Conditions: Metastatic Breast Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 96
Healthy volunteers: no

Brief summary:
This study will evaluate the efficacy, safety and patient-reported outcomes of trastuzumab emtansine plus atezolizumab compared with trastuzumab emtansine plus placebo in participants with HER2-positive and PD-L1-positive LABC or MBC.Participants must have progressed either during or after prior trastuzumab- (+/- pertuzumab) and taxane-based therapy for LABC/MBC; or during (or within 6 months after completing) trastuzumab- (+/-pertuzumab) and taxane-based therapy in the neoadjuvant and/or adjuvant setting.

Detailed description:

Arms:
arm 1: Placebo matched to atezolizumab followed by trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) intravenous (IV) infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the sponsor. arm 2: Atezolizumab 1200 mg IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the Sponsor.

Interventions: intervention 1: Trastuzumab Emtansine intervention 2: Atezolizumab intervention 3: Placebo
Intervention descriptions: intervention 1: Trastuzumab emtansine 3.6 mg/kg IV infusion intervention 2: Atezolizumab 1200 mg IV infusion intervention 3: Placebo matched to atezolizumab

Protocol document:
Prot_000.pdf: 
 
Official Title: 
A Randomized, Multicenter, Double-Blind, Placebo-Controlled Phase 
III Study of the Efficacy and Safety of Trastuzumab Emtansine in 
Combination with Atezolizumab or Placebo in Patients with HER2-
Positive and PD-L1-Positive Locally Advanced or Metastatic Breast 
Cancer Who Have Received Prior Trastuzumab- (+/- Pertuzumab) 
and Taxane-Based Therapy (KATE3) 
NCT Number: 
NCT04740918 
Document Date: 
Protocol Version 4: 02-March-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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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. 
 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
Protocol MO42319, Version 4 
PROTOCOL 
TITLE: 
A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, 
PLACEBO-CONTROLLED PHASE III STUDY OF THE 
EFFICACY AND SAFETY OF TRASTUZUMAB 
EMTANSINE IN COMBINATION WITH ATEZOLIZUMAB 
OR PLACEBO IN PATIENTS WITH HER2-POSITIVE AND 
PD-L1-POSITIVE LOCALLY ADVANCED OR 
METASTATIC BREAST CANCER WHO HAVE 
RECEIVED PRIOR TRASTUZUMAB- (+/- PERTUZUMAB) 
AND TAXANE-BASED THERAPY (KATE3) 
PROTOCOL NUMBER: MO42319 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2020-002818-41 
IND NUMBER: 
71,072 
NCT NUMBER: 
NCT04740918 
TEST PRODUCT: 
Trastuzumab Emtansine (RO5304020) 
Atezolizumab (RO5541267) 
MEDICAL MONITOR: 
 MD 
SPONSOR: 
F. Hoffmann-La Roche Ltd 


Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
2/Protocol MO42319, Version 4  
APPROVAL: 
See electronic signature and date stamp on the final page 
of this document 


Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
3/Protocol MO42319, Version 4 
PROTOCOL HISTORY 
Protocol 
Associated Country-and/or Region-Specific Protocol 
Version 
Date Final 
Country and/or Region 
Version 
Date Final 
4 
See electronic date 
stamp on the final 
page of this document 
 
3 
24 February 2022 
 
3 
2 
15 March 2021 
Germany 
2 
8 October 2021 
1 
17 September 2020 
VHP 
1 
7 December 2020 


 
 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
4/Protocol MO42319, Version 4 
PROTOCOL AMENDMENT, VERSION 4: 
RATIONALE 
Protocol MO42319 has been amended to include  the Sponsor’s decision to prematurely 
terminate the study due to low enrollment rate and to align with the atezolizumab 
Investigator’s Brochure (Version 19, and Addenda 1 and 2).  Several aspects of the 
study design have also been clarified.  Substantive changes to the protocol, along with a 
rationale for each change, are summarized below.  
The following changes have been made following on the Sponsor’s decision to 
prematurely terminate the study: 
• 
Revisions have been made to the study objectives to indicate which objectives are 
no longer applicable and the corresponsing analyses that will no longer be performed 
(Section 2 and Section 6).  
• 
Section 3.1 has been updated with the decision to unblind the study. 
• 
Section 3.2 has been added to provide the rationale for unblinding and the 
implications of unblinding on the study design and assessments. 
• 
Section 3.2.1 has been added to provide further guidance on revised study 
assessments following the decision to prematurely terminate the study; the schedule 
for tumor assessments may now be carried out as per the standard of care at the 
study site.  Blood samples no longer need to be collected for biomarker, 
pharmacokinetic (PK), and anti-drug antibody (ADA) analyses.  Patient-reported 
outcome (PRO) assessments also no longer need to be completed. 
• 
It has been clarified that the objective of enrolling 350 patients will not be achieved 
(Section 3.3). 
• 
The end of study and length of study have been updated. It is clarified that time to 
closure of study sites may vary locally (Section 3.4).  
• 
Section 4.3.5, Continued Access to Trastuzumab Emtansine and Atezolizumab has 
been updated with information on continued access treatment options for patients 
who are still on treatment, either as part of an extension study (BO25430) or as part 
of a post-trial access program.  The treatment solution for each patient may vary, 
taking into account local regulations and requirements.  
• 
Wording has been amended to clarify that vital sign readings should be taken before 
and after each infusion of trastuzumab emtansine (Section 4.5.4 and Table 4).  


 
 
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• 
Tumor and response evaluations have been updated to state that tumor 
assessments may now be performed as per the study site’s standard of care, and 
are no longer required to be done every 6 weeks (Section 4.5.5.) 
• 
Tumor assessment scans will no longer be collected prospectively by the Sponsor as 
an independent review facility will not be utilized (Section 4.5.5.2). 
• 
Sections on sample collection have been updated to clarify that biomarker and other 
biological samples are no longer required to be collected (Section 4.5.7 and 
Appendix 2). 
• 
Clinical outcome assessments have been updated to clarify that PRO assessments 
no longer need to be collected (Section 4.5.9 and Appendix 3).   
• 
Wording on discontinuations is updated to require that patients in follow-up have a 
final site visit and check that any ongoing AEs have resolved before discontinuation 
from the study (Section 4.6.1).  
• 
A statement has been added that the investigators were informed of premature study 
termination on 15 December 2022 (Section 4.6.3).  
• 
Information on risks associated with trastuzumab emtansine has been updated with 
guidance for pneumonitis and ILD toxicities that are Grade 1 – 2 (Section 5.1.1.1).  
• 
The planned analyses for both PFS and OS in the context of the premature study 
termination have been clarified, as well as the impact of the premature study 
termination on the study sample size (Section 6.1). 
• 
Sections 6.4 through 6.9 (Efficacy Analyses through Health Status Utility Analyses) 
have been updated to account for the revisions made to the study objectives 
following the Sponsor’s decision to prematurely terminate the study. 
• 
Clarification has been added that an interim analysis is no longer planned given that 
the study is being prematurely terminated (Section 6.10). 
• 
Appendix 1, Schedule of Activities, has been updated with the recommendation to 
perform additional laboratory tests in Follow-up (footnote ff) and with revised sample 
collection guidance as per Sections 4.5.5, 4.5.7, and 4.5.9. 
 
The protocol has been updated to align with the Atezolizumab Investigator's Brochure, 
Version 19, and with Addendum 1 and 2, as follows: 


 
 
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6/Protocol MO42319, Version 4 
• 
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 15) 
• 
Hemophagocytic lymphohistiocytosis has been updated from a potential risk to an 
identified risk associated with atezolizumab and language has been revised 
accordingly.  The list of identified risks for atezolizumab has been revised to include 
myelitis , facial paresis, and pericardial disorders (Section 5.1.2).  
• 
Myelitis and facial paresis have been added to adverse events of special interest for 
atezolizumab (Section 5.2.3).  
• 
Appendix 15 has been revised to include autoimmune myelitis 
• 
Appendix 19 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.  
• 
The adverse event management guidelines have been updated to align with the 
Atezolizumab Investigator's Brochure, Version 19, and with Addendum 1 and 2. 
The following additional changes have been made to Appendix 20:  
• 
The option to continue treatment with trastuzumab alone and the provision of 
trastuzumab has been removed as this was added in error to the previous protocol 
version.   
• 
Management guidelines for pneumonitis and ILD (Table 1) have been updated to 
permit continuation of treatment with trastuzumab emtansine if the adverse event is 
Grade 1 –−2 and if resolved within 42 days, at the same dose level for Grade 1 and 
at one dose-level reduction for Grade 2 toxicities 
The following administrative changes have been made:  
• 
The email address for withdrawal from the Research Biosample Repository after site 
closure has been corrected (Section 4.5.11.6) 
• 
A description of the technical and organizational security measures taken to protect 
personal data has been added to align with Clinical Trials Regulation requirements 
(Section 8.4).  
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. 


 
 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
7/Protocol MO42319, Version 4 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 15 
PROTOCOL SYNOPSIS .................................................................................... 16 
1. 
BACKGROUND ............................................................................ 34 
1.1 
Background on HER2-positive Metastatic Breast Cancer ........ 34 
1.2 
Background on Trastuzumab Emtansine ................................. 35 
1.2.1 
Study TDM4370g/BO21977 (EMILIA) ...................................... 36 
1.2.2 
Study TDM4997g/BO25734 (TH3RESA) ................................. 37 
1.3 
Background on Atezolizumab .................................................. 37 
1.3.1 
Study GO29831 ....................................................................... 38 
1.3.2 
Study WO30085 (KATE2) ........................................................ 39 
1.3.2.1 
Preplanned Subgroup Analysis of Patients with PD-L1-
Positive Tumors ....................................................................... 43 
1.3.3 
Study WO29522 (IMpassion130) ............................................. 44 
1.4 
Study Rationale and Benefit-Risk Assessment ........................ 45 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 49 
2.1 
Efficacy Objectives .................................................................. 49 
2.1.1 
Primary Efficacy Objective ....................................................... 49 
2.1.2 
Secondary Efficacy Objective .................................................. 50 
2.1.3 
Exploratory Efficacy Objective ................................................. 51 
2.2 
Safety Objective ....................................................................... 51 
2.3 
Pharmacokinetic Objective ...................................................... 52 
2.4 
Immunogenicity Objective ........................................................ 52 
2.5 
Biomarker Objective ................................................................ 52 
2.6 
Health Status Objective ........................................................... 53 
3. 
STUDY DESIGN ........................................................................... 53 
3.1 
PREMATURE TERMINATION AT STUDY LEVEL .................. 53 
3.2 
Rationale and Implications of Unblinding on Study Design 
and Assessments .................................................................... 53 
3.2.1 
Revised Study Assessments ................................................... 54 
3.3 
Description of the Study ........................................................... 55 
3.3.1 
Independent Data Monitoring Committee ................................ 58 


 
 
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3.4 
End of Study and Length of Study ........................................... 59 
3.5 
Rationale for Study Design ...................................................... 60 
3.5.1 
Rationale for Atezolizumab Dose and Schedule ...................... 60 
3.5.2 
Rationale for Trastuzumab Emtansine Dose and Schedule .... 60 
3.5.3 
Rationale for Patient Population .............................................. 60 
3.5.4 
Rationale for Control Group ..................................................... 61 
3.5.5 
Rationale for Progression-Free Survival and Overall 
Survival as Multiple Primary Endpoints .................................... 61 
3.5.6 
Rationale for Biomarker Assessments ..................................... 62 
3.5.7 
Rationale for Immunogenicity Assessments ............................ 64 
3.5.8 
Rationale for Non-Standard Clinical Outcome 
Assessments ........................................................................... 65 
4. 
MATERIALS AND METHODS ...................................................... 65 
4.1 
Patients .................................................................................... 65 
4.1.1 
Inclusion Criteria ...................................................................... 65 
4.1.2 
Exclusion Criteria ..................................................................... 68 
4.2 
Method of Treatment Assignment and Blinding ....................... 73 
4.2.1 
Treatment Assignment ............................................................. 73 
4.2.2 
Blinding .................................................................................... 73 
4.3 
Study Treatment and Other Treatments Relevant to the 
Study Design ........................................................................... 75 
4.3.1 
Study Treatment Formulation and Packaging .......................... 75 
4.3.1.1 
Trastuzumab Emtansine .......................................................... 75 
4.3.1.2 
Atezolizumab and Placebo ...................................................... 75 
4.3.2 
Study Treatment Dosage, Administration, and Compliance .... 76 
4.3.2.1 
Trastuzumab Emtansine .......................................................... 76 
4.3.2.2 
Atezolizumab and Placebo ...................................................... 77 
4.3.3 
Sequence of Study Drug Administration .................................. 78 
4.3.4 
Investigational Medicinal Product Handling and 
Accountability ........................................................................... 78 
4.3.5 
Continued Access to Trastuzumab Emtansine and 
Atezolizumab ........................................................................... 79 
4.4 
Concomitant Therapy, Prohibited Food, and Additional 
Restrictions .............................................................................. 80 


 
 
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4.4.1 
Permitted Therapy ................................................................... 80 
4.4.2 
Cautionary Therapy ................................................................. 81 
4.4.2.1 
Corticosteroids, Immunosuppresive Medications and 
TNF-α Inhibitors ....................................................................... 81 
4.4.2.2 
Medications Given with Precaution due to Effects Related 
to CYP Enzymes ...................................................................... 82 
4.4.2.3 
Herbal Therapies ..................................................................... 82 
4.4.2.4 
Therapies Given for Chemotherapy Induced 
Thrombocytopenia ................................................................... 82 
4.4.3 
Prohibited Therapy .................................................................. 83 
4.4.4 
Prohibited Food ....................................................................... 83 
4.4.5 
Additional Restrictions ............................................................. 83 
4.5 
Study Assessments ................................................................. 83 
4.5.1 
Informed Consent Forms and Screening Log .......................... 84 
4.5.2 
Medical History, Baseline Conditions, Concomitant 
Medication, and Demographic Data ......................................... 84 
4.5.3 
Physical Examinations ............................................................. 84 
4.5.4 
Vital Signs ................................................................................ 85 
4.5.5 
Tumor and Response Evaluations ........................................... 85 
4.5.5.1 
Radiographic Assessments ..................................................... 86 
4.5.5.2 
Response Evaluation ............................................................... 87 
4.5.6 
Left Ventricular Ejection Fraction Assessment......................... 87 
4.5.7 
Laboratory, Biomarker, and Other Biological Samples ............ 87 
4.5.8 
Electrocardiograms .................................................................. 91 
4.5.9 
Clinical Outcome Assessments ............................................... 91 
4.5.9.1 
Data Collection Methods for Clinical Outcome 
Assessments ........................................................................... 91 
4.5.9.2 
Description of Clinical Outcome Assessment Instruments ....... 93 
4.5.10 
Blood Samples for Whole Genome Sequencing or Whole 
Exome Sequencing (Patients at Participating Sites) ................ 94 
4.5.11 
Optional Samples for Research Biosample Repository ........... 95 
4.5.11.1 
Overview of the Research Biosample Repository .................... 95 
4.5.11.2 
Approval by the Institutional Review Board or Ethics 
Committee ............................................................................... 96 
4.5.11.3 
Sample Collection .................................................................... 96 


 
 
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4.5.11.4 
Data Protection, Use, and Sharing .......................................... 96 
4.5.11.5 
Consent to Participate in the Research Biosample 
Repository................................................................................ 97 
4.5.11.6 
Withdrawal from the Research Biosample Repository ............. 98 
4.5.11.7 
Monitoring and Oversight ......................................................... 98 
4.6 
Treatment, Patient, Study, and Site Discontinuation ................ 98 
4.6.1 
Study Treatment Discontinuation ............................................. 98 
4.6.2 
Patient Discontinuation from the Study .................................. 100 
4.6.3 
Study Discontinuation ............................................................ 100 
4.6.4 
Site Discontinuation ............................................................... 100 
5. 
ASSESSMENT OF SAFETY ....................................................... 101 
5.1 
Safety Plan ............................................................................ 101 
5.1.1 
Risks Associated with Trastuzumab Emtansine .................... 102 
5.1.1.1 
Pulmonary Toxicity ................................................................ 102 
5.1.1.2 
Hepatotoxicity ........................................................................ 103 
5.1.1.3 
Left Ventricular Dysfunction ................................................... 104 
5.1.1.4 
Infusion-Related Reactions and Hypersensitivity Reactions .. 104 
5.1.1.5 
Hematologic Toxicity (Thrombocytopenia) ............................. 105 
5.1.1.6 
Hemorrhage ........................................................................... 106 
5.1.1.7 
Neurotoxicity .......................................................................... 106 
5.1.1.8 
Extravasation ......................................................................... 106 
5.1.2 
Risks Associated with Atezolizumab ...................................... 106 
5.1.3 
Risks Associated with Combination Use of Atezolizumab 
and Trastuzumab Emtansine ................................................. 107 
5.1.4 
Management of Adverse Events ............................................ 107 
5.1.4.1 
Dose Modification .................................................................. 107 
5.2 
Safety Parameters and Definitions ........................................ 109 
5.2.1 
Adverse Events ...................................................................... 109 
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) .................................................... 110 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................. 111 


 
 
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5.3.1 
Adverse Event Reporting Period ............................................ 112 
5.3.2 
Eliciting Adverse Event Information ....................................... 112 
5.3.3 
Assessment of Severity of Adverse Events ........................... 112 
5.3.4 
Assessment of Causality of Adverse Events.......................... 113 
5.3.5 
Procedures for Recording Adverse Events ............................ 114 
5.3.5.1 
Infusion-Related Reactions and Cytokine Release 
Syndrome .............................................................................. 114 
5.3.5.2 
Diagnosis versus Signs and Symptoms ................................. 115 
5.3.5.3 
Adverse Events That Are Secondary to Other Events ........... 115 
5.3.5.4 
Persistent or Recurrent Adverse Events ................................ 115 
5.3.5.5 
Abnormal Laboratory Values ................................................. 116 
5.3.5.6 
Abnormal Vital Sign Values ................................................... 117 
5.3.5.7 
Abnormal Liver Function Tests .............................................. 117 
5.3.5.8 
Deaths ................................................................................... 117 
5.3.5.9 
Preexisting Medical Conditions .............................................. 118 
5.3.5.10 
Lack of Efficacy or Worsening of Locally Advanced or 
Metastatic Breast Cancer ...................................................... 118 
5.3.5.11 
Hospitalization or Prolonged Hospitalization .......................... 119 
5.3.5.12 
Cases of Accidental Overdose or Medication Error ............... 119 
5.3.5.13 
Patient-Reported Outcome Data ............................................ 120 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................. 120 
5.4.1 
Medical Monitors and Emergency Medical Contacts ............. 121 
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 .............................. 122 
5.4.3.1 
Pregnancies in Female Patients ............................................ 122 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ................. 123 
5.4.3.3 
Abortions................................................................................ 123 
5.4.3.4 
Congenital Anomalies/Birth Defects ...................................... 124 
5.5 
Follow-Up of Patients after Adverse Events........................... 124 
5.5.1 
Investigator Follow-Up ........................................................... 124 


 
 
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5.5.2 
Sponsor Follow-Up ................................................................ 124 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period .................................................................... 125 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............. 125 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....... 126 
6.1 
Determination of Sample Size ............................................... 126 
6.2 
Summaries of Conduct of Study ............................................ 126 
6.3 
Summaries of Treatment Group Comparability ...................... 126 
6.4 
Efficacy Analyses ................................................................... 127 
6.4.1 
Primary Efficacy Endpoint ...................................................... 127 
6.4.2 
Secondary Efficacy Endpoints ............................................... 128 
6.4.3 
Exploratory Efficacy Endpoints .............................................. 129 
6.5 
Safety Analyses ..................................................................... 129 
6.5.1 
Analyses of Exposure, Adverse Event, Laboratory, Vital 
Sign, and ECG Data .............................................................. 129 
6.5.2 
Exploratory Analyses of PRO-CTCAE Data .......................... 130 
6.6 
Pharmacokinetic Analyses ..................................................... 130 
6.7 
Immunogenicity Analyses ...................................................... 130 
6.8 
Biomarker Analyses ............................................................... 130 
6.9 
Health Status Utility Analyses ................................................ 130 
6.10 
Interim Analyses .................................................................... 131 
7. 
DATA COLLECTION AND MANAGEMENT ............................... 131 
7.1 
Data Quality Assurance ......................................................... 131 
7.2 
Electronic Case Report Forms ............................................... 131 
7.3 
Electronic Patient-Reported Outcome Data ........................... 131 
7.4 
Source Data Documentation .................................................. 132 
7.5 
Use of Computerized Systems .............................................. 133 
7.6 
Retention of Records ............................................................. 133 
8. 
ETHICAL CONSIDERATIONS .................................................... 133 
8.1 
Compliance with Laws and Regulations ................................ 133 
8.2 
Informed Consent .................................................................. 134 
8.3 
Institutional Review Board or Ethics Committee .................... 135 


 
 
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8.4 
Confidentiality ........................................................................ 135 
8.5 
Financial Disclosure ............................................................... 136 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................... 136 
9.1 
Study Documentation ............................................................ 136 
9.2 
Protocol Deviations ................................................................ 136 
9.3 
Management of Study Quality ................................................ 137 
9.4 
Site Inspections ..................................................................... 137 
9.5 
Administrative Structure ......................................................... 137 
9.6 
Dissemination of Data and Protection of Trade Secrets ........ 138 
9.7 
Protocol Amendments ........................................................... 139 
10. 
REFERENCES............................................................................ 140 
 
 
LIST OF TABLES 
Table 1 
KATE2 Safety Profile According to Study Arms .......................... 41 
Table 2 
Administration of First and Subsequent Infusions of 
Trastuzumab Emtansine ............................................................. 77 
Table 3 
Administration of First and Subsequent Atezolizumab 
Infusions...................................................................................... 78 
Table 4 
Timing for Vital Sign Measurements for First and 
Subsequent Infusions ................................................................. 85 
Table 5 
Dose Modification Scheme for Trastuzumab Emtansine .......... 109 
Table 6 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 113 
Table 7 
Causal Attribution Guidance ..................................................... 114 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 58 
 
 
LIST OF APPENDICES 
Appendix 1 
 Schedule of Activities ............................................................... 147 
Appendix 2 
 Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples ................................................................... 153 
Appendix 3 
 Schedule of Patient-Reported Outcome Assessments ............ 158 


 
 
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Appendix 4 
 Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1)........................................................ 160 
Appendix 5 
 Ventana HER2 IHC Assay ....................................................... 169 
Appendix 6 
 Ventana HER2 Dual ISH DNA Probe Cocktail ......................... 171 
Appendix 7 
 Ventana PD-L1 (SP142) Assay ................................................ 174 
Appendix 8 
 New York Heart Association Classification .............................. 176 
Appendix 9 
 ECOG Performance Status Scale ............................................ 177 
Appendix 10 
 European Organisation for Research and Treatment of 
Cancer Quality-of-Life Questionnaire:  EORTC QLQ-C30 ........ 178 
Appendix 11 
 EORTC QLQ-Breast Cancer Module (BR23) Questionnaire.... 180 
Appendix 12 
 EuroQol 5-Dimension 5 Levels Questionnaire: EQ-5D-5L ....... 182 
Appendix 13 
 National Cancer Institute Patient Reported Outcomes 
Common Terminology Criteria for Adverse Events (PRO-
CTCAE) instrument ................................................................... 185 
Appendix 14 
 Burden of Treatment Item from EORTC .................................. 188 
Appendix 15 
 Preexisting Autoimmune Diseases and Immune Deficiencies . 189 
Appendix 16 
 Guidelines for Liver Biopsy ...................................................... 191 
Appendix 17 
 Anaphylaxis Precautions .......................................................... 192 
Appendix 18 
 Guidelines for Management of Adverse Events Associated 
with Trastuzumab Emtansine .................................................... 193 
Appendix 19 
 Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab ............................................................................ 197 
Appendix 20 
 Guidelines for Management of Adverse Events that are 
Potential Overlapping Toxicities Associated with 
Trastuzumab Emtansine in Combination with Atezolizumab .... 225 
 


 
 
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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, 
PLACEBO-CONTROLLED PHASE III STUDY OF 
THE EFFICACY AND SAFETY OF TRASTUZUMAB 
EMTANSINE IN COMBINATION WITH 
ATEZOLIZUMAB OR PLACEBO IN PATIENTS WITH 
HER2-POSITIVE AND PD-L1-POSITIVE LOCALLY 
ADVANCED OR METASTATIC BREAST CANCER 
WHO HAVE RECEIVED PRIOR TRASTUZUMAB- 
(+/- PERTUZUMAB) AND TAXANE-BASED 
THERAPY (KATE3) 
PROTOCOL NUMBER: MO42319 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2020-002818-41 
IND NUMBER: 
71,072 
NCT NUMBER: 
To be determined 
TEST PRODUCT: 
Trastuzumab Emtansine (RO5304020) 
Atezolizumab (RO5541267) 
MEDICAL MONITOR: 
 
 MD 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator's Name  (print) 
 
 
 
 
 
Principal Investigator's Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your local study monitor. 
 


 
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PROTOCOL SYNOPSIS 
TITLE: 
A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, PLACEBO-
CONTROLLED PHASE III STUDY OF THE EFFICACY AND 
SAFETY OF TRASTUZUMAB EMTANSINE IN COMBINATION 
WITH ATEZOLIZUMAB OR PLACEBO IN PATIENTS WITH HER2-
POSITIVE AND PD-L1-POSITIVE LOCALLY ADVANCED OR 
METASTATIC BREAST CANCER WHO HAVE RECEIVED PRIOR 
TRASTUZUMAB- (+/- PERTUZUMAB) AND TAXANE-BASED 
THERAPY (KATE3) 
PROTOCOL NUMBER: 
MO42319 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2020-002818-41 
IND NUMBER: 
71,072 
NCT NUMBER: 
To be determined 
TEST PRODUCT: 
Trastuzumab Emtansine (RO5304020) 
Atezolizumab (RO5541267) 
PHASE: 
Phase III 
INDICATION: 
Locally advanced / metastatic breast cancer 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy, safety, pharmacokinetics, and patient-reported outcomes of 
trastuzumab emtansine plus atezolizumab compared with trastuzumab emtansine plus placebo 
in patients with human epidermal growth factor 2 (HER2)-positive and programmed death-
ligand 1 (PD-L1)-positive locally advanced (LABC) or metastatic breast cancer (MBC). Patients 
must have progressed either during or after prior trastuzumab- (+/- pertuzumab) and taxane-
based therapy for LABC/MBC; or during (or within 6 months after completing) trastuzumab- 
(+/- pertuzumab) and taxane-based therapy in the neoadjuvant and/or adjuvant setting.  
Specific objectives and corresponding endpoints for the study are outlined below. 
PRIMARY EFFICACY OBJECTIVE 
The trial will compare trastuzumab emtansine given at a dose of 3.6 mg/kg by IV infusion, q3w 
plus atezolizumab administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each 21-
day cycle with trastuzumab emtansine given at a dose of 3.6 mg/kg by IV infusion, q3w plus 
placebo administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each 21-day cycle 
in patients with HER2-positive and PD-L1-positive LABC or MBC who have progressed either 
during or after prior trastuzumab- (+/- pertuzumab) and taxane-based therapy for LABC/MBC, 
or during (or within 6 months after completing) trastuzumab- (+/- pertuzumab) and taxane-
based therapy in the neoadjuvant and/or adjuvant setting. 
The two primary comparisons of interest will be the hazard ratios for PFS and OS as defined 
below. The primary trial objective is to demonstrate superiority of the experimental over the 
control treatment in either or both comparisons. 


 
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• 
Progression-free survival (PFS), defined as the time from randomization to the first 
occurrence of documented disease progression, as determined by investigator assessment 
using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or death from any 
cause, whichever occurs first 
• 
Overall survival (OS), defined as the time from randomization to death from any cause 
Following the Sponsor’s decision to prematurely terminate the study, these objectives are no 
longer applicable. Accordingly, the analyses of PFS and OS will only be reported in a 
descriptive way. No formal testing will be performed and no control for the overall type I 
error (α) accounting for the two primary endpoints will be implemented. Consequently, p-
values will not be able to be claimed as statistically significant and therefore will be reported 
as descriptive in nature. 
 
SECONDARY EFFICACY OBJECTIVE 
The secondary efficacy objective for this study is to evaluate the efficacy of trastuzumab 
emtansine plus atezolizumab compared with trastuzumab emtansine plus placebo on the basis 
of the following endpoints: 
• 
Objective response rate (ORR), defined as a complete response (CR) or partial response 
(PR) on two consecutive assessments, at least 28 days apart, as determined by 
investigator assessment using RECIST version 1.1 
• 
Duration of objective response (DOR), defined as the time from first occurrence of a 
documented objective response to disease progression, as determined by investigator 
assessment using RECIST v1.1 or death from any cause, whichever occurs first 
• 
PFS, defined as the time from randomization to the first occurrence of disease progression, 
as determined by a blinded independent central review committee using RECIST v1.1, or 
death from any cause, whichever occurs first 
• 
PFS in patients with baseline brain metastases as determined by investigator assessment 
using RECIST version 1.1 
• 
OS in patients with baseline brain metastases defined as the time from randomization to 
death from any cause 
• 
Central nervous system (CNS) PFS as determined by investigator assessment using 
RECIST version 1.1 in patients with or without baseline CNS metastases 
• 
Mean absolute and mean change-from-baseline scores in function (Physical, Role) and 
global health status (GHS)/quality of life (QoL) as measured by the scales of the European 
Organisation for Research and Treatment of Cancer (EORTC QLQ-C30) 
• 
The proportion of patients with clinically meaningful deterioration in GHS/QoL physical, and 
role function as measured by scales of the EORTC QLQ-C30  
Following the Sponsor’s decision to prematurely terminate the study, analysis of PFS as 
determined by a blinded independent central review committee will no longer be conducted. 
Similarly, analysis based on the EORTC QLQ-C30 data will no longer be conducted. 
 
EXPLORATORY EFFICACY OBJECTIVE 
The exploratory efficacy objective for this study is to evaluate the efficacy of trastuzumab 
emtansine plus atezolizumab compared with trastuzumab emtansine plus placebo on the basis 
of the following endpoints: 
• 
Mean absolute and mean change-from-baseline scores in the remaining functions 
(Cognitive, Emotional, and Social), and disease- or treatment-related symptom scores of 
the EORTC QLQ-C30 and EORTC QLQ-Breast Cancer Module 23 Questionnaire (EORTC 
QLQ-BR23) 
Following the Sponsor’s decision to prematurely terminate the study, this exploratory 
efficacy objective is no longer applicable and corresponding analysis will no longer be 
performed. 
 


 
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SAFETY OBJECTIVE 
The safety objective for this study is to evaluate the safety of trastuzumab emtansine plus 
atezolizumab compared with trastuzumab emtansine plus placebo 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 (NCI CTCAE) 
Version 5.0 
• 
Change from baseline in targeted clinical laboratory test results 
 
The exploratory safety objective for this study is to evaluate the safety of trastuzumab 
emtansine plus atezolizumab compared with trastuzumab emtansine plus placebo on the basis 
of the following endpoints: 
• 
Presence, frequency of occurrence, severity, and/or degree of interference with daily 
function of selected symptomatic treatment toxicities (i.e., fatigue, chills, headache, cough, 
peripheral neuropathy, rash, aching muscles, aching joints, pain), as measured by the 
National Cancer Institute (NCI) Patient Reported Outcomes Common Terminology Criteria 
for Adverse Events (PRO-CTCAE) instrument 
• 
Change from baseline in symptomatic treatment toxicities, as measured by the PRO-
CTCAE at pre-specified time points and an additional item regarding the overall burden 
experienced due to side effects of treatment from the EORTC item library 
Following the Sponsor’s decision to prematurely terminate the study, the exploratory safety 
objectives related to the PRO-CTCAE instrument are no longer applicable. The corresponding 
analyses will not be performed.  
 
PHARMACOKINETIC OBJECTIVE 
The pharmacokinetic (PK) objectives for this study are as follows: 
• 
To characterize the PK of trastuzumab emtansine when given in combination with 
atezolizumab 
• 
To characterize the PK of atezolizumab when given in combination with trastuzumab 
emtansine 
Following the Sponsor’s decision to prematurely terminate the study, these objectives are no 
longer applicable.  Accordingly, the corresponding analyses will not be performed.  
 
IMMUNOGENICITY OBJECTIVE 
The immunogenicity objective for this study is to evaluate the immune response to atezolizumab 
and trastuzumab emtansine when given in combination on the basis of the following endpoints: 
• 
To characterize the prevalence and incidence of anti-drug antibodies (ADA) to atezolizumab 
in the presence of trastuzumab emtansine at pre-specified timepoints 
• 
To characterize the prevalence and incidence of ADA to trastuzumab emtansine in the 
presence and absence of atezolizumab at pre-specified timepoints 
 
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  
• 
Following the Sponsor’s decision to prematurely terminate the study, these objectives are 
no longer applicable. Accordingly, the corresponding analyses will not be performed.  
 
BIOMARKER OBJECTIVE 
The exploratory biomarker objective for this study is to identify and/or evaluate biomarkers that 
are predictive of response to atezolizumab in combination with trastuzumab emtansine 
(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 and trastuzumab emtansine, are associated with susceptibility to 


 
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developing adverse events or can lead to improved adverse event monitoring or investigation 
(i.e., safety biomarkers), can provide evidence of atezolizumab and/or trastuzumab emtansine 
activity (i.e., pharmacodynamic biomarkers), or can increase the knowledge and understanding 
of disease biology and drug safety, on the basis of the following endpoints: 
• 
Association of baseline immune status (may include but not limited to: protein, mRNA 
markers, T cell markers based on CD8 immunohistochemistry [IHC], and stromal tumor-
infiltrating lymphocytes [TILs]) with efficacy 
• 
Association of baseline HER2 expression level (protein and/or gene copy number/ratio) with 
efficacy 
• 
Association of baseline PD-L1 expression level (≥1% and <5% IC vs ≥5% IC) with efficacy  
• 
Relationship between biomarkers in blood, plasma, and tumor tissue and efficacy, safety, 
PK, immunogenicity, tumor immunobiology, mechanisms of resistance 
Following the Sponsor’s decision to prematurely terminate the study, the objectives 
associated with efficacy are no longer applicable. Some descriptive analyses may be conducted 
as deemed appropriate.  
 
HEALTH STATUS OBJECTIVE 
The exploratory health status utility objective for this study is to evaluate health status utility 
scores of patients treated with trastuzumab emtansine plus atezolizumab compared with 
trastuzumab emtansine plus placebo on the basis of the following endpoint: 
• 
Health utility and visual analog score (VAS) of the European Quality of Life 5-Dimension 
Questionnaire (5-level version; EQ-5D-5L) for pharmacoeconomic modeling at specified 
timepoints 
Following the Sponsor’s decision to prematurely terminate the study, these objectives are no 
longer applicable and the corresponding analyses will not be performed. 
 
 
STUDY DESIGN 
PREMATURE TERMINATION AND UNBLINDING AT STUDY LEVEL   
The Sponsor has decided to prematurely terminate the study due to a lower-than-expected 
enrolment rate, which significantly extended the recruitment timelines. The investigators 
were informed of premature study termination on 15 December 2022 by a study memo 
communicating this decision. 
Following a discussion between the investigator and the patient regarding the premature 
termination, the patient may consent to continue study treatment (i.e., either trastuzumab 
emtansine and atezolizumab or trastuzumab emtansine as a single agent; placebo will no 
longer be administered following unblinding of treatment assignment) if considered clinically 
appropriate by the investigator.  
Patients should continue to receive study treatment and undergo the revised study 
assessments as described below: 
 
Following the Sponsor’s decision to prematurely terminate the study, tumor assessments will 
be conducted as per standard of care at the site.  
After unblinding, patients will continue to be followed for tumor assessments until disease 
progression or until the patient discontinues from the study. All tumor assessments must be 
recorded in the eCRF. Tumor assessment scans will no longer be collected prospectively by the 
Sponsor as an independent review facility will not be utilized.  
Blood samples will no longer be drawn for PK and ADA analyses or for biomarker analyses, 
as these analyses will no longer take place. Patient-Reported Outcome (PRO) assessments 
will also no longer be collected.  
All safety assessments in the Schedule of Activities (Appendix 1) should be continued. All 
data should be recorded in the eCRF. 


 
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DESCRIPTION OF STUDY 
This is a Phase III, randomized, multicenter, international, two-arm, double-blind, placebo-
controlled clinical trial. The study will evaluate the efficacy, safety, pharmacokinetics, and 
patient-reported outcomes of trastuzumab emtansine plus atezolizumab compared with 
trastuzumab emtansine plus placebo in patients with HER2-positive and PD-L1-positive locally 
advanced (LABC) or metastatic breast cancer (MBC) who have progressed either during or 
after prior trastuzumab- (+/- pertuzumab) and taxane-based therapy for LABC/MBC, or during 
(or within 6 months after completing) trastuzumab- (+/- pertuzumab) and taxane-based therapy 
in the neoadjuvant and/or adjuvant setting. Previous adjuvant treatment with trastuzumab 
emtansine is not allowed if progression occurred during, or within 6 months after completing 
treatment. 
HER2 positivity and PD-L1 positivity of the tumor tissues will be determined by a central 
laboratory. Patients whose tumors are not centrally determined to be both HER2-positive and 
PD-L1-positive will not be eligible.  
Patients may be prescreened for HER2 and PD-L1 status at a central laboratory by participating 
in a separate prescreening consent. 
Approximately 350 patients will be enrolled in the study at approximately 175 sites worldwide.  
Patients will be randomized into one of the following treatment arms in a 1:1 ratio by means of a 
permuted block randomization scheme through the use of an interactive Web or voice response 
system: 
• 
Arm A: trastuzumab emtansine 3.6 mg/kg and placebo, q3w 
• 
Arm B: trastuzumab emtansine 3.6 mg/kg and atezolizumab 1200 mg, q3w  
 
Arm A and Arm B will be blinded with respect to administration of atezolizumab or placebo. 
Crossover between treatment arms will not be permitted. 
Randomization will be stratified according to:  
• 
Local hormonal status (estrogen receptor [ER] and/or progesterone receptor [PgR] positive 
vs. ER and PgR negative/unknown), 
• 
Disease status (visceral metastasis without brain metastasis vs. non-visceral metastasis 
only without brain metastasis [including locally advanced disease] vs. brain metastasis), 
• 
World Region (Western Europe vs U.S. vs. Rest of World).  
 
Patients must have measurable disease at baseline that is evaluable per RECIST v1.1.  
Patients must also have unresectable, locally advanced or metastatic disease. Locally 
advanced disease must not be amenable to resection or other local therapy with curative intent.    
Patients will continue treatment until investigator-assessed radiographic disease progression 
per RECIST v1.1, withdrawal of consent, death, or intolerable toxicity, whichever occurs first. 
Patients with isolated CNS progression that require local therapy only will be allowed to 
continue with study treatment as per investigator decision. These patients will be recorded as 
disease progression for PFS analysis but will remain blinded and continue with treatment as per 
initial randomization until further disease progression in whichever location, withdrawal of 
consent, death, or intolerable toxicity, whichever occurs first. 
Patients will undergo scheduled tumor assessment every 6 weeks (± 7 days) that will continue 
until investigator-assessed radiographic disease progression per RECIST v1.1, withdrawal of 
consent, death, or study termination by the Sponsor, whichever occurs first. Patients who 
discontinue study treatment for reasons other than disease progression, even if they start new 
anti-cancer therapy, will continue to undergo tumor assessment every 6 weeks (± 7 days) until 
disease progression.  Following the Sponsor’s decision to prematurely terminate the study, 
tumor assessments will be conducted as per standard of care at the site.  
Tumor response will be based on RECIST v1.1 for estimation of PFS, ORR, and DOR. Tumor 
assessment scans will be collected prospectively by an independent review facility. Response 
will also be assessed by a blinded independent central review committee. Following premature 


 
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study termination, tumor assessment scans will no longer be collected prospectively by the 
Sponsor as an independent review facility will not be utilized. 
Safety assessments will include the incidence, nature, 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. 
Serum samples will be collected to monitor pharmacokinetics and to detect presence of 
antibodies to trastuzumab emtansine and atezolizumab.  Tumor tissues, plasma and whole 
blood samples will be collected for exploratory biomarker assessments. Following the 
Sponsor’s decision to prematurely terminate the study, samples for PK, ADA and exploratory 
biomarker research will no longer be collected.. 
Tumor tissue (historical sample or by new biopsy) will be collected at screening. A tissue 
sample from mandatory biopsy will be collected at the time of first evidence of radiographic 
disease progression per RECIST v1.1 (prior to the start of new anti-cancer treatment), unless 
not clinically feasible as assessed by the investigator.  These samples will enable analysis of 
tumor tissue biomarkers related to resistance, disease progression, and clinical benefit of 
trastuzumab emtansine in combination with atezolizumab. 
After the Study Drug Completion Visit, all patients (regardless of reason for discontinuation) will 
be followed up for their survival status and new anti-cancer therapy every 3 months until death, 
loss to follow-up, withdrawal of consent, or study termination by the Sponsor.  After patients 
discontinue from study treatment, information on subsequent anti-cancer therapies will be 
collected according to the same schedule as survival follow-up. 
NUMBER OF PATIENTS 
Approximately 350 patients will be enrolled in the study at approximately 175 sites worldwide. 
Following the Sponsor’s decision to prematurely terminate the study, the objective of 
enrolling 350 patients will not be achieved. 
TARGET POPULATION 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form by patient or legally-authorized representative 
• 
Age ≥ 18 years at time of signing Informed Consent Form 
• 
Ability to comply with the study protocol 
• 
Histologically determined (in a central laboratory) HER2+/PD-L1+ LABC or MBC that is 
unresectable and previously treated with multimodality therapy: 
– 
Progression must have occurred during or after most recent treatment for LABC/MBC 
or during, or within 6 months after completing, neoadjuvant and/or adjuvant therapy 
– 
Prior treatment for breast cancer with trastuzumab (+/- pertuzumab) and taxane in the 
neoadjuvant and/or adjuvant, unresectable locally advanced, or metastatic settings 
– 
Patients must not have received more than two prior lines of therapy in the metastatic 
setting 
– 
Previous exposure to trastuzumab emtansine in the early breast cancer (EBC) setting 
is allowed only if disease recurrence occurred more than 6 months after completing, 
adjuvant trastuzumab emtansine. Previous exposure to trastuzumab emtansine in the 
metastatic setting is not allowed 
– 
Previous treatment with anti-HER2 agents (including, but not limited to, lapatinib, 
neratinib, tucatinib, trastuzumab deruxtecan, pyrotinib) and CD137 agonists, anti-
programmed death−1 (PD-1), or anti-PD-L1 therapeutic antibody or pathway−targeting 
agents is allowed 
– 
Patients who are receiving bisphosphonate therapy specifically to prevent skeletal 
events and who do not have a history of clinically significant hypercalcemia are eligible 
– 
Concurrent hormonal treatment for patients with hormone-positive disease is not 
allowed in the study 


 
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– 
Localized palliative radiation therapy is allowed for symptom management if finalized 
before enrollment. The patient must have recovered from any resulting acute toxicity (to 
Grade ≤ 1) prior to study treatment initiation. There is no required minimum recovery 
period 
• 
Measurable disease per RECIST v1.1 
Previously irradiated lesions can be considered as measurable disease only if 
progressive disease has been unequivocally documented at that site since 
radiation 
• 
Prospective central determination of representative tumor tissue specimen(s) prior to 
randomization of: 
– 
HER2-positive breast cancer as defined by an IHC score of 3+ or gene amplified by in 
situ hybridization (ISH) as defined by a ratio of ≥ 2.0 for the number of gene copies to 
the number of chromosome 17 copies 
– 
PD-L1 positivity defined by expression on tumor-infiltrating immune cells (IC) covering 
≥ 1% of tumor area by IHC using the PD-L1 (SP142) assay 
• 
For patients with bilateral breast cancer (synchronous or developed at a later stage), HER2 
positivity must be centrally determined preferably in a metastatic biopsy or if not available in 
primary tumor from both left and right breast; at least one biopsy must be centrally 
determined as PD-L1 positive. 
• 
For patients with initially multicentric tumors (multiple tumors involving more than one 
quadrant) or multifocal tumors (more than one mass confined to the same quadrant as the 
primary tumor), HER2 positivity must be centrally determined preferably in a metastatic 
biopsy or if not available in primary tumor, provided that: 
– 
For multicentric tumors all discrete lesions are centrally confirmed as HER2-positive 
and at least one lesion is centrally determined as PD-L1 positive 
– 
For multifocal tumors at least one focus is centrally confirmed as HER2-positive and 
PD-L1 positive 
• 
A formalin-fixed, paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) 
or at least 17 slides containing unstained, freshly cut, serial sections must be submitted 
(preferably along with an associated pathology report) prior to study enrollment. The 
unstained slides for staining must be within the current documented cutslide stability 
window.  The sample needs to be of good quality based on total and viable tumor content.   
If archival tumor tissue is unavailable or is determined to be unsuitable for required testing, 
tumor tissue must be obtained from a biopsy performed at screening.  A biopsy may also be 
performed at screening if a patient's archival tissue test results do not meet eligibility 
criteria. 
Cytological or fine-needle aspiration samples and bone specimens are not 
acceptable for central testing to determine eligibility. 
• 
Willing to provide blood samples before treatment start, while on-study, and at progression, 
for standard of care follow-up and exploratory research on biomarkers 
• 
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 
• 
Life expectancy ≥ 6 months 
• 
Adequate hematologic and end-organ function, defined by the following laboratory test 
results, obtained within 7 days prior to initiation of study treatment: 
– 
ANC ≥ 1.5 x 109/L (≥ 1500/µL) without granulocyte colony-stimulating factor support  
– 
Lymphocyte count ≥ 0.5 x 109/L (≥ 500/µL) 
– 
Platelet count ≥ 100 x 109/L (≥ 100,000/µL) without transfusion   
– 
Hemoglobin ≥ 90 g/L (≥ 9 g/dL) 
Patients may be transfused to meet this criterion 


 
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– 
AST, ALT, and alkaline phosphatase (ALP) ≤ 2.5 x upper limit of normal (ULN), with the 
following exceptions: 
Patients with documented liver metastases: AST and ALT ≤ 5 x ULN 
Patients with documented liver or bone metastases: ALP ≤ 5 x ULN 
– 
Total bilirubin ≤ 1.5 x ULN with the following exception: 
Patients with known Gilbert disease:  total bilirubin ≤ 3 x ULN 
– 
Creatinine ≤ 1.5 x ULN or Creatinine clearance ≥ 30 mL/min (calculated using the 
Cockcroft-Gault formula) 
– 
Albumin ≥ 25 g/L (≥ 2.5 g/dL) 
– 
For patients not receiving therapeutic anticoagulation: INR and aPTT ≤ 1.5 x ULN 
– 
For patients receiving therapeutic anticoagulation: stable anticoagulant regimen 
• 
Negative HIV test at screening 
• 
For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, 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 7 months after the final dose of 
study treatment. 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 is not permanently infertile due to surgery (i.e., removal of ovaries, 
fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian 
agenesis). Per this definition, a woman with a tubal ligation is considered to be of childbearing 
potential. 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, hormonal contraceptives that inhibit ovulation, and hormone-releasing 
intrauterine devices and copper intrauterine devices; 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 
If required per local guidelines or regulations, locally recognized adequate methods 
of contraception and information about the reliability of abstinence will be described 
in the local Informed Consent Form 
• 
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 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 
7 months after the final dose of study treatment. Men must refrain from donating 
sperm during this same period 
With a pregnant female partner, men must remain abstinent or use a condom 
during the treatment period and for 7 months after the final dose of study treatment 
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 


 
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abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) 
and withdrawal are not acceptable methods of contraception 
If required per local guidelines or regulations, locally recognized adequate methods 
of contraception and information about the reliability of abstinence will be described 
in the local Informed Consent Form 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding 
fungal infections of nail beds) at study enrollment, or any major episode of infection 
requiring treatment with IV antibiotics or hospitalization (for complications of infections or 
relating to the completion of the course of antibiotics) within 4 weeks prior to Cycle 1, Day 1 
This also applies to patients with suspected or confirmed COVID-19 infection 
• 
Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study 
treatment 
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection 
or chronic obstructive pulmonary disease exacerbation) are eligible for the study 
• 
Receipt of any anti-cancer drug/biologic or investigational treatment 21 days prior to Cycle 
1, Day 1 except hormone therapy, which can be given up to 7 days prior to Cycle 1, Day 1; 
recovery of treatment-related toxicity consistent with other eligibility criteria 
• 
Prior treatment with trastuzumab emtansine in metastatic setting 
• 
History of exposure to the following cumulative doses of anthracyclines as specified below: 
– 
Doxorubicin > 500 mg/m2 
– 
Liposomal doxorubicin > 500 mg/m2 
– 
Epirubucin > 720 mg/m2 
– 
Mitoxantrone > 120 mg/m2 
– 
Idarubicin > 90 mg/m2 
If another anthracycline or more than one anthracycline has been used, then the 
cumulative dose must not exceed the equivalent of 500 mg/m2 doxorubicin 
• 
Symptomatic or actively progressing central nervous system (CNS) metastases 
Asymptomatic CNS lesions ≤ 2cm without clinical requirement for local intervention 
(whole brain radiation therapy and/or stereotactic radiosurgery and/or surgery) are 
eligible, provided that all of the following criteria are met; it is for investigator to 
decide if local intervention is indicated  
Asymptomatic patients with treated CNS lesions are eligible, provided that all of the 
following criteria are met: 
 
Measurable disease, per RECIST v1.1, must be present outside the CNS 
 
No brain lesions thought to require immediate local therapy 
 
Only supratentorial and cerebellar metastases allowed (i.e., no 
metastases to midbrain, pons, medulla, or spinal cord) 
 
The patient has no history of intracranial hemorrhage or spinal cord 
hemorrhage 
 
The patient has not undergone stereotactic radiotherapy within 7 days 
prior to initiation of study treatment, whole-brain radiotherapy within 21 
days prior to initiation of study treatment, or neurosurgical resection 
within 28 days prior to initiation of study treatment 
 
Anticonvulsant therapy at a stable dose is permitted 
No ongoing use of systemic corticosteroids for control of symptoms of 
brain metastases at a total daily dose of >2 mg of dexamethasone (or 


 
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equivalent). Subjects on a chronic stable dose of ≤2 mg total daily of 
dexamethasone (or equivalent) are eligible 
Note: Patients with new asymptomatic CNS metastases detected at the screening 
scan who require radiation therapy and/or surgery for CNS metastases, must 
receive it before screening. Following local intervention, these patients may be 
eligible without the need for an additional brain scan prior to enrollment, if all other 
criteria are met. 
• 
History of leptomeningeal disease 
• 
Spinal cord compression not definitively treated with surgery and/or radiation, or previously 
diagnosed and treated spinal cord compression without evidence that disease has been 
clinically stable for > 2 weeks prior to randomization 
• 
Uncontrolled tumor-related pain 
Patients requiring pain medication must be on a stable regimen at study entry 
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated ≥ 14 days prior 
to Cycle 1, Day 1. The patient must have recovered from any resulting acute 
toxicity (to Grade ≤ 1) prior to study treatment initiation 
Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not currently 
associated with spinal cord compression) should be considered for loco-regional 
therapy, if appropriate, prior to enrollment 
• 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently) 
Patients with indwelling catheters (e.g., PleurX®) are allowed 
• 
Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, 
calcium > 12 mg/dL, or corrected calcium greater than ULN) 
• 
Current Grade ≥ 3 peripheral neuropathy (according to the NCI CTCAE v5.0) 
• 
Active hepatitis B (defined as having a positive hepatitis B surface antigen [HbsAg] test at 
screening) or hepatitis C 
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection 
(defined as having a negative HbsAg test and a positive antibody to hepatitis B 
core antigen [anti-HBc] antibody test accompanied by a negative HBV DNA test) 
are eligible 
Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase 
chain reaction is negative for HCV RNA 
• 
Current treatment with anti-viral therapy for HBV 
• 
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, anti-phospholipid antibody syndrome, 
granulomatosis with polyangiitis, Sjögren syndrome, Guillain-Barré syndrome, or multiple 
sclerosis, 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 of following conditions are met: 
 
Rash must cover < 10% of body surface area 


 
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 
Disease is well controlled at baseline and requires only low-potency 
topical corticosteroids 
 
There has been 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 
 
Patients with psoriasis must have a baseline ophthalmologic exam to 
rule out ocular manifestations 
• 
Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia 
• 
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 CT scan 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted 
• 
Active tuberculosis 
• 
Cardiopulmonary dysfunction as defined by: 
– 
Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg with or 
without medication) 
– 
Inadequate left ventricular ejection fraction at baseline, < 50% by either ECHO or 
MUGA 
– 
History of symptomatic congestive heart failure (CHF)-Grade ≥ 3 per NCI CTCAE 
version 5.0 or Class ≥ II New York Health Association 
– 
History of a decrease in left ventricular ejection fraction to < 40% or symptomatic CHF 
with prior trastuzumab treatment 
– 
Myocardial infarction or unstable angina within 6 months of randomization  
– 
Current dyspnea at rest due to complications of advanced malignancy, or other disease 
requiring continuous oxygen therapy 
– 
Evidence of transmural infarction on ECG 
– 
Significant symptoms (Grade ≥ 2) relating to LVEF, cardiac arrhythmia, or cardiac 
ischemia 
– 
High-risk uncontrolled arrhythmias (i.e., supraventricular 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]) 
• 
Major surgical procedure, other than for diagnosis, or significant traumatic injury within 4 
weeks prior to initiation of study treatment, or anticipation of need for a major surgical 
procedure during the study 
• 
History of malignancy within 5 years prior to initiation of study treatment, with the exception 
of the cancer under investigation in this study and malignancies with a negligible risk of 
metastasis or death (e.g., 5-year OS rate > 90%), such as adequately treated carcinoma in 
situ of the cervix, non melanoma skin carcinoma, localized prostate cancer, ductal 
carcinoma in situ, or Stage I uterine cancer  
• 
Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, 
pulmonary or metabolic disease; wound healing disorders; ulcers; bone fractures) 
• 
Prior allogeneic stem cell or solid organ transplantation 
• 
Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that contraindicates the use of an investigational drug, may affect the 
interpretation of the results, or may render the patient at high risk from treatment 
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• 
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during atezolizumab treatment or 
within 5 months after the final dose of study treatment 
• 
Treatment with systemic immunostimulatory agents (including, but not limited to, interferon 
and interleukin 2 [IL-2]) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) 
prior to initiation of study treatment 
• 
Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-α 
agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for 
systemic immunosuppressive medication during study treatment, with the following 
exceptions: 
– 
Patients who received acute, low-dose systemic immunosuppressant medication or a 
one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of 
corticosteroids for a contrast allergy) are eligible for the study  
– 
Patients who received mineralocorticoids (e.g., fludrocortisone), inhaled or low-dose 
corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-
dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for 
the study 
• 
History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies, excipients of any drugs formulated in polysorbate 80 or 20 or fusion 
proteins 
• 
Known hypersensitivity to Chinese hamster ovary cell products or to any component of the 
atezolizumab formulation 
• 
Known allergy or hypersensitivity to any component of the trastuzumab emtansine 
formulation 
• 
Pregnancy or breastfeeding, or intention of becoming pregnant during the study or within 
7 months after the last dose of study treatment 
Women of childbearing potential must have a negative serum pregnancy test result 
within 7 days prior to initiation of study treatment 
 
END OF STUDY 
The end of study is planned to occur after approximately 184 OS events are obtained 
(approximately 40 months after the primary efficacy analysis of PFS [and concurrent first interim 
analysis of OS]). The end of this study is defined as the date when the last patient, last visit 
occurs, or the date at which the last data point required for statistical analysis or safety follow-up 
is received from the last patient, whichever occurs later.  
The Sponsor has decided to prematurely terminate the study due to a lower-than-expected 
enrolment rate. The investigators were informed of this decision on 15 December 2022. 
Patients have the option to remain on the study and continue treatment until arrangements 
are put in place for continuing treatment on an extension study (BO25430) or in a Post-Trial 
Access Program or other local options. The treatment solution for each patient may vary, 
taking into account local regulations and requirements. 
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 78.1 months. The length of study will now be determined by the 
time taken at each study site to implement the off-study patient treatment solutions, which 
should be approximately by the end of 2023 
INVESTIGATIONAL MEDICINAL PRODUCTS 
Trastuzumab emtansine, atezolizumab, and placebo are investigational medicinal products for 
this study. 
TEST PRODUCT (INVESTIGATIONAL DRUG) 
Trastuzumab emtansine will be given at a dose of 3.6 mg/kg by IV infusion, q3w.  The dose of 
trastuzumab emtansine will be administered on the basis of the patient’s baseline weight.  


