Clinical trial NCT02924883
Conditions: Metastatic Breast Cancer
Sponsor: Hoffmann-La Roche
Start date: 2016-09-26; Completion date: 2020-02-06
Enrollment: 202 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase II, double-blind, randomized, placebo-controlled multicenter study will investigate the efficacy and safety of trastuzumab emtansine in combination with atezolizumab or atezolizumab-placebo in participants with HER2-positive locally advanced or metastatic BC who have received prior trastuzumab and taxane based therapy, either alone or in combination, and/or who have progressed within 6 months after completing adjuvant therapy.

Detailed description:

Arms: arm 1: Atezolizumab 1200 milligrams (mg) intravenous (IV) infusion or matching Placebo followed by trastuzumab emtansine 3.6 milligrams per kilogram (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 (approximately 29 months) arm 2: Placebo matched to atezolizumab 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 (approximately 29 months)
Interventions: intervention 1: Atezolizumab intervention 2: Trastuzumab emtansine intervention 3: Placebo
Intervention descriptions: intervention 1: Atezolizumab 1200 mg IV infusion intervention 2: Trastuzumab emtansine 3.6 mg/kg IV infusion intervention 3: Placebo matched to atezolizumab

Protocol documents:
Prot_000.pdf: 
Official Title: 
A Randomized, Multicenter, Double-Blind, Placebo-Controlled 
Phase II Study Of The Efficacy And Safety Of Trastuzumab 
Emtansine In Combination With Atezolizumab Or Atezolizumab-
Placebo In Patients With HER2-Positive Locally Advanced Or 
Metastatic Breast Cancer Who Have Received Prior Trastuzumab 
And Taxane Based Therapy 
NCT Number: 
NCT02924883 
Document Date: 
Protocol Version 3: 09 Aug 2017 


PROTOCOL AMENDMENT APPROVAL 
 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
Protocol WO30085, Version 3 
PROTOCOL 
TITLE: 
A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, 
PLACEBO-CONTROLLED PHASE II STUDY OF 
THE EFFICACY AND SAFETY OF TRASTUZUMAB 
EMTANSINE IN COMBINATION WITH 
ATEZOLIZUMAB OR ATEZOLIZUMAB-PLACEBO 
IN PATIENTS WITH HER2-POSITIVE LOCALLY 
ADVANCED OR METASTATIC BREAST CANCER 
WHO HAVE RECEIVED PRIOR TRASTUZUMAB 
AND TAXANE BASED THERAPY 
PROTOCOL NUMBER: WO30085 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2015-004189-27 
IND NUMBER: 
71,072 
TEST PRODUCT: 
Trastuzumab Emtansine (RO5304020) 
Atezolizumab (RO5541267) 
MEDICAL MONITOR: 
, M.D. 
, Ph.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 1:  14 April 2016 
DATE AMENDED: 
Version 2:  21 December 2016 
Version 3:  See electronic date stamp below. 
 
09-Aug-2017 16:54:13
Title
Approver's Name
Company Signatory
Date and Time (UTC)


 
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PROTOCOL AMENDMENT, VERSION 3: 
RATIONALE 
Changes to the protocol, along with a rationale for each change, are summarized below: 
• 
The following changes to the study design have been made given the emerging 
scientific understanding of delayed therapeutic effects with immunotherapy agents 
and the need for more mature progression-free survival (PFS) and overall survival 
(OS) data to gauge efficacy: 
The interim analysis for PFS has been removed (Sections 6.4.1 and 6.9). 
The number of PFS events for the primary PFS analysis has been increased 
from 95 to 115 (Sections 3.2. 6.1, and 6.4.1). 
• 
The first analysis of OS will be performed at the time of the primary PFS analysis.  
Another update for OS will be performed at approximately 12 months after the 
primary PFS analysis.  The final OS analysis will be performed at approximately 
24 months after the primary PFS analysis or when ~50% OS events from 
200 patients can be obtained, whichever occurs first.  The Sponsor may consider 
additional OS updates beyond 24 months after primary PFS analysis if more mature 
OS data are requested by the Health Authority.  The changes allow for a better 
understanding of the therapeutic effects of the experimental treatment on OS and 
provide more mature data for benefit-risk assessment with the additional follow-up 
period for survival data (Section 6.4.2). 
• 
The assumed median PFS time for the control arm, trastuzumab emtansine plus 
placebo, has been changed from 9.6 months (observed in EMILIA study) to 
6.2 months (observed in TH3RESA study) to reflect the observed prior treatment 
demographics of patients enrolled in the study (Section 6.1). 
• 
The estimated time for primary PFS analysis has been changed from approximately 
19−21 months after first patient enrolled to approximately 15−17 months after first 
patient enrolled, due to the updated assumption of median PFS time for the control 
arm and the updated number of events for primary PFS analysis (Sections 3.2 and 
6.4.2). 
• 
The pregnancy reporting process has been clarified (Sections 5.4.3.1 and 5.4.3.2). 
• 
The safety risks for trastuzumab emtansine and atezolizumab have been updated, 
in line with the respective Investigator’s Brochure updates (Sections 5.1.1.5 and 
5.1.2, respectively).  
• 
Brain assessment has been clarified (Section 4.5.5). 
• 
The reporting of the term “sudden death” has been updated to also require the 
presumed cause of death (Section 5.3.5.8). 
• 
Event reporting for hospitalization has been clarified (Section 5.3.5.11). 
• 
Brain computed tomography (CT)/ magnetic resonance imaging (MRI) requirements 
have been clarified (Sections 4.5.5 and Appendix 1) 


 
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• 
The process for reviewing and handling protocol deviations has been updated per 
internal standard operating procedures (Section 9.2). 
 
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.   


 
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PROTOCOL AMENDMENT, VERSION 3: 
SUMMARY OF CHANGES 
GLOBAL CHANGES 
The Medical Monitor for the study has been changed from 
 M.D., Ph.D. to 
 M.D. 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 1.4:  STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
The safety and tolerability of the combination of trastuzumab emtansine and 
atezolizumab is currently unknown and is being evaluated in an ongoing, Phase Ib study 
(Study GO29831); Section 1.3.4); whilst no dose-limiting toxicities have been observed 
in the the safety cohort of 6 pstients treated with trastzumab emtansine+atezolizumab, 
there remains the potential for unknown and overlapping toxicity.  To minimize this risk, 
stringent inclusion and exclusion criteria (Section 4.1), close safety monitoring 
(Section 5.3) together with rules for dose modifications and safety management 
guidelines for known risks of single-agent trastuzumab emtansine and atezolizumab 
have been implemented in the current study.  Furthermore, guidance on management of 
potential overlapping toxicities is described in Section 5.1.4.  An independent Data 
Monitoring Committee (iDMC) (Section 5.1) has also been incorporated into the trial 
design to periodically review aggregate safety data (refer to the iDMC Charter for a 
detailed monitoring plan). 
SECTION 2.1.1:  Primary Efficacy Objective 
The primary efficacy objective for this study is to evaluate the efficacy of the combination 
of trastuzumab emtansine plus atezolizumab/placebo compared with trastuzumab 
emtansine plus placebo on the basis of the following endpoint: 
SECTION 2.1.2:  Secondary Efficacy Objectives 
The secondary efficacy objectives for this study are to evaluate the efficacy of the 
combination of trastuzumab emtansine plus atezolizumab/placebo compared with 
trastuzumab emtansine plus placebo on the basis of the following endpoints: 
SECTION 2.1.3:  Exploratory Efficacy Objectives 
The exploratory efficacy objectives for this study are to evaluate the efficacy of the 
combination of trastuzumab emtansine plus atezolizumab/placebo compared with 
trastuzumab emtansine plus placebo on the basis of the following endpoints: 
SECTION 3.1:  DESCRIPTION OF THE STUDY 
Patients will be treated in one of the following arms: 
• 
Arm B: trastuzumab emtansine 3.6 mg/kg and atezolizumab/placebo 1200 mg, q3w 
(approximately 133 patients) 
 


