In general, atezolizumab therapy should be continued with close monitoring for 
Grade 1 toxicities, with the exception of some neurologic toxicities. 
 
Consider holding atezolizumab for most Grade 2 toxicities and resume when 
symptoms and/or laboratory values resolve to Grade 1 or better.  Corticosteroids 
(initial dose of 0.51 mg/kg/day of prednisone or equivalent) may be administered. 
 
For Grade 2 recurrent or persistent (lasting for more than 5 days) events, treat as a 
Grade 3 event.   
 
Hold atezolizumab for Grade 3 toxicities and initiate treatment with high-dose 
corticosteroids (12 mg/kg/day prednisone or equivalent).  Corticosteroids should 
be tapered over 1 month to 10 mg/day oral prednisone or equivalent, before 
atezolizumab can be resumed.  If symptoms do not improve within 48 to 72 hours 
of high-dose corticosteroid use, other immunosuppressants may be offered for some 
toxicities. 
 
In general, Grade 4 toxicities warrant permanent discontinuation of atezolizumab 
treatment, with the exception of endocrinopathies that are controlled by 
hormone-replacement therapy. 


Appendix 12: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
  
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 
The investigator should consider the benefitrisk balance a given patient may be 
experiencing prior to further administration of atezolizumab.  Resumption of 
atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  The decision to re-challenge patients 
with atezolizumab should be based on the investigator’s assessment of the benefits 
and risks and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
PULMONARY EVENTS 
Pulmonary events may present as new or worsening cough, chest pain, fever, dyspnea, 
fatigue, hypoxia, pneumonitis, and pulmonary.  Patients will be assessed for pulmonary 
signs and symptoms throughout the study and will also have computed tomography (CT) 
scans of the chest performed as clinically indicated. 
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies, such as pneumonia or other infection, lymphangitic carcinomatosis, 
pulmonary embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension.  COVID-19 evaluation should be performed per institutional guidelines 
where relevant.  Management guidelines for pulmonary events are provided in Table 1. 
Table 1 
Management Guidelines for Pulmonary Events, Including 
Pneumonitis 
Event 
Management 
Pulmonary 
event, Grade 1  
 Continue atezolizumab and monitor closely. 
 Re-evaluate on serial imaging. 
 Consider patient referral to pulmonary specialist. 
 For Grade 1 pneumonitis, consider withholding atezolizumab. 
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 based on the investigator's benefitrisk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  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.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator’s 
benefitrisk assessment and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 
d In case of pneumonitis, atezolizumab should not be resumed after permanent 
discontinuation. 


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Table 1 
Management Guidelines for Pulmonary Events, Including 
Pneumonitis (cont.) 
Event 
Management 
Pulmonary 
event, Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL with or without transbronchial 
biopsy. 
 Initiate treatment with 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 
the Medical Monitor. c, d 
 For recurrent events, or events with no improvement after 
4872 hours of corticosteroids, treat as a Grade 3 or 4 event. 
Pulmonary 
event, Grade 3 
or 4 
 Permanently discontinue atezolizumab and contact the 
Medical Monitor. c, d 
 Oral or IV broad-spectrum antibiotics should be administered in 
parallel to the immunosuppressive treatment. 
 Bronchoscopy or BAL with or without transbronchial biopsy is 
recommended. 
 Initiate treatment with 12 mg/kg/day IV methylprednisolone. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
BAL  bronchoscopic alveolar lavage. 
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 based on the investigator's benefitrisk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  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.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator’s 
benefitrisk assessment and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 
d In case of pneumonitis, atezolizumab should not be resumed after permanent 
discontinuation.  
 


Appendix 12: Risks Associated with Atezolizumab and Guidelines for Management of 
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HEPATIC EVENTS 
Eligible patients must have adequate liver function, as manifested by measurements of 
total bilirubin and hepatic transaminases, and liver function will be monitored throughout 
study treatment.  Management guidelines for hepatic events are provided in Table 2. 
Patients with right upper quadrant abdominal pain and/or unexplained nausea or 
vomiting should have liver function tests (LFTs) performed immediately and reviewed 
before administration of the next dose of study drug. 
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate. 
Table 2 
Management Guidelines for Hepatic Events 
Event 
Management 
Hepatic event, 
Grade 1 
 Continue atezolizumab. 
 Monitor LFTs until values resolve to within normal limits.  
Hepatic event, 
Grade 2 
All events: 
 Monitor LFTs more frequently until return to baseline values.  
Events of   5 days’ duration: 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact the 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 based on the investigator’s benefitrisk assessment and in alignment with 
the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to 
 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.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator’s 
benefitrisk assessment and documented by the investigator.  The Medical 
Monitor is available to advise as needed. 


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Table 2 
Management Guidelines for Hepatic Events (cont.)  
Event 
Management 
Hepatic event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab and contact the 
Medical Monitor. c 
 Consider patient referral to gastrointestinal specialist for 
evaluation and liver biopsy to establish etiology of hepatic 
injury. 
 Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
LFT  liver function 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 based on the investigator's benefitrisk assessment and in alignment with 
the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to 
 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.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator’s 
benefitrisk assessment and documented by the investigator.  The Medical 
Monitor is available to advise as needed.  
 
GASTROINTESTINAL EVENTS 
Management guidelines for diarrhea or colitis are provided in Table 3. 
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies.  For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute-phase reactants (e.g., increased C-reactive protein, 
platelet count, or bandemia):  Perform sigmoidoscopy (or colonoscopy, if appropriate) 
with colonic biopsy, with three to five specimens for standard paraffin block to check for 
inflammation and lymphocytic infiltrates to confirm colitis diagnosis. 
 
 


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Table 3 
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) 
Event 
Management 
Diarrhea or 
colitis, Grade 1 
 Continue atezolizumab. 
 Initiate symptomatic treatment. 
 Endoscopy is recommended if symptoms persist for  7 days. 
 Monitor closely. 
Diarrhea or 
colitis, Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Initiate symptomatic treatment. 
 If strong clinical suspicion for immune-mediated colitis, start 
empiric IV steroids while waiting for definitive diagnosis. 
 Patient referral to GI specialist is recommended. 
 For recurrent events or events that persist  5 days, initiate treatment 
with 12 mg/kg/day oral prednisone or equivalent.  If the event does 
not improve within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact the 
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 
based on the investigator’s benefitrisk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  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.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as 
needed. 


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Table 3 
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) (cont.) 
Event 
Management 
Diarrhea or 
colitis, Grade 3 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to GI specialist for evaluation and confirmatory biopsy. 
 Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.  If event does not improve within 
48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact the 
Medical Monitor. c 
Diarrhea or 
colitis, Grade 4 
 Permanently discontinue atezolizumab and contact the 
Medical Monitor. c 
 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 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 
based on the investigator’s benefitrisk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  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.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as 
needed.  
 
ENDOCRINE EVENTS 
Management guidelines for endocrine events are provided in Table 4. 


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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. 
Table 4 
Management Guidelines for Endocrine Events 
Event 
Management 
Grade 1 
hypothyroidism 
 Continue atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH closely. 
Grade 2 
hypothyroidism 
 Consider withholding atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH closely. 
 Consider patient referral to endocrinologist. 
 Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
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 based on the investigator’s benefitrisk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  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-related event.  The decision to 
re-challenege patients with atezolizumab should be based on the investigator’s 
benefitrisk assessment and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 
 
 


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Table 4 
Management Guidelines for Endocrine Events (cont.) 
Event 
Management 
Grade 3 and 4 
hypothyroidism 
 Withhold atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH closely. 
 Refer to an endocrinologist. 
 Admit patient to the hospital for developing myxedema 
(bradycardia, hypothermia, and altered mental status). 
 Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
 Permanently discontinue atezolizumab and contact the 
Medical Monitor for life-threatening immune-mediated 
hypothyroidism. c 
Grade 1 
hyperthyroidism 
TSH  0.1 mU/L and  0.5 mU/L: 
 Continue atezolizumab. 
 Monitor TSH every 4 weeks. 
 Consider patient referral to endocrinologist. 
TSH  0.1 mU/L: 
 Follow guidelines for Grade 2 hyperthyroidism. 
 Consider patient referral to endocrinologist. 
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 based on the 
investigator’s benefitrisk assessment and in alignment with the protocol requirements for 
the duration of treatment and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  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-related event.  The decision to re-challenege patients with 
atezolizumab should be based on the investigator’s benefitrisk assessment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
 
 


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Table 4 
Management Guidelines for Endocrine Events (cont.) 
Event 
Management 
Grade 2 
hyperthyroidism 
 Consider withholding atezolizumab. 
 Initiate treatment with anti-thyroid drug such as 
methimazole or carbimazole as needed. 
 Consider patient referral to endocrinologist. 
 Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
Grade 3 and 4 
hyperthyroidism 
 Withhold atezolizumab. 
 Initiate treatment with anti-thyroid drugs such as methimazole 
or carbimazole as needed. 
 Refer to an endocrinologist. 
 Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
 Permanently discontinue atezolizumab and contact the 
Medical Monitor for life-threatening immune-mediated 
hyperthyroidism. c 
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 based on the investigator’s benefitrisk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  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-related event.  The decision to 
re-challenege patients with atezolizumab should be based on the investigator’s 
benefitrisk assessment and documented by the investigator.  The Medical Monitor is 
available to advise as needed.  
 
 


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Table 4 
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 the Medical Monitor. c 
Hyperglycemia, 
Grade 1 or 2  
 Continue atezolizumab. 
 Investigate for diabetes.  If patient has Type 1 diabetes, treat 
as a Grade 3 event.  If patient does not have Type 1 
diabetes, treat as per institutional guidelines. 
 Monitor for glucose control. 
Hyperglycemia, 
Grade 3 or 4 
 Withhold atezolizumab. 
 Initiate treatment with insulin. 
 Evaluate for diabetic ketoacidosis and manage as per 
institutional guidelines. 
 Monitor for glucose control. 
 Resume atezolizumab when symptoms resolve and glucose 
levels are stable. 
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 the investigator’s benefitrisk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  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.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator’s 
benefitrisk assessment and documented by the investigator.  The Medical Monitor is 
available to advise as needed.  


Appendix 12: Risks Associated with Atezolizumab and Guidelines for Management of 
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Table 4 
Management Guidelines for Endocrine Events (cont.) 
Event 
Management 
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3  
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to endocrinologist. 
 Perform brain MRI (pituitary protocol). 
 Initiate treatment with 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 the Medical Monitor. c 
 For recurrent hypophysitis, treat as a Grade 4 event. 
Hypophysitis 
(pan-hypopituitarism), 
Grade 4  
 Permanently discontinue atezolizumab and contact the 
Medical Monitor. c 
 Refer patient to endocrinologist. 
 Perform brain MRI (pituitary protocol). 
 Initiate treatment with 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 based on the investigator’s benefitrisk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  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.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator’s 
benefitrisk assessment and documented by the investigator.  The Medical Monitor is 
available to advise as needed.  
 


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OCULAR EVENTS 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 5. 
Table 5 
Management Guidelines for Ocular Events 
Event 
Management 
Ocular event, 
Grade 1  
 Continue atezolizumab. 
 Patient referral to ophthalmologist is strongly recommended. 
 Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
 If symptoms persist, treat as a Grade 2 event. 
Ocular event, 
Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Patient referral to ophthalmologist is strongly recommended. 
 Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
the Medical Monitor. c 
Ocular event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab and contact 
Medical Monitor. c 
 Refer patient to ophthalmologist. 
 Initiate treatment with 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 
based on the investigator’s benefitrisk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to 
 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.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefitrisk 
assessment and documented by the investigator.  The Medical Monitor is available to 
advise as needed.  
 


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


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Pericardiocentesis should be considered for diagnostic or therapeutic purposes, if 
clinically indicated. 
Patients with signs and symptoms of pericarditis, pericardial effusion, or cardiac 
tamponade, in the absence of an identified alternate etiology, should be treated 
according to the guidelines in Table 6.  Withhold treatment with atezolizumab for 
Grade 1 pericarditis and conduct a detailed cardiac evaluation to determine the etiology 
and manage accordingly. 
Table 6 
Management Guidelines for Immune-Mediated Cardiac Events 
Event 
Management 
Immune-mediated 
myocarditis, 
Grades 24 
 
Immune-mediated 
pericardial disorders, 
Grades 24 
 Permanently discontinue atezolizumab and contact the 
Medical Monitor. 
 Refer patient to cardiologist. 
 Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, VAD, or 
pericardiocentesis as appropriate. 
 Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
ECMO  extracorporeal membrane oxygenation; VAD  ventricular assist device. 
 
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, 
antipyretic medications, and/or analgesics (e.g., acetaminophen) for subsequent 
infusions.  Metamizole (dipyrone) is prohibited in treating atezolizumab-associated IRRs 
because of its potential for causing agranulocytosis. 
IRRs are known to occur with the administration of monoclonal antibodies and have 
been reported with atezolizumab.  These reactions, which are thought to be due to 
release of cytokines and/or other chemical mediators, occur within 24 hours of 
atezolizumab administration and are generally mild to moderate in severity. 
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T cells and/or 


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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 
(Riegler 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, including atezolizumab 
(Rotz et al. 2017; Adashek and Feldman 2019). 
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 during Cycle 1 are provided 
in Table 7. 
Severe COVID-19 appears to be associated with a CRS involving the inflammatory 
cytokines interleukin (IL)-6, IL-10, IL-2, and IFN- (Merad and Martin 2020).  If a patient 
develops suspected CRS during the study, a differential diagnosis should include 
COVID-19, which should be confirmed or refuted through assessment of exposure 
history, appropriate laboratory testing, and clinical or radiologic evaluations per 
investigator’s judgment.  If a diagnosis of COVID-19 is confirmed, the disease should be 
managed as per local or institutional guidelines. 
Table 7 
Management Guidelines for Infusion-Related Reactions and 
Cytokine Release Syndrome 
Event 
Management 
Grade 1a 
Fever b with or 
without 
constitutional 
symptoms  
 Immediately interrupt infusion. 
 Upon symptom resolution, wait for 30 minutes and then restart 
infusion at half the rate being given at the time of event onset. 
 If the infusion is tolerated at the reduced rate for 30 minutes, the 
infusion rate may be increased to the original rate. 
 If symptoms recur, discontinue infusion of this dose. 
 Administer symptomatic treatment, c including maintenance of 
IV fluids for hydration. 
 In case of rapid decline or prolonged CRS ( 2 days) or in patients 
with significant symptoms and/or comorbidities, consider 
managing as per Grade 2. 
 For subsequent infusions, consider administration of oral 
premedication with antihistamines, antipyretic medications, and/or 
analgesics, and monitor closely for IRRs and/or CRS. 
 
 


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Table 7 
Management Guidelines for Infusion-Related Reactions and 
Cytokine Release Syndrome (cont.) 
Event 
Management 
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. 
 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. 
 Consider anti-cytokine therapy. 
 Consider hospitalization until complete resolution of symptoms.  
If no improvement within 24 hours, manage as per Grade 3, that 
is, hospitalize patient (monitoring in the ICU is recommended), 
permanently discontinue atezolizumab, and contact the 
Medical Monitor. 
 If symptoms resolve to Grade 1 or better for 3 consecutive days, 
the next dose of atezolizumab may be administered. 
 For subsequent infusions, consider administration of oral 
premedication with antihistamines, antipyretic medications, and/or 
analgesics and monitor closely for IRRs and/or CRS. 
 If symptoms do not resolve to Grade 1 or better for 3 consecutive 
days, contact the Medical Monitor. 


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


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


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Table 8 
Management Guidelines for Pancreatic Events, Including 
Pancreatitis 
Event 
Management 
Amylase and/or lipase 
elevation, Grade 2 
Amylase and/or lipase  1.52.0  ULN: 
 Continue atezolizumab. 
 Monitor amylase and lipase weekly. 
 For prolonged elevation (e.g.,  3 weeks), consider treatment 
with 10 mg/day oral prednisone or equivalent. 
Asymptomatic with amylase and/or lipase  2.05.0  ULN: 
 Treat as a Grade 3 event. 
Amylase and/or lipase 
elevation, Grade 3 or 4 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to GI specialist. 
 Monitor amylase and lipase every other day. 
 If no improvement, consider treatment with 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 the Medical Monitor. c 
 For recurrent events, permanently discontinue atezolizumab 
and contact the 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 based on the 
investigator’s benefitrisk assessment and in alignment with the protocol requirements for 
the duration of treatment and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  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.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as 
needed.  


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Table 8 
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 the Medical Monitor. c 
 For recurrent events, permanently discontinue atezolizumab 
and contact the Medical Monitor. c 
Immune-mediated 
pancreatitis, Grade 4 
 Permanently discontinue atezolizumab and contact the 
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 based the 
investigator’s benefitrisk assessment and in alignment with the protocol requirements for 
the duration of treatment and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  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.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as 
needed.  
 


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DERMATOLOGIC EVENTS 
The majority of cases of rash reported with the use of atezolizumab were mild in severity 
and self-limited, with or without pruritus.  A dermatologist should evaluate persistent 
and/or severe rash or pruritus.  Although uncommon, cases of severe cutaneous 
adverse reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis 
have been reported with atezolizumab.  A biopsy should be considered unless 
contraindicated.  Management guidelines for dermatologic events are provided 
in Table 9. 
Table 9 
Management Guidelines for Dermatologic Events 
Event 
Management 
Dermatologic 
event, Grade 1  
 Continue atezolizumab. 
 Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines). 
Dermatologic 
event, Grade 2  
 Continue atezolizumab. 
 Consider patient referral to dermatologist for evaluation and, 
if indicated, biopsy. 
 Initiate treatment with topical corticosteroids. 
 Consider treatment with higher-potency topical corticosteroids if 
event does not improve. 
 If unresponsive to topical corticosteroids, consider oral 
prednisone 0.5 mg/kg/day. 
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 based on the investigator’s benefitrisk assessment and in alignment with 
the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to 
 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.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator’s 
benefitrisk assessment and documented by the investigator.  The Medical 
Monitor is available to advise as needed. 
 