 
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Weight will be measured at each visit (or in the 3 days prior) and dose must be re-adjusted for 
weight changes ≥ 10% compared to the previous visit or baseline. Administration may be 
delayed to assess or treat adverse events.  Dose reduction will be allowed for trastuzumab 
emtansine.  Once a dose has been reduced for adverse event(s), it must not be re-escalated.  
If trastuzumab emtansine is discontinued because of toxicity, it should not be re-administered. 
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, on the earliest 
following date with subsequent protocol-specified procedures rescheduled accordingly. 
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each 
21-day cycle. Dose reductions for atezolizumab are not allowed during this study.  
Both trastuzumab emtansine and atezolizumab/placebo 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.   
Atezolizumab or placebo will be administered first, followed by trastuzumab emtansine. 
COMPARATOR 
Placebo will be administered IV according to the same schedule as atezolizumab. 
NON-INVESTIGATIONAL MEDICINAL PRODUCTS 
None. 
STATISTICAL METHODS 
PRIMARY ANALYSIS 
The multiple primary efficacy endpoints for this study are PFS based on investigator tumor 
assessment and OS.  The ITT population is the primary analysis population for the primary 
efficacy endpoints and includes all patients who are randomized to the study, whether or not 
they receive any study medication.  Treatment group for the ITT population will be defined 
according to the treatment assigned at randomization. 
The primary PFS analysis (and first interim OS analysis) is planned to be performed when 
approximately 229 PFS events had occurred. It is expected to have approximately 87 OS 
events at that point in time. The estimated time from first-patient-in to primary PFS/first interim 
OS analysis is approximately 38 months. 
Following the Sponsor’s decision to prematurely terminate the study, there will be only a 
single analysis timepoint for both PFS and OS primary efficacy endpoints. Interim analyses 
will no longer be conducted.  Considering the expected lack of maturity of the data, 
theanalysis of PFS and OS primary efficacy endpoints will only be reported in a descriptive 
way. No formal testing will be performed and no control for the overall type I error (α) 
accounting for the two primary endpoints will be implemented. Consequently, p-values will 
not be able to be claimed as statistically significant and therefore will be reported as descriptive 
in nature. 
PROGRESSION-FREE SURVIVAL 
PFS is defined as the time from randomization to first documented disease progression as 
determined by the investigator using RECIST 1.1 or death from any cause, whichever occurs 
earlier. The first documented disease progression will be used in the main analysis of the 
primary efficacy endpoint of PFS. Data for patients without disease progression or death from 
any cause as of the data cut-off date will be censored at the time of the last tumor assessment 
with an outcome other than “unevaluable” (or, if no tumor assessment was performed after the 
baseline visit, at the time of randomization plus 1 day). Data from patients who are lost to follow-
up will be included in the analysis as censored observations on the date of the last tumor 
assessment that the patient was known to be progression-free.  
The Kaplan-Meier method will be used to estimate median PFS and the corresponding 95% Cis 
for each treatment arm. The 2-sided log-rank test, stratified by the factors specified in the 
protocol (excluding world region) will be used to compare PFS between the treatment arms. If 
less than 5 events are observed in any combination, only the unstratified analysis will be done. 
The stratification factors will be based on data collected by the IxRS rather than on data 
collected on the eCRFs. The unstratified log-rank test result will also be provided. The Cox 


 
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proportional hazards model, stratified by the previous noted stratification factors will be used to 
estimate the HR and to calculate the 95% CI of the HR. 
In order to assess the consistency of treatment benefit with respect to the multiple primary 
efficacy endpoints PFS and OS across important subgroups, forest plots (including estimated 
HRs) will be provided, including, but not limited, to the following variables: race, age, sex, world 
region, baseline HER2 and PD-L1 expression, ECOG status, hormone receptor status, and line 
of treatment in the metastatic setting (first or second line vs. third line).  
OVERALL SURVIVAL 
OS is defined as the time from randomization to death from any cause.  Patients who are alive 
as of the data cut-off date of the analysis will be censored at the last known date they were 
alive.  Patients with no post-baseline information will be censored at the date of randomization 
plus 1 day.  Methods for data analysis are analogous to those described for the primary efficacy 
endpoint PFS. The 2-sided log-rank test, stratified by the factors specified in the protocol 
(excluding world region) will be used to compare OS between the treatment arms. 
DETERMINATION OF SAMPLE SIZE   
The two primary efficacy endpoints for this study are PFS based on investigator tumor 
assessment and OS.  
This study has been designed to detect a substantial magnitude of benefit in the ITT population, 
that is, improvement in median PFS from 7 months in the control arm to 11.67 months in the 
experimental arm, corresponding to a target PFS hazard ratio of 0.60, and improvement in 
median OS from 31 months in the control arm to 47.7 months in the experimental arm, 
corresponding to a target OS hazard ratio of 0.65. 
Approximately 350 patients randomized according to a 1:1 randomization (approximately 175 
patients will be randomized to Arm A and to Arm B) will be enrolled in the study. The sample 
size assumes an annual dropout rate of 10% in both treatment arms and result in an estimated 
recruitment time of about 32 months (with ramp up in the first 8 months). Following the 
Sponsor’s decision to prematurely terminate the study, the initially planned number of 
randomized patients will not be reached.  
Furthermore, in the context of premature study termination, there will be only a single 
analysis timepoint for the PFS and OS  primary efficacy endpoints. Interim analyses will no 
longer be conducted.  Considering the expected lack of maturity of the data the analysis of 
PFS and OS primary efficacy endpoints will only be reported in a descriptive way. No formal 
testing will be performed and no control for the overall type I error (α) accounting for the two 
primary endpoints will be implemented. Consequently, p-values will not be able to be claimed 
as statistically significant and therefore will be reported as descriptive in nature. 
INTERIM ANALYSES  
Following the Sponsor’s decision to prematurely terminate the study, the interim analyses 
will no longer be conducted.  


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Definition 
ADA 
anti-drug antibody 
ADC 
antibody-drug conjugate 
AE 
adverse event 
AESI 
adverse events of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AV 
atrioventricular 
BC 
breast cancer 
BFI 
Brief Fatigue Inventory 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CCOD 
clinical cut-off date 
CHF 
congestive heart failure 
CI 
confidence interval 
Cmax 
maximum serum concentrations observed 
Cmin 
minimum serum concentration under steady-state 
conditions within a dosing interval 
CNS 
central nervous system 
COPD 
chronic obstructive pulmonary disease 
COVID-19 
coronavirus disease 2019 
CR 
complete response 
CRO 
contract research organization 
CRS 
cytokine release syndrome 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
CTLA4 
cytotoxic T-lymphocyte-associated protein 4 
CYP 
cytochrome p450 
 
 


 
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Abbreviation 
Definition 
DM1 
N2’-deacetyl-N2’-(3-mercapto-1-oxopropyl)-maytansine 
(the thiol-containing maytansinoid anti-microtubule 
agent conjugated to trastuzumab in trastuzumab 
emtansine) 
DMC 
Data Monitoring Committee 
DOR 
duration of response 
EBC 
early breast cancer 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECHO 
echocardiography 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EMA 
European Medicines Agency 
EORTC 
European Organisation for Research and Treatment of 
Cancer 
ePRO 
electronic patient-reported outcome 
EQ-5D-5L 
EuroQol 5-Dimension Questionnaire, 5-level version 
ER 
estrogen receptor 
FDA 
Food and Drug Administration 
FDG 
fluorodeoxyglucose 
FFPE 
formalin-fixed paraffin-embedded 
GHS 
global health status 
HER2 
human epidermal growth factor 2 
HbcAb 
hepatitis B core antibody 
HbsAb 
hepatitis B surface antibody 
HbsAg 
hepatitis B surface antigen 
HBV/HCV 
hepatitis B virus/ hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HLH 
hemophagocytic lymphohistiocytosis 
HR 
hazard ratio 
IC 
tumor-infiltrating immune cell 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
iDCC 
independent Data Coordinating Center 
iDMC 
independent Data Monitoring Center 
IFNγ 
interferon gamma 


 
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Abbreviation 
Definition 
IHC 
immunohistochemistry 
IL 
interleukin 
ILD 
interstitial lung disease 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRF 
Independent review facility 
IRR 
infusion-related reactions 
ISH 
in situ hybridization 
ITT 
intent-to-treat 
IV 
intravenous(ly) 
IxRS 
interactive voice or web-based response system 
LABC 
locally advanced breast cancer 
LPLV 
last patient, last visit 
LVEF 
left ventricular ejection fraction 
MAS 
macrophage activation syndrome 
MBC 
metastatic breast cancer 
MDASI 
MD Anderson Symptom Inventory 
MHC1 
major histocompatibility complex class 1 
MRI 
magnetic resonance imaging 
MUGA 
multigated acquisition (scan) 
nab-paclitaxel 
protein-bound paclitaxel 
NCCN 
National Comprehensive Cancer Network 
NIMP 
non-investigational medicinal product 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria 
for Adverse Events 
NGS 
next-generation sequencing 
NRH 
nodular regenerative hyperplasia 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
pCR 
pathologic complete response 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed death-ligand 1 


 
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Abbreviation 
Definition 
PET 
positron emission tomography 
PFS 
progression-free survival 
PgR 
progesterone receptor 
PIK3CA 
phosphatidylinositol-4,5-bisphosphate 3-kinase 
catalytic subunit alpha 
PK 
pharmacokinetic 
PO 
orally 
PR 
partial response 
PRO 
patient-reported outcome 
PRO-CTCAE 
Patient Reported Outcomes Common Terminology 
Criteria for Adverse Events 
q2w 
every 2 weeks 
q3w 
every 3 weeks 
QLQ-C30 
quality-of-life questionnaire for cancer 
QoL 
quality of life 
RBC 
red blood cell 
RBR 
Research Biosample Repository 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rh-TPO 
human recombinant thrombopoeitin 
SAE 
serious adverse events 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SITC 
Society for Immunotherapy of Cancer 
SLD 
sum of the longest diameters 
SC 
Steering Committee 
TC 
tumor cell 
TIL 
tumor-infiltrating lymphocyte 
TNBC 
triple-negative breast cancer 
TNF-α 
tumor necrosis factor alpha 
TPC 
treatment of physician’s choice 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
VAS 
visual analog scale 
WBC 
white blood cell 
WES 
whole exome sequencing 
WGS 
whole genome sequencing 
 
 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON HER2-POSITIVE METASTATIC BREAST 
CANCER 
Breast cancer is the most common cancer among women in the world with an estimated 
2.1 million cases diagnosed globally per year and approximately 627,000 deaths (Bray 
et al. 2018). While advances in early diagnosis and adjuvant therapy have led to a 
decrease in mortality rates from breast cancer in developed countries, the prevalence of 
metastatic breast cancer (MBC) is still high.  MBC is not considered curable and median 
overall survival (OS) ranges from approximately 1 year to approximately 5 years, 
depending on subtype (Waks and Winer 2019).  Numerous cytotoxic chemotherapy 
agents have demonstrated anti-tumor activity for MBC, including anti-tubulin drugs. 
Treatment choices are generally guided by disease characteristics (i.e., HER2/hormone 
receptor status of the disease, number and specific location of metastatic sites, 
treatment history in both adjuvant and metastatic settings), the toxicity of the potential 
treatments, the physical well-being of the patient, as well as physician and patient 
preferences. The main goals of treatment are to improve patients’ quality of life and 
prolong survival (Gennari et al. 2021). 
Human epidermal growth factor receptor 2 (HER2), also known as erbB2, neu, and 
p185HER2, represents a prominent target in breast cancer with approximately 
15%−20% of patients with primary invasive breast cancers overexpressing the HER2 
receptor (Reese and Slamon 1997; Owens et al. 2004; Wolff et al. 2013; Zhang et al. 
2015). In the absence of HER2-targeted therapy, primary breast cancers that 
overexpress HER2 are associated with a poorer prognosis, including a greater risk of 
relapse and shortened survival compared with that of HER2 normal tumors (Slamon 
et al. 1987; Toikkanen et al. 1992; Andrulis et al. 1998; Pauletti et al. 2000; Rubin and 
Yarden 2001).   
Since its first approval in 1998, the combination of trastuzumab and a taxane was widely 
accepted as the first-line treatment option of choice for patients with HER2-positive MBC 
on the basis of the survival advantage demonstrated in two large pivotal trials (Studies 
H0648g [Slamon et al. 2001] and M77001 [Marty et al. 2005]). The regimen of 
pertuzumab in combination with trastuzumab and docetaxel has shown clear superiority 
in terms of both progression-free survival (PFS) and OS with a generally similar safety 
profile (Study WO20698/TOC4129g [Baselga et al. 2012]) and is the standard of care in 
many countries.  
For second-line treatment of MBC, trastuzumab emtansine was established as the 
standard of care, based on the results of the EMILIA study (TDM4370g/BO21977; see 
Section 1.2.1). Data from the DESTINY-Breast 03 trial are likely to result in trastuzumab 
deruxtecan becoming the new standard of care second-line therapy in regions where 
this drug is available, moving trastuzumab emtansine potentially to the third line setting 
(Gennari et al. 2021; National Comprehensive Cancer Network [NCCN] 2021a).  Several 


 
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other treatment options are available for further lines of therapy in MBC (Gennari et al. 
2021; Giordano et al. 2018), including tucatinib which was recently approved in 
combination with trastuzumab and capecitabine for use in patients with HER2-positive 
MBC who have received one or more prior anti-HER2-based regimens in the metastatic 
setting (NCCN 2021a).  
Although the treatment of MBC is palliative rather than curative in intent, improvement in 
survival is an important treatment goal.  There is a significant need for new agents with 
novel mechanisms of action and acceptable toxicity, which can be combined with 
established treatments for breast cancer. 
1.2 
BACKGROUND ON TRASTUZUMAB EMTANSINE  
Trastuzumab emtansine (Kadcyla®) is an antibody-drug conjugate (ADC).  Linkage of a 
cytotoxic agent to highly specific monoclonal antibodies targeting unique and/or 
overexpressed cell-surface tumor antigens focuses the delivery of such agents to tumor 
cells (TCs), creating a more favorable therapeutic window than can be achieved by their 
administration as free drugs.  Trastuzumab emtansine is specifically designed for the 
treatment of HER2-positive cancer.  It is composed of the cytotoxic agent DM1 (a thiol-
containing maytansinoid anti-microtubule agent; N2’-deacetyl-N2’-(3-mercapto-1-
oxopropyl)-maytansine) conjugated to trastuzumab via lysine side chains, with an 
average drug-to-antibody ratio of approximately 3.5:1. 
Trastuzumab emtansine binds to HER2 with an affinity similar to that of trastuzumab; 
such binding is required for its anti-tumor activity.  After binding to HER2, trastuzumab 
emtansine undergoes receptor-mediated internalization, followed by intracellular release 
of DM1 and subsequent cytotoxicity. 
Phase I, II, and III studies of trastuzumab emtansine have demonstrated clinical activity 
when trastuzumab emtansine is given as a single agent to patients with HER2-positive 
MBC who have progressed on a trastuzumab-containing regimen. In patients with 
HER2-positive advanced breast cancer previously treated with trastuzumab and a 
taxane, trastuzumab emtansine has significantly prolonged PFS and OS with a more 
favorable safety profile than lapatinib plus capecitabine (Study BO21977/TDM4370g, 
EMILIA [Verma et al. 2012; Diéras et al. 2017]) or compared to a treatment of 
physicians’ choice in patients who previously received trastuzumab, taxane and lapatinib 
(Study BO25734/TDM4997g, TH3RESA [Krop et al. 2014; Krop et al. 2017]). Single-
agent trastuzumab emtansine is also active in the HER2-positive early breast cancer 
(EBC) setting (von Minckwitz et al. 2019). 
Data from clinical trials of trastuzumab emtansine that are relevant to the design of the 
current trial are summarized in Section 1.2.  Refer to the most recent version of the 
trastuzumab emtansine Investigator’s Brochure for further information on all of the 
completed and ongoing trastuzumab emtansine studies. 


 
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1.2.1 
Study TDM4370g/BO21977 (EMILIA) 
Study TDM4370g/BO21977 (EMILIA) was a randomized Phase III study of trastuzumab 
emtansine versus lapatinib plus capecitabine in patients with HER2-positive, 
unresectable locally advanced breast cancer (LABC) or MBC previously treated with 
trastuzumab and a taxane (n = 991).  Patients received trastuzumab emtansine 
(3.6 mg/kg intravenously [IV] every 3 weeks [q3w]) or capecitabine (1000 mg/m2 orally 
[PO] twice daily, Days 1−14 q3w) plus lapatinib (1250 mg PO daily) until progressive 
disease (PD) or unmanageable toxicity. 
Primary endpoints were PFS by independent review, OS, and safety.  An interim OS 
analysis was planned at the time of the final PFS analysis.  A total of 991 patients were 
enrolled, and 978 patients received treatment.  Baseline patient demographics, prior 
therapy, and disease characteristics were balanced.  There was a significant 
improvement in PFS favoring trastuzumab emtansine (hazard ratio [HR] = 0.650, 95% 
confidence interval [CI] = 0.549, 0.771; p < 0.0001; median: 9.6 vs.6.4 months).  
Objective response rate (ORR) was 43.6% for the trastuzumab emtansine arm versus 
30.8% for the lapatinib plus capecitabine arm, with a median duration of response (DOR) 
of 12.6 months versus 6.5 months, respectively (Verma et al. 2012).   
Trastuzumab emtansine was well tolerated, with no unexpected safety signals at the 
time of the primary analysis.  The most common Grade ≥ 3 adverse events (Aes) in the 
trastuzumab emtansine arm were thrombocytopenia (12.9% vs. 0.2%, respectively), 
increased aspartate aminotransferase (AST) (4.3% vs. 0.8%), and increased alanine 
aminotransferase (ALT) (2.9% vs. 1.4%); the most common Grade ≥ 3 Aes in the 
lapatinib plus capecitabine arm were diarrhea (20.7% vs. 1.6%), palmar plantar 
erythrodysesthesia (16.4% vs. 0%), and vomiting (4.5% vs. 0.8%).  The incidence of 
Grade 3 Aes in the trastuzumab emtansine arm was 40.8% versus 57.0% in the lapatinib 
plus capecitabine arm (Verma et al. 2012). 
A second Interim analysis for OS demonstrated that the co-primary endpoint of OS 
was met.  OS was significantly improved in patients receiving trastuzumab emtansine, 
with a 31.8% reduction in the risk of death associated with trastuzumab emtansine 
compared with lapatinib and capecitabine (HR = 0.682, 95% CI: 0.548, 0.849; 
p = 0.0006).  The median duration of survival was 25.1 months in patients treated with 
lapatinib plus capecitabine, compared with 30.9 months in patients treated with 
trastuzumab emtansine (Verma et al. 2012).   
The final descriptive OS analysis showed a consistent survival benefit for trastuzumab 
emtansine compared with lapatinib plus capecitabine (median OS 29.9 vs 25.9 months, 
stratified HR = 0.75), despite 27% of patients crossing over from the control arm to 
trastuzumab emtansine.  The safety profile of trastuzumab emtansine remained largely 
consistent between the time of the primary, second interim and final OS analyses, with a 
median follow-up time of 48 months in the final analysis (Diéras et al. 2017). 


 
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1.2.2 
Study TDM4997g/BO25734 (TH3RESA) 
Study TDM4997g/BO25734 (TH3RESA) was a Phase III, randomized, open-label trial to 
evaluate trastuzumab emtansine compared with treatment of physician’s choice (TPC; 
these were approved or standard of care therapies based on frequently-used regimens) 
in patients with HER2-positive MBC.  Patients had received prior treatments with 
trastuzumab, lapatinib, and a taxane in any setting, and disease progression occurred 
after at least two regimens of HER2-directed therapy in the metastatic or unresectable 
locally advanced/recurrent setting. 
Analysis of the co-primary efficacy endpoints of PFS per investigator assessment and 
the first OS interim analysis, plus all secondary efficacy endpoints, was based on a data 
cutoff date of 11 February 2013 (Krop et al. 2014).  The study demonstrated a 
statistically significant and clinically meaningful improvement in PFS for trastuzumab 
emtansine compared with TPC.  The median PFS for trastuzumab emtansine was 6.2 
months and for TPC 3.3 months with a stratified HR = 0.528 (95% CI: 0.422, 0.661); 
p < 0.0001.  The ORR was 31% for the trastuzumab emtansine arm versus 9% for the 
TPC arm, with a median DOR of difference 22.7% [95% CI: 16.2, 29.2]; p < 0·0001).  The 
median DOR was 9.7 months (95% CI: 6.6, 10.5) in the trastuzumab emtansine group, 
but it had not been reached at the data cutoff in the patients with an objective response 
in the physician’s choice group. 
Interim OS analysis showed a trend favoring trastuzumab emtansine (stratified 
HR = 0.552 [95% CI: 0.369, 0.826]; p = 0.0034), but the stopping boundary was not 
crossed.  Fewer patients receiving trastuzumab emtansine than those receiving TPC 
had Grade ≥ 3 aEs (32.3% vs. 43.5%).  Grade ≥ 3 aEs reported in at least 2% of patients 
receiving trastuzumab emtansine were: thrombocytopenia (4.7%), anemia (2.7%), 
neutropenia (2.5%), AST increased (2.2%), fatigue (2.0%), and dyspnea (2.0%) (Krop et 
al. 2014).  
At the second OS interim analysis, which constituted the final OS analysis, trastuzumab 
emtansine demonstrated a clinically meaningful and statistically significant improvement 
in OS compared with TPC.  The median OS improved from 15.8 months (TPC) to 
22.7 months (trastuzumab emtansine (stratified HR 0.58 [95% CI: 0.43, 0.71]; 
p = 0.0002).  Despite the longer treatment duration relative to control (4.1 months; 
[0.03 − 31.2)], trastuzumab emtansine (7.9 months [0.03 − 38] had a favorable safety 
profile which was consistent with prior studies (Krop et al. 2017). 
1.3 
BACKGROUND ON ATEZOLIZUMAB 
Atezolizumab is a humanized IgG1 monoclonal antibody that targets programmed death-
ligand 1 (PD-L1) and inhibits the interaction between PD-L1 and its receptors, 
programmed cell death protein 1 (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 


 
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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 therapy 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), hepatocellular cancer, small-cell lung cancer, melanoma, and triple-
negative breast cancer (TNBC).  Differences in approval may exist across countries. 
For details on nonclinical studies and clinical studies evaluating atezolizumab 
monotherapy and in combination with other agents, and in other indications, refer to the 
Atezolizumab Investigator’s Brochure. 
1.3.1 
Study GO29831 
Study GO29831 is a completed Phase Ib open-label, multi-cohort study evaluating the 
safety, tolerability, and pharmacokinetics of atezolizumab in combination with 
trastuzumab emtansine or with trastuzumab and pertuzumab (with or without 
chemotherapy agents) in patients with HER2-positive MBC, treatment-naive patients 
with operable LABC, or inflammatory EBC. HER2-negative patients were also eligible for 
one cohort only.  The primary objective for this study was to evaluate the safety and 
tolerability of the following combination treatments: 
• 
Atezolizumab + trastuzumab + pertuzumab or atezolizumab + trastuzumab 
emtansine in patients with HER2-positive MBC or patients who are treatment-naive 
with operable LABC or inflammatory EBC 
• 
Atezolizumab + trastuzumab + pertuzumab + docetaxel in patients with 
HER2positive MBC 
• 
Atezolizumab + doxorubicin + cyclophosphamide in patients with HER2-negative 
MBC 
 
A total of 76 patients were enrolled and treated in this two-stage study: 36 patients with 
MBC and 40 patients with LABC/EBC. Of these, 40 patients were treated with 
trastuzumab emtansine (3.6 mg/kg q3w) plus atezolizumab (1200 mg q3w).  
• 
6 patients with MBC in the safety evaluation stage (Cohort 1B) 
• 
14 patients with MBC in a safety expansion cohort (Cohort 2C) 
• 
20 patients with LABC/EBC in the neoadjuvant window stage (Cohort 2B) 
 


 
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Confirmed responses by RECIST v1.1 were seen in both MBC cohorts (Cohort 1B: one 
CR and one PR [ORR: 33%]; Cohort 2C: one CR and 4 PR [ORR: 35.7%]). Confirmed 
response rates per immune-modified RECIST (imRECIST) were consistent with those 
reported using standard RECIST. The pathologic complete response (pCR) rate in 
Cohort 2B was 14/20 (70%; 95% CI: 46, 88). 
AEs in Cohort 1B (n=6) occurring in more than one patient comprised fatigue (83.3%), 
nausea, thrombocytopenia (each 50%), asthenia, pneumonia and anemia (each 33.3%). 
AEs in Cohort 2C (n=14) occurring in >20% of patients comprised fatigue (64.3%), 
decreased appetite (50.0%), chills, pyrexia, headache, anemia, cough, constipation 
(42.9%), nausea, dry mouth, upper respiratory tract infection, vomiting (35.7%), diarrhea, 
urinary tract infection, pneumonia, dyspnea, back pain, aspartate aminotransferase 
increased (28.6%), nasopharyngitis, thrombocytopenia, epistaxis, hypomagnesemia, 
bone pain, platelet count decreased (21.4%). The most frequent AEs in Cohort 2B were: 
diarrhea, fatigue (75.0%), nausea (70.0%), anemia, constipation (45%), headache, 
epistaxis, decreased appetite, hypomagnesemia (40%), hypokalemia, alopecia (35%), 
mucosal inflammation (30%), peripheral edema, neutropenia, thrombocytopenia, 
dehydration, rash, increased AST, and ALT (25%). 
One (16.7%) patient in Cohort 1B discontinued treatment due to an AE (Grade 4 
hypercalcemia) and two (14.3%) patients in Cohort 2C (Grade 2 increased AST and 
Grade 2 interstitial lung disease). Four (20.0%) patients in Cohort 2B discontinued 
treatment due to an AE (Grade 5 AE of death, Grade 3 AEs of transaminase increased, 
diarrhea and Grade1 or 2 AEs of chest pain, dyspnea and dehydration. 
Grade ≥3 AEs occurring in more than one patient in Cohort 1B were thrombocytopenia 
and pneumonia; in Cohort 2C only pneumonia occurred in more than one patient (n = 2 
[14.3%]). No fatal AEs occurred in Cohorts 1B and 2C. Grade ≥3 AEs occurring in more 
than one patient on Cohort 2B were anemia, neutropenia, thrombocytopenia, diarrhea, 
hypokalemia, hypomagnesemia, increased transaminase, peripheral neuropathy, 
mucosal inflammation, and hypertension. 
1.3.2 
Study WO30085 (KATE2) 
Study WO30085 is a completed randomized, multicenter, double-blind, placebo-
controlled Phase II study of the efficacy, safety, and pharmacokinetics of trastuzumab 
emtansine in combination with atezolizumab or placebo (atezolizumab/placebo) in 
patients with HER2-positive, LABC or MBC, who have received prior trastuzumab and 
taxane based therapy, either alone or in combination, and/or who have progressed 
during, or within 6 months after completing, adjuvant therapy. 
Patients were randomized (2:1) to receive trastuzumab emtansine (3.6 mg/kg) combined 
with atezolizumab (1200 mg) or placebo, given intravenously every 3 weeks. 
Randomization was stratified by PD-L1 immunohistochemistry (IHC) status, world 
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well balanced at baseline, except that the proportion of patients with an ECOG 
performance status of zero was numerically higher in the combination therapy arm (70% 
vs 58%). 
The primary efficacy objective for this study was to evaluate the efficacy of the 
combination of trastuzumab emtansine plus atezolizumab compared with trastuzumab 
emtansine plus placebo as measured by investigator-assessed PFS.  The primary PFS 
analysis was planned for when approximately 115 PFS events had occurred.  Secondary 
efficacy endpoints were OS, ORR (according to RECIST v1.1), and duration of objective 
response, defined as the time from first occurrence of a documented objective response 
to disease progression, as determined by investigator assessment using RECIST v1.1 or 
death from any cause, whichever occurs first. 
On 22 November 2017, the 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.  This recommendation was based on 
the following factors: 
• 
Improbability of meeting the PFS endpoint 
• 
Numerically higher rates of SAEs that included one fatal event (hemophagocytic 
syndrome) in the atezolizumab arm 
• 
Numerically higher AEs leading to discontinuation of study drugs in the 
atezolizumab arm. 
 
As of the clinical cut-off date (CCOD) of 11 December 2017, 202 patients had been 
randomized in a 1:2 ratio, comprising the ITT population (69 patients in the trastuzumab 
emtansine plus placebo arm and 133 patients in the trastuzumab emtansine 
plus atezolizumab arm).   
The study did not demonstrate a clinically meaningful PFS benefit from the addition of 
atezolizumab to trastuzumab emtansine in the ITT population.  The stratified HR was 
0.82 (95% CI: 0.55, 1.23; p = 0.3332).  The median PFS for trastuzumab emtansine plus 
placebo was 6.8 months (95% CI: 4.0, 11.1) and for the trastuzumab emtansine plus 
atezolizumab was 8.2 months (95% CI: 5.8, 10.7) (Emens et al. 2019a). 
At the final analysis (CCOD: 11 December 2018), 52 OS events were reported (20 
[29.0%] deaths in the trastuzumab emtansine plus placebo arm and 32 [24.1%] deaths 
in the trastuzumab emtansine plus atezolizumab arm) (Emens et al. 2019b).  Median OS 
was not reached in either arm (stratified HR = 0.74 [95% CI: 0.42, 1.30] and 1-year OS 
was similar (89.0% with trastuzumab emtansine plus placebo and 89.1% with 
trastuzumab emtansine plus atezolizumab). 
At the primary analysis (CCOD: 11 December 2017; Report No. 1087133), the safety 
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with the known profiles of each study drug, and AEs for the combination were 
manageable.  The proportion of patients experiencing AEs was similar between the two 
arms: 95.6% of patients receiving trastuzumab emtansine plus placebo, and 99.2% of 
patients receiving trastuzumab emtansine plus atezolizumab had at least one AE.  
Despite higher rate of SAEs in the trastuzumab emtansine plus atezolizumab arm, the 
overall incidence of Grade ≥3 AEs was similar between the two arms (Table 1).  
The most common Grade ≥3 AEs (in at least 4% of patients) in patients receiving 
trastuzumab emtansine plus atezolizumab were thrombocytopenia (12.9%), AST 
increased (8.3%), anemia (5.3%), ALT increased, and neutropenia (4.5% each).  The 
most common Grade ≥3 AEs (in at least 4% of patients) in patients receiving 
trastuzumab emtansine plus placebo were thrombocytopenia, neutropenia, and urinary 
tract infection (all 4.4% each). All other Grade ≥3 AEs occurred in <4% of patients in 
each arm. 
Table 1 
KATE2 Safety Profile According to Study Arms 
Patients with 
T-DM1 + Placebo 
(N=68) 
[Grade 3-4] 
T-DM1 + Atezo 
(N=132) 
[Grade 3-4] 
AE leading to death 
0 
1 (0.8%) * 
SAE 
13 (19.1%) 
43 (32.6%) 
AE Grade ≥3 
28 (41.2%) 
58 (43.9%) 
AE leading to T-DM1 discontinuation 
9 (13.2%) 
20 (15.2%) 
AE leading to T-DM1 dose reduction/interruption 
13 (19.1%) 
46 (34.8%) 
AE leading to atezolizumab/placebo 
discontinuation 
10 (14.7) 
33 (25.0) 
AE leading to atezolizumab/placebo interruption 
14 (20.6) 
54 (40.9) 
Hepatotoxicity 
16 (23.5%) 
[4 (5.9%)] 
44 (33.3%) 
[14 (10.6%)] 
Cardiac dysfunction 
4 (5.9%) 
[0] 
1 (0.8%) 
[0] 
Thrombocytopenia 
9 (13.2%) 
[3 (4.4%)] 
38 (28.8%) 
[13 (9.8%)] 
IRR/Hypersensitivity Type I 
22 (32.4%) 
[0] 
66 (50%) 
[5 (3.8%)] 
Pulmonary Toxicity 
3 (4.4%) 
[1 (1.5%)] 
6 (4.5%) 
[1 (0.8%)] 
Peripheral neuropathy 
16 (23.5%) 
[2 (2.9%)] 
39 (29.5%) 
[3 (2.3%)] 
Hemorrhage 
15 (22.1%) 
[1 (1.5%)] 
33 (25%) 
[2 (1.5%)] 
AE = adverse event; IRR = infusion-related reaction; T-DM1 = trastuzumab emtansine. 
*histiocytosis hematophagic. 


 
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Hepatotoxicity was mostly Grade 1 or 2 and the most commonly reported AEs were 
increased AST and increased ALT. Grade ≥3 hepatoxicity AEs were reported in 4 (5.9%) 
patients in the trastuzumab emtansine plus placebo arm and 14 (10.6%) patients in the 
trastuzumab emtansine plus atezolizumab arm; one event in each group was a Grade 4 
AE.  No patients from the trastuzumab emtansine plus atezolizumab arm fulfilled the 
Hy’s Law criteria and there were no deaths due to hepatotoxicity in the study. 
The majority of cases of thrombocytopenia in the atezolizumab arm were reported as 
non-serious.  Grade ≥3 thrombocytopenia was reported in 3 (4.4%) patients in the 
trastuzumab emtansine plus placebo arm (none of which were Grade 4) and 13 (9.8%) 
patients in the trastuzumab emtansine plus atezolizumab arm (5 [3.8%] of which were 
with Grade 4 events).  The higher incidence of thrombocytopenia in the trastuzumab 
emtansine plus atezolizumab arm did not lead to increased hemorrhage (Table 1).  
The difference in IRR/hypersensitivity in the two arms was mainly driven by pyrexia 
occurring during infusion or within 24 hours. 
Fewer patients (8.8%) in the trastuzumab emtansine plus placebo arm had AEs that led 
to dose reduction of trastuzumab emtansine compared to patients (16.7%) in the 
trastuzumab emtansine plus atezolizumab arm.  The most common AEs leading to 
trastuzumab emtansine dose reduction were thrombocytopenia (2.9% vs. 6.8%) and 
AST/ALT increase (both 1.5% vs. 3.0%), which are known toxicities associated with 
trastuzumab emtansine. 
A similar percentage of patients reported AEs that led to discontinuation of trastuzumab 
emtansine in both treatment arms (13.2% in the trastuzumab emtansine plus placebo 
arm and 15.2% in the trastuzumab emtansine plus atezolizumab arm).  The most 
common AEs that led to discontinuation of trastuzumab emtansine were 
thrombocytopenia (1.5% in the trastuzumab emtansine plus placebo arm vs. 5.3% in the 
trastuzumab emtansine plus atezolizumab arm), AST increase (2.9% vs. 1.5%), ALT 
increase (2.9% vs. 0.8%), and pneumonitis (1.5% vs. 3.8%).  A higher proportion of 
patients discontinued atezolizumab vs placebo due to an AE (25.8% vs 14.7%, 
respectively).  More frequently, AEs were managed with interruption of atezolizumab or 
reduction/interruption of trastuzumab emtansine in the combination arm.   
One death due to an AE was reported: a case of histiocytosis hematophagic 
(hemophagocytic syndrome) in a patient treated with trastuzumab emtansine plus 
atezolizumab that was judged to be study treatment related. 
At the final analysis (CCOD: 11 December 2018; Emens et al. 2019b), the incidence of 
AEs was comparable between the two arms, however the overall incidence of Grade ≥3 
AEs was higher in the combination arm: 45% with trastuzumab emtansine plus placebo 
and 53% with trastuzumab emtansine plus atezolizumab.  In particular, the incidence of 
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the combination arm.  A higher incidence of SAEs, AEs leading to atezolizumab 
discontinuation, and AEs leading to dose reduction of trastuzumab emtansine were 
reported in the combination arm.  Two patients had died due to AEs in the combination 
arm (hemophagocytic syndrome and brain hemorrhage due to fall [judged unrelated]) 
and one patient in the placebo arm (cardiac failure judged to be related to trastuzumab 
emtansine).  Notably, the final analysis was conducted after the study was unblinded 
with respect to treatment assignment as per the iDMC recommendation (see above) and 
both investigators and the patients in study were informed accordingly. 
Of the trastuzumab emtansine selected AEs, the incidence of thrombocytopenia, 
hepatotoxicity, peripheral neuropathy and infusion related reaction / hypersensitivity 
Type 1 were also numerically increased in the combination arm.  Among atezolizumab 
AEs of special interest (AESI), the incidence of immune-mediated rash, immune-
mediated hypothyroidism, and immune-mediated pancreatitis toxicity were numerically 
increased in the combination arm compared with the placebo arm. 
Overall, the safety profile of trastuzumab emtansine and atezolizumab in the ITT 
population was consistent with what is already known about the individual drugs.   
1.3.2.1 
Preplanned Subgroup Analysis of Patients with PD-L1-Positive 
Tumors 
At baseline, approximately 40% of patients in Study WO30085 (KATE2) were positive for 
PD-L1 expression by IHC (57 [43%] for trastuzumab emtansine plus atezolizumab and 
27 [39%] for trastuzumab emtansine plus placebo).  PD-L1-positive disease was defined 
as tumor-infiltrating immune cells (IC) covering ≥ 1% of tumor area by IHC using the 
investigational VENTANA anti-PD-L1 (SP142) Rabbit Monoclonal Primary Antibody [PD-
L1 (SP142) assay]. 
A pre-planned subgroup analysis according to baseline tumor PD-L1 expression status 
(CCOD: 11 December 2017) suggested a potential benefit of trastuzumab emtansine 
plus atezolizumab in the PD-L1-positive subgroup, with a median PFS of 8.5 months 
with combination therapy vs 4.1 months in the placebo arm (stratified HR = 0.60, 95% CI: 
0.32, 1.11, p = 0.099) (Emens et al. 2019a).  The ORR was also numerically higher in the 
PD-L1-positive subgroup with combination therapy (54%) compared with the placebo 
arm (33%).  
At the final analysis (CCOD: 11 December 2018), the OS data suggested a survival 
advantage with the combination treatment in the PD-L1-positive subgroup compared 
with the placebo arm.  One-year OS was numerically higher with combination therapy 
(94.3%) compared with placebo (87.9%; stratified HR = 0.55 [95% CI: 0.22, 1.38]). 
Median OS was not reached in either arm (Emens et al. 2019b). 
While the magnitude of benefit in the PD-L1-positive subgroup is uncertain, given the 
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prognostic factors between the treatment arms (ECOG PS 0, lower HER2 expression, 
and PIK3CA mutation) that might have favored the combination arm, the data do 
indicate that further investigation of trastuzumab emtansine plus atezolizumab is 
warranted in patients with HER2-positive and PD-L1-positive MBC. 
1.3.3 
Study WO29522 (IMpassion130) 
Study WO29522 (IMpassion130) is an ongoing Phase III multicenter, randomized, 
placebo-controlled study of atezolizumab in combination with nab-paclitaxel (protein-
bound paclitaxel) compared to placebo with nab-paclitaxel for patients with previously 
untreated metastatic triple-negative breast cancer.  A total of 902 patients were enrolled 
and randomized to either atezolizumab (840mg IV, q2w) or placebo in combination with 
nab-paclitaxel (100 mg/m2, q2w) on a 3 week on/1 week off schedule.  The co-primary 
endpoints of the study are PFS by independent review and OS. 
At the first interim analysis (the primary [and definitive] analysis for PFS and first interim 
analysis for OS; median follow-up 12.9 months), treatment with atezolizumab plus nab-
paclitaxel compared to placebo plus nab-paclitaxel resulted in a statistically significant 
reduction in the risk of disease worsening or death in the intent-to-treat (ITT) population 
(median PFS 7.2 vs. 5.5 months, respectively; HR = 0.80; 95% CI: 0.69, 0.92; p=0.002) 
(Schmid et al. 2018).  In the PD-L1-positive population, median PFS was 7.5 vs. 5.0 
months, respectively; HR = 0.62, 95% CI: 0.49, 0.78; p < 0.001.  There was a trend for 
prolonged OS in the ITT population (median OS 21.3 months and 17.6 months, 
respectively (HR for death = 0.84; 95% CI: 0.69, 1.02; p = 0.08) with a clinically 
meaningful 9.5-month OS improvement in the PD-L1-positive subpopulation (median OS 
25.0 vs 15.5 months, respectively; HR = 0.62, 95% CI: 0.45, 0.86).  Due to the 
hierarchical statistical design, OS results were not formally tested in the PD-L1-positive 
subpopulation. 
At the preplanned second OS interim analysis (data cutoff 2 January, 2019, median 
follow-up 18 months), the co-primary endpoint of OS was again not significant in the ITT 
population as the pre-specified boundary (HR ≤ 0.818, available α = 0.021) was not 
crossed (stratified HR = 0.86, 95% CI: 0.72, 1.02; p = 0.078).  In the exploratory OS 
analysis in patients with PD-L1 immune cell-positive tumors, median OS was 25.0 
months with atezolizumab versus 18.0 months with placebo (stratified HR = 0.71, 0.54, 
0.94]; not formally tested) (Schmid et al. 2020).  An improvement in investigator-
assessed PFS was demonstrated with atezolizumab plus nab-paclitaxel relative to 
placebo plus nab-paclitaxel in both the ITT population (stratified HR = 0.80; 95% CI: 0.69, 
0.92; p = 0.0021) and the PD-L1-positive population (stratified HR = 0.63, 95% CI: 0.50, 
0.80; p < 0.0001).  Results were similar at the final OS analysis (data cutoff 14 April, 
2020, median follow-up 18.8 months; Emens et al. 2020).  OS was not significant in the 
ITT population as the prespecified boundary (HR ≤ 0.853, available α = 0.041) was not 
crossed (stratified HR = 0.87, 95% CI: 0.75, 1.02, p = 0.0770).  In the exploratory OS 
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months with atezolizumab versus 17.9 months with placebo (stratified HR = 0.67, 95% 
CI: 0.53, 0.86; not formally tested). 
Overall, the combination of atezolizumab plus nab-paclitaxel had a tolerable safety 
profile.  As of an updated data cutoff of 3 September 2018 (median 15.6 months follow-
up), aggregate safety data were available for 890 patients.  Grade 3–4 AEs were 
reported in 49% of the atezolizumab plus nab-paclitaxel group and in 43% of the placebo 
plus nab-paclitaxel group.  The only Grade 3–4 AEs occurring in > 5% of patients were 
neutropenia (reported in 8.2% of patients in each group), and peripheral neuropathy 
(reported in 5.5% of patients in the atezolizumab plus nab-paclitaxel group compared to 
2.7% of patients in the placebo plus nab-paclitaxel group).  Serious AEs (SAEs) 
occurred in 23% and 18% of patients in the two groups, respectively.  The only between-
group differences in any-Grade AESI frequencies were for rash (34% vs 26%, 
respectively), hypothyroidism (17% vs 4%, respectively), hyperthyroidism (4% vs 1%, 
respectively), and pneumonitis (3% vs < 1%, respectively). 
Refer to the most recent version of the Atezolizumab Investigator’s Brochure for updated 
details on studies described above and clinical activity and safety in all patients, 
regardless of tumor type. 
1.4 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Trastuzumab emtansine is an active regimen in HER2-positive MBC (see Section 1.2). 
In addition to its cytotoxic activity, trastuzumab emtansine targets intratumoral dendritic 
cells to potentiate antitumor immunity (Müller et al. 2015).  Therefore, combining 
trastuzumab emtansine with atezolizumab, an anti-PD-L1 antibody that restores 
antitumor immunity, may result in greater clinical activity than with either drug alone. 
Preclinical 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 trastuzumab 
in a 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 
HER2-targetting antibodies such as trastuzumab emtansine may further enhance the 
anti-tumor efficacy of these established anti-HER2 treatments. 
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 emtansine, trastuzumab, and pertuzumab (all 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 emtansine with an anti-PD-L1 
inhibitor such as atezolizumab might further enhance anti-tumor immune responses, 


 
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thereby improving clinical outcomes for patients with minimal increases in clinically 
significant toxicities. 
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 an extracellular protein that downregulates immune responses through binding 
to its two receptors, PD-1 and B7-1 (CD80).  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 standard-of-care therapies.  Objective 
responses have been observed across a broad range of malignancies, including 
NSCLC, urothelial carcinoma, renal cell cancer, hepatocellular cancer, melanoma, 
colorectal cancer, head and neck cancer, gastric cancer, breast cancer, and sarcoma 
(see Atezolizumab Investigator's Brochure for detailed efficacy results). 
While Study WO30085 failed to demonstrate that combining trastuzumab emtansine with 
atezolizumab would improve outcomes compared with trastuzumab emtansine plus 
placebo in the overall population, it did indicate a potential benefit of the combination in 
the pre-planned analysis of the subgroup of PD-L1-positive patients (see Section 
1.3.2.1) in metastatic HER2-positve breast cancer.  Similarly, Study WO29522 indicated 
that the combination of atezolizumab with nab-paclitaxel was beneficial in the subgroup 
of patients with PD-L1-positive tumors (see Section 1.3.3) in the TNBC subtype. 
Study MO42319 will employ a similar study design to that used in Study WO30085; 
however, all patients enrolled to Study MO42319 will have HER2-positive and PD-L1-
positive tumors at baseline, building on the proof-of-concept results in the PD-L1-positive 
subgroup in Study MO42319.  
The safety of trastuzumab emtansine is well established and has been evaluated as 
single-agent in 1871 patients with MBC in clinical studies.  The most common AEs for 
single-agent trastuzumab emtansine (AEs in  ≥ 25% of patients) were nausea, fatigue 
and headache (see Trastuzumab emtansine Investigator's Brochure for detailed safety 
results).  Atezolizumab has been generally well tolerated.  Adverse events with 
potentially immune-mediated causes consistent with an immunotherapeutic agent, 
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pneumonitis, colitis, and myasthenia gravis, have been observed (see Atezolizumab 
Investigator's Brochure for detailed safety results).  To date, these events have been 
manageable with treatment or interruption of atezolizumab treatment. 
Study WO30085 demonstrated that the safety profile of trastuzumab emtansine in 
combination with atezolizumab was consistent with what is already known about the 
individual drugs (see Section 1.3.2).  To date, no new safety signals have been 
observed with the combination of trastuzumab emtansine plus atezolizumab in Studies 
WO30085 and G029831.  
Several measures will be taken to ensure the safety of patients participating in this 
study.  Stringent eligibility criteria (Section 4.1) have been designed to exclude patients 
at higher risk for toxicities from study participation.  Administration of trastuzumab 
emtansine and atezolizumab/placebo 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.  Close safety monitoring (Section 5.3) rules for 
dose modifications (Section 5.1.4.1) will be implemented.  Patients will undergo periodic 
safety monitoring by an independent data monitoring committee (iDMC) during the study 
(Section 3.3.1), including assessment of the nature, frequency, and severity of AEs; 
details of this safety monitoring will be specified in the iDMC Charter.  Furthermore, 
guidance on management of potential trastuzumab emtansine toxicities (Appendix 18), 
atezolizumab toxicities (Appendix 19) and potential overlapping toxicities (Appendix 20) 
is provided. 
In the setting of the coronavirus disease 2019 (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 severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) infection.  However, it is unclear whether or how 
systemic cancer therapies such as chemotherapy, targeted therapy, or immunotherapy 
impact the incidence or severity of SARS-CoV-2 infection. 
A possible consequence of inhibiting the PD-1/PD-L1 pathway may be the modulation of 
the host immune response to acute infection, which may result in immunopathology or 
dysregulated immune system defenses.  In nonclinical models, PD 1/PD L1 blockade 
appears to be associated with serious exacerbation of inflammation in the setting of 
acute (as opposed to chronic) viral infection with lymphocytic choriomeningitis virus 
(Clone 13) (Frebel et al. 2012).  However, there are insufficient and inconsistent clinical 
data to assess if outcome from SARS-CoV-2 infection is altered by cancer 
immunotherapy. 
Severe SARS-CoV-2 infection appears to be associated with a cytokine release 
syndrome (CRS) involving the inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and 
interferon-γ (IFNγ; Merad and Martin 2020).  While it is not known, there may be a 
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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 SARS-CoV-2 infection. 
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 
SARS-CoV-2–related interstitial pneumonia.  Thus, investigators should use their clinical 
judgment when evaluating and managing patients with pulmonary symptoms. 
While it is not known there may be a potential for an increased risk of an enhanced 
inflammatory response if a patient develops SARS-Co-2 infection while receiving 
trastuzumab emtansine.    
Pulmonary toxicity has been observed in patients treated with atezolizumab and/or 
trastuzumab emtansine. Symptoms of interstitial lung disease and pneumonitis may 
overlap with manifestations of COVID-19 infection and should be carefully evaluated in 
the diagnostic process.  In this study, atezolizumab is discontinued for all grades of 
interstitial lung disease and pneumonitis, and trastuzumab emtansine is discontinued 
for Grade 3 – 4 adverse events of interstitial lung disease and pneumonitis. 
There are limited data concerning the possible interactions between cancer 
immunotherapy treatment and COVID-19 vaccination, and it is recognized that human 
immune responses are highly regulated and that immune-modifying therapies may 
positively or negatively impact the efficacy and safety of COVID-19 vaccination (Society 
for Immunotherapy of Cancer [SITC] 2020). 
Per recommendations of the NCCN COVID-19 Vaccination Advisory Committee, 
COVID-19 vaccination is recommended for all patients with cancer receiving active 
therapy (including immune checkpoint inhibitors), with the understanding that there are 
limited safety and efficacy data in such patients (NCCN 2021b).  Given the lack of 
clinical data, currently no recommendations can be made regarding the optimal 
sequence of COVID-19 vaccination in patients who are receiving cancer immunotherapy 
(SITC 2020).  For patients enrolling in this study and receiving atezolizumab treatment, a 
decision to administer the vaccine to a patient should be made on an individual basis by 
the investigator in consultation with the patient. 
In alignment with clinical practice procedures, factors to consider when making the 
individualized decision for patients receiving atezolizumab treatment to receive 
COVID-19 vaccination include the following:  the risk of SARS-CoV-2 infection and 
potential benefit from the vaccine, the general condition of the patient and potential 
complications associated with SARS-CoV-2 infection, underlying disease, and the 
severity of COVID19 outbreak in a given- area or region.   