 
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In patients who continue treatment beyond radiographic disease progression per 
RECIST v1.1, tumor response will also continue to be assessed using immune-modified 
RECIST criteria (Appendix 5) every 6 weeks (± 7 days) until study treatment 
discontinuation.  Immune-modified RECIST criteria may account for the possibility of 
delayed anti-tumor activity that may be preceded by initial apparent radiological 
progression, including the appearance of new lesions. 
SECTION 3.2:  END OF STUDY AND LENGTH OF STUDY 
This study is anticipated to have a recruitment period of approximately 9 months.  
The final analysis of the primary efficacy endpoint will be conducted when approximately 
95115 PFS events have occurred, based on investigator assessments.  This is assumed 
to be approximately 20 15−17 months after the enrollment of the first patient (FPI). 
The end of study is triggered by the final OS analysis following last patient last visit 
(LPLV) which that is planned to occur approximately 9 24 months after the primary 
efficacy analysis or at approximately 50% OS events from 200 patients can be obtained, 
whichever occurs first.  The Sponsor may consider additional OS update(s) beyond 
24 months after primary PFS analysis if more mature OS data are requested by the 
Health Authority.  The Sponsor may also terminate the study at any time. 
The total duration of the study is expected to be approximately 29 40 months.  
SECTION 3.3.6:  Rationale for Collection of PK and ATA Samples 
Both atezolizumab and trastuzumab emtansine single-agent pharmacokinetics have 
been characterized in multiple Phase I, II, and III studies.  Refer to the latest versions of 
the Trastuzumab Emtansine and Atezolizumab IBs for further details.  In this study, 
PK/ATA samples will be collected from all patients in both Arm A and Arm B as detailed 
in Appendix 2.  Sparse sampling will be used in this study.  PK and immunogenicity of 
atezolizumab (Arm B A) and trastuzumab emtansine (Arm A and Arm B) will be 
assessed… 
SECTION 4.2.2:  Stratification 
Randomization will be stratified based on the following two three factors: 
SECTION 4.3.5:  Post-Trial Access to Trastuzumab Emtansine and 
Atezolizumab 
The Sponsor will evaluate the appropriateness of continuing to provide trastuzumab 
emtansine and atezolizumab (where applicable) to patients on protocol treatment at the 
end of the study as defined in (see Section 3.2). in accordance with the Roche Global 
Policy on Continued Access to Investigational Medicinal Product, available at the 
following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 


 
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SECTION 4.5.5:  Tumor and Response Evaluations 
All known sites of disease must be documented at screening and re-assessed at each 
subsequent tumor evaluation.  Tumor assessments performed after the screening period 
should consist of the following assessments every 6 weeks:  1) CT and/or MRI of the 
chest/abdomen/pelvis, as well as other known sites of disease, including brain, 2) If a 
patient has only bone as a site of involvement at screening which is determined to be 
measurable disease as per RECIST 1.1, then a bone scan or PET scan is mandated at 
every tumor assessment,. O otherwise, a bone scan or PET scan is to be performed as 
clinically indicated, e.g., suspicion of disease progression, 3) in cases where patients 
demonstrate control of their systemic disease but who newly develop isolated brain 
metastases and are eligible to remain on study treatment, brain MRI or CT are 
performed along with regularly scheduled tumor assessments, and 4) any other imaging 
studies felt to be clinically indicated by the treating physician. 
At the investigator’s discretion, CT or other clinically appropriate scans may be repeated 
at any time if PD is suspected.  If the initial screening bone scan or PET scan indicates 
bone metastases and this is the only site of involvement and is determined to be 
measurable disease per RECIST 1.1, then a bone scan or PET scan needs to be 
performed every 6 weeks.  If the screening scan shows evidence of either non-
measurable bone metastases or no bone metastases, then these procedures do not 
need to be repeated unless clinically indicated or at the treating physician’s discretion.  
Similarly, If the brain is not identified as a site of involvement at screening, then brain 
CT or MRI only needs to be repeated beyond screening, if clinically indicated.  In cases 
where a patient demonstrates control of their systemic disease but who newly develops 
isolated brain metastases and is eligible to remain on study treatment, brain MRI or CT 
are performed along with regularly scheduled tumor assessments (Section 3.1). 
SECTION 5.1.1.5:  Hematologic Toxicity 
Cases of bleeding events with a fatal outcome have been observed.  Severe cases of 
hemorrhagic events, including central nervous system hemorrhage, have been reported 
in clinical trials of trastuzumab emtansine; these events were independent of ethnicity.  
In some of the observed cases, the patients were also receiving anti-coagulation therapy. 
Patients with thrombocytopenia (≤ 100,000/mm3) and patients on anti-coagulant 
treatment should be monitored closely during treatment with trastuzumab emtansine.  
It is recommended that platelet counts are monitored prior to each trastuzumab 
emtansine dose.  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). 
SECTION 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 


 
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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 other cases, 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. 
SECTION 5.1.2:  Risks Associated with Atezolizumab 
The PD-L1/PD-1 pathway is involved in peripheral tolerance; therefore, such 
atezolizumab therapy may increase the risk of immune-mediated adverse events, 
specifically the induction or enhancement of autoimmune conditions.  To date, 
immune-related adverse events associated with atezolizumab include hepatitis, 
pneumonitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, hyperthyroidism, 
adrenal insufficiency, Guillain-Barré syndrome, myasthenic syndrome/myasthenia gravis, 
myocarditis, hypophysitis, and meningoencephalitis.  In addition, systemic immune 
activation (described below) is a potential risk when atezolizumab is given in 
combination with other immunomodulating agents.  For further details regarding the 
up-to-date clinical safety of atezolizumab, see the most recent version of the 
Atezolizumab IB. 
Systemic immune activation is a rare condition characterized by an excessive immune 
response.  Given the mechanism of action of atezolizumab, systemic immune activation 
is considered a potential risk when atezolizumab is given in combination with other 
immunomodulating agents.  Systemic immune activation should be included in the 
differential diagnosis for patients who, in the absence of an alternative etiology, develop 
a sepsis-like syndrome after administration of atezolizumab, and the initial evaluation 
should include the following: 
• 
CBC with peripheral smear 
• 
PT, PTT, fibrinogen, and D-dimer 
• 
Ferritin 
• 
Triglycerides 
• 
AST, ALT, and total bilirubin 
• 
LDH 
• 
Complete neurologic and abdominal examination (assess for hepatosplenomegaly) 
 
If systemic immune activation is still suspected after the initial evaluation, contact the 
Medical Monitor for additional recommendations. 
SECTION 5.1.3.2.1:  Cardiotoxicity 
The decision to stop or continue trastuzumab emtansine treatment should be on the 
basis of the algorithm shown in Figure 3 for asymptomatic declines in LVEF.  
Trastuzumab emtansine must be discontinued in all patients for whom a confirmed 


 
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decrease of LVEF to < 40% is documented (with a confirmation assessment carried out 
within 21 days)… 
SECTION 5.1.3.3:  Management of Patients Who Have 
Atezolizumab/Placebo Related Specific Adverse Events 
Guidelines for the management of patients who experience specific adverse events (other 
than systemic immune activation) are provided in the most recent version of the 
Atezolizumab IB. 
No dose modification for atezolizumab is allowed. 
SECTION 5.3.5.8:  Deaths 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  The term "sudden death" should be used only for the occurrence of an abrupt 
and unexpected death due to presumed cardiac causes in a patient with or without 
preexisting heart disease, within 1 hour after the onset of acute symptoms or, in the case 
of an unwitnessed death, within 24 hours after the patient was last seen alive and stable.  
If the cause of death is unknown and cannot be ascertained at the time of reporting, 
"unexplained death" should be recorded on the Adverse Event eCRF.  If the 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"). 
SECTION 5.3.5.11:  Hospitalization or Prolonged Hospitalization 
The following hospitalization scenarios are not considered to be adverse events: 
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
The following hospitalization scenarios are An event that leads to hospitalization under 
the following circumstances is not considered to be serious adverse events, but should 
be reported as adverse events instead: 
SECTION 5.4.1:  Emergency Medical Contacts 
Medical Monitor Contact Information 
Medical Monitor 
 M.D., Ph.D. 
Telephone No.: 
 
 
Mobile Telephone No.: 
 
 
 
SECTION 5.4.3.1:  Pregnancies in Female Patients 
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 