 
 


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Table 9 
Management Guidelines for Dermatologic Events (cont.) 
Event 
Management 
Dermatologic 
event, Grade 3  
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to dermatologist for evaluation and, if indicated, 
biopsy. 
 Initiate treatment with 10 mg/day oral prednisone or equivalent, 
increasing dose to 12 mg/kg/day if event does not improve 
within 4872 hours. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact the Medical Monitor. c 
Dermatologic 
event, Grade 4 
 Permanently discontinue atezolizumab and contact the 
Medical Monitor. c 
Stevens-Johnson 
syndrome or 
toxic epidermal 
necrolysis 
(any grade) 
Additional guidance for Stevens-Johnson syndrome or toxic 
epidermal necrolysis: 
 Withhold atezolizumab for suspected Stevens-Johnson 
syndrome or toxic epidermal necrolysis. 
 Confirm diagnosis by referring patient to a specialist 
(dermatologist, ophthalmologist, or urologist as relevant) for 
evaluation and, if indicated, biopsy. 
 Follow the applicable treatment and management guidelines 
above. 
 If Stevens-Johnson syndrome or toxic epidermal necrolysis is 
confirmed, permanently discontinue atezolizumab. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to  10 mg/day 
oral prednisone or equivalent.  The acceptable length of the extended period of time 
must be based on the investigator’s benefitrisk assessment and in alignment with 
the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to 
 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.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator’s 
benefitrisk assessment and documented by the investigator.  The Medical 
Monitor is available to advise as needed.  
 
NEUROLOGIC DISORDERS 
Patients may present with signs and symptoms of sensory and/or motor neuropathy.  
Diagnostic workup is essential for an accurate characterization to differentiate between 
alternative etiologies.  Management guidelines for neurologic disorders are provided in 
Table 10, with specific guidelines for myelitis provided in Table 11. 


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Table 10 Management Guidelines for Neurologic Disorders 
Event 
Management 
Immune-mediated 
neuropathy, 
Grade 1 
 Continue atezolizumab. 
 Investigate etiology. 
 Any cranial nerve disorder (including facial paresis) should be 
managed as per Grade 2 management guidelines below. 
Immune-mediated 
neuropathy, 
including facial 
paresis, Grade 2  
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Investigate etiology and refer patient to neurologist. 
 Initiate treatment as per institutional guidelines. 
 For general immune-mediated neuropathy: 
– 
If event resolves to Grade 1 or better, resume 
atezolizumab. b 
– 
If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact the Medical Monitor. c 
 For facial paresis: 
– 
If event resolves fully, resume atezolizumab. b 
– 
If event does not resolve fully while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact the Medical Monitor. c 
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 based on the investigator’s benefitrisk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to 
 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.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator’s 
benefitrisk assessment and documented by the investigator.  The Medical Monitor 
is available to advise as needed. 
 
 
 


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Table 10 Management Guidelines for Neurologic Disorders (cont.) 
Event 
Management 
Immune-mediated 
neuropathy, 
including facial 
paresis, 
Grade 3 or 4 
 Permanently discontinue atezolizumab and contact the 
Medical Monitor. c  
 Refer patient to neurologist. 
 Initiate treatment as per institutional guidelines. 
Myasthenia gravis 
and Guillain-Barré 
syndrome 
(any grade) 
 Permanently discontinue atezolizumab and contact the 
Medical Monitor. 
 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 based on the investigator’s benefitrisk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to 
 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.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator’s 
benefitrisk assessment and documented by the investigator.  The Medical Monitor 
is available to advise as needed.  
 


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Table 11 Management Guidelines for Immune-Mediated Myelitis 
Event 
Management 
Immune-mediated myelitis, 
Grade 1 
 
Continue atezolizumab unless symptoms worsen or do not 
improve. 
 
Investigate etiology and refer patient to a neurologist. 
Immune-mediated myelitis, 
Grade 2 
 
Permanently discontinue atezolizumab and contact the 
Medical Monitor. 
 
Investigate etiology and refer patient to a neurologist. 
 
Rule out infection. 
 
Initiate treatment with corticosteroids equivalent to 
1-2 mg/kg/day oral prednisone. 
Immune-mediated myelitis, 
Grade 3 or 4 
 
Permanently discontinue atezolizumab and contact the 
Medical Monitor. 
 
Refer patient to a neurologist. 
 
Initiate treatment as per institutional guidelines. 
 
IMMUNE-MEDIATED MENINGOENCEPHALITIS 
Immune-mediated meningoencephalitis should be suspected in any patient presenting 
with signs or symptoms suggestive of meningitis or encephalitis, including but not limited 
to headache, neck pain, confusion, seizure, motor or sensory dysfunction, and altered or 
depressed level of consciousness.  Encephalopathy from metabolic or electrolyte 
imbalances needs to be distinguished from potential meningoencephalitis resulting from 
infection (bacterial, viral, or fungal) or progression of malignancy, or secondary to a 
paraneoplastic process. 
All patients being considered for meningoencephalitis should be urgently evaluated with 
a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or 
edema.  If deemed safe by the treating physician, a lumbar puncture should be 
performed and a neurologist should be consulted. 
Patients with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in Table 12. 
 
 


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Table 12 Management Guidelines for Immune-Mediated 
Meningoencephalitis 
Event 
Management 
Immune-mediated 
meningoencephalitis, 
all grades 
 Permanently discontinue atezolizumab and contact the 
Medical Monitor. 
 Refer patient to neurologist. 
 Initiate treatment with 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. 
 
RENAL EVENTS 
Eligible patients must have adequate renal function.  Renal function, including serum 
creatinine, should be monitored throughout study treatment.  Patients with abnormal 
renal function should be evaluated and treated for other more common etiologies 
(including prerenal and postrenal causes, and concomitant medications such as 
non-steroidal anti-inflammatory drugs).  Refer the patient to a renal specialist if clinically 
indicated.  A renal biopsy may be required to enable a definitive diagnosis and 
appropriate treatment. 
Patients with signs and symptoms of nephritis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 13. 
 
 


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Table 13 Management Guidelines for Renal Events  
Event 
Management 
Renal event, 
Grade 1 
 Continue atezolizumab. 
 Monitor kidney function, including creatinine and urine protein, 
closely until values resolve to within normal limits or to baseline 
values. 
Renal event, 
Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to renal specialist. 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact the Medical Monitor. c 
Renal event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab and contact the 
Medical Monitor. c 
 Refer patient to renal specialist and consider renal biopsy. 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of  10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be based on the investigator’s benefitrisk assessment and in alignment 
with the protocol requirements for the duration of treatment and documented by 
the investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator’s 
benefitrisk assessment and documented by the investigator.  The Medical 
Monitor is available to advise as needed.  
 
IMMUNE-MEDIATED MYOSITIS 
Myositis or inflammatory myopathies are a group of disorders sharing the common 
feature of inflammatory muscle injury; dermatomyositis and polymyositis are among the 
most common disorders.  Initial diagnosis is based on clinical (muscle weakness, muscle 
pain, skin rash in dermatomyositis), biochemical (serum creatine kinase increase), and 


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imaging (electromyography/MRI) features, and is confirmed with a muscle biopsy.  
Patients with possible myositis should be referred to a rheumatologist or neurologist.  
Patients with possible myositis should be monitored for signs of myocarditis. 
Patients with signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 14. 
Table 14 Management Guidelines for Immune-Mediated Myositis 
Event 
Management 
Immune-mediated 
myositis, Grade 1 
 Continue atezolizumab. 
 Refer patient to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines. 
Immune-mediated 
myositis, Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset a 
and contact the Medical Monitor. 
 Refer patient to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines. 
 Consider treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 If corticosteroids are initiated and event does not improve 
within 48 hours after initiating corticosteroids, consider adding 
an immunosuppressive agent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact the Medical Monitor. c 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of  10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be based on the investigator’s benefitrisk assessment and in alignment 
with the protocol requirements for the duration of treatment and documented by 
the investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator’s 
benefitrisk assessment and documented by the investigator.  The Medical 
Monitor is available to advise as needed. 


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Table 14 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 the Medical Monitor. 
 Refer patient to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines. 
 Respiratory support may be required in more severe cases. 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone, or higher-dose bolus if 
patient is severely compromised (e.g., cardiac or respiratory 
symptoms, dysphagia, or weakness that severely limits 
mobility); convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact the Medical Monitor. c 
 For recurrent events, treat as a Grade 4 event.  Permanently 
discontinue atezolizumab and contact the Medical Monitor. c 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of  10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be based on the investigator’s benefitrisk assessment by the 
investigator and in alignment with the protocol requirements for the duration of 
treatment and documented by the investigator.  The Medical Monitor is available 
to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator’s 
benefitrisk assessment and documented by the investigator.  The Medical 
Monitor is available to advise as needed. 
 
 
 


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


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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) 
– 
Platelet count  100  109/L (100,000/L) 
– 
ANC  1.0  109/L (1000/L) 
 
Fasting triglycerides  2.992 mmol/L (265 mg/dL) and/or fibrinogen  1.5 g/L 
(150 mg/dL) 
 
Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
 
Low or absent natural killer cell activity 
 
Ferritin  500 mg/L (500 ng/mL) 
 
Soluble IL-2 receptor (soluble CD25) elevated  2 standard deviations above age-
adjusted laboratory-specific norms 
 
Patients with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should be 
classified as having MAS if the following criteria are met: 
 
Ferritin  684 mg/L (684 ng/mL) 
 
At least two of the following: 
– 
Platelet count  181  109/L (181,000/L) 
– 
AST  48 U/L 
– 
Triglycerides  1.761 mmol/L (156 mg/dL) 
– 
Fibrinogen  3.6 g/L (360 mg/dL) 
 
Patients with suspected HLH or MAS should be treated according to the guidelines 
in Table 15. 
 
 


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Table 15 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome 
Event 
Management 
Suspected HLH 
or MAS 
 Permanently discontinue atezolizumab and contact the 
Medical Monitor. 
 Consider patient referral to hematologist. 
 Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines. 
 Consider initiation of IV corticosteroids, an immunosuppressive 
agent, and/or anti-cytokine therapy. 
 If event does not respond to treatment within 24 hours, contact the 
Medical Monitor and initiate treatment as appropriate according to 
published guidelines (La Rosée 2015; Schram and Berliner 2015; 
La Rosée et al. 2019). 
 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. 
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology 
Am Soc Hematol Educ Protram 2015;1:1906. 
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of 
hemophagocytic lymphohistiocytosis in adults. Blood 2019;133:246577. 
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resource on the Internet]. 2014 [updated 
29 October 2018; cited: 17 May 2019]. Available from: 
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-
hemophagocytic-lymphohistiocytosis. 
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for 
monocytes and macrophages. Nat Rev Immunol 2020;20:35562. 
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation 
syndrome complicating systemic juvenile idiopathic arthritis: a European League 
Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology 
International Trials Organisation Collaborative Initiative. Ann Rheum Dis 
2016;75:4819. 


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Adverse Events Associated with Atezolizumab 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
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Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of 
cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin 
Risk Manag 2019;15:32335. 
Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient 
receiving PD-1-directed therapy. Pediatr Blood Cancer 2017;64:e26642. 
Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult 
patient. Blood 2015;125:290814. 
 


 
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Appendix 13  
Eastern Cooperative Oncology Group 
Scale of Performance Status 
Grade 
Performance Status 
0 
Fully active, able to carry on all pre-disease 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 house work, office work). 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities.  Up and about  50% of waking hours. 
3 
Capable of only limited selfcare, confined to bed or chair   50% of waking 
hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
 
REFERENCES 
Oken MM, Creech RH, Tormey DC, et al:  Toxicity and response criteria of the eastern 
cooperative oncology group. Am J Clin Oncol 1982;5:64955. 
 


 
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Appendix 14  
Guidelines for Management of Adverse Events Associated with 
Trastuzumab Emtansine 
Guidelines for managing specific adverse events are provided in the table below.  
For adverse events not listed in the table, the following guidance should be used:  for 
Grade 3 non-hematologic adverse events not adequately managed by standard medical 
intervention or for any Grade 4 non-hematologic adverse event, study treatment should 
be held until recovery to Grade  1.  A maximum dose delay of 42 days from the last 
administered dose of study drug will be allowed for recovery.  After appropriate recovery, 
trastuzumab emtansine may be resumed with one dose level reduction 
(e.g., trastuzumab emtansine reduced from 3.6 mg/kg to 3 mg/kg or from 3 mg/kg to 
2.4 mg/kg).  For patients who have an event while being treated with trastuzumab 
emtansine 2.4 mg/kg, trastuzumab emtansine will be discontinued.  The dose of 
trastuzumab emtansine, once reduced, may not be re-escalated. 
 


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Table 1 
Guidelines for Managing Specific Adverse Events 
 
Event 
Action to Be Taken 
Infusion reactions (caused by cytokine release)/Hypersensitivity (allergic reactions) 
Life threatening 
infusion-related reaction/ 
Hypersensitivity (allergic 
reaction) 
Stop infusion, study treatment permanently discontinued. 
Supportive care with oxygen, -agonists, antihistamines, antipyretics, or corticosteroids may be used, 
as appropriate, at the investigator's discretion. 
Patients should be monitored until complete resolution of symptoms. 
Infusion-related or clinically 
significant hypotension 
Stop infusion.  Administer supportive care with oxygen, -agonists, antihistamines, antipyretics, or 
corticosteroids, as appropriate, at the investigator’s discretion.  Monitor patients until complete resolution of 
symptoms.  May re-treat at investigator’s discretion.  In the event of a true hypersensitivity reaction (in which 
severity of reaction increases with subsequent infusions), trastuzumab emtansine treatment must be 
permanently discontinued. 
Infusion-related symptoms 
(e.g., chills, fever) 
Decrease infusion rate by 50% or interrupt infusion for patients who experience any other infusion-related 
symptoms (e.g., chills, fever). 
When symptoms have completely resolved, infusion may be restarted at  50% of prior rate and increased in 
50% increments every 30 minutes as tolerated.  Infusions may be restarted at the full rate at the next cycle, 
with appropriate monitoring. 
Supportive care with oxygen, -agonists, antihistamines, antipyretics, or corticosteroids may be used as 
appropriate at the investigator's discretion. 
Premedication with corticosteroids, antihistamines, and antipyretics may be used before subsequent infusions 
at the investigator’s discretion. 
Patients should be monitored until complete resolution of symptoms. 
Hematologic toxicity 
 
Grade  3 hematologic 
toxicity (other than 
thrombocytopenia) 
Withhold study treatment until recovery to Grade  1.  Weekly CBC assessments should be 
performed until recovery, or as medically indicated. 
A maximum dose delay of 42 days from the last administered dose to Grade  1 or baseline will be allowed; 
otherwise, patients must be discontinued from study treatment. 


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Table 1 
Guidelines for Managing Specific Adverse Events (cont.)  
Event 
Action to Be Taken 
Hematologic toxicity (cont.) 
 
Grade 2 or 3 
thrombocytopenia on day of 
scheduled treatment 
Assess platelet counts weekly or as medically indicated until recovery.  Hold trastuzumab emtansine 
treatment until Grade  1.  Resume treatment without dose reduction.  If a patient requires two delays due to 
thrombocytopenia, consider reducing dose by one level. 
Grade 4 thrombocytopenia 
at any time 
Assess platelet counts weekly or as medically indicated until recovery.  Hold trastuzumab emtansine until 
Grade  1, then resume with one dose level reduction (i.e., from 3.6 mg/kg to 3 mg/kg or from 3 mg/kg to 
2.4 mg/kg) in subsequent cycles.  If event occurs with 2.4 mg/kg dose, discontinue study treatment. 
Hepatotoxicity 
 
ALT 
For a Grade 2 or 3 ALT increase that occurs on the laboratory evaluation for cycle Day 1 or the planned day 
of dosing, hold trastuzumab emtansine until ALT recovers to Grade  1.  Resume with dose reduction by 
one level for Grade 2 or 3 elevations.  Grade 2 or 3 ALT elevations that are noted between cycles do not 
require dose delay or reduction unless ALT remains elevated (Grade  2) at the time of planned dosing. 
 
For Grade 4 ALT increase, discontinue trastuzumab emtansine.  Repeat laboratory evaluation (within 
24 hours) may be performed to exclude laboratory error prior to discontinuing study treatment. 
AST 
For Grade 2 AST increase on the laboratory evaluation for cycle Day 1 or the planned day of dosing, hold 
trastuzumab emtansine until AST recovers to Grade  1.  Resume without dose reduction when recovered. 
 
For Grade 3 AST increase on the laboratory evaluation for cycle Day 1 or the planned day of dosing, hold 
trastuzumab emtansine until AST recovers to Grade  1.  Resume with dose reduction by one level when 
recovered. 
 
For Grade 4 AST increase, discontinue trastuzumab emtansine.  Repeat laboratory evaluation (within 
24 hours) may be performed to exclude laboratory error prior to discontinuing study treatment. 
 
 


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Table 1 
Guidelines for Managing Specific Adverse Events (cont.) 
Event 
Action to Be Taken 
Hepatotoxicity (cont.) 
 
TBILI  
For TBILI  1.0  ULN to  2.0  ULN that occurs on the laboratory evaluation for cycle Day 1 or the day of 
planned dosing, hold trastuzumab emtansine until TBILI recovers to  1.0  ULN (or direct bilirubin recovers 
to  1.0  ULN for patients with Gilbert’s syndrome).  For TBILI elevations  1.0  ULN to  2.0  ULN, 
resume when recovered with a one level dose reduction. 
 
For TBILI  2  ULN at any time (or direct bilirubin  2  ULN for Gilbert’s syndrome), discontinue 
trastuzumab emtansine and report the event as an serious adverse event (if applicable) or non-serious 
expedited adverse event (if applicable). 
 
Assess AST, ALT, and TBILI weekly or as medically indicated until recovery.  Allow a maximum dose delay 
of 42 days from the last administered dose to recovery as described above or otherwise discontinue study 
treatment. 
Nodular Regenerative Hyperplasia 
For any clinical signs of liver dysfunction, discontinue trastuzumab emtansine and have the patient 
evaluated by a hepatologist.  If there are signs of portal hypertension (e.g., ascites and/or varices) and a 
cirrhosis-like pattern is seen on CT scan of the liver, the possibility of NRH should be considered.  
Trastuzumab emtansine should be discontinued in the event of a diagnosis of NRH. 
Neurotoxicity 
 
Grade  3 peripheral 
neuropathy 
Discontinue trastuzumab emtansine if event does not resolve to Grade  2 or baseline value within 42 days 
after the last administered dose. 
Cardiotoxicity 
 
LVSD 
See Figure 3 for the algorithm for continuation and discontinuation of study treatment on the basis of 
asymptomatic LVEF assessment. 
Grade 3 or 4 LVSD or 
Grade 3 or 4 heart failure 
Discontinue study treatment. 
 


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Table 1 
Guidelines for Managing Specific Adverse Events (cont.)  
Event 
Action to Be Taken 
Cardiotoxicity (cont.) 
 
Grade 2 heart failure 
accompanied by LVEF  45% 
Discontinue study treatment. 
Interstitial lung disease 
 
Grade 3 or 4 pneumonitis 
Discontinue study treatment regardless of attribution. 
Grade 1 or 2 pneumonitis 
Discontinue study treatment if not radiotherapy-related.  For symptomatic (Grade 2) radiotherapy-related 
pneumonitis, discontinue if not resolving with standard treatment (e.g., steroids).  Relationship to 
radiotherapy should be determined on the basis of timing and location of radiographic abnormalities 
relative to the radiation treatment. 
Upon diagnosis of drug-related ILD/pneumonitis, trastuzumab emtansine treatment has to be permanently 
discontinued. 
 