 
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A risk assessment was also performed by the team on the possible interaction between 
trastuzumab emtansine and COVID-19 vaccination.  The outcome was that a COVID-19 
vaccine given to a trial participant has no anticipated drug-vaccine interaction and does 
not require advice on timing of the vaccination or the implementation of any other risk 
mitigation activities.  
SITC and NCCN recommendations along with institutional guidelines should be used by 
the investigator when deciding on administering COVID-19 vaccines.  When 
administered, COVID-19 vaccines must be given in accordance with the approved or 
authorized vaccine label.  Receipt of the COVID-19 vaccine is considered a concomitant 
medication and should be documented as such (see Section 4.4.1). 
This trial will enroll patients with HER2-positive and PD-L1-positive LABC or MBC, who 
have progressed during or after prior trastuzumab- (+/- pertuzumab) and taxane-based 
therapy for LABC/MBC, or during (or within 6 months after completing) trastuzumab- (+/- 
pertuzumab) and taxane-based therapy in the neoadjuvant and/or adjuvant setting.  
Given the relatively poor prognosis, this population is considered appropriate for trials of 
novel therapeutic candidates.  The benefit-risk ratio for trastuzumab emtansine in 
combination with atezolizumab is expected to be acceptable in this setting. 
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy, safety, pharmacokinetics, and patient-reported 
outcomes of trastuzumab emtansine plus atezolizumab compared with trastuzumab 
emtansine plus placebo in patients with HER2-positive and PD-L1-positive LABC or 
MBC.  Patients must have progressed during or after prior trastuzumab- (+/- 
pertuzumab) and taxane-based therapy for LABC/MBC, or during (or within 6 months 
after completing) trastuzumab- (+/- pertuzumab) and taxane-based therapy in the 
neoadjuvant and/or adjuvant setting. Specific objectives and corresponding endpoints for 
the study are outlined below. 
In this protocol, "study treatment" refers to the combination of treatments assigned to 
patients as part of this study (i.e., trastuzumab emtansine and atezolizumab or 
trastuzumab emtansine and placebo). 
2.1 
EFFICACY OBJECTIVES 
2.1.1 
Primary Efficacy Objective 
The trial will compare trastuzumab emtansine given at a dose of 3.6 mg/kg by IV 
infusion, q3w plus atezolizumab administered by IV infusion at a fixed dose of 1200 mg 
on Day 1 of each 21-day cycle with trastuzumab emtansine given at a dose of 3.6 mg/kg 
by IV infusion, q3w plus placebo administered by IV infusion at a fixed dose of 1200 mg 
on Day 1 of each 21-day cycle in patients with HER2-positive and PD-L1-positive LABC 
or MBC who have progressed either during or after prior trastuzumab- (+/- pertuzumab) 
and taxane-based therapy for LABC/MBC, or during (or within 6 months after 


 
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completing) trastuzumab- (+/- pertuzumab) and taxane-based therapy in the 
neoadjuvant and/or adjuvant setting. 
The two primary comparisons of interest will be the hazard ratios for PFS and OS as 
defined below. The primary trial objective is to demonstrate superiority of the 
experimental over the control treatment in either or both comparisons. 
• 
PFS, defined as the time from randomization to the first occurrence of documented 
disease progression, as determined by investigator assessment using Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1, or death from any cause, 
whichever occurs first 
• 
OS, defined as the time from randomization to death from any cause 
Following the Sponsor’s decision to prematurely terminate the study, these objectives 
are no longer applicable.  Accordingly, the analyses of PFS and OS will only be 
reported in a descriptive way. No formal testing will be performed and no control for 
the overall type I error (α) accounting for the two primary endpoints will be 
implemented.  Consequently, p-values will not be able to be claimed as statistically 
significant and therefore will be reported as descriptive in nature. 
 
2.1.2 
Secondary Efficacy Objective 
The secondary efficacy objective for this study is to evaluate the efficacy of trastuzumab 
emtansine plus atezolizumab compared with trastuzumab emtansine plus placebo on 
the basis of the following endpoints: 
• 
ORR, defined as a complete response (CR) or partial response (PR) on two 
consecutive assessments, at least 28 days apart, as determined by investigator 
assessment using RECIST version 1.1 
• 
DOR, defined as the time from first occurrence of a documented objective response 
to disease progression, as determined by investigator assessment using RECIST 
v1.1 or death from any cause, whichever occurs first 
• 
PFS, defined as the time from randomization to the first occurrence of disease 
progression, as determined by a blinded independent central review committee 
using RECIST v1.1, or death from any cause, whichever occurs first 
• 
PFS in patients with baseline brain metastases as determined by investigator 
assessment using RECIST version 1.1 
• 
OS in patients with baseline brain metastases defined as the time from 
randomization to death from any cause 
• 
CNS PFS as determined by investigator assessment using RECIST version 1.1 in 
patients with or without baseline CNS metastases 
• 
Mean absolute and mean change-from-baseline scores in function (Physical, Role) 
and global health status/QoL as measured by the scales of the EORTC QLQ-C30 
• 
The proportion of patients with clinically meaningful deterioration in GHS/QoL 
physical, and role function as measured by scales of the EORTC QLQ-C30  


 
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Following the Sponsor’s decision to prematurely terminate the study, analysis of PFS 
as determined by a blinded independent central review committee will no longer be 
conducted.  Similarly, analysis based on the EORTC QLQ-C30 data will no longer be 
conducted. 
  
2.1.3 
Exploratory Efficacy Objective 
The exploratory efficacy objective for this study is to evaluate the efficacy of trastuzumab 
emtansine plus atezolizumab compared with trastuzumab emtansine plus placebo on 
the basis of the following endpoints: 
• 
Mean absolute and mean change-from-baseline scores in the remaining functions 
(Cognitive, Emotional, and Social), and disease- or treatment-related symptom 
scores of the EORTC QLQ-C30 and EORTC QLQ-Breast Cancer Module 23 
Questionnaire (EORTC QLQ-BR23) 
Following the Sponsor’s decision to prematurely terminate the study, this exploratory 
efficacy objective is no longer applicable and the corresponding analysis will no longer 
be performed. 
 
2.2 
SAFETY OBJECTIVE 
The safety objective for this study is to evaluate the safety of trastuzumab emtansine 
plus atezolizumab compared with trastuzumab emtansine plus placebo on the basis of 
the following endpoints: 
• 
Incidence and severity of AEs, with severity determined according to National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
Version 5.0 
• 
Change from baseline in targeted clinical laboratory test results 
 
The exploratory safety objective for this study is to evaluate the safety of trastuzumab 
emtansine plus atezolizumab compared with trastuzumab emtansine plus placebo on 
the basis of the following endpoints: 
• 
Presence, frequency of occurrence, severity, and/or degree of interference with 
daily function of selected symptomatic treatment toxicities (i.e., fatigue, chills, 
headache, cough, peripheral neuropathy, rash, aching muscles, aching joints, pain), 
as measured by the National Cancer Institute (NCI) Patient Reported Outcomes 
Common Terminology Criteria for Adverse Events (PRO-CTCAE) instrument 
• 
Change from baseline in symptomatic treatment toxicities, as measured by the 
PRO-CTCAE at pre-specified time points and an additional item regarding the 
overall burden experienced due to side effects of treatment from the EORTC item 
library 
Following the Sponsor’s decision to prematurely terminate the study, the exploratory 
safety objectives related to the PRO-CTCAE instrument are no longer applicable.  The 
corresponding analyses will not be performed.  


 
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2.3 
PHARMACOKINETIC OBJECTIVE 
The pharmacokinetic (PK) objectives for this study are as follows: 
• 
To characterize the PK of trastuzumab emtansine when given in combination with 
atezolizumab 
• 
To characterize the PK of atezolizumab when given in combination with 
trastuzumab emtansine 
Following the Sponsor’s decision to prematurely terminate the study, these objectives 
are no longer applicable.  Accordingly, the corresponding analyses will not be 
performed. 
 
2.4 
IMMUNOGENICITY OBJECTIVE 
The immunogenicity objective for this study is to evaluate the immune response to 
atezolizumab and trastuzumab emtansine when given in combination on the basis of the 
following endpoints: 
• 
To characterize the prevalence and incidence of ADA to atezolizumab in the 
presence of trastuzumab emtansine at pre-specified timepoints 
• 
To characterize the prevalence and incidence of ADA to trastuzumab emtansine in 
the presence and absence of atezolizumab at pre-specified timepoints 
 
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 
Following the Sponsor’s decision to prematurely terminate the study, these objectives 
are no longer applicable.  Accordingly, the corresponding analyses will not be 
performed. 
 
2.5 
BIOMARKER OBJECTIVE 
The exploratory biomarker objective for this study is to identify and/or evaluate 
biomarkers that are predictive of response to atezolizumab in combination with 
trastuzumab emtansine (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 and trastuzumab emtansine, 
are associated with susceptibility to developing AEs or can lead to improved AE 
monitoring or investigation (i.e., safety biomarkers), can provide evidence of 
atezolizumab and/or trastuzumab emtansine activity (i.e., pharmacodynamic 
biomarkers), or can increase the knowledge and understanding of disease biology and 
drug safety, on the basis of the following endpoints: 
• 
Association of baseline immune status (may include but not limited to: protein, 
mRNA markers, T cell markers based on CD8 IHC, and stromal tumor-infiltrating 
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• 
Association of baseline HER2 expression level (protein and/or gene copy 
number/ratio) with efficacy 
• 
Association of baseline PD-L1 expression level (≥1% and <5% IC vs ≥5% IC) with 
efficacy  
• 
Relationship between biomarkers in blood, plasma, and tumor tissue and efficacy, 
safety, PK, immunogenicity, tumor immunobiology, mechanisms of resistance 
Following the Sponsor’s decision to prematurely terminate the study, the objectives 
associated with efficacy are no longer applicable. Some descriptive analyses may be 
conducted as deemed appropriate. 
 
2.6 
HEALTH STATUS OBJECTIVE 
The exploratory health status utility objective for this study is to evaluate health status 
utility scores of patients treated with trastuzumab emtansine plus atezolizumab 
compared with trastuzumab emtansine plus placebo on the basis of the following 
endpoint: 
• 
Health utility and visual analog score (VAS) of the European Quality of Life 5-
Dimension Questionnaire (5-level version; EQ-5D-5L) for pharmacoeconomic 
modeling at specified timepoints 
Following the Sponsor’s decision to prematurely terminate the study, these objectives 
are no longer applicable and the corresponding analyses will not be performed. 
 
3. 
STUDY DESIGN 
3.1 
PREMATURE TERMINATION AT STUDY LEVEL   
The Sponsor has decided to prematurely terminate the study due to a lower-than-
expected enrolment rate, which significantly extended the recruitment timelines. The 
investigators were informed of premature study termination on 15 December 2022 by a 
study memo communicating this decision. 
Following a discussion between the investigator and the patient regarding the 
premature termination, the patient may consent to continue study treatment (i.e., 
either trastuzumab emtansine and atezolizumab or trastuzumab emtansine as a single 
agent; placebo will no longer be administered following unblinding of treatment 
assignment) if considered clinically appropriate by the investigator.  
Patients should continue to receive study treatment and undergo the revised study 
assessments as described in Section 3.2.1 and Appendix 1 . 
3.2 
RATIONALE AND IMPLICATIONS OF UNBLINDING ON 
STUDY DESIGN AND ASSESSMENTS 
The Sponsor’s rationale for unblinding the study is to allow investigators and patients 
to have an open discussion of the potential benefits and risks of continuing the 
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study (Section 4.3.5).  The Sponsor’s decision to unblind the study with respect to 
treatment assignment, was made after consideration of the following factors. 
The analysis of the two primary efficacy endpoints of PFS based on investigator tumor 
assessment and OS will no longer be conducted as per the original study protocol.  The 
analyses of PFS and OS will only be reported in a descriptive way. No formal testing 
will be performed and no control for the overall type I error (α) accounting for the two 
primary endpoints will be implemented.  Consequently, p-values will not be able to be 
claimed as statistically significant and therefore will be reported as descriptive in 
nature.  
Unblinding will be required for patients to continue with off-study treatment options. 
After unblinding of patients’ treatment assignment, patients will continue to receive 
study treatments until off-study treatment options are put into place, as follows: 
• 
Patients randomized to Arm A (trastuzumab emtansine and atezolizumab-
placebo) who are receiving study treatment will no longer receive placebo (see 
Section 4.3.2.2). 
• 
There is no crossover permitted for patients randomized to Arm A to receive 
atezolizumab in combination with trastuzumab emtansine. 
• 
Patients randomized to Arm B (trastuzumab emtansine and atezolizumab) who are 
receiving study treatment may continue treatment with both study drugs if 
considered clinically appropriate, after discussion with the investigator.  
Trastuzumab emtansine can be continued without atezolizumab if this is in the 
best interest of the patient (Section 4.6.1 ).  
• 
Until a revised Informed Consent Form is available, clinical notes should clearly 
document that this discussion took place between the patient and investigator 
and that the patient's verbal consent was obtained. 
• 
In the event of toxicity leading to trastuzumab emtansine discontinuation, 
atezolizumab must also be discontinued (Section 4.3.2.1 ) 
 
3.2.1 
Revised Study Assessments 
Following the Sponsor’s decision to prematurely terminate the study, tumor 
assessments will be conducted as per standard of care at the site.  
After unblinding, patients will continue to be followed for tumor assessments until 
disease progression ( Section 4.5.5 ) or until the patient discontinues from the study.  
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longer be collected prospectively by the Sponsor as an independent review facility (IRF) 
will not be utilized (see Section 4.5.5 ).  
Blood samples will no longer be drawn for PK and ADA analyses, or for biomarker 
analyses, as these analyses will no longer take place.  Patient-Reported Outcome (PRO) 
assessments will no longer be collected.  
All safety assessments as per the Schedule of Activities (Appendix 1) should be 
continued.  All data should be recorded in the eCRF. 
 
3.3 
DESCRIPTION OF THE STUDY 
This is a Phase III, randomized, multicenter, international, two-arm, double-blind, 
placebo-controlled clinical trial.  The study will evaluate the efficacy, safety, 
pharmacokinetics, and patient-reported outcomes of trastuzumab emtansine plus 
atezolizumab compared with trastuzumab emtansine plus placebo in patients with 
HER2-positive and PD-L1-positive locally advanced (LABC) or metastatic breast cancer 
(MBC) who have progressed either during or after prior trastuzumab- (+/- pertuzumab) 
and taxane-based therapy for LABC/MBC, or during (or within 6 months after 
completing) trastuzumab- (+/- pertuzumab) and taxane-based therapy in the 
neoadjuvant and/or adjuvant setting.  Previous adjuvant treatment with trastuzumab 
emtansine is not allowed if progression occurred during, or within 6 months after 
completing treatment. 
HER2 positivity and PD-L1 positivity of the tumor tissues will be determined by a central  
positive and PD-L1-positive will not be eligible.  
The analysis of tumor tissue PD-L1 status and HER2 gene status will be performed by a 
central laboratory per diagnostic testing protocol no. RD005510 (D158258) using the 
investigational VENTANA PD-L1 (SP142) Assay (Appendix 7 ) and VENTANA HER2 
Dual ISH DNA Probe Cocktail ( Appendix 6 ) as performance evaluation for these 
assays as companion diagnostics for the investigational treatment of atezolizumab and 
trastuzumab emtansine, respectively, in the target patient population (patients with 
HER2-positive and PD-L1-positive locally advanced or metastatic breast cancer). 
Patients may be prescreened for HER2 and PD-L1 status at a central laboratory by 
participating in a separate prescreening consent.  The prescreening test can be 
performed up to 12 months before randomization from archival tumor tissue.  If a patient 
consents to prescreening for determination of HER2 and PD-L1, these tests would not 
need to be repeated during the screening period.  
Up to two prescreening samples can be sent for analysis (i.e., one sample for 
prescreening and an additional sample in the case of a prescreen failure).  Pre-


 
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screening does not guarantee patient entry into the study as there is a chance that study 
enrollment could be completed during the 12-month patient prescreen period. 
Approximately 350 patients will be enrolled in the study at approximately 175 sites 
worldwide. Following the Sponsor’s decision to prematurely terminate the study, the 
objective of enrolling 350 patients will not be achieved. 
Patients will be randomized into one of the following treatment arms in a 1:1 ratio by 
means of a permuted block randomization scheme through the use of an interactive 
Web or voice response system: 
• 
Arm A: trastuzumab emtansine 3.6 mg/kg and placebo, q3w 
• 
Arm B: trastuzumab emtansine 3.6 mg/kg and atezolizumab 1200 mg, q3w  
 
Arm A and Arm B will be blinded with respect to administration of atezolizumab or 
placebo. 
Crossover between treatment arms will not be permitted. 
Randomization will be stratified according to:  
• 
Local hormonal status (ER and/or PgR positive vs. ER and PgR negative/unknown), 
• 
Disease status (visceral metastasis without brain metastasis vs. non-visceral 
metastasis only without brain metastasis [including locally advanced disease] vs. 
brain metastasis), 
• 
World Region (Western Europe vs U.S. vs. Rest of World).  
 
Patients who do not meet the criteria for participation in this study (screen failure) may 
qualify for one re-screening opportunity (for a total of two screenings per patient) at the 
investigator's discretion.  The investigator will maintain a record of reasons for screen 
failures (see Section 4.5.1). 
Patients must have measurable disease at baseline that is evaluable per RECIST v1.1 
( Appendix 4 ).  Patients must also have unresectable, locally advanced or metastatic 
disease.  Locally advanced disease must not be amenable to resection or other local 
therapy with curative intent.   
Patients will continue treatment until investigator-assessed radiographic disease 
progression per RECIST v1.1, withdrawal of consent, death, or intolerable toxicity, 
whichever occurs first.  Patients with isolated CNS progression that require local therapy 
only will be allowed to continue with study treatment as per investigator decision.  These 
patients will be recorded as disease progression for PFS analysis but will remain blinded 
and continue with treatment as per initial randomization until further disease progression 
in whichever location, withdrawal of consent, death, or intolerable toxicity, whichever 
occurs first. 


 
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Patients will undergo scheduled tumor assessment every 6 weeks (± 7 days), see 
Appendix 1 , that will continue until investigator-assessed radiographic disease 
progression per RECIST v1.1, withdrawal of consent, death, or study termination by the 
Sponsor, whichever occurs first.  Patients who discontinue study treatment for reasons 
other than disease progression, even if they start new anti-cancer therapy, will continue 
to undergo tumor assessment every 6 weeks (± 7 days) until disease progression (see).  
Following the Sponsor’s decision to prematurely terminate the study, tumor 
assessments will be conducted as per standard of care at the site.  
Tumor response will be based on RECIST v1.1 (Appendix 4) for estimation of PFS, 
ORR, and DOR.  Tumor assessment scans will be collected prospectively by an 
independent review facility.  Response will also be assessed by a blinded independent 
central review committee.  Following premature study termination, tumor assessment 
scans will no longer be collected prospectively by the Sponsor as an IRF will not be 
utilized (Section 4.5.5 ).  
Safety assessments will include the incidence, nature, and severity of AEs and 
laboratory abnormalities graded per NCI CTCAE v5.0.  Laboratory safety assessments 
will include the regular monitoring of hematology and blood chemistry. 
Serum samples will be collected to monitor pharmacokinetics and to detect presence of 
antibodies to trastuzumab emtansine and atezolizumab.  Tumor tissues, plasma, and 
whole blood samples, will be collected for exploratory biomarker assessments 
( Appendix 2 ).  Following the Sponsor’s decision to prematurely terminate the study, 
samples for PK, ADA and exploratory biomarker research will no longer be collected.  
Tumor tissue (historical sample or by new biopsy) will be collected at screening.  A 
tissue sample from mandatory biopsy will be collected at the time of first evidence of 
radiographic disease progression per RECIST v1.1 (prior to the start of new anti-cancer 
treatment), unless not clinically feasible as assessed by the investigator.  These samples 
will enable analysis of tumor tissue biomarkers related to resistance, disease 
progression, and clinical benefit of trastuzumab emtansine in combination with 
atezolizumab. 
After the Study Drug Completion Visit, all patients (regardless of reason for 
discontinuation) will be followed up for their survival status and new anti-cancer therapy 
every 3 months until death, loss to follow-up, withdrawal of consent, or study termination 
by the Sponsor.  After patients discontinue from study treatment, information on 
subsequent anti-cancer therapies will be collected according to the same schedule as 
survival follow-up. 
Figure 1 presents an overview of the study design.  A schedule of activities is provided in 
Appendix 1 . 




 
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Unblinded safety data will be reviewed on a periodic basis, approximately every 
6 months from the time of enrollment of the first patient.  The summaries and analyses of 
safety data for the iDMC review will be prepared by an independent Data Coordinating 
Center (iDCC).  The safety data will include demographic data, adverse events, serious 
adverse events, and relevant laboratory data.  
After reviewing the data, the iDMC will provide recommendations to the Sponsor as to 
whether the study should continue, be amended, or stopped, on the basis of the risk–
benefit balance to the patient.  The Sponsor’s Data Review Board (a group consisting of 
employees of the Sponsor empowered to make critical decisions) will make a decision 
on the basis of the iDMC’s recommendations.  Final decisions will rest with the Sponsor. 
Any outcomes of these safety data reviews that affect study conduct will be 
communicated in a timely manner to the investigators for notification of their respective 
Institutional Review Boards/Ethics Committees (IRBs/ECs). 
As per the iDMC charter, the iDMC will perform review of unblinded safety data until 
the study is unblinded, after which the study team will be responsible for the ongoing 
monitoring of patient safety in the study. Accordingly, the iDMC review activities will 
stop once the unblinding of the study will have been performed following the Sponsor’s 
decision for premature study termination as outlined in Section 3.2. 
3.4 
END OF STUDY AND LENGTH OF STUDY 
The end of study is planned to occur after approximately 184 OS events are obtained 
(approximately 40 months after the primary efficacy analysis of PFS [and concurrent first 
interim analysis of OS]).  The end of this study is defined as the date when the last 
patient, last visit occurs, or the date at which the last data point required for statistical 
analysis or safety follow-up is received from the last patient, whichever occurs later.  
In addition, the Sponsor may decide to terminate the study at any time.  The Sponsor has 
decided to prematurely terminate the study due to a lower-than-expected enrolment 
rate.  The investigators were informed of this decision on 15 December 2022.  Patients 
have the option to remain on the study and continue treatment until arrangements are 
put in place for continuing treatment on an extension study (BO25430) or in a Post-
Trial Access Program or other options.  The treatment solution for each patient may 
vary, taking into account local regulations and requirements. 
The total length of the study, from screening of the first patient to the end of the study, 
was originally expected to be approximately 78.1 months.  The length of study will now 
be determined by the time taken at each study site to implement the off-study patient 
treatment solutions, which should be approximately by the end of 2023. 


 
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3.5 
RATIONALE FOR STUDY DESIGN 
3.5.1 
Rationale for Atezolizumab Dose and Schedule 
Atezolizumab will be administered at a fixed dose of 1200 mg q3w (1200 mg on Day 1 of 
each 21-day cycle), which is an approved dosage for atezolizumab as either in 
monotherapy or in combination with other anti-cancer agents, as outlined in the 
prescribing information.  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 
(Deng et al. 2016) and available clinical pharmacokinetic, efficacy, and safety data (refer 
to the Atezolizumab Investigator's Brochure for details). 
3.5.2 
Rationale for Trastuzumab Emtansine Dose and Schedule 
The globally approved regimen of trastuzumab emtansine is 3.6 mg/kg q3w as 
confirmed in Study TDM4370g/BO21977 (Verma et al. 2012), the pivotal Phase III trial 
comparing trastuzumab emtansine to lapatinib plus capecitabine in patients with 
HER2-positive MBC who were previously treated with trastuzumab and a taxane.  This 
dose was investigated in combination with atezolizumab in the Phase Ib study GO29831 
and Phase II study WO30085, which offer proof of concept for this dose.  Overall, the 
safety profile of trastuzumab emtansine and atezolizumab in these studies was 
consistent with what is already known about the individual drugs.  As described in 
Section 1.4, several measures will be taken to ensure the safety of patients participating 
in this study, including guidance on the management of potential toxicities and dose 
modifications for trastuzumab emtansine.   
3.5.3 
Rationale for Patient Population 
This study will enroll patients with HER2-positive and PD-L1-positive LABC or MBC. 
Therapy with trastuzumab emtansine has been demonstrated to improve PFS and OS 
compared to lapatinib plus capecitabine in a randomized study for patients with 
HER2-positive MBC who have received prior trastuzumab or taxane (Verma et al. 2012).  
However, the PFS of 9 months and OS of 30 months for this patient population still 
represent an unmet medical need.  Despite advances in care for patients with 
HER2-positive MBC, it remains an incurable disease.  Nearly all patients with 
HER2-positive MBC will eventually suffer disease progression and die from their 
disease.  There is thus still a pressing need for more efficacious therapies with improved 
safety profiles in patients with HER2-positive disease. 
Atezolizumab showed promising anti-tumor activity, as determined by RECIST v1.1 
response, across multiple advanced tumor types, including MBC. Inhibition of PD-1/PD-
L1 signaling has been shown to produce durable responses in some patients, and 
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(Topalian et al. 2012; Herbst et al. 2014; Borghaei et al. 2015; Fehrenbacher et al. 2016; 
Herbst et al. 2016; Rosenberg et al. 2016; Spigel et al. 2018). 
In the Phase II Study WO30085, the subgroup of patients with LABC or MBC whose 
tumors expressed PD-L1 (IC 1/2/3) had improved PFS and a trend towards improved 
OS when treated with trastuzumab emtansine plus atezolizumab compared with 
trastuzumab emtansine plus placebo (see Section 1.3.2).  These data provide a 
rationale for evaluating the efficacy and safety of adding atezolizumab to trastuzumab in 
a population of patients with LABC or MBC with HER2-positive and PD-L1-positive 
tumors. 
3.5.4 
Rationale for Control Group 
Based on the results the EMILIA study (TDM4370g/BO21977; Section 1.2.1; Verma et 
al. 2012), trastuzumab emtansine was established as the standard of care in patients 
with HER2-positive MBC who have been previously exposed to trastuzumab and or 
taxane; the patient population being studied in the current trial (NCCN 2021a; Gennari et 
al. 2021). 
The control arm will be used to ascertain the individual contribution of atezolizumab to 
efficacy with trastuzumab emtansine in patients with HER2-positive and PD-L1-positive 
breast cancer.  Patients who are randomized to the control group will not be deprived of 
active therapy because all patients, regardless of treatment assignment, will receive an 
active, standard-of-care anti-HER2 treatment (i.e., trastuzumab emtansine). 
3.5.5 
Rationale for Progression-Free Survival and Overall Survival 
as Multiple Primary Endpoints 
In this study, the multiple primary efficacy endpoints will be investigator-assessed PFS 
and OS.  This study will test the hypothesis that treatment with trastuzumab emtansine 
plus atezolizumab will prolong PFS and OS compared with treatment with trastuzumab 
emtansine plus placebo.   
PFS as an endpoint can reflect tumor growth and can be assessed before the 
determination of a survival benefit; additionally, its determination is not generally 
confounded by subsequent therapies.  Meta-analyses have indicated that PFS can be 
considered a good measure of clinical benefit for patients with advanced breast cancer 
(Li and Pan 2018; Adunlin et al. 2015).  Whether an improvement in PFS represents a 
direct clinical benefit or a surrogate for clinical benefit depends on the magnitude of the 
effect and the benefit-risk profile of the new treatment compared with available therapies 
(FDA 2007; European Medicines Agency 2012). 
Multiple indicators support the integrity of Investigator-determined radiographic 
assessments and, therefore, this study is designed to use INV-PFS as primary endpoint. 
Appendix 1 to the EMA Guideline on the Evaluation of Anticancer Medicinal Products in 
Man (2013) states: “Investigator bias is generally not an issue in properly double-blinded 


 
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randomized studies” (EMA 2013; possible caveats specific to anti-cancer therapy studies 
follow this statement).  However, there could be a risk of discordance between 
assessments performed by independent central review committee and investigator 
assessments in some adjuvant cancers or where cancer immunotherapies are being 
used (Stone et al, 2019). 
Responses will be assessed by a blinded independent central review committee and 
further sensitivity analyses will be conducted. 
Improvement in OS is generally accepted as the best objective measure of clinical 
benefit for patients with MBC.  Recent data also suggest that OS may be a sensitive 
endpoint for cancer immunotherapy.  For example, in a randomized Phase II study 
(GO28753), patients with advanced NSCLC in the ITT population had a significant 
improvement in OS when treated with atezolizumab compared with docetaxel, with a 
stratified HR of 0.73 (95% CI: 0.53, 0.99).  PFS in the ITT population was similar in the 
two treatment arms:  HR of 0.94 (95% CI: 0.72, 1.23) (Fehrenbacher et al. 2016).  
This study has been designed to detect a substantial magnitude of benefit in the ITT 
population, that is, improvement in median PFS from 7 months in the control arm to 
11.67 months in the experimental arm, corresponding to a target PFS hazard ratio of 
0.60, and improvement in median OS from 31 months in the control arm to 51.7 months 
in the experimental arm, corresponding to a target OS hazard ratio of 0.60.  The median 
PFS estimated for the control arm (7 months) is based on the PFS observed in Study 
WO30085 in the subgroup of patients with prior trastuzumab and pertuzumab treatment 
who were randomized to treatment with trastuzumab emtansine plus placebo.  
3.5.6 
Rationale for Biomarker Assessments 
Published results suggest that the expression of PD-L1 in tumors correlates with 
response to anti−PD-1 and anti−PD-L1 therapy in the metastatic setting (Topalian et al. 
2012; Herbst et al. 2014; Borghaei et al. 2015; Fehrenbacher et al. 2016; Herbst et al. 
2016; Rosenberg et al. 2016; Spigel et al. 2018; Schmid et al. 2018).  In the current 
study, archival or baseline tumor specimens will be collected from patients and tested for 
PD-L1 expression by a central laboratory during the screening period. As previously 
described (Section 1.3.2.1), an exploratory analysis in Study WO30085 (KATE2) 
suggested a possible PFS benefit with atezolizumab in combination with trastuzumab 
emtansine vs trastuzumab emtansine and placebo in the PD-L1–positive subgroup, 
which was not observed in the PD-L1-negative subgroup. However, the magnitude of the 
potential benefit is uncertain due to the small sample size and imbalances in baseline 
factors (Emens et al. 2019a). Interestingly, the predictive nature of PD-L1 expression 
was also observed in metastatic TNBC. In Study WO29522 (IMpassion130), patients 
with first line metastatic TNBC treated with atezolizumab plus nab-paclitaxel experienced 
a prolonged PFS and OS compared with patients treated with placebo plus nab-
paclitaxel in the PD-L1-positive but not in the PD-L1-negative subgroup (Schmid et al. 
2018). The same result was demonstrated by the Keynote-355 study in patients with 


 
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locally recurrent, inoperable or metastatic TNBC treated with pembrolizumab vs placebo 
in combination with chemotherapy (Cortes et al. 2020). Therefore, only patients with 
tumor PD-L1 expression defined by expression on tumor-infiltrating immune cells (IC) 
covering ≥ 1% of tumor area by the PD-L1 SP142 assay will be enrolled in the study. 
The relationship between PD-L1 expression level measured by various IHC assays and 
clinical outcomes may be assessed in a retrospective manner.  
In addition, other exploratory biomarkers, such as potential predictive and prognostic 
markers that are related to PD-L1 activity, tumor immunobiology (e.g. CD8, TILs), 
mechanisms of resistance or tumor type may also be analyzed if supported by either 
nonclinical or clinical data.  KATE2 showed that immune-related biomarker data, such as 
CD8 IHC expression, and TILs were consistent with the subgroup data in the PD-L1–
positive subgroup, showing a treatment benefit with atezolizumab in tumors with high 
immune biomarkers expression compared to those with low expression.  These results 
support that benefit from atezolizumab-plus-trastuzumab emtansine regimen is likely 
dependent on pre-existing immunity (Emens et al. 2019a). 
Activating PIK3CA mutations in tumors have been evaluated as a resistance marker 
for HER2-targeted therapies in prior trials.  In metastatic HER2−positive breast cancer, 
(Study WO20698/TOC4129g) worse PFS was observed in patients with 
PIK3CA mutations (Baselga et al. 2014) while treatment effect was maintained.  
Study TDM4370g/BO21977 (Verma et al. 2012) showed that no difference in PFS and 
OS was seen in patients with and without an activating PIK3CA mutation in their tumor 
when treated with trastuzumab emtansine (Baselga et al. 2016).  In the current study, 
PIK3CA mutations may be measured in baseline tumor tissue to confirm the finding from 
Study TDM4370g/BO21977.  
Müller et al. (2015) demonstrated that trastuzumab emtansine increases tumor 
infiltrating lymphocytes (TILs) in human primary breast cancer and induces infiltration by 
effector T cells in murine breast tumors.  Additionally, they showed that combining 
trastuzumab emtansine treatment with blockade of the PD-1/CTLA-4 inhibitory pathway 
resulted in complete cures in murine models and greatly enhanced T cell responses.  
Chen et al. (2014) showed in a study in patients with HER2-positive EBC (n = 22) that 
trastuzumab in combination with granulocyte−macrophage colony-stimulating 
factor/HER2 vaccine triggered a HER2-specific T-cell response.  The presence of 
HER2-specific CD8 T cells in peripheral blood increased over the course of the multiple 
trastuzumab/vaccination treatment.  An exploratory endpoint of this study is to test 
whether the combination of atezolizumab with trastuzumab emtansine changes 
expression levels of biomarkers or biomarker panels in the peripheral blood and/or in the 
tumor compared to those receiving trastuzumab emtansine alone.   
Pre-treatment tumor samples and biopsies collected at the time of progression (if 
clinically feasible) will assist in the study of pharmacodynamic changes related to the 
activity of trastuzumab emtansine with and without combination treatment with 


 
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atezolizumab (changes in infiltration of CD8-positive T cells and other exploratory 
biomarkers).  Peripheral blood samples will also be collected prior to treatment and 
throughout the course of treatment to evaluate biomarkers (e.g. ctDNA).  
In addition, potential correlations of pharmacodynamic markers with the dose, safety, 
and anti-tumor activity of combination treatment with atezolizumab plus trastuzumab 
emtansine will be explored.  
Tissue samples will be collected for DNA extraction to enable whole genome sequencing 
(WGS) or whole exome sequencing (WES) to identify variants that are predictive of 
response to study treatment, are associated with progression to a more severe disease 
state, are associated with acquired resistance to study treatment, are associated with 
susceptibility to developing AEs, can lead to improved AE monitoring or investigation, or 
can increase the knowledge and understanding of disease biology and drug safety.  
Genomics is increasingly informing researcher's 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 AEs.  Data will be analyzed in the context of this study but may 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. 
3.5.7 
Rationale for Immunogenicity Assessments 
Immunogenicity assessments will be used to determine whether patients develop ADAs 
against trastuzumab emtansine and/or atezolizumab, and assess whether the presence 
of ADAs impact safety, efficacy, or PK (as data allow).  Refer to the schedule of activities 
( Appendix 1 ) and the schedule of PK, immunogenicity, and biomarker samples 
( Appendix 2 ) for details regarding the timing and frequency of blood sample collection 
to assess ADAs.  
A three-tiered analytical testing approach will be used to detect, confirm, and 
characterize the ADAs against trastuzumab emtansine and atezolizumab.  First, 
screening for the potential emergence of ADAs using bridging immunoassays. Second, 
confirming the specificity of the response in all screen positive samples through 
competition with the therapeutic protein in confirmatory immunoassays.  Third, 
characterization of the response in all confirm positive samples in a titration 
immunoassay (a titer is the log10 of the reciprocal of the sample dilution factor at the cut 
point used to define positivity). All immunogenicity samples will be analyzed at central 
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3.5.8 
Rationale for Non-Standard Clinical Outcome Assessments 
Cancer treatments, particularly combination therapies, can produce significant 
symptomatic AEs.  Recent research has shown that clinicians may underreport the 
incidence and severity of symptoms experienced by patients receiving treatment for 
cancer (Fromme et al. 2004; Trotti et al. 2007; Pakhomov et al. 2008; Basch 2010; 
Quinten et al. 2011; Atkinson et al. 2012; Basch et al. 2014).  Collecting AE information 
directly from patients can provide a better understanding of treatment characteristics and 
their effects.  In order to evaluate the tolerability of trastuzumab emtansine in 
combination with atezolizumab, patients will be asked to report on their experience 
related to study treatment-related symptoms selected from the validated PRO-CTCAE 
item bank (see Section 4.5.9 and Appendix 13 for further details).  These symptoms 
were identified as being salient to patients' experience with trastuzumab emtansine and 
atezolizumab on the basis of the AEs anticipated for these drugs.  
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
The study will enroll patients with HER2-positive and PD-L1-positive LABC or MBC who 
have received prior trastuzumab- (+/- pertuzumab) and taxane-based therapy that is 
incurable, unresectable, and previously treated with multimodality therapy.  Patients 
must comply with the following inclusion and exclusion criteria. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form by patient or legally-authorized representative 
• 
Age ≥ 18 years at time of signing Informed Consent Form 
• 
Ability to comply with the study protocol 
• 
Histologically determined (in a central laboratory) HER2+/PD-L1+ LABC or MBC 
that is unresectable and previously treated with multimodality therapy: 
– 
Progression must have occurred during or after most recent treatment for 
LABC/MBC or during, or within 6 months after completing, neoadjuvant and/or 
adjuvant therapy 
– 
Prior treatment for breast cancer with trastuzumab (+/- pertuzumab) and taxane 
in the neoadjuvant and/or adjuvant, unresectable locally advanced, or 
metastatic settings 
– 
Patients must not have received more than two prior lines of therapy in the 
metastatic setting 
– 
Previous exposure to trastuzumab emtansine in the EBC setting is allowed only 
if disease recurrence occurred more than 6 months after completing, adjuvant 
trastuzumab emtansine. Previous exposure to trastuzumab emtansine in the 
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– 
Previous treatment with anti-HER2 agents (including, but not limited to, 
lapatinib, neratinib, tucatinib, trastuzumab deruxtecan, pyrotinib) and CD137 
agonists, anti-programmed death−1 (PD-1), or anti-PD-L1 therapeutic antibody 
or pathway−targeting agents is allowed 
– 
Patients who are receiving bisphosphonate therapy specifically to prevent 
skeletal events and who do not have a history of clinically significant 
hypercalcemia are eligible 
– 
Concurrent hormonal treatment for patients with hormone-positive disease is 
not allowed in the study 
– 
Localized palliative radiation therapy is allowed for symptom management if 
finalized before enrollment. The patient must have recovered from any resulting 
acute toxicity (to Grade ≤ 1) prior to study treatment initiation. There is no 
required minimum recovery period 
• 
Measurable disease per RECIST v1.1 
Previously irradiated lesions can be considered as measurable disease only 
if progressive disease has been unequivocally documented at that site since 
radiation 
• 
Prospective central determination of representative tumor tissue specimen(s) prior 
to randomization of: 
– 
HER2-positive breast cancer as defined by an IHC score of 3+ or gene 
amplified by in situ hybridization (ISH) as defined by a ratio of ≥ 2.0 for the 
number of gene copies to the number of chromosome 17 copies 
– 
PD-L1 positivity defined by expression on tumor-infiltrating immune cells (IC) 
covering ≥ 1% of tumor area by IHC using the PD-L1 (SP142) assay  
• 
For patients with bilateral breast cancer (synchronous or developed at a later stage), 
HER2 positivity must be centrally determined preferably in a metastatic biopsy or if 
not available in primary tumor from both left and right breast; at least one biopsy 
must be centrally determined as PD-L1 positive. 
• 
For patients with initially multicentric tumors (multiple tumors involving more than 
one quadrant) or multifocal tumors (more than one mass confined to the same 
quadrant as the primary tumor), HER2 positivity must be centrally determined 
preferably in a metastatic biopsy or if not available in primary tumor, provided that: 
– 
For multicentric tumors all discrete lesions are centrally confirmed as HER2-
positive and at least one lesion is centrally determined as PD-L1 positive 
– 
For multifocal tumors at least one focus is centrally confirmed as HER2-positive 
and PD-L1 positive 
• 
A formalin-fixed, paraffin-embedded (FFPE) tumor specimen in a paraffin block 
(preferred) or at least 17 slides containing unstained, freshly cut, serial sections 
must be submitted (preferably along with an associated pathology report) prior to 
study enrollment. The unstained slides for staining must be within the current 
documented cutslide stability window. The sample needs to be of good quality 
based on total and viable tumor content. If archival tumor tissue is unavailable or is 


 
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determined to be unsuitable for required testing, tumor tissue must be obtained from 
a biopsy performed at screening.  A biopsy may also be performed at screening if a 
patient's archival tissue test results do not meet eligibility criteria.  Refer to Section 
4.5.7 for additional information on tumor specimens collected at screening. 
Cytological or fine-needle aspiration samples and bone specimens are not 
acceptable for central testing to determine eligibility. 
• 
Willing to provide blood samples before treatment start, while on-study, and at 
progression, for standard of care follow-up and exploratory research on biomarkers 
• 
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 
• 
Life expectancy ≥ 6 months 
• 
Adequate hematologic and end-organ function, defined by the following laboratory 
test results, obtained within 7 days prior to initiation of study treatment: 
– 
ANC ≥ 1.5 x 109/L (≥ 1500/µL) without granulocyte colony-stimulating factor 
support 
– 
Lymphocyte count ≥ 0.5 x 109/L (≥ 500/µL) 
– 
Platelet count ≥ 100 x 109/L (≥ 100,000/µL) without transfusion 
– 
Hemoglobin ≥ 90 g/L (≥ 9 g/dL) 
Patients may be transfused to meet this criterion 
– 
AST, ALT, and alkaline phosphatase (ALP) ≤ 2.5 x upper limit of normal (ULN), 
with the following exceptions: 
Patients with documented liver metastases:  AST and ALT ≤ 5 x ULN 
Patients with documented liver or bone metastases:  ALP ≤ 5 x ULN 
– 
Total bilirubin ≤ 1.5 x ULN with the following exception: 
Patients with known Gilbert disease:  total bilirubin ≤ 3 x ULN 
– 
Creatinine ≤ 1.5 x ULN or Creatinine clearance ≥ 30 mL/min (calculated using 
the Cockcroft-Gault formula) 
– 
Albumin ≥ 25 g/L (≥ 2.5 g/dL) 
– 
For patients not receiving therapeutic anticoagulation:  INR and aPTT 
≤ 1.5 x ULN 
• 
For patients receiving therapeutic anticoagulation: stable anticoagulant regimen 
• 
Negative HIV test at screening 
• 
For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, 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 7 months after the 
final dose of study treatment.  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 


 
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months of amenorrhea with no identified cause other than menopause), and 
is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian 
tubes, and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  Per this definition, a woman with a tubal ligation 
is considered to be of childbearing potential.  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, hormonal contraceptives 
that inhibit ovulation, and hormone-releasing intrauterine devices and copper 
intrauterine devices; 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. 
If required per local guidelines or regulations, locally recognized adequate 
methods of contraception and information about the reliability of abstinence 
will be described in the local Informed Consent Form 
• 
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 
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 7 months after the final dose of study treatment. 
Men must refrain from donating sperm during this same period. 
With a pregnant female partner, men must remain abstinent or use a 
condom during the treatment period and for 7 months after the final dose of 
study treatment 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. 
If required per local guidelines or regulations, locally recognized adequate 
methods of contraception and information about the reliability of abstinence 
will be described in the local Informed Consent Form. 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection 
(excluding fungal infections of nail beds) at study enrollment, or any major episode 
of infection requiring treatment with IV antibiotics or hospitalization (for 
complications of infections or relating to the completion of the course of antibiotics) 
within 4 weeks prior to Cycle 1, Day 1 


 
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This also applies to patients with suspected or confirmed COVID-19 
infection. 
• 
Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of 
study treatment 
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract 
infection or chronic obstructive pulmonary disease exacerbation) are eligible 
for the study. 
• 
Receipt of any anti-cancer drug/biologic or investigational treatment 21 days prior to 
Cycle 1, Day 1 except hormone therapy, which can be given up to 7 days prior to 
Cycle 1, Day 1; recovery of treatment-related toxicity consistent with other eligibility 
criteria 
• 
Prior treatment with trastuzumab emtansine in metastatic setting 
• 
History of exposure to the following cumulative doses of anthracyclines as specified 
below: 
– 
Doxorubicin > 500 mg/m2 
– 
Liposomal doxorubicin > 500 mg/m2 
– 
Epirubucin > 720 mg/m2 
– 
Mitoxantrone > 120 mg/m2 
– 
Idarubicin > 90 mg/m2 
If another anthracycline or more than one anthracycline has been used, then 
the cumulative dose must not exceed the equivalent of 500 mg/m2 
doxorubicin. 
• 
Symptomatic or actively progressing central nervous system (CNS) metastases 
Asymptomatic CNS lesions ≤ 2cm without clinical requirement for local 
intervention (whole brain radiation therapy and/or stereotactic radiosurgery 
and/or surgery) are eligible, provided that all of the following criteria are met; 
it is for investigator to decide if local intervention is indicated. 
Asymptomatic patients with treated CNS lesions are eligible, provided that all 
of the following criteria are met: 
• 
Measurable disease, per RECIST v1.1, must be present outside 
the CNS 
• 
No brain lesions thought to require immediate local therapy 
• 
Only supratentorial and cerebellar metastases allowed (i.e., no 
metastases to midbrain, pons, medulla, or spinal cord) 
• 
The patient has no history of intracranial hemorrhage or spinal 
cord hemorrhage 
• 
The patient has not undergone stereotactic radiotherapy within 7 
days prior to initiation of study treatment, whole-brain radiotherapy 
within 21 days prior to initiation of study treatment, or 
neurosurgical resection within 28 days prior to initiation of study 
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• 
Anticonvulsant therapy at a stable dose is permitted. 
• 
No ongoing use of systemic corticosteroids for control of 
symptoms of brain metastases at a total daily dose of >2 mg of 
dexamethasone (or equivalent).  Subjects on a chronic stable 
dose of ≤2 mg total daily of dexamethasone (or equivalent) are 
eligible. 
Note: Patients with new asymptomatic CNS metastases detected at the 
screening scan who require radiation therapy and/or surgery for CNS 
metastases, must receive it before screening.  Following local intervention, 
these patients may be eligible without the need for an additional brain scan 
prior to enrollment, if all other criteria are met. 
• 
History of leptomeningeal disease 
• 
Spinal cord compression not definitively treated with surgery and/or radiation, or 
previously diagnosed and treated spinal cord compression without evidence that 
disease has been clinically stable for > 2 weeks prior to randomization 
• 
Uncontrolled tumor-related pain 
Patients requiring pain medication must be on a stable regimen at study 
entry. 
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated 
≥ 14 days prior to Cycle 1, Day 1.  The patient must have recovered from 
any resulting acute toxicity (to Grade ≤ 1) prior to study treatment initiation. 
Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not 
currently associated with spinal cord compression) should be considered for 
loco-regional therapy, if appropriate, prior to enrollment. 
• 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently) 
Patients with indwelling catheters (e.g., PleurX®) are allowed. 
• 
Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, 
calcium > 12 mg/dL, or corrected calcium greater than ULN) 
• 
Current Grade ≥ 3 peripheral neuropathy (according to the NCI CTCAE v5.0) 
• 
Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] 
test at screening) or hepatitis C 
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection 
(defined as having a negative HBsAg test and a positive antibody to hepatitis 
B core antigen [anti-HBc] antibody test accompanied by a negative HBV 
DNA test) are eligible. 
Patients positive for hepatitis C virus (HCV) antibody are eligible only if 
polymerase chain reaction is negative for HCV RNA. 
• 
Current treatment with anti-viral therapy for HBV 
• 
Active or history of autoimmune disease or immune deficiency, including, but not 
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erythematosus, rheumatoid arthritis, inflammatory bowel disease, anti-phospholipid 
antibody syndrome, granulomatosis with polyangiitis, Sjögren syndrome, Guillain-
Barré syndrome, or multiple sclerosis (see Appendix 15 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 of following conditions are met: 
• 
Rash must cover < 10% of body surface area. 
• 
Disease is well controlled at baseline and requires only low-
potency topical corticosteroids. 
• 
There has been 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. 
• 
Patients with psoriasis must have a baseline ophthalmologic exam 
to rule out ocular manifestations. 
• 
Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia 
• 
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 CT scan 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted 
• 
Active tuberculosis 
• 
Cardiopulmonary dysfunction as defined by: 
– 
Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg 
with or without medication) 
– 
Inadequate left ventricular ejection fraction at baseline, <  50% by either ECHO 
or MUGA 
– 
History of symptomatic congestive heart failure (CHF)-Grade ≥ 3 per 
NCI CTCAE version 5.0 or Class ≥ II New York Health Association 
– 
History of a decrease in left ventricular ejection fraction to < 40% or 
symptomatic CHF with prior trastuzumab treatment 
– 
Myocardial infarction or unstable angina within 6 months of randomization 
– 
Current dyspnea at rest due to complications of advanced malignancy, or other 
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– 
Evidence of transmural infarction on ECG 
– 
Significant symptoms (Grade ≥ 2) relating to LVEF, cardiac arrhythmia, or 
cardiac ischemia 
– 
High-risk uncontrolled arrhythmias (i.e., supraventricular 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]) 
• 
Major surgical procedure, other than for diagnosis, or significant traumatic injury 
within 4 weeks prior to initiation of study treatment, or anticipation of need for a 
major surgical procedure during the study 
• 
History of malignancy within 5 years prior to initiation of study treatment, with the 
exception of the cancer under investigation in this study and malignancies with a 
negligible risk of metastasis or death (e.g., 5-year OS rate > 90%), such as 
adequately treated carcinoma in situ of the cervix, non melanoma skin carcinoma, 
localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer 
• 
Current severe, uncontrolled systemic disease (e.g., clinically significant 
cardiovascular, pulmonary or metabolic disease; wound healing disorders; ulcers; 
bone fractures) 
• 
Prior allogeneic stem cell or solid organ transplantation 
• 
Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that contraindicates the use of an investigational drug, may affect 
the interpretation of the results, or may render the patient at high risk from treatment 
complications 
• 
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during atezolizumab treatment 
or within 5 months after the final dose of study treatment 
• 
Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferon and interleukin 2 [IL-2]) within 4 weeks or 5 drug-elimination half-lives 
(whichever is longer) prior to initiation of study treatment 
• 
Treatment with systemic immunosuppressive medication (including, but not limited 
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
anti-TNF-α agents) within 2 weeks prior to initiation of study treatment, or 
anticipation of need for systemic immunosuppressive medication during study 
treatment, with the following exceptions: 
– 
Patients who received acute, low-dose systemic immunosuppressant 
medication or a one-time pulse dose of systemic immunosuppressant 
medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible 
for the study. 
– 
Patients who received mineralocorticoids (e.g., fludrocortisone), inhaled or low-
dose corticosteroids for chronic obstructive pulmonary disease (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, or other hypersensitivity reactions to 
chimeric or humanized antibodies, excipients of any drugs formulated in polysorbate 
80 or 20 or fusion proteins 
• 
Known hypersensitivity to Chinese hamster ovary cell products or to any component 
of the atezolizumab formulation 
• 
Known allergy or hypersensitivity to any component of the trastuzumab emtansine 
formulation 
• 
Pregnancy or breastfeeding, or intention of becoming pregnant during the study or 
within 7 months after the last dose of study treatment 
Women of childbearing potential must have a negative serum pregnancy test 
result within 7 days prior to initiation of study treatment. 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
4.2.1 
Treatment Assignment 
This is a randomized, double-blind study.  After written informed consent has been 
obtained, all screening procedures and assessments have been completed, and 
eligibility has been established for a patient, the study site will obtain the patient's 
identification number and treatment assignment from the interactive voice or web-based 
response system (IxRS). 
Patients will be randomly assigned to one of two treatment arms: trastuzumab 
emtansine plus atezolizumab or trastuzumab emtansine plus placebo.  Randomization 
will occur in a 1:1 ratio through use of a permuted-block randomization method to ensure 
a balanced assignment to each treatment arm.  Randomization will be stratified 
according to the following criteria: 
• 
Local hormonal status (ER and/or PgR positive vs. ER and PgR negative/unknown), 
• 
Disease status (visceral metastasis without brain metastasis vs. non-visceral 
metastasis only without brain metastasis [including locally advanced disease] vs. 
brain metastasis), 
• 
World Region (Western Europe vs U.S. vs. Rest of World).  
 