 
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number or email address provided to investigators.  Pregnancy should not be recorded 
on the Adverse Event eCRF.  The investigator should discontinue study treatment and 
counsel the patient, discussing the risks of the pregnancy and the possible effects on the 
fetus.  Monitoring of the patient should continue until conclusion of the pregnancy.  
Any serious adverse events associated with the pregnancy (e.g., an event in the fetus, 
an event in the mother during or after the pregnancy, or a congenital anomaly/birth 
defect in the child) should be reported on the Adverse Event eCRF.  Additional 
information on any atezolizumab/placebo or trastuzumab emtansine-exposed pregnancy 
and infant will be requested by Roche Drug Safety at specific time points (i.e., after 
having received the initial report during the first trimester, at the end of the second 
trimester, 2 weeks after the expected date of delivery, and at 3, 6, and 12 months of the 
infant’s life).  In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available.  
A Pregnancy Report eCRF should be completed by the investigator immediately (i.e., no 
more than 24 hours after learning of the pregnancy) and submitted via the EDC system.  
A pregnancy report will automatically be generated by the EDC system and will be sent 
to Roche Safety Risk Management.  Additional information on any atezolizumab/placebo 
or trastuzumab emtansine-exposed pregnancy and infant will be requested by Roche 
Drug Safety at specific time points (i.e., after having received the initial report during the 
first trimester at the end of the second trimester, 2 weeks after the expected date of 
delivery, and at 3, 6, and 12 months of the infant’s life).  Pregnancy should not be 
recorded on the Adverse Event eCRF.  The investigator should immediately and 
permanently discontinue the study drug and counsel the patient, discussing the risks of 
the pregnancy and the possible effects on the fetus.  Monitoring of the patient should 
continue until conclusion of the pregnancy.  Any serious adverse events associated with 
the pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF. 
In the event that the EDC system is unavailable, the Clinical Trial Pregnancy Reporting 
Form provided to investigators should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Once the EDC system is available again, all 
information will need to be entered and submitted via the EDC system. 
SECTION 5.4.3.2:  Pregnancies in Female Partners of Male Patients 
A paper Clinical Trial Pregnancy Reporting Form should be completed and submitted 
to the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of 
the pregnancy), either by faxing or by scanning and emailing the form using the fax 
number or email address provided to investigators.  Attempts should be made to collect 
and report details of the course and outcome of any pregnancy in the partner of a male 


 
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patient exposed to study drug.  When permitted by the site, the pregnant partner would 
need to sign an Authorization for Use and Disclosure of Pregnancy Health Information 
to allow for follow up on her pregnancy.  If the authorization has been signed, the 
investigator should submit a Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available.  Additional 
information on any atezolizumab/placebo or trastuzumab emtansine-exposed pregnancy 
and infant will be requested by Roche Drug Safety at specific time points (i.e., after 
having received the initial report during the first trimester, at the end of the second 
trimester, 2 weeks after the expected date of delivery, and at 3, 6, and 12 months of the 
infant’s life).  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. 
A Pregnancy Report eCRF should be completed by the investigator immediately (i.e., no 
more than 24 hours after learning of the pregnancy) and submitted via the EDC system.  
Additional information on any atezolizumab/placebo or trastuzumab emtansine exposed 
pregnancy and infant will be requested by Roche Drug Safety at specific time points 
(i.e., after having received the initial report during the first trimester at the end of the 
second trimester, 2 weeks after the expected date of delivery, and at 3, 6, and 
12 months of the infant’s life).  Attempts should be made to collect and report details of 
the course and outcome of any pregnancy in the partner of a male patient exposed to 
study drug.  The pregnant partner will need to sign an Authorization for Use and 
Disclosure of Pregnancy Health Information to allow for follow up on her pregnancy.  
Once the authorization has been signed, the investigator will update the Pregnancy 
Report eCRF with additional information on the course and outcome of the pregnancy.  
An investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
In the event that the EDC system is unavailable, follow reporting instructions provided in 
Section 5.4.3.1. 
SECTION 6.1:  DETERMINATION OF SAMPLE SIZE  
The primary efficacy endpoint for this study is PFS based on investigator tumor 
assessment.  The primary PFS analysis will be performed when approximately 115 PFS 
events have occurred.The timing of the primary efficacy analysis will be event driven.   
With approximately 200 patients randomized according to a 2:1 1:2 randomization 
(approximately 133 67 patients will be randomized to Arm A and approximately 67 
133 patients will be randomized to Arm B) the study has the estimated power for the 
PFS HRs presented in Table 14.  


 
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The above study design considerations assume proportional hazards, a cumulative 
dropout rate of 10% in each treatment arm and result in an estimated recruitment time of 
about 9 months (with ramp up in the first 4 months).  The estimated time from FPI to final 
primary PFS analysis is 19 to 21 15 to 17 months, depending on PFS HR assumption.   
SECTION 6.4.1:  Primary Efficacy Endpoint 
The primary efficacy endpoint for this study is PFS based on investigator tumor 
assessment.  The intention-to-treat (ITT) population is the primary analysis population 
for the primary efficacy endpoint 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 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 Section 4.2.2 (excluding liver metastases), will be used to compare PFS 
between the treatment arms at the overall two-sided significance level of 5%.  Liver 
metastases will be excluded because of the potential that some of the strata may have 
very few patients, which would result in a loss of power.  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 liver metastases, 
will be used to estimate the HR and to calculate the 95% CI of the HR. 
The Kaplan-Meier method will be used to estimate median PFS for each treatment arm.  
The 2-sided log-rank test, stratified by world region (Western Europe vs U.S. vs Rest of 
World) and PD-L1 status (IC 0 vs IC 1-3) will be used to compare PFS between the 
treatment arms.  The unstratified log-rank test result will also be provided.  The stratified 
Cox regression model will be used to estimate the HR and to calculate the 95% CI of the 
HR. 
A group sequential design will be used for testing the primary efficacy endpoint PFS to 
account for the conduct of interim analyses.  An alpha spending using a gamma function 
with parameter -1 will be utilized to control the overall Type I error rate.  The interim PFS 
analysis will be conducted when approximately 63 investigator-assessed PFS events 
(66.7% information fraction) have been observed and is anticipated to occur 
approximately 14 months from FPI.  Key design characteristics of the interim PFS 
analysis are detailed in Table 15.   


 
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Table 15 
PFS Interim Analysis Design Characteristics using Gamma (-1) 
Alpha Spending Function  
Number of 
PFS Events 
Information 
Fraction 
Cumulative 
Alpha Spent 
Crossing 
Boundary in HR 
Crossing Boundary in 
P-Value 
63 
66.7% 
0.028 
HR ≤ 0.571 
p ≤ 0.014 
HR = hazard ratio; PFS = progression-free survival. 
 
The sponsor may decide to consider adding an additional interim analysis including 
efficacy data which will be pre-specified in the SAP as appropriate. 
The interim analyses will be conducted by an iDMC with the support of an independent 
Data Coordinating Center (iDCC).  Interactions between the iDMC and the sponsor will 
follow the iDMC charter.  The decision to conduct the interim analysis, rationale, timing, 
and statistical details will be documented in the SAP.  Additional interim analyses may 
be conducted if requested by health authorities.  The primary final PFS analysis will be 
performed when approximately 95 115 investigator-assessed PFS events have been 
observed and is anticipated to occur approximately 19 to 21 15 to 17 months from FPI, 
depending on PFS HR assumptions (Section 6.1).   
SECTION 6.4.2: Secondary Efficacy Endpoints 
Overall Survival 
The first analysis of OS will be performed at the time of the primary PFS analysis.  
Another update for OS will be performed at approximately 12 months after the primary 
PFS analysis.  The final OS analysis will be performed at approximately 24 months 
after the primary PFS analysis or when ~50% OS events from 200 patients can be 
obtained, whichever occurs first.  The Sponsor may consider additional OS updates 
beyond 24 months after primary PFS analysis if more mature OS data are requested by 
the Health Authority. 
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 (Blyth-Still-Casella) 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 liver metastases) 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. 


 
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PFS in Subgroups of Patients Defined as PD-L1Dx + and PD-L1Dx 
The analysis methods are similar to those described for the primary efficacy endpoint.  
SECTION 6.4.3:  Exploratory Efficacy Endpoints 
Objective Response Rate based on Immune Modified RECIST 
Objective response, defined as a complete response (CR) or partial response (PR), will 
be determined by investigator tumor assessment using immune-modified RECIST.  
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 (Blyth-Still-Casella) 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 liver metastases) 
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 based on Immune-Modified RECIST   
[Note:  title change only] 
  
SECTION 6.5:  SAFETY ANALYSES 
Adverse Events 
Safety will be assessed through summaries of adverse events, changes in laboratory test 
results, changes in vital signs, study treatment exposures, and immunogenicity as 
measured by ATA and will be presented by treatment arm. 
Verbatim descriptions of adverse events will be mapped to Medical Dictionary for 
Regulatory Activities (MedDRA) thesaurus terms and graded according to the 
NCI CTCAE v4.0.  The following events occurring on or after the first dose of study drug 
(i.e., treatment-emergent adverse events) will be summarized by NCI CTCAE grade: 
• 
Sponsor-defined adverse events of special interest 
 
Deaths and causes of death will be summarized.  Selected adverse events will be 
summarized by NCI CTCAE grade for each treatment arm based on pre-specified 
category definitions, including (but not limited to) hepatotoxicity, cardiac dysfunction, and 
thrombocytopenia.  In addition, adverse eventsoccurring within 1 day (24 hours) of the 
first dose of each treatment cycle will be summarized to help characterize potential 
infusion-related reactions.  
Additional safety analyses may be performed as indicated.  