Patients discontinued from trastuzumab emtansine for pneumonitis may not switch study treatment to 
trastuzumab and pertuzumab and have to discontinue all study treatment. 
Radiotherapy-related skin toxicity 
 
Grade 3 or 4 
Do not administer study treatment until recovery to Grade  1. 
CBC  complete blood count; CT  computed tomography; ILD  interstitial lung disease; LVEF  left ventricular ejection fraction; LVSD  left 
ventricular systolic dysfunction; NRH  nodular regenerative hyperplasia; ULN  upper limit of normal. 
 


 
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Appendix 15  
Guidelines for Management of Adverse Events that are Potential 
Overlapping Toxicities Associated with Trastuzumab Emtansine 
in Combination with Atezolizumab 
The following adverse events are potential overlapping toxicities associated with 
combination use of trastuzumab emtansine and atezolizumab:  pulmonary and hepatic 
events.  If trastuzumab emtansine is held for toxicity, then atezolizumab/placebo must 
also be held.  If trastuzumab emtansine is discontinued for toxicity, 
atezolizumab/placebo must not be continued as single agent and must either be 
discontinued also or may be continued in combination with trastuzumab and pertuzumab 
to complete a total of 1 year of HER2-targeted therapy if the investigator considers the 
toxicity to be related to trastuzumab emtansine without compromising the continued use 
of trastuzumab.  If treatment with atezolizumab/placebo had been discontinued prior to 
the discontinuation of trastuzumab emtansine or if both treatments are discontinued 
concurrently, it is at the investigator’s discretion to switch treatment to trastuzumab and 
pertuzumab if the toxicity is not considered related to the trastuzumab component of 
trastuzumab emtansine. 
PULMONARY EVENTS 
Pulmonary events may present as new or worsening cough, chest pain, fever, dyspnea, 
fatigue, hypoxia, pneumonitis, and pulmonary infiltrates and have primarily been 
observed in patients with underlying nonsmall cell lung cancer. 
Mild to moderate events of pneumonitis have been reported with atezolizumab.  
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia/infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension: 
 
Measurement of oxygen saturation (i.e., arterial blood gas) 
 
High-resolution CT scan of the chest 
 
Bronchoscopy with bronchoalveolar lavage and biopsy 
 
Pulmonary function tests (diffusion capacity of the lung for carbon monoxide) 
 
Pulmonary function testing with a pulmonary embolism protocol 
 
Patients will be assessed for pulmonary signs and symptoms throughout the study.  
COVID-19 evaluation should be performed per institutional guidelines where relevant.  
See Table 1 for management guidelines for pulmonary events and pneumonitis. 
 
 


Appendix 15:  Guidelines for Management of Adverse Events that are Potential Overlapping 
Toxicities Associated with Trastuzumab Emtansine in Combination with 
Atezolizumab 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
228/Protocol BO40747, Version 6 
Table 1 
Management Guidelines for Interstitial Lung Disease and 
Pneumonitis 
Severity 
Atezolizumab/Placebo 
Trastuzumab Emtansine 
Grade 1 or 2 
Grade 2:  withhold treatment and 
initiate corticosteroids if 
radiotherapy-related.  If not 
radiotherapy-related, discontinue all 
study treatment. 
Discontinue all study treatment if not 
radiotherapy-related.  For 
symptomatic (Grade 2) 
radiotherapy-related pneumonitis, 
discontinue if not resolving with 
standard treatment (e.g., steroids). 
Grade 3 or 4 
Discontinue atezolizumab/placebo 
treatment. 
Discontinue trastuzumab emtansine 
treatment. 
Note:  Patients discontinued from trastuzumab emtansine for pneumonitis may not switch study 
treatment to trastuzumab and pertuzumab and have to discontinue all study treatment. 
 
HEPATIC EVENTS 
Eligible patients must have adequate liver function, as manifested by measurements of 
total bilirubin and hepatic transaminases.  Liver function will be monitored throughout 
study treatment. 
While in this study, patients who present 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. 
If outcome of LFTs is worsening, concurrent medications, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate.  Imaging of 
the liver, gall bladder, and biliary tree should be performed to rule out neoplastic or other 
causes for worsening outcome of LFTs.  Anti-nuclear antibody, perinuclear 
anti-neutrophil cytoplasmic antibody, anti-liver kidney microsomal antibodies, and 
antismooth muscle antibody tests should be performed if an autoimmune etiology 
is considered.  See Table 2 for management guidelines for increased transaminases 
(AST/ALT) and hepatic events.  See Table 3 for dose modifications of trastuzumab 
emtansine for hyperbilirubinemia.  Note:  No dose modification for atezolizumab/placebo 
is indicated on the basis of hyperbilirubinemia alone. 
 
 


Appendix 15:  Guidelines for Management of Adverse Events that are Potential Overlapping 
Toxicities Associated with Trastuzumab Emtansine in Combination with 
Atezolizumab 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
229/Protocol BO40747, Version 6 
Table 2 
Management Guidelines for Increased Transaminases (AST/ALT) 
and Hepatic Events 
Severity 
Atezolizumab/Placebo 
Trastuzumab Emtansine 
ALT or AST 
increase that meets 
Hy's Law criteria:  
ALT or AST 
 3  ULN in 
combination with 
TBILI  2  ULN or 
clinical jaundice 
Discontinue atezolizumab/placebo 
treatment. 
Discontinue trastuzumab 
emtansine treatment. 
ALT/AST Grade 2 
( 3.05.0  ULN)  
Withhold atezolizumab/placebo dose. 
If persists  57 days:  Consider 
starting 12 mg/kg/day prednisone or 
equivalent per day; when recovered to 
Grade  1, taper steroids over 
 1 month. 
Resume therapy when systemic 
steroid dose is  10mg oral prednisone 
equivalent per day and when 
recovered to Grade  1 within 
12 weeks. 
Permanently discontinue 
atezolizumab/placebo and contact the 
Medical Monitor if event does not 
resolve to Grade  1 within 12 weeks. 
Withhold trastuzumab 
emtansine dose until 
recovery to Grade  1.  
Resume with dose reduction 
by one level when recovered 
from Grade 2 ALT elevation.  
No dose reduction needed 
after recovery from Grade 2 
AST elevation. 
ALT/AST Grade 3 
( 5.020.0  ULN) 
Discontinue atezolizumab/placebo 
treatment. 
Consider patient referral to 
gastrointestinal specialist for 
evaluation and liver biopsy to 
establish etiology of hepatic injury if 
necessary. 
Start 60 mg prednisone or equivalent 
per day. 
If LFT results do not decrease within 
48 hours after initiation of systemic 
steroids, addition of an alternative 
immunosuppressive agent 
(e.g., mycophenolate or TNF- 
antagonist) may be considered. 
Taper steroids over  1 month, when 
symptoms improve to Grade 0 or 
Grade 1. 
Withhold trastuzumab 
emtansine dose until 
recovery to Grade  1.  
Resume with dose reduction 
by one level when 
recovered. 
 


Appendix 15:  Guidelines for Management of Adverse Events that are Potential Overlapping 
Toxicities Associated with Trastuzumab Emtansine in Combination with 
Atezolizumab 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
230/Protocol BO40747, Version 6 
Table 2 
Management Guidelines for Increased Transaminases (AST/ALT) 
and Hepatic Events (cont.)  
Severity 
Atezolizumab/Placebo 
Trastuzumab Emtansine 
ALT/AST Grade 4 
( 20.0  ULN) 
Discontinue atezolizumab/placebo 
treatment. 
Consider patient referral to 
gastrointestinal specialist for 
evaluation and liver biopsy to 
establish etiology of hepatic injury if 
necessary. 
Start 60 mg prednisone or equivalent 
per day. 
If LFT results do not decrease within 
48 hours after initiation of systemic 
steroids, addition of an alternative 
immunosuppressive agent 
(e.g., mycophenolate or TNF- 
antagonist) may be considered. 
Taper steroids over  1 month, when 
symptoms improve to Grade 0 or 
Grade 1. 
Discontinue trastuzumab 
emtansine treatment.  
Laboratory tests may be 
repeated (within 24 hours) to 
exclude laboratory error prior 
to discontinuing trastuzumab 
emtansine. 
NRH 
If there are signs of 
portal hypertension 
(e.g., ascites and/or 
varices) and/or a 
cirrhosis-like pattern 
is seen on a 
CT scan of the liver, 
the possibility of 
NRH should be 
considered. 
Discontinue atezolizumab/placebo 
treatment.  
For any clinical signs of liver 
dysfunction, discontinue 
trastuzumab emtansine and 
have the patient evaluated 
by a hepatologist.  If there 
are signs of portal 
hypertension (e.g., ascites 
and/or varices) and a 
cirrhosis-like pattern is seen 
on CT scan of the liver, the 
possibility of NRH should be 
considered.  Trastuzumab 
emtansine should be 
discontinued in the event of 
a diagnosis of NRH. 
CT  computed tomography; GI  gastrointestinal; LFT  liver function test; NRH  Nodular 
Regenerative Hyperplasia; TNF  tumor necrosis factor; ULN  upper limit of normal.  
 


Appendix 15:  Guidelines for Management of Adverse Events that are Potential Overlapping 
Toxicities Associated with Trastuzumab Emtansine in Combination with 
Atezolizumab 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
231/Protocol BO40747, Version 6 
Table 3 
Trastuzumab Emtansine Dose Modification Guidelines for 
Hyperbilirubinemia 
Event 
Action to be Taken 
TBILI  
For TBILI  1.0  ULN to  2.0  ULN that occurs on the laboratory evaluation for 
cycle Day 1 or the day of planned dosing, hold trastuzumab emtansine until 
TBILI recovers to  1.0  ULN (or direct bilirubin recovers to  1.0  ULN for 
patients with Gilbert’s syndrome).  For TBILI elevations  1.0  ULN 
to  2.0  ULN, resume when recovered with a one level dose reduction. 
For TBILI  2  ULN at any time (or direct bilirubin  2  ULN for Gilbert’s 
syndrome), discontinue trastuzumab emtansine and report the event as an 
serious adverse event (if applicable) or non-serious expedited adverse event 
(if applicable). 
Assess AST, ALT, and TBILI weekly or as medically indicated until recovery.  
Allow a maximum dose delay of 42 days from the last administered dose to 
recovery as described above or otherwise discontinue study treatment. 
ULN  upper limit of normal. 
 


Signature Page for Protocol - BO40747 - TECENTRIQ - v6 - Global/Core - Published
System identifier: RIM-CLIN-469025
Approval Task
Company Signatory
23-Feb-2023 17:21:48 GMT+0000

SAP_001.pdf: 
Official Title: 
A Phase III, Randomized, Double-Blind, Placebo Controlled Clinical 
Trial To Evaluate The Efficacy And Safety Of Atezolizumab Or 
Placebo In Combination With Neoadjuvant Doxorubicin + 
Cyclophosphamide Followed By Paclitaxel + Trastuzumab + 
Pertuzumab In Early Her2-Positive Breast Cancer 
NCT Number: 
NCT03726879 
Document Date: 
SAP Version 2: 20 November 2020 


STATISTICAL ANALYSIS PLAN APPROVAL
CONFIDENTIAL
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd.
Atezolizumab—F. Hoffmann-La Roche Ltd
STATISTICAL ANALYSIS PLAN
TITLE:
A PHASE III, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED CLINICAL TRIAL TO EVALUATE THE 
EFFICACY AND SAFETY OF ATEZOLIZUMAB OR 
PLACEBO IN COMBINATION WITH NEOADJUVANT
DOXORUBICIN CYCLOPHOSPHAMIDE FOLLOWED BY 
PACLITAXEL TRASTUZUMAB PERTUZUMAB IN EARLY 
HER2-POSITIVE BREAST CANCER
PROTOCOL NUMBER:
BO40747
STUDY DRUG:
Atezolizumab
VERSION NUMBER:
2
IND NUMBER:
123277
EUDRACT NUMBER:
2018-001881-40
SPONSOR:
F. Hoffmann-La Roche Ltd
PLAN PREPARED BY:
DATE FINAL:
Version 1: 19 November 2019
DATE AMENDED:
Version 2: See electronic date stamp below.
Statistical Analysis Plan BO40747
Date and Time(UTC)        Reason for Signing                              Name
20-Nov-2020 13:32:17
Company Signatory


Atezolizumab—F. Hoffmann-La Roche Ltd
2/Statistical Analysis Plan BO40747
STATISTICAL ANALYSIS PLAN AMENDMENT
RATIONALE
German(BA) Disease-free survival including contralateral or ipsilateral ductal carcinoma 
in situ (DCIS) and second primary non-breast invasive cancer (with the exception of non-
melanoma skin cancers and in situ carcinomas) was added as exploratory efficacy 
endpoint.
Minor changes have been made to the covariates of the subgroup analyses.  
Additional minor changes have been made to improve clarity and consistency.


Atezolizumab—F. Hoffmann-La Roche Ltd
3/Statistical Analysis Plan BO40747
TABLE OF CONTENTS
1.
BACKGROUND ............................................................................................ 6
2.
STUDY DESIGN........................................................................................... 6
2.1
Protocol Synopsis.................................................................... 8
2.2
Endpoints................................................................................. 8
2.2.1
Primary Efficacy Endpoint........................................................ 8
2.2.2
Secondary Efficacy Endpoints................................................. 8
2.2.3
Exploratory Efficacy Endpoints................................................ 9
2.2.4
Pharmacokinetic Efficacy Endpoints...................................... 10
2.2.5
Safety Endpoints ................................................................... 10
2.2.6
Immunogenicity Endpoints..................................................... 10
2.2.7
Biomarker Endpoints ............................................................. 10
2.3
Determination of Sample Size ............................................... 11
2.4
Analysis Timing ..................................................................... 11
3.
STUDY CONDUCT..................................................................................... 11
3.1
Randomization....................................................................... 11
3.2
Independent Review Facility.................................................. 12
3.3
Data Monitoring ..................................................................... 12
4.
STATISTICAL METHODS .......................................................................... 12
4.1
Analysis Populations ............................................................. 12
4.1.1
Randomized Population......................................................... 12
4.1.1.1
Intention-to-Treat (ITT) Population ........................................ 13
4.1.1.2
PD-L1 Positive Population..................................................... 13
4.1.1.3
DFS-evaluable Population..................................................... 13
4.1.1.4
PD-L1 positiveDFS-evaluable Population............................ 13
4.1.1.5
PRO-evaluable Population .................................................... 13
4.1.2
Pharmacokinetic-Evaluable Population ................................. 13
4.1.3
Safety Population .................................................................. 13
4.2
Analysis of Study Conduct..................................................... 13
4.3
Analysis of Treatment Group Comparability .......................... 14
4.4
Efficacy Analysis.................................................................... 14
4.4.1
Primary Efficacy Endpoint...................................................... 14


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4/Statistical Analysis Plan BO40747
4.4.2
Secondary Efficacy Endpoints............................................... 15
4.4.2.1
pCR in Subgroups ................................................................. 15
4.4.2.2
Event Free Survival ............................................................... 15
4.4.2.3
Disease Free Survival............................................................ 15
4.4.2.4
Overall Survival ..................................................................... 16
4.4.2.5
Patient Reported Outcomes of Role and Physical 
Function and GHS/HrQOL: EORTC Data.............................. 16
4.4.3
Exploratory Efficacy Endpoints.............................................. 17
4.4.3.1
Patient Reported Outcomes of 
Disease/Treatment-Related Symptoms, and 
Emotional and Social Function: EORTC Data ....................... 17
4.4.3.2
Patient-Reported Outcome of Treatment Burden:  
FACT-G, GP5 Single-Item Data ............................................ 17
4.4.3.3
Health Economic EQ-5D-5L Data.......................................... 17
4.4.4
Sensitivity Analyses............................................................... 17
4.4.5
Subgroup Analyses ............................................................... 17
4.5
Pharmacokinetic and Pharmacodynamic 
Analyses................................................................................ 18
4.6
Safety Analyses..................................................................... 18
4.6.1
Exposure of Study Medication............................................... 18
4.6.2
Adverse Events ..................................................................... 18
4.6.3
Laboratory Data..................................................................... 19
4.6.4
Vital Signs.............................................................................. 19
4.7
immunogenicity analyses....................................................... 19
4.8
Biomarker analyses ............................................................... 20
4.9
Missing Data.......................................................................... 20
4.10
Interim Analyses .................................................................... 21
4.10.1
Planned Interim analysis........................................................ 21
4.10.2
Optional Interim Analysis....................................................... 21
4.11
China Subpopulation Analyses.............................................. 21
5.
REFERENCES ........................................................................................... 23


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5/Statistical Analysis Plan BO40747
LIST OF FIGURES
Figure 1   Study Schema...................................................................................... 7
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ...................................................................... 24
Appendix 2
Schedule of Assessments.......................................................... 39


Atezolizumab—F. Hoffmann-La Roche Ltd
6/Statistical Analysis Plan BO40747
1.
BACKGROUND
This Statistical Analysis Plan (SAP) describes the analyses planned to be performed for 
Study BO40747 (IMpassion050). In relation to the China extension patients, a high-level 
overview of plans for the China subgroup analyses is provided.
2.
STUDY DESIGN
Study BO40747 (IMpassion050) is a global Phase III, randomized, double-blind, 
placebo-controlled study designed to evaluate the efficacy, safety, and pharmacokinetics 
of atezolizumab compared with placebo when given in combination with neoadjuvant 
ddAC-PacHP in patients eligible for surgery with early HER2-positive breast cancer at 
high risk of recurrence (T24, N13, M0).
Patients who have histologically confirmed invasive HER2-positive breast cancer with a 
primary tumor size2 cm by radiologic measurement and who are node positive (node-
positivity pathologically confirmed by fine-needle aspiration or core-needle biopsy) are 
eligible.  Axillary surgery (including incisional and/or excisional biopsy) prior to 
neoadjuvant treatment is prohibited.  HER2 positivity will be confirmed by a central 
laboratory.  Patients whose tumor tissue is not evaluable for PD-L1 testing by the central 
laboratory will not be eligible.  
Figure 1 presents an overview of the study design. 