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.  These roles include the unblinding group 
responsible, clinical supply chain managers, sample handling staff, operational assay 
group personnel, IxRS service provider, and iDMC members. 
While PK and immunogenicity samples must be collected from patients assigned to the 
comparator arm to maintain the blinding of treatment assignment, PK and ADA assay 
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interpretation of the study data.  Laboratories responsible for performing study drug PK 
and ADA assays will be unblinded to patient treatment assignments to identify 
appropriate samples for analysis. Trastuzumab emtansine, total trastuzumab, and DM1 
PK and trastuzumab emtansine ADAs will be analyzed for all patients. PK samples 
collected from patients assigned to the comparator arm will not be analyzed for 
atezolizumab levels, except by request (e.g., to evaluate a possible error in dosing).  
Immunogenicity samples from patients assigned to the comparator arm will not be 
analyzed for atezolizumab ADAs except by request. 
If unblinding is necessary for a medical emergency (e.g., in the case of an SAE 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 
treatment code should not be broken except in emergency situations.  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 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. Unblinding 
is permitted for medical management of immune mediated toxicity and to guide initiation 
of steroids and other immunosuppressives.  When the unblinding is requested, the date 
and reason for unblinding must be fully documented in source documents and recorded 
in the case report forms.  If unblinding occurs, the site staff should make every effort to 
ensure that the treatment arm in which the unblinded patient was assigned is not 
communicated to any Sponsor personnel or designee involved in the study. The 
investigator should document and provide an explanation for any non-emergency 
unblinding. If the Medical Monitor agrees to patient unblinding, the investigator will be 
able to break the treatment code by contacting the IxRS. 
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 an 
investigational medicinal product (IMP; defined in Section 4.3).  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. 
The Sponsor’s rationale for unblinding the study, is to allow investigators and patients 
to have an open discussion of the potential benefits and risks of continuing the 
experimental therapy and to allow them to continue with treatment options off this 
study (Section 4.3.5 ).  The Sponsor’s decision to unblind the study with respect to 
treatment assignment, was made after consideration of the following factors. 


 
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The analysis of the two primary efficacy endpoints of PFS based on investigator tumor 
assessment and OS will no longer be conducted as per the original study protocol.  The 
analyses of PFS and OS will only be reported in a descriptive way. No formal testing 
will be performed and no control for the overall type I error (α) accounting for the two 
primary endpoints will be implemented.  Consequently, p-values will not be able to be 
claimed as statistically significant and therefore will be reported as descriptive in 
nature. 
Unblinding will be required for patients to continue with off-study treatment options. 
After unblinding of patients’ treatment assignment, patients will continue to receive 
study treatments until off-study treatment options are put into place.  
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
The investigational medicinal products (IMP) for this study are trastuzumab emtansine, 
atezolizumab, and placebo.   
There are no non-investigational medicinal products (NIMPs) in this study.  
4.3.1 
Study Treatment Formulation and Packaging 
4.3.1.1 
Trastuzumab Emtansine  
Trastuzumab emtansine will be supplied by the Sponsor as a vial containing 160 mg 
powder for concentrate for solution for infusion.  After reconstitution one vial of 8 mL 
solution contains 20 mg/mL of trastuzumab emtansine.  For information on the 
trastuzumab emtansine formulation, see the pharmacy manual and the Trastuzumab 
emtansine Investigator's Brochure. 
4.3.1.2 
Atezolizumab and Placebo 
The atezolizumab Drug Product will be supplied by the Sponsor as a sterile liquid in a 
single-use, 20-mL glass vial.  The vial contains approximately 20 mL (1200 mg) of 
atezolizumab solution. 
For information on the atezolizumab formulation, see the pharmacy manual and the 
Atezolizumab Investigator's Brochure. 
Placebo will be supplied by the Sponsor as a sterile liquid in a single-use, 20-mL glass 
vial, equivalent to atezolizumab but without the active agent. 


 
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4.3.2 
Study Treatment Dosage, Administration, and Compliance 
The treatment regimens are summarized in Section 3.3. 
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 
Details on treatment administration (e.g., dose and timing) should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Cases of accidental 
overdose or medication error, along with any associated AEs, should be reported as 
described in Section 5.3.5.12. 
Guidelines for dosage modification (allowed for trastuzumab emtansine only) and 
treatment interruption or discontinuation for patients who experience AEs are provided in 
Section 5.1.4 and Appendix 18 (trastuzumab emtansine), Appendix 19 (atezolizumab), 
and Appendix 20 (potential overlapping toxicities). 
4.3.2.1 
Trastuzumab Emtansine 
Trastuzumab emtansine will be given at a dose of 3.6 mg/kg by IV infusion, q3w.  
The dose of trastuzumab emtansine will be administered on the basis of the patient’s 
baseline weight.  Weight will be measured at each visit (or in the 3 days prior) and dose 
must be re-adjusted for weight changes ≥ 10% compared to the previous visit or 
baseline.  Administration may be delayed to assess or treat AEs.  Dose reduction of 
trastuzumab emtansine will be allowed, following the dose reduction levels provided in 
Table 5.  Once a dose has been reduced for AE(s), it must not be re-escalated.  
If trastuzumab emtansine is discontinued because of toxicity, it should not be 
re-administered.  If trastuzumab emtansine is discontinued for any reason, 
atezolizumab/placebo should also be discontinued. 
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, on the 
earliest following date with subsequent protocol-specified procedures rescheduled 
accordingly. 
Refer to Table 2 for guidelines on administration of first and subsequent infusions of 
trastuzumab emtansine. 
 
 


 
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Table 2 
Administration of First and Subsequent Infusions of 
Trastuzumab Emtansine 
First Infusion 
Subsequent Infusions 
• 
No premedication is administered. 
• 
Record patient’s vital signs as 
indicated in Appendix 1 
• 
Administer the initial dose as a 
90-minute ( ± 10 min) intravenous 
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. 
• 
Record patient’s vital signs as indicated in 
Appendix 1 
• 
If the patient experienced an IRR with any 
previous infusion, premedication for nausea and 
infusion reactions (e.g., analgesics, etc.) may be 
administered at the investigator's discretion. 
• 
If prior infusions were well tolerated, subsequent 
doses may be administered as 30-minute 
( ± 10 min) infusions  
• 
Patient should be observed during the infusions 
and for at least 30 minutes after infusion. 
IRR = infusion related reaction. 
 
4.3.2.2 
Atezolizumab and Placebo 
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of 
each 21-day cycle until disease progression or unacceptable toxicity (see Section 3.3 for 
details). 
Administration of atezolizumab will be performed in a monitored setting where 
there is immediate access to trained personnel and adequate equipment and 
medicine to manage potentially serious reactions.  For anaphylaxis precautions, 
see Appendix 17 .  Atezolizumab infusions will be administered per the 
instructions outlined in  Table 3. 
 
 


 
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Table 3 
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 IRR with 
any previous infusion, premedication with 
antihistamines, anti-pyretics, and/or 
analgesics may be administered for 
subsequent doses, as clinically indicated. 
• 
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 IRR, or 60 (± 15) 
minutes if the patient experienced an IRR 
with the previous infusion. 
• 
If the patient experienced an IRR with the 
previous infusion or if clinically indicated, 
vital signs should be measured during the 
infusion and at 30 (± 10) minutes after the 
infusion. 
IRR = infusion related reaction. 
 
Guidelines for medical management of infusion-related reactions (IRRs) are provided in 
Appendix 19 . 
No dose modification for atezolizumab is allowed. If atezolizumab/placebo is 
discontinued for toxicity, treatment with trastuzumab emtansine may continue, if clinically 
indicated. 
4.3.3 
Sequence of Study Drug Administration 
All the study drugs are to be administered to patients intravenously. Atezolizumab or 
placebo will be administered first followed by trastuzumab emtansine.   
Guidelines for treatment interruption or discontinuation and the management of specific 
AEs are provided in Section 5.1.4 and Appendix 18 (trastuzumab emtansine),  
Appendix 19 (atezolizumab), and Appendix 20 (potential overlapping toxicities). 
Refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, 
and administration of atezolizumab/placebo. 
4.3.4 
Investigational Medicinal Product Handling and Accountability 
All IMPs required for completion of this study will be provided by the Sponsor.  The study 
site (i.e., investigator or other authorized personnel [e.g., pharmacist]) is responsible for 
maintaining records of IMP delivery to the site, IMP inventory at the site, IMP use by 
each patient, and disposition or return of unused IMP, thus enabling reconciliation of all 
IMP received, and for ensuring that patients are provided with doses specified by the 
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The study site should follow all instructions included with each shipment of IMP.  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.  
The investigator or designee must confirm that appropriate temperature conditions have 
been maintained during transit, either by time monitoring (shipment arrival date and 
time) or temperature monitoring, for all IMPs received and that any discrepancies have 
been reported and resolved before use of the IMPs.  All IMPs must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions, with access limited to the investigator 
and authorized staff. 
Only patients enrolled in the study may receive IMPs, and only authorized staff may 
supply or administer IMPs. 
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 with the appropriate 
documentation.  The site's method of destroying Sponsor-supplied IMPs must be agreed 
to by the Sponsor.  The site must obtain written authorization from the Sponsor before 
any Sponsor-supplied IMP is destroyed, and IMP destruction must be documented on 
the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the drug accountability log. 
Refer to the pharmacy manual and/or the applicable Investigator's Brochure for 
information on IMP handling, including preparation and storage, and accountability.  
4.3.5 
Continued Access to Trastuzumab Emtansine and 
Atezolizumab 
The Sponsor will offer continued access to Roche IMPs (trastuzumab emtansine and 
atezolizumab) free of charge to eligible patients in accordance with the Roche Global 
Policy on Continued Access to Investigational Medicinal Product, as outlined below. 
A patient will be eligible to receive Roche IMPs (trastuzumab emtansine and 
atezolizumab) after completing the study if all of the following conditions are met: 
• 
The patient has a life-threatening or severe medical condition and requires 
continued Roche IMP treatment for his or her well-being 
• 
There are no appropriate alternative treatments available to the patient 
• 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
 


 
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A patient will not be eligible to receive Roche IMPs (trastuzumab emtansine and 
atezolizumab) after completing the study if any of the following conditions are met: 
• 
The Roche IMP is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient). 
• 
The Sponsor has discontinued development of the IMP or data suggest that the IMP 
is not effective for breast cancer. 
• 
The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
breast cancer. 
• 
Provision of the Roche IMP is not permitted under the laws and regulations of the 
patient's country. 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
Following the Sponsor’s decision to terminate the study, patients may be eligible to 
receive trastuzumab emtansine or trastuzumab emtansine in combination with 
atezolizumab as part of an extension study (BO25430) or as part of a Post-Trial Access 
Program or other local option.  The treatment solution for each patient and country 
may vary, taking into account local regulations and requirements. 
4.4 
CONCOMITANT THERAPY, PROHIBITED FOOD, AND 
ADDITIONAL RESTRICTIONS 
Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-
counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used 
by a patient in addition to protocol-mandated treatment from 7 days prior to initiation of 
study drug to the study treatment discontinuation visit.  All such medications should be 
reported to the investigator and recorded on the Concomitant Medications eCRF. 
Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use. 
Patients on anti-coagulant treatment should have their platelet count monitored closely 
during treatment with trastuzumab emtansine. 
Patients must be instructed not to take any concomitant medications (over-the-counter 
or other products) during the study without prior consultation with the investigator. 
4.4.1 
Permitted Therapy  
Patients are permitted to use the following therapies during the study: 
• 
Oral contraceptives with a failure rate of < 1% per year (see Section 4.1.1) 
• 
Hormone-replacement therapy 


 
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• 
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 vaccinations such as influenza, COVID-19 
• 
Live, attenuated vaccines are not permitted (see Section 4.4.3). 
• 
Megestrol acetate administered as an appetite stimulant  
• 
Mineralocorticoids (e.g., fludrocortisone) 
• 
Inhaled or low-dose corticosteroids administered for COPD or asthma 
• 
Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency 
• 
Bisphosphonates for prevention of skeletal related events 
• 
Palliative radiotherapy to treat pre-existing bone metastases only 
 
Premedication with antihistamines, anti-pyretics, and/or analgesics may be administered 
for the second and subsequent atezolizumab infusions only, as clinically indicated.  
In general, investigators should manage a patient's care (including preexisting 
conditions) with supportive therapies other than those defined as cautionary or 
prohibited therapies (see Sections 4.4.2 and 4.4.3) 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 β2-adrenergic agonists; see Appendix 17 ). 
4.4.2 
Cautionary Therapy  
4.4.2.1 
Corticosteroids, Immunosuppresive Medications and TNF-α 
Inhibitors 
Systemic corticosteroids, immunosuppressive medications, and TNF-α inhibitors may 
attenuate potential beneficial immunologic effects of treatment with atezolizumab.  
Therefore, in situations in which systemic corticosteroids, immunosuppressive 
medications, or TNF-α inhibitors would be routinely administered, alternatives, including 
antihistamines, should be considered.  If the alternatives are not feasible, systemic 
corticosteroids, immunosuppressive medications, and TNF-α inhibitors may be 
administered as clinically indicated. 
Systemic corticosteroids or immunosuppressive medications are recommended, as 
clinically indicated, for the treatment of specific AEs when associated with atezolizumab 
therapy (refer to Appendix 19 for details). 


 
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Corticosteroids may also be used for the treatment of isolated brain metastases 
according to local standard of care.  Corticosteroids should be tapered to a stable total 
daily dose equivalent to ≤ 2 mg of dexamethasone before the patient receives the next 
cycle of treatment. 
4.4.2.2 
Medications Given with Precaution due to Effects Related to 
CYP Enzymes 
In vitro data suggest that DM1, a component of trastuzumab emtansine is metabolized 
mainly by cytochrome p450 (CYP) CYP3A4 and, to a lesser extent, by CYP3A5, and 
there is a moderate to high potential for drug-drug interaction with any medication that is 
metabolized by or strongly inhibits or induces these enzymes.  DM1 does not induce or 
inhibit P450-mediated metabolism in vitro.  Therefore, the medications listed below 
should be avoided.  If use of one of these medications is necessary, the risks and 
benefits should be assessed by the investigator prior to concomitant administration with 
trastuzumab emtansine.  The Medical Monitor is available to advise as needed. 
• 
Strong CYP3A4/CYP3A5 inhibitors, including, but not limited to, ketoconazole and 
itraconazole  
 
The investigator should consult the prescribing information when determining whether a 
concomitant medication can be safely administered with study treatment.  In addition, 
the Medical Monitor is available to advise if questions arise regarding medications not 
listed above.  If a strong CYP3A4/5 inhibitor needs to be co-administered with 
trastuzumab emtansine, patients should be closely monitored for adverse reactions. 
4.4.2.3 
Herbal Therapies 
Any traditional Chinese medication/Herbal remedies with approval for use as anti-cancer 
treatment (regardless of the type of cancer) will not be permitted.  Traditional Chinese 
medication/Herbal remedies for indications other than anti-cancer treatment, such as 
supportive care, are discouraged but are permitted at the discretion of the investigator 
and must be reported on the appropriate eCRF. 
4.4.2.4 
Therapies Given for Chemotherapy Induced Thrombocytopenia 
Concomitant use of therapies for prevention and treatment of thrombocytopenia induced 
by chemotherapy, e.g. thrombopoietin receptor agonists, recombinant thrombopoietins, 
recombinant interleukin, 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 18 ).  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 
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4.4.3 
Prohibited Therapy 
Use of the following concomitant therapies is prohibited as described below: 
• 
Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy), whether health authority−approved or experimental, for various time 
periods prior to starting study treatment, depending on the agent (Section 4.1.2), 
and during study treatment, until disease progression is documented and the patient 
has discontinued study treatment 
• 
Investigational therapy within 21 days prior to initiation of study treatment and during 
study treatment 
• 
Live, attenuated vaccines (e.g., FluMist) within 4 weeks prior to initiation of study 
treatment, during atezolizumab treatment, and for 5 months after the final dose of 
study treatment 
• 
Systemic immunostimulatory agents (including, but not limited to, interferons and 
IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to 
initiation of study treatment and during study treatment because these agents could 
potentially increase the risk for autoimmune conditions when given in combination 
with atezolizumab 
• 
RANKL inhibitor (denosumab): Patients who are receiving denosumab prior to 
enrollment must be willing and eligible to receive a bisphosphonate instead while on 
study. 
• 
Use of steroids to premedicate patients for whom CT scans with contrast are 
contraindicated (i.e., patients with contrast allergy or impaired renal clearance); in 
such patients, MRI scans of the chest, abdomen, and pelvis with a non-contrast 
CT scan of the chest must be performed 
 
4.4.4 
Prohibited Food 
Consumption of grapefruit or grapefruit juice, a potent CYP3A4 enzyme inhibitor, is 
prohibited during the study and for 30 days after the final dose of study treatment. 
4.4.5 
Additional Restrictions 
Excessive alcohol intake should be avoided (occasional to moderate use is permitted). 
4.5 
STUDY ASSESSMENTS  
The schedule of activities to be performed during the study is provided in Appendix 1 .  
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. 


 
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4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained from the patient 
or a legally-authorized representative 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. 
Prior to signing the main Informed Consent Form for the study, patients may consent to 
the collection of archival tumor tissue for determination of HER2 and PD-L1 expression 
at a central laboratory to determine eligibility by signing a Prescreening Informed 
Consent Form.  The test results must be obtained 12 months prior to randomization. If a 
patient consents to prescreening for determination of HER2 and PD-L1, these tests 
would not need to be repeated during the screening period.  
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a detailed record of 
all patients screened, to document eligibility or record reasons for screening failure, as 
applicable. 
4.5.2 
Medical History, Baseline Conditions, Concomitant Medication, 
and Demographic Data 
Medical history, including clinically significant diseases, surgeries, cancer history 
(including hormone receptor status, prior cancer therapies, and procedures), 
reproductive status, smoking history, and use of alcohol and drugs of abuse, will be 
recorded at baseline.  In addition, all medications (e.g., prescription drugs, over-the-
counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used 
by the patient within 7 days prior to the Cycle 1, Day 1 visit will be recorded.   
Hormone receptor status will be determined in the local laboratory according to 
guidelines from the American Society of Clinical Oncology/College of American 
Pathologists (Allison et al. 2020). 
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. 
Breast cancer history includes prior cancer therapies and procedures. 
Demographic data will include age, sex, and self-reported race or ethnicity.  
4.5.3 
Physical Examinations 
A complete physical examination, performed at screening, should include an evaluation 
of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF. 


 
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Limited, symptom-directed physical examinations should be performed at specified 
postbaseline 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 AEs 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.  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. 
Vital signs are to be measured before, during, and after each infusion as outlined in 
Table 4, and at other specified timepoints as outlined in the schedule of activities (see 
Appendix 1 ). 
Table 4 
Timing for Vital Sign Measurements for First and Subsequent 
Infusions 
Drug 
Timing for Vital Sign Measurements 
First Infusion 
Subsequent Infusions 
Atezolizumab/ 
placebo 
• Within 60 minutes prior to the 
atezolizumab infusion 
• If clinically indicated, vital signs 
should be measured every 
15 (± 5) minutes during the infusion 
and at 30 (± 10) minutes after the 
infusion. 
• Within 60 minutes prior to the 
atezolizumab 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. 
Trastuzumab 
emtansine 
• Vital signs must be assessed before 
and after each dose administration. 
• Vital signs must be assessed before 
and after each dose administration. 
 
4.5.5 
Tumor and Response Evaluations 
Patients will undergo tumor assessments at baseline (screening) and then every 6 
weeks (± 7 days) following treatment initiation, regardless of dose delays, until 
investigator-assessed radiographic disease progression per RECIST v1.1, withdrawal of 
consent, death, or study termination by the Sponsor.  Thus, tumor assessments are to 
continue according to schedule in patients who discontinue study treatment for reasons 
other than disease progression, even if they start new anti-cancer therapy.  If clinically 
indicated, tumor assessments may be repeated at any time if progressive disease is 
suspected. 
All measurable (and non-measurable) lesions should be assessed and documented at 
screening.  Tumor assessments performed as standard of care prior to obtaining 


 
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informed consent and within 28 days prior to initiation of study treatment do not have to 
be repeated at screening, so long as they meet criteria outlined below. 
Following the announcement of premature study termination, tumor assessments will 
be conducted as per standard of care and recorded in the eCRF until disease progression 
or discontinuation of the study.  
4.5.5.1 
Radiographic Assessments 
Screening assessments must include CT scans (with contrast) or MRI scans of the 
chest, abdomen, and pelvis.  If a CT scan with contrast is contraindicated (e.g., in 
patients with impaired renal clearance), a non-contrast CT scan of the chest may be 
performed and MRI scans of the abdomen, and pelvis should be performed.  A CT scan 
with contrast or MRI scan of the brain must be done at screening to evaluate CNS 
metastasis in all patients (MRI scan must be performed if CT scan is contraindicated).  
An MRI scan of the brain is required to confirm or refute the diagnosis of CNS 
metastases at baseline in the event of an equivocal CT scan.  See Section 4.1.2 for 
CNS-related exclusion criteria.  A bone scan (or other suitable modality for bone 
imaging, e.g., NaF or FDG-PET) will also be performed at screening.  If clinically 
indicated, other methods of assessment of measurable disease as per RECIST v1.1 
may be used. 
If a CT scan for tumor assessment is performed in a positron emission tomography 
(PET)/CT scanner, the CT acquisition must be consistent with the standards for a 
full-contrast diagnostic CT scan. 
All measurable (and non-measureable) lesions identified at baseline should be 
re-assessed at subsequent tumor evaluations according to the schedule described 
above.  The same radiographic procedures used to assess disease sites at screening 
should be used for subsequent tumor assessments (e.g., the same contrast protocol for 
CT scans).  Brain scans (preferably MRI) must be conducted at all subsequent tumor 
evaluations in patients with known brain metastases.  Patients without brain metastases 
at baseline should have brain scans (preferably MRI) as clinically indicated.  A bone 
scan (or other suitable modality for bone imaging e.g., NaF or FDG-PET) should be 
repeated in the event of clinical suspicion of progression of existing bone lesions and/or 
the development of new bone lesions.   
The use of radiopharmaceutical products (e.g., 18F-FDG, Tc-99m, MIBG) and contrast 
agents (e.g., gadolinium-based or iodinated contrast media) in study imaging 
assessments will be consistent with standard/local practice, and will not involve a route 
of administration, dose, patient population, or any other factor that significantly increases 
the risk (or decreases the acceptability of the risk) to patients.  The products employed in 
these procedures will be at the discretion of participating investigators and shall be 
locally authorized or otherwise used in compliance with local regulations.  The results of 


 
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this study (MO42319) will not be used to support any new indication or change in 
labeling for these products. 
4.5.5.2 
Response Evaluation 
Objective response will be determined by the investigator at specified timepoints 
according to RECIST v1.1 ( Appendix 4 ).  Assessments should be performed by the 
same individual, if possible, to ensure internal consistency across visits. 
Tumor assessment scans will be collected prospectively by an independent review 
facility.  Response will also be assessed by a blinded independent central review 
committee.  Following premature study termination, tumor assessment scans will no 
longer be collected prospectively by the Sponsor and an IRF will not be utilized (see 
Section 4.5.5 ). 
4.5.6 
Left Ventricular Ejection Fraction Assessment 
Left Ventricular Ejection Fraction (LVEF) will be assessed by ECHO or MUGA.  LVEF 
will be monitored at baseline, and on Day 15–21 of Cycle 1, and every fourth cycle 
thereafter.  Additional LVEF measurements may be performed as clinically indicated. 
4.5.7 
Laboratory, Biomarker, and Other Biological Samples 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
• 
Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
other cells) 
• 
Chemistry panel (serum or plasma):  bicarbonate or total carbon dioxide (if 
considered standard of care for the region), sodium, potassium, chloride, glucose, 
BUN or urea, creatinine, total protein, albumin, phosphate, calcium, total bilirubin, 
ALP, ALT, AST, and LDH 
• 
Coagulation (aPTT and INR) 
• 
Serum or urine pregnancy test for women of childbearing potential, including women 
who have had a tubal ligation as indicated in Appendix 1 .  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 is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by sthe investigator (e.g., 
Müllerian agenesis).  Childbearing potential is defined as not having undergone 
surgical sterilization, hysterectomy, and/or bilateral oophorectomy or not being 
post-menopausal ( ≥ 12 months of amenorrhea).  


 
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• 
Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood); dipstick 
permitted 
• 
Thyroid-function test (thyroid-stimulating hormone [TSH], free triiodothyronine (T3) 
(or total T3 for sites where free T3 is not performed), and free T4) 
• 
HIV serology: (tested prior to patient enrollment in the study) 
HIV-positive patients are excluded from study participation. 
• 
HBV serology (tested prior to patient enrollment in the study):  HBsAg, HBsAb, and 
total HBcAb for all patients; HBV DNA for patients with a negative HBsAg test and a 
positive total HBcAb test  
• 
HCV serology (tested prior to patient enrollment in the study): HCV antibody for all 
patients; HCV RNA for patients with a positive HCV antibody test 
• 
C-reactive protein 
  
The following samples will be sent to one or several central laboratories or to the 
Sponsor or a designee for analysis: 
• 
Archival or newly collected tumor tissue sample obtained at screening for 
determination of PDL1 expression and HER2 expression and for exploratory 
research on biomarkers and biomarker assay development 
A representative FFPE tumor specimen in a paraffin block (preferred) or at least 
17 slides containing unstained, freshly cut, serial sections must be submitted 
(preferably along with an associated pathology report) prior to study enrollment. 
The unstained slides for staining must be within the current documented 
cutslide stability window. 
Tumor tissue should be of good quality as determined on the basis of total and 
viable tumor content.  Samples collected via resection, core-needle biopsy (at 
least three cores, embedded in a single paraffin block), or excisional, incisional, 
punch, or forceps biopsy are acceptable.  These requirements are requested in 
order to maximize the chances of receiving valid results which would allow the 
patient to enter the study. 
Fine-needle aspiration (defined as samples that do not preserve tissue 
architecture and yield cell suspension and/or smears), brushing, cell pellets 
from pleural effusion, and lavage samples are not acceptable.  Tumor tissue 
from bone metastases is not acceptable. 
If archival tumor tissue is unavailable or is determined to be unsuitable for 
required testing, a pretreatment tumor biopsy is required.  A pretreatment tumor 
biopsy may also be performed if a patient's archival tissue test results do not 
meet eligibility criteria.  
• 
Tumor tissue sample obtained at the time of progression, if deemed clinically 
feasible and the patient would not be put at risk, for exploratory research on 
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A representative FFPE tumor specimen in a paraffin block (preferred) or a 
minimum of 10 slides containing unstained, freshly cut, serial sections must be 
submitted, preferably along with an associated pathology report, if available.  
Biopsies at the time of progression should be performed within 40 days after 
progression or prior to the next anti-cancer therapy, whichever is sooner. In 
case new line therapy is purely anti-hormonal, biopsy could be taken after it is 
started. 
Samples collected via resection, core-needle biopsy (preferably three cores), or 
excisional, incisional, punch, or forceps biopsy are preferred. 
• 
Blood and plasma samples for exploratory research on biomarkers at baseline and 
during treatment and at disease progression.  Following the announcement of 
premature study termination, these samples will no longer be collected. 
• 
Serum sample for analysis of autoantibodies: anti-nuclear antibody, anti-double 
stranded DNA, circulating anti-neutrophil cytoplasmic antibody, and perinuclear anti 
neutrophil cytoplasmic antibody 
The baseline sample will be collected prior to the first dose of study drug on 
Cycle 1, Day 1.  For patients who show evidence of immune-mediated toxicity, 
additional samples may be collected and will be analyzed centrally. 
• 
PK samples: 
Serum samples will be assayed for atezolizumab, trastuzumab emtansine, and 
total trastuzumab concentrations using validated immunoassays. 
Plasma samples will be assayed for DM1 concentration using a validated liquid 
chromatography-tandem mass spectrometry.  
• 
Serum samples for assessment of anti-drug antibodies (ADAs) to atezolizumab and 
trastuzumab emtansine through use of validated immunoassays 
• 
Following the announcement of premature study termination, samples for 
autoantibodies, PK or ADA samples will no longer be collected.  
 
Instruction manuals and supply kits will be provided for all central laboratory 
assessments. 
Exploratory biomarker research may include, but will not be limited to, analysis of 
proteins, genes or gene signatures associated with HER2 pathway, tumor immune 
biology, PD-L1 by various IHC assays, lymphocyte subpopulations (e.g. CD8, TIL), 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.  Genomic research will focus on somatic variants.  NGS methods may include 
whole genome sequencing (WGS)/whole exome sequencing (WES), but only at 
participating sites (see Section 4.5.10). 


 
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For China only, collection and submission of blood and plasma samples for biomarker 
analysis and the number of required slides for the exploratory analyses using tumor 
tissue samples are 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. 
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 4.5.11), biological samples will be destroyed 
no later than the time of completion of the final Clinical Study Report, 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 [pretreatment] and at disease 
progression as well as whole blood and plasma samples collected for biomarker 
research (including their derivatives) will be destroyed no later than 5 years after the 
final Clinical Study Report has been completed.  
• 
For enrolled patients, remaining archival tissue blocks will be returned to the site 
upon request or no later than the time when the final Clinical Study Report has been 
completed, whichever occurs first.  For patients who are not enrolled, remaining 
tissue blocks will be returned to the site no later than 2 months after eligibility 
determination.  Slides will not be returned. 
 
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 genomic variants, will be subject to 
the confidentiality standards described in Section 8.4. 
Data generated from samples collected for exploratory biomarker research will be 
analyzed in aggregate rather than on an individual patient basis.  Thus, there will be no 
identification and reporting of incidental findings to investigators or patients.  In addition, 
given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to 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. 


 
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4.5.8 
Electrocardiograms 
A 12-lead ECG is required at screening and as clinically indicated.  Refer to Appendix 1 
for the schedule of ECG assessments. 
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 
reports.  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. 
4.5.9 
Clinical Outcome Assessments 
Patient-reported outcome (PRO) instruments will be completed to more fully characterize 
the clinical profile of atezolizumab.  In addition, PRO instruments will enable the capture 
of each patient's direct experience with atezolizumab. 
PRO data will be collected through use of the following instruments: European 
Organisation for Research and Treatment of Cancer (EORTC) quality-of-life 
questionnaires for cancer (EORTC QLQ-C30) and breast cancer (EORTC QLQ-BR23), 
NCI (PRO-CTCAE), EuroQol 5-Dimension Questionnaire, 5-level version (EQ-5D-5L), 
and the ‘Treatment Burden’ item from the EORTC IL46 library. 
All patients will complete the EORTC QLQ-C30, EQ-5D-5L, EORTC QLQ-BR23, and 
NCI PRO-CTCAE at 3 months after radiographic disease progression per RECIST v1.1. 
Following the announcement of premature study termination, PRO assessments will no 
longer be collected. 
 
4.5.9.1 
Data Collection Methods for Clinical Outcome Assessments 
PRO instruments will be self-administered or interviewer-administered (as appropriate) 
at the clinic or at home at specified timepoints during the study (see schedule of PRO 
assessments in Appendix 3 ).  At the clinic, instruments will be administered before the 
patient receives any information on disease status, prior to the performance of non-PRO 
assessments, and prior to the administration of study treatment, unless otherwise 
specified. Laboratory and weight assessments can be completed before the PROs are 
administered; however, the results of these assessments should not be given to the 
patient prior to completing the PROs. 
PRO instruments, translated into the local language as appropriate, will be completed 
through use of an electronic device provided by the Sponsor at site, or using the online 
ePRO completion tool at home (at timepoints specified below only).  Instructions for 
phone administration of PROs will be provided to sites. 


 
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The electronic device will be pre-programmed to enable the appropriate instruments to 
be administered in the correct order at each specified timepoint (refer to Appendix 3 for 
the frequency and timing of PRO assessments in clinic).  The electronic device and 
instructions for completing the instruments electronically will be provided by the site staff.  
The data will be transmitted to a centralized database maintained by the electronic 
device vendor.  The data will be available for access by appropriate study personnel.  
During clinic visits, PRO instruments should be administered as outlined below: 
• 
Patients' health status should not be discussed prior to administration of the 
instruments. 
• 
Sites must administer the official version of each instrument, as provided by the 
Sponsor.  Instruments must not be copied from the protocol. 
• 
Sites should allow sufficient time for patients to complete the instruments, estimated 
to be 10–15 minutes at each specified visit. 
• 
Sites should administer the instruments in a quiet area with minimal distractions and 
disruptions. 
• 
Patients should be instructed to answer questions to the best of their ability; there 
are no right or wrong answers. 
• 
Site staff should not interpret or explain questions, but may read questions verbatim 
upon request. 
• 
Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments. 
 
The patient should complete the PRO-CTACE assessments on Day 8 and Day 15 of 
Cycles 1, 2, and 3 at home using the online ePRO completion tool (see Appendix 3 ).  If 
the patient does not have access to the online ePRO completion tool at home, and 
cannot come to the study site to use the electronic device, the site can call the patient 
and collect the PRO-CTCAE assessments on Day 8 and Day 15 of Cycles 1, 2, and 3 by 
telephone.  The telephone is not to be used to collect PRO data at any other timepoint. 
PRO assessments at other timepoints in the treatment period, and the follow-up PRO 
assessments (3 months after study completion/early discontinuation visit), will be 
completed at the study site through the use of an electronic device.  For the follow-up 
PRO assessments only, the online ePRO completion tool (but not the telephone option) 
may be used if the patient cannot attend the study site. 
Patients should be given the following instructions for completing the PRO instrument at 
home: 
• 
Patients should complete the instruments in a quiet area with minimal distractions 
and disruptions. 
• 
Patients should answer questions to the best of their ability; there are no right or 
wrong answers. 


 
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• 
Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments. 
 
4.5.9.2 
Description of Clinical Outcome Assessment Instruments 
EORTC QLQ-C30 
The EORTC QLQ-C30 is a validated, reliable self-report measure (Aaronson et al.1993; 
Fitzsimmons et al. 1999) (see Appendix 10 ).  It consists of 30 questions that assess five 
aspects of patient functioning (physical, emotional, role, cognitive, and social), 
three symptom scales (fatigue, nausea and vomiting, and pain), global health status and 
quality of life (QoL), and six 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 functioning and symptoms items 
are scored on a 4-point scale that ranges from "not at all" to "very much," and the global 
health status and QoL items are scored on a 7-point scale that ranges from "very poor" 
to "excellent."  The EORTC QLQ-C30 module takes approximately 10 minutes to 
complete.   
EORTC QLQ-BR23 
The QLQ-BR23 is a modular supplement to the EORTC quality-of-life questionnaire for 
use in breast cancer (Sprangers et al. 1996; see Appendix 11 .  This module consists of 
23 additional self-reported items assessing disease or treatment symptoms (systemic 
therapy side effects, breast symptoms, arm symptoms, and hair loss) and aspects of 
patient functioning (body image, sexual functioning, and future perspective).  One 
question that is specific to women will not be answered by men. The QLQ-BR23 module 
takes approximately 5−10 minutes to complete. 
EuroQol EQ-5D-5L 
The EuroQol 5-Dimension Questionnaire, 5-level version (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 12).  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 VAS that 
measures health state.  The EQ-5D-5L is designed to capture the patient's current health 
status.  Published weighting systems allow for creation of a single composite score of 
the patient's health status.  The EQ-5D-5L takes approximately 3 minutes to complete.  It 
will be used in this study for informing pharmacoeconomic evaluations. 
PRO-CTCAE 
The PRO-CTCAE is a validated item bank that is used to characterize the presence, 
frequency of occurrence, severity, and/or degree of interference with daily function of 
78 patient-reportable symptomatic treatment toxicities (Basch et al. 2014; Dueck et al. 
2015) (see Appendix 13 ).  The PRO-CTCAE contains 124 questions that are rated 
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scale (for determination of frequency of occurrence, severity, and interference with daily 
function).  Treatment toxicities can occur with observable signs (e.g., vomiting) or 
non-observable symptoms (e.g., nausea).  The standard PRO-CTCAE recall period is 
the previous 7 days.  
A subset of nine symptoms deemed most applicable to the current treatments has been 
selected for this study (fatigue, chills, headache, cough, peripheral neuropathy, rash, 
aching muscles, aching joints, pain; see Appendix 13).  Symptoms have been selected 
on the basis of the AEs anticipated for trastuzumab emtansine and atezolizumab.  
Treatment Burden Item (EORTC IL46) 
The treatment burden item from the EORTC item library, “To what extent have you been 
troubled with side-effects from your treatment?”, will be administered to assess the 
overall burden of treatment (Appendix 14).  
4.5.10 
Blood Samples for Whole Genome Sequencing or Whole 
Exome Sequencing (Patients at Participating Sites) 
At participating sites, blood samples will be collected for DNA extraction to enable WGS 
or WES to identify variants 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 AEs, can lead 
to improved AE monitoring or investigation, or can increase the knowledge and 
understanding of disease biology and drug safety.  Research may include exploration of 
germline variants.  The samples may be sent to one or more laboratories for analysis. 
Collection and submission of blood samples for WGS or WES 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 or WES, this section of the protocol 
(Section 4.5.10) will not be applicable at that site. 
Genomics is increasingly informing researcher's 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 AEs.  Data will be analyzed in the context of this study but may 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 
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Blood samples collected for WGS or WES 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). 
Data generated from blood samples collected for WGS or WES will be analyzed in 
aggregate rather than on an individual patient basis.  Thus, there will be no identification 
and reporting of incidental findings to investigators or patients. 
If permitted by local law, a patient may request access to uninterpreted WGS or WES 
data derived from analysis of his or her blood sample.  If a patient wishes to access 
these data, the investigator must inform the Sponsor, using the following email address:  
global.return-genomics-results@roche.com.  The Sponsor will provide available data to 
the investigator in the form of a raw genomic sequencing data file, but will not provide 
any interpretation of the data.  The investigator should not include the data file in the 
patient's medical record.  Samples may be stored and analyzed in the future, and some 
samples may never be analyzed.  Thus, data may not be available at the time of the 
request or may never be available. 
The aggregate results of any conducted research will be available in accordance with 
the effective Sponsor policy on study data publication.  Refer to Section 4.5.7 for details 
on use of samples after patient withdrawal, confidentiality standards for data, and 
availability of data from biomarker analyses. 
4.5.11 
Optional Samples for Research Biosample Repository 
4.5.11.1 
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 analyzed to achieve one or 
more of the following objectives: 
• 
To study the association of biomarkers with efficacy or disease progression 
• 
To identify safety biomarkers that are associated with susceptibility to developing 
AEs or can lead to improved AE 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 
 
4.5.11.2 
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 Institutional Review Board or Ethics Committee (IRB/EC) and, if 
applicable, an appropriate regulatory body.  If a site has not been granted approval for 
RBR sampling, this section of the protocol (Section 4.5.11) will not be applicable at that 
site. 
4.5.11.3 
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 trastuzumab emtansine 
and atezolizumab, diseases, or drug safety: 
• 
Leftover blood, plasma, serum, 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 variants via whole genome sequencing (WGS), whole exome sequencing 
(WES), or other genomic analysis methods.  Genomics is increasingly informing 
researcher's 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 AEs. 
Data generated from RBR samples will be analyzed in the context of this study but may 
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). 
4.5.11.4 
Data Protection, Use, and Sharing 
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. 
Data generated from RBR samples will be analyzed in aggregate rather than on an 
individual patient basis.  Thus, there will be no identification and reporting of incidental 
findings to investigators or patients.  In addition, 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, with the 
exception of data generated from blood samples collected for WGS or WES as 
described below. 
If permitted by local law, a patient may request access to uninterpreted WGS or WES 
data derived from analysis of his or her sample(s).  If a patient wishes to access these 
data, the investigator must inform the Sponsor, using the following email address:  
global.return-genomics-results@roche.com.  The Sponsor will provide available data to 
the investigator in the form of a raw genomic sequencing data file but will not provide 
any interpretation of the data.  The investigator should not include the data file in the 
patient's medical record.  Samples may be stored and analyzed in the future, and some 
samples may never be analyzed.  Thus, data may not be available at the time of the 
request or may never be available.   
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. 
4.5.11.5 
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 
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The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date of consent, by completing the Sample Informed 
Consent/Withdrawal 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. 
4.5.11.6 
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.  After withdrawal of consent, any remaining samples 
will be destroyed or will no longer be linked to the patient.  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 Sample Informed 
Consent/Withdrawal eCRF.  If a patient wishes to withdraw consent to the testing of his 
or her RBR samples after closure of the site, the investigator must inform the Sponsor by 
emailing the study number and patient number to the following email address: 
global.rcr-withdrawal@roche.com 
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. 
4.5.11.7 
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 (trastuzumab emtansine plus 
atezolizumab/placebo) if any of the following are met: 
• 
Radiographic disease progression per RECIST v1.1 or symptomatic deterioration 
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Patients with isolated CNS progression that require local therapy only will be 
allowed to continue with study treatment as per investigator decision.  These 
patients will be recorded as disease progression for PFS analysis but will 
remain blinded and continue with treatment as per initial randomization. 
• 
Intolerable toxicity related to study treatment, including development of an 
immunemediated AE 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 or use of a prohibited therapy (see 
Section 4.4.3) 
• 
Pregnancy 
• 
Patient withdrawal of consent 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 
Patients will return to the clinic for a treatment discontinuation visit 28 – 42 days after the 
final dose of study treatment.  The visit at which response assessment shows 
progressive disease may be used as the treatment discontinuation visit.  Patients who 
discontinue study treatment for any reason other than progressive disease will continue 
to undergo tumor response assessments and PRO assessments as outlined in the 
schedule of activities (see Appendix 1 and Appendix 3 , respectively). 
After treatment discontinuation, information on survival follow-up and new anti-cancer 
therapy will be collected via telephone calls, patient medical records, and/or clinic visits 
approximately every 3 months until death, loss to follow-up, withdrawal of consent, or the 
Sponsor terminates the study.  Study staff may use a public information source (e.g., 
county records) to obtain information about survival status only.  At 3 months after the 
treatment completion/discontinuation visit, patients will undergo the PRO assessments 
described in Appendix 3 .  
Following the announcement of premature study termination, data on survival and new 
anti-cancer therapies will no longer be collected.  If patients are already in follow-up, it 
is recommended that patients in follow-up return to the site for a final visit before 
being discontinued from the study.  If there are unresolved AEs, these should be checked 
for resolution and any laboratory tests should be performed as necessary or clinically 
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4.6.2 
Patient Discontinuation from the 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 patient discontinuation from the study may include, but are not limited to, 
the following: 
• 
Patient withdrawal of consent 
• 
Study termination or site closure 
• 
Adverse event 
• 
Loss to follow-up 
• 
Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor 
 
Every effort should be made to obtain a reason for patient discontinuation from the 
study.  The primary reason for discontinuation 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. 
Study staff may use a public information source (e.g., county records) to obtain 
information about survival status. 
4.6.3 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
• 
The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients 
• 
Patient enrollment is unsatisfactory 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.   
The Sponsor informed all investigators of premature study termination on 15t 
December 2022.  
4.6.4 
Site Discontinuation 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 


 
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• 
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 has been developed considering the risk measures for each IMP as well 
as the potential overlapping toxicities.  While the safety profile of trastuzumab emtansine 
is generally well understood given its approval for treatment of HER2-positive LABC and 
MBC in patients treated previously with trastuzumab and or a taxane, atezolizumab is 
currently in clinical development and human experience is currently limited, and the 
entire safety profile of atezolizumab is not known at this time.  The safety considerations 
are based on results from nonclinical and ongoing clinical studies and published data on 
similar molecules.  
Several measures will be taken to ensure the safety of patients participating in this 
study.  Eligibility criteria (Section 4.1) have been designed to exclude patients at higher 
risk for toxicities from study participation.  Administration of trastuzumab emtansine and 
atezolizumab/placebo 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.  Patients will undergo safety monitoring by an 
iDMC (Section 9.5) during the study, including assessment of the nature, frequency, and 
severity of AEs; details of this safety monitoring will be specified in the iDMC Charter.   
Guidelines for managing patients who experience anticipated AEs, including criteria for 
dosage modification (allowed for trastuzumab emtansine only) and treatment interruption 
or discontinuation, are provided in Section 5.1.4 and Appendix 18 (trastuzumab 
emtansine), Appendix 19 (atezolizumab), and Appendix 20 (potential overlapping 
toxicities).  Refer to Sections 5.2−5.6 for details on safety reporting (e.g., AEs, 
pregnancies) for this study.  
Patients with active infection are excluded from study participation. In the setting of a 
pandemic or epidemic, screening for infections (including SARS-CoV-2) prior to and 
during study participation should be considered according to local/institutional guidelines 
or those of applicable professional societies (e.g., ASCO/ESMO). 
Severe SARS-CoV-2 infection appears to be associated with a cytokine release 
syndrome involving the inflammatory cytokines IL-6, IL-10, IL-2 and interferon-gamma 
(IFNγ) (Merad and Martin 2020).  If a patient develops suspected CRS during the study, 
a differential diagnosis should include SARS-CoV-2 infection, which should be confirmed 
or refuted through assessment of exposure history, appropriate laboratory testing, and 
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SARS-CoV-2 infection is confirmed, the disease should be managed as per local or 
institutional guidelines. 
Please refer to the latest versions of the trastuzumab emtansine and atezolizumab 
Investigator Brochure’s for a complete and most up to date summary of safety 
information.  
5.1.1 
Risks Associated with Trastuzumab Emtansine 
The safety plan for patients in this study is based on the known nonclinical toxicities of 
trastuzumab emtansine, on clinical experience with trastuzumab emtansine in completed 
and ongoing studies, and clinical toxicities related to its components (trastuzumab and 
maytansine-, the parent drug of DM1).  The anticipated important safety risks and 
potential safety risks of trastuzumab emtansine are outlined below and detailed in the 
Investigator’s Brochure.  Please refer to the Investigator’s Brochure for a complete 
summary of safety.  Guidance to manage such anticipated toxicities is detailed in 
Appendix 18 and Appendix 20 . 
5.1.1.1 
Pulmonary Toxicity 
Cases of interstitial lung disease (ILD), including pneumonitis, some leading to acute 
respiratory distress syndrome or death, have been reported in patients receiving 
trastuzumab emtansine.  Signs and symptoms may include dyspnea, cough, fatigue, and 
pulmonary infiltrates.  These events may or may not occur as sequelae of infusion 
reactions.  
Patients with dyspnea at rest due to complications of advanced malignancy, 
comorbidities, and receiving concurrent pulmonary radiation therapy may be at risk of 
pulmonary events. 
Patients who have experienced a pulmonary event should be carefully evaluated before 
commencing trastuzumab emtansine treatment. 
Patients diagnosed with Grade ≥ 3 ILD or pneumonitis must permanently discontinue 
treatment with trastuzumab emtansine.  If the patient experiences a Grade 1 event, the 
dose should be withheld for up to 42 days, to allow resolution to Grade 0.  Upon 
resolution, trastuzumab emtansine can be continued at the same dose level.  If not 
resolved within 42 days, treatment should be discontinued.  Dose reductions are 
recommended for Grade 2 pulmonary events (i.e., pneumonitis, ILD).  The dose should 
be held to allow resolution to Grade 0 prior to resuming trastuzumab emtansine at a 
lower dose level (Table 5).  If not resolved within 42 days, treatment should be 
discontinued. 
Guidelines for management of trastuzumab emtansine in patients who develop ILD or 
pneumonitis are provided in Appendix 20.  


 
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5.1.1.2 
Hepatotoxicity 
The following events have been reported with administration of trastuzumab emtansine: 
• 
Serious he.patobiliary 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.   
Patients must meet specified hepatic laboratory test requirements to be included in this 
study (Section 4.1).  
Hepatic laboratory parameters will be monitored as described in the schedule of 
assessments (Appendix 1). 
Guidelines for management of trastuzumab emtansine in patients who develop 
increased serum transaminases, increased serum bilirubin, or NRH are provided 
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5.1.1.3 
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. 
Patients must meet specified LVEF requirements to be included in this study 
(Section 4.1).  
Left ventricular function will be monitored by measurement of ejection fraction using 
ECHO) or MUGA scans as described in Section 4.5.6 and the schedule of assessments 
(Appendix 1). 
Guidelines for patient monitoring and management of trastuzumab emtansine in patients 
who develop left ventricular dysfunction are provided in Appendix 18.  
Patients who discontinue study treatment 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, or death.  Additional LVEF 
assessments may be conducted 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 in the eCRF. 
5.1.1.4 
Infusion-Related Reactions and Hypersensitivity Reactions 
Infusion-related 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 will be excluded from this study (Section 4.1).  
Administration of study treatment will be performed in a setting with access to 
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emergencies.  Patients should be closely monitored for IRRs during and after each 
infusion of study treatment, as described in Section 4.3.2.1.   
Guidelines for management of patients who experience IRRs or hypersensitivity 
reactions are provided in Appendix 18.  
5.1.1.5 
Hematologic Toxicity (Thrombocytopenia) 
Thrombocytopenia has been reported in patients enrolled in clinical trials evaluating 
trastuzumab emtansine.  The majority of these patients had Grade 1 or 2 events (platelet 
count ≥ 50,000/µL), with the nadir occurring by Day 8 and generally improving to Grade 0 
or 1 (platelet count ≥ 75,000/µL) by the next scheduled dose (i.e., within 3 weeks).  
Evolution of the 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 recommended that platelet counts are monitored prior to each trastuzumab 
emtansine dose.  Rare cases of severe prolonged thrombocytopenia (≥ Grade 3 
thrombocytopenia lasting for more than 90 days) have been reported with trastuzumab 
emtansine based on cumulative data review. In most of these cases, patients received 
concomitant recombinant human thrombopoietin (rh-TPO).  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 or greater 
(< 50,000/mm3), do not administer trastuzumab emtansine until platelet counts recover to 
Grade 1 (≥ 75,000/mm3). 
Declines in other hematopoietic lineages, for example, leukopenia, neutropenia, and 
anemia, were less frequent than that observed for platelets. 
Patients must meet specified hematologic laboratory test requirements to be included in 
this study (Section 4.1).  
Hematologic laboratory parameters will be monitored as described in Section 4.5 and 
the schedule of assessments (Appendix 1).  Patients on anticoagulant or antiplatelet 
treatment should be monitored closely.  
Guidelines for management of trastuzumab emtansine in patients who develop 
hematologic toxicity are provided in Appendix 18 . 