 
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SECTION 6.9.1:  Planned Interim Analysis 
There is no planned interim efficacy analysis for PFS. 
An interim efficacy analysis is planned for the primary efficacy endpoint PFS when 
approximately 63 investigator-assessed PFS events have been observed, anticipated to 
occur around 14 months after FPI.  An alpha spending using a gamma function with 
parameter -1 will be utilized to control the overall Type I error rate for PFS.  Further 
details are given in Section 6.4.1.   
The sponsor may decide to consider adding an additional interim analysis including 
efficacy data which will be pre-specified in the SAP as appropriate. 
The interim analyses will be conducted by an iDMC with the support of an independent 
iDCC.  Interactions between the iDMC and the sponsor will follow the iDMC charter.  
The decision to conduct the interim analysis, rationale, timing, and statistical details will 
be documented in the SAP.  Additional interim analyses may be conducted if requested 
by health authorities. 
SECTION 9.2:  PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
SECTION 9.4:  ADMINISTRATIVE STRUCTURE 
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 
patient safety data in unblinded fashion during course of the study, as well as conducting 
efficacy interim analyses as specified in the SAP.  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. 
SECTION 9.5:  PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS  
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.pdf 
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf 
FIGURE 3:  Algorithm for Continuation and Discontinuation of Trastuzumab 
Emtansine Treatment Based on LVEF Assessments in Patients 
Figure 3 has been revised to reflect changes in the protocol.  


 
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TABLE 10:  Management Guidelines for Increased Transaminases 
(AST/ALT) and Hepatic Events 
Table 10 has been revised to reflect most recent version of Investigator’s Brochure.  
TABLE 14:  Estimated Power at Primary Final PFS Analysis for Different 
PFS HRs 
Table 12 has been revised to reflect changes in the protocol.  
TABLE 15:  PFS Interim Analysis Design Characteristics using Gamma (-1) 
Alpha Spending Function 
Table 15 has been deleted.  
APPENDIX 1:  Schedule of Assessments 
The schedule of assessments has been revised to reflect the changes to the protocol. 
 


 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 24 
PROTOCOL SYNOPSIS .................................................................................... 25 
1. 
BACKGROUND .......................................................................................... 39 
1.1 
Background on Breast Cancer ............................................... 39 
1.2 
Background on Trastuzumab Emtansine ............................... 40 
1.2.1 
Study TDM4370g/BO21977 (EMILIA) ................................... 40 
1.2.2 
Study TDM4997g/BO25734 (TH3RESA) ............................... 41 
1.3 
Background on Atezolizumab ................................................ 42 
1.3.1 
Study PCD4989g ................................................................... 43 
1.3.2 
Study GP28328 ..................................................................... 44 
1.3.3 
Study WO29522 .................................................................... 45 
1.3.4 
Study GO29831 ..................................................................... 46 
1.4 
Study Rationale and Benefit-Risk Assessment ...................... 47 
2. 
OBJECTIVES AND ENDPOINTS ............................................................... 48 
2.1 
Efficacy Objectives ................................................................ 48 
2.1.1 
Primary Efficacy Objective ..................................................... 48 
2.1.2 
Secondary Efficacy Objectives .............................................. 48 
2.1.3 
Exploratory Efficacy Objectives ............................................. 48 
2.2 
Safety Objectives ................................................................... 49 
2.3 
Pharmacokinetic Objectives .................................................. 49 
2.4 
Immunogenicity Objectives .................................................... 49 
2.5 
Biomarker Objectives............................................................. 49 
3. 
STUDY DESIGN ......................................................................................... 50 
3.1 
Description of the Study......................................................... 50 
3.2 
End of Study and Length of Study ......................................... 54 
3.3 
Rationale for Study Design .................................................... 54 
3.3.1 
Rationale for Atezolizumab Dose and Schedule .................... 54 
3.3.2 
Rationale for Trastuzumab Emtansine Dose and 
Schedule ................................................................................ 54 
3.3.3 
Rationale for Patient Population ............................................ 54 


 
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3.3.4 
Rationale for Control Group ................................................... 55 
3.3.5 
Rationale for Biomarker Assessments ................................... 55 
3.3.5.1 
Rationale for Collection of Archival and 
Metastatic Tumor Specimens ................................................ 56 
3.3.5.2 
Rationale for Collection of Optional Pre-Treatment 
and Cycle 2 Biopsies ............................................................. 57 
3.3.5.3 
Rationale for the Collection of Biopsy at the Time 
of Radiographic Progression ................................................. 57 
3.3.6 
Rationale for Collection of PK and ATA Samples .................. 58 
3.3.7 
Rationale for Allowing Patients to Continue 
Treatment Beyond Initial Progression per 
RECIST 1.1 ........................................................................... 58 
4. 
MATERIALS AND METHODS .................................................................... 59 
4.1 
Patients .................................................................................. 59 
4.1.1 
Inclusion Criteria .................................................................... 59 
4.1.2 
Exclusion Criteria ................................................................... 62 
4.2 
Method of Treatment Assignment and Blinding ..................... 66 
4.2.1 
Number of Patients/Assignment to Treatment 
Groups ................................................................................... 66 
4.2.2 
Stratification ........................................................................... 66 
4.2.3 
Study Treatment Unblinding .................................................. 66 
4.2.3.1 
Unblinding at Patient Level .................................................... 67 
4.2.3.2 
Unblinding at Study Level ...................................................... 67 
4.3 
Study Treatment .................................................................... 67 
4.3.1 
Formulation, Packaging, and Handling .................................. 68 
4.3.1.1 
Trastuzumab Emtansine ........................................................ 68 
4.3.1.2 
Atezolizumab ......................................................................... 68 
4.3.1.3 
Placebo .................................................................................. 68 
4.3.2 
Dosage, Administration, and Compliance .............................. 68 
4.3.2.1 
Trastuzumab Emtansine ........................................................ 68 
4.3.2.2 
Atezolizumab/Placebo ........................................................... 69 
4.3.3 
Sequence of Study Drug Administration ................................ 70 
4.3.4 
Investigational Medicinal Product Accountability ................... 70 
4.3.5 
Post-Trial Access to Trastuzumab Emtansine 
and Atezolizumab .................................................................. 71 


 
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4.4 
Concomitant Therapy ............................................................ 71 
4.4.1 
Permitted Therapy ................................................................. 71 
4.4.2 
Prohibited Therapy ................................................................ 72 
4.5 
Study Assessments ............................................................... 73 
4.5.1 
Informed Consent Forms and Screening Log ........................ 73 
4.5.2 
Medical History and Demographic Data ................................ 73 
4.5.3 
Physical Examinations ........................................................... 73 
4.5.4 
Vital Signs .............................................................................. 74 
4.5.5 
Tumor and Response Evaluations ......................................... 74 
4.5.6 
Left Ventricular Ejection Fraction Assessment ...................... 76 
4.5.7 
Electrocardiogram ................................................................. 76 
4.5.8 
Laboratory, Biomarker, and Other Biological 
Samples ................................................................................. 76 
4.5.8.1 
Laboratory Samples .............................................................. 76 
4.5.8.2 
Biomarker Samples ............................................................... 78 
4.5.9 
Biomarker Sample Handling and Biomarker 
Results ................................................................................... 82 
4.5.10 
Optional Samples for Research Biosample 
Repository ............................................................................. 83 
4.5.10.1 
Overview of the Research Biosample Repository .................. 83 
4.5.10.2 
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 83 
4.5.10.3 
Sample Collection .................................................................. 83 
4.5.10.4 
Confidentiality ........................................................................ 84 
4.5.10.5 
Consent to Participate in the Research 
Biosample Repository ............................................................ 84 
4.5.10.6 
Withdrawal from the Research Biosample 
Repository ............................................................................. 85 
4.5.10.7 
Monitoring and Oversight ....................................................... 85 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation ...................................................................... 85 
4.6.1 
Patient Discontinuation .......................................................... 85 
4.6.2 
Study Treatment Discontinuation ........................................... 86 
4.6.3 
Study and Site Discontinuation .............................................. 86 
5. 
ASSESSMENT OF SAFETY ....................................................................... 87 