Atezolizumab—F. Hoffmann-La Roche Ltd
7/Statistical Analysis Plan BO40747
Figure 1   Study Schema


Atezolizumab—F. Hoffmann-La Roche Ltd
8/Statistical Analysis Plan BO40747
Approximately 453 patients will be randomized in a 1:1 ratio to receive either 
atezolizumab or placebo administered IV in combination with the current standard-of-
care therapy for early HER2-positive breast cancer.  Treatment assignment will not be 
unblinded following pCR evaluation. Patients will remain assigned to their initial 
randomized treatment (atezolizumab or placebo) during the adjuvant phase, irrespective 
of their pCR result.
Randomization will be stratified by the following factors:

Stage at diagnosis (T2, T34) as determined by the American Joint Committee on 
Cancer (AJCC) staging system, 8th edition (specifically according to the Anatomic 
Stage Group rules)

Hormone receptor status (ER positive and/or PgR positive; ER negative and 
PgR negative)
Patients with hormone receptorpositive disease will be capped at 50%.

PD-L1 status (IC 0; IC 1/2/3)
The co-primary efficacy objective for this study is to evaluate the efficacy of 
atezolizumabddAC-PacHP compared with placebo ddAC-PacHP in the EBC setting
in the PD-L1-positive (IC 1/2/3) and the ITT population on the basis of pathologic 
complete response (pCR), defined as the absence of residual invasive cancer on 
hematoxylin and eosin evaluation of the complete resected breast specimen and all 
sampled regional lymph nodes following completion of neoadjuvant systemic therapy 
(NAST) (i.e., ypT0/is ypN0 in the current AJCC staging system, 8th edition).
2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis is in Appendix 1.  For additional details, see the Schedule of 
Assessments in Appendix 2.
2.2
ENDPOINTS
2.2.1
Primary Efficacy Endpoint
The co-primary efficacy endpoint of the study is pathological complete response rate 
(pCR) in the PD-L1-positive (IC 1/2/3) and the ITT populations, defined as the absence 
of residual invasive cancer on hematoxylin and eosin evaluation of the complete 
resected breast specimen and all sampled regional lymph nodes following completion of 
neoadjuvant systemic therapy (NAST) (i.e., ypT0/is ypN0 in the current AJCC staging 
system, 8th edition).
2.2.2
Secondary Efficacy Endpoints

pCR (ypT0/is ypN0) in the PD-L1-negative (IC 0) population

pCR (ypT0/is ypN0) based upon hormone receptor status (estrogen receptor 
[ER]/progesterone receptor [PgR] positive or ER/PgR negative)


Atezolizumab—F. Hoffmann-La Roche Ltd
9/Statistical Analysis Plan BO40747

Event-free survival (EFS), defined as the time from randomization to the first 
documented disease recurrence, unequivocal tumor progression determined by the 
treating investigator, or death from any cause, whichever occurs first, in all patients 
and based upon hormone receptor status (ER/PgR positive or ER/PgR negative) 
and PD-L1 status (IC 0; IC 1/2/3)

DFS, defined as the time from surgery to the first documented disease recurrence or 
death from any cause, whichever occurs first, in all patients who undergo surgery
and based upon hormone receptor status (ER/PgR positive or ER/PgR negative) 
and PD-L1 status (IC 0; IC 1/2/3)

OS, defined as the time from randomization to death from any cause in all patients
and based upon hormone receptor status (ER/PgR positive or ER/PgR negative) 
and PD-L1 status (IC 0; IC 1/2/3)

Mean and mean changes from baseline score in function (role, physical) and global 
health status (GHS)/HRQoL, as measured by scales of the European Organisation
for Research and Treatment of Cancer (EORTC) Quality of Life 
QuestionnaireCore 30 (QLQ-C30) by assessment timepoint, and between 
treatment arms 
2.2.3
Exploratory Efficacy Endpoints

Mean and mean changes from baseline score in disease/treatment-related 
symptoms and emotional function, social function by assessment timepoint and 
between treatment arms as assessed by all symptom items/scales and the 
emotional, social function scales of the EORTC QLQ-C30

Treatment burden as measured by a single item (GP5: “I am bothered by side 
effects of treatment”) from the physical well-being subscale of the Functional 
Assessment of Cancer TherapyGeneral (FACT-G) quality-of-life instrument by 
assessment of the proportion of patients reporting each response option at each
assessment timepoint by treatment arm for item GP5 from the FACT-G
–
Utility scores of the EuroQol 5 Dimension, 5-Level (EQ-5D-5L) questionnaire
German(BA) Disease-free survival (G(BA)DFS) is the time from surgery to the first 
occurrence of disease recurrence or death from any cause.
Events defining G(BA)DFS:
–
Ipsilateral invasive breast tumor recurrence (i.e., an invasive breast cancer 
involving the same breast parenchyma as the original primary lesion)
–
Ipsilateral local-regional invasive breast cancer recurrence (i.e., an invasive 
breast cancer in the axilla, regional lymph nodes, chest wall, and/or skin of the 
ipsilateral breast)
–
Distant recurrence (i.e., evidence of breast cancer in any anatomic site – other 
than the two above mentioned sites—that has either been histologically 
confirmed or clinically diagnosed as recurrent invasive breast cancer)
–
Contralateral invasive breast cancer
–
Ipsilateral or contralateral ductal carcinoma in situ (DCIS)


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10/Statistical Analysis Plan BO40747
–
Second primary non-breast invasive cancer (with the exception of non-
melanoma skin cancers and in situ carcinoma of any site)
–
Death attributable to any cause including breast cancer, non-breast cancer, or 
unknown cause (but cause of death should be specified if at all possible).
2.2.4
Pharmacokinetic Endpoints

Peak and trough (maximum serum concentration observed [Cmax] and minimum 
serum concentration under steady-state conditions within a dosing interval [Cmin])
concentrations of atezolizumab in serum at specified timepoints

Trough concentration for pertuzumab and trastuzumab in serum at specified 
timepoints

Peak and trough concentration for trastuzumab emtansine in serum at specified 
timepoints
2.2.5
Safety Endpoints

Incidence and severity of adverse events, with severity determined according to 
National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 5.0 (NCI CTCAE v5.0)

Change from baseline in targeted vital signs

Change from baseline in targeted clinical laboratory test results
2.2.6
Immunogenicity Endpoints

Incidence of treatment-emergent anti-drug antibodies (ADAs) to atezolizumab

Incidence of treatment-emergent ADAs to trastuzumab, pertuzumab, and 
trastuzumab emtansine
The exploratory immunogenicity endpoint is as follows:

Relationship between ADA status and efficacy, safety, or PK endpoints
2.2.7
Biomarker Endpoints
The secondary biomarker endpoints are as follows:

pCR (ypT0/is ypN0), EFS, DFS, and OS based upon PIK3CA mutation status
Exploratory biomarker endpoints may include the following:

pCR (ypT0/is ypN0) based upon stromal TIL infiltration level

pCR (ypT0/is ypN0) based upon immune gene expression level

Relationship between biomarkers (and/or changes in biomarkers) in blood and 
tumor tissue and efficacy, safety, PK, immunogenicity, or other biomarker endpoints

Association of biomarkers with EFS, DFS and OS

Association between post-surgical circulating-tumor DNA (ctDNA) and outcome

On-treatment changes of ctDNA associated with atezolizumab ddAC-PacHP 
compared with placebo+ddAC-PacHP and its association with EFS, DFS, and OS


Atezolizumab—F. Hoffmann-La Roche Ltd
11/Statistical Analysis Plan BO40747
2.3
DETERMINATION OF SAMPLE SIZE
The Type I error () for this study is 0.05 (two-sided).  The Type I error will be controlled 
for the following efficacy endpoints:

Co-primary efficacy endpoint pCR in the PD-L1-positive population with an 
allocated of 0.048

Co-primary efficacy endpoint pCR in the ITT population with an allocated of 
0.002
The global study will randomize approximately 453 patients in total.  Assuming a 
prevalence of 40% of PD-L1-positive patients, the PD-L1-positive population is 
estimated to comprise approximately 181 patients.
This sample size will allow for 80% power to detect an improvement in pCR proportion 
from 70% in the placeboddAC-PacHP group to 90% (20%) in the 
atezolizumabddAC-PacHP group at the 4.8% level of significance (two-sided) 
assuming a dropout of 7% of the patients (i.e., patients without pCR assessment will be 
regarded as not achieving pCR resulting in an improvement in pCR proportion from 65% 
vs. 83%; 18%) in the PD-L1-positive population.
In the ITT population, this sample size will allow for 82.8% power to detect an 
improvement in pCR proportion from 60% in the placeboddAC-PacHP group to 80% 
(20%) in the atezolizumabddAC-PacHP group at the 0.2% significance level, 
assuming a dropout of 10% of the patients (i.e., patients without pCR assessment will be 
regarded as not achieving pCR resulting in an improvement in pCR proportion from 54% 
vs. 72%; (18%).
If the co-primary efficacy endpoint pCR in the PD-L1-positive population is significant, 
the available of 0.048 will be allocated additionally to the co-primary efficacy endpoint 
pCR in the ITT population in a hierarchical manner resulting in an alpha of 0.05.
2.4
ANALYSIS TIMING
The primary analysis will take place once all randomized patients have completed 
neoadjuvant treatment and undergone surgery. The administrative interim efficacy 
analysis will occur once 227 (50%) patients have completed neoadjuvant treatment and 
undergone surgery.
3.
STUDY CONDUCT
3.1
RANDOMIZATION 
Patients are randomized in a 1:1 ratio using a permuted-block randomization method to 
one of two treatment arms:  atezolizumab neoadjuvant ddAC-PacHP or 
placebo neoadjuvant ddAC-PacHP.  The randomization scheme is designed to ensure 
that an approximately equal number of patients will be enrolled in each treatment arm 
within the categories defined for the following stratification factors at baseline: 


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12/Statistical Analysis Plan BO40747

Stage at diagnosis (T2, T34)

Hormone receptor status (ER positive and/or PgR positive; ER negative and 
PgR negative)

PD-L1 status (IC 0; IC 1/2/3)
Enrollment of patients with hormone receptor positive disease will be capped at 50%. 
3.2
INDEPENDENT REVIEW FACILITY
No Independent Review Facility is in place for this study. 
3.3
DATA MONITORING
The independent Data Monitoring Committee (iDMC) shares with the Sponsor the 
responsibility to monitor overall patient safety of the Investigational Medicinal Products
(IMPs).  The iDMC will evaluate unblinded safety data on a regular basis during the 
study until the analysis of the primary endpoint of pCR, once all patients have completed 
neoadjuvant therapy and undergone surgery, after which iDMC review of the study data 
will be discontinued.
The iDMC will also review the unblinded efficacy data at the administrative interim 
analysis, as described in Section 4.10.1.
The iDMC will work according to the guidelines defined in the iDMC Charter. The iDMC 
Charter contains details regarding the frequency of meetings, guidelines for decision 
making and process for requesting further information. The iDMC members will review 
and sign off the charter before the first safety review. 
4.
STATISTICAL METHODS
The analyses outlined in this SAP supersede those specified in the protocol for the 
purpose of a regulatory filing.
If extended enrollment 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 the China 
subpopulation (i.e. patients enrolled from mainland China and Taiwan during both global 
enrollment phase and the extended China enrollment phase).
4.1
ANALYSIS POPULATIONS
4.1.1
Randomized Population
For all efficacy analyses, patients will be assigned to the treatment group to which they 
were randomized.


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4.1.1.1
Intention-to-Treat (ITT) Population
The ITT population is defined as all randomized patients, regardless of whether the 
assigned study treatment was received.
4.1.1.2
PD-L1-Positive Population
The PD-L1-positive population is defined as patients in the ITT population whose PD-L1 
status is IC1/2/3 at the time of randomization.
4.1.1.3
DFS-Evaluable Population
The DFS-evaluable population is defined as patients in the ITT population who undergo
surgery.
4.1.1.4
PD-L1-PositiveDFS-Evaluable Population
The DFS-evaluable population is defined as patients in the PD-L1-positive population
who undergo surgery.
4.1.1.5
PRO-Evaluable Population
The PRO-evaluable population is defined as patients in the ITT population with a 
baseline and at least 1 post-baseline PRO assessment.
4.1.2
Pharmacokinetic-Evaluable Population
The pharmacokinetic (PK)-evaluable population is defined as all patients who received 
any dose of study medication and who have at least one post-baseline PK sample 
available.
4.1.3
Safety Population
The safety-evaluable population is defined as patients who received at least one dose of
any study drug. For safety analyses, patients will be assigned to treatment groups as 
treated (atezolizumab vs. placebo), and all patients who received any dose of 
atezolizumab will be included in the atezolizumab treatment arm.
4.2
ANALYSIS OF STUDY CONDUCT
For all randomized patients (i.e., ITT population), a participant flowchart for depicting the 
progress of subjects through the phases of the trial will be provided by treatment arm in 
the CSR, including a complete description of patient disposition specifying the number of 
randomized, completed and discontinued patients from trial treatment and study with 
reasons for premature discontinuation.  
Documented major protocol deviations including major deviations with regard to the 
inclusion and exclusion criteria, conduct of the study, patient management, or patient 
assessment will be tabulated by treatment arm.


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4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
Demographic variables such as age, sex, race/ethnicity, and baseline characteristics 
(in particular, stratification variables) will be summarized by treatment arm for the ITT 
and PD-L1-positive populations.  Only descriptive analyses are planned; no formal 
statistical tests will be applied.  Continuous variables will be reported and summarized 
by use of standard measures of central tendency and dispersion (mean, standard 
deviation, median, ranges and inter-quartile ranges), and categorical (i.e., discrete) data 
will be reported and summarized by frequencies and percentages.  
The baseline value of any variable will be defined as the last available value prior to the 
first administration of study treatment.
Previous and concomitant cancer therapy will also be summarized, including 
radiotherapy and surgery, as well as subsequent anti-cancer therapy.  Previous and 
concurrent diseases and medications will also be summarized.
4.4
EFFICACY ANALYSIS
4.4.1
Co-Primary Efficacy Endpoint
The co-primary efficacy objective for this study is to evaluate the efficacy of 
atezolizumab compared with placebo when given in combination with neoadjuvant 
ddAC-PacHP in patients eligible for surgery with early HER2-positive breast cancer at 
high risk of recurrence (T24, N13) as measured by pCR in the ITT and in the 
PD-L1-positive populations.  pCR is established following completion of neoadjuvant 
therapy and surgery.
pCR is defined as the absence of residual invasive cancer on hematoxylin and eosin 
evaluation of the complete resected breast specimen and all sampled regional lymph 
nodes following completion of NAST (i.e., ypT0/is ypN0 in the current AJCC staging 
system).
Patients with missing pCR assessment will be counted as not achieving a pCR.  
Treatment comparison of pCR will be made using Cochran-Mantel-Haenszel test 
stratified by disease stage (T2 vs. T34), hormone receptor status (positive vs. negative) 
and PD-L1 status (IC 0 vs. IC 1/2/3), if applicable. The 2-sided significance level in the 
PD-L1-positive population is 4.8% and in the ITT population 0.2%. The stratification 
factors will be based on data collected by the IxRS at the time of randomization.  
Confidence intervals for the difference in pCR rate between the two arms will be 
determined using the normal approximation to the binomial distribution.
A summary table that presents the number and proportion of pCR in each treatment 
arm, together with the 2-sided 95% CI with use of the Clopper-Pearson method
(Clopper and Pearson 1934) will be produced. 


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4.4.2
Secondary Efficacy Endpoints
4.4.2.1
pCR in Subgroups
pCR in subgroups by hormone receptor status and PD-L1-negative status are defined as 
secondary efficacy endpoints.
pCR is defined in analogous manner to the primary endpoint and will be analyzed with 
the same methodology in the subgroups.  The stratification factors in the subgroup 
analysis will be as defined below:

pCR by hormone receptor status:  The stratification factors will be disease stage 
and PD-L1 status. This endpoint will be additionally analyzed in the subgroups 
defined by PD-L1 status.

pCR in PD-L1-negative patients:  The stratification factors will be disease stage 
and hormone receptor status.
4.4.2.2
Event-Free Survival
EFS is defined as the time from randomization to the first documented disease 
recurrence, unequivocal tumor progression determined by the treating investigator, or 
death from any cause, whichever occurs first.
Patients without an event at the time of the analysis will be censored on the date on 
which they are last known to be alive and event free, on or before the clinical data cutoff 
date of the respective analysis.  Patients with no post baseline information will be 
censored at the date of randomization.
EFS will be compared between treatment arms with the use of the log-rank test stratified 
by the randomization stratification factors collected by the IxRS at the time of 
randomization and by the adjuvant treatment regimen.  The HR for EFS will be 
estimated using a Cox proportional hazards model.  The 95% CI for the HR will be 
provided.  Kaplan-Meier methodology will be used to estimate the median EFS (if 
reached) for each treatment arm, and Kaplan-Meier curves will be produced.  
Brookmeyer-Crowley methodology will be used to construct the 95% CI for the median 
EFS for each treatment arm (Brookmeyer and Crowley 1982). The Kaplan-Meier 
approach will be also used to estimate landmark EFS rates, including 3-year EFS rates
at the final analysis 1-year rates at the primary analysis, and corresponding 95% CIs for 
each treatment arm.  Results from an unstratified analysis will also be provided.
The EFS analysis will be performed approximately 36 months after the randomization of 
the last patient during the global enrollment phase.
4.4.2.3
Disease-Free Survival
DFS is defined as the time from surgery (i.e., the first date of no disease) to the first 
documented disease recurrence or death from any cause, whichever occurs first.  


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Patients who do not undergo surgery at the end of neoadjuvant treatment will be 
excluded from the analysis of DFS.
Patients without a DFS event at the time of analysis will be censored at the date when 
they were last known to be alive and event free. Patients who do not have information 
after surgery will be censored at the date of surgery.
DFS will be analyzed with the use of the same methodology as specified for EFS.  The 
DFS analysis will be performed approximately 36 months after the randomization of the 
last patient during the global enrollment phase.
The exploratory endpoint German(BA) Disease-Free Survival defined in Section 2.2.3
will be analysed in the same way as DFS.
4.4.2.4
Overall Survival
OS is defined as the time from randomization to death from any cause.  Patients who 
are not reported as having died at the time of analysis will be censored at the date when 
they were last known to be alive.  Patients who do not have information after baseline 
will be censored at the date of randomization.  OS will be analyzed with the use of the 
same methodology as specified for EFS.  The OS analysis will be performed 
approximately 36 months after the randomization of the last patient during the global 
enrollment phase.
4.4.2.5
Patient Reported Outcomes of Role and Physical Function and 
GHS/HRQOL: EORTC Data
The secondary PRO endpoints are mean and mean changes from baseline score in 
function (role, physical) and GHS/HRQoL.  Summary statistics (mean, standard 
deviation, median, and range) of linearly transformed absolute scores and mean 
changes from baseline will be calculated for the role function ([Question {Q6, Q7], 
physical function [Q1-Q5]), and the GHS/HRQoL (Q29, Q30) scales of the EORTC QLQ-
C30 at each assessment timepoint for each arm.  The mean (and 95% CI) and median 
of the absolute scores and the changes from baseline will be reported on patients with a 
baseline and at least one post-baseline assessment.  Previously published minimally 
important differences will be used to identify meaningful change from baseline within 
each treatment group on the functional and GHS/HRQoL scales (Osoba et al. 1998; 
Cocks et al. 2011).
The EORTC QLQ-C30 (Version 3) data will be scored according to the EORTC scoring 
manual (Fayers et al. 2001).  Missing data will be assessed and reported by cycle. In the 
event of incomplete data, if the scale has more than 50% of the constituent items
completed, a pro-rated score will be computed consistent with the scoring manual and
validation papers of the measure. For subscales with less than 50% of the items
completed, the subscale will be considered missing.  PRO completion, compliance rates, 
and reasons for missing data will be summarized at each timepoint by treatment arm.