 
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5.1.1.6 
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 anti-coagulation therapy, antiplatelet 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 with trastuzumab emtansine is medically necessary. 
5.1.1.7 
Neurotoxicity 
Peripheral neuropathy, mainly Grade 1 and predominantly sensory, has been reported in 
clinical trials of trastuzumab emtansine.   
Patients with Grade ≥ 3 peripheral neuropathy will be excluded from this study 
(Section 4.1). 
Patients will be clinically monitored on an ongoing basis for signs or symptoms of 
peripheral neuropathy as described in Section 4.5 and the schedule of assessments 
(Appendix 1). 
Guidelines for management of trastuzumab emtansine in patients who develop 
peripheral neuropathy are provided in Appendix 18. 
5.1.1.8 
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.  Rare reports of more 
severe events, such as cellulitis, pain (tenderness and burning sensation), and skin 
irritation, have been reported as part of the continuing surveillance of trastuzumab 
emtansine safety.  These reactions have been observed more frequently within 24 hours 
of infusion. 
The infusion site will be closely monitored for possible subcutaneous infiltration during 
drug administration, as described in Section 4.3.2.1.  Specific treatment for trastuzumab 
emtansine extravasation is unknown at this time.  Patients should be managed 
symptomatically per local institutional guidelines. 
5.1.2 
Risks Associated with Atezolizumab 
Atezolizumab has been associated with risks such as the following:  IRRs and immune-
mediated: pneumonitis, hepatitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, 
hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, 
myasthenic syndrome/myasthenia gravis, facial paresis, myelitis, meningoencephalitis, 
myocarditis, pericardial disorders, nephritis, myositis, and severe cutaneous adverse 
reactions.  In addition, immune-mediated reactions may involve any organ system and 


 
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lead to hemophagocytic lymphohistiocytosis (HLH).  Refer to Appendix 19 and Section 
6 of the atezolizumab Investigator's Brochure for a detailed description of anticipated 
safety risks for atezolizumab.   
5.1.3 
Risks Associated with Combination Use of Atezolizumab and 
Trastuzumab Emtansine 
The following AEs are potential overlapping toxicities associated with combination use of 
atezolizumab and trastuzumab emtansine: suspected hepatotoxicity and pneumonitis. 
Suggested workup and management guidelines for overlapping toxicities between 
atezolizumab and trastuzumab emtansine are provided in Appendix 20 . 
5.1.4 
Management of Adverse Events 
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and laboratory test values are acceptable as described in the 
protocol.  Dose delays, reductions and management guidelines are designed to ensure 
patient safety. 
Guidelines for management of AEs associated with study treatment are provided in 
Appendix 18 (trastuzumab emtansine), Appendix 19 (atezolizumab), and Appendix 20 
(potential overlapping toxicities). 
5.1.4.1 
Dose Modification 
Dose reductions for atezolizumab are not allowed during this study.  Dose reductions for 
trastuzumab emtansine are allowed as described below. 
Reasons for dose modifications or delays, the supportive measures taken, and the 
outcomes will be documented in the patient's chart and recorded on the eCRF.  
The severity of AEs will be graded according to the NCI CTCAE v5.0. 
• 
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 (i.e., trastuzumab emtansine, atezolizumab 
or placebo), then the dose of that component should be delayed or modified in 
accordance with the guidelines below.  If trastuzumab emtansine is held or 
discontinued for toxicity, then atezolizumab or placebo must also be held or 
discontinued, respectively. 
• 
When 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/+trastuzumab emtansine infusions 
remain synchronized. 
• 
Study treatment may be suspended for reasons other than toxicity (e.g., surgical 
procedures).  The acceptable length of treatment interruption must be based on an 
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requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
• 
There will be no dose reduction for atezolizumab or placebo in this study.  Patients 
may temporarily suspend study treatment if they experience toxicity that is 
considered related to atezolizumab or placebo and requires a dose to be withheld.  
If atezolizumab/placebo is withheld because of related AEs for > 12 weeks after 
event onset, then the patient will be discontinued from atezolizumab or placebo 
treatment and will be followed for safety and efficacy as specified in Section 3.3.  
Treatment with trastuzumab emtansine may continue according to the judgement of 
the investigator.  If, in the judgment of the investigator, the patient is likely to derive 
clinical benefit from resuming atezolizumab or placebo after a hold > 12 weeks, 
study drug may be restarted.  The acceptable length of the extended period of time 
must be based on the investigator's assessment of benefit-risk and in alignment with 
the protocol requirements for the duration of treatment, and should be documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
If patients must be tapered off steroids for the treatment of AEs related to 
atezolizumab or placebo, study treatment may be withheld for > 12 weeks until 
steroids are discontinued or reduced to prednisone dose (or dose equivalent) 
≤ 10 mg/day.  The acceptable length of the extended period of time must be 
based on the investigator's assessment of benefit-risk and in alignment with the 
protocol requirements for the duration of treatment, and should be documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
• 
If significant trastuzumab emtansine-related toxicities have not recovered to Grade 1 
or baseline, the next scheduled dose may be delayed for ≤ 42 days after the last 
dose was received.  “Significant” and “related” will be based on the judgment of the 
investigator.  The Medical Monitor is available to advise as needed.  For example, 
alopecia even if considered related to trastuzumab emtansine would most likely not 
be considered to be significant.  Fatigue may or may not be considered either 
related or significant.  In general, when the significant related toxicity (or any other 
toxicity that the investigator chooses to delay 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 (Table 5), at the discretion 
of the investigator.  Subsequent cycles should remain q3w, and patients should 
be assessed for toxicity as described in Appendix 18 to Appendix 20 .  If a 
patient requires a dose reduction, dosing will be reduced by one dose level as 
per Table 5.  
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 AE requiring a dose reduction must 
discontinue study treatment and will be followed for safety, disease progression 
and survival (Appendix 1). 


 
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Patients who experience a Grade 3 or 4 hematologic events, other than 
thrombocytopenia, 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 study treatment and will be followed for 
safety, disease progression, and survival (Appendix 1). 
 
Table 5 
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 
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.  
 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording AEs, including SAEs and 
AESI, performing protocol-specified safety laboratory assessments, measuring protocol-
specified vital signs, and conducting other protocol-specified tests that are deemed 
critical to the safety evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an AE is any untoward 
medical occurrence in a clinical investigation subject administered a pharmaceutical 
product, regardless of causal attribution.  An AE can therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.9 
and 5.3.5.10 for more information) 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
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• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, Xray) 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) 
An SAE is any adverse event that meets any of the following criteria: 
• 
Is fatal (i.e., the AE actually causes or leads to death) 
• 
Is life threatening (i.e., the AE, in the view of the investigator, places the patient at 
immediate risk of death) 
This does not include any AE 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 AE 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 AE (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; see 
Section 5.3.3); the event itself may be of relatively minor medical significance (such as 
severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each AE recorded on 
the eCRF. 
Serious AEs 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 (AESI) 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 


 
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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) 
• 
Hepatitis, including AST or ALT > 10 × ULN 
• 
Transaminitis Grade ≥ 2 (AST or ALT > 3 × the ULN and bilirubin > 2 × the ULN or 
AST/ALT > 10 × the ULN) 
• 
Suspected transmission of an infectious agent by a 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 a study treatment is suspected. 
• 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine release 
syndrome (CRS), hemophagocytic lymphohistiocytosis (HLH), and macrophage 
activation syndrome (MAS) 
• 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis) 
• 
Myelitis 
• 
Facial paresis 
• 
Systemic lupus erythematosus 
• 
Autoimmune hemolytic anemia 
• 
Nephritis 
• 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
• 
Grade ≥ 2 cardiac disorders  
• 
Vasculitis 
  
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all AEs (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 AE 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 AEs at each patient contact.  All AEs, 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 
SAEs 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 SAEs). 
After initiation of study treatment, all AEs 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 SAEs and AESI 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. 
Instructions for reporting AEs that occur after the AE 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 AE 
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 AE severity grading scale for the NCI CTCAE (v5.0) will be used for assessing AE 
severity.  Table 6 will be used for assessing severity for AEs that are not specifically 
listed in the NCI CTCAE. 


 
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Table 6 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (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 
AE is considered to be related to study treatment, indicating "yes" or "no" accordingly.  
The following guidance should be taken into consideration (see also Table 7): 
• 
Temporal relationship of event onset to the initiation of study treatment 
• 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study treatment, or reintroduction of study treatment (as 
applicable) 
• 
Known association of the event with study treatment or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 


 
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Table 7 
Causal Attribution Guidance 
Is the AE 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 AE and 
administration of study treatment, and the AE cannot be readily explained by the 
patient's clinical state, intercurrent illness, or concomitant therapies; and/or the AE 
follows a known pattern of response to study treatment; and/or the AE abates or 
resolves upon discontinuation of study treatment or dose reduction and, if applicable, 
reappears upon rechallenge. 
NO 
An AE will be considered related, unless it fulfills the criteria specified below.   
Evidence exists that the AE has an etiology other than study treatment (e.g., preexisting 
medical condition, underlying disease, intercurrent illness, or concomitant medication); 
and/or the AE 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 AEs on 
the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one AE 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 (CRS).  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 on the 
Adverse Event eCRF as a diagnosis (e.g., "infusion-related reaction" or “cytokine 
release syndrome”).  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 of an IRR should be recorded on the 
dedicated Infusion-Related Reaction eCRF.   
If a patient experiences both a local and systemic reaction to a single administration of 
study treatment, each reaction should be recorded as a separate event on the Adverse 


 
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Event eCRF, with associated signs and symptoms of an IRR also recorded separately 
on the dedicated Infusion-Related Reaction eCRF. 
In recognition of the challenges in clinically distinguishing between these IRRs and CRS, 
consolidated guidelines for medical management of IRRs and CRS are provided in 
Appendix 19. 
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 AEs based on 
signs and symptoms should be nullified and replaced by one AE 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, AEs 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 AE 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 AEs 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 AE is one that extends continuously, without resolution, between patient 
evaluation timepoints.  Such events should only be recorded once on the Adverse Event 
eCRF.  The initial severity (intensity or grade) of the event will be recorded at the time 
the event is first reported.  If a persistent AE becomes more severe, the most extreme 


 
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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 SAEs. 
A recurrent AE is one that resolves between patient evaluation timepoints and 
subsequently recurs.  Each recurrence of an AE 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 AE.  A laboratory test result must be 
reported as an AE 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 AEs. 
 
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 AE. 
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 AE.  For example, an elevated serum potassium 
level of 7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent AEs). 


 
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5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an AE.  A vital sign result must be reported 
as an AE 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 AE. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (e.g., 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 AEs). 
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 AE 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 an SAE or an AESI (see Section 5.4.2). 
5.3.5.8 
Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the protocol-
specified AE reporting period (see Section 5.3.1) that are attributed by the investigator 
solely to progression of locally advanced or metastatic breast cancer should be recorded 
on the Death Attributed to Progressive Disease eCRF.  All other deaths that occur during 
the AE reporting period, regardless of relationship to study treatment, must be recorded 
on the Adverse Event eCRF and immediately reported to the Sponsor (see 


 
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Section 5.4.2). An iDMC will monitor the frequency of deaths from all causes, along with 
other safety data. 
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 AE 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 AE 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 Locally Advanced or 
Metastatic Breast Cancer 
Deterioration that is judged by the investigator to have unexpectedly worsened in 
severity or frequency or changed in nature (i.e., deterioration beyond the expected 
pattern of progression of the underlying disease) should be recorded as an adverse 
event.  When recording an unanticipated worsening of breast cancer on the Adverse 
Event eCRF, it is important to convey the concept that the condition has changed by 
including applicable descriptors (e.g., "accelerated worsening of breast cancer"). 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as AEs.  These data will be captured as 
efficacy assessment data only.  In most cases, the expected pattern of progression will 
be based on both clinical and laboratory findings (physical exam, biopsy, breast imaging, 
radiologic evidence, etc.).  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 AE. 


 
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5.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any AE that results in hospitalization (i.e., inpatient admission to a hospital) or prolonged 
hospitalization should be documented and reported as an SAE (per the definition of SAE 
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 AE or an SAE: 
• 
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 AE. 
• 
Hospitalization due solely to progression of the underlying cancer 
 
An event that leads to hospitalization under the following circumstances is not 
considered to be an SAE, but should be reported as an AE instead: 
• 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
• 
Hospitalization for a minor condition for which the patient suffers an AE, but does 
not meet the definition of an overnight admission (e.g., tooth extraction) 
 
5.3.5.12 
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. 
 
Note: Special situations are not in themselves AEs, but may result in AEs.  Each AE 
associated with a special situation should be recorded separately on the Adverse Event 
eCRF.  If the associated AE fulfills seriousness criteria or qualifies as an adverse event 
of special interest, the event should be reported to the Sponsor immediately 
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trastuzumab emtansine and atezolizumab (or matching placebo), AEs associated with 
special situations should be recorded as described below for each situation: 
• 
Accidental overdose:  Enter the AE term.  Check the "Accidental overdose" and 
"Medication error" boxes. 
• 
Medication error that does not qualify as an overdose:  Enter the AE term.  Check 
the "Medication error" box. 
• 
Medication error that qualifies as an overdose:  Enter the AE term.  Check the 
"Accidental overdose" and "Medication error" boxes. 
 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries. 
In addition, all special situations associated with trastuzumab emtansine and 
atezolizumab (or matching placebo), regardless of whether they result in an AE, should 
be recorded on the Adverse Event eCRF 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. 
• 
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. 
 
5.3.5.13 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO-CTCAE or other PRO data by the 
Sponsor.  In addition, the Sponsor will make no attempt to reconcile patient reports of 
treatment-related symptoms (via PRO-CTCAE) with investigator reports of AEs.  Sites 
are not expected to review the PRO-CTCAE or other PRO data for AEs. 
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 
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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) 
 
For SAEs and AESI, the investigator must report new significant follow-up information 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 SAEs to the local 
health authority and IRB/EC. 
5.4.1 
Medical Monitors and Emergency Medical Contacts 
Contact Information for all sites 
Medical Monitor: 
 
Telephone No.: 
 
Mobile Telephone No.: 
 
 
Emergency Medical Contact: 
 MD  
Telephone No.: 
 
Mobile Telephone No.: 
 
  
To ensure the safety of study patients, an Emergency Medical Call Center will be 
available 24 hours per day, 7 days per week, in case the above-listed contacts cannot 
be reached.  The Emergency Medical Call Center will connect the investigator with an 
Emergency Medical Contact, provide medical translation service if necessary, and track 
all calls.  Contact information, including toll-free numbers for the Emergency Medical Call 
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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 
SAEs 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, SAEs and AESI 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 electronic data capture (EDC) system.  A report will be 
generated and sent to Roche Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial 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 SAEs 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 through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the study or 
within 7 months after the last dose of study treatment.  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 SAEs 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 


 
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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 6 and 
12 months after birth.   
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 
7 months after the last dose of study treatment.  The investigator should report the 
pregnancy on the paper Clinical Trial Pregnancy Reporting Form and submit the form 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 the 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 with 
additional information on the pregnant partner and the course and outcome of the 
pregnancy as it 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 6 and 
12 months after birth. 
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. 
5.4.3.3 
Abortions 
A spontaneous abortion should be classified as an SAE (as the Sponsor considers 
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reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as an SAE, recorded on the 
Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no more than 24 
hours after learning of the event; see Section 5.4.2).  A therapeutic or elective abortion 
performed for reasons other than an underlying maternal or embryofetal toxicity is not 
considered an AE. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.  
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
treatment or the female partner of a male patient exposed to study treatment should be 
classified as an SAE, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each AE until the event has resolved to baseline grade or 
better, or the event is assessed as stable by the investigator, or the patient is lost to follow-
up, or the patient withdraws consent.  Every effort should be made to follow all SAEs 
considered to be related to study treatment or trial-related procedures until a final outcome 
can be reported. 
During the adverse event reporting period (defined in Section 5.3.1), resolution of AEs (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, 
with follow-up information on the infant collected according to procedures outlined in 
Section 5.4.3. 
5.5.2 
Sponsor Follow-Up 
For SAEs, AESI, 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 
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5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
After the end of the reporting period for SAEs and AESI (defined as 90 days after the 
final dose of study treatment or until initiation of new systemic anti-cancer therapy, 
whichever occurs first), all deaths, regardless of cause, should be reported through use 
of the Long-Term Survival Follow-Up eCRF.   
In addition, if the investigator becomes aware of an SAE that is believed to be related to 
prior exposure to study treatment, the event should be reported through use of the 
Adverse Event eCRF.  However, if the EDC system is not available, the investigator 
should report these events directly to the Sponsor or its designee, either by faxing or by 
scanning and 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 SAEs and AESI 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 AE cases, the Sponsor will assess the 
expectedness of these events through use of the reference safety information in the 
documents listed below: 
Drug 
Document 
Trastuzumab emtansine 
Trastuzumab emtansine Investigator's Brochure 
Atezolizumab 
Atezolizumab Investigator's Brochure 
 
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. 
An iDMC will monitor the incidence of the above-listed anticipated events during the 
study.  An aggregate report of any clinically relevant imbalances that do not favor the 
test product will be submitted to health authorities. 
 
 
 


 
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6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The statistical considerations and analysis plan are summarized below.  All details of the 
analyses will be described in the Statistical Analysis Plan (SAP) as part of the Data 
Analysis Plan.  The SAP overrides the analyses described in the statistical section of the 
protocol, as applicable. 
6.1 
DETERMINATION OF SAMPLE SIZE 
The two primary efficacy endpoints for this study are PFS based on investigator tumor 
assessment and OS.   
This study has been designed to detect a substantial magnitude of benefit in the ITT 
population, that is, improvement in median PFS from 7 months in the control arm to 
11.67 months in the experimental arm, corresponding to a target PFS hazard ratio of 
0.60, and improvement in median OS from 31 months in the control arm to 47.7 months 
in the experimental arm, corresponding to a target OS hazard ratio of 0.65. 
Approximately 350 patients randomized according to a 1:1 randomization (approximately 
175 patients will be randomized to Arm A and to Arm B) will be enrolled in the study.  
The sample size assumes an annual dropout rate of 10% in both treatment arm and 
result in an estimated recruitment time of about 32 months (with ramp up in the first 8 
months).  Following the Sponsor’s decision to prematurely terminate the study as 
outlined in Section 3.1, the initially planned number of randomized patients will not be 
reached.  
Furthermore, in the context of premature study termination, there will be only a single 
analysis timepoint for both PFS and OS primary efficacy endpoints.  Interim analyses 
will no longer be conducted.  Considering the expected lack of maturity of the data, the 
analysis of PFS and OS primary efficacy endpoints will only be reported in a 
descriptive way.  No formal testing will be performed and no control for the overall type 
I error (α) accounting for the two primary endpoints will be implemented.  
Consequently, p-values will not be able to be claimed as statistically significant and 
therefore will be reported as descriptive in nature.  
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Patient enrollment, duration of follow-up, discontinuation from study treatment, and 
discontinuation reasons will be descriptively summarized by the treatment arm to which 
patients were randomized.  In addition, protocol violations will be summarized by 
treatment arm.  
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
The evaluation of treatment arm comparability will include summaries of demographics, 
breast cancer history, baseline disease characteristics, and patient treatment history.  
Data will be summarized by the treatment arm to which patients were randomized.  


 
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Descriptive statistics (mean, median, standard deviation, 25th percentile, 75th percentile, 
and range) will be presented by treatment arm for continuous variables such as age or 
time since initial breast cancer diagnosis.  Frequency counts will be presented by 
treatment arm for categorical variables such as gender, race, and age category. 
The baseline value of any variable will be defined as the last available data point prior to 
the first administration of study medication. 
6.4 
EFFICACY ANALYSES 
6.4.1 
Primary Efficacy Endpoint 
The multiple primary efficacy endpoints for this study are PFS based on investigator 
tumor assessment and OS.  The ITT population is the primary analysis population for the 
primary efficacy endpoints and includes all patients who are randomized to the study, 
whether or not they receive any study medication.  Treatment group for the ITT 
population will be defined according to the treatment assigned at randomization. 
Progression-free Survival 
PFS is defined as the time from randomization to first documented disease progression 
as determined by the investigator using RECIST 1.1 or death from any cause, whichever 
occurs earlier.  The first documented disease progression will be used in the main 
analysis of the primary efficacy endpoint of PFS.  Data for patients without disease 
progression or death from any cause as of the data cut-off date will be censored at the 
time of the last tumor assessment with an outcome other than “unevaluable” (or, if no 
tumor assessment was performed after the baseline visit, at the time of randomization 
plus 1 day).  Data from patients who are lost to follow-up will be included in the analysis 
as censored observations on the date of the last tumor assessment that the patient was 
known to be progression-free.  
The Kaplan-Meier method will be used to estimate median PFS and the corresponding 
95% CIs for each treatment arm.  The 2-sided log-rank test, stratified by the factors 
specified in the protocol (excluding world region) will be used to compare PFS between 
the treatment arms.  If less than 5 events are observed in any combination, only the 
unstratified analysis will be done. The stratification factors will be based on data 
collected by the IxRS rather than on data collected on the eCRFs.  The unstratified log-
rank test result will also be provided. The Cox proportional hazards model, stratified by 
the previous noted stratification factors, excluding world region, will be used to estimate 
the HR and to calculate the 95% CI of the HR.  
In order to assess the consistency of treatment benefit with respect to the multiple 
primary efficacy endpoints PFS and OS across important subgroups, forest plots 
(including estimated HRs) will be provided, including, but not limited, to the following 
variables: race, age, sex, world region, baseline HER2 and PD-L1 expression, ECOG 
status, hormone receptor status, and line of treatment in the metastatic setting (first or 
second line vs. third line). 


 
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Overall Survival 
OS is defined as the time from randomization to death from any cause.  Patients who 
are alive as of the data cut-off date of the analysis will be censored at the last known 
date they were alive.  Patients with no post-baseline information will be censored at the 
date of randomization plus 1 day.  Methods for data analysis are analogous to those 
described for the primary efficacy endpoint PFS. The 2-sided log-rank test, stratified by 
the factors specified in the protocol (excluding world region) will be used to compare OS 
between the treatment arms. 
6.4.2 
Secondary Efficacy Endpoints 
The ITT population will be the analysis population used for evaluation of the secondary 
efficacy endpoints. 
Objective Response Rate 
Objective response, defined as a CR or PR, will be determined by investigator tumor 
assessment using RECIST 1.1.  Only patients with measurable disease at baseline will 
be included in the analysis of objective response.  Patients without a post-baseline tumor 
assessment will be considered non-responders.  Objective responses must be confirmed 
at least 28 days after the initial documentation of response.  An estimate of the ORR 
and its 95% CI (Wilson score confidence interval) will be calculated for each treatment 
arm.  The Cochran-Mantel-Haenszel Chi-squared test stratified according to the factors 
specified in Section 4.2.2 (excluding world region) will be used to compare response 
rates between treatment arms.  An unstratified Chi-squared test will also be provided.  
Finally, the difference in response rates between treatment arms will be computed with 
95% CIs, using the normal approximation to the binomial distribution. 
Duration of Response 
DOR is defined as the time from first occurrence of a documented objective response 
(PR or CR) to disease progression, as determined by investigator tumor assessment 
using RECIST 1.1, or death from any cause, whichever occurs first.  The analysis 
methods are similar to those described for the primary efficacy endpoint PFS.  
The limitations of this responder analysis are acknowledged. 
PFS as determined by a blinded independent central review committee 
Following the Sponsor’s decision to prematurely terminate the study, this endpoint will 
not be analyzed. 
PFS in patients with baseline brain metastases 
PFS as defined above in the subset of patients with brain metastases at baseline. 
OS in patients with baseline brain metastases 
OS as defined above in the subset of patients with brain metastases at baseline. 


 
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CNS progression-free survival 
CNS progression-free survival (CNS-PFS) is defined as the time from randomization 
until CNS disease progression, or first occurrence of symptomatic CNS disease, as 
determined by the investigator using RECIST v1.1, or death from any cause, whichever 
occurs first.  Patients who have experienced non-CNS progression at the time of 
analysis will be censored at the date of this progression.  Patients who have experienced 
no disease progression and are alive at the time of analysis will be censored at the date 
of their last post-baseline tumor assessment or, if they have no post-baseline tumor 
assessment, on the date of randomization + 1 day. 
The analysis of CNS-PFS will follow the same methodology as the PFS primary 
endpoint.  CNS-PFS will be analyzed in the subgroups of patients with or without CNS 
metastases at baseline. 
In addition, in order to account for the competing risks inherent in the comparison of 
CNS progression between treatments, a stratified two-sided log-rank test will be 
computed on the basis of a cause-specific hazard function.  Results from unstratified 
tests will also be presented as supportive analyses. 
The probability of CNS progression, non-CNS progression, and death by treatment 
group with 95% CIs will each be estimated using cumulative incidence functions.  Gray’s 
test to compare the risk of CNS progression between treatments will also be presented. 
Patient-Reported Outcomes Analysis (Secondary and Exploratory 
Endpoints) 
Following the Sponsor’s decision to prematurely terminate the study, the analysis of 
PRO data from the EORTC QLQ-C30 and BR23 questionnaire will no longer be 
performed. 
6.4.3 
Exploratory Efficacy Endpoints 
Following the Sponsor’s decision to prematurely terminate the study, the analysis of 
exploratory efficacy endpoints will no longer be performed.  
6.5 
SAFETY ANALYSES 
The safety analysis population will include all randomized patients who received at least 
one full or partial dose of study drug.  Safety analyses will be performed based on the 
treatment the patient actually received. 
6.5.1 
Analyses of Exposure, Adverse Event, Laboratory, Vital Sign, 
and ECG Data 
Safety will be assessed through summaries of exposure to study treatment, AEs, 
changes in laboratory test results, and changes in vital signs and ECGs. 


 
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Study treatment exposure (such as treatment duration, total dose received, and number 
of cycles and dose modifications) will be summarized with descriptive statistics. 
All verbatim AE terms will be mapped to Medical Dictionary for Regulatory Activities 
(MedDRA) thesaurus terms, and AE severity will be graded according to NCI CTCAE 
v5.0.  All AEs, SAEs, AEs leading to death, AESI, and AEs leading to study treatment 
discontinuation that occur on or after the first dose of study treatment 
(i.e., treatment-emergent AEs) will be summarized by mapped term, appropriate 
thesaurus level, and severity grade.  For events of varying severity, the highest grade 
will be used in the summaries.  Deaths and cause of death will be summarized. 
Relevant laboratory, vital sign (pulse rate, respiratory rate, blood pressure, pulse 
oximetry, and temperature), and ECG data will be displayed by time, with grades 
identified where appropriate.  Additionally, a shift table of selected laboratory tests will be 
used to summarize the baseline and maximum postbaseline severity grade.  Changes in 
vital signs and ECGs will be summarized. 
6.5.2 
Exploratory Analyses of PRO-CTCAE Data 
Exploratory analyses of PRO CTCAE data will not be performed following the 
Sponsor’s decision to prematurely terminate the study. 
6.6 
PHARMACOKINETIC ANALYSES 
No PK analyses will be performed following the Sponsor’s decision to prematurely 
terminate the study. 
6.7 
IMMUNOGENICITY ANALYSES 
No ADA analyses will be performed following the Sponsor’s decision to prematurely 
terminate the study. 
6.8 
BIOMARKER ANALYSES 
Some descriptive biomarker analyses will be performed.  Further details can be found in 
the SAP. 
6.9 
HEALTH STATUS UTILITY ANALYSES 
The EQ-5D-5L will be scored according to its manual (van Reenen and Janssen 2019). 
Absolute score and change from baseline in EQ-5D-5L health utility index-based and 
VAS scores will be calculated over time.  
No health status utility analyses will be performed following the Sponsor’s decision to 
prematurely terminate the study. 


 
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6.10 
INTERIM ANALYSES 
Following the Sponsor’s decision to prematurely terminate the study, interim analyses 
will no longer be conducted. 
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 other 
electronic 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 through the use of an electronic device provided by a vendor 
or with an online ePRO completion tool (see Section 7.3 for details).  Sites will be 
responsible for entering PRO data collected by telephone (see Section 4.5.9.1) into the 
electronic device or the online ePRO completion tool. 
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 
ELECTRONIC PATIENT-REPORTED OUTCOME DATA 
An electronic device will be used to capture PRO data.  The device is designed for entry 
of data in a way that is attributable, secure, and accurate, in compliance with U.S. Food 
and Drug Administration (FDA) regulations for electronic records (21 CFR Part 11).  The 


 
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data will be transmitted to a centralized database maintained by the electronic device 
vendor.  For PRO assessments that are completed at home (see Appendix 3), an online 
ePRO completion tool will be used. 
The electronic data will be available for view access only, via a secure method.  Only 
identified and trained users may view the data, and their actions will become part of the 
audit trail.  The Sponsor will have view access only.  System backups for data stored by 
the Sponsor and records retention for the study data will be consistent with the 
Sponsor's standard procedures. 
Once the study is complete, the data, audit trail, and trial and system documentation will 
be archived.  The investigator will receive patient data for the site in both human- and 
machine-readable formats that must be kept with the study records as source data.  
Acknowledgement of receipt of the data is required.  In addition, the Sponsor will receive 
all data in a machine-readable format. 
7.4 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6. 
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities. 


 
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7.5 
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. 
7.6 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic PRO data (if applicable), Informed Consent Forms, 
laboratory test results, medication inventory records, and images 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. 
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. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC) 
and applicable local, regional, and national laws.  Studies conducted in China will be in 
accordance with the approved local Informed Consent Form and applicable laws and will 
comply with the approved HGRAC (Human Genetics Resources Administration of 
China) main and exploratory applications (when applicable). 


 
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8.2 
INFORMED CONSENT 
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as the Prescreening Informed Consent Form) will be provided to each site.  
If applicable, it will be provided in a certified translation of the local language.  The 
Sponsor or its designee must review and approve any proposed deviations from the 
Sponsor's sample Informed Consent Forms or any alternate consent forms proposed by 
the site (collectively, the "Consent Forms") before IRB/EC submission.  The final 
IRB/EC−approved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
If the Consent Forms are revised (through an amendment or an addendum) to 
communicate information that might affect a patient's willingness to continue in the 
study, the patient or a legally authorized representative must re-consent by signing the 
most current version of the Consent Forms or the addendum, in accordance with 
applicable laws and IRB/EC policy.  For any updated or revised Consent Forms, the 
case history or clinical records for each patient shall document the informed consent 
process and that written informed consent was obtained using the updated/revised 
Consent Forms 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. 


 
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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 9.6). 
In addition to the requirements for reporting all AEs to the Sponsor, investigators must 
comply with requirements for reporting SAEs to the local health authority and IRB/EC.  
Investigators may receive written IND safety reports or other safety-related 
communications from the Sponsor.  Investigators are responsible for ensuring that such 
reports are reviewed and processed in accordance with health authority requirements 
and the policies and procedures established by their IRB/EC, and archived in the site's 
study file.  
8.4 
CONFIDENTIALITY 
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. 


 
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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 imaging data and data on genomic variants, 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 (see 
Section 9.6). 
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 3.4). 
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 


 
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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 has implemented a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  Prior 
to study initiation, the Sponsor identified potential risks associated with critical trial 
processes and data and implemented plans for evaluating and controlling these risks.  
Risk evaluation and control included the selection of risk-based parameters (e.g., AE 
rate, protocol deviation rate) and the establishment of quality tolerance limits for these 
parameters prior to study initiation.  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 are 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 
or designated, region specific, service providers will provide clinical operations 
management, medical monitoring and pharmacovigilance support. Data Management 
will be provided by the Sponsor’s Data Management provider.  
Patient enrollment and treatment assignment will be handled through an interactive 
voice or web-based response system (IxRS).  Central facilities will be used for study 
assessments throughout the study (e.g., specified laboratory tests, PK and biomarker 
analyses).  Accredited local laboratories will be used for routine monitoring; local 
laboratory ranges will be collected.  An independent review facility will be used to collect 
and retain copies of tumor assessment scans for centralized review. 
A Steering Committee (SC) will be set up to provide guidance on the protocol, study 
design and the SAP, and to provide guidance on review of any relevant study-related 
documents or procedures in order to be confident that the data collected will be timely, 
accurate and complete.  A separate SC Charter will outline the committee’s composition, 
meeting timelines and the members’ roles and responsibilities. 
An iDMC composed of a group of independent experts external to the Sponsor, with the 
aid of an independent Data Coordinating Center (iDCC), will be installed to monitor 


 
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unblinded patient safety data and blinded efficacy data during course of the study.  The 
iDMC members will not be Principal Investigators for the study.  A separate iDMC 
Charter will detail the committee’s composition, meeting timelines, and the members’ 
roles and responsibilities. 
An independent review facility will collect, store, and review imaging data. 
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, and in peer-reviewed journals.  The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request.  For more information, refer to the Roche Global Policy on Sharing of Clinical 
Study Information at the following website: 
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 (including data from analyses of study samples donated to the RBR) 
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. 
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. 


 
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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). 


 
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10. 
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Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
147/Protocol MO42319, Version 4 
Appendix 1 Schedule of Activities 
Assessment  
or Procedure 
Screening a 
Treatment Period (21-Day Cycles) 
(Cycles 1 through Study Treatment 
Discontinuation) 
Study Treatment 
Completion/Early 
Discontinuation 
28–42 days after  
Last Dose 
Follow-Up b 
 
Days −28 
to −1 
Day 1 of each cycle 
(± 3 Days) unless otherwise indicated 
Informed consent c 
x 
 
 
 
Demographics d 
x 
 
 
 
Medical history e 
x 
 
 
 
HER2 and PD-L1 testing f  
x 
 
 
 
Complete physical examination g 
x 
 
 
 
Limited physical examination h 
 
x ee 
x 
 
ECOG performance status 
x 
x 
x 
 
Height 
x 
 
 
 
Weight i 
x 
x 
 
 
Vital signs j 
x 
x ee 
x 
 
Hematology k 
x l 
x m, ee 
x 
x ff 
Serum chemistry n 
x l 
x m, ee 
x 
x ff 
TSH, free T3 (or total T3), free T4 o 
x 
x o 
x 
x ff 
Coagulation (INR, aPTT) 
x l 
As clinically indicated 
 
 
HIV, HCV, and HBV serology p 
x 
 
 
 
Urinalysis q 
x 
As clinically indicated 
 
 
Pregnancy test r 
x 
x 
x 
x 
C-reactive protein 
x 
 
 
 
Tumor and response assessment s 
x  
x t 
 
x t 


Appendix 1: Schedule of Activities (cont.) 
 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
148/Protocol MO42319, Version 4 
Assessment 
or Procedure 
Screening a 
Treatment Period (21-Day Cycles) 
(Cycles 1 through Study Treatment 
Discontinuation) 
Study Treatment 
Completion/Early 
Discontinuation
28–42 days after 
Last Dose 
Follow-Up b
Days −28 
to −1 
Day 1 of each cycle 
(± 3 Days) unless otherwise indicated 
Bone scan/PET u 
x 
As clinically indicated 
CT or MRI of brain v 
Mandatory 
at screening 
As clinically indicated or as 
scheduled tumor assessment v 
ECG (12-lead) w 
x 
As clinically indicated 
NYHA classification 
x 
ECHO or MUGA scan x 
x 
x 
Day 15–21 of Cycle 1, Day 15–21 of 
every fourth cycle thereafter, and as 
clinically indicated 
x 
If not performed 
within 6 weeks prior 
to this visit 
x ff 
Atezolizumab/placebo administration y 
x 
Trastuzumab emtansine administration y 
x 
PROs: QLQ-C30, EORTC Treatment Burden 
Item, QLQ-BR23, EQ-5D-5L, PRO-CTCAE z 
x (See Appendix 3) 
x (See Appendix 3) 
x (See Appendix 3) 
PK/ADA 
x (See Appendix 2) 
x (See Appendix 2) 
Blood samples for biomarker analysis 
x (See Appendix 2) 
x (See Appendix 2) 
Sample for auto-antibodies aa 
X 
Tissue sample for biomarker analysis
x (See 
Appendix 2) 
x (See Appendix 2) bb 
Concomitant medications 
X 
x 
x 
Adverse events cc 
x 
x ee 
x 
x 
Survival follow-up dd 
x 
Initiation of anti-cancer treatments dd 
x 
x 


Appendix 1: Schedule of Activities (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
149/Protocol MO42319, Version 4 
CT = computed tomography; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; 
eCRF = electronic Case Report Form; HBV = hepatitis B virus; HER2 = human epidermal growth factor receptor 2; IV = intravenous; LVEF = left 
ventricular ejection fraction; MBC = metastatic breast cancer; MRI = magnetic resonance imaging; MUGA = multiple-gated acquisition; 
PET = positron emission tomography; PK = pharmacokinetic; RECIST = Response Evaluation Criteria in Solid Tumors; SOC = standard of care; 
TSH = thyroid-stimulating hormone; ULN = upper limit of normal. 
Notes:  With the exception of Day 1 of Cycle 1, all assessments should be performed within 3 days of the scheduled visit, unless otherwise 
specified.  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified.  If the timing of a protocol-
mandated procedure coincides with a holiday or weekend, it should be performed on the nearest following date.  
a Results of standard-of-care assessments performed prior to obtaining informed consent and within 28 days prior to Day 1 may be used; such 
assessments do not need to be repeated for screening. 
b The follow up period begins from the date of treatment completion / early termination visit. Visits will be conducted every 3 months, until the 
study end. Visits windows are +/-14 days for all follow up visits.  
c Informed consent by the patient or the patient’s legally-authorized representative must be documented before any study-specific screening 
procedure is performed, and may be obtained more than 28 days before initiation of study treatment. 
d Demographics include age, sex, and self-reported race/ethnicity. 
e Medical history includes clinically significant diseases, surgeries, cancer history (including hormone receptor status, prior cancer therapies and 
procedures), reproductive status, smoking history, and use of alcohol and drugs of abuse, and all medications (e.g., prescription drugs, over-the-
counter drugs, vaccines, herbal or homeopathic remedies, and nutritional supplements) used by the patient within 7 days prior to the Cycle 1, 
Day 1 visit. 
f Conducted in the central laboratory. If archival tissue is unavailable or is determined to be unsuitable for required testing, a pretreatment tumor 
biopsy is required.  A pretreatment tumor biopsy may also be performed if a patient's archival tissue test results do not meet eligibility criteria. 
Refer to Appendix 2 for tissue sample requirements. For patients who sign the separate prescreening informed consent form, these 
assessments can be made in the central laboratory (using archival tissue only) up to 12 months before randomization. Up to two prescreening 
samples can be sent for analysis (i.e., if the first sample fails the prescreening, a second one can be sent). If a patient consents to prescreening 
for determination of HER2 and PD-L1, these tests would not need to be repeated during the screening period. If patients are being rescreened, 
then HER2 and PD-L1 testing do not need to be repeated. 
g A complete physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems. Any abnormality identified at baseline should be recorded 
on the General Medical History and Baseline Conditions eCRF. 
h Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated at other timepoints. 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. 
i Weight is to be measured up to 3 days prior to Day 1 of each cycle and compared with baseline to determine if the dose of trastuzumab 
emtansine should be adjusted (see Section 4.3.2.1).  
j Vital signs include respiratory rate, pulse rate, systolic and diastolic blood pressure, and temperature. See Section 4.5.4 for guidance on timing 


Appendix 1: Schedule of Activities (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
150/Protocol MO42319, Version 4 
for vital sign measurements for first and subsequent infusions of trastuzumab emtansine and atezolizumab/placebo. 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. 
k Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells).   
l Specified screening laboratory tests must be obtained within 7 days prior to initiation of study treatment. Results must be reviewed and 
documented prior to administration of the first dose of study treatment. 
m Specified laboratory tests must be completed prior to dosing on Day 1 of each indicated cycle (or up to 3 days before [up to 7 days before for 
Cycle 1, Day 1]). 
n Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, 
potassium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphate, calcium, total bilirubin, ALP, ALT, AST, and LDH.  
o 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 four cycles 
thereafter (i.e., Cycles 5, 9, 13, etc.). 
p At screening, patients will be tested for HIV, HBsAg, HBsAb, total HBcAb, and HCV antibody.  If a patient has a negative HBsAg test and a 
positive total HBcAb test at screening, an HBV DNA test must also be performed.  If a patient has a positive HCV antibody test at screening, an 
HCV RNA test must also be performed.   
q Urinalysis includes specific gravity, pH, glucose, protein, ketones, and blood; dipstick permitted. 
r All women of childbearing potential will have a serum pregnancy test within 7 days prior to initiation of study treatment. Urine or serum 
pregnancy tests will be performed every cycle, within 3 days prior to study treatment administration.  If a urine pregnancy test is positive, it must 
be confirmed by a serum pregnancy test. All patients will have a urine or serum pregnancy test at the study completion/early termination visit and 
at 3 months (± 28 days) and 7 months (± 28 days) after the last dose of trastuzumab emtansine. 
s All measurable (and non-measurable) lesions should be assessed and documented at screening.  Tumor assessments performed as standard of 
care prior to obtaining informed consent and within 28 days prior to initiation of study treatment do not have to be repeated at screening, so long 
as they meet criteria outlined in Section 4.5.5.  Screening assessments must include CT scans with contrast or MRI scans of the chest, 
abdomen, and pelvis.  If a CT scan with contrast is contraindicated (e.g., in patients with impaired renal clearance), a non-contrast CT scan of 
the chest may be performed and MRI scans of the abdomen and pelvis should be performed.  A CT scan with contrast or MRI scan of the brain 
must be done at screening to evaluate CNS metastasis in all patients (MRI scan must be performed if CT scan is contraindicated).  An MRI scan 
of the brain is required to confirm or refute the diagnosis of CNS metastases at baseline in the event of an equivocal CT scan.  A bone scan (or 
other suitable modality for bone imaging, e.g., NaF or FDG-PET) will also be performed at screening.  If clinically indicated, other methods 
of assessment of measurable disease as per RECIST v1.1 may be used. 


Appendix 1: Schedule of Activities (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
151/Protocol MO42319, Version 4 
t Patients will undergo tumor assessments at baseline (screening) and then every 6 weeks (± 7 days) following treatment initiation, regardless of 
dose delays, until investigator-assessed radiographic disease progression per RECIST v1.1, withdrawal of consent, death, or study termination 
by the Sponsor.  Thus, tumor assessments are to continue according to schedule in patients who discontinue treatment for reasons other than 
disease progression, even if they start new anti-cancer therapy, until disease progression. All measurable (and non-measureable) lesions 
identified at baseline should be re-assessed at each subsequent tumor evaluation. The same radiographic procedures used to assess disease 
sites at screening should be used for subsequent tumor assessments (e.g., the same contrast protocol for CT scans). Brain scans (preferably 
MRI) must be conducted at all subsequent tumor evaluations in patients with known brain metastases. Patients without brain metastases at 
baseline should have brain scans (preferably MRI) as clinically indicated.  A bone scan (or other suitable modality for bone imaging e.g., NaF or 
FDG-PET) should be repeated in the event of clinical suspicion of progression of existing bone lesions and/or the development of new bone 
lesions. Tumor response will be evaluated using RECIST v1.1 (Appendix 4). Tumor assessments may be done according to standard of care at 
the site, following premature study termination.  
u A bone scan and/or FDG PET will be performed at screening and should be repeated in the event of clinical suspicion of progression of existing 
bone lesions and/or the development of new bone lesions. 
v CT/MRI scan of the brain is mandatory at screening and should be performed 1) with scheduled tumor assessments when identified as a site of 
involvement at baseline, 2) as clinically indicated. 
w ECG recordings will be obtained during screening and as clinically indicated at other timepoints.  Patients should be resting in a supine position 
for at least 10 minutes prior to ECG recording. 
x LVEF assessment by ECHO is preferred, but LVEF may also be assessed by MUGA scan.  The same method should be used throughout the 
study for each patient and preferably performed and evaluated by the same assessor. 
y Atezolizumab or placebo will be administered first by IV infusion at a dose of 1200 mg on Cycle 1, and on Day 1 of each 21-day cycle thereafter. 
Trastuzumab emtansine will be administered second by IV infusion at a dose of 3.6 mg/kg on Day 1 of Cycle 1, and on Day 1 of each 21-day 
cycle thereafter. 
z Questionnaires will be self-administered before the patient receives any information on disease status, prior to the performance of all other 
assessments, and prior to the administration of study treatment (See Appendix 3).  Laboratory and weight assessments can be completed 
before the PROs are administered; however, the results of these assessments should not be given to the patient prior to completing the PROs.  
PROs do not need to be collected after premature study termination.  
aa Auto-antibody testing includes anti-nuclear antibody, anti−double-stranded DNA, and circulating and perinuclear cytoplasmic antibody.  The 
baseline sample will be collected prior to the first dose of study drug on Cycle 1, Day 1.  For patients who show evidence of immune-mediated 
toxicity, additional samples may be collected.  All samples will be analyzed centrally, if necessary.  Samples no longer need to be collected after 
premature study termination. 
bb A tissue sample from mandatory biopsy will be collected at the time of first evidence of radiographic disease progression per RECIST v1.1 (prior 
to the start of new anti-cancer treatment), if deemed clinically feasible and the patient would not be put at risk, as assessed by the investigator.   


Appendix 1: Schedule of Activities (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
152/Protocol MO42319, Version 4 
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 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.  After this period, all deaths, regardless of cause, should be reported. In addition, 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). 
dd After treatment discontinuation, information on survival status and new anti-cancer therapy will be collected via telephone calls, patient medical 
records, and/or clinic visits approximately every 3 months until death, loss to follow-up, withdrawal of consent, or the Sponsor terminates the 
study.  Study staff may use a public information source (e.g., county records) to obtain information about survival status only.  Following the 
announcement of premature study termination, data on survival and new anti-cancer therapies will no longer be collected.  
ee In addition to Day 1, the following assessments will also be conducted on Day 10 (±3 days) of Cycle 1 and Cycle 2: limited physical examination, 
vital signs, hematology, serum chemistry, and adverse events. 
ff To be performed if patient has unresolved AEs at the time of treatment discontinuation and/or if clinically indicated.  If patients are already 
in follow-up, it is recommended that patients in follow-up return to the site for a final visit before being discontinued from the study. 
 
 


 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
153/Protocol MO42319, Version 4 
Appendix 2 Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples 
CONTENTS 
• 
Table 1 Anti-Drug Antibody and Pharmacokinetic Assessments for Atezolizumab 
• 
Table 2 Anti-Drug Antibody and Pharmacokinetic Assessments for Trastuzumab 
 
Emtansine for Arm A and Arm B 
• 
Table 3 Blood Samples for Biomarker Analysis  
• 
Table 4 Tissue Sample for Biomarker Analysis 
Table 1 
Anti-Drug Antibody and Pharmacokinetic Assessments for 
Atezolizumaba 
Visit 
Timepoint 
Sample Type c 
Cycle 1, Day 1 and Cycle 4 
Day 1 
Pre-infusion of atezolizumab 
or placebo b 
Serum sample for atezolizumab 
pharmacokinetics  
Serum sample for ADA to 
atezolizumab  
Cycle 1, Day 1 and Cycle 4 
Day 1 
30 minutes (± 10 mins) after 
end of atezolizumab or 
placebo infusion 
Serum sample for atezolizumab 
pharmacokinetics  
Cycles 2, 3, 8, and every 
8 cycles thereafter, Day 1 
(± 3 days) 
Pre-infusion of atezolizumab 
or placebo b 
Serum sample for atezolizumab 
pharmacokinetics  
Serum sample for ADA to 
atezolizumab c 
Study treatment 
completion/early 
discontinuation visit 
At any time during visit 
Serum sample for atezolizumab 
pharmacokinetics  
Serum sample for ADA to 
atezolizumab  
ADA = anti-drug antibody, also called anti-therapeutic antibody; PK = pharmacokinetic. 
a Due to double-blinded study design, the samples should be collected for both treatment arms 
but analyses will only be conducted for patients randomized to the trastuzumab emtansine plus 
atezolizumab arm.  Samples are no longer to be collected after the Sponsor’s decision for 
premature study termination. 
b Within 24 hours prior to atezolizumab or placebo infusion. 
c Blood for PK/ ADA should not be obtained through the same line that atezolizumab or placebo 
is infused. 
 
 


Appendix 2: Schedule of PK, Immunogenicity, and Biomarker Samples 
(cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
154/Protocol MO42319, Version 4 
Table 2 
Anti-Drug Antibody and Pharmacokinetic Assessments for 
Trastuzumab Emtansine for Arm A and Arm B 
Visit 
Timepoint 
Sample Type 
Cycle 1, Day 1 and 
Cycle 4 Day 1 
Pre-infusion of trastuzumab 
emtansine a 
Serum sample for trastuzumab 
emtansine pharmacokinetics  
Serum sample for total 
trastuzumab pharmacokinetics  
Serum sample for ADA to 
trastuzumab emtansine 
Cycle 1, Day 1 and 
Cycle 4 Day 1 
30 minutes (± 10 mins) after 
end of trastuzumab emtansine 
infusion 
Serum sample for trastuzumab 
emtansine pharmacokinetics  
Serum sample for total 
trastuzumab pharmacokinetics  
Plasma sample for DM1 
pharmacokinetics 
Cycle 2, Day 1  
Pre-infusion of trastuzumab 
emtansine a 
Serum sample for trastuzumab 
emtansine pharmacokinetics  
Serum sample for total 
trastuzumab pharmacokinetics  
Study treatment 
completion /early 
discontinuation visit 
At any time during visit 
Serum sample for trastuzumab 
emtansine pharmacokinetics  
Serum sample for total 
trastuzumab pharmacokinetics  
Serum sample for ADA to 
trastuzumab emtansine 
a Within 24 hours prior to trastuzumab emtansine infusion.  Samples are no longer to be 
collected after the Sponsor’s decision for premature study termination. 
 
 
 


Appendix 2: Schedule of PK, Immunogenicity, and Biomarker Samples 
(cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
155/Protocol MO42319, Version 4 
Table 3 
Blood Samples for Biomarker Analysis  
Visit 
Timepoint 
Sample Type 
Cycle 1, Day 1  
Pre-infusion   
Blood sample for WGS/WES a,b 
Plasma sample for biomarkers 
Cycle 2, Day 1  
Pre-infusion   
Plasma sample for biomarkers 
Cycle 3, Day 1 
Pre-infusion   
Plasma sample for biomarkers 
Cycle 8, Day 1 
Pre-infusion   
Plasma sample for biomarkers 
Cycle 16, Day 1 
Pre-infusion   
Plasma sample for biomarkers 
Disease Progression 
At any time during 
visit 
Plasma sample for biomarkers 
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.  Samples 
are no longer to be collected after the Sponsor’s decision for premature study termination. 
 