 
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5.1 
Safety Plan ............................................................................ 87 
5.1.1 
Risks Associated with Trastuzumab Emtansine .................... 87 
5.1.1.1 
Pulmonary Toxicity ................................................................ 87 
5.1.1.2 
Hepatotoxicity ........................................................................ 88 
5.1.1.3 
Left Ventricular Dysfunction ................................................... 89 
5.1.1.4 
Infusion-Related Reactions and Hypersensitivity 
Reactions ............................................................................... 89 
5.1.1.5 
Hematologic Toxicity ............................................................. 90 
5.1.1.6 
Hemorrhage ........................................................................... 90 
5.1.1.7 
Neurotoxicity .......................................................................... 90 
5.1.1.8 
Extravasation ......................................................................... 91 
5.1.2 
Risks Associated with Atezolizumab ..................................... 91 
5.1.3 
Management of Adverse Events ............................................ 92 
5.1.3.1 
Dose Modification .................................................................. 92 
5.1.3.2 
Management of Patients who have Trastuzumab 
Emtansine Related Specific Adverse Events ......................... 94 
5.1.3.3 
Management of Patients Who Have 
Atezolizumab/Placebo-Related Specific Adverse 
Events.................................................................................... 97 
5.1.4 
Management of Patients who have Potential 
Overlapping Toxicities Associated with 
Trastuzumab Emtansine and 
Atezolizumab/Placebo ........................................................... 97 
5.1.4.1 
Infusion-Related Reactions .................................................... 97 
5.1.4.2 
Pulmonary Events:  Atezolizumab and 
Trastuzumab Emtansine ........................................................ 98 
5.1.4.3 
Hepatic Events:  Atezolizumab and Trastuzumab 
Emtansine .............................................................................. 99 
5.1.4.4 
Hyperbilirubinemia:  Trastuzumab Emtansine ..................... 102 
5.2 
Safety Parameters and Definitions ...................................... 102 
5.2.1 
Adverse Events ................................................................... 103 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) .................................................................... 103 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................. 104 


 
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5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters .............................................. 105 
5.3.1 
Adverse Event Reporting Period ......................................... 105 
5.3.2 
Eliciting Adverse Event Information ..................................... 105 
5.3.3 
Assessment of Severity of Adverse Events ......................... 106 
5.3.4 
Assessment of Causality of Adverse Events ....................... 106 
5.3.5 
Procedures for Recording Adverse Events .......................... 107 
5.3.5.1 
Infusion-Related Reactions .................................................. 107 
5.3.5.2 
Diagnosis versus Signs and Symptoms............................... 107 
5.3.5.3 
Adverse Events That Are Secondary to Other 
Events.................................................................................. 108 
5.3.5.4 
Persistent or Recurrent Adverse Events .............................. 108 
5.3.5.5 
Abnormal Laboratory Values ............................................... 109 
5.3.5.6 
Abnormal Vital Sign Values ................................................. 109 
5.3.5.7 
Abnormal Liver Function Tests ............................................ 110 
5.3.5.8 
Deaths ................................................................................. 110 
5.3.5.9 
Preexisting Medical Conditions ............................................ 111 
5.3.5.10 
Lack of Efficacy or Worsening of Metastatic 
Breast Cancer ...................................................................... 111 
5.3.5.11 
Hospitalization or Prolonged Hospitalization ........................ 111 
5.3.5.12 
Adverse Events Associated with an Overdose or 
Error in Drug Administration ................................................ 112 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor ........................................................ 112 
5.4.1 
Emergency Medical Contacts .............................................. 113 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest ................... 114 
5.4.2.1 
Events That Occur prior to Study Drug Initiation .................. 114 
5.4.2.2 
Events That Occur after Study Drug Initiation ...................... 114 
5.4.3 
Reporting Requirements for Pregnancies ............................ 114 
5.4.3.1 
Pregnancies in Female Patients .......................................... 114 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ............... 115 
5.4.3.3 
Abortions ............................................................................. 115 
5.4.3.4 
Congenital Anomalies/Birth Defects .................................... 116 
5.5 
Follow-Up of Patients after Adverse Events ........................ 116 


 
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5.5.1 
Investigator Follow-Up ......................................................... 116 
5.5.2 
Sponsor Follow-Up .............................................................. 116 
5.6 
Adverse Events that 2ccur after the $dverse 
Event Reporting Period ........................................................ 116 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ............................................................... 117 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ..................... 117 
6.1 
Determination of Sample Size ............................................. 117 
6.2 
Summaries of Conduct of Study .......................................... 118 
6.3 
Summaries of Treatment Group Comparability ................... 118 
6.4 
Efficacy Analyses ................................................................ 119 
6.4.1 
Primary Efficacy Endpoint .................................................... 119 
6.4.2 
Secondary Efficacy Endpoints ............................................. 120 
6.4.3 
Exploratory Efficacy Endpoints ............................................ 121 
6.5 
Safety Analyses ................................................................... 122 
6.6 
Pharmacokinetic Analyses ................................................... 123 
6.7 
Immunogenicity Analyses .................................................... 123 
6.8 
Biomarker Analyses ............................................................. 123 
6.9 
Interim Analysis ................................................................... 124 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 124 
7.1 
Data Quality Assurance ....................................................... 124 
7.2 
Electronic Case Report Forms ............................................. 124 
7.3 
Source Data Documentation ................................................ 124 
7.4 
Use of Computerized Systems ............................................ 125 
7.5 
Retention of Records ........................................................... 125 
8. 
ETHICAL CONSIDERATIONS .................................................................. 126 
8.1 
Compliance with Laws and Regulations .............................. 126 
8.2 
Informed Consent ................................................................ 126 
8.3 
Institutional Review Board or Ethics Committee .................. 127 
8.4 
Confidentiality ...................................................................... 127 
8.5 
Financial Disclosure ............................................................ 128 


 
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9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 128 
9.1 
Study Documentation .......................................................... 128 
9.2 
Protocol Deviations .............................................................. 128 
9.3 
Site Inspections ................................................................... 128 
9.4 
Administrative Structure....................................................... 129 
9.5 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 129 
9.6 
Protocol Amendments ......................................................... 130 
10. REFERENCES ......................................................................................... 131 
 
LIST OF TABLES 
Table 1 
Administration of First and Subsequent Infusions of 
Trastuzumab Emtansine ............................................................. 69 
Table 2 
Administration of First and Subsequent Infusions of 
Atezolizumab/Placebo ................................................................ 70 
Table 3 
Proposed Biomarkers for Exploratory Research ......................... 79 
Table 4 
Dose Modification Scheme for Trastuzumab Emtansine ............ 94 
Table 5 
Trastuzumab Emtansine Dose Modification Guidelines for 
Hematological Toxicity ................................................................ 96 
Table 6 
Trastuzumab Emtansine Dose Modification Guidelines for 
Neuropathy ................................................................................. 96 
Table 7 
Management Guidelines for Atezolizumab/Placebo 
Infusion-Related Reactions ......................................................... 97 
Table 8 
Management Guidelines for Trastuzumab Emtansine 
Infusion-Related Reactions (Caused by Cytokine Release) or 
Hypersensitivity (Allergic) Reaction ............................................. 98 
Table 9 
Management Guidelines for Interstitial Lung Disease and 
Pneumonitis ................................................................................ 99 
Table 10 
Management Guidelines for Increased Transaminases 
(AST/ALT) and Hepatic Events ................................................. 100 
Table 11 
Trastuzumab Emtansine Dose Modification Guidelines for 
Hyperbilirubinemia in Patients with Metastatic Breast Cancer .. 102 
Table 12 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE v4.0 ...................................... 106 
Table 13 
Causal Attribution Guidance ..................................................... 107 
Table 14 
Estimated Power at Primary PFS Analysis for Different PFS 
HRs ........................................................................................... 118 
 
 


 
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LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 53 
Figure 2 
Overview of Tissue Flow in the Study ......................................... 81 
Figure 3 
Algorithm for Continuation and Discontinuation of 
Trastuzumab Emtansine Treatment Based on LVEF 
Assessments in Patients ............................................................. 95 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments ......................................................... 135 
Appendix 2 
Schedule of Pharmacokinetic and Immunogenicity Samples .... 141 
Appendix 3 
Schedule of Biomarker Samples ............................................... 143 
Appendix 4 
Response Evaluation Criteria in Solid Tumors, Version 1.1 ...... 145 
Appendix 5 
Immune-Modified Response Evaluation Criteria in Solid 
Tumors ...................................................................................... 156 
Appendix 6 
Ventana HER2 IHC Assay ........................................................ 164 
Appendix 7 
Ventana HER2 ISH Assay ........................................................ 165 
Appendix 8 
New York Heart Association Classification ............................... 166 
Appendix 9 
ECOG Performance Status Scale ............................................. 167 
Appendix 10 Preexisting Autoimmune Diseases ........................................... 168 
Appendix 11 Guidelines for Liver Biopsy ....................................................... 169 


 
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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, 
PLACEBO-CONTROLLED PHASE II STUDY OF 
THE EFFICACY AND SAFETY OF TRASTUZUMAB 
EMTANSINE IN COMBINATION WITH 
ATEZOLIZUMAB OR ATEZOLIZUMAB-PLACEBO 
IN PATIENTS WITH HER2-POSITIVE LOCALLY 
ADVANCED OR METASTATIC BREAST CANCER 
WHO HAVE RECEIVED PRIOR TRASTUZUMAB 
AND TAXANE BASED THERAPY 
PROTOCOL NUMBER: WO30085 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2015-004189-27 
IND NUMBER: 
71,072 
TEST PRODUCT: 
Trastuzumab Emtansine (RO5304020) 
Atezolizumab (RO5541267)  
MEDICAL MONITOR: 
 M.D. 
 Ph.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please return the signed original of this form as instructed by your local study monitor.  
Please retain a copy for your study files. 
 