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4.4.3
Exploratory Efficacy Endpoints
4.4.3.1
Patient Reported Outcomes of Disease/Treatment-Related 
Symptoms, and Emotional and Social Function: EORTC Data
Summary statistics (mean, standard deviation, median, and range) of linearly 
transformed absolute scores and mean changes from baseline will be calculated for all 
disease/treatment-related symptom items and scales, and the emotional and social 
function scales of the EORTC QLQ-C30 at each assessment timepoint for each arm.
Rules for handling missing data will be the same as those defined in Section 4.4.2.5 for 
the secondary PRO endpoints measured by the EORTC QLQ-C30.
4.4.3.2
Patient-Reported Outcome of Treatment Burden:  FACT-G, GP5 
Single-Item Data
A descriptive analysis of absolute scores, change from baseline 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.  Item GP5 from Version 4 of the FACT-G 
Questionnaire will be scored according to the Functional Assessment of Chronic Illness 
Therapy scoring manual (Cella 1997).
4.4.3.3
Health Economic EQ-5D-5L Data
Health utility data from the EQ-5D-5L will be evaluated in pharmacoeconomic models.  
The results from the health economic data analyses will be reported separately from the 
clinical study report.
4.4.4
Sensitivity Analyses
4.4.5
Subgroup Analyses
To assess the consistency of the study results in patient subgroups defined by key 
demographic and baseline characteristics, including the stratification factors, subgroup 
analyses of pCR, EFS, DFS and OS will be performed. Subgroups will include but are 
not limited to the following characteristics:

PD-L1 status (IC 0; IC 1/2/3)

Primary Tumor Stage at diagnosis (T2; T3-4)

Lymph Node Stage at diagnosis (N1; 2; 3)

AJCC Stage at diagnosis (II, III)

Hormone receptor status (ER positive and/or PgR positive; ER negative and 
PgR negative)

Age-group (<65; ≥65)

Race (White; Black; Asian; Other)

ECOG Performance Status (0; 1)

Outcome of surgery (pCR, non-pCR) (subgroup analyses of EFS, DFS and OS only)


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The analysis of pCR in the PD-L1+ subgroup is a co-primary endpoint and as such is 
subject to type I error control, as described in Section 4.4.1. All other subgroup analyses 
will be considered exploratory in nature.
Summary statistics for pCR will include the n (%) of patients achieving pCR by treatment 
arm within each subgroup level.
Summaries for EFS, DFS and OS, including the unstratified hazard ratio estimated from 
the Cox-proportional hazards model and Kaplan-Meier estimates of the median (if 
reached) will be produced separately for each subgroup level.
4.5
PHARMACOKINETIC ANALYSES
Atezolizumab serum concentration data (Cmin and Cmax) will be tabulated and 
summarized.  Descriptive statistics will include means, medians, ranges, standard 
deviations, coefficient of variation (%CV), and others as appropriate. 
The pertuzumab, trastuzumab, and trastuzumab emtansine concentrations in serum will 
also be tabulated and summarized.  Additional PK and PD analyses may be conducted 
as appropriate.
4.6
SAFETY ANALYSES
Safety will be assessed through summaries of study treatment exposures, adverse 
events, changes in targeted laboratory and diagnostic test results, changes in vital signs, 
and immunogenicity as measured by ADAs and will be presented by treatment arm.  Full 
safety analyses will be provided for the neoadjuvant therapy portion of the trial. Selected 
safety data will also be presented separately according to adjuvant treatment regimen.
4.6.1
Exposure to Study Treatment
Study drug exposure, including but not limited to treatment duration, number of cycles, 
and dose intensity, will be summarized with descriptive statistics for each study 
treatment on each treatment arm if deemed appropriate.
4.6.2
Adverse Events
Verbatim descriptions of adverse events will be mapped to MedDRA thesaurus terms 
and graded according to NCI CTCAE v5.0.
Treatment-emergent adverse events, defined as events occurring on or after the first 
dose of study treatment, will be summarized by MedDRA term, appropriate MedDRA 
levels, and NCI CTCAE v5.0 grade, regardless of relationship to study drug as assessed 
by the investigator.  For each patient, if multiple incidences of the same adverse events 
occur, the maximum severity reported will be used in the summaries.
The following treatment-emergent adverse events will be summarized separately:

Adverse Events 


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
Adverse events leading to withdrawal of study drug

Adverse events leading to dose reduction or interruption

Grade 3/4 adverse events

Grade 5 adverse events

Serious adverse events 

Adverse events of special interest

Selected adverse events on the basis of the safety profile of the study drug
All deaths and causes of death will be summarized.
4.6.3
Laboratory Data
Laboratory data with values outside of the normal ranges will be identified.  Relevant 
laboratory values will be summarized by treatment arm over time, with NCI CTCAE v5.0 
Grade 3 and Grade 4 values identified, where appropriate.  Clinically relevant shifts from 
baseline in NCI CTCAE v5.0 grade (defined as shifts from Grade 0, 1, or 2 at baseline to 
Grade 3 or 4 post baseline) will be also provided by treatment arm.  Of note, abnormal 
laboratory data that are clinically significant will be reported as adverse events and 
summarized in the adverse event tables.
A Hy’s Law analysis will be provided:  the finding of an elevated ALT or AST (3ULN) 
in combination with either an elevated total bilirubin (2ULN) or clinical jaundice in the 
absence of cholestasis or other causes of hyperbilirubinemia is considered to be an 
indicator of severe liver injury (as defined by Hy's Law).
4.6.4
Vital Signs
Change from baseline in selected vital signs will be summarized by treatment arm.
4.7
IMMUNOGENICITY ANALYSES
The immunogenicity analyses will include all safety evaluable patients, with patients 
grouped according to treatment received.
The numbers and proportions of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) and after baseline (post-baseline incidence) will be 
summarized by treatment group.  When determining post-baseline incidence, patients 
are considered to be ADA-positive if they are ADA-negative or have missing data at 
baseline but develop an ADA response following study drug exposure 
(treatment-induced ADA response), or if they are ADA-positive at baseline and the titer 
of one or more post-baseline samples is at least 0.60 titer units greater than the titer of 
the baseline sample (treatment-enhanced ADA response).  Patients are considered to 
be ADA-negative if they are ADA-negative or are missing data at baseline and all 
post-baseline samples are negative, or if they are ADA-positive at baseline but do not 


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have any post-baseline samples with a titer that is at least 0.60 titer units greater than 
the titer of the baseline sample (treatment unaffected).
The relationship between ADA status and safety, efficacy, and pharmacokinetics may be 
investigated.
4.8
BIOMARKER ANALYSES
Biomarker analyses will be performed as follows:
Analysis of pCR by biomarker levels will be stratified by disease stage (T2 vs T3-4), 
central hormone receptor status, and PD-L1 status.
Central HER2 status by IHC are

0/1+

2+

3+
Central HER2 status by ISH are

pos

neg
PD-L1 expression level on tumor-infiltrating immune cells

IC 0

IC 1

IC 2

IC 3
PIK3CA mutation status 

mutated

wildtype
of pCR, EFS, DFS, and OS may be analyzed according to the status of other
biomarkers , e.g. for PIK3CA mutation status, as appropriate.
Main results are presented in the CSR, the remaining results will be presented in a 
separate report.
4.9
MISSING DATA
In efficacy analyses of pCR, patients with a missing pCR assessment will be counted as 
not achieving pCR in the analysis.
The analyses of EFS and OS will include all randomized patients, and the analysis of 
DFS will include all patients who undergo surgery. No patients will be excluded from 
analysis due to missing data. Censoring strategies for patients without an event are 
described in section 4.4.2. 


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The rules for missing data associated with the patient reported outcome questionnaires 
are detailed in Section 4.4.2.5.
4.10
INTERIM ANALYSES
4.10.1
Planned Interim analysis
In order to extract information from data accumulated thus far for reasons external to the 
study (administrative objective, to inform the initiation of a possible subsequent trial), an
administrative interim efficacy analysis of pCR is planned to take place once 
227 patients have been enrolled, completed neoadjuvant treatment and undergone 
surgery. The administrative interim analysis is performed without any intention to stop 
the trial. However, a minimum alpha of 0.0001 will be spent to protect the overall type I 
error. The interim analysis will be performed by the iDCC, an external statistical group, to 
ensure the Sponsor study team personnel remain blinded. The results will be reviewed 
by the iDMC. Interactions between the iDMC and the Sponsor will be carried out as 
specified in the iDMC Charter.
The iDMC should give a positive recommendation for the possible subsequent trial if the 
protocol assumptions are met in either the PD-L1-positive or ITT population. The 
difference in pCR rates should be at least 18% in either the PD-L1-positive or the ITT 
population.
4.10.2
Optional Interim Analysis
The Sponsor may choose to conduct interim efficacy analyses after the primary analysis 
for pCR and before the final analysis for EFS and OS, if needed (e.g., for regulatory or 
publication purposes).  The decision to conduct an optional interim analysis, along with 
the rationale, timing, and statistical details for the analysis will be documented in an 
amendment to the Sponsor’s Statistical Analysis Plan prior to the conduct of the interim 
analysis.  The interim analysis will be performed and interpreted by Sponsor study team 
personnel who will have full access to unblinded data.  Access to treatment assignment 
information will follow the Sponsor’s standard procedures.
4.11
CHINA SUBPOPULATION ANALYSES
After completion of the global enrollment phase, additional patients may continue to be 
enrolled in China in an extended China enrollment phase to achieve a total of 
approximately 70 patients from mainland China and Taiwan.  The China subpopulation 
will include all patients of Chinese ancestry enrolled from mainland China and Taiwan 
during both the global enrollment phase and the extended China enrollment phase.  
The China subgroup analysis will be performed based on the China subpopulation.  The 
sample size of the China subpopulation will provide >70% probability of showing 
consistent treatment benefit assessed by pCR rate compared with that estimated from 
the global populations.  The China subpopulation is not powered to demonstrate


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statistical significance in terms of efficacy; thus, no formal hypothesis testing will be 
performed.  
The analyses for the China subpopulation will be performed in a similar way as done for 
the global population, or summarized descriptively as appropriate.  Results from these 
analyses will be summarized separately.  


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5.
REFERENCES
Brookmeyer R, Crowley J. A k-sample median test for censored data. J Am Stat Assoc 
1982;77:43340.
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of 
the binomial, Biometrika 1934;26:40416.
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;29:8996.
Fayers PM, Aaronson NK, Bjordal K, et al. The EORTC QLQ-C30 scoring manual, 
3rd ed. Brussels: European Organisation for Research and Treatment of Cancer, 
2001.
Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in health-
related quality of life score. J Clin Oncol 1998;16:13944.


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Appendix 1
Protocol Synopsis
TITLE:
A PHASE III, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 
CLINICAL TRIAL TO EVALUATE THE EFFICACY AND SAFETY OF 
ATEZOLIZUMAB OR PLACEBO IN COMBINATION WITH NEOADJUVANT 
DOXORUBICIN CYCLOPHOSPHAMIDE FOLLOWED BY 
PACLITAXEL TRASTUZUMAB PERTUZUMAB IN EARLY 
HER2-POSITIVE BREAST CANCER
PROTOCOL NUMBER:
BO40747
VERSION NUMBER:
4
EUDRACT NUMBER:
2018-001881-40
NCT NUMBER:
NCT03726879
IND NUMBER:
123277
TEST PRODUCT:
Atezolizumab (RO5541267),
Pertuzumab (RO4368451),
Trastuzumab (RO0452317),
Trastuzumab emtansine (RO5304020)
PHASE:
Phase III
INDICATION:
Early HER2-positive breast cancer
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study (also known as IMpassion050) will evaluate the efficacy and safety of atezolizumab 
compared with placebo when given in combination with neoadjuvant dose-dense anthracycline 
(doxorubicin)cyclophosphamide followed by paclitaxeltrastuzumabpertuzumab 
(ddAC-PacHP) in patients with early human epidermal growth factor 2 (HER2)-positive breast
cancer at high risk of recurrence (T2-4, N1-3, M0).  Specific objectives and corresponding 
endpoints for the study are outlined below. 
Efficacy Objectives
Co-Primary Efficacy Objective
The co-primary efficacy objective for this study is to evaluate the efficacy of 
atezolizumabddAC-PacHP compared with placeboddAC-PacHP in the early breast cancer 
(EBC) setting in the PD-L1-positive (IC 1/2/3) and the intent-to-treat (ITT) populations on the 
basis of the following endpoint:

Pathological complete response (pCR), defined as the absence of residual invasive cancer 
on hematoxylin and eosin evaluation of the complete resected breast specimen and all 
sampled regional lymph nodes following completion of neoadjuvant systemic therapy 
(i.e., ypT0/is ypN0 in the current American Joint Committee on Cancer [AJCC] staging 
system, 8th edition) in the PD-L1-positive and ITT populations


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Secondary Efficacy Objectives
The secondary efficacy objectives for this study are as follows:

To evaluate the efficacy of atezolizumabddAC-PacHP compared with 
placeboddAC-PacHP in the EBC setting on the basis of the following endpoints:
-
pCR (ypT0/is ypN0) based upon hormone receptor status (estrogen receptor 
[ER]/progesterone receptor [PgR] positive or ER/PgR negative)
-
pCR (ypT0/is ypN0) in the PD-L1-negative (IC 0) population
-
Event-free survival (EFS), defined as the time from randomization to the first 
documented disease recurrence, unequivocal tumor progression determined by the 
treating investigator, or death from any cause, whichever occurs first, in all patients and 
based upon hormone receptor status (ER/PgR positive or ER/PgR negative) and PD-L1 
status (IC 0; IC 1/2/3)
-
Disease-free survival (DFS), defined as the time from surgery to the first documented 
disease recurrence or death from any cause, whichever occurs first, in all patients who 
undergo surgery and based upon hormone receptor status (ER/PgR positive or ER/PgR 
negative) and PD-L1 status (IC 0; IC 1/2/3)
-
Overall survival (OS), defined as the time from randomization to death from any cause 
in all patients and based upon hormone receptor status (ER/PgR positive or ER/PgR 
negative) and PD-L1 status (IC 0; IC 1/2/3)

To evaluate patient-reported outcomes (PROs) of function (role, physical) and 
healthrelated quality of life (HRQoL) associated with atezolizumabddAC-PacHP 
compared with placebo+ddAC-PacHP, as measured by the European Organisation for 
Research and Treatment of Cancer (EORTC) Quality of Life QuestionnaireCore 30 (QLQ-
C30), on the basis of the following endpoint:
-
Mean and mean changes from baseline score in function (role, physical) and global 
health status (GHS)/HRQoL by assessment timepoint, and between treatment arms as 
assessed by the functional and GHS/HRQoL scales of the EORTC QLQ-C30
Exploratory Efficacy Objectives
The exploratory efficacy objectives for this study are as follows:

To evaluate PROs of disease/treatment-related symptoms and emotional, social function 
associated with atezolizumabddAC-PacHP by the EORTC QLQ-C30 on the basis of the 
following endpoint:
-
Mean and mean changes from baseline score in disease/treatment-related symptoms 
and emotional, social function by assessment timepoint and between treatment arms as 
assessed by all symptom items/scales and the emotional, social function scales of the 
EORTC QLQ-C30

To evaluate any treatment burden patients may experience associated with the addition of 
atezolizumab to ddAC-PacHP compared with placebo+ddAC-PacHP, as measured by a 
single item (GP5: “I am bothered by side effects of treatment”) from the physical well-being 
subscale of the Functional Assessment of Cancer TherapyGeneral (FACT-G) quality-of-life 
instrument on the basis of the following endpoint:
-
Proportion of patients reporting each response option at each assessment timepoint by 
treatment arm for item GP5 from the FACT-G

To evaluate patient’s health utility as measured by the EuroQol 5 Dimension, 5-Level 
(EQ-5D-5L) questionnaire to generate utility scores for use in economic models for 
reimbursement on the basis of the following endpoint:
-
Utility scores of the EQ-5D-5L questionnaire


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Safety Objective
The safety objective for this study is to evaluate the safety of atezolizumabddAC-PacHP 
compared with placeboddAC-PacHP in the neoadjuvant setting and the safety of atezolizumab 
combined with trastuzumab+pertuzumab (or combined with trastuzumab emtansine) compared 
with placebo combined with trastuzumab+pertuzumab (or combined with trastuzumab 
emtansine) in the adjuvant EBC setting on the basis of the following endpoints:

Incidence and severity of adverse events, with severity determined according to National 
Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 
(NCI CTCAE v5.0)

Change from baseline in targeted vital signs

Change from baseline in targeted clinical laboratory test results
Pharmacokinetic Objective
The pharmacokinetic (PK) objective for this study is to characterize the PK profile of 
atezolizumab, pertuzumab, and trastuzumab when given in combination and of atezolizumab 
and trastuzumab emtansine when given in combination on the basis of the following endpoints:

Peak and trough (maximum serum concentration observed [Cmax] and minimum serum 
concentration under steady-state conditions within a dosing interval [Cmin]) of atezolizumab 
concentrations in serum at specified timepoints

Trough concentration for pertuzumab and trastuzumab in serum at specified timepoints

Peak and trough concentration for trastuzumab emtansine in serum at specified timepoints
Immunogenicity Objectives
The immunogenicity objective for this study is to evaluate the immune response to 
atezolizumab, trastuzumab, pertuzumab, and trastuzumab emtansine on the basis of the 
following endpoints:

Incidence of treatment-emergent anti-drug antibodies (ADAs) to atezolizumab and its 
impact on pharmacokinetics, efficacy, and safety

Incidence of treatment-emergent ADAs to trastuzumab, pertuzumab, and trastuzumab 
emtansine
The exploratory immunogenicity objective for this study is to evaluate potential effects of ADAs 
on the basis of the following endpoint:

Relationship between ADA status and efficacy, safety, or PK endpoints
Biomarker Objectives
The secondary biomarker objectives for this study are as follows:

To evaluate pCR (ypT0/is ypN0), EFS, DFS, and OS based upon PIK3CA mutation status
The exploratory biomarker objectives for this study are as follows:

To evaluate pCR (ypT0/is ypN0) based upon stromal tumor-infiltrating lymphocyte (TIL)
infiltration level 

To evaluate pCR (ypT0/is ypN0) based upon immune gene expression level

To identify biomarkers and/or changes in biomarkers that are predictive of response to 
atezolizumab ddAC-PacHP (i.e., predictive biomarkers), are early surrogates of efficacy, 
are associated with progression to a more severe disease state (i.e., prognostic 
biomarkers), are associated with acquired resistance to atezolizumabddAC-PacHP, are 
associated with susceptibility to developing adverse events or can lead to improved adverse 
event monitoring or investigation (i.e., safety biomarkers), can provide evidence of 
atezolizumabddAC-PacHP activity (i.e., pharmacodynamic biomarkers), or can increase 
the knowledge and understanding of disease biology and drug safety, on the basis of the 
following endpoint:
-
Relationship between biomarkers (or changes in biomarkers) in blood and tumor tissue 
and efficacy, safety, PK, immunogenicity, or other biomarker endpoints


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
To evaluate biomarkers in association with EFS, DFS, and OS

To evaluate post-surgical circulating-tumor DNA (ctDNA) with outcome 

To evaluate ctDNA on-treatment changes associated with atezolizumabddAC-PacHP 
compared with placeboddAC-PacHP and to evaluate its association with EFS, DFS, 
and OS
Study Design
Overview of Study Design
This is a global Phase III, randomized, double-blind, placebo-controlled study designed to 
evaluate the efficacy, safety, and pharmacokinetics of atezolizumab compared with placebo 
when given in combination with neoadjuvant ddAC-PacHP in patients eligible for surgery with 
early HER2-positive breast cancer at high risk of recurrence (T24, N13, M0).
Patients who have histologically confirmed invasive HER2-positive breast cancer with a primary 
tumor size 2 cm by any radiologic measurement and who are node positive (node-positivity 
pathologically confirmed by fine-needle aspiration or core-needle biopsy) are eligible.  Axillary 
surgery (including sentinel-node biopsy) prior to neoadjuvant treatment is prohibited.  HER2 
positivity of the primary breast tumor will be confirmed by a central laboratory.  Patients whose
tumors are not centrally confirmed to be HER2-positive will not be eligible.  Patients whose 
tumor tissue is not evaluable for PD-L1 by central laboratory will not be eligible.  Patients who 
do not initially meet eligibility criteria may be rescreened once.
Patients who have consented and are eligible will be randomized in a 1:1 ratio to receive either 
atezolizumab or placebo administered IV in combination with the current standard neoadjuvant
therapy for early HER2-positive breast cancer.  
Randomization will be stratified by the following factors:

Stage at diagnosis (T2, T34) as determined by the AJCC staging system, 8th edition 
(specifically according to the Anatomic Stage Group rules)

Hormone receptor status (ER positive and/or PgR positive; ER negative and PgR negative)
Hormone receptorpositive status will be capped at 50%

PD-L1 status (IC 0; IC 1/2/3)
Study treatment administration should begin within 7 days after randomization.
During the neoadjuvant phase (i.e., prior to surgery; Cycles 18), all patients will receive:

Atezolizumab or placebo 840 mg IV every 2 weeks (Q2W) for 4 cycles (Cycles 14) 

ddAC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 IV) given with granulocyte 
colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor, or 
pegylated granulocyte colony-stimulating factor support in accordance to local guidelines 
Q2W for 4 cycles (Cycles 14)
Followed by:

Atezolizumab or placebo 1200 mg IV every 3 weeks (Q3W) for 4 cycles (Cycles 58) 

Paclitaxel 80 mg/m2 IV every week (QW) for 4 cycles (Cycles 58)

Trastuzumab 6 mg/kg IV (with an initial 8-mg/kg IV loading dose) Q3W for 4 cycles 
(Cycles 58)

Pertuzumab 420 mg IV (with an initial 840-mg IV loading dose) Q3W for 4 cycles
(Cycles 58)
A cycle will be considered missed during the neoadjuvant phase if the subsequent cycle cannot 
be administered within 28 days of the last dose for Cycles 14 or within 42 days of the last dose 
for Cycles 58.  In this situation, make-up treatment of missed cycles of chemotherapies is
permitted post-surgery prior to the adjuvant phase (described below).


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During the adjuvant phase (i.e., post-surgery; Cycles 922), the following study treatments will 
be continued Q3W to complete up to a total duration of 52 weeks (i.e., maximum of 18 cycles 
within 1 year) of HER2-targeted therapy, inclusive of therapy given both in the neoadjuvant and 
adjuvant setting:

Atezolizumab/placebo 1200 mg IV Q3W

Trastuzumab 6 mg/kg IV (with an initial 8-mg/kg IV loading dose) Q3W

Pertuzumab 420 mg IV (with an initial 840-mg IV loading dose) Q3W
Patients who do not achieve a pCR as defined in the protocol (i.e., ypT0/is ypN0 in the current 
AJCC staging system, 8th edition) have the option of receiving adjuvant treatment as outline 
above or alternatively:

Atezolizumab or placebo as per initial treatment assignment 1200 mg IV Q3W combined 
with trastuzumab emtansine 3.6 mg/kg IV Q3W
Treatment assignment will not be unblinded following pCR evaluation.  The treatment decision 
for patients who do not achieve a pCR after neoadjuvant therapy is per investigator discretion.
Atezolizumab/placebo+trastuzumab+pertuzumab will be given to complete 52 weeks of
HER2-directed therapy, regardless of the number of cycles administered.  Adjuvant 
atezolizumab/placebotrastuzumab emtansine will be given for 14 cycles.  If trastuzumab 
emtansine is discontinued for toxicity not considered related to the trastuzumab component of 
the drug, treatment can be switched to trastuzumab and pertuzumab with atezolizumab/placebo 
to complete a total of 1 year of HER2-targeted therapy.
Patients who discontinue neoadjuvant therapy early as a result of disease progression must be 
discontinued from all study treatment, will be managed as per local practice, and will be 
followed for survival only.  Any patient who receives non-protocol therapy prior to surgery will be 
discontinued from study treatment and will be managed as per local practice; these patients will 
remain on study for survival follow-up.  For patients who do not achieve pCR, it is 
recommended to continue on study treatment with the option to receive 
atezolizumab/placebo HP or atezolizumab/placebo trastuzumab emtansine on the basis of a 
benefit-risk assessment for the individual patient.  Alternatively, as per investigator discretion, 
local clinical guidelines for management of non-pCR patients may be followed; the patient 
should be followed for survival and subsequent anti-cancer therapy.
Patients who discontinue one or more of the study treatment components due to toxicity should 
not be automatically withdrawn from all study treatments.  Guidelines for dosage modification 
and treatment interruption or discontinuation for patients who experience adverse events are 
provided in the protocol.
Patients who discontinue early from all components of the pre- or post-operative study 
treatment should still remain in survival follow-up.  Patients who discontinue prematurely from 
the study will not be replaced. 
The primary efficacy endpoint (pCR; ypT0/is ypN0) will be established via local review following 
completion of neoadjuvant therapy and surgery.  In line with pCR guidance from U.S. Food and 
Drug Administration (FDA), pathologists who review study specimens will conduct review of 
study specimens in a blinded manner.  Pathologists must utilize the evaluations and 
assessments outlined in the study pathology manual.  Surgery should be performed at least 
14 days after the last dose of neoadjuvant study treatment but no later than 6 weeks after the 
last infusion.  Platelet counts should be checked prior to surgery and should be 
75,000 cells/L.  Patients must undergo full axillary lymph node dissection at the time of 
definitive surgery.  Sentinel lymph node procedure alone is not permitted.  If surgically 
feasible, it is recommended that at least 10 lymph nodes are removed for pathologic 
examination.  For sentinel nodes involving the internal mammary chain, refer to local, national, 
or international guidelines.  Level III axillary dissections should be performed for patients with 
gross disease in the Level II nodes.  The first dose of postoperative treatment should not start
until 2 weeks after surgery but should be administered within 45 days of surgery.  Postoperative 
patient management for those in either treatment arm may include radiotherapy and hormonal 
therapy as clinically indicated and in accordance with standard local clinical practice.
An independent Data Monitoring Committee (iDMC) will evaluate safety data and study conduct 
on a regular basis during the study until the analysis of the primary endpoint of pCR, after which 


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iDMC review of the study data will be discontinued.  An administrative interim analysis of 
efficacy will also take place once 227 patients have been enrolled, completed neoadjuvant 
treatment, and undergone surgery.  Sponsor affiliates will be excluded from iDMC membership.  
The iDMC will follow a charter that outlines the iDMC roles, responsibilities, and timing of iDMC 
meetings.  To assess the potential cardiac toxicity of the combination of anthracyclines and 
atezolizumab, the iDMC will review data from a cardiac safety cohort involving additional 
cardiac monitoring in the first 26 patients enrolled (approximately 13 patients in the control arm 
and approximately 13 patients in the atezolizumab arm) after all 26 patients have completed or 
have discontinued the neoadjuvant portion of the study.  
A real-time safety assessment of the first 12 patients enrolled (approximately 6 patients in the 
control arm and approximately 6 patients in the atezolizumab arm) will be conducted without 
stopping accrual.  This safety evaluation by the Sponsor of blinded data and the IDMC of 
unblinded data will be conducted after the first 12 patients have completed 6 cycles of 
neoadjuvant therapy (4 cycles of atezolizumab/placeboddAC and 2 cycles of 
atezolizumab/placeboPacHP). 
See the protocol for details regarding the iDMC.
Following completion of study treatment and surgery, all patients will continue to be followed for 
efficacy, safety, and PRO objectives until the end of the study.  No interim efficacy analyses for 
early stopping are planned, although an administrative interim analysis of efficacy is planned.  
Safety assessments will include the occurrence and severity of adverse events and laboratory 
abnormalities graded per NCI CTCAE v5.0.  Laboratory safety assessments will include the 
regular monitoring of hematology and blood chemistry. 
Tumor tissue will also be collected by biopsy, unless not clinically feasible as assessed and 
documented by the investigator, at the time of disease recurrence.  These samples will enable 
analysis of tumor tissue biomarkers related to resistance, disease progression, and clinical 
benefit of atezolizumab.
Number of Patients
Approximately 453 patients with cT 24, cN13, cM0 HER2-positive breast cancer 
(tumor 2 cm and lymph node positive) will be enrolled in this study.  After completion of the 
global enrollment phase, additional patients may be enrolled at sites in China in an extended 
China enrollment phase to ensure a total of approximately 70 patients in a China subpopulation 
(patients of Chinese ancestry from mainland China and Taiwan).
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years at time of signing Informed Consent Form

Ability to comply with the study protocol, in the investigator’s judgment

Confirmed diagnosis of HER2-positive breast cancer, and hormonal and PD-L1 status, as 
documented through central testing of a representative tumor tissue specimen, is required.
A formalin-fixed paraffin-embedded tumor specimen in a paraffin block (preferred) or at 
least 20 slides containing unstained, freshly cut, serial sections must be submitted prior 
to study enrollment.  Any deviation of the material requirements are only allowed after 
Sponsor’s approval has been obtained.
HER2-positive status will be determined based on pretreatment breast biopsy material 
and defined as an immunohistochemistry (IHC) score of 3or positive by in situ 
hybridization (ISH) prospectively assessed by a central laboratory prior to study 
enrollment.  ISH positivity is defined as a ratio of 2 for the number of HER2 gene 
copies to the number of signals for chromosome 17 copies.  A central laboratory will 
perform both IHC and ISH assays; however, only one positive result is required for 
eligibility.
PD-L1 status through measurement of IHC will be used for stratification.  The 
maximum PD-L1 score assessed among samples submitted for eligibility will be used 
as the PD-L1 score for the patient.


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ER/PgR status will be determined centrally based on pretreatment breast biopsy 
material according to the American Society of Clinical Oncology (ASCO) and the 
College of American Pathologists guidelines.

Primary breast tumor size of 2 cm by any radiographic measurement (see the protocol for 
additional details)

Stage at presentation:  T2T4, N1N3, M0 as determined by AJCC staging system, 8th
edition (specifically in accordance with Anatomic Stage group rules)

Pathologic confirmation of nodal involvement with malignancy must be determined by 
fine-needle aspiration or core-needle biopsy.  Surgical excision of lymph nodes 
(e.g., sentinel lymph node biopsy and axillary lymph node biopsy) is not permitted.

Patients with multifocal tumors (more than one mass confined to the same quadrant as the 
primary tumor) are eligible provided at least one focus is sampled and centrally confirmed 
as HER2-positive.

Patients with multicentric tumors (multiple tumors involving more than one quadrant) are 
eligible provided all discrete lesions are sampled and centrally confirmed as HER2-positive.
In patients with multifocal or multicentric breast cancer, the largest lesion should be 
measured to determine T stage.

Patient agreement to undergo appropriate surgical management, including axillary lymph 
node surgery and partial or total mastectomy, after completion of neoadjuvant treatment

Eastern Cooperative Oncology Group Performance Status of 0 or 1

Baseline left ventricular ejection fraction (LVEF) 55% measured by echocardiogram 
(ECHO) or multiple-gated acquisition (MUGA) scans

Adequate hematologic and end-organ function, defined by the following laboratory test 
results, obtained within 14 days prior to initiation of study treatment:
-
ANC 1.5 109/L (1500 cells/L) without granulocyte colony-stimulatong factor 
(GCSF) support
-
Lymphocyte count 0.5 109/L (500 cells/L)
-
Platelet count 100 109/L (100,000 cells/L) without transfusion 
-
Hemoglobin 90 g/L (9 g/dL)
Patients may be transfused to meet this criterion
-
AST, ALT, and ALP 2.5 upper limit of normal (ULN)
-
Serum bilirubin 1.5 ULN with the following exception:
Patients with known Gilbert disease:  serum bilirubin level 3 ULN
-
Creatinine clearance 30 mL/min (calculated using the Cockcroft-Gault formula)
-
Serum albumin 25 g/L (2.5 g/dL)
-
For patients not receiving therapeutic anticoagulation:  international normalized ratio 
(INR) or activated partial thromboplastin time (aPTT) 1.5 ULN within 14 days prior 
to initiation of study treatment
-
For patients receiving therapeutic anticoagulation:  
INR or aPTT within therapeutic limits for at least 1 week immediately prior to 
initiation of study treatment
Stable anticoagulant regimen and stable INR during the 14 days immediately 
preceding initiation of study treatment

Negative HIV test at screening

Negative hepatitis B surface antigen (HbsAg) test at screening

Negative total hepatitis B core antibody (HbcAb) test at screening, or positive total 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 total HbcAb 
test.


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
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.

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods, and agreement to refrain from 
donating eggs, as defined below:
Women must remain abstinent or use contraceptive methods with a failure rate of 
1% per year during the treatment period and for 5 months after the final dose of 
atezolizumab/placebo, 6 months after the final dose of doxorubicin, 12 months after 
the final dose of cyclophosphamide, 6 months after the final dose of paclitaxel, and 
7 months after the final dose of trastuzumab. pertuzumab, or trastuzumab emtansine, 
whichever occurs last.  Women must refrain from donating eggs during this same 
period.
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or requirements.
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, copper intrauterine devices, hormonal 
contraceptives that inhibit ovulation, and hormone-releasing intrauterine devices in 
women with hormone receptor-negative tumors only; the use of hormonal 
contraceptives and hormone releasing intrauterine devices are prohibited in women 
with hormone receptor-positive tumors.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential who is not pregnant, men who are not 
surgically sterile must remain abstinent or use a condom plus an additional 
contraceptive method that together result in a failure rate of 1% per year during the 
treatment period and for 6 months after the final dose of doxorubicin and/or 
cyclophosphamide, 6 months after the final dose of paclitaxel, and 7 months after the 
final dose of trastuzumab, pertuzumab, or trastuzumab emtansine, whichever occurs 
last.  Men must refrain from donating sperm during this same period.  Male patients are 
encouraged to seek advice regarding cryoconservation of sperm prior to commencing 
study treatment because of the possibility of infertility with chemotherapy.
With a pregnant female partner, men must remain abstinent or use a condom during 
the treatment period and for 6 months after the final dose of doxorubicin and/or 
cyclophosphamide, 6 months after the final dose of paclitaxel, and 7 months after the 
final dose of trastuzumab, pertuzumab, or trastuzumab emtansine, whichever occurs 
last to avoid exposing the embryo.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.

For patients enrolled in the extended China enrollment phase:  current resident of mainland 
China and of Chinese ancestry
The China subpopulation will consist of patients enrolled at sites in mainland China 
and Taiwan who are of Chinese ancestry.


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Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Prior history of invasive breast cancer 

Stage IV (metastatic) breast cancer 
Baseline tumor staging determination should be performed in alignment with AJCC
staging system, 8th edition (specifically in accordance with Anatomic Stage group 
rules).

Patients with synchronous bilateral invasive breast cancer

Patients with hormone receptor positive disease (estrogen receptor positive and/or 
progesterone receptor positive) will be excluded once approximately 227 patients (50% of 
the total target sample size) with hormone receptor positive disease have been enrolled

Prior systemic therapy for treatment of breast cancer

Previous therapy with anthracyclines or taxanes for any malignancy

Ulcerating or inflammatory breast cancer (e.g., erythema and/or dermal involvement, and/or 
pathologic detection of tumor cells in dermal lymphatics)

Undergone incisional and/or excisional biopsy of primary tumor and/or axillary lymph nodes

Sentinel lymph node procedure or axillary lymph node dissection prior to initiation of 
neoadjuvant therapy

History of other malignancy within 5 years prior to screening, with the exception of those 
patients who have a negligible risk of metastasis or death (e.g., 5-year OS of 90%), such 
as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, 
localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer 

Cardiopulmonary dysfunction as defined by any of the following prior to randomization: 
-
History of congestive heart failure of any classification
-
Angina pectoris requiring anti-anginal medication, serious cardiac arrhythmia not 
controlled by adequate medication, severe conduction abnormality, or clinically 
significant valvular disease 
-
High-risk uncontrolled arrhythmias (i.e., atrial tachycardia with a heart rate 100/min at 
rest, significant ventricular arrhythmia [ventricular tachycardia], or higher-grade 
atrioventricular [AV]-block [second-degree AV-block Type 2 [Mobitz 2] or third degree 
AV-block])
-
Significant symptoms (Grade 2) relating to left ventricular dysfunction, cardiac 
arrhythmia, or cardiac ischemia 
-
Myocardial infarction within 12 months prior to randomization 
-
Uncontrolled hypertension (systolic blood pressure 180 mmHg and/or diastolic blood 
pressure 100 mmHg)
-
Evidence of transmural infarction on ECG
-
Requirement for oxygen therapy

Dyspnea at rest

Active or history of autoimmune disease or immune deficiency, including, but not limited to, 
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, 
rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, 
Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis 
(see the protocol for a more comprehensive list of autoimmune diseases and immune 
deficiencies), with the following exceptions:
Patients with a history of autoimmune-related hypothyroidism who are on a stable dose 
of thyroid-replacement hormone are eligible for the study.
Patients with controlled type 1 diabetes mellitus who are on a stable insulin regimen 
are eligible for the study.