 
 
 


Appendix 2: Schedule of PK, Immunogenicity, and Biomarker Samples 
(cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
156/Protocol MO42319, Version 4 
Table 4 
Tissue Sample for Biomarker Analysis 
Visit 
Timepoint 
Sample Type 
Screening 
(mandatory) 
Pre-infusion 
Preferred: FFPE archival tumor block (most recently 
collected, available tumor tissue) or FFPE fresh tumor block 
(at least 3 cores, embedded in a single paraffin block). 
In case of site regulations that prevent sending a paraffin 
block, at least 17 slides (9 slides for screening tests and 8 
slides for additional biomarker tests) containing unstained, 
freshly cut, serial sections must be submitted. The unstained 
slides for staining must be within the current documented 
cutslide stability window. Leftover slides after screening tests 
may also be used for additional biomarker tests. 
The sample needs to be of good quality based on total and 
viable tumor content. 
For patients with bilateral breast cancer (synchronous or 
developed at a later stage), HER2 positivity must be centrally 
determined preferably in a metastatic biopsy or if not 
available in primary tumor from both left and right breast; at 
least one biopsy must be centrally determined as PD-L1 
positive. In case of submission of lesions from left and right 
breast: a representative FFPE tumor specimen in a paraffin 
block of each lesion is preferred (if slides are provided: at 
least 9 slides containing unstained, freshly cut, serial 
sections are required from each lesion for screening tests. In 
addition to this requirement, a total of 8 slides are required 
for the additional biomarker tests. Preferably, these additional 
8 slides are derived from the lesion which was determined 
HER2 and PD-L1-positive). 
For patients with initially multicentric tumors (multiple 
tumors involving more than one quadrant) or multifocal 
tumors (more than one mass confined to the same quadrant 
as the primary tumor), HER2 positivity must be centrally 
determined preferably in a metastatic biopsy or if not 
available in primary tumor, provide that: 
• For multicentric tumors all discrete lesions are centrally 
confirmed as HER2-positive and at least one lesion is 
centrally determined as PD-L1 positive. 
A representative FFPE tumor specimen in a paraffin block of 
all lesions (preferred) or at least 9 slides are required from 
each lesion.  In addition to this requirement, a total of 8 slides 
is required for the remaining biomarker tests.  Preferably, 
these additional 8 slides are derived from the lesion which 
was determined HER2 and PD-L1-positive. 
• For multifocal tumors at least one focus is centrally 
confirmed as HER2-positive and PD-L1 positive.  
– 
A representative FFPE tumor specimen in a 
paraffin block (preferred) or at least 17 slides 
containing unstained, freshly cut, serial sections 
must be submitted. 


Appendix 2: Schedule of PK, Immunogenicity, and Biomarker Samples 
(cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
157/Protocol MO42319, Version 4 
Visit 
Timepoint 
Sample Type 
Disease 
progression  
(if deemed 
clinically 
feasible and 
the patient 
would not be 
put at risk) 
Must be taken 
before next 
line of therapy 
begins. a   
In case new 
line therapy is 
purely anti-
hormonal, 
biopsy could 
be taken after 
it is started.  
Fresh core biopsy (preferably 3 cores) at site of progression 
if accessible or from any other lesion. 
A representative FFPE tumor specimen in a paraffin block 
(preferred) or a minimum of 10 slides containing unstained, 
freshly cut, serial sections must be submitted. 
 
a 
Within 40 days after progression or prior to the next anti-cancer therapy, whichever is 
sooner.


 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
158/Protocol MO42319, Version 4 
Appendix 3 Schedule of Patient-Reported Outcome Assessments 
Questionnaires will be self-administered before the patient receives any information on disease status, prior to the performance of all 
other assessments, and prior to the administration of study treatment.  PRO assessments are no longer to be collected after the 
Sponsor’s decision for premature study termination. 
TIMING OF PRO ASSESSMENTS 
PRO a 
Treatment period 
(Cycle 1 through study treatment discontinuation) 
Cycles (Day 1 unless otherwise indicated) 
Study treatment completion 
/ Early discontinuation visit 
28–42 days after last dose 
Follow-up 
3 months after study 
treatment completion / 
Early discontinuation visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 
12 
13 
 
EORTC QLQ-C30 
(Appendix 10) and 
EQ-5D-5L  
(Appendix 12)  
x 
X 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
Every second 
cycle thereafter 
x 
x 
EORTC Treatment 
Burden Item 
(Appendix 14) 
x 
X 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
Every second 
cycle thereafter 
x 
x 
EORTC QLQ-BR23 b 
(Appendix 11) 
x 
 
x 
 
x 
 
 
 
x 
 
 
 
x 
Every fourth 
cycle thereafter 
x 
x 
NCI PRO-CTCAE 
(Appendix 13) 
x 3c x 3c x 3c 
 
x 
 
x 
 
x 
 
x 
 
x 
Every second 
cycle thereafter 
x 
x 


Appendix 3: Schedule of PRO assessments 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
159/Protocol MO42319, Version 4 
a 
PROs should be administered on planned Day 1 of the indicated cycles, except where indicated. The Day 1 PROs for any cycle are not to be 
completed again in the event that it is determined following completion of the PROs that the treatment on Day 1 of the given treatment cycle will be 
delayed. Additionally, the timing of any subsequent PRO assessments will be based on the actual Day 1 of the given cycle (e.g., if it is determined 
that the start of treatment at Cycle 3 will be delayed a week, the Day 8 PRO-CTCAE will occur one week after the start of treatment, and the Cycle 
4 Day 1 assessment will occur when the next Day 1 administration of treatment is planned). 
b 
On days when both the QLQ-C30 and QLQ-BR23 are administered, the QLQ-BR23 must be administered immediately after the QLQ-C30. 
c 
PRO-CTCAE items are completed three times (on Day 1, Day 8, and Day 15) for the indicated cycles. The patient should complete the PRO-
CTCAE assessments on Day 8 and Day 15 of Cycles 1, 2, and 3 at home using the online ePRO completion tool. If the patient does not have 
access to the online ePRO completion tool at home and cannot come to the study site to use the electronic device, the site can call the patient and 
collect the PRO-CTCAE assessments on Day 8 and Day 15 of Cycles 1, 2, and 3 by telephone. The telephone is not to be used to collect PRO 
data at any other timepoint.  
 


 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
160/Protocol MO42319, Version 4 
Appendix 4 Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) 
Selected sections from the Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1), (Eisenhauer et al. 2009) are presented below, with the addition of 
explanatory text as needed for clarity.1 
TUMOR MEASURABILITY 
At baseline, tumor lesions and lymph nodes will be categorized as measurable or 
non-measurable as described below.  All measurable and non-measurable lesions 
should be assessed at screening and at subsequent protocol-specified tumor 
assessment timepoints.  Additional assessments may be performed as clinically 
indicated for suspicion of progression. 
DEFINITION OF MEASURABLE LESIONS 
Tumor Lesions 
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size as follows:  
• 
10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval ≤ 5 mm) 
• 
10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable) 
• 
20 mm by chest X-ray 
 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable a lymph node must be 
≥ 15 mm in the short axis when assessed by CT scan (CT scan slice thickness 
recommended to be ≤ 5 mm).  At baseline and follow-up, only the short axis will be 
measured and followed.  Additional information on lymph node measurement is provided 
below (see "Identification of Target and Non-Target Lesions" and "Calculation of Sum of 
Diameters"). 
                                            
 
1 For clarity and for consistency within this document, the section numbers and cross-references 
to other sections within the article have been deleted and minor changes have been made. 


Appendix 4: RECIST Criteria (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
161/Protocol MO42319, Version 4 
DEFINITION OF NON-MEASURABLE LESIONS 
Non-measurable tumor lesions encompass small lesions (longest diameter < 10 mm or 
pathological lymph nodes with short axis ≥ 10 mm but < 15 mm) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lungs, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques. 
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
Bone Lesions: 
• 
Technetium-99m bone scans, positron emission tomography (PET) scans, and plain 
films are not considered adequate imaging techniques for measuring bone lesions.  
However, these techniques can be used to confirm the presence or disappearance 
of bone lesions. 
• 
Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue 
components that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered measurable lesions if the soft tissue component 
meets the definition of measurability described above. 
• 
Blastic bone lesions are non-measurable. 
 
Cystic Lesions: 
• 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
• 
Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 
Lesions with Prior Local Treatment: 
• 
Tumor lesions situated in a previously irradiated area or in an area subjected to 
other loco-regional therapy are usually not considered measurable unless there has 
been demonstrated progression in the lesion. 
 
METHODS FOR ASSESSING LESIONS 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and not usually more than 4 weeks prior to the beginning of the 
treatment. 


Appendix 4: RECIST Criteria (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
162/Protocol MO42319, Version 4 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option. 
CLINICAL LESIONS 
Clinical lesions will only be considered measurable when they are superficial and 
≥ 10 mm in diameter assessed using calipers (e.g., skin nodules).  For the case of skin 
lesions, documentation by color photography, including a ruler to estimate the size of the 
lesion, is suggested. 
CHEST X-RAY 
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint because CT is more sensitive than X-ray, particularly in identifying new lesions.  
However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
CT AND MRI SCANS 
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  In this guideline, the definition of measurability of lesions on 
CT scan is based on the assumption that CT slice thickness is ≤ 5 mm.  When CT scans 
have slice thickness of > 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable.  
If prior to enrollment it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a non-contrast CT or MRI (with or without MRI IV contrast) will be used to 
evaluate the patient at baseline and during the study should be guided by the tumor type 
under investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (with or without MRI IV contrast) will be performed 
should also be based on the tumor type and the anatomic location of the disease, and 
should be optimized to allow for comparison with the prior studies if possible.  Each case 
should be discussed with the radiologist to determine if substitution of these other 
approaches is possible and, if not, the patient should be considered not evaluable from 
that point forward.  Care must be taken in measurement of target lesions and 
interpretation of non-target disease or new lesions on a different modality because the 
same lesion may appear to have a different size using a new modality. 
ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOR MARKERS, 
CYTOLOGY, AND HISTOLOGY 
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be 
used for objective tumor evaluation. 


Appendix 4: RECIST Criteria (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
163/Protocol MO42319, Version 4 
ASSESSMENT OF TUMOR BURDEN 
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements. 
IDENTIFICATION OF TARGET AND NON-TARGET LESIONS 
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions (two 
sites), respectively, will be recorded.  Other lesions (albeit measurable) in those organs 
will be considered non-target lesions.   
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and should be representative of all involved organs, but in addition should lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be 
selected. 
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of ≥ 15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Lymph node size is 
normally reported as two dimensions in the plane in which the image is obtained (for CT, 
this is almost always the axial plane; for MRI, the plane of acquisition may be axial, 
sagittal, or coronal).  The smaller of these measures is the short axis.  For example, an 
abdominal node that is reported as being 20 × 30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node.  In this example, 20 mm should be recorded 
as the node measurement.  All other pathological nodes (those with short axis ≥ 10 mm 
but < 15 mm) should be considered non-target lesions.  Nodes that have a short axis of 
< 10 mm are considered non-pathological and should not be recorded or followed. 
All lesions (or sites of disease) not selected as target lesions (measurable or 
non-measurable), including pathological lymph nodes, should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements are not required.  It is 
possible to record multiple non-target lesions involving the same organ as a single item 
on the Case Report Form (CRF) (e.g., "multiple enlarged pelvic lymph nodes" or 
"multiple liver metastases"). 


Appendix 4: RECIST Criteria (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
164/Protocol MO42319, Version 4 
CALCULATION OF SUM OF DIAMETERS 
A sum of the diameters (longest diameter for non−lymph node lesions, short axis for 
lymph node lesions) will be calculated for all target lesions at baseline and at each 
subsequent tumor assessment as a measure of tumor burden. 
Measuring Lymph Nodes 
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the node regresses to < 10 mm during the study.  Thus, when 
lymph nodes are included as target lesions, the sum of diameters may not be zero even 
if complete response criteria are met, given that a normal lymph node is defined as 
having a short axis of < 10 mm. 
Measuring Lesions That Become Too Small to Measure 
During the study, all target lesions (lymph node and non−lymph node) recorded at 
baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm).  However, sometimes lesions or lymph 
nodes that are recorded as target lesions at baseline become so faint on CT scan that 
the radiologist may not feel comfortable assigning an exact measurement and may 
report them as being too small to measure.  When this occurs, it is important that a value 
be recorded on the CRF, as follows: 
• 
If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. 
• 
If the lesion is believed to be present and is faintly seen but is too small to measure, 
a default value of 5 mm should be assigned and "too small to measure" should be 
ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat 
such as in the retroperitoneum; however, if a lymph node is believed to be present 
and is faintly seen but is too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well and "too small to measure" should also be 
ticked). 
 
To reiterate, however, if the radiologist is able to provide an actual measurement, that 
should be recorded, even if it is < 5 mm, and in that case "too small to measure" should 
not be ticked. 
Measuring Lesions That Split or Coalesce During Treatment 
When non−lymph node lesions fragment, the longest diameters of the fragmented 
portions should be added together to calculate the sum of diameters.  Similarly, as 
lesions coalesce, a plane between them may be maintained that would aid in obtaining 
the maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximum longest diameter for the coalesced lesion. 


Appendix 4: RECIST Criteria (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
165/Protocol MO42319, Version 4 
EVALUATION OF NON-TARGET LESIONS 
Measurements are not required for non-target lesions, except that malignant lymph node 
non-target lesions should be monitored for reduction to < 10 mm in the short axis.  
Non-target lesions should be noted at baseline and should be identified as "present" or 
"absent" and (in rare cases) may be noted as "unequivocal progression" at subsequent 
evaluations.  In addition, if a lymph node lesion shrinks to a non-malignant size (short 
axis < 10 mm), this should be captured on the CRF as part of the assessment of non-
target lesions. 
RESPONSE CRITERIA 
CRITERIA FOR TARGET LESIONS 
Definitions of the following criteria used to determine objective tumor response for target 
lesions are provided: 
• 
Complete response (CR):  Disappearance of all target lesions 
Any pathological lymph nodes must have reduction in short axis to < 10 mm. 
• 
Partial response (PR):  At least a 30% decrease in the sum of diameters of all target 
lesions, taking as reference the baseline sum of diameters, in the absence of CR 
• 
Progressive disease (PD):  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum of diameters at prior timepoints 
(including baseline)  
In addition to the relative increase of 20%, the sum of diameters must also 
demonstrate an absolute increase of ≥ 5 mm. 
• 
Stable disease (SD):  Neither sufficient shrinkage to qualify for a CR or a PR nor 
sufficient increase to qualify for PD 
 
CRITERIA FOR NON-TARGET LESIONS 
Definitions of the criteria used to determine the tumor response for the group of non-
target lesions are provided below.  While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints specified in the schedule of activities. 
• 
CR:  Disappearance of all non-target lesions  
All lymph nodes must be non-pathological in size (< 10 mm short axis). 
• 
Non-CR/Non-PD:  Persistence of one or more non-target lesions 
• 
PD:  Unequivocal progression of existing non-target lesions 
 
SPECIAL NOTES ON ASSESSMENT OF PROGRESSION OF NON-TARGET 
LESIONS 
Patients with Measurable and Non-Measurable Disease 
For patients with both measurable and non-measurable disease to achieve unequivocal 
progression on the basis of the non-target lesions, there must be an overall level of 


Appendix 4: RECIST Criteria (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
166/Protocol MO42319, Version 4 
substantial worsening in non-target lesions in a magnitude that, even in the presence of 
SD or PR in target lesions, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest increase in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status.  The 
designation of overall progression solely on the basis of change in non-target lesions in 
the face of SD or PR in target lesions will therefore be extremely rare. 
NEW LESIONS 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some "new" bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient's baseline lesions show PR or 
CR.  For example, necrosis of a liver lesion may be reported on a CT scan report as a 
"new" cystic lesion, which it is not. 
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it truly represents new disease.  If repeat scans confirm 
there is definitely a new lesion, progression should be declared as of the date of the 
initial scan. 
CRITERIA FOR OVERALL RESPONSE AT A SINGLE TIMEPOINT 
Table 1 provides a summary of the overall response status calculation at each 
response assessment timepoint for patients. 
 
 


Appendix 4: RECIST Criteria (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
167/Protocol MO42319, Version 4 
Table 1 
Criteria for Overall Response at a Single Timepoint 
Target Lesions 
Non-Target Lesions 
New Lesions 
Timepoint 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD or NE 
No 
PR 
PR 
CR, non-CR/Non-PD, or NE 
No 
PR 
SD 
CR, non-CR/Non-PD, or NE 
No 
SD 
NE 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR 
NED b 
No 
CR 
PR 
NED b 
No 
PR 
SD 
NED b 
No 
SD 
NED a 
Non-CR/non-PD 
No 
Non-CR/non-PD 
NED a 
CR 
No 
CR 
NED a 
NE 
No 
NE 
NED a 
NED b 
No 
NED 
CR = complete response; NE = not evaluable; NE = not evaluable disease; 
PD = progressive disease; PR = partial response; SD = stable disease. 
a 
No target lesions identified at baseline  
b 
No non-target lesions identified at baseline. 
 
MISSING ASSESSMENTS AND NOT-EVALUABLE DESIGNATION 
When no imaging or measurement is performed at all at a particular timepoint, the 
patient is not evaluable at that timepoint.  If measurements are made on only a subset of 
target lesions at a timepoint, usually the case is also considered not evaluable at that 
timepoint, unless a convincing argument can be made that the contribution of the 
individual missing lesions would not change the assigned timepoint response.  This 
would be most likely to happen in the case of PD.  For example, if a patient had a 
baseline sum of 50 mm with three measured lesions and during the study only two 
lesions were assessed, but those gave a sum of 80 mm, the patient will have achieved 
PD status, regardless of the contribution of the missing lesion.  
SPECIAL NOTES ON RESPONSE ASSESSMENT 
Patients with a global deterioration in health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
"symptomatic deterioration."  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study treatment.  The 


Appendix 4: RECIST Criteria (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
168/Protocol MO42319, Version 4 
objective response status of such patients is to be determined by evaluation of target 
and non-target lesions as shown in Table 1 . 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
Fluorodeoxyglucose (FDG)-PET is not yet validated for use in clinical trials to determine 
response but may complement CT/MRI in the assessment of progression. 
FDG-PET imaging to identify new lesions is described in the following table. 
Baseline FDG-PET 
Post-Baseline FDG-PET  
Determination 
Negative FDG-PET 
Positive FDG-PET  
New lesion (PD) 
None 
Positive FDG-PET 
corresponds to a new site of 
disease confirmed by CT/MRI 
New lesion (PD) 
None 
Positive FDG-PET not 
confirmed as a new site of 
disease on CT/MRI 
Additional follow-up CT/MRI scans are 
needed to determine if there is truly 
progression occurring at that site. 
If so, new lesion (PD) with the date of 
PD being the date of the initial 
abnormal FDG-PET scan date 
If not, it is not a new lesion. 
None 
Positive FDG-PET that 
corresponds to a preexisting 
site of disease on CT/MRI that 
is not progressing on the basis 
of the anatomic images 
Not a new lesion 
CT = computed tomography; FDG = fluorodeoxyglucose; MRI = magnetic resonance imaging; 
PD = progressive disease; PET = positron emission tomography. 
Note:  A positive FDG-PET scan lesion indicates one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 
REFERENCES 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228−47. 
Schwartz LH., Litiére S, de Vries SE, et al. RECIST 1.1−update and clarification: from 
RECIST Committee. Eur J Cancer 2016; 62:132−7. 
   
 


 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
169/Protocol MO42319, Version 4 
Appendix 5 Ventana HER2 IHC Assay 
VENTANA anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody (VENTANA HER2 
(4B5) antibody) is intended for the semi-quantitative detection of HER2 antigen in 
sections of formalin-fixed, paraffin-embedded normal and neoplastic breast and gastric 
tissue on a BenchMark IHC/ISH instrument. 
This product is indicated as an aid in the assessment of breast and gastric cancer 
patients for whom Herceptin treatment is considered and for breast cancer patients for 
whom KADCYLA® (ado-trastuzumab emtansine) or PERJETA® (pertuzumab) 
treatments are being considered.  
This product should be interpreted by a qualified pathologist in conjunction with 
histological examination, relevant clinical information, and proper controls.  
This antibody is intended for in vitro diagnostic (IVD) use. 
DEVICE DESCRIPTION 
VENTANA HER2 (4B5) antibody is a rabbit monoclonal antibody, which binds to HER2 
in paraffin-embedded tissue sections. The specific antibody can be localized by either a 
biotin conjugated secondary antibody formulation that recognizes rabbit 
immunoglobulins followed by the addition of a streptavidin-horseradish peroxidase 
(HRP) conjugate (iVIEW DAB Detection Kit) or a secondary antibody-HRP conjugate 
(ultraView Universal DAB Detection Kit). The specific antibody-enzyme complex is then 
visualized with a precipitating enzyme reaction product. Each step is incubated for a 
precise time and temperature. At the end of each incubation step, the BenchMark 
IHC/ISH instrument washes the sections to stop the reaction and to remove unbound 
material that would hinder the desired reaction in subsequent steps. It also applies 
Liquid Coverslip, which minimizes evaporation of the aqueous reagents from the 
specimen slide. 
Clinical cases should be evaluated within the context of the performance of appropriate 
controls. Ventana recommends the inclusion of a positive tissue control fixed and 
processed in the same manner as the patient specimen (for example, a weakly positive 
breast or gastric carcinoma). In addition to staining with VENTANA HER2 (4B5) 
antibody, a second slide should be stained with CONFIRM Negative Control Rabbit Ig. 
For the test to be considered valid, the positive control tissue should exhibit membrane 
staining of the tumor cells. These components should be negative when stained with 
CONFIRM Negative Control Rabbit Ig. In addition, it is recommended that a negative 
tissue control slide (for example, a HER2 negative breast or gastric carcinoma) be 
included for every batch of samples processed and run on the BenchMark IHC/ISH 
instrument. This negative tissue control should be stained with VENTANA HER2 (4B5) 
antibody to ensure that the antigen enhancement and other pretreatment procedures did 
not create false positive staining. 


Appendix 5: Ventana HER2 IHC Assay (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
170/Protocol MO42319, Version 4 
Details of the staining protocol and scoring criteria can be found in instruction for use 
and interpretation guide published by Ventana Medical Systems Inc. 
(https://dialog.roche.com)


 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
171/Protocol MO42319, Version 4 
Appendix 6 Ventana HER2 Dual ISH DNA Probe Cocktail 
The VENTANA HER2 Dual ISH DNA Probe Cocktail is intended to determine HER2 
gene status by enumeration of the ratio of the HER2 gene to Chromosome 17 by light 
microscopy. The HER2 and Chromosome 17 probes are detected using two-color 
chromogenic in situ hybridization (ISH) in formalin-fixed, paraffin embedded human 
breast carcinoma tissue specimens, following staining on the Benchmark ULTRA 
instruments. 
The VENTANA HER2 Dual ISH DNA Probe Cocktail is indicated as an aid in the 
assessment of patients for whom HER2-directed therapy is being considered. This 
product should be interpreted by a qualified pathologist in conjunction with histological 
examination, relevant clinical information, and proper controls. 
CAUTION:  Investigational device. Limited by Federal (or United States) law to 
investigational use. 
DEVICE DESCRIPTION 
The VENTANA HER2 Dual ISH DNA Probe Cocktail is optimally formulated for use with 
VENTANA Silver ISH DNP Detection Kit, VENTANA Red ISH DIG Detection Kit, and 
accessory reagents on a BenchMark IHC/ISH instrument.  
The detection kit contains a primary antibody and an enzyme-labeled secondary 
antibody conjugated to horseradish peroxidase (HRP) or alkaline phosphatase (ALP) 
which is used as the chromogenic enzyme. During the Dual in situ hybridization (Dual 
ISH) staining process, DNP and DIG labeled probes are co-hybridized to their respective 
specific target DNA sequences within the cell nuclei. Detection of the DNP-labeled 
HER2 probe occurs first, using the VENTANA Silver ISH (SISH) DNP Detection Kit, 
which contains the following dispensers: mouse anti-DNP primary antibody labeled with 
hydroxyquinoxaline (HQ), mouse anti-HQ secondary antibody conjugated to horseradish 
peroxidase (HRP), Chromogen A (Silver A), Chromogen B (Silver B) and Chromogen C 
(Silver C). Following incubation with the HQ-labeled mouse anti-DNP primary antibody 
and then mouse anti HQ HRP secondary antibody conjugate, the SISH reaction occurs. 
Briefly described, this reaction is driven by the sequential addition of Chromogens A 
(silver acetate), B (hydroquinone) and C (H2O2). Here, the silver ions (Ag+) are reduced 
by hydroquinone to metallic silver atoms (Ag0). This reaction is fueled by the substrate 
for HRP, hydrogen peroxide (Chromogen C). The silver precipitate is deposited in the 
nuclei and a single copy of the HER2 gene is visualized as a black dot. 
Following SISH detection for HER2, the DIG-labeled Chromosome 17 probe is detected 
with the ultraView Red ISH DIG Detection Kit. This kit includes the following dispensers: 
a mouse anti-DIG monoclonal antibody, Red ISH Multimer solution which contains a 
goat anti-mouse IgG antibody conjugated to ALP, pH Enhancer, Naphthol, and Fast 
Red.  Following development of the SISH signal, the slide is incubated with the mouse 


Appendix 6: Ventana HER2 Dual ISH DNA Probe Cocktail (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
172/Protocol MO42319, Version 4 
anti-DIG antibody, which binds to the DIG hapten on the Chromosome 17 probe. The 
anti-hapten primary antibody is detected with the Multimer solution (goat anti-mouse IgG 
conjugated to ALP enzyme).  The slide is incubated with the pH Enhancer solution which 
provides the proper salt components/concentrations and buffered pH for optimal ALP 
enzyme performance.  Next, naphthol phosphate is applied, which serves as the 
substrate for the ALP enzyme (ALP dephosphorylates naphthol).  Fast Red, added to 
the slide next, combines with the dephosphorylated naphthol to form a red precipitate, 
which is readily visualized by light microscopy.  The specimen is then counterstained 
with Hematoxylin II for interpretation by light microscopy. 
The staining protocol consists of numerous steps in which reagents are incubated for 
pre-determined times at specific temperatures.  At the end of each incubation step, the 
BenchMark ULTRA instrument washes the sections to remove unbound material and 
applies a liquid coverslip which minimizes the evaporation of the aqueous reagents from 
the slide.  Results are interpreted using a light microscope.  
Details of the staining protocol and scoring criteria can be found in the investigational 
instructions for use included with the associated diagnostic study protocol. 
BENEFIT-RISK ASSESSMENT 
The CE-marked VENTANA HER2 Dual ISH DNA Probe Cocktail is indicated as an aid in 
the assessment of patients for whom Herceptin (trastuzumab) is being considered but is 
investigational as an aid in the assessment of patients for whom HER2-directed therapy 
is being considered, including trastuzumab emtansine. 
As with any diagnostic test, there is possibility for an incorrect test result when 
determining the HER2 expression level for a patient tumor specimen.  The potential 
impact to patients associated with false test results must be considered both in light of 
the safety profile of the investigational therapeutic product and the potential for clinical 
benefit from therapeutic product exposure.   
The consequence of a false HER2 negative status result is that a patient would be 
erroneously excluded from enrolling into the study and would not receive the potential 
clinical benefit imparted by investigational HER2-targeted and PD-L1-targeted therapy. 
The consequence of a false HER2 positive status result is that a patient may be 
erroneously enrolled into the treatment phase of the study.  In this case, the patient may 
be subjected to the potential side effects of the investigational therapy combination of 
trastuzumab emtansine plus atezolizumab/placebo and may not experience any 
additional clinical benefit beyond what they would have experienced with standard of 
care.   
The analytical performance of VENTANA HER2 Dual ISH DNA Probe Cocktail has been 
validated for its intended use within the context of this clinical study.  Analytical 


Appendix 6: Ventana HER2 Dual ISH DNA Probe Cocktail (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
173/Protocol MO42319, Version 4 
performance testing included sensitivity, robustness, repeatability and reproducibility in 
staining HER2 DNA target sequences in breast carcinoma tissue, as well as reader 
precision using the scoring algorithms.  The results of the analytical performance testing 
demonstrated that the assay robustly and specifically stains the HER2 targets in breast 
carcinoma tissue and that trained pathologists can assess and score HER2 expression 
with precision according to the scoring algorithms. 
The VENTANA HER2 Dual ISH DNA Probe Cocktail utilizes the presence of normal 
HER2 and Chromosome 17 signals (1 to 2 copies per cell) as an internal positive control 
to minimize potential of a false result.  
Note the following factors that mitigate the risk of a false positive HER2 ISH result in 
Study MO42319:  
All patient samples will be tested for HER2 expression by both the investigational 
VENTANA HER2 Dual ISH DNA Probe Cocktail and the VENTANA anti-HER2/neu 
(4B5) Rabbit Monoclonal Primary Antibody IHC assay, which is CE marked for the 
identification of breast carcinoma patients for treatment with trastuzumab emtansine.  
VENTANA HER2 Dual ISH DNA Probe Cocktail is CE marked to identify patients for 
treatment with trastuzumab, which has a similar binding affinity with trastuzumab 
emtansine for HER2.  
Furthermore, all enrolled patients will be closely monitored for adverse events and 
evidence of disease progression.  
Risks have been analyzed per ISO14971.  All possible residual risks associated with the 
identified hazards and harms to the operator/patients have been reduced as far as 
possible by the controls implemented during the design and development of the product. 
The benefit-risk ratio of the companion diagnostic investigational product is expected to 
be acceptable in this study.


 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
174/Protocol MO42319, Version 4 
Appendix 7 Ventana PD-L1 (SP142) Assay 
VENTANA anti-PD-L1 (SP142) Rabbit Monoclonal Primary Antibody is intended for the 
qualitative immunohistochemical assessment of the programmed death ligand 1 (PD-L1) 
protein in formalin-fixed, paraffin-embedded (FFPE) breast carcinoma (BC) tissue 
stained with a BenchMark ULTRA instrument.  It is indicated as an aid in identifying 
patients eligible for treatment with therapy targeting the interaction of PD-1 and PD-L1. 
The clinical interpretation of any staining, or the absence of staining, must be 
complemented by histological studies and evaluation of proper controls.  Evaluation 
must be made by a qualified pathologist within the context of the patient’s clinical history 
and other diagnostic tests. 
CAUTION: Investigational device. Limited by Federal (or United States) law to 
investigational use.  
DEVICE DESCRIPTION 
VENTANA anti-PD-L1 (SP142) Rabbit Monoclonal Primary Antibody assay (VENTANA 
PD-L1 (SP142) assay) utilizes VENTANA anti-PD-L1 (SP142) Rabbit Monoclonal 
Primary Antibody (VENTANA PD-L1 (SP142) antibody) to recognize the PD-L1 protein.  
This assay is being developed as a companion diagnostic for identifying patients with 
breast carcinoma eligible for treatment with therapy targeting the interaction of PD-1 and 
PD-L1. 
Details of the staining protocol and scoring criteria can be found in the investigational 
instructions for use included with the associated diagnostic study protocol. 
VENTANA PD-L1 (SP142) assay utilizes a rabbit monoclonal primary antibody which 
binds to PD-L1 in paraffin-embedded tissue sections.  The specific antibody can be 
localized using OptiView DAB IHC Detection Kit (Cat. No. 760-700 / 06396500001) 
followed by OptiView Amplification Kit (Cat. No. 760-099 / 06396518001 (50 test) or 860-
099 / 06718663001 (250 test)).  Refer to the appropriate OptiView DAB IHC Detection 
Kit and OptiView Amplification Kit package inserts for further information 
(https://diagnostics.roche.com). 
BENEFIT-RISK ASSESSMENT 
The CE-marked VENTANA PD-L1 (SP142) Assay is indicated as an aid for identifying 
patients for treatment with TECENTRIQ (atezolizumab) in indications such as Triple-
Negative Breast Carcinoma (TNBC) but is considered investigational for HER2- positive 
breast cancer. 
As with any diagnostic test, there is possibility for an incorrect test result when 
determining the PD-L1 expression level for a patient tumor specimen.  The potential 
impact to patients associated with false test results must be considered both in light of 


Appendix 7: Ventana PD-L1 (SP142) Assay (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
175/Protocol MO42319, Version 4 
the safety profile of the investigational therapeutic product and the potential for clinical 
benefit from therapeutic product exposure.   
The consequence of a false PD-L1 negative status result is that a patient would be 
erroneously excluded from enrolling into the study and would not receive the potential 
clinical benefit imparted by investigational HER2-targeted and PD-L1-targeted therapy.  
The consequence of a false PD-L1 positive status result is that a patient may be 
erroneously enrolled into the treatment phase of the study.  In this case, the patient may 
be subjected to the potential side effects of the investigational therapy combination of 
trastuzumab emtansine plus atezolizumab/placebo and may not experience any 
additional clinical benefit beyond what they would have experienced with standard of 
care.   
The analytical performance of the PD-L1 (SP142) Assay has been validated for its 
intended use within the context of this clinical study.  Analytical performance testing 
included sensitivity, robustness, repeatability and reproducibility in staining PD-L1 
protein in breast carcinoma tissue, as well as reader precision using the scoring 
algorithms.  The results of the analytical performance testing demonstrated that the 
assays robustly and specifically stain the PD-L1 targets in breast carcinoma tissue and 
that trained pathologists can assess and score PD-L1 expression with precision 
according to the scoring algorithms.   
The PD-L1 (SP142) Assay requires the use of proper staining run controls, including a 
system level control for each run and a negative reagent control for each tissue 
specimen, to minimize possibility of a false result. 
Furthermore, all enrolled patients will be closely monitored for adverse events and 
evidence of disease progression.  
Risks have been analyzed per ISO14971.  All possible residual risks associated with the 
identified hazards and harms to the operator/patients have been reduced as far as 
possible by the controls implemented during the design and development of the product. 
The benefit-risk ratio of the companion diagnostic investigational product is expected to 
be acceptable in this study. 
 


 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
176/Protocol MO42319, Version 4 
Appendix 8 New York Heart Association Classification 
 
Class 
Description 
I 
Patients with cardiac disease but without resulting limitations of physical activity.  
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or 
anginal pain. 
II 
Patients with cardiac disease resulting in slight limitation of physical activity.  
They are comfortable at rest.  Ordinary physical activity results in fatigue, 
palpitation, dyspnea, or anginal pain. 
III 
Patients with cardiac disease resulting in marked limitation of physical activity.  
They are comfortable at rest.  Less than ordinary physical activity causes fatigue, 
palpitation, dyspnea, or anginal pain. 
IV 
Patients with cardiac disease resulting in inability to carry on physical activity 
without discomfort.  Symptoms of cardiac insufficiency or of the anginal 
syndrome may be present event at rest.  If any physical activity is undertaken, 
discomfort is increased. 
Note: Excerpted from Oxford Textbook of Medicine. Vol 2, p. 2228. Oxford Press 1997. 


 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
177/Protocol MO42319, Version 4 
Appendix 9 ECOG Performance Status Scale 
 
Grade 
Description 
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 
housework or office work 
2 
Ambulatory and capable of all self-care but unable to carry 
out any work activities. Up and about > 50% of waking hours 
3 
Capable of only limited self-care, confined to a bed or 
chair > 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair 
5 
Dead 
  
 
















 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
185/Protocol MO42319, Version 4 
Appendix 13  
National Cancer Institute Patient Reported 
Outcomes Common Terminology Criteria for Adverse Events 
(PRO-CTCAE) instrument 
 
NCI PRO-CTCAE ™ ITEMS 
Item Library Version 1.0 
English 
Form Created on 25 June 2020 
As individuals go through treatment for their cancer they sometimes experience different 
symptoms and side effects. For each question, please select the one response that best 
describes your experiences over the past 7 days… 
 
1a.  In the last 7 days, what was the SEVERITY of your COUGH at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
1b.  In the last 7 days, how much did COUGH INTERFERE with your usual or daily 
activities? 
Ο Not at all 
Ο A little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 
 
2a.  In the last 7 days, did you have any RASH? 
Ο Yes 
Ο No 
 
3a.  In the last 7 days, what was the SEVERITY of your NUMBNESS OR TINGLING 
IN YOUR HANDS OR FEET at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
3b.  In the last 7 days, how much did NUMBNESS OR TINGLING IN YOUR HANDS 
OR FEET INTERFERE with your usual or daily activities? 
Ο Not at all 
Ο A little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 
 
4a.  In the last 7 days, how OFTEN did you have PAIN? 
Ο Never 
Ο Rarely 
Ο Occasionally 
Ο Frequently 
Ο Almost 
constantly 
4b.  In the last 7 days, what was the SEVERITY of your PAIN at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
4c.  In the last 7 days, how much did PAIN INTEREFERE with your usual or daily 
activities? 
Ο Not at all 
Ο A little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 
 


Appendix 13 
National Cancer Institute (PRO-CTCAE) instrument (cont.) 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
186/Protocol MO42319, Version 4 
5a.  In the last 7 days, how OFTEN did you have a HEADACHE? 
Ο Never 
Ο Rarely 
Ο Occasionally 
Ο Frequently 
Ο Almost 
constantly 
5b.  In the last 7 days, what was the SEVERITY of your HEADACHE at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
5c.  In the last 7 days, how much did your HEADACHE INTERFERE with your usual 
or daily activities? 
Ο Not at all 
Ο A little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 
 
6a.  In the last 7 days, how OFTEN did you have ACHING MUSCLES? 
Ο Never 
Ο Rarely 
Ο Occasionally 
Ο Frequently 
Ο Almost 
constantly 
6b.  In the last 7 days, what was the SEVERITY of your ACHING MUSCLES at their 
WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
6c.  In the last 7 days, how much did ACHING MUSCLES INTEREFERE with your 
usual or daily activities? 
Ο Not at all 
Ο A little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 
 
7a.  In the last 7 days, how OFTEN did you have ACHING JOINTS (SUCH AS 
ELBOWS, KNEES, SHOULDERS)? 
Ο Never 
Ο Rarely 
Ο Occasionally 
Ο Frequently 
Ο Almost 
constantly 
7b.  In the last 7 days, what was the SEVERITY of your ACHING JOINTS (SUCH AS 
ELBOWS, KNEES, SHOULDERS) at their WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
7c.  In the last 7 days, how much did ACHING JOINTS (SUCH AS ELBOWS, KNEES, 
SHOULDERS) INTEREFERE with your usual or daily activities? 
Ο Not at all 
Ο A little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 
 
8a.  In the last 7 days, what was the SEVERITY of your FATIGUE, TIREDNESS, OR 
LACK OF ENERGY at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
8b.  In the last 7 days, how much did FATIGUE, TIREDNESS, OR LACK OF 
ENERGY INTERFERE with your usual or daily activities? 
Ο Not at all 
Ο A little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 
 


Appendix 13 
National Cancer Institute (PRO-CTCAE) instrument (cont.) 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
187/Protocol MO42319, Version 4 
9a.  In the last 7 days, how OFTEN did you have SHIVERING OR SHAKING 
CHILLS? 
Ο Never 
Ο Rarely 
Ο Occasionally 
Ο Frequently 
Ο Almost 
constantly 
9b.  In the last 7 days, what was the SEVERITY of your SHIVERING OR SHAKING 
CHILLS at their WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
 
OTHER SYMPTOMS 
Do you have any other symptoms that you wish to report? 
Ο Yes 
Ο No 
Please list any other symptoms: 
1. 
In the last 7 days, what was the SEVERITY of this symptom at its 
WORST? 
O None 
O Mild 
O Moderate 
O Severe 
O Very Severe 
2. 
In the last 7 days, what was the SEVERITY of this symptom at its 
WORST? 
O None 
O Mild 
O Moderate 
O Severe 
O Very Severe 
3. 
In the last 7 days, what was the SEVERITY of this symptom at its 
WORST? 
O None 
O Mild 
O Moderate 
O Severe 
O Very Severe 
4. 
In the last 7 days, what was the SEVERITY of this symptom at its 
WORST? 
O None 
O Mild 
O Moderate 
O Severe 
O Very Severe 
5. 
In the last 7 days, what was the SEVERITY of this symptom at its 
WORST? 
O None 
O Mild 
O Moderate 
O Severe 
O Very Severe 
 




 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
189/Protocol MO42319, Version 4 
Appendix 15  
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. 
 
 


Appendix 15 
Preexisting Autoimmune Diseases and Immune Deficiencies (cont.) 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
190/Protocol MO42319, Version 4 
Autoimmune Diseases and Immune Deficiencies 
• Acute disseminated 
encephalomyelitis 
• Addison disease 
• Ankylosing spondylitis 
• Anti-phospholipid 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 


 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
191/Protocol MO42319, Version 4 
Appendix 16  
Guidelines for Liver Biopsy 
Because nodular regenerative hyperplasia (NRH) can be a very subtle diagnosis to 
make on liver biopsy, every attempt should be made to maximize the amount of tissue 
obtained. 
A minimum size of an 18-gauge needle and percutaneous biopsies of at least 1.5 cm in 
length are recommended if clinically appropriate. In order to diagnose NRH, reticulin and 
trichrome stains are necessary. 
Smaller biopsies obtained via a transjugular approach as well as smaller biopsy gun 
needle biopsies are discouraged. Small wedge biopsies should also be discouraged. 


 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
192/Protocol MO42319, Version 4 
Appendix 17  
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 administration in a clinical setting: 
• 
Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer 
• 
Oxygen 
• 
Epinephrine for intramuscular (preferred route), subcutaneous, intravenous, 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 administration, 
the following procedures should be performed: 
1. 
Stop the study treatment administration. 
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. 
 


 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
193/Protocol MO42319, Version 4 
Appendix 18  
Guidelines for Management of Adverse Events 
Associated with Trastuzumab Emtansine 
Suggested workup and management guidelines for overlapping toxicities between 
atezolizumab and trastuzumab emtansine (i.e., suspected hepatotoxicity and 
pneumonitis) are provided in Appendix 20. 
CARDIOTOXICITY 
Patients without significant cardiac history and with a baseline LVEF of ≥ 50% as 
determined by ECHO or MUGA scan are eligible for study participation.  Cardiac 
monitoring (ECHO/MUGA) will be performed in all patients enrolled in the Study. 
Assessments will occur during the screening period, and on Day 15–21 of Cycle 1, and 
every fourth cycle thereafter.  ECHO or MUGA will be performed following study 
treatment discontinuation only if the most recent follow-up ECHO/MUGA was performed 
≥ 28 days after last study treatment administration or if no post-treatment evaluation was 
performed (Appendix 1). 
Figure 1 summarizes the management of trastuzumab emtansine on the basis of LVEF 
measurements and changes in LVEF from baseline in patients.  If an investigator is 
concerned that an adverse event may be related to cardiac dysfunction, an additional 
LVEF measurement may be performed.  Trastuzumab emtansine will be discontinued in 
any patient who develops symptomatic CHF.  CHF should be treated and monitored 
according to standard medical practice. 
The decision to stop or continue trastuzumab emtansine treatment should be on the 
basis of the algorithm shown in Figure 1 or asymptomatic declines in LVEF.  
Trastuzumab emtansine must be discontinued in all patients for whom a confirmed 
decrease of LVEF to < 40% is documented (with a confirmation assessment carried out 
within 21 days).  For patients whose LVEF decreases to values of 40%−45% with an 
absolute decrease in LVEF of ≥ 10% points from baseline, trastuzumab emtansine dose 
should be held.  For these patients, the LVEF measurement should be repeated within 
21 days, and trastuzumab emtansine treatment should be discontinued if the LVEF has 
not recovered to within a 10% absolute difference below baseline.  If clinically significant 
cardiac dysfunction or cardiac failure develops or persists or if significant medical 
management is required to maintain LVEF, the patient should be discontinued from all 
study treatment. 




Appendix 18:Guidelines for Management of Adverse Events Associated with 
Trastuzumab Emtansine (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
195/Protocol MO42319, Version 4 
INFUSION-RELATED REACTIONS AND HYPERSENSITIVITY REACTIONS 
See Table 1 for management guidelines for trastuzumab emtansine−associated 
infusion-related reactions and hypersensitivity reactions. 
Table 1 
Management Guidelines for Trastuzumab Emtansine 
Infusion-Related Reactions (Caused by Cytokine Release) or 
Hypersensitivity (Allergic) Reaction 
Event 
Action to Be Taken  
Grade 2 
reaction  
Decrease trastuzumab emtansine infusion rate or interrupt infusion.  Administer 
supportive care with oxygen, β-agonists, antihistamines, antipyretics, 
or corticosteroids, as clinically indicated.  Monitor patient until complete resolution of 
symptoms. When symptoms have completely resolved, infusion may be restarted at 
no more than 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.  
May continue trastuzumab emtansine at the same dose level at the investigator’s 
discretion.   In the event of a true hypersensitivity reaction (in which severity of 
reaction increases with subsequent infusions), discontinue trastuzumab emtansine. 
Premedication for infusion reactions (e.g., antihistamines such as diphenhydramine 
or corticosteroids) may be given as clinically indicated. 
Grade 3 
reaction  
Stop trastuzumab emtansine infusion.  Administer supportive care with oxygen, 
β−agonists, antihistamines, antipyretics, or corticosteroids, as clinically indicated.  
Monitor patient until complete resolution of symptoms.   
May continue trastuzumab emtansine at the same dose level at the investigator’s 
discretion.  In the event of a true hypersensitivity reaction (in which severity of 
reaction increases with subsequent infusions), discontinue trastuzumab 
emtansine.   
Premedication for infusion reactions (e.g., antihistamines such as diphenhydramine 
or corticosteroids) may be given as clinically indicated.  
Grade 4 
reaction 
Stop trastuzumab emtansine infusion.  Administer supportive care with oxygen, 
β-agonists, antihistamines, antipyretics, or corticosteroids, as appropriate, as 
clinically indicated.  Monitor patient until complete resolution of symptoms. 
Discontinue trastuzumab emtansine. 
 
 
 


Appendix 18:Guidelines for Management of Adverse Events Associated with 
Trastuzumab Emtansine (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
196/Protocol MO42319, Version 4 
HEMATOLOGIC TOXICITIES 
See Table 2 for trastuzumab emtansine dose modification guidelines for hematological 
toxicities, including thrombocytopenia. 
Table 2 
Trastuzumab Emtansine Dose Modification Guidelines for 
Hematological Toxicity 
Event 
Action to Be Taken 
Grade 2 thrombocytopenia 
(50,000 to 75,0000/µL) 
Assess platelet counts weekly or as medically indicated until 
recovery.  Withhold study treatment until Grade ≤ 1.  Resume 
treatment without dose reduction.   
Grade 3 thrombocytopenia 
(25,000 to < 50,000/µL) 
Withhold trastuzumab emtansine until recovery to Grade ≤ 1 
(≥ 75,000/µL).  Following recovery, resume trastuzumab 
emtansine at the same dose level.  Discontinue trastuzumab 
emtansine if the event has not resolved to Grade ≤ 1 within 
42 days after the last dose received. 
Grade 4 thrombocytopenia 
(< 25,000/µL) at any time 
Withhold trastuzumab emtansine until recovery to Grade ≤ 1 
(≥ 75,000/µL).  Following recovery, resume trastuzumab 
emtansine with one dose level reduction.  Discontinue 
trastuzumab emtansine if the event has not resolved to 
Grade ≤ 1 within 42 days after the last dose received. 
Grade ≥ 3 hematologic toxicity 
other than thrombocytopenia 
Withhold trastuzumab emtansine until recovery to Grade ≤ 2.  
Following recovery, resume trastuzumab emtansine at the 
same dose level.  Discontinue trastuzumab emtansine if the 
event has not resolved to Grade ≤ 2 within 42 days after the 
last dose received. 
 
NEUROPATHY 
See Table 3 for trastuzumab emtansine dose modification guidelines for 
neuropathy. 
Table 3 
Trastuzumab Emtansine Dose Modification Guidelines for 
Neuropathy 
Event 
Action to Be Taken 
Grade ≥ 3 peripheral 
neuropathy 
Withhold trastuzumab emtansine until recovery to Grade ≤ 2.  
Following recovery, resume trastuzumab emtansine at the 
same dose level or with one dose level reduction, at the 
investigator's discretion.  Discontinue trastuzumab emtansine 
if the event has not resolved to Grade ≤ 2 within 42 days after 
the last dose received. 
 


 
Tr a st u z u m a b E mt a n si n e  a n d At e z oli z u m a b — F.  H off m a n n -L a R o c h e Lt d  
1 9 7 /Pr ot o c ol M O 4 2 3 1 9, V er si o n 4 
A p p e n di x  1 9   
Ri s k s A s s o ci at e d wit h At e z oli z u m a b  a n d 
G ui d eli n e s f or M a n a g e m e nt of A d v er s e E v e nt s  A s s o ci at e d wit h 
At e z oli z u m a b   
T o xi citi e s a s s o ci at e d or p o s si bl y a s s o ci at e d wit h at e z oli z u m a b tr e at m e nt s h o ul d b e 
m a n a g e d a c c or di n g t o st a n d ar d m e di c al pr a cti c e.  A d diti o n al t e st s, s u c h a s a ut oi m m u n e 
s er ol o g y or bi o p si e s, s h o ul d b e u s e d t o e v al u at e f or a p o s si bl e i m m u n o g e ni c eti ol o g y , 
w h e n cli ni c all y i n di c at e d . 
Alt h o u g h m o st i m m u n e-m e di at e d  a d v er s e e v e nt s o b s er v e d wit h at e z oli z u m a b  h a v e 
b e e n mil d a n d s elf -li miti n g, s u c h e v e nt s s h o ul d b e r e c o g ni z e d e arl y a n d tr e at e d pr o m ptl y 
t o a v oi d p ot e nti al m aj or c o m pli c ati o n s.  Di s c o nti n u ati o n of at e z oli z u m a b m a y n ot h a v e 
a n i m m e di at e t h er a p e uti c eff e ct, a n d i n s e v e r e c a s e s, i m m u n e-m e di at e d  t o xi citi e s m a y 
r e q uir e a c ut e m a n a g e m e nt wit h t o pi c al c orti c o st er oi d s, s y st e mi c c orti c o st er oi d s, or ot h er 
i m m u n o s u p pr e s si v e a g e nt s.  
T he f oll o wi n g are ge ner al re c o m me n d ati o ns f or m a n a ge me nt of a n y ot her a d verse e ve nts 
t h at m a y o cc ur a n d are n ot s pe cifi c all y liste d i n t he f oll o wi n g s u bse cti o ns.  
•  
P atie nts a n d f a mil y c are gi vers s h o ul d re cei ve ti mel y a n d u p -t o-d ate i nf or m ati o n 
a b o ut i m m u n ot her a pies, t heir me c h a nis m of a cti o n, a n d t he cli ni c al pr ofile of 
p ossi ble i m m u ne -rel ate d a d verse e ve nts pri or t o i niti ati n g t her a p y a n d t hr o u g h o ut 
tre at me nt a n d s ur vi v al f oll o w-u p.  T here s h o ul d be a hi g h le vel of s us pi ci o n t h at 
ne w s y m pt o ms are tre at me nt rel ate d.  
•  
I n ge ner al, ate z oli z u m a b t her a p y s h o ul d be c o nti n ue d wit h cl ose m o nit ori n g f or 
Gr a de 1 t o xi cities, wit h t he e xce pti o n of s o me ne ur ol o gi c t o xi cities.  
•  
C o nsi der h ol di n g ate z oli z u m a b f or m ost Gr a de 2 t o xi cities a n d res u me w he n 
s y m pt o ms a n d/ or l a b or at or y v al ues res ol ve t o Gr a de 1 or better.  C orti c oster oi ds 
(i niti al d ose of 0. 51 m g/ k g/ d a y of pre d n is o ne or e q ui v ale nt) m a y be a d mi nistere d. 
•  
F or Gr a de 2 re c urre nt or persiste nt (l asti n g f or m ore t h a n 5 d a ys) e ve nts, tre at as a 
Gr a de 3 e ve nt.   
•  
H ol d ate z oli z u m a b f or Gr a de 3 t o xi cities a n d i niti ate tre at me nt wit h hi g h -d ose 
c orti c oster oi ds ( 1 2 m g/ k g/ d a y p re d nis o ne or e q ui v ale nt).  C orti c oster oi ds s h o ul d 
be t a pere d o ver 1 m o nt h t o 1 0 m g/ d a y or al pre d nis o ne or e q ui v ale nt, bef ore 
ate z oli z u m a b c a n be res u me d.  If s y m pt o ms d o n ot i m pr o ve wit hi n 4 8 t o 7 2 h o urs 
of hi g h -d ose c orti c oster oi d use, ot her i m m u n os u p press a nts m a y be offere d f or s o me 
t o xi cities. 
•  
I n ge ner al, Gr a de 4 t o xi cities w arr a nt per m a ne nt dis c o nti n u ati o n of ate z oli z u m a b 
tre at me nt, wit h t he e xce pti o n of e n d o cri n o p at hies t h at are c o ntr olle d b y 
h or m o ne -re pl a ce me nt t her a p y.  
T h e i n v e sti g at or s h o ul d c o n si d er t h e b e n efit −ri s k b al a n c e f or a gi v e n p ati e nt pri or 
t o f urt h er a d mi ni str ati o n of at e z oli z u m a b.  R e s u m pti o n of at e z oli z u m a b m a y b e 
c o n si d er e d i n p atie nts w h o are d eri vi n g b e n efit a n d h a ve f ull y r e c o v er e d fr o m t h e 
i m m u n e-m e di at e d  e v e nt.  T h e d e ci si o n t o r e -c h all e n g e p ati e nt s wit h at e z oli z u m a b 


Appendix 19:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
198/Protocol MO42319, Version 4 
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. 
Guidelines for managing patients who experience selected adverse events are provided 
in the following sections.   
PULMONARY EVENTS 
Pulmonary events may present as new or worsening cough, chest pain, fever, dyspnea, 
fatigue, hypoxia, pneumonitis, and pulmonary infiltrates.  Patients will be assessed for 
pulmonary signs and symptoms throughout the study and will have CT scans of the 
chest performed at every tumor assessment.   
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension.  COVID-19 evaluation should be performed per institutional guidelines 
where relevant.  Management guidelines for pulmonary events are provided in 
Appendix 20. 
HEPATIC EVENTS 
Patients eligible for study treatment must have adequate liver function, as manifested by 
measurements of total bilirubin and hepatic transaminases; liver function will be 
monitored throughout study treatment.  Management guidelines for hepatic events are 
provided in Appendix 20. 
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. 
GASTROINTESTINAL EVENTS 
Management guidelines for diarrhea or colitis are provided in Table 1. 
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies.  For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute-phase reactants (e.g., increased C-reactive protein, 
platelet count, or bandemia):  Perform sigmoidoscopy (or colonoscopy, if appropriate) 
with colonic biopsy, with three to five specimens for standard paraffin block to check for 
inflammation and lymphocytic infiltrates to confirm colitis diagnosis.  