 
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PROTOCOL SYNOPSIS 
TITLE: 
A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, 
PLACEBO-CONTROLLED PHASE II STUDY OF THE EFFICACY 
AND SAFETY OF TRASTUZUMAB EMTANSINE IN COMBINATION 
WITH ATEZOLIZUMAB OR ATEZOLIZUMAB-PLACEBO IN 
PATIENTS WITH HER2-POSITIVE LOCALLY ADVANCED OR 
METASTATIC BREAST CANCER WHO HAVE RECEIVED PRIOR 
TRASTUZUMAB AND TAXANE BASED THERAPY 
PROTOCOL NUMBER: 
WO30085 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2015-004189-27 
IND NUMBER: 
71,072 
TEST PRODUCT: 
Trastuzumab Emtansine (RO5304020) 
Atezolizumab (RO5541267) 
PHASE: 
Phase II 
INDICATION: 
Locally advanced or metastatic breast cancer 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives and Endpoints 
This study will evaluate the efficacy, safety, and pharmacokinetics of trastuzumab emtansine 
in combination with atezolizumab or placebo (atezolizumab-placebo) in patients with human 
epidermal growth factor 2 (HER2)-positive, locally advanced or metastatic breast cancer (MBC), 
who have received prior trastuzumab and taxane based therapy, either alone or in combination, 
and/or who have progressed within 6 months after completing adjuvant therapy.  Specific 
objectives and corresponding endpoints for the study are outlined below. 
Primary Efficacy Objective 
The primary efficacy objective for this study is to evaluate the efficacy of the combination of 
trastuzumab emtansine plus atezolizumab compared with trastuzumab emtansine plus placebo 
on the basis of the following endpoint: 
• 
Progression-free survival (PFS), defined as the time from randomization to the first 
occurrence of disease progression, as determined by investigator assessment using 
RECIST v1.1, or death from any cause, whichever occurs first 
Secondary Efficacy Objective 
The secondary efficacy objectives for this study are to evaluate the efficacy of the combination 
of trastuzumab emtansine plus atezolizumab compared with trastuzumab emtansine plus 
placebo on the basis of the following endpoints: 
• 
Overall survival (OS), defined as the time from randomization to death from any cause 
• 
Objective response, 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 Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 
• 
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 


 
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Exploratory Efficacy Objective 
The exploratory efficacy objectives for this study are to evaluate the efficacy of the combination 
of trastuzumab emtansine plus atezolizumab compared with trastuzumab emtansine plus 
placebo on the basis of the following endpoints: 
• 
PFS, defined as the time from randomization to the first occurrence of disease progression, 
as determined by investigator assessment using RECIST v1.1 or death from any cause, 
whichever occurs first, in the programmed death−ligand 1 (PD-L1) selected subgroup of 
patients defined as having tumor immune infiltrating cell (IC) expression of IC 1/2/3, as 
assessed by immunohistochemistry 
• 
PFS, defined as the time from randomization to the first occurrence of disease progression, 
as determined by investigator assessment using immune-modified RECIST or death from 
any cause, whichever occurs first 
• 
Objective response, defined as a CR or PR on two consecutive assessments, at least 
28 days apart, as determined by investigator assessment using immune modified RECIST 
• 
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 
immune-modified RECIST or death from any cause, whichever occurs first 
• 
1-year survival rate 
Safety Objective 
The primary safety objectives for this study are to evaluate the overall safety of trastuzumab 
emtansine in combination with atezolizumab compared with trastuzumab emtansine in 
combination with placebo on the basis of the following:  
• 
Nature, frequency, severity, and timing of adverse events including cardiac, hepatic and 
pulmonary events 
• 
Clinical laboratory results during and following trastuzumab emtansine and atezolizumab 
administration 
Pharmacokinetic Objective 
The secondary pharmacokinetic (PK) objectives for this study are: 
• 
To characterize the pharmacokinetics of atezolizumab in the presence of trastuzumab 
emtansine 
• 
To characterize the pharmacokinetics of trastuzumab emtansine in the presence and 
absence of atezolizumab 
Immunogenicity Objective  
The secondary immunogenicity objectives for this study are: 
• 
To characterize the incidence of anti-therapeutic antibody (ATA) to atezolizumab in the 
presence of trastuzumab emtansine  
• 
To characterize the incidence of ATA to trastuzumab emtansine in the presence and 
absence of atezolizumab 
The exploratory immunogenicity objectives for this study are as follows: 
• 
To evaluate the relationship between ATA status, efficacy, safety, and/or pharmacokinetics 
Biomarker Objective  
• 
To assess if baseline PD-L1 expression is associated with efficacy 
• 
To assess if baseline immune status is associated with efficacy  
• 
To assess if baseline immune status together with HER2 expression level (mRNA, protein 
and/or gene copy number/ratio) are associated with efficacy 
• 
To assess changes in expression levels of biomarkers or biomarker panels during and after 
investigational treatment with atezolizumab in combination with trastuzumab emtansine 
• 
To evaluate the relationship between tumor biomarkers and efficacy 
• 
To identify candidate biomarkers that correlate with safety signals  


 
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Study Design 
Description of Study 
This is a Phase II, randomized, multicenter, international, two-arm, double-blind, 
placebo-controlled clinical trial designed to compare the efficacy and safety of trastuzumab 
emtansine in combination with either atezolizumab or placebo for patients with HER2-positive 
locally advanced or MBC who have received prior trastuzumab and taxane based therapy. 
Approximately 200 patients will be enrolled in the study at 100 sites worldwide.  Patients will be 
randomized to treatment arms A and B in a 1:2 ratio by means of a permuted block 
randomization scheme through the use of an interactive Web or voice response system.  
Randomization will be stratified according to 1) PD-L1 status (IC0 vs IC1/2/3), 2) World Region 
(Western Europe vs U.S. vs Rest of World) and 3) Presence of liver metastases (yes vs. no).   
Patients will be treated in one of the following arms: 
• 
Arm A: trastuzumab emtansine 3.6 mg/kg and placebo, every 3 weeks (q3w) 
(approximately 67 patients) 
• 
Arm B: trastuzumab emtansine 3.6 mg/kg and atezolizumab 1200 mg, q3w (approximately 
133 patients) 
Arm A and Arm B will be blinded with respect to administration of atezolizumab or placebo.  
Cross-over between treatment arms will not be permitted. 
Number of Patients 
Approximately 200 patients will be enrolled in the study and randomized to treatment arms A 
and B in a 1:2 ratio (approximately 67 patients in Arm A and 133 patients in Arm B). 
Target Population 
Inclusion Criteria 
Patients must meet ALL of the following inclusion criteria to be eligible for study entry: 
• 
Age ≥ 18 years. 
• 
Signed written informed consent approved by the institution’s Independent Ethical 
Committee/Institutional Review Board.  
• 
Archival tumor samples must be obtained from primary and/or metastatic sites. 
Representative FFPE tumor specimens in paraffin blocks for central testing is required.  
Different material as described in Appendix 3 may be accepted in exceptional cases.  
Tumor tissue should be of good quality based on total and viable tumor content and must 
be evaluated for HER2 and PD-L1 expression prior to enrollment. 
• 
Patients must submit tumor tissue that is evaluable for PD-L1 expression to be eligible for 
this study.  If multiple tumor specimens are submitted (e.g., an archival specimen [from 
initial BC diagnosis] and tissue from metastatic or locally advanced breast cancer [LABC] 
disease), patients may be eligible if at least one specimen is evaluable for PD-L1.  
For the purpose of stratification, the PD-L1 score of the patient will be the maximum 
PD-L1 score among the samples.  Tumor tissue from bone metastases is not 
evaluable for PD-L1 expression and is therefore not acceptable.  
Patients who do not have tissue specimens that meet eligibility requirements may 
undergo a biopsy during the screening period.  Acceptable samples include core 
needle biopsies for deep tumor tissue (minimum three cores) or excisional, incisional, 
punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions.  
Fine-needle aspiration, brushing, cell pellet from pleural effusion, bone metastases, 
and lavage samples are not acceptable. 
• 
HER2-positive breast cancer (BC) as defined by an immunohistochemistry (IHC) score of 
3 +  or gene amplified by in situ hybridization (ISH) as defined by a ratio of ≥ 2.0 for the 
number of HER2 gene copies to the number of chromosome 17 copies, prospectively 
tested by a Sponsor- designated central laboratory prior to enrollment.  Both IHC and ISH 
assays will be performed; however, only one positive result is required for eligibility.  
If multiple tumor specimens are submitted, the HER2 IHC score and or ISH amplification 
ratio will first be assessed on the archival specimen for the purpose of determining 