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Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for 
the study provided all of following conditions are met:
-
Rash must cover 10% of body surface area (BSA).
-
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids.
-
No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral 
calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 
12 months.

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest computed tomography (CT) scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Active tuberculosis

Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study 
treatment or anticipation of need for a major surgical procedure during the study

Severe infection within 4 weeks prior to initiation of study treatment, including, but not 
limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia

Treatment with therapeutic antibiotics within 2 weeks (IV antibiotics) or 5 days (oral 
antibiotics) prior to initiation of study treatment
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or 
chronic obstructive pulmonary disease [COPD] exacerbation) are eligible for the study. 

Prior allogeneic stem cell or solid organ transplantation

Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that contraindicates the use of an investigational drug and may affect the 
interpretation of the results, or may render the patient at high risk from treatment 
complications

Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during atezolizumab/placebo treatment 
or within 5 months after the final dose of atezolizumab/placebo

Treatment with investigational therapy within 28 days prior to initiation of study treatment

Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including 
anticytotoxic T lymphocyte-associated protein-4, antiPD-1, and antiPD-L1 therapeutic 
antibodies 

Treatment with systemic immunostimulatory agents (including, but not limited to, interferon 
and interleukin-2 [IL-2]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior 
to initiation of study treatment

Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antitumor 
necrosis factor-[TNF-] agents) within 2 weeks prior to initiation of study treatment, or 
anticipation of need for systemic immunosuppressive medication during study treatment, 
with the following exceptions:
Cyclophosphamide as part of the study treatment
Patients who received acute, low-dose systemic immunosuppressant medication or a 
one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of 
corticosteroids for a contrast allergy) are eligible for the study after Medical Monitor 
approval has been obtained.
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for 
COPD or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal 
insufficiency are eligible for the study.


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
History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or 
fusion proteins

Known hypersensitivity to Chinese hamster ovary cell products or to any component of the 
atezolizumab formulation

Known allergy or hypersensitivity to the components of the paclitaxel, cyclophosphamide, or 
doxorubicin formulations 

Known allergy or hypersensitivity to trastuzumab or pertuzumab formulations

Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or 
within 5 months after the final dose of atezolizumab/placebo, 6 months after the final dose 
of doxorubicin, 12 months after the final dose of cyclophosphamide, 6 months after the final 
dose of paclitaxel, or 7 months after the final dose of trastuzumab, pertuzumab, or 
trastuzumab emtansine, whichever occurs last
Women of childbearing potential must have a negative serum pregnancy test result 
within 7 days prior to initiation of study treatment.
Exclusions Related to Trastuzumab Emtansine in the Adjuvant Setting:

Patients who achieved pCR defined as the absence of residual invasive cancer on 
hematoxylin and eosin evaluation of the complete resected breast specimen and all 
sampled regional lymph nodes following completion of neoadjuvant systemic therapy 
(i.e., ypT0/is ypN0 in the current AJCC staging system, 8th edition)

Evidence of clinically evident gross residual or recurrent disease following neoadjuvant 
therapy and surgery

Unable to complete surgery with curative intent after conclusion of neoadjuvant systemic 
therapy

Patient discontinued treatment with trastuzumab because of toxicity during the neoadjuvant 
phase of the study

Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, 
autoimmune hepatic disorders, or sclerosis cholangitis

Patients with current Grade 2 peripheral neuropathy

Prior treatment with trastuzumab emtansine

Serum AST, ALT, and alkaline phosphatase not within 1.5 ULN

Serum total bilirubin not within normal range (1.0 ULN)
Except for patients with Gilbert’s syndrome, for whom direct bilirubin should be within 
the normal range

Serum creatinine not within <1.5 x ULN
End of Study
The end of this study is defined as the date when the last patient, last visit occurs.  The end of 
the study is expected to occur approximately 36 months after the last patient is enrolled in the 
global study (i.e., excluding the extended China enrollment phase).  
For patients randomized during the extended China enrollment phase, the end of the study is 
set as the same date as the end of the global study (i.e., expected to occur approximately 
36 months after the last patient is enrolled in the global study).
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 54 months, assuming a recruitment period of approximately 
18 months, and follow-up for 36 months from the date of enrollment of the last patient in the 
global study.  The Sponsor may decide to terminate the study at any time.
Investigational Medicinal Products
The investigational medicinal products (IMPs) for this study are atezolizumab, trastuzumab, 
pertuzumab, trastuzumab emtansine, doxorubicin, cyclophosphamide, and paclitaxel.


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Atezolizumab and Placebo
During the neoadjuvant phase, atezolizumab/placebo will be administered by IV infusion at a 
fixed dose of 840 mg on Day 1 of each 14-day cycle during Cycles 14, and 1200 mg on Day 1 
of each 21-day cycle during Cycles 58.  During the adjuvant phase (post-operatively), 
atezolizumab/placebo will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of 
each 21-day cycle (maximum of 22 cycles [neoadjuvantadjuvant phases]).  
Atezolizumab/placebo should be administered as the first infusion.
Treatment will continue as scheduled or until disease progression, recurrence of disease, or 
unmanageable toxicity.
Administration of atezolizumab will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to manage 
potentially serious reactions.  For anaphylaxis precautions, see the protocol.  Atezolizumab 
infusions will be administered per the instructions outlined in the protocol.
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration.
Guidelines for medical management of infusion-related reactions (IRRs) are provided in the 
protocol.
No dose modification for atezolizumab is allowed.
Pertuzumab
Pertuzumab is given as a fixed nonweight-based dose of 840-mg IV loading dose, then 
420 mg IV Q3W.  Pertuzumab will be administered on Day 1 of a 21-day cycle, to complete up 
to a total duration of 52 weeks (i.e., maximum of 18 cycles within 1 year) of HER2-targeted 
therapy, inclusive of therapy given both in the neoadjuvant and adjuvant setting.  
Atezolizumab/placebo should be administered prior to pertuzumab and trastuzumab.  The order 
of administration of pertuzumab and trastuzumab is according to investigator preference.  
The initial dose of pertuzumab will be administered over 60 (10) minutes, and patients will be 
observed for a further 60 minutes.  The infusion should be slowed or interrupted if the patient 
experiences infusion-related symptoms.  If the infusion is well tolerated, subsequent doses may 
be administered over 30 (10) minutes, and patients will be observed for a further 30 minutes 
for infusion-related symptoms such as fever or chills.  All infusion-related symptoms must have 
resolved before trastuzumab or chemotherapy is given or the patient is discharged.  Patients 
who experience infusion-related symptoms may be premedicated with analgesics and 
antihistamines for subsequent infusions.
Guidelines for dosage modification and treatment interruption or discontinuation are provided in 
the protocol.  No dose reductions are allowed for pertuzumab.  If the patient misses a dose of 
pertuzumab for any cycle and the time between doses is 6 weeks, a reloading dose of 
pertuzumab (840 mg) should be given.  Subsequent maintenance pertuzumab (420 mg) will 
then be given Q3W, starting 3 weeks later. 
If the interval between the first dose of adjuvant pertuzumab and the last dose of neoadjuvant 
pertuzumab exceeds 6 weeks, a reloading dose of 840 mg of pertuzumab is required.
Trastuzumab
Trastuzumab is given as an 8-mg/kg IV loading dose and then 6 mg/kg IV Q3W.  Trastuzumab 
will be administered on Day 1 of a 21-day cycle, to complete up to a total duration of 52 weeks 
(i.e., maximum of 18 cycles within 1 year) of HER2-targeted therapy, inclusive of therapy given 
both in the neoadjuvant and adjuvant setting.  Atezolizumab/placebo should be administered 
prior to pertuzumab and trastuzumab.  The order of administration of pertuzumab and 
trastuzumab is according to investigator preference.  
Weight should be recorded during screening and on Day 1 of each cycle for all patients. The 
baseline weight for a patient will be that measured on Cycle 1, Day 1.  The amount of 
trastuzumab to be administered must be recalculated if the patient’s body weight has changed 
by 10% (increased or decreased) from the Cycle 1, Day 1 weight.  The amount of trastuzumab 
administered is calculated according to the patient’s actual body weight, with no upper limit.
The initial dose of trastuzumab will be administered over 90 (10) minutes, and patients will be 
observed for at least 30 minutes from the end of the infusion for infusion-related symptoms such 
as fever or chills.  Interruption or slowing of the infusion may help control such symptoms and 


Atezolizumab—F. Hoffmann-La Roche Ltd
36/Statistical Analysis Plan BO40747
may be resumed when symptoms abate.  If the infusion is well tolerated, subsequent infusions 
may be administered over 30 (10) minutes, and patients will be observed for a further 
30 minutes.  All infusion-related symptoms must have resolved before pertuzumab or 
chemotherapy is given or the patient is discharged. Patients who experience infusion-related 
symptoms may be premedicated with analgesics and antihistamines for subsequent infusions.
Guidelines for dosage modification and treatment interruption or discontinuation are provided in 
the protocol.  No dose reductions are allowed for trastuzumab.  If the patient misses a dose of 
trastuzumab for any cycle and the time between doses is 6 weeks, a reloading dose of 
trastuzumab (8 mg/kg) should be given.  Subsequent maintenance trastuzumab (6 mg/kg) 
doses will then be given Q3W, starting 3 weeks later.
If the interval between the first dose of adjuvant trastuzumab and the last dose of neoadjuvant 
trastuzumab exceeds 6 weeks, a reloading dose of 8 mg/kg of trastuzumab is required.
Trastuzumab Emtansine
Trastuzumab emtansine will be given at a dose of 3.6 mg/kg by IV infusion Q3W.  The dose of 
trastuzumab emtansine administered will be determined on the basis of the baseline weight of 
the patient.  Weight will be measured at each visit and the dose must be re-adjusted for weight 
changes 10% compared with the previous visit or baseline.  The investigator may choose to 
recalculate the dose at every cycle using actual weight at that time, in accordance to local 
practice.  Administration may be delayed to assess or treat adverse events.  Dose reduction will 
be allowed, following the dose reduction levels provided in the protocol.  Once a dose has been 
reduced for an adverse event(s), it must not be re-escalated.
If the timing of a protocol-mandated procedure, such as administration of trastuzumab 
emtansine, coincides with a holiday that precludes the procedure, the procedure should be 
performed within 3 business days of the scheduled date and, when possible, at the earliest 
following date with subsequent protocol-specified procedures rescheduled accordingly.
Trastuzumab emtansine should be administered in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to manage 
potentially serious reactions.  Trastuzumab emtansine will be administered after the infusion of 
atezolizumab or placebo.
Chemotherapy
Chemotherapy will be administered in the neoadjuvant setting as follows:

Doxorubicin 60 mg/m2 IV on Day 1 of a 14-day cycle for 4 cycles (Cycles 14); with 

Cyclophosphamide 600 mg/m2 IV on Day 1 of a 14-day cycle for 4 cycles (Cycles 14); 
followed by

Paclitaxel 80 mg/m2 IV weekly for 12 continuous weeks (Cycles 58)
The dose of chemotherapy is calculated according to the patient’s BSA.  The BSA and the 
amount of drug administered must be recalculated if the patient’s body weight has changed by 
10% (increased or decreased) from baseline.  Recalculation of the amount of drug 
administered on the basis of smaller changes in body weight or BSA is at the investigators’ 
discretion.
There is no mandatory delay between atezolizumab/placebo and ddAC chemotherapy, 
assuming the infusion is well tolerated.
See the protocol for details on the dosage and administration of doxorubicin, 
cyclophosphamide, and paclitaxel.
Statistical Methods
Primary Analysis
The co-primary efficacy objective for this study is to evaluate the efficacy of atezolizumab 
compared with placebo when given in combination with neoadjuvant ddAC-PacHP in patients 
eligible for surgery with early HER2-positive breast cancer at high risk of recurrence (T24, 
N13) as measured by pCR in the ITT and in the PD-L1-positive populations.  pCR is 
established following completion of neoadjuvant therapy and surgery.


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pCR is defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation 
of the complete resected breast specimen and all sampled regional lymph nodes following 
completion of NAST (i.e., ypT0/is ypN0 in the current AJCC staging system).
Patients with missing pCR assessment will be counted as not achieving a pCR.  Treatment 
comparison of pCR will be made using Cochran-Mantel-Haenszel test stratified by disease 
stage (T2 vs. T34), hormone receptor status (positive vs. negative) and PD-L1 status (IC 0 vs. 
IC 1/2/3), if applicable.  The 2-sided significance level in the PD-L1-positive population is 4.8% 
and in the ITT population 0.2%. The stratification factors will be based on data collected by the 
interactive voice/web response system (IxRS) at the time of randomization.  Confidence 
intervals for the difference in pCR rate between the two arms will be determined using the 
normal approximation to the binomial distribution.
A summary table that presents the number and proportion of pCR in each treatment arm, 
together with the 2-sided 95% CI with use of the Clopper-Pearson method (Clopper and 
Pearson 1934) will be produced. 
Determination of Sample Size
The global study will randomize approximately 453 patients in total.  Assuming a prevalence of 
40% of PD-L1-positive patients (defined as tumors with a PD-L1 expression level of IC 1/2/3), 
the PD-L1-positive population is estimated to comprise approximately 181 patients.  
Type I Error Control
The Type I error () for this study is 0.05 (two-sided).  The Type I error will be controlled for the 
following efficacy endpoints:

Co-primary efficacy endpoint of pCR, as defined in the protocol, in the PD-L1-positive 
population with an allocated of 0.048

Co-primary efficacy endpoint of pCR, as defined in the protocol, in the ITT population with 
an allocated of 0.002
In the PD-L1-positive population, this sample size will allow for 80% power to detect an 
improvement in pCR proportion from 70% in the placeboddAC-PacHP to 90% (20%) in the 
atezolizumabddAC-PacHP group at the 4.8% level of significance (two-sided) assuming a 
dropout of 7% of the patients (i.e., patients without pCR assessment will be regarded as not 
achieving pCR resulting in an improvement in pCR proportion from 65% to 83%; 18%).
In the ITT population, this sample size will allow for 82.8% power to detect an improvement in 
pCR proportion from 60% in the placebo ddAC-PacHP to 80% (20%) in the 
atezolizumabddAC-PacHP group at the 0.2% level of significance (two-sided), assuming a 
dropout of 10% of the patients (i.e., patients without pCR assessment will be regarded as not 
achieving pCR resulting in an improvement in pCR proportion from 54% to 72%; 18%). 
Interim Analyses
In order to extract information from data accumulated thus far for reasons external to the study 
(administrative objective to inform the initiation of a possible subsequent trial), an 
administrative interim efficacy analysis of pCR is planned to take place once 227 patients have 
been enrolled, completed neoadjuvant treatment and undergone surgery.  The administrative 
interim analysis is performed without any intention to stop the trial.  However, a minimum alpha 
of 0.0001 will be spent to protect the overall type I error.  The interim analysis will be performed 
by the independent Data Coordinating Center (iDCC), an external statistical group, to ensure 
the Sponsor study team personnel remain blinded. The results will be reviewed by iDMC. 
Interactions between the iDMC and the Sponsor will be carried out as specified in the iDMC 
Charter.
The rationale and methods, including those to be used for the assessment and protection of the 
overall type I error, will be documented in the SAP.  Details will also be included in the iDMC 
Charter.
China Subpopulation Analyses
After completion of the global enrollment phase, additional patients may continue to be enrolled
in China in an extended China enrollment phase to achieve a total of approximately 70 patients 
from mainland China and Taiwan.  The China subpopulation will include all patients of Chinese 


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ancestry enrolled from mainland China and Taiwan during both the global enrollment phase and 
the extended China enrollment phase.  
The China subgroup analysis will be performed based on the China subpopulation.  The sample 
size of the China subpopulation will provide >70% probability of showing consistent treatment 
benefit assessed by pCR rate compared with that estimated from the global populations.  The 
China subpopulation is not powered to demonstrate statistical significance in terms of efficacy,
thus no formal hypothesis testing will be performed.  
The analyses for the China subpopulation will be performed in a similar way as done for the 
global population, or summarized descriptively as appropriate.  Results from these analyses will
be summarized separately.  Further details can be found in the Statistical Analysis Plan.


Atezolizumab—F. Hoffmann-La Roche Ltd
39/Statistical Analysis Plan BO40747
Appendix 2
Schedule of Assessments
Screening/
Baseline a
Treatment Cycles 
Treatment 
Discontinuation/Early 
Termination Visit d
Follow-
Up e
Neoadjuvant Phase
Cycles14: 14-Day Cycles
Cycles 58: 21-Day Cycles
Pre-
Surgery 
Visit/
Surgery b
Adjuvant Phase c
(Cycles 922)
21-Day Cycles
Days –28 
to –1 
Days –14 
to –1
Day 1 of Each Cycle (3 days)
Day 1 of Each 
Cycle (3 days)
30 Days after
Final Dose
1
2
3
4
5
6
7
8
Informed consent f
x
Baseline tumor tissue sample g
x
Demographic data
x
Medical history and baseline 
conditions
x
Disease status assessment h
x
x
x
x
x
x
x
x
x
x
x
x
Tumor staging i
x
Bilateral mammogram j
x
x
x
Surgical treatment plan k
x
x
Pathologic response 
assessment l
x
Vital signs m
x
x
x
x
x
x
x
x
x
x
x
Weight
x
x
x
x
x
x
x
x
x
x
Height
x
Complete physical examination n 
x
x
x
Limited physical examination o
x
x
x
x
x
x
x
x


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Screening/
Baseline a
Treatment Cycles 
Treatment 
Discontinuation/Early 
Termination Visit d
Follow-
Up e
Neoadjuvant Phase
Cycles14: 14-Day Cycles
Cycles 58: 21-Day Cycles
Pre-
Surgery 
Visit/
Surgery b
Adjuvant Phase c
(Cycles 922)
21-Day Cycles
Days –28 
to –1 
Days –14 
to –1
Day 1 of Each Cycle (3 days)
Day 1 of Each 
Cycle (3 days)
30 Days after
Final Dose
1
2
3
4
5
6
7
8
ECOG Performance Status p
x
x
x
x
x
x
ECHO/MUGA scan q
x
Refer to footnote "q"
x
x
ECG (12-lead) r
x
As clinically indicated
Hematology s
x t
x
x
x
x
x
x
x
x
x
x
Chemistry u
x t
x
x
x
x
x
x
x
x
x
x
Pregnancy test v
x
x
x
x
x
x
x
x
x
x
x
x
Coagulation (INR, aPTT)
x t
x
x
TSH, free T3 (or total T3), 
free T4 w
x t
x
x
x
x
HIV, HBV, and HCV serologies
x
Urinalysis x
x
As clinically indicated
EORTC QLQ-C30, EQ-5D-5Ly
x
x
x
x
x
x
x
x
x
x
x
FACT-G, single-item GP5 y, z
x
x
x
x
x
x
x
x
x
x
Serum autoantibody sample aa
x
PK samples and ADA samples
See Appendix 2 for detailed schedule.
Blood and plasma sample for 
biomarkers
See Appendix 3 for detailed schedule.