Appendix 19:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
199/Protocol MO42319, Version 4 
Table 1 
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) 
Event 
Management 
Diarrhea or 
colitis, Grade 1 
• Continue atezolizumab. 
• Initiate symptomatic treatment. 
• Endoscopy is recommended if symptoms persist for > 7 days. 
• Monitor closely. 
Diarrhea or 
colitis, Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Initiate symptomatic treatment. 
• Patient referral to GI specialist is recommended. 
• For recurrent events or events that persist > 5 days, initiate treatment 
with corticosteroids equivalent to 1−2 mg/kg/day oral prednisone.  
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c 
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 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 event does not improve within 
48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent.  
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c 
 
 
 
 


Appendix 19:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
200/Protocol MO42319, Version 4 
Table 1 
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) (cont.) 
 
Event 
Management 
Diarrhea or 
colitis, Grade 4 
• Permanently discontinue atezolizumab and contact Medical Monitor. c 
• Refer patient to GI specialist for evaluation and confirmatory biopsy. 
• Initiate 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 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 the equivalent of 
≤ 10 mg/day oral prednisone.   The acceptable length of the extended period of time must 
be based on an assessment of benefit–risk 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 investigator’s assessment of benefit–risk 
and documented by the investigator (or an appropriate delegate).  The Medical Monitor is 
available to advise as needed.  
 
ENDOCRINE EVENTS 
Management guidelines for endocrine events are provided in Table 2. 
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.  Patients 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 
MRI of the brain (with detailed pituitary sections) may help to differentiate primary 
pituitary insufficiency from primary adrenal insufficiency. 
 
 


Appendix 19:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
201/Protocol MO42319, Version 4 
Table 2 
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. 
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 lifethreatening 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. 
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. 
 
 
 


Appendix 19:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
202/Protocol MO42319, Version 4 
Table 2 
Management Guidelines for Endocrine Events (cont.) 
Event 
Management 
Grade 3 and 4 
hyperthyroidism 
• Withhold atezolizumab. 
• Initiate treatment with anti-thyroid drugs such as methimazole or 
carbimazole as needed. 
• Refer to endocrinologist. 
• Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
• Permanently discontinue atezolizumab and contact the Medical 
Monitor for lifethreatening immune-mediated hyperthyroidism. c 
Symptomatic adrenal 
insufficiency, 
Grades 2−4  
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to endocrinologist. 
• Perform appropriate imaging. 
• Initiate 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 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 the contact 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. 
 
 
 


Appendix 19:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
203/Protocol MO42319, Version 4 
Table 2 
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 corticosteroids equivalent to 
1−2 mg/kg/day IV methylprednisolone 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 corticosteroids equivalent to 
1−2 mg/kg/day IV methylprednisolone 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 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.  
 
 
 


Appendix 19:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
204/Protocol MO42319, Version 4 
OCULAR EVENTS 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 3. 
Table 3 
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 corticosteroids equivalent to 1−2 mg/kg/day 
oral prednisone.   
• 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 CARDIAC EVENTS 
Management guidelines for cardiac events are provided in Table 4. 
. 


Appendix 19:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
205/Protocol MO42319, Version 4 
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 4. 


Appendix 19:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
206/Protocol MO42319, Version 4 
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.  
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 4.  Withhold treatment with atezolizumab for 
Grade 1 pericarditis and conduct a detailed cardiac evaluation to determine the etiology 
and manage accordingly. 
 
 


Appendix 19:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
207/Protocol MO42319, Version 4 
Table 4 
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 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 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 
other immune effector cells.  Symptoms can be progressive, always include fever at the 
onset, and may include hypotension, capillary leak (hypoxia), and end-organ dysfunction 
(Lee et al. 2019).  CRS has been well documented with chimeric antigen receptor T-cell 
therapies and bispecific T-cell engager antibody therapies but has also been reported 
with immunotherapies that target PD-L1 or PD-1 (Rotz et al. 2017; Adashek and 
Feldman 2019), including atezolizumab. 
There may be significant overlap in signs and symptoms of IRRs and CRS, and 
in recognition of the challenges in clinically distinguishing between the two, 
consolidated guidelines for the medical management of IRRs and CRS are 
provided in Table 5. 


Appendix 19:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
208/Protocol MO42319, Version 4 
Severe SARS-CoV-2 infection appears to be associated with a CRS involving the 
inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and IFN-γ (Merad and Martin 2020).  
If a patient develops suspected CRS during the study, a differential diagnosis should 
include SARS-CoV-2 infection, 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 SARS-CoV-2 infection is 
confirmed, the disease should be managed as per local or institutional guidelines. 
 
 


Appendix 19:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
209/Protocol MO42319, Version 4 
Table 5 
Management Guidelines for Infusion-Related Reactions and 
Cytokine Release Syndrome 
Event 
Management 
Grade 1 a 
Fever b with or 
without 
constitutional 
symptoms  
• Immediately interrupt infusion. 
• Upon symptom resolution, wait for 30 minutes and then restart infusion 
at half the rate being given at the time of event onset. 
• If the infusion is tolerated at the reduced rate for 30 minutes, the 
infusion rate may be increased to the original rate. 
• If symptoms recur, discontinue infusion of this dose. 
• Administer symptomatic treatment, c including maintenance of IV fluids 
for hydration. 
• In case of rapid decline or prolonged CRS (> 2 days) or in patients with 
significant symptoms and/or comorbidities, consider managing as per 
Grade 2. 
• For subsequent infusions, consider administration of oral premedication 
with antihistamines, antipyretic medications, and/or analgesics, and 
monitor closely for IRRs and/or CRS. 
Grade 2 a 
Fever b with 
hypotension not 
requiring 
vasopressors 
and/or 
Hypoxia requiring 
low-flow oxygen d 
by nasal cannula 
or blow-by 
• Immediately interrupt infusion. 
• Upon symptom resolution, wait for 30 minutes and then restart infusion 
at half the rate being given at the time of event onset. 
• If symptoms recur, discontinue infusion of this dose. 
• Administer symptomatic treatment. c 
• For hypotension, administer IV fluid bolus as needed. 
• Monitor cardiopulmonary and other organ function closely (in the ICU, if 
appropriate).  Administer IV fluids as clinically indicated, and manage 
constitutional symptoms and organ toxicities as per institutional 
practice. 
• Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS. 
• Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
• 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. 


Appendix 19:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
210/Protocol MO42319, Version 4 
Table 5 
Management Guidelines for Infusion-Related Reactions and 
Cytokine Release Syndrome (cont.) 
Event 
Management 
Grade 3 a 
Fever b with 
hypotension 
requiring a 
vasopressor (with 
or without 
vasopressin) 
and/or 
Hypoxia requiring 
high-flow oxygen d 
by nasal cannula, 
face mask, 
non-rebreather 
mask, or Venturi 
mask 
• Permanently discontinue atezolizumab and contact 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 4 a 
Fever b with 
hypotension 
requiring multiple 
vasopressors 
(excluding 
vasopressin) 
and/or 
Hypoxia requiring 
oxygen by positive 
pressure (e.g., 
CPAP, BiPAP, 
intubation and 
mechanical 
ventilation) 
• Permanently discontinue atezolizumab and contact 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. 


Appendix 19:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
211/Protocol MO42319, Version 4 
Table 5 
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; IV = 
intravenous; 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 who then receive anti-pyretic, anti-cytokine, or corticosteroid 
therapy, fever is no longer required when subsequently determining event severity 
(grade).  In this case, the grade is driven by the presence of hypotension and/or 
hypoxia. 
c Symptomatic treatment may include oral or IV antihistamines, 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 theinvestigator’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 medication, and/or analgesics, and monitor closely for IRRs 
and/or CRS.  Premedication with corticosteroids and extending the infusion time may 
also be considered after consulting the Medical Monitor and considering the 
benefit−risk ratio. 
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 6. 
 
 


Appendix 19:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
212/Protocol MO42319, Version 4 
Table 6 
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 corticosteroids equivalent to 10 mg/day oral prednisone. 
Asymptomatic with amylase and/or lipase > 2.0−5.0 × ULN: 
• Treat as Grade 3. 
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 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 
• For recurrent events, permanently discontinue atezolizumab 
and contact the Medical Monitor. c 


Appendix 19:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
213/Protocol MO42319, Version 4 
Table 6 
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 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 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 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 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 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. 
 


Appendix 19:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
214/Protocol MO42319, Version 4 
DERMATOLOGIC EVENTS 
The majority of cases of rash reported with the use of atezolizumab were mild in severity 
and self-limiting, with or without pruritus.  Although uncommon, cases of severe 
cutaneous adverse reactions such as Stevens-Johnson syndrome and toxic epidermal 
necrolysis have been reported with atezolizumab.  A dermatologist should evaluate 
persistent and/or severe rash or pruritus.  A biopsy should be considered unless 
contraindicated.  Management guidelines for dermatologic events are provided in 
Table 7. 
Table 7 
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. 
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 corticosteroids equivalent to 10 mg/day 
oral prednisone, 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 Medical 
Monitor. c 
 
 
 


Appendix 19:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
215/Protocol MO42319, Version 4 
Table 7 
Management Guidelines for Dermatologic Events (cont.) 
Event 
Management 
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 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.  
 
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 8 , with specific guidelines for myelitis provided in Table 9 . 
 
 


Appendix 19:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
216/Protocol MO42319, Version 4 
Table 8 
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 
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. c 
• Refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
• Consider initiation of corticosteroids equivalent to 1−2 mg/kg/day 
oral or IV prednisone. 


Appendix 19:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
217/Protocol MO42319, Version 4 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event 
onset) to allow for corticosteroids (if initiated)f 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.  
 
Table 9 
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. 


Appendix 19:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
218/Protocol MO42319, Version 4 
Patients with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in Table 10. 
Table 10 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 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 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 11. 
Table 11 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 


Appendix 19:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
219/Protocol MO42319, Version 4 
• 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 
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 12. 
 
 


Appendix 19:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
220/Protocol MO42319, Version 4 
Table 12 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 
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 Monitorc 
 
 
 


Appendix 19:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
221/Protocol MO42319, Version 4 
Table 12 Management Guidelines for Immune-Mediated Myositis (cont.) 
Event 
Management 
Immune-
mediated 
myositis, Grade 4 
• Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
• Refer patient to rheumatologist or neurologist. 
• Initiate treatment as per institutional guidelines. 
• Respiratory support may be required in more severe cases. 
• Initiate treatment with corticosteroids equivalent to 
1−2 mg/kg/day IV methylprednisolone, or higher-dose bolus if 
patient is severely compromised (e.g., cardiac or respiratory 
symptoms, dysphagia, or weakness that severely limits 
mobility); convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids 
over ≥ 1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of  ≤ 10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be 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.  
 
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.   
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 


Appendix 19:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
222/Protocol MO42319, Version 4 
• 
Peripheral blood cytopenia consisting of at least two of the following: 
– 
Hemoglobin < 90 g/L (9 g/dL) (< 100 g/L [10 g/dL] for infants < 4 weeks old) 
– 
Platelet count < 100 × 109/L (< 100,000/µL) 
– 
ANC < 1.0 × 109/L (< 1000/µL) 
• 
Fasting triglycerides > 2.992 mmol/L (> 265 mg/dL) and/or fibrinogen < 1.5 g/L 
(< 150 mg/dL) 
• 
Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
• 
Low or absent natural killer cell activity 
• 
Ferritin > 500 mg/L (> 500 ng/mL) 
• 
Soluble IL−2 receptor (soluble CD25) elevated ≥ 2 standard deviations above age-
adjusted laboratory-specific norms 
 
Patients with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should be 
classified as having MAS if the following criteria are met: 
• 
Ferritin > 684 mg/L (> 684 ng/mL) 
• 
At least two of the following: 
– 
Platelet count ≤ 181 × 109/L (≤ 181,000/µL) 
– 
AST ≥ 48 U/L 
– 
Triglycerides > 1.761 mmol/L (> 156 mg/dL) 
– 
Fibrinogen ≤ 3.6 g/L (≤ 360 mg/dL) 
 
Patients with suspected HLH or MAS should be treated according to the guidelines in 
Table 13. 
 
 


Appendix 19:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
223/Protocol MO42319, Version 4 
Table 13 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; IV = intravenous; 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. 
Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine 
release syndrome and neurologic toxicity associated with immune effector cells. 
Biol Blood Marrow Transplant 2019;25:625−38. 
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 


Appendix 19:Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
224/Protocol MO42319, Version 4 
International Trials Organisation Collaborative Initiative. Ann Rheum Dis 
2016;75:481−9. 
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of 
cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin 
Risk Manag 2019;15:323−35. 
Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient 
receiving PD-1-directed therapy. Pediatr Blood Cancer 2017;64:e26642. 
Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult 
patient. Blood 2015;125:2908−14. 


 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
225/Protocol MO42319, Version 4 
Appendix 20  
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, atezolizumab/placebo must also be 
discontinued.  The Medical Monitor is available to the investigator to consult and answer 
any questions about assigning causality of the toxicity.   
PULMONARY EVENTS 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been 
associated with the administration of atezolizumab and trastuzumab emtansine. 
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, and 
will also have CT scans of the chest at every tumor assessment.  See Table 1 for 
management guidelines for interstitial lung disease and pneumonitis.  See Appendix 19 
for atezolizumab guidelines for all other pulmonary events. 
In this study, atezolizumab is to be discontinued for all grades of interstitial lung disease 
and pneumonitis. 


A p p e n di x 2 0: G ui d eli n e s f or M a n a g e m e nt of A d v er s e E v e nt s t h at ar e P ot e nti al 
O v erl a p pi n g T o xi citi e s A s s o ci at e d wit h Tr a st u z u m a b E mt a n si n e i n 
C o m bi n ati o n wit h At e z oli z u m a b  ( c o nt.) 
  
Tr a st u z u m a b E mt a n si n e  a n d At e z oli z u m a b — F.  H off m a n n -L a R o c h e Lt d  
2 2 6 /Pr ot o c ol M O 4 2 3 1 9, V er si o n  4 
T a bl e  1 
M a n a g e m e nt G ui d eli n e s f or I nt er stiti al L u n g Di s e a s e a n d 
P n e u m o niti s  
S e v erit y  
Tr a st u z u m a b E mt a n si n e  
At e z oli z u m a b  
Gr a d e 1   
Wit h h ol d  t r ast u z u m a b 
e mt a nsi ne t re at m e nt u ntil 
res ol v e d t o G r a de 0  
If r e s ol v e d wit hi n 4 2 d a y s, 
tr e at at t h e s a m e d o s e l e v el.  
If n ot r e s ol v e d wit hi n 4 2 d a y s, 
di s c o nti n u e tr a st u z u m a b 
e mt a n si n e tr e at m e nt . 
Di s c o nti n u e at e z oli z u m a b 
tr e at m e nt. 
Gr a d e 2   
Wit h h ol d t r ast u z u m a b  
e mt a nsi ne t re at m e nt  
If res ol ve d to G r a de 0 wit hi n 
4 2 d a ys, tre at wit h o ne d ose 
le vel re d u cti o n 
If n ot res ol v e d wit hi n 4 2 
d a ys, dis c o nti n ue  
tr ast u z u m a b e mt a nsi ne 
tre at m e nt a n d c o nt a ct 
Me di c al M o nit or.
b  
 
Dis c o nti n ue ate z oli z u m a b 
tre at m e nt. 
 
Gr a d e 3 –  4  
Dis c o nti n ue tr ast u z u m a b 
e mt a nsi ne t re at m e nt.   
 
Dis c o nti n ue ate z oli z u m a b 
tre at m e nt. 
 
•  
a M o nit or a n d cl osel y f oll o w u p i n 2 −7 d a ys f or o nset of cli ni c al s y m pt o ms a n d p ulse 
o xi metr y (resti n g a n d a m b ul ati o n) . C o nsi der f oll o w-u p i m a gi n g wit h C hest C T i n 1 -2 
wee ks ( or as cli ni c all y i n di c ate d)  
b T he Me di c al M o nit or is a v ail a ble t o a d vise as nee de d.  
H E P A TI C E V E N T S  
I m m u n e-m e di at e d h e p atiti s h a s b e e n a s s o ci at e d wit h t h e a d mi ni str ati o n of 
at e z oli z u m a b.  P ati e nt s eli gi bl e f or st u d y tr e at m e nt  m u st h a v e a d e q u at e li v er 
f u n cti o n, a s m a nif e st e d b y m e a s ur e m e nt s of t ot al bilir u bi n a n d h e p ati c 
tr a n s a mi n a s e s.  Li v er f u n cti o n will b e m o nit or e d t hr o u g h o ut st u d y tr e at m e nt. 
P ati e nt s  wit h ri g ht u p p er -q u a dr a nt a b d o mi n al p ai n a n d/ or u n e x pl ai n e d n a u s e a or 
v o miti n g s h o ul d h a v e li v er f u n cti o n t e st s ( L F T s) p erf or m e d i m m e di at el y a n d 
r e vi e w e d b ef or e a d mi ni str ati o n of t h e n e xt d o s e of st u d y dr u g. 
If o ut c o m e of L F T s i s w or s e ni n g, c o n c urr e nt m e di c ati o n s, vir al h e p atiti s, a n d 
t o xi c or n e o pl a sti c eti ol o gi e s s h o ul d b e c o n si d er e d a n d a d dr e s s e d, 
a s  a p pr o pri at e.  I m a gi n g of t h e li v er,  g all bl a d d er, a n d bili ar y tr e e s h o ul d b e 
p erf or m e d t o r ul e o ut n e o pl a sti c or ot h er c a u s e s f or w or s e ni n g o ut c o m e of L F T s.  
A nti -n u cl e ar a nti b o d y, p eri n u cl e ar a nti -n e utr o p hil c yt o pl a s mi c a nti b o d y, a nti -li v er 


Appendix 20:Guidelines for Management of Adverse Events that are Potential 
Overlapping Toxicities Associated with Trastuzumab Emtansine in 
Combination with Atezolizumab (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
227/Protocol MO42319, Version 4 
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 atezolizumab and trastuzumab emtansine hepatic 
events. 
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 20:Guidelines for Management of Adverse Events that are Potential 
Overlapping Toxicities Associated with Trastuzumab Emtansine in 
Combination with Atezolizumab (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
228/Protocol MO42319, Version 4 
Table 2 
Management Guidelines for Increased Transaminases (AST/ALT) 
and Hepatic Events 
Severity 
Trastuzumab Emtansine 
Atezolizumab/Placebo 
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 trastuzumab 
emtansine treatment. 
Discontinue 
atezolizumab/placebo treatment. 
ALT or AST increase 
that does not meet 
Hy's law criteria 
ALT/AST Grade 1 
(> 1-0−3.0 × ULN) 
 
Continue with the trastuzumab 
emtansine without dose 
modification and monitor LFTs. 
Treat at the same dose level. 
Continue LFT monitoring. 
ALT/AST Grade 2 
(> 3.0−5.0 × ULN)  
Treat at the same dose level. 
Withhold atezolizumab/placebo 
dose. 
If persists > 5−7 days:  Intiate 
1−2 mg/kg/day prednisone or 
equivalent per day; when recover 
to Grade ≤ 1, taper steroids over 
≥ 1 month. 
Resume therapy when systemic 
steroid dose is ≤ 10mg oral 
prednisone equivalent per day 
and resume when recovery to 
Grade ≤ 1 at same dose within 
12 weeks. 
Permanently discontinue 
atezolizumab/placebo and 
contact the Medical Monitor if 
event does not resolve to Grade 
1 or better within 12 weeks. 


Appendix 20:Guidelines for Management of Adverse Events that are Potential 
Overlapping Toxicities Associated with Trastuzumab Emtansine in 
Combination with Atezolizumab (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
229/Protocol MO42319, Version 4 
Table 2 
Management Guidelines for Increased Transaminases (AST/ALT) 
and Hepatic Events (cont.)  
Severity 
Trastuzumab Emtansine 
Atezolizumab/Placebo 
ALT/AST Grade 3 
(> 5.0−20.0 × ULN) 
Withhold trastuzumab 
emtansine dose. 
Do not administer trastuzumab 
emtansine until recovery to 
Grade ≤ 2, and then resume 
with dose reduction by one 
level. Discontinue trastuzumab 
emtansine treatment if the 
event has not resolved to 
Grade ≤ 2 within 42 days after 
the last dose received. 
Discontinue atezolizumab/placebo 
dose. 
Consider GI consult and liver biopsy 
to establish etiology of hepatic injury 
if necessary. 
Start corticosteroids equivalent to  
1–2 mg/kg/day oral prednisone. 
If LFT results do not decrease within 
48 hours after initiation of systemic 
steroids, addition of an alternative 
immunosuppressive agent may be 
considered. 
Taper steroids over ≥ 1 month, when 
symptoms improve to Grade 0 or 
Grade 1. 
Contact the Medical Monitor if 
atezolizumab/placebo treatment is 
discontinued. 
ALT/AST Grade 4 
(> 20.0 × ULN) 
Discontinue trastuzumab 
emtansine treatment. 
Laboratory tests may be 
repeated (within 24 hours) to 
exclude laboratory error prior 
to discontinuing trastuzumab 
emtansine. 
Discontinue atezolizumab/placebo 
treatment. 
Consider GI consult and liver biopsy 
to establish etiology of hepatic injury 
if necessary. 
Start corticosteroids equivalent to  
1–2 mg/kg/day oral prednisone. 
If LFT results do not decrease within 
48 hours after initiation of systemic 
steroids, addition of an alternative 
immunosuppressive agent (may be 
considered. 
Taper steroids over ≥ 1 month, when 
symptoms improve to Grade 0 or 
Grade 1.  
Contact the Medical Monitor if 
atezolizumab/placebo treatment is 
discontinued. 
 


Appendix 20:Guidelines for Management of Adverse Events that are Potential 
Overlapping Toxicities Associated with Trastuzumab Emtansine in 
Combination with Atezolizumab (cont.) 
  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
230/Protocol MO42319, Version 4 
Table 2 
Management Guidelines for Increased Transaminases (AST/ALT) 
and Hepatic Events (cont.)  
Severity 
Trastuzumab Emtansine 
Atezolizumab/Placebo 
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 all study treatment 
and have the patient evaluated 
by a hepatologist. 
Discontinue all study treatment and 
have the patient evaluated by a 
hepatologist 
GI = gastrointestinal; LFT = liver function test; MBC = metastatic breast cancer; NRH = Nodular 
Regenerative Hyperplasia; TNF = tumor necrosis factor; ULN = upper limit of normal.  
 
Table 3 
Trastuzumab Emtansine Dose Modification Guidelines for 
Hyperbilirubinemia in Patients with Metastatic Breast Cancer 
Severity 
Action to be Taken 
Grade 2 
(> 1.5 to ≤ 3 × ULN) 
Withhold trastuzumab emtansine until total bilirubin recovers 
to Grade ≤ 1 and then resume at the same dose level. 
Grade 3 
(> 3 to ≤ 10 × ULN) 
Withhold trastuzumab emtansine until total bilirubin recovers 
to Grade ≤ 1 and then resume by one dose level reduction.   
Grade 4 
(> 10 × ULN) 
Discontinue trastuzumab emtansine treatment. 
ULN = upper limit of normal. 
 


Signature Page for Protocol - MO42319 - KADCYLA - v4 - Global/Core - Published
System identifier: RIM-CLIN-470730
Approval Task
Company Signatory
02-Mar-2023 17:00:55 GMT+0000

SAP_001.pdf: 
 
Official Title: 
A Randomized, Multicenter, Double-Blind, Placebo-Controlled Phase 
III Study of the Efficacy and Safety of Trastuzumab Emtansine in 
Combination with Atezolizumab or Placebo in Patients with HER2-
Positive and PD-L1-Positive Locally Advanced or Metastatic Breast 
Cancer Who Have Received Prior Trastuzumab- (+/- Pertuzumab) 
and Taxane-Based Therapy (KATE3) 
NCT Number: 
NCT04740918 
Document Date: 
SAP Version 1: 28-March-2023 
 
 


STATISTICAL ANALYSIS PLAN APPROVAL 
SPONSOR: 
LEGAL REGISTERED 
ADDRESS: 
F. Hoffmann-La Roche Ltd 
Grenzacherstrasse 124 
4070 Basel, Switzerland 
DATE FINAL: 
See electronic date stamp on the last page of this 
document. 
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. 
 
Trastuzumab Emtansine, Atezolizumab—F. Hoffmann-La Roche Ltd. 
Statistical Analysis Plan MO42319 
STATISTICAL ANALYSIS PLAN 
STUDY TITLE: 
A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, 
PLACEBO-CONTROLLED PHASE III STUDY OF THE 
EFFICACY AND SAFETY OF TRASTUZUMAB 
EMTANSINE IN COMBINATION WITH ATEZOLIZUMAB 
OR PLACEBO IN PATIENTS WITH HER2-POSITIVE AND 
PD-L1POSITIVE LOCALLY ADVANCED OR 
METASTATIC BREAST CANCER WHO HAVE RECEIVED 
PRIOR TRASTUZUMAB ( PERTUZUMAB) AND TAXANE-
BASED THERAPY 
STUDY NUMBER: 
MO42319 
STUDY NAME:  
KATE3 
VERSION NUMBER: 
1 
ROCHE COMPOUND(S): 
Trastuzumab Emtansine (RO5304020) 
Atezolizumab (RO5541267) 
EUDRACT NUMBER: 
2020-002818-41 
IND NUMBER: 
71,072 
NCT NUMBER: 
NCT04740918 
PLAN PREPARED BY: 
 (Cytel) and 
 (Roche) 


 
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Statistical Analysis Plan MO42319 
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STATISTICAL ANALYSIS PLAN VERSION HISTORY 
This SAP was developed based on Roche SAP model document dated 28 February 
2022. 
SAP Version 
Approval Date 
Based on Protocol  
(Version, Approval Date) 
1 
See electronic date stamp on the final 
page of this document. 
Version 4, 2 March 2023 
 


 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ............................................................................. 7 
1.1 
Objectives and Endpoints .......................................................... 7 
1.2 
Study Design ............................................................................. 9 
1.2.1 
Treatment Assignment and Blinding ........................................ 10 
1.2.2 
Independent Review Facility .................................................... 12 
1.2.3 
Data Monitoring ....................................................................... 12 
2. 
STATISTICAL HYPOTHESES AND SAMPLE SIZE 
DETERMINATION ........................................................................ 12 
2.1 
Statistical Hypotheses ............................................................. 12 
2.2 
Sample Size Determination ..................................................... 13 
3. 
ANALYSIS SETS .......................................................................... 13 
4. 
STATISTICAL ANALYSES ........................................................... 14 
4.1 
General Considerations ........................................................... 14 
4.2 
Participant Disposition ............................................................. 14 
4.3 
Primary Endpoints Analysis ..................................................... 15 
4.3.1 
Definition of Primary Endpoint(s)/Estimand(s) ......................... 15 
4.3.2 
Main Analytical Approach for Primary Endpoint(s) ................... 16 
4.3.3 
Sensitivity Analyses ................................................................. 17 
4.3.4 
Supplementary Analyses ......................................................... 17 
4.3.5 
Subgroup Analyses for Primary Endpoint(s) ............................ 17 
4.4 
Secondary Endpoints Analyses ............................................... 18 
4.4.1 
Objective Response Rate ........................................................ 18 
4.4.2 
Duration of Response .............................................................. 19 
4.4.3 
Progression-Free Survival in Patients with Baseline Brain 
Metastases .............................................................................. 19 
4.4.4 
Overall Survival in Patients with Baseline Brain Metastases ... 20 
4.4.5 
Central Nervous System Progression-Free Survival ................ 20 
4.5 
Safety Analyses ....................................................................... 21 
4.5.1 
Extent of Exposure .................................................................. 22 
4.5.2 
Adverse Events ........................................................................ 22 
4.5.3 
Additional Safety Assessments ................................................ 22 


 
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4.5.3.1 
Laboratory Data ....................................................................... 22 
4.5.3.2 
Vital Signs ................................................................................ 23 
4.5.3.3 
ECGs ....................................................................................... 23 
4.5.3.4 
Left Ventricular Ejection Fraction ............................................. 23 
4.6 
Other Analyses ........................................................................ 23 
4.6.1 
Summaries of Conduct of Study .............................................. 23 
4.6.2 
Summaries of Treatment Group Comparability ........................ 23 
4.6.3 
Biomarker Analyses ................................................................. 24 
4.6.4 
Screen Failure Analysis ........................................................... 24 
4.7 
Interim Analyses ...................................................................... 24 
4.7.1 
Planned Interim Analyses ........................................................ 24 
4.7.2 
Optional Interim Analyses ........................................................ 24 
5. 
SUPPORTING DOCUMENTATION .............................................. 25 
6. 
REFERENCES.............................................................................. 25 
PROTOCOL SYNOPSIS .................................................................................... 26 
 
 
LIST OF TABLES 
Table 1 
Objectives and Corresponding Endpoints ..................................... 8 
Table 2 
Analysis Sets .............................................................................. 13 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 10 
 
 
LIST OF APPENDICES 
Appendix 1 
Protocol Synopsis ....................................................................... 26 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Term 
Description 
AE 
adverse event 
AESI 
Adverse event of special interest 
CI 
confidence interval 
CNS 
central nervous system 
CR 
complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DOR 
duration of response 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ER 
estrogen receptor 
eCRF 
electronic Case Report Form 
HER2 
Human Epidermal Growth Factor Receptor 
HR 
hazard ratio 
iDCC 
Independent Data Coordinating Center 
IDMC 
Independent Data Monitoring Committee 
IHC 
immunohistochemistry 
Inv-PFS 
Investigator-based PFS 
IRB 
Institutional Review Board 
IRF 
Independent Review Facility 
ITT 
intent to treat 
IxRS 
interactive voice/web response system 
LABC 
locally advanced breast cancer 
LVEF 
left ventricular ejection fraction 
MBC 
metastatic breast cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NPT 
non-protocol anti-cancer therapy 
ORR 
objective response rate 
OS 
overall survival 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed death ligand 1 
PFS 
progression-free survival 
PgR 
progesterone receptor 


 
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Abbreviation or Term 
Description 
PR 
partial response 
q3w 
every 3 weeks 
RECIST 
Response Evaluation Criteria In Solid Tumors  
SAP 
Statistical Analysis Plan 
T-DM1 
Trastuzumab Emtansine 
TIL 
tumor-infiltrating lymphocyte 
ULN 
upper limit normal 
US 
United States of America 


 
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1. 
INTRODUCTION 
The analyses described in this Statistical Analysis Plan (SAP) will supersede those 
specified in Protocol MO42319 for the purposes of a regulatory filing. 
This SAP details the planned analyses and statistical methods for Study MO42319 
(KATE3), "A Phase III, Randomized, Multicenter, Double-Blind, Placebo-Controlled 
Clinical Trial to Evaluate the Efficacy and Safety of Trastuzumab Emtansine in 
Combination with Atezolizumab or Placebo in patients with HER2-Positive and PD-L1-
Positive Locally Advanced or Metastatic Breast Cancer who have received Prior 
Trastuzumab ( Pertuzumab) and Taxane-Based Therapy". For background information 
about the study, refer to Protocol MO42319.  
Of note, the Sponsor has decided to prematurely terminate the study due to a lower-
than-expected enrolment rate, which significantly extended the recruitment timelines. For 
more details, refer to Protocol MO42319.   
There are no changes to the planned analyses described in the Protocol MO42319 
version 4. 
1.1 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy, safety, and pharmacokinetics and patient-reported 
outcomes of trastuzumab emtansine plus atezolizumab compared with trastuzumab 
emtansine plus placebo in patients with human epidermal growth factor 2 (HER2)-
positive and programmed death-ligand 1 (PD-L1)-positive locally advanced (LABC) or 
metastatic breast cancer (MBC). Patients must have progressed either during or after 
prior trastuzumab- ( pertuzumab) and taxane-based therapy for LABC or MBC; or 
during (or within 6 months after completing) trastuzumab- ( pertuzumab) and taxane-
based therapy in the neoadjuvant and/or adjuvant setting.  
In this SAP, "study treatment" refers to the combination of treatments assigned to 
patients as part of this study (i.e., trastuzumab emtansine and atezolizumab or 
trastuzumab emtansine and placebo).  
Following the Sponsor’s decision to prematurely terminate the study, as outlined in 
protocol, specific study objectives are no longer applicable and corresponding analyses 
will not be conducted. Specific objectives and corresponding endpoints for the study 
which are still applicable after the Sponsor’s decision to prematurely terminate the study 
are outlined in Table 1.   
Study objectives and endpoints will be further described using the estimand framework, 
in accordance with the International Conference on Harmonization E9 (R1) statistical 
principles for clinical trials (ICH 2020). 


 
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Table 1 
Objectives and Corresponding Endpoints 
Primary Efficacy Objective 
Corresponding Endpoints 
 
To demonstrate superiority of the 
experimental over the control 
treatment in either or both 
comparisons 
 
PFS, defined as the time from randomization 
to the first occurrence of any of the events 
defined below (whichever occurs first): 
– 
Disease progression, as determined by 
investigator assessment using RECIST 
v1.1 
– 
Death from any cause 
 
OS, defined as the time from randomization to 
death from any cause 
Secondary Efficacy Objective 
Corresponding Endpoints 
 
To evaluate the efficacy of 
trastuzumab emtansine plus 
atezolizumab compared with 
trastuzumab emtansine plus 
placebo  
 
ORR, defined as CR or PR on two 
consecutive assessments at least 28 days 
apart, as determined by investigator 
assessment using RECIST v1.1 
 
DOR, defined as the time from first 
occurrence of a documented objective 
response to disease progression, as 
determined by investigator assessment using 
RECIST v1.1 or death from any cause, 
whichever occurs first  
 
PFS in patients with baseline brain 
metastases as determined by investigator 
assessment using RECIST version 1.1 
 OS in patients with baseline brain metastases 
defined as the time from randomization to 
death from any cause 
 
CNS PFS as determined by investigator 
assessment using RECIST v1.1 in patients 
with or without baseline CNS metastases 
Safety Objective 
Corresponding Endpoints 
 
To evaluate the safety of 
trastuzumab emtansine plus 
atezolizumab compared with 
trastuzumab emtansine plus 
placebo 
 
Incidence and severity of AEs, with severity 
determined according to NCI CTCAE v5.0 
 
Change from baseline in targeted clinical 
laboratory test results  


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Statistical Analysis Plan MO42319 
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Exploratory Biomarker Objective 
Corresponding Endpoints 

To identify and/or evaluate
biomarkers that are predictive of
response to atezolizumab in
combination with trastuzumab
emtansine (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
and trastuzumab emtansine, are
associated with susceptibility to
developing AEs or can lead to
improved AE monitoring or
investigation (i.e., safety
biomarkers), can provide evidence
of atezolizumab and/or trastuzumab
emtansine activity (i.e.,
pharmacodynamic biomarkers), or
can increase the knowledge and
understanding of disease biology
and drug safety

Association of baseline stromal TILs with
efficacy

Association of baseline HER2 expression
level (protein and/or gene amplification status)
with efficacy

Association of baseline PD-L1 expression
level ( 1% and   5% IC vs   5% IC) with
efficacy

Description of prevalence and correlation
among biomarkers in tumor tissue
AE  adverse event; CNS  central nervous system; CR  complete response; DOR  duration of 
response; HER2  Human Epidermal growth factor Receptor; IC  tumor-infiltrating immune cell; 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events; 
ORR  objective response rate; OS  overall survival; PD-L1  programmed death ligand 1; 
PFS  progression free survival; PR  partial response; RECIST  response evaluation criteria in 
solid tumors; TIL  tumor-infiltrating lymphocytes. 
1.2 
STUDY DESIGN 
This is a Phase III, randomized, multicenter, international, two-arm, double-blind, 
placebo-controlled study. Patients will be randomized to one of the following treatment 
arms in a 1:1 ratio: 

Arm A: trastuzumab emtansine 3.6mg/kg and placebo, every 3 weeks (q3w)

Arm B: trastuzumab emtansine 3.6mg/kg and atezolizumab 1200 mg, q3w
This study initially planned to enroll approximately 350 patients in approximately 
175 sites worldwide.  
Following the Sponsor’s decision to prematurely terminate the study, the initially planned 
number of randomized patients will not be reached.   
The study schema is shown in Figure 1. 
Table 1 
Objectives and Corresponding Endpoints (Cont.) 




 
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Statistical Analysis Plan MO42319 
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eligibility has been established for a patient, the study site will obtain the patient’s 
identification number and treatment assignment from the interactive voice or web-based 
response system (IxRS). 
Patient will be randomly assigned to one of two treatment arms: trastuzumab emtansine 
plus atezolizumab or trastuzumab emtansine plus placebo. Randomization will occur in a 
1:1 ratio through use of a permuted-block randomization method to ensure a balanced 
assignment to each treatment arm. Arm A and Arm B will be blinded with respect to 
administration of atezolizumab or placebo. Crossover between treatment arms will not 
be permitted. 
Randomization will be stratified according to the following criteria: 
 
Local hormonal status (estrogen receptor [ER] and/or progesterone receptor [PgR] 
positive vs. ER and PgR negative/unknown), 
 
Disease status (visceral metastasis without brain metastasis vs. non-visceral 
metastasis only without brain metastasis [including locally advanced disease] vs. 
brain metastasis), 
 
World Region (Western Europe vs. U.S. vs. Rest of World). 
 
The Sponsor has decided to prematurely terminate the study due to a lower-than-
expected enrolment rate, which significantly extended the recruitment timelines. The 
investigators were informed of premature study termination on 15 December 2022 by a 
study memo communicating this decision. 
Following a discussion between the investigator and the patient regarding the premature 
termination, the patient may consent to continue study treatment (i.e., either trastuzumab 
emtansine and atezolizumab or trastuzumab emtansine as a single agent; placebo will 
no longer be administered following unblinding of treatment assignment) if considered 
clinically appropriate by the investigator.  
The Sponsor’s rationale for unblinding the study is to allow investigators and patients to 
have an open discussion of the potential benefits and risks of continuing the 
experimental therapy and to allow them to continue with treatment options off this study. 
The Sponsor’s decision to unblind the study with respect to treatment assignment, was 
made after consideration of the following factors.  
The analysis of the two primary efficacy endpoints of progression-free survival (PFS) 
based on investigator tumor assessment and overall survival (OS) will no longer be 
conducted under an alpha-controlled framework as per the original study design. The 
analyses of PFS and OS will be reported in a descriptive way with no formal statistical 
testing performed and no control for the overall type I error () accounting for the two 
primary endpoints. Consequently, the p-values will not be able to be claimed as 
statistically significant and therefore will be reported as descriptive in nature.  


 
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Unblinding will be required for patients to continue with off-study treatment options. 
After unblinding of patients’ treatment assignment, patients will continue to receive study 
treatments until off-study treatment options are put into place. More details are provided 
in the study protocol. 
1.2.2 
Independent Review Facility 
An independent review facility will be used for this study to collect and retain copies of 
tumor assessment scans for centralized review. The independent reading will be blinded 
to the treatment information as well as subject demographics and tumor assessments 
from the site (more details described in the imaging charter). 
Following premature study termination, tumor assessment scans will no longer be 
collected prospectively by the Sponsor and an IRF will not be utilized. 
1.2.3 
Data Monitoring 
An independent data monitoring committee (iDMC) will evaluate safety and efficacy data 
during the study. Sponsor affiliates will be excluded from iDMC membership. The iDMC 
will follow a charter that outlines the iDMC roles and responsibilities. 
Unblinded safety data will be reviewed on a periodic basis, approximately every 6 
months from the time of the enrollment of the first patient. All summaries and analyses 
for the iDMC review will be prepared by an independent Data Coordinating Center 
(iDCC).  
Any outcomes of these data reviews that affect study conduct will be communicated in a 
timely manner to the investigators for notification of their respective Institutional Review 
Boards/Ethics Committees (IRBs/ECs). 
As per the iDMC charter, the iDMC will perform review of unblinded safety data until the 
study is unblinded, after which the study team will be responsible for the ongoing 
monitoring of patient safety in the study. Accordingly, the iDMC review activities will stop 
once the unblinding of the study will have been performed following the Sponsor’s 
decision for premature study termination. 
2. 
STATISTICAL HYPOTHESES AND SAMPLE SIZE 
DETERMINATION 
2.1 
STATISTICAL HYPOTHESES 
Following the Sponsor’s decision to prematurely terminate the study, the analysis of the 
two primary efficacy endpoints of PFS based on investigator tumor assessment and OS 
will no longer be conducted under an alpha-controlled framework as per the original 
study design.  The analyses of PFS and OS will be reported in a descriptive way with no 
formal statistical testing performed and no control for the overall type I error () 


 
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accounting for the two primary endpoints.  Consequently, p-values will not be able to be 
claimed as statistically significant and therefore will be reported as descriptive in nature. 
2.2 
SAMPLE SIZE DETERMINATION 
The two primary efficacy endpoints for this study are PFS based on investigator tumor 
assessment and OS.  
This study has been designed to detect a substantial magnitude of benefit in the intent to 
treat (ITT) population, that is, improvement in median PFS from 7 months in the control 
arm to 11.67 months in the experimental arm, corresponding to a target PFS hazard 
ratio of 0.60, and improvement in median OS from 31 months in the control arm to 47.7 
months in the experimental arm, corresponding to a target OS hazard ratio of 0.65.  
Initially, it was planned that approximately 350 patients randomized according to a 1:1 
randomization (approximately 175 patients will be randomized to Arm A and to Arm B) 
would be enrolled in the study. The sample size assumed an annual dropout rate of 10% 
in both treatment arm and resulted in an estimated recruitment time of about 32 months 
(with ramp up in the first 8 months). Following the Sponsor’s decision to prematurely 
terminate the study, the initially planned number of randomized patients will not be 
reached.  
Furthermore, in the context of premature study termination, there will be only a single 
analysis timepoint for both PFS and OS primary efficacy endpoints.  Interim analyses will 
no longer be conducted.  Considering the expected lack of maturity of the data, the 
analysis of PFS and OS primary efficacy endpoints will no longer be conducted under an 
alpha-controlled framework as per the original study design.  The analyses of PFS and 
OS will be reported in a descriptive way with no formal testing performed and no control 
for the overall type I error () accounting for the two primary endpoints.  Consequently, 
p-values will not be able to be claimed as statistically significant and therefore will be 
reported as descriptive in nature. 
3. 
ANALYSIS SETS 
The analysis sets for this study are defined in Table 2 below.  
Table 2 
Analysis Sets 
Population 
Definition 
Intention-to-treat (ITT) 
All randomized participants, whether or not they received 
any study medication. Patients will be grouped according 
to the treatment assigned at randomization by the IxRS. 
Safety-evaluable 
All participants randomly assigned to study treatment and 
who received at least one full or partial dose of study 
drug. Patients will be analyzed based on the treatment 
they actually received (which may be different from the 
treatment the patient was randomized to).  


 
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Population 
Definition 
Subset ITT with brain metastases 
at baseline 
All participants included in the ITT with brain metastasis 
at randomization as collected by the IxRS 
Subset ITT with CNS metastases 
at baseline 
All participants included in the ITT with CNS metastasis at 
baseline as collected by eCRF 
Subset ITT without CNS 
metastases at baseline 
All participants included in the ITT without CNS 
metastasis at baseline as collected by eCRF 
Subset ITT with measurable 
disease 
All participants included in the ITT with a measurable 
disease at baseline. 
Screen Failed population with PD-
L1 negative status 
All screen failed patients with a PD-L1 negative status  
CNS  Central Nervous System; ITT  intent-to-treat; IxRS  interactive voice/web response 
system 
  
4. 
STATISTICAL ANALYSES 
4.1 
GENERAL CONSIDERATIONS 
All efficacy analyses will be performed on the ITT population, unless otherwise specified.  
Participants will be analyzed according to the treatment assigned at randomization by 
the IxRS. 
All safety analyses will be performed in the safety-evaluable population, unless 
otherwise specified.  Participants will be analyzed according to the treatment they 
actually received.   
Analyses of demographics and other baseline information will be based on the ITT 
population, and per treatment assigned by the IxRS, unless otherwise specified. 
The baseline value of any variable will be defined as the last available data point prior to 
the first administration of study medication. 
In safety analyses, all deaths are included, from all sources, regardless of completeness 
of death date; participants who died with only a partial death date available will be 
included.  In efficacy analyses, a death is considered an event if and only if a complete 
death date is available; participants who died with only a partial death date available will 
be censored on their last date known to be alive plus 1 day. 
4.2 
PARTICIPANT DISPOSITION 
Patient enrollment will be tabulated by study site for each treatment arm.  Duration of 
follow-up, discontinuation from study treatment and study, and reasons for 
discontinuation, will be summarized by treatment arm to which patients were 
randomized. In addition, major protocol violations will be summarized by treatment arm. 


 
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4.3 
PRIMARY ENDPOINTS ANALYSIS 
4.3.1 
Definition of Primary Endpoint(s)/Estimand(s) 
The multiple primary efficacy endpoints for this study are PFS based on investigator 
tumor assessment and OS. 
Investigator-based PFS (Inv-PFS) is defined as the time from randomization to the 
date of first occurrence of any of the events defined below (whichever occurs first): 
 
First documented disease progression as determined by the investigator using 
RECIST 1.1  
 
Death from any cause 
 
The first documented disease progression will be used in the analysis of the primary 
efficacy endpoint of PFS.  
Data for patients without an event as of the data cut-off date will be censored at the time 
of the last tumor assessment with an outcome other than “unevaluable” (or, if no tumor 
assessment was performed after the baseline visit, at the time of randomization plus 
1 day).  
Data from patients who are lost to follow-up will be included in the analysis as censored 
observations on the date of the last tumor assessment that the patient was known to be 
progression-free. Data from patients who have had two or more missing or unevaluable 
tumor assessments prior to a PFS event will be censored in the same approach. These 
scenarios are considered non-informative missing data.  
The primary estimand for Inv-PFS is defined as follows:  
 
Population:  Patients with HER2-positive and PD-L1-positive locally advanced or 
metastatic breast cancer who have received prior trastuzumab ( pertuzumab) 
and taxane-based therapy, as defined by the inclusion and exclusion criteria in 
Protocol MO42319  
 
Variables:  Time from randomization to the first occurrence of a PFS event, as 
defined above 
 
Treatments: 
– 
Experimental:  trastuzumab emtansine 3.6 mg/kg by IV infusion q3w plus 
atezolizumab 1200 mg by IV infusion q3w 
– 
Control:  trastuzumab emtansine 3.6 mg/kg by IV infusion q3w plus placebo by 
IV infusion q3w 
 
Intercurrent events: 
– 
Start of non-protocol anti-cancer therapy (NPT) prior to a PFS event 
– 
Early discontinuation from study treatment for any reason prior to a PFS event  
 
Handling of intercurrent events: 


 
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– 
A treatment policy with regards to the listed intercurrent events will be applied 
for the main analysis (i.e., taking the date of the recorded PFS event ignoring 
the occurrence of those intercurrent events) 
 
Summary measure:  Hazard ratio for PFS  
 
OS is defined as the time from randomization to death from any cause.  
Patients who are alive as of the data cut-off date of the analysis will be censored at the 
last known date, they were alive. Patients with no post-baseline information will be 
censored at the date of randomization plus one day. 
The primary estimand for OS is defined as follows:  
 
Population: Patients with HER2-positive and PD-L1-positive locally advanced or 
metastatic breast cancer who have received prior trastuzumab ( pertuzumab) 
and taxane-based therapy, as defined by the inclusion and exclusion criteria in 
Protocol MO42319 
 
Variables: Time from randomization to death from any cause 
 
Treatments: 
– 
Experimental:  trastuzumab emtansine 3.6mg/kg by IV infusion q3w plus 
atezolizumab 1200 mg by IV infusion q3w 
– 
Control:  trastuzumab emtansine 3.6mg/kg by IV infusion q3w plus placebo by 
IV infusion q3w 
 
Intercurrent events: 
– 
Start of NPT  
– 
Early discontinuation from study treatment for any reason  
 
Handling of intercurrent events: 
– 
A treatment policy with regards to the listed intercurrent events will be applied 
for the main analysis (i.e., taking the date of the recorded OS event ignoring the 
occurrence of those intercurrent events) 
 
Summary measure: Hazard ratio for OS 
 
4.3.2 
Main Analytical Approach for Primary Endpoint(s) 
Progression-Free Survival 
The Kaplan-Meier method will be used to estimate median PFS and the corresponding 
95% CIs for each treatment arm. The two-sided log-rank test, stratified by the factors 
specified in the protocol (excluding world region) will be used to compare PFS between 
the treatment arms. If less than five events are observed in any combination of 
stratification factors, only the unstratified analysis will be done. The stratification factors 
will be based on data collected by the IxRS rather than on data collected on the eCRFs.  