 
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eligibility.  For patients with bilateral BC, HER2 positivity must be demonstrated in both 
locations for archival tissue or in a metastatic biopsy. 
Centrally confirmed HER2 results (either IHC or ISH) from a current or previous Sponsor 
study can be used to determine eligibility for this study.  Approval must be obtained from 
the Medical Monitor prior to randomization.  
Progression must have occurred during or after most recent treatment for LABC or MBC 
or within 6 months after completing adjuvant therapy. 
• 
Histologically or cytologically confirmed invasive BC: incurable, unresectable, locally 
advanced BC previously treated with multimodality therapy or MBC. 
• 
Prior treatment for BC in the: adjuvant; unresectable locally advanced; or metastatic 
settings; which must include both, a taxane and trastuzumab (alone or in combination with 
another agent)  
• 
Progression must have occurred during or after most recent treatment for LABC/MBC or 
within 6 months after completing adjuvant therapy. 
• 
Patients must have measurable disease that is evaluable per RECIST 1.1.  
• 
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.  
• 
Adequate hematologic and end-organ function, as evidenced by the following local 
laboratory results obtained within 7 days prior to the first study treatment (Cycle 1, Day 1): 
Absolute neutrophil count ≥ 1500 cells/µL (without granulocyte-colony stimulating factor 
[support) within 7 days prior to Cycle 1, Day 1 
Platelet count ≥ 100,000/µL (without transfusion within 7 days prior to Cycle 1, Day 1) 
Hemoglobin ≥ 9.0 g/dL 
Patients may be transfused or receive erythropoietic treatment to meet this 
criterion. 
Albumin > 2.5g/dL 
AST, ALT, and alkaline phosphatase ≤ 2.5 × the upper limit of normal (ULN) with the 
following exceptions: 
Patients with documented bone metastases: alkaline phosphatase ≤ 5 × the ULN 
Total bilirubin ≤ 1.5 × the ULN 
INR and aPTT ≤ 1.5 × the ULN 
This applies only to patients who are not receiving therapeutic anticoagulation; 
patients receiving therapeutic anticoagulation should be on a stable dose. 
Calculated creatinine clearance ≥ 30 mL/min 
• 
Negative serum pregnancy test within 7 days of enrollment for pre-menopausal women and 
for women less than 12 months after the onset of menopause. 
• 
For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% 
per year during the treatment period and for at least 7 months after the last dose of 
trastuzumab emtansine, or 5 months after the last dose of atezolizumab/placebo, whichever 
is later. 
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus). 
Examples of contraceptive methods with a failure rate of < 1% per year include bilateral 
tubal ligation, male sterilization, established, proper use of hormonal contraceptives 
that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices. 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception. 


 
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• 
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm, as defined below: 
With female partners of childbearing potential, men must remain abstinent or use a 
condom plus an additional contraceptive method that together result in a failure rate 
of < 1% per year during the treatment period and for at least 7 months after the last 
dose trastuzumab emtansine.  Men must refrain from donating sperm during this same 
period. 
With pregnant female partners, men must remain abstinent or use a condom during 
the treatment period and for at least 7 months after the last dose of trastuzumab 
emtansine 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. 
Exclusion Criteria 
Patients who meet any ONE of the following criteria will be excluded from study entry: 
• 
Prior treatment with trastuzumab emtansine, CD137 agonists, anti- programmed death−1 
(PD-1), or anti-PD-L1 therapeutic antibody or pathway−targeting agents. 
• 
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. 
• 
Radiation therapy within 2 weeks prior to Cycle 1, Day 1 
The patient must have recovered from any resulting acute toxicity (to Grade ≤ 1) prior 
to randomization.  
• 
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.   
• 
History of other malignancy within the previous 5 years, except for appropriately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or 
patients who have undergone potentially curative therapy with no evidence of disease and 
are deemed by the treating physician to be at low risk for recurrence. 
• 
Cardiopulmonary dysfunction as defined by: 
Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg) 
Inadequate left ventricular ejection function at baseline, < 50% by either ECHO or 
MUGA 
History of symptomatic congestive heart failure (CHF)-Grade ≥ 3 per National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 
or Class ≥ II New York Health Association  
History of a decrease in left ventricular ejection function to < 40% or symptomatic CHF 
with prior trastuzumab treatment 
Myocardial infarction or unstable angina within 6 months of randomization  
Current dyspnoea at rest due to complications of advanced malignancy, or other 
disease requiring continuous oxygen therapy 
Serious cardiac arrhythmia not controlled by adequate medication 
• 
Patients with severe infection within 4 weeks prior to randomization, including but not 
limited to hospitalization for complications of infection, bacteremia, or severe pneumonia. 


 
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• 
Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, 
pulmonary or metabolic disease; wound healing disorders; ulcers; bone fractures).  
• 
Major surgical procedure or significant traumatic injury within 28 days prior to randomization 
or anticipation of the need for major surgery during the course of study treatment. 
• 
Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, 
autoimmune hepatic disorders, sclerosis cholangitis or active infection with HIV, hepatitis B 
virus (HBV), or hepatitis C virus (HCV) 
Active infection is defined as requiring treatment with antiviral therapy or presence of 
positive test results for hepatitis B (hepatitis B surface antigen and/or total hepatitis B 
core antibody) or HCV antibody.  HIV, HBV, or HCV assessments are required at 
screening.  
Patients who test positive for hepatitis B core antibody are eligible only if test results 
are also positive for hepatitis B surface antibody and polymerase chain reaction is 
negative for HBV DNA. 
Patients who are positive for HCV serology are only eligible if testing for HCV RNA is 
negative. 
• 
Need for current chronic corticosteroid therapy (≥ 10 mg of prednisone per day or an 
equivalent dose of other anti-inflammatory corticosteroids) 
Stable use (i.e., no change in dose within 3 months prior to Cycle 1, Day 1) of inhaled 
corticosteroids is allowed. 
• 
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. 
• 
Patients with known central nervous system (CNS) disease are not eligible, except for 
treated asymptomatic CNS metastases, provided that all of the following criteria are met: 
Only supratentorial and cerebellar metastases allowed (i.e., no metastases to midbrain, 
pons, medulla, or spinal cord) 
No ongoing requirement for corticosteroids as therapy for CNS disease  
No stereotactic radiation within 14 days prior to randomization 
No evidence of interim progression between the completion of CNS-directed therapy 
and the screening radiographic study 
• 
Note: Patients with new asymptomatic CNS metastases detected at the screening scan 
must receive radiation therapy and/or surgery for CNS metastases.  Following treatment, 
these patients may be eligible without the need for an additional brain scan prior to 
enrollment, if all other criteria are met. 
• 
Leptomeningeal disease 
• 
Symptomatic pleural effusion, pericardial effusion, or ascites.  
• 
Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or calcium > 12 mg/dL or 
corrected serum calcium greater than the ULN) or symptomatic hypercalcemia requiring 
continued use of bisphosphonate therapy.  
Patients who are receiving denosumab must discontinue use of denosumab and 
replace it with a bisphosphonate instead while on study. 
Patients who are receiving bisphosphonate therapy specifically to prevent skeletal 
events and who do not have a history of clinically significant hypercalcemia are 
eligible. 
• 
Current Grade ≥ 3 peripheral neuropathy (according to the NCI CTCAE v4.0). 
• 
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. 