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Screening/
Baseline a
Treatment Cycles 
Treatment 
Discontinuation/Early 
Termination Visit d
Follow-
Up e
Neoadjuvant Phase
Cycles14: 14-Day Cycles
Cycles 58: 21-Day Cycles
Pre-
Surgery 
Visit/
Surgery b
Adjuvant Phase c
(Cycles 922)
21-Day Cycles
Days –28 
to –1 
Days –14 
to –1
Day 1 of Each Cycle (3 days)
Day 1 of Each 
Cycle (3 days)
30 Days after
Final Dose
1
2
3
4
5
6
7
8
Blood sample for WGS or WES
x
Whole blood sample types for 
RBR (optional)
x
Tumor tissue (fresh sample 
preferred) at screening, 
on-study, and at time of disease 
progression or recurrence
See Appendix 3 for detailed schedule.
Concomitant medications bb
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events cc
x
x
x
x
x
x
x
x
x
x
x
x
x
Atezolizumab/placebo 
administration dd
x
x
x
x
x
x
x
x
x
Dose-dense doxorubicin 
administration ee
x
x
x
x
Dose-dense cyclophosphamide 
administration ff
x
x
x
x
Pertuzumab administration gg
x
x
x
x
x
Trastuzumab administration hh
x
x
x
x
x
Paclitaxel administration ii
x
x
x
x
Trastuzumab emtansine 
administration kk
x


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Screening/
Baseline a
Treatment Cycles 
Treatment 
Discontinuation/Early 
Termination Visit d
Follow-
Up e
Neoadjuvant Phase
Cycles14: 14-Day Cycles
Cycles 58: 21-Day Cycles
Pre-
Surgery 
Visit/
Surgery b
Adjuvant Phase c
(Cycles 922)
21-Day Cycles
Days –28 
to –1 
Days –14 
to –1
Day 1 of Each Cycle (3 days)
Day 1 of Each 
Cycle (3 days)
30 Days after
Final Dose
1
2
3
4
5
6
7
8
Survival follow-up and 
anti-cancer treatment jj
x
ADAanti-drug antibody; AJCCAmerican Joint Committee on Cancer; CT computed tomography (scan); ddACdose-dense anthracycline 
(doxorubicin)cyclophosphamide; ECHO echocardiogram; eCRF electronic Case Report Form; EORTCEuropean Organisation for Research 
and Treatment of Cancer; EQ-5D-5LEuroQol 5-Dimension, 5-Level (questionnaire); FACT-GFunctional Assessment of Cancer 
TherapyGeneral; FFPEformalin-fixed, paraffin-embedded; HBVhepatitis B virus; HCVhepatitis C virus; MUGAmultiple-gated acquisition 
(scan); NAST neoadjuvant systemic therapy; pCRpathological complete response; PKpharmacokinetic; PRO patient-reported outcome; 
Q3W every 3 weeks; QLQ-C30Quality of Life QuestionnaireCore 30; RBRResearch Biosample Repository; SOCstandard of care; 
T3triiodothyronine; T4thyroxine; TSHthyroid-stimulating hormone; WESwhole exome sequencing; WGSwhole genome sequencing.
Notes:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified.
a Results of SOC tests or examinations performed prior to obtaining informed consent and within 28 days prior to Day 1 may be used; such tests 
do not need to be repeated for screening. 
b Pre-surgical visit and associated assessments should occur within 14 days of surgery.  Surgery should be conducted no earlier than 14 days and 
no later than 6 weeks after last dose of neoadjuvant therapy.  Platelet counts should be checked prior to surgery and should be 
75,000 cells/L.
c All study therapy will be completed when the patient has received up to a total duration of 52 weeks of HER2-targeted study therapy 
(neoadjuvantadjuvant), regardless of the number of cycles administered.
d Patients who discontinue study treatment will return to the clinic for a treatment discontinuation visit not more than 30 days after their final dose 
of study treatment. 
e The survival follow-up period begins from the date of treatment completion/early termination with a duration of 36 months from the date of the 
enrollment of the last patient during the global enrollment phase.  Follow-up visits will occur every 3 months for 1 year and then every 6 months
thereafter until the end of the study.  Follow-up visits have a window of 28 days.
f
Informed consent must be documented before any study-specific screening procedure is performed, and may be obtained more than 28 days 
before initiation of study treatment.


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g After signing of the Informed Consent Form, retrieval and submission of tumor tissue sample can occur outside the 28-day screening period.  
Tumor tissue should be of good quality based on total and viable tumor content (sites will be informed if the quality of the submitted specimen is 
inadequate to determine tumor PD-L1 status).  An FFPE block (preferred) or at least 20 slides containing unstained, freshly cut, serial sections 
should be provided.  Fine-needle aspiration is not acceptable.  For core-needle biopsy specimens, at least three cores should be submitted for 
evaluation.  See Section 4.5.9 for additional details.
h Assessment of primary tumor and regional lymph nodes should be done by physical examination at baseline and prior to administration at each 
cycle of study treatment during neoadjuvant therapy and within 14 days prior to surgery.  During the post-operative portion of this study, disease 
status should be clinically evaluated and documented every 3 months for 2 years, and then every 6 months thereafter until the end of the study.  
In addition, liver function tests, brain imaging, bone scans, chest X-ray/diagnostic CT scan, liver imaging, and/or other radiographic modalities 
may be considered when clinically indicated to exclude metastatic disease; these assessments should be performed within a timeline as per 
current local SOC practice.  Whenever possible, disease recurrence should be confirmed pathologically.  If disease recurrence is diagnosed at 
any time during the study, patients will discontinue scheduled study assessments and will be followed for survival, anti-cancer medications, and 
new relapse events.  See Section 4.5.5 for additional details.
i
Baseline tumor staging procedures should be performed in alignment with AJCC, 8th edition (specifically in accordance with Anatomic Stage 
group rules) at diagnosis, within 28 days of randomization.  Tumor size is to be determined via radiologic measurement and node positivity 
pathologically confirmed by fine needle aspiration or core needle biopsy.  See Section 4.5.6 for requirements related to baseline distant sites 
tumor staging procedures. 
j
Bilateral mammogram should be obtained within 28 days prior to randomization.  Alternatively, provided that the clinical status of the patients has 
not changed, the screening mammogram can be performed up to 42 days prior to the start of study treatment.  Subsequent mammograms are 
optional during neoadjuvant treatment and prior to surgery and should be performed per investigator’s discretion.  Bilateral mammogram should 
occur at study completion/early termination visit and every 12 months (± 4 weeks) during the follow-up period.  Patients who have undergone 
mastectomy do not require mammograms on side of mastectomy. 
k The patient should be evaluated by a surgeon prior to initiation of neoadjuvant therapy as well as after completion of neoadjuvant therapy/prior to 
surgery.  At baseline, the surgeon should evaluate the patient and create a surgical treatment plan. Then after completion of NAST, the surgeon 
should reassess the patient and modify the surgical treatment plan as needed.
l
Pathological response assessment to be performed using the resected specimen by the local pathologist on the basis of guidelines provided in 
the pathology manual.  Breast cancer surgery and pathological assessment will be performed and reported according to protocol requirements 
for patients who discontinue study treatment during the neoadjuvant phase (for any reason other than disease progression) and who proceed 
to surgery without receiving any other non-study anti-cancer therapy prior to surgery.  Patients who discontinue neoadjuvant study 
treatment due to disease progression contribute a non-pCR result and their disease progression must be reported.


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m Includes respiratory rate, pulse rate, systolic and diastolic blood pressure, and temperature.  Record abnormalities observed at baseline on the 
General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on the 
Adverse Event eCRF.  For the first infusion, vital signs should be measured within 60 minutes prior to each infusion and, if clinically indicated, 
every 15 (5) minutes during the infusion and at 30 (10) minutes after the infusion.  For subsequent infusions, vital signs should be measured 
within 60 minutes prior to each infusion and, if clinically indicated or if symptoms occurred during the previous infusion, during the infusion and at 
30 (10) minutes after the infusion.  The vital signs measured prior to the infusion of the first study drug at each cycle are required to be reported 
on the Vital Sign eCRF.  Other vital signs are not required to be entered into the eCRF unless abnormal and clinically significant, in which case 
they are to be reported as adverse events.
n Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurologic systems.  See Section 4.5.3 for additional details.  Record abnormalities observed at baseline on 
the General Medical History and Baseline Conditions eCRF. At subsequent visits, record new or worsened clinically significant abnormalities on 
the Adverse Event eCRF.
o Perform a limited, symptom-directed physical examination at specified timepoints and as clinically indicated.  Record new or worsened clinically 
significant abnormalities on the Adverse Event eCRF.
p Refer to Appendix 13.
q Cardiac monitoring (ECHO or MUGA scan) will be performed on all patients enrolled in the study.  ECHO/MUGA results need to be reviewed 
and acted upon as soon as they are available, but study interventions may continue while ECHO/MUGA results are being read assuming that the 
subject is asymptomatic from a cardiac standpoint. ECHO is the preferred method.  The same method used for a given patient at screening 
should be used throughout the study, unless clinically indicated.  ECHO or MUGA scan should be obtained at baseline, after the second dose of 
ddAC for the cardiac safety cohort (first 26 patients enrolled), after the fourth dose of ddAC (and prior to Cycle 5, Day 1), and then every 3 
months (1 week) during study treatment. ECHO or MUGA scan should be obtained at the early termination visit if not performed within the 
previous 6 weeks. During the survival follow-up period, ECHO or MUGA scan should be obtained every 6 months (1 week) for the first 2 years 
and then annually until the end of study.  Patients who discontinue study drug(s) for heart failure or LVEF decline should continue to undergo 
LVEF assessments according to this schedule of activitiesirrespective of the initiation of alternative systemic anti-cancer therapyuntil 
resolution, improvement to baseline status, and no further improvement can be expected, or death.  Additional ECHO or MUGA scans should be 
obtained if clinically indicated.
r
ECG recordings will be obtained during screening and as clinically indicated at other timepoints.  ECGs for each patient should be obtained from 
the same machine wherever possible.  Patients should be resting in a supine position for at least 10 minutes prior to ECG recording.
s Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, and other cells).  Local laboratory assessment can be performed up to 3 days prior to study treatment administration 
with the option of repeating on the day of study treatment, including the weekly administration of paclitaxel during Cycles 58.  Local assessment 
must be reviewed prior to every study treatment administration.
t
If screening laboratory assessments were performed within 3 days prior to Day 1 of Cycle 1, they do not have to be repeated.


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u Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if considered SOC for the region), sodium, potassium, 
magnesium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, ALP, ALT, AST, and LDH.  
Local laboratory assessments can be performed up to 3 days prior to study treatment administration with the option of repeating on the day of
study treatment, including the weekly administration of paclitaxel during Cycles 58.  Local assessments must be reviewed prior to every study 
treatment administration. 
v All women of childbearing potential (as defined in Section 4.1.1) will have a serum pregnancy test at screening, within 7 days prior to initiation of 
study treatment.  Urine pregnancy tests will be performed within 24 hours of Day 1 of every cycle until treatment discontinuation.  A pregnancy 
test must be done at the completion/early termination visit, and at 3 months and 7 months after the discontinuation of study treatment.  If a urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
w TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed on Day 1 of Cycle 1 and every fourth cycle 
thereafter.
x Includes pH, specific gravity, glucose, protein, ketones, and blood; dipstick permitted.
y The PRO assessments (EORTC QLQ-C30, followed by the FACT-G single item GP5, and then the EQ-5D-5L questionnaire) will be completed 
by the patient at the start of the clinic visit before discussion of the patient’s health state, laboratory results, or health record; before 
administration of study treatment; and/or prior to the performance of any other study assessments that could bias the patient’s responses. In 
scenarios where laboratory assessments (e.g., blood draws) are done in a different clinic than the one providing treatment or when they are 
done on a different day than study treatment administration, laboratory assessments can be completed before the completion of PROs as long 
as results have not been discussed with patients. Study personnel should review all questionnaires for completeness before the patient leaves 
the investigational site.  EORTC QLQ-C30 and EQ-5D-5L questionnaires will be completed by patients at baseline (Cycle 1, Day 1) ( 3 days); 
on Day 1 (3 days) of every cycle thereafter until Cycle 8; on Cycle 9, Day 1 (3 days); on Day 1 (3 days) of every other cycle thereafter until 
Cycle 22; and at the treatment discontinuation or early termination visit.  If cycles are missed or delayed as permitted by the protocol 
(Appendix 11), the PRO questionnaires should be completed on the day that the patient receives treatment for that cycle, before administration 
of study treatment.  Patients who discontinue study treatment for any reason will continue to complete the EORTC QLQ-C30, FACT-G single 
item GP5, and EQ-5D-5L questionnaires in-clinic during the follow-up period at the following timepoints:  every 3 months (28 days) for the first 
year and then every 6 months (28 days) thereafter until the end of the study.
z While on study treatment, all patients will complete the FACT-G, single item GP5 beginning on Cycle 2, Day 1 (3 days); on Day 1 (3 days) of 
every cycle thereafter until Cycle 8; on Cycle 9, Day 1 (3 days); on Day 1 (3 days) of every other cycle thereafter until Cycle 22; and at the 
treatment discontinuation or early termination visit.
aa Auto-antibody testing includes anti-nuclear antibody, antidouble-stranded DNA, and circulating anti-neutrophil cytoplasmic antibody, and 
perinuclear anti-neutrophil cytoplasmic antibody.  The baseline sample will be obtained pre-treatment Cycle 1, Day 1, before the first dose of 
study drug and stored.  For patients who show evidence of immune mediated toxicity, additional samples may be collected and assessed 
(including the baseline sample) at that time point.  All samples will be analyzed centrally.


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bb Includes any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements)
used by a patient in addition to protocol-mandated study treatment from 30 days prior to initiation of study treatment (for the purposes of 
screening) until the treatment discontinuation visit.  Medication used by the patient within 7 days prior to initiation of study treatment should be 
recorded.  Record all prior anti-cancer therapies, regardless of when they were received.
cc After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study treatment, all adverse events will be reported until 30 days after the last dose of study 
treatment or until initiation of new systemic anti-cancer therapy, whichever occurs first, and serious adverse events and adverse events of 
special interest will continue to be reported until 90 days after the last dose of study treatment or until initiation of new systemic anti-cancer 
therapy, whichever occurs first.  After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event 
that is believed to be related to prior exposure to study treatment (see Section 5.6).  For reporting instructions for deaths, please see 
Section 5.3.5.8.
dd During the neoadjuvant phase, atezolizumab/placebo will be administered by IV infusion at a fixed dose of 840 mg on Day 1 of each 14-day 
cycle during Cycles 14, and 1200 mg on Day 1 of each 21-day cycle during Cycles 58.  During the adjuvant phase (post-operatively), 
atezolizumab/placebo will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each 21-day cycle (maximum of 22 cycles 
[neoadjuvant adjuvant phases]).  Atezolizumab/placebo should be administered as the first infusion.  The initial dose of atezolizumab/placebo 
will be delivered over 60 (15) minutes.  Subsequent infusions will be delivered over 30 (10) minutes if the previous infusion was tolerated 
without infusion-associated adverse events, or 60 (15) minutes if the patient experienced an infusion-associated adverse event with the 
previous infusion.  See Section 4.3.2.1 for additional details.
ee Doxorubicin 60 mg/m2 IV on Day 1 of a 14-day cycle for 4 cycles (Cycles 14) according to local practice guidelines.  See Section 4.3.2.4 for 
additional details.
ff Cyclophosphamide 600 mg/m2 IV on Day 1 of a 14-day cycle for 4 cycles (Cycles 14) according to local practice guidelines.  See 
Section 4.3.2.4 for additional details.
gg Pertuzumab is given as a fixed nonweight-based dose of 840-mg IV loading dose, then 420 mg IV Q3W.  Pertuzumab will be administered on 
Day 1 of a 21-day cycle, to complete up to a total duration of 52 weeks (i.e., maximum of 18 cycles within 1 year) of HER2-targeted therapy, 
inclusive of therapy given both in the neoadjuvant and adjuvant setting.  See Section 4.3.2.2 for additional details.
hh Trastuzumab is given as an 8-mg/kg IV loading dose, and then 6 mg/kg IV Q3W.  Trastuzumab will be administered on Day 1 of a 21-day cycle, 
to complete up to a total duration of 52 weeks (i.e., maximum of 18 cycles within 1 year) of HER2-targeted therapy, inclusive of therapy given 
both in the neoadjuvant and adjuvant setting.  See Section 4.3.2.3 for additional details.
ii Paclitaxel is given 80 mg/m2 IV weekly for 12 continuous weeks (Cycles 58) according to local practice guidelines. Chemotherapy should be 
given after pertuzumab and trastuzumab.  See Section 4.3.2.4 for additional details.


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jj After treatment discontinuation, information on survival follow-up and new anti-cancer therapy (including targeted therapy and immunotherapy) 
will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months for 1 year, then every 6 months 
until the end of the study (unless the patient withdraws consent or the Sponsor terminates the study).  If a patient requests to be withdrawn from 
follow-up, this request must be documented in the source documents and signed by the investigator.  If the patient withdraws from study, the 
study staff shall use a public information source (e.g., county records) to obtain information about survival status only, where allowable by local 
regulation.
kk Trastuzumab emtansine in combination with atezolizumab/placebo (as per randomized therapy) will be an option for patients who did not 
achieve pCR after completion of neoadjuvant treatment.  Trastuzumab emtansine will be given as 3.6 mg/kg IV infusion on Day 1 of a 21-day 
cycle for a maximum of 14 cycles in the adjuvant setting.  See Section 4.3.2.4 for additional details.