 
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The Cox proportional hazards model, stratified by the previous noted stratification 
factors, excluding world region, will be used to estimate the hazard ratio (HR) and to 
calculate the 95% confidence interval (CI) of the HR.  
Overall Survival 
Methods for data analysis are analogous to those described for the primary efficacy 
endpoint PFS.  
4.3.3 
Sensitivity Analyses  
No sensitivity analyses are planned for the primary endpoints. 
4.3.4 
Supplementary Analyses  
No supplementary analyses are planned for the primary endpoints. 
4.3.5 
Subgroup Analyses for Primary Endpoint(s) 
Subgroup analyses related to stratification factors will be conducted based on 
stratification factors as reported in the IxRS system and repeated based on stratification 
factors as reported on the eCRF. 
In order to further assess the consistency of treatment benefit with respect to the 
multiple primary efficacy endpoints PFS and OS across important subgroups, forest 
plots (including estimated HRs) will be provided for the following variables: 
 
Age category ( 65 vs 65-74 vs.  75 years) 
 
Race (Caucasian, black, Asian, and other) 
 
World region (US, Western-Europe, Asia, Other)  
 
Eastern Cooperative Oncology Group (ECOG) status (0, 1, or unknown) 
 
Hormone receptor status (ER/PgR negative vs ER and/or PgR positive vs unknown)  
 
Disease involvement (visceral disease vs non-visceral disease) 
 
Brain metastasis (Y/N) 
 
Liver metastasis (Y/N) 
 
Number of lines of prior therapy for metastatic disease (0, 1 or  2) 
 
Prior pertuzumab for metastatic (Y/N) 
 
Prior trastuzumab deruxtecan for metastatic (Y/N) 
 
Prior PD-1/PD-L1 therapy (Y/N) 
 
Status of disease (metastatic, locally advanced) 
 
Prior neoadjuvant therapy (pertuzumab, other, or no prior neoadjuvant therapy) 
 
Prior adjuvant therapy (trastuzumab emtansine, pertuzumab, other, or no prior 
adjuvant therapy) 
 


 
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4.4 
SECONDARY ENDPOINTS ANALYSES 
All secondary efficacy analyses will be performed based on the ITT population. 
4.4.1 
Objective Response Rate 
Objective response, defined as a complete response (CR) or partial response (PR), will 
be determined by investigator tumor assessment using RECIST v1.1. Objective 
response rate (ORR) is the percentage of patients who are determined to have an 
objective response. Patients without a post-baseline tumor assessment will be 
considered non-responders. For patients who received a NPT, only tumor assessments 
prior to the start of non-protocol anti-cancer therapy will be considered in the derivation 
of ORR. 
Objective responses must be confirmed at least 28 days after the initial documentation 
of response. An estimate of the ORR and its 95% CI (Wilson score confidence interval) 
will be calculated for each treatment arm. The Cochran-Mantel-Haenszel Chi-squared 
test stratified by local hormonal status and disease status will be used to compare 
response rates between treatment arms.   
The estimand for ORR will be as follows: 
 
Population:  As defined for the primary endpoint in Section 4.3.1 and with 
measurable disease at baseline 
 
Variable:  Objective response, defined as a confirmed CR or PR, as determined by 
investigator tumor assessment using RECIST v1.1 
 
Treatments:  As defined for the primary endpoint in Section 4.3.1 
 
Intercurrent events: 
– 
Start of NPT prior to response 
– 
Early discontinuation from study treatment for any reason prior to response 
 
Handling of intercurrent events: 
– 
While not having started NPT (i.e., only tumor assessments prior to the start of 
non-protocol anti-cancer therapy are included for derivation of ORR) 
– 
Treatment policy for early treatment discontinuation (i.e., this intercurrent event 
is ignored for derivation of ORR). 
 
Summary measure:  Odds ratio for ORR 
 
An unstratified Chi-squared test will also be provided as sensitivity analysis. Finally, the 
difference in response rates between treatment arms will be computed with 95% CIs, 
using the normal approximation to the binomial distribution.  
Descriptive analysis on the same subgroup analyses for primary endpoints will also be 
performed for ORR. 


 
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4.4.2 
Duration of Response 
Duration of response is defined as the time from first occurrence of a documented 
objective response (PR or CR) to disease progression, as determined by investigator 
tumor assessment using RECIST v1.1, or death from any cause, whichever occurs first.  
Patients who have not progressed and who have not died at the time of analysis will be 
censored at the time of last tumor assessment date. If no tumor assessments were 
performed after the date of the first occurrence of a response, duration of response will 
be censored at the date of the first occurrence of a response. Patients who received a 
NPT before their documented disease progression or death will be censored at the last 
tumor assessment date prior to the start date of this non-protocol anti-cancer therapy. 
The estimand for the key secondary endpoint is defined as follows: 
 
Population:  As defined for the primary endpoint in Section 4.3.1 and also 
experienced an objective response 
 
Treatments:  As defined for the primary endpoint Section 4.3.1  
 
Variable:  Time interval from the date of the first occurrence of an objective 
response (PR or CR) determined by investigator tumor assessment using RECIST 
v1.1 until the first date that progressive disease or death for any cause, whichever 
occurs first  
 
Intercurrent events: 
– 
Early discontinuation from treatment for any reason while responding  
– 
Start of NPT while responding 
 
Handling of intercurrent events: 
– 
In case of early discontinuation from treatment for any reason, a treatment 
policy will be applied (i.e., taking the date of the recorded event ignoring the 
occurrence of this intercurrent event) 
– 
In case of start of NPT while responding, an hypothetical strategy will be 
applied (i.e., censoring patient at the last tumor assessment date prior to the 
start date of this non-protocol anti-cancer therapy) 
 
Summary measure:  Hazard ratio for duration of response (DOR) 
 
The analysis methods are similar to those described for the primary efficacy endpoints 
PFS and OS in Section 4.3.2. 
4.4.3 
Progression-Free Survival in Patients with Baseline Brain 
Metastases 
PFS, defined as the time from randomization to first occurrence of disease progression, 
will be determined by investigator assessment using RECIST v1.1 or death from any 
cause, whichever occurs first, in patients with baseline brain metastases. 
The estimand for the secondary endpoint is defined as follows: 


 
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 
Population:  Subset of ITT with brain metastasis at baseline 
 
Treatments: As defined for the primary endpoint in Section 4.3.1 
 
Variable: Time from randomization to the first occurrence of a PFS event  
 
Intercurrent events: 
– 
Start of NPT prior to a PFS event 
– 
Early discontinuation from study treatment for any reason prior to a PFS event 
 
Handling of intercurrent events:  A treatment policy with regards to the listed 
intercurrent events will be applied for the secondary analysis (i.e., taking the date of 
the record PFS event ignoring the occurrence of those intercurrent events) 
 
Summary measure:  Hazard ratio for PFS  
 
The analysis methods are similar to those described for the primary efficacy endpoints 
PFS and OS in Section 4.3.2. 
4.4.4 
Overall Survival in Patients with Baseline Brain Metastases 
Overall survival, defined as the time from randomization to the date of death from any 
cause, in patients with baseline brain metastases. 
The estimand for the secondary endpoint is defined as follows: 
 
Population:  Subset of ITT with brain metastasis at baseline 
 
Treatments:  As defined for the primary endpoint in Section 4.3.1 
 
Variable:  Time from randomization to death from any cause 
 
Intercurrent events: 
– 
Start of NPT  
– 
Early discontinuation from study treatment for any reason  
 
Handling of intercurrent events:  A treatment policy with regards to the listed 
intercurrent events will be applied for the secondary analysis (i.e., taking the date of 
the recorded OS event ignoring the occurrence of those intercurrent events) 
 
Summary measure:  Hazard ratio for OS  
 
The analysis methods are similar to those described for the primary efficacy endpoints 
PFS and OS in Section 4.3.2.  
4.4.5 
Central Nervous System Progression-Free Survival 
Central nervous system (CNS) PFS is defined as the time from randomization until CNS 
disease progression, or first occurrence of symptomatic CNS disease, as determined by 
the investigator using RECIST v1.1, or death from any cause, whichever occurs first, in 
the subgroups of patients with or without CNS metastases at baseline.  


 
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Patients who have experienced non-CNS progression at the time of analysis will be 
censored at the date of this progression. Patients who have experienced no disease 
progression and are alive at the time of analysis will be censored at the date of their last 
post-baseline tumor assessment or, if they have no post-baseline tumor assessment, on 
the date of randomization  1 day.  
The estimand for the secondary endpoint is defined for population 1 and 2 separately as 
follows: 
 
Population 1:  Subset of ITT with CNS metastases at baseline 
 
Population 2:  Subset of ITT without CNS metastases at baseline 
 
Treatments:  As defined for the primary endpoint in Section 4.3.1 
 
Variable:  
– 
Time from randomization until CNS disease progression, or first occurrence of 
symptomatic CNS disease or death from any cause, as defined above 
 
Intercurrent events: 
– 
Start of NPT prior to a CNS-PFS event 
– 
Early discontinuation from study treatment for any reason prior to a CNS-PFS 
event 
 
Handling of intercurrent events:  A treatment policy with regards to the listed 
intercurrent events will be applied for the secondary analysis (i.e., taking the date of 
the recorded CNS-PFS event ignoring the occurrence of those intercurrent events) 
 
Summary measure:  Hazard ratio for CNS-PFS  
 
The analysis methods are similar to those described for the primary efficacy endpoints 
PFS and OS in Section 4.3.2.  
In addition, in order to account for the competing risks inherent in the comparison of 
CNS progression between treatments, a stratified two-sided log-rank test will be 
computed on the basis of a cause-specific hazard function. Results from unstratified 
tests will also be presented as supportive analyses. 
The probability of CNS progression, non-CNS progression, and death by treatment 
group with 95% CIs will each be estimated using cumulative incidence functions. Gray’s 
test to compare the risk of CNS progression between treatments will also be presented. 
4.5 
SAFETY ANALYSES 
Patients who receive any amount of study treatment will be included in the safety 
analyses. Safety results will be summarized based on the treatment patients actually 
received. Specifically, a patient will be included in the trastuzumab emtansine plus 
atezolizumab arm in safety analyses if the patient received any amount of atezolizumab. 


 
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Safety will be assessed through summaries of exposure to study treatment, AEs, 
changes in laboratory test results, and changes in vital signs and ECGs. 
4.5.1 
Extent of Exposure 
Study treatment exposure, such as treatment duration, total dose received, number of 
cycles, and dose modification (including dose delay, dose reduction, etc.) will be 
summarized for each study treatment on each treatment arm with descriptive statistics.  
Reasons for study treatment discontinuation will also be summarized. 
4.5.2 
Adverse Events 
Verbatim descriptions of AEs will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms and graded according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. The 
following events occurring on or after the first dose of study treatment (i.e., treatment-
emergent AEs) will be summarized by NCI CTCAE v5.0 grade: 
 
All AEs 
 
Serious adverse events 
 
AEs leading to death 
 
AEs of special interest (AESI) 
 
AEs leading to study drug discontinuation 
 
AEs leading to dose reduction (T-DM1) 
 
AEs leading to drug interruption 
 
AEs reported as COVID-19 
 
Selected AEs  
 
For events of varying severity, the highest grade will be used in the summaries.  
Deaths and cause of death will be summarized. 
4.5.3 
Additional Safety Assessments  
4.5.3.1 
Laboratory Data 
Relevant laboratory values and change from baseline will be summarized by treatment 
arm over time, with NCI CTAE v5.0 Grade 3 and Grade 4 value identified, where 
appropriate. 
Summary tables of shifts in NCI CTCAE v5.0 grades from baseline to the worst post-
baseline value will be presented. 
A Hy’s Law analysis will be provided: the finding of an elevated ALT or AST ( 3  upper 
limit of normal [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 an 
indicator of severe liver injury (as defined by Hy's Law). 


 
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In order to describe the AESI as well, the number of patients with ALT or AST  10  ULN 
will be provided. 
4.5.3.2 
Vital Signs 
Vital signs parameters (pulse rate, respiratory rate, blood pressure and temperature) will 
be summarized descriptively over time including change from baseline. 
4.5.3.3 
ECGs 
Electrocardiogram (ECG) data will be summarized over time including change from 
baseline.  
4.5.3.4 
Left Ventricular Ejection Fraction 
Change in left ventricular ejection fraction (LVEF) from baseline over time will be 
summarized for each treatment arm. 
The number of patients with a drop in LVEF of  10 ejection fraction points from baseline 
to an LVEF of  50% will be summarized.  The maximum decrease in LVEF from 
baseline will be summarized by treatment arm.  In addition, the lowest available LVEF 
measurements at any time on the study and the lowest post baseline value from each 
patient will be summarized.  
Further analyses will be performed if indicated by the data. 
4.6 
OTHER ANALYSES 
4.6.1 
Summaries of Conduct of Study 
Patient disposition will be summarized as outlined in Section 4.2.  
Duration of follow-up will be summarized by treatment arm to which patients were 
randomized. 
In addition, major protocol deviations, including major deviations with regards to the 
inclusion and exclusion criteria, and major deviations resulting from the COVID-19 
pandemic, will be summarized by treatment arm.   
4.6.2 
Summaries of Treatment Group Comparability 
The evaluation of treatment group comparability between the two treatment arms will 
include summaries of demographics, breast cancer history, baseline characteristics, 
patient treatment history, prior cancer therapy and a summary of randomization 
stratification factors. 
Descriptive statistics (mean, median, standard deviation, 25th percentile, 75th percentile, 
and range) will be presented for continuous variables such as age or time since initial 
breast cancer diagnosis. Frequency counts will be presented by treatment arm for 
categorical variables such as gender, race, and age category ( 65, 6574,  75).  


 
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The baseline value of any variable will be defined as the last available data point prior to 
the first administration of study medication. 
4.6.3 
Biomarker Analyses 
Baseline biomarker expression levels will be summarized by treatment arm. Descriptive 
statistics (mean, median, standard deviation, and range) will be presented for continuous 
biomarker data. Frequency counts will be presented for categorical biomarker data. 
Exploratory biomarkers analyses will be conducted to assess the relationship between 
biomarkers in tumor tissue as appropriate. 
Descriptive analysis of PFS and OS will be conducted within following biomarker 
subgroups: 
 
Stroma tumor-infiltrating lymphocytes (TIL) 
– 
 median vs.  median 
– 
 5% vs.  5%  
– 
low (0-10%) vs intermediate (11-60%) vs high ( 60%) 
 
Intratumoral TILs ( 1% vs.  1%)  
 
PD-L1 status ( 1% and  5% IC vs  5% IC and tumor cell %) 
 
HER2 immunohistochemistry (IHC) status IHC0 vs IHC1  vs IHC2  vs IHC3  
 
HER2 IHC focal ( 30% tumor cells) vs heterogeneous (3079% tumor cells) vs 
homogeneous ( 80% tumor cells) 
 
Patients with HER2 in situ hybridization amplified vs non-amplified 
 
4.6.4 
Screen Failure Analysis 
The Screen Failure Analysis is an exploratory analysis, which will consist into 
comparisons of the screen failed patients with a PD-L1 negative status versus the 
patient included in the ITT population. Note that all patients included in the ITT 
population should have a PD-L1 positive status as per the inclusion criteria. The 
comparisons will include demographics, breast cancer history, prior cancer therapy and 
tissue sample collection data. Further data may be included as deemed appropriate. The 
data will be summarized by patient group (ITT population and Screen Failures with 
negative PD-L1 Status) and overall. 
4.7 
INTERIM ANALYSES  
4.7.1 
Planned Interim Analyses 
Following the Sponsor’s decision to prematurely terminate the study, interim analyses 
will no longer be conducted. 
4.7.2 
Optional Interim Analyses 
No optional interim analyses are planned for this study. 


 
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5. 
SUPPORTING DOCUMENTATION 
This section is not applicable since there is no additional supporting document. 
6. 
REFERENCES 
References are available on request. 


 
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Appendix 1  
Protocol Synopsis 
PROTOCOL SYNOPSIS 
TITLE: 
A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, PLACEBO-
CONTROLLED PHASE III STUDY OF THE EFFICACY AND 
SAFETY OF TRASTUZUMAB EMTANSINE IN COMBINATION 
WITH ATEZOLIZUMAB OR PLACEBO IN PATIENTS WITH HER2-
POSITIVE AND PD-L1-POSITIVE LOCALLY ADVANCED OR 
METASTATIC BREAST CANCER WHO HAVE RECEIVED PRIOR 
TRASTUZUMAB- (+/- PERTUZUMAB) AND TAXANE-BASED 
THERAPY (KATE3) 
PROTOCOL NUMBER: 
MO42319 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2020-002818-41 
IND NUMBER: 
71,072 
NCT NUMBER: 
NCT04740918 
TEST PRODUCT: 
Trastuzumab Emtansine (RO5304020) 
Atezolizumab (RO5541267) 
PHASE: 
Phase III 
INDICATION: 
Locally advanced / metastatic breast cancer 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy, safety, pharmacokinetics, and patient-reported outcomes of 
trastuzumab emtansine plus atezolizumab compared with trastuzumab emtansine plus placebo 
in patients with human epidermal growth factor 2 (HER2)-positive and programmed death-
ligand 1 (PD-L1)-positive locally advanced (LABC) or metastatic breast cancer (MBC). Patients 
must have progressed either during or after prior trastuzumab- ( pertuzumab) and taxane-
based therapy for LABC/MBC; or during (or within 6 months after completing) trastuzumab- 
( pertuzumab) and taxane-based therapy in the neoadjuvant and/or adjuvant setting.  
Specific objectives and corresponding endpoints for the study are outlined below. 
PRIMARY EFFICACY OBJECTIVE 
The trial will compare trastuzumab emtansine given at a dose of 3.6 mg/kg by IV infusion, q3w 
plus atezolizumab administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each 21-
day cycle with trastuzumab emtansine given at a dose of 3.6 mg/kg by IV infusion, q3w plus 
placebo administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each 21-day cycle 
in patients with HER2-positive and PD-L1-positive LABC or MBC who have progressed either 
during or after prior trastuzumab- ( pertuzumab) and taxane-based therapy for LABC/MBC, or 
during (or within 6 months after completing) trastuzumab- ( pertuzumab) and taxane-based 
therapy in the neoadjuvant and/or adjuvant setting. 


 
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The two primary comparisons of interest will be the hazard ratios for PFS and OS as defined 
below. The primary trial objective is to demonstrate superiority of the experimental over the 
control treatment in either or both comparisons. 
 
Progression-free survival (PFS), defined as the time from randomization to the first 
occurrence of documented disease progression, as determined by investigator assessment 
using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or death from any 
cause, whichever occurs first 
 
Overall survival (OS), defined as the time from randomization to death from any cause 
Following the Sponsor’s decision to prematurely terminate the study, these objectives are no 
longer applicable. Accordingly, the analyses of PFS and OS will only be reported in a 
descriptive way. No formal testing will be performed and no control for the overall type I error 
(α) accounting for the two primary endpoints will be implemented. Consequently, p-values will 
not be able to be claimed as statistically significant and therefore will be reported as descriptive 
in nature. 
 
SECONDARY EFFICACY OBJECTIVE 
The secondary efficacy objective for this study is to evaluate the efficacy of trastuzumab 
emtansine plus atezolizumab compared with trastuzumab emtansine plus placebo on the basis 
of the following endpoints: 
 
Objective response rate (ORR), defined as a complete response (CR) or partial response 
(PR) on two consecutive assessments, at least 28 days apart, as determined by 
investigator assessment using RECIST version 1.1 
 
Duration of objective response (DOR), defined as the time from first occurrence of a 
documented objective response to disease progression, as determined by investigator 
assessment using RECIST v1.1 or death from any cause, whichever occurs first 
 
PFS, defined as the time from randomization to the first occurrence of disease progression, 
as determined by a blinded independent central review committee using RECIST v1.1, or 
death from any cause, whichever occurs first 
 
PFS in patients with baseline brain metastases as determined by investigator assessment 
using RECIST version 1.1 
 
OS in patients with baseline brain metastases defined as the time from randomization to 
death from any cause 
 
Central nervous system (CNS) PFS as determined by investigator assessment using 
RECIST version 1.1 in patients with or without baseline CNS metastases 
 
Mean absolute and mean change-from-baseline scores in function (Physical, Role) and 
global health status (GHS)/quality of life (QoL) as measured by the scales of the European 
Organisation for Research and Treatment of Cancer (EORTC QLQ-C30) 
 
The proportion of patients with clinically meaningful deterioration in GHS/QoL physical, and 
role function as measured by scales of the EORTC QLQ-C30  
Following the Sponsor’s decision to prematurely terminate the study, analysis of PFS as 
determined by a blinded independent central review committee will no longer be conducted. 
Similarly, analysis based on the EORTC QLQ-C30 data will no longer be conducted. 
 
EXPLORATORY EFFICACY OBJECTIVE 
The exploratory efficacy objective for this study is to evaluate the efficacy of trastuzumab 
emtansine plus atezolizumab compared with trastuzumab emtansine plus placebo on the basis 
of the following endpoints: 
 
Mean absolute and mean change-from-baseline scores in the remaining functions 
(Cognitive, Emotional, and Social), and disease- or treatment-related symptom scores of 
the EORTC QLQ-C30 and EORTC QLQ-Breast Cancer Module 23 Questionnaire (EORTC 
QLQ-BR23) 
Following the Sponsor’s decision to prematurely terminate the study, this exploratory efficacy 
objective is no longer applicable and corresponding analysis will no longer be performed. 


 
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SAFETY OBJECTIVE 
The safety objective for this study is to evaluate the safety of trastuzumab emtansine 
plus atezolizumab compared with trastuzumab emtansine plus placebo 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 (NCI CTCAE) 
Version 5.0 
 
Change from baseline in targeted clinical laboratory test results 
 
The exploratory safety objective for this study is to evaluate the safety of trastuzumab 
emtansine plus atezolizumab compared with trastuzumab emtansine plus placebo on 
the basis of the following endpoints: 
 
Presence, frequency of occurrence, severity, and/or degree of interference with daily 
function of selected symptomatic treatment toxicities (i.e., fatigue, chills, headache, cough, 
peripheral neuropathy, rash, aching muscles, aching joints, pain), as measured by the 
National Cancer Institute (NCI) Patient Reported Outcomes Common Terminology Criteria 
for Adverse Events (PRO-CTCAE) instrument 
 
Change from baseline in symptomatic treatment toxicities, as measured by the PRO-
CTCAE at pre-specified time points and an additional item regarding the overall burden 
experienced due to side effects of treatment from the EORTC item library 
Following the Sponsor’s decision to prematurely terminate the study, the exploratory safety 
objectives related to the PRO-CTCAE instrument are no longer applicable. The corresponding 
analyses will not be performed.  
 
PHARMACOKINETIC OBJECTIVE 
The pharmacokinetic (PK) objectives for this study are as follows: 
 
To characterize the PK of trastuzumab emtansine when given in combination with 
atezolizumab 
 
To characterize the PK of atezolizumab when given in combination with trastuzumab 
emtansine 
Following the Sponsor’s decision to prematurely terminate the study, these objectives are no 
longer applicable.  Accordingly, the corresponding analyses will not be performed.  
 
IMMUNOGENICITY OBJECTIVE 
The immunogenicity objective for this study is to evaluate the immune response to atezolizumab 
and trastuzumab emtansine when given in combination on the basis of the following endpoints: 
 
To characterize the prevalence and incidence of anti-drug antibodies (ADA) to atezolizumab 
in the presence of trastuzumab emtansine at pre-specified timepoints 
 
To characterize the prevalence and incidence of ADA to trastuzumab emtansine in the 
presence and absence of atezolizumab at pre-specified timepoints 
 
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  
 
Following the Sponsor’s decision to prematurely terminate the study, these objectives are 
no longer applicable. Accordingly, the corresponding analyses will not be performed.  
 
BIOMARKER OBJECTIVE 
The exploratory biomarker objective for this study is to identify and/or evaluate biomarkers that 
are predictive of response to atezolizumab in combination with trastuzumab emtansine 
(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 


 
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resistance to atezolizumab and trastuzumab emtansine, 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 and/or trastuzumab emtansine 
activity (i.e., pharmacodynamic biomarkers), or can increase the knowledge and understanding 
of disease biology and drug safety, on the basis of the following endpoints: 
 
Association of baseline immune status (may include but not limited to: protein, mRNA 
markers, T cell markers based on CD8 immunohistochemistry [IHC], and stromal tumor-
infiltrating lymphocytes [TILs]) with efficacy 
 
Association of baseline HER2 expression level (protein and/or gene copy number/ratio) with 
efficacy 
 
Association of baseline PD-L1 expression level (≥1% and <5% IC vs ≥5% IC) with efficacy  
 
Relationship between biomarkers in blood, plasma, and tumor tissue and efficacy, safety, 
PK, immunogenicity, tumor immunobiology, mechanisms of resistance 
Following the Sponsor’s decision to prematurely terminate the study, the objectives associated 
with efficacy are no longer applicable. Some descriptive analyses may be conducted as 
deemed appropriate.  
 
HEALTH STATUS OBJECTIVE 
The exploratory health status utility objective for this study is to evaluate health status utility 
scores of patients treated with trastuzumab emtansine plus atezolizumab compared with 
trastuzumab emtansine plus placebo on the basis of the following endpoint: 
 
Health utility and visual analog score (VAS) of the European Quality of Life 5-Dimension 
Questionnaire (5-level version; EQ-5D-5L) for pharmacoeconomic modeling at specified 
timepoints 
Following the Sponsor’s decision to prematurely terminate the study, these objectives are no 
longer applicable and the corresponding analyses will not be performed. 
 
STUDY DESIGN 
PREMATURE TERMINATION AND UNBLINDING AT STUDY LEVEL   
The Sponsor has decided to prematurely terminate the study due to a lower-than-expected 
enrolment rate, which significantly extended the recruitment timelines. The investigators were 
informed of premature study termination on 15 December 2022 by a study memo 
communicating this decision. 
Following a discussion between the investigator and the patient regarding the premature 
termination, the patient may consent to continue study treatment (i.e., either trastuzumab 
emtansine and atezolizumab or trastuzumab emtansine as a single agent; placebo will no 
longer be administered following unblinding of treatment assignment) if considered clinically 
appropriate by the investigator.  
Patients should continue to receive study treatment and undergo the revised study 
assessments as described below: 
 
Following the Sponsor’s decision to prematurely terminate the study, tumor assessments will be 
conducted as per standard of care at the site.  
After unblinding, patients will continue to be followed for tumor assessments until disease 
progression or until the patient discontinues from the study. All tumor assessments must be 
recorded in the eCRF. Tumor assessment scans will no longer be collected prospectively by the 
Sponsor as an independent review facility will not be utilized.  
Blood samples will no longer be drawn for PK and ADA analyses or for biomarker analyses, as 
these analyses will no longer take place. Patient-Reported Outcome (PRO) assessments will 
also no longer be collected.  
All safety assessments in the Schedule of Activities (Appendix 1) should be continued. All data 
should be recorded in the eCRF. 
 


 
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DESCRIPTION OF STUDY 
This is a Phase III, randomized, multicenter, international, two-arm, double-blind, placebo-
controlled clinical trial. The study will evaluate the efficacy, safety, pharmacokinetics, and 
patient-reported outcomes of trastuzumab emtansine plus atezolizumab compared with 
trastuzumab emtansine plus placebo in patients with HER2-positive and PD-L1-positive locally 
advanced (LABC) or metastatic breast cancer (MBC) who have progressed either during or 
after prior trastuzumab- (+/- pertuzumab) and taxane-based therapy for LABC/MBC, or during 
(or within 6 months after completing) trastuzumab- (+/- pertuzumab) and taxane-based therapy 
in the neoadjuvant and/or adjuvant setting. Previous adjuvant treatment with trastuzumab 
emtansine is not allowed if progression occurred during, or within 6 months after completing 
treatment. 
HER2 positivity and PD-L1 positivity of the tumor tissues will be determined by a central 
laboratory. Patients whose tumors are not centrally determined to be both HER2-positive and 
PD-L1-positive will not be eligible.  
Patients may be prescreened for HER2 and PD-L1 status at a central laboratory by participating 
in a separate prescreening consent. 
Approximately 350 patients will be enrolled in the study at approximately 175 sites worldwide.  
Patients will be randomized into one of the following treatment arms in a 1:1 ratio by means of a 
permuted block randomization scheme through the use of an interactive Web or voice response 
system: 
 
Arm A: trastuzumab emtansine 3.6 mg/kg and placebo, q3w 
 
Arm B: trastuzumab emtansine 3.6 mg/kg and atezolizumab 1200 mg, q3w  
 
Arm A and Arm B will be blinded with respect to administration of atezolizumab or placebo. 
Crossover between treatment arms will not be permitted. 
Randomization will be stratified according to:  
 
Local hormonal status (estrogen receptor [ER] and/or progesterone receptor [PgR] positive 
vs. ER and PgR negative/unknown), 
 
Disease status (visceral metastasis without brain metastasis vs. non-visceral metastasis 
only without brain metastasis [including locally advanced disease] vs. brain metastasis), 
 
World Region (Western Europe vs U.S. vs. Rest of World).  
 
Patients must have measurable disease at baseline that is evaluable per RECIST v1.1.  
Patients must also have unresectable, locally advanced or metastatic disease. Locally 
advanced disease must not be amenable to resection or other local therapy with curative intent.    
Patients will continue treatment until investigator-assessed radiographic disease progression 
per RECIST v1.1, withdrawal of consent, death, or intolerable toxicity, whichever occurs first. 
Patients with isolated CNS progression that require local therapy only will be allowed to 
continue with study treatment as per investigator decision. These patients will be recorded as 
disease progression for PFS analysis but will remain blinded and continue with treatment as per 
initial randomization until further disease progression in whichever location, withdrawal of 
consent, death, or intolerable toxicity, whichever occurs first. 
Patients will undergo scheduled tumor assessment every 6 weeks (± 7 days) that will continue 
until investigator-assessed radiographic disease progression per RECIST v1.1, withdrawal of 
consent, death, or study termination by the Sponsor, whichever occurs first. Patients who 
discontinue study treatment for reasons other than disease progression, even if they start new 
anti-cancer therapy, will continue to undergo tumor assessment every 6 weeks (± 7 days) until 
disease progression.  Following the Sponsor’s decision to prematurely terminate the study, 
tumor assessments will be conducted as per standard of care at the site.  
Tumor response will be based on RECIST v1.1 for estimation of PFS, ORR, and DOR. Tumor 
assessment scans will be collected prospectively by an independent review facility. Response 
will also be assessed by a blinded independent central review committee. Following premature 
study termination, tumor assessment scans will no longer be collected prospectively by the 
Sponsor as an independent review facility will not be utilized. 


 
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Safety assessments will include the incidence, nature, 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. 
Serum samples will be collected to monitor pharmacokinetics and to detect presence of 
antibodies to trastuzumab emtansine and atezolizumab.  Tumor tissues, plasma and whole 
blood samples will be collected for exploratory biomarker assessments. Following the Sponsor’s 
decision to prematurely terminate the study, samples for PK, ADA and exploratory biomarker 
research will no longer be collected.. 
Tumor tissue (historical sample or by new biopsy) will be collected at screening. A tissue 
sample from mandatory biopsy will be collected at the time of first evidence of radiographic 
disease progression per RECIST v1.1 (prior to the start of new anti-cancer treatment), unless 
not clinically feasible as assessed by the investigator.  These samples will enable analysis of 
tumor tissue biomarkers related to resistance, disease progression, and clinical benefit of 
trastuzumab emtansine in combination with atezolizumab. 
After the Study Drug Completion Visit, all patients (regardless of reason for discontinuation) will 
be followed up for their survival status and new anti-cancer therapy every 3 months until death, 
loss to follow-up, withdrawal of consent, or study termination by the Sponsor.  After patients 
discontinue from study treatment, information on subsequent anti-cancer therapies will be 
collected according to the same schedule as survival follow-up. 
NUMBER OF PATIENTS 
Approximately 350 patients will be enrolled in the study at approximately 175 sites worldwide. 
Following the Sponsor’s decision to prematurely terminate the study, the objective of enrolling 
350 patients will not be achieved. 
TARGET POPULATION 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
Signed Informed Consent Form by patient or legally-authorized representative 
 
Age ≥ 18 years at time of signing Informed Consent Form 
 
Ability to comply with the study protocol 
 
Histologically determined (in a central laboratory) HER2+/PD-L1+ LABC or MBC that is 
unresectable and previously treated with multimodality therapy: 
– 
Progression must have occurred during or after most recent treatment for LABC/MBC 
or during, or within 6 months after completing, neoadjuvant and/or adjuvant therapy 
– 
Prior treatment for breast cancer with trastuzumab (+/- pertuzumab) and taxane in the 
neoadjuvant and/or adjuvant, unresectable locally advanced, or metastatic settings 
– 
Patients must not have received more than two prior lines of therapy in the metastatic 
setting 
– 
Previous exposure to trastuzumab emtansine in the early breast cancer (EBC) setting 
is allowed only if disease recurrence occurred more than 6 months after completing, 
adjuvant trastuzumab emtansine. Previous exposure to trastuzumab emtansine in the 
metastatic setting is not allowed 
– 
Previous treatment with anti-HER2 agents (including, but not limited to, lapatinib, 
neratinib, tucatinib, trastuzumab deruxtecan, pyrotinib) and CD137 agonists, anti-
programmed death−1 (PD-1), or anti-PD-L1 therapeutic antibody or pathway−targeting 
agents is allowed 
– 
Patients who are receiving bisphosphonate therapy specifically to prevent skeletal 
events and who do not have a history of clinically significant hypercalcemia are eligible 
– 
Concurrent hormonal treatment for patients with hormone-positive disease is not 
allowed in the study 


 
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– 
Localized palliative radiation therapy is allowed for symptom management if finalized 
before enrollment. The patient must have recovered from any resulting acute toxicity (to 
Grade ≤ 1) prior to study treatment initiation. There is no required minimum recovery 
period 
 
Measurable disease per RECIST v1.1 
Previously irradiated lesions can be considered as measurable disease only if 
progressive disease has been unequivocally documented at that site since 
radiation 
 
Prospective central determination of representative tumor tissue specimen(s) prior to 
randomization of: 
– 
HER2-positive breast cancer as defined by an IHC score of 3+ or gene amplified by in 
situ hybridization (ISH) as defined by a ratio of ≥ 2.0 for the number of gene copies to 
the number of chromosome 17 copies 
– 
PD-L1 positivity defined by expression on tumor-infiltrating immune cells (IC) covering 
≥ 1% of tumor area by IHC using the PD-L1 (SP142) assay 
 
For patients with bilateral breast cancer (synchronous or developed at a later stage), HER2 
positivity must be centrally determined preferably in a metastatic biopsy or if not available in 
primary tumor from both left and right breast; at least one biopsy must be centrally 
determined as PD-L1 positive. 
 
For patients with initially multicentric tumors (multiple tumors involving more than one 
quadrant) or multifocal tumors (more than one mass confined to the same quadrant as the 
primary tumor), HER2 positivity must be centrally determined preferably in a metastatic 
biopsy or if not available in primary tumor, provided that: 
– 
For multicentric tumors all discrete lesions are centrally confirmed as HER2-positive 
and at least one lesion is centrally determined as PD-L1 positive 
– 
For multifocal tumors at least one focus is centrally confirmed as HER2-positive and 
PD-L1 positive 
 
A formalin-fixed, paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) 
or at least 17 slides containing unstained, freshly cut, serial sections must be submitted 
(preferably along with an associated pathology report) prior to study enrollment. The 
unstained slides for staining must be within the current documented cutslide stability 
window.  The sample needs to be of good quality based on total and viable tumor content.   
If archival tumor tissue is unavailable or is determined to be unsuitable for required testing, 
tumor tissue must be obtained from a biopsy performed at screening.  A biopsy may also be 
performed at screening if a patient's archival tissue test results do not meet eligibility 
criteria. 
Cytological or fine-needle aspiration samples and bone specimens are not 
acceptable for central testing to determine eligibility. 
 
Willing to provide blood samples before treatment start, while on-study, and at progression, 
for standard of care follow-up and exploratory research on biomarkers 
 
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 
 
Life expectancy ≥ 6 months 
 
Adequate hematologic and end-organ function, defined by the following laboratory test 
results, obtained within 7 days prior to initiation of study treatment: 
– 
ANC ≥ 1.5 x 109/L (≥ 1500/µL) without granulocyte colony-stimulating factor support  
– 
Lymphocyte count ≥ 0.5 x 109/L (≥ 500/µL) 
– 
Platelet count ≥ 100 x 109/L (≥ 100,000/µL) without transfusion   
– 
Hemoglobin ≥ 90 g/L (≥ 9 g/dL) 
Patients may be transfused to meet this criterion 


 
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– 
AST, ALT, and alkaline phosphatase (ALP) ≤ 2.5 x upper limit of normal (ULN), with the 
following exceptions: 
Patients with documented liver metastases: AST and ALT ≤ 5 x ULN 
Patients with documented liver or bone metastases: ALP ≤ 5 x ULN 
– 
Total bilirubin ≤ 1.5 x ULN with the following exception: 
Patients with known Gilbert disease:  total bilirubin ≤ 3 x ULN 
– 
Creatinine ≤ 1.5 x ULN or Creatinine clearance ≥ 30 mL/min (calculated using the 
Cockcroft-Gault formula) 
– 
Albumin ≥ 25 g/L (≥ 2.5 g/dL) 
– 
For patients not receiving therapeutic anticoagulation: INR and aPTT ≤ 1.5 x ULN 
– 
For patients receiving therapeutic anticoagulation: stable anticoagulant regimen 
 
Negative HIV test at screening 
 
For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, 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 7 months after the final dose of 
study treatment. 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 is not permanently infertile due to surgery (i.e., removal of ovaries, 
fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian 
agenesis). Per this definition, a woman with a tubal ligation is considered to be of childbearing 
potential. 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, hormonal contraceptives that inhibit ovulation, and hormone-releasing 
intrauterine devices and copper intrauterine devices; 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 
If required per local guidelines or regulations, locally recognized adequate methods 
of contraception and information about the reliability of abstinence will be described 
in the local Informed Consent Form 
 
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 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 
7 months after the final dose of study treatment. Men must refrain from donating 
sperm during this same period 
With a pregnant female partner, men must remain abstinent or use a condom 
during the treatment period and for 7 months after the final dose of study treatment 
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 


 
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abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) 
and withdrawal are not acceptable methods of contraception 
If required per local guidelines or regulations, locally recognized adequate methods 
of contraception and information about the reliability of abstinence will be described 
in the local Informed Consent Form 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding 
fungal infections of nail beds) at study enrollment, or any major episode of infection 
requiring treatment with IV antibiotics or hospitalization (for complications of infections or 
relating to the completion of the course of antibiotics) within 4 weeks prior to Cycle 1, Day 1 
This also applies to patients with suspected or confirmed COVID-19 infection 
 
Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study 
treatment 
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection 
or chronic obstructive pulmonary disease exacerbation) are eligible for the study 
 
Receipt of any anti-cancer drug/biologic or investigational treatment 21 days prior to Cycle 
1, Day 1 except hormone therapy, which can be given up to 7 days prior to Cycle 1, Day 1; 
recovery of treatment-related toxicity consistent with other eligibility criteria 
 
Prior treatment with trastuzumab emtansine in metastatic setting 
 
History of exposure to the following cumulative doses of anthracyclines as specified below: 
– 
Doxorubicin > 500 mg/m2 
– 
Liposomal doxorubicin > 500 mg/m2 
– 
Epirubucin > 720 mg/m2 
– 
Mitoxantrone > 120 mg/m2 
– 
Idarubicin > 90 mg/m2 
If another anthracycline or more than one anthracycline has been used, then the 
cumulative dose must not exceed the equivalent of 500 mg/m2 doxorubicin 
 
Symptomatic or actively progressing central nervous system (CNS) metastases 
Asymptomatic CNS lesions ≤ 2cm without clinical requirement for local intervention 
(whole brain radiation therapy and/or stereotactic radiosurgery and/or surgery) are 
eligible, provided that all of the following criteria are met; it is for investigator to 
decide if local intervention is indicated  
Asymptomatic patients with treated CNS lesions are eligible, provided that all of the 
following criteria are met: 
▪ 
Measurable disease, per RECIST v1.1, must be present outside the CNS 
▪ 
No brain lesions thought to require immediate local therapy 
▪ 
Only supratentorial and cerebellar metastases allowed (i.e., no 
metastases to midbrain, pons, medulla, or spinal cord) 
▪ 
The patient has no history of intracranial hemorrhage or spinal cord 
hemorrhage 
▪ 
The patient has not undergone stereotactic radiotherapy within 7 days 
prior to initiation of study treatment, whole-brain radiotherapy within 21 
days prior to initiation of study treatment, or neurosurgical resection 
within 28 days prior to initiation of study treatment 
▪ 
Anticonvulsant therapy at a stable dose is permitted 
No ongoing use of systemic corticosteroids for control of symptoms of 
brain metastases at a total daily dose of >2 mg of dexamethasone (or 


 
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equivalent). Subjects on a chronic stable dose of ≤2 mg total daily of 
dexamethasone (or equivalent) are eligible 
Note: Patients with new asymptomatic CNS metastases detected at the screening 
scan who require radiation therapy and/or surgery for CNS metastases, must 
receive it before screening. Following local intervention, these patients may be 
eligible without the need for an additional brain scan prior to enrollment, if all other 
criteria are met. 
 
History of leptomeningeal disease 
 
Spinal cord compression not definitively treated with surgery and/or radiation, or previously 
diagnosed and treated spinal cord compression without evidence that disease has been 
clinically stable for > 2 weeks prior to randomization 
 
Uncontrolled tumor-related pain 
Patients requiring pain medication must be on a stable regimen at study entry 
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated ≥ 14 days prior 
to Cycle 1, Day 1. The patient must have recovered from any resulting acute 
toxicity (to Grade ≤ 1) prior to study treatment initiation 
Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not currently 
associated with spinal cord compression) should be considered for loco-regional 
therapy, if appropriate, prior to enrollment 
 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently) 
Patients with indwelling catheters (e.g., PleurX®) are allowed 
 
Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, 
calcium > 12 mg/dL, or corrected calcium greater than ULN) 
 
Current Grade ≥ 3 peripheral neuropathy (according to the NCI CTCAE v5.0) 
 
Active hepatitis B (defined as having a positive hepatitis B surface antigen [HbsAg] test at 
screening) or hepatitis C 
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection 
(defined as having a negative HbsAg test and a positive antibody to hepatitis B 
core antigen [anti-HBc] antibody test accompanied by a negative HBV DNA test) 
are eligible 
Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase 
chain reaction is negative for HCV RNA 
 
Current treatment with anti-viral therapy for HBV 
 
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, anti-phospholipid antibody syndrome, 
granulomatosis with polyangiitis, Sjögren syndrome, Guillain-Barré syndrome, or multiple 
sclerosis, 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 of following conditions are met: 
▪ 
Rash must cover < 10% of body surface area 


 
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▪ 
Disease is well controlled at baseline and requires only low-potency 
topical corticosteroids 
▪ 
There has been 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 
▪ 
Patients with psoriasis must have a baseline ophthalmologic exam to 
rule out ocular manifestations 
 
Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia 
 
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 CT scan 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted 
 
Active tuberculosis 
 
Cardiopulmonary dysfunction as defined by: 
– 
Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg with or 
without medication) 
– 
Inadequate left ventricular ejection fraction at baseline, < 50% by either ECHO or 
MUGA 
– 
History of symptomatic congestive heart failure (CHF)-Grade ≥ 3 per NCI CTCAE 
version 5.0 or Class ≥ II New York Health Association 
– 
History of a decrease in left ventricular ejection fraction to < 40% or symptomatic CHF 
with prior trastuzumab treatment 
– 
Myocardial infarction or unstable angina within 6 months of randomization  
– 
Current dyspnea at rest due to complications of advanced malignancy, or other disease 
requiring continuous oxygen therapy 
– 
Evidence of transmural infarction on ECG 
– 
Significant symptoms (Grade ≥ 2) relating to LVEF, cardiac arrhythmia, or cardiac 
ischemia 
– 
High-risk uncontrolled arrhythmias (i.e., supraventricular 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]) 
 
Major surgical procedure, other than for diagnosis, or significant traumatic injury within 4 
weeks prior to initiation of study treatment, or anticipation of need for a major surgical 
procedure during the study 
 
History of malignancy within 5 years prior to initiation of study treatment, with the exception 
of the cancer under investigation in this study and malignancies with a negligible risk of 
metastasis or death (e.g., 5-year OS rate > 90%), such as adequately treated carcinoma in 
situ of the cervix, non melanoma skin carcinoma, localized prostate cancer, ductal 
carcinoma in situ, or Stage I uterine cancer  
 
Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, 
pulmonary or metabolic disease; wound healing disorders; ulcers; bone fractures) 
 
Prior allogeneic stem cell or solid organ transplantation 
 
Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that contraindicates the use of an investigational drug, may affect the 
interpretation of the results, or may render the patient at high risk from treatment 
complications 


 
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 
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during atezolizumab treatment or 
within 5 months after the final dose of study treatment 
 
Treatment with systemic immunostimulatory agents (including, but not limited to, interferon 
and interleukin 2 [IL-2]) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) 
prior to initiation of study treatment 
 
Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-α 
agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for 
systemic immunosuppressive medication during study treatment, with the following 
exceptions: 
– 
Patients who received acute, low-dose systemic immunosuppressant medication or a 
one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of 
corticosteroids for a contrast allergy) are eligible for the study  
– 
Patients who received mineralocorticoids (e.g., fludrocortisone), inhaled or low-dose 
corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-
dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for 
the study 
 
History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies, excipients of any drugs formulated in polysorbate 80 or 20 or fusion 
proteins 
 
Known hypersensitivity to Chinese hamster ovary cell products or to any component of the 
atezolizumab formulation 
 
Known allergy or hypersensitivity to any component of the trastuzumab emtansine 
formulation 
 
Pregnancy or breastfeeding, or intention of becoming pregnant during the study or within 
7 months after the last dose of study treatment 
Women of childbearing potential must have a negative serum pregnancy test result 
within 7 days prior to initiation of study treatment 
 
END OF STUDY 
The end of study is planned to occur after approximately 184 OS events are obtained 
(approximately 40 months after the primary efficacy analysis of PFS [and concurrent first interim 
analysis of OS]). The end of this study is defined as the date when the last patient, last visit 
occurs, or the date at which the last data point required for statistical analysis or safety follow-up 
is received from the last patient, whichever occurs later.  
The Sponsor has decided to prematurely terminate the study due to a lower-than-expected 
enrolment rate. The investigators were informed of this decision on 15 December 2022. Patients 
have the option to remain on the study and continue treatment until arrangements are put in 
place for continuing treatment on an extension study (BO25430) or in a Post-Trial Access 
Program or other local options. The treatment solution for each patient may vary, taking into 
account local regulations and requirements. 
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 78.1 months. The length of study will now be determined by the 
time taken at each study site to implement the off-study patient treatment solutions, which 
should be approximately by the end of 2023. 
INVESTIGATIONAL MEDICINAL PRODUCTS 
Trastuzumab emtansine, atezolizumab, and placebo are investigational medicinal products for 
this study. 
TEST PRODUCT (INVESTIGATIONAL DRUG) 
Trastuzumab emtansine will be given at a dose of 3.6 mg/kg by IV infusion, q3w.  The dose of 
trastuzumab emtansine will be administered on the basis of the patient’s baseline weight.  


 
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Weight will be measured at each visit (or in the 3 days prior) and dose must be re-adjusted for 
weight changes  10% compared to the previous visit or baseline. Administration may be 
delayed to assess or treat adverse events.  Dose reduction will be allowed for trastuzumab 
emtansine.  Once a dose has been reduced for adverse event(s), it must not be re-escalated.  
If trastuzumab emtansine is discontinued because of toxicity, it should not be re-administered. 
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, on the earliest 
following date with subsequent protocol-specified procedures rescheduled accordingly. 
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each 
21-day cycle. Dose reductions for atezolizumab are not allowed during this study.  
Both trastuzumab emtansine and atezolizumab/placebo 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.   
Atezolizumab or placebo will be administered first, followed by trastuzumab emtansine. 
COMPARATOR 
Placebo will be administered IV according to the same schedule as atezolizumab. 
NON-INVESTIGATIONAL MEDICINAL PRODUCTS 
None. 
STATISTICAL METHODS 
PRIMARY ANALYSIS 
The multiple primary efficacy endpoints for this study are PFS based on investigator tumor 
assessment and OS.  The ITT population is the primary analysis population for the primary 
efficacy endpoints and includes all patients who are randomized to the study, whether or not 
they receive any study medication.  Treatment group for the ITT population will be defined 
according to the treatment assigned at randomization. 
The primary PFS analysis (and first interim OS analysis) is planned to be performed when 
approximately 229 PFS events had occurred. It is expected to have approximately 87 OS 
events at that point in time. The estimated time from first-patient-in to primary PFS/first interim 
OS analysis is approximately 38 months. 
Following the Sponsor’s decision to prematurely terminate the study, there will be only a single 
analysis timepoint for both PFS and OS primary efficacy endpoints. Interim analyses will no 
longer be conducted.  Considering the expected lack of maturity of the data, the analysis of PFS 
and OS primary efficacy endpoints will only be reported in a descriptive way. No formal testing 
will be performed and no control for the overall type I error (α) accounting for the two primary 
endpoints will be implemented. Consequently, p-values will not be able to be claimed as 
statistically significant and therefore will be reported as descriptive in nature. 
PROGRESSION-FREE SURVIVAL 
PFS is defined as the time from randomization to first documented disease progression as 
determined by the investigator using RECIST 1.1 or death from any cause, whichever occurs 
earlier. The first documented disease progression will be used in the main analysis of the 
primary efficacy endpoint of PFS. Data for patients without disease progression or death from 
any cause as of the data cut-off date will be censored at the time of the last tumor assessment 
with an outcome other than “unevaluable” (or, if no tumor assessment was performed after the 
baseline visit, at the time of randomization plus 1 day). Data from patients who are lost to follow-
up will be included in the analysis as censored observations on the date of the last tumor 
assessment that the patient was known to be progression-free.  
The Kaplan-Meier method will be used to estimate median PFS and the corresponding 95% Cis 
for each treatment arm. The 2-sided log-rank test, stratified by the factors specified in the 
protocol (excluding world region) will be used to compare PFS between the treatment arms. If 
less than 5 events are observed in any combination, only the unstratified analysis will be done. 
The stratification factors will be based on data collected by the IxRS rather than on data 
collected on the eCRFs. The unstratified log-rank test result will also be provided. The Cox 


 
Trastuzumab Emtansine, Atezolizumab—F. Hoffmann-La Roche Ltd. 
Statistical Analysis Plan MO42319 
39 
proportional hazards model, stratified by the previous noted stratification factors will be used to 
estimate the HR and to calculate the 95% CI of the HR. 
In order to assess the consistency of treatment benefit with respect to the multiple primary 
efficacy endpoints PFS and OS across important subgroups, forest plots (including estimated 
HRs) will be provided, including, but not limited, to the following variables: race, age, sex, world 
region, baseline HER2 and PD-L1 expression, ECOG status, hormone receptor status, and line 
of treatment in the metastatic setting (first or second line vs. third line).  
OVERALL SURVIVAL 
OS is defined as the time from randomization to death from any cause.  Patients who are alive 
as of the data cut-off date of the analysis will be censored at the last known date they were 
alive.  Patients with no post-baseline information will be censored at the date of randomization 
plus 1 day.  Methods for data analysis are analogous to those described for the primary efficacy 
endpoint PFS. The 2-sided log-rank test, stratified by the factors specified in the protocol 
(excluding world region) will be used to compare OS between the treatment arms. 
DETERMINATION OF SAMPLE SIZE   
The two primary efficacy endpoints for this study are PFS based on investigator tumor 
assessment and OS.  
This study has been designed to detect a substantial magnitude of benefit in the ITT population, 
that is, improvement in median PFS from 7 months in the control arm to 11.67 months in the 
experimental arm, corresponding to a target PFS hazard ratio of 0.60, and improvement in 
median OS from 31 months in the control arm to 47.7 months in the experimental arm, 
corresponding to a target OS hazard ratio of 0.65. 
Approximately 350 patients randomized according to a 1:1 randomization (approximately 175 
patients will be randomized to Arm A and to Arm B) will be enrolled in the study. The sample 
size assumes an annual dropout rate of 10% in both treatment arms and result in an estimated 
recruitment time of about 32 months (with ramp up in the first 8 months). Following the 
Sponsor’s decision to prematurely terminate the study, the initially planned number of 
randomized patients will not be reached.  
Furthermore, in the context of premature study termination, there will be only a single analysis 
timepoint for the PFS and OS primary efficacy endpoints. Interim analyses will no longer be 
conducted.  Considering the expected lack of maturity of the data the analysis of PFS and OS 
primary efficacy endpoints will only be reported in a descriptive way. No formal testing will be 
performed and no control for the overall type I error (α) accounting for the two primary endpoints 
will be implemented. Consequently, p-values will not be able to be claimed as statistically 
significant and therefore will be reported as descriptive in nature. 
INTERIM ANALYSES  
Following the Sponsor’s decision to prematurely terminate the study, the interim analyses will 
no longer be conducted.  


Signature Page for Statistical Analysis Plan - KATE3 (MO42319) - Published
System identifier: RIM-CLIN-473966
Approval Task
Company Signatory
28-Mar-2023 15:25:03 GMT+0000