 
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• 
History of autoimmune disease, including, but not limited to, myasthenia gravis, 
autoimmune myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid 
arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid 
syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, multiple 
sclerosis, vasculitis, or glomerulonephritis.  
Patients with a history of autoimmune-related hypothyroidism on a stable dose of 
thyroid replacement hormone may be eligible for this study. 
History of inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis) or 
active bowel inflammation (e.g., diverticulitis). 
Patients with Type 1 diabetes mellitus will not be eligible unless controlled with the 
patient on a stable insulin regimen 
Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis would be excluded) are 
excluded unless they meet the following conditions: 
Rash must cover < 10% of body surface area. 
Disease is well controlled at baseline and requiring only low-potency topical 
steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, 
flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%) 
No acute exacerbations of underlying condition within the last 12 months 
(not requiring psoralen plus ultraviolet.  A radiation, methotrexate, retinoids, 
biologic agents, oral calcineurin inhibitors, or high-potency or oral steroids) 
Patients with psoriasis must have a baseline ophthalmologic exam to rule out 
ocular manifestations. 
• 
Prior allogeneic stem cell or solid organ transplantation. 
• 
History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, 
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or 
evidence of active pneumonitis on screening chest computed tomography scan. 
Patients with a history of radiation pneumonitis in the radiation field (fibrosis) are 
eligible. 
• 
Active tuberculosis. 
• 
Receipt of a live, attenuated vaccine within 4 weeks prior to randomization or anticipation 
that such a live, attenuated vaccine will be required during the study. 
• 
Treatment with systemic immunostimulatory agents (including, but not limited to, interferons 
or IL-2) within 4 weeks or five half-lives of the drug (whichever is shorter) prior to 
randomization. 
• 
Treatment with systemic corticosteroids or other systemic immunosuppressive medications 
(including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, 
methotrexate, thalidomide, and anti-tumor necrosis factor agents) within 2 weeks prior to 
randomization, or anticipated requirement for systemic immunosuppressive medications 
during the trial. 
Patients who need current chronic corticosteroid therapy (≥ 10 mg of prednisone per 
day or an equivalent dose of other anti-inflammatory corticosteroids) will be excluded 
Patients who have received acute, low−dose, systemic immunosuppressant 
medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled in 
the study. 
Stable use (i.e., no change in dose within 3 months prior to Cycle 1, Day 1) of inhaled 
corticosteroids is allowed 
• 
Breastfeeding, or intending to become pregnant during the study 
End of Study 
The end of study is triggered by the final OS analysis following last patient last visit that is 
planned to occur approximately 24 months after the primary efficacy analysis or at 
approximately 50% OS events from 200 patients can be obtained, whichever occurs first.  
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analysis if more mature OS data are requested by the Health Authority.  The Sponsor may 
also terminate the study at any time. 
Length of Study 
The total duration of the study is expected to be approximately 40 months. 
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 intravenous (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 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.  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. 
Patients will receive 1200 mg of atezolizumab/placebo administered by IV infusion q3w.   
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.   
All the study drugs are to be administered to patients intravenously.  Atezolizumab or placebo 
will be administered first, followed by trastuzumab emtansine.   
Statistical Methods 
Primary Efficacy Analysis 
The primary efficacy endpoint for this study is PFS based on investigator tumor assessment.  
The intention-to-treat (ITT) population is the primary analysis population for the primary efficacy 
endpoint 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. 
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.  When disease progression or 
death occurs after two or more consecutive missed (or “unevaluable”) tumor assessments, 
these events will not be counted; rather, the patient will be censored at the patient’s last tumor 
assessment prior to the first missing (or “unevaluable”) assessment.  If disease progression or 
death occurs after one missed (or “unevaluable”) tumor assessment, the event will be counted 
at the respective event date. 
The Kaplan-Meier method will be used to estimate median PFS and the corresponding 
95% confidence intervals (CIs) for each treatment arm.  The 2-sided log-rank test, stratified 
by the factors specified in the protocol (excluding liver metastases), will be used to compare 
PFS between the treatment arms at the overall two-sided significance level of 5%.  Liver 
metastases will be excluded because of the potential that some of the strata may have very few 
patients, which would result in a loss of power.  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 


 
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the previous noted stratification factors, excluding liver metastases, will be used to estimate 
the HR and to calculate the 95% CI of the HR. 
The primary PFS analysis will be performed when approximately 115 investigator-assessed 
PFS events have been observed and is anticipated to occur approximately 15 to 17 months 
from first patient enrolled (FPI), depending on PFS HR assumptions.   
Several sensitivity analyses will be performed to assess the robustness of the primary efficacy 
analysis, see the SAP for details.   
In order to assess the consistency of treatment benefit with respect to the primary efficacy 
endpoint PFS 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 PD-L1 expression, ECOG status and hormone receptor status.  A multivariate Cox 
regression analysis will be performed on the primary efficacy endpoint of investigator-assessed 
PFS controlling for important baseline characteristics.  
Secondary Efficacy Analysis 
The ITT population will be the analysis population used for evaluation of the secondary efficacy 
endpoints. 
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.  
The first analysis of OS will be performed at the time of the primary PFS analysis.  Another 
update for OS will be performed at approximately 12 months after the primary PFS analysis.  
The final OS analysis will be performed at approximately 24 months after the primary PFS 
analysis or when ~50% OS events from 200 patients can be obtained, whichever occurs first.  
The Sponsor may consider additional OS updates beyond 24 months after primary PFS 
analysis if more mature OS data are requested by the Health Authority.  
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 objective response 
rate (ORR) and its 95% CI (Blyth-Still-Casella) will be calculated for each treatment arm.  The 
Cochran-Mantel-Haenszel Chi-squared test stratified according to the factors specified in the 
protocol (excluding liver metastases) 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.  
Exploratory Efficacy Analysis 
The exploratory efficacy endpoints will be evaluated at time of primary efficacy analysis.  The 
ITT population will be the analysis population used for evaluation of the exploratory efficacy 
endpoints. 
PFS Assessed in the PD-L1 Selected Subgroup 
The analysis methods are similar to those described for the primary efficacy endpoint. 


 
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PFS Assessed Using Immune-Modified RECIST 
PFS is defined as the time from randomization to first occurrence of disease progression as 
determined by investigator assessment using immune-modified RECIST or death from any 
cause, whichever occurs earlier.  Only patients who are clinically eligible for treatment beyond 
disease progression will be included in this analysis.  The analysis methods are similar to those 
described for the primary efficacy endpoint.  
Objective Response Rate based on Immune Modified RECIST 
Objective response, defined as a complete response (CR) or partial response (PR), will be 
determined by investigator tumor assessment using immune-modified RECIST.  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 (Blyth-Still-Casella) will be calculated for each treatment 
arm.  The Cochran-Mantel-Haenszel Chi-squared test stratified according to the factors 
specified in the protocol (excluding liver metastases) 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 based on Immune-Modified RECIST 
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 
immune-modified RECIST, or death from any cause, whichever occurs first.  The analysis 
methods are similar to those described for the primary efficacy endpoint PFS.  
1-Year Survival Rate 
Kaplan-Meier methodology will be used to estimate 1-year survival rates and 95% CIs for each 
treatment arm.  Also, differences in 1-year survival rates between treatment arms will be 
calculated together with 95% CIs. 
Safety Analysis 
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. 
Study Drug Exposure  
The number of patients who experience any dose modification (including dose delay, dose 
reduction and dose interruption), or dose discontinuation, and reasons for study treatment 
discontinuation will be summarized for each of the treatment arm regimens.  In addition, the 
number of patients that discontinue from trastuzumab emtansine-containing and/or 
atezolizumab-containing treatment because of toxicity and/or receive other non-protocol 
anti-cancer therapy will be summarized.   
Descriptive statistics will be presented for total cumulative dose, number of cycles, dose 
intensity, infusion time by cycle, and weeks of exposure for trastuzumab emtansine, and 
atezolizumab. 
Adverse Events  
Safety will be assessed through summaries of adverse events, changes in laboratory test 
results, changes in vital signs, study treatment exposures, and immunogenicity as measured 
by ATA and will be presented by treatment arm. 
Verbatim descriptions of adverse events will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms and graded according to the NCI CTCAE v4.0.  The 
following events occurring on or after the first dose of study drug (i.e., treatment-emergent 
adverse events) will be summarized by NCI CTCAE grade: 
• 
All adverse events 
• 
Serious adverse events 
• 
Adverse eventsleading to death 
• 
Adverse eventsleading to study drug discontinuation 


 
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• 
Adverse eventsleading to dose reduction 
• 
Sponsor-defined adverse events of special interest 
For events of varying severity, the highest grade will be used in the summaries. 
Deaths and causes of death will be summarized.  Selected adverse events will be summarized 
by NCI CTCAE grade for each treatment arm based on pre-specified category definitions, 
including (but not limited to) hepatotoxicity, cardiac dysfunction, and thrombocytopenia.  
In addition, adverse eventsoccurring within 1 day (24 hours) of the first dose of each treatment 
cycle will be summarized to help characterize potential infusion-related reactions.   
Additional safety analyses may be performed as indicated. 
Laboratory Data  
For laboratory parameters, descriptive summary tables of change from baseline over time 
based on System International units will be produced.  Summary tables for the shifts in 
NCI CTCAE v4.0 grades from baseline to the worst grade observed during treatment will be 
presented. 
Pharmacokinetic Analysis 
The PK analyses will include patients with at least one post-dose PK assessment. 
Individual serum atezolizumab, trastuzumab emtansine, total trastuzumab levels and plasma 
DM1 concentrations versus time will be tabulated and summarized by treatment arm and study 
visit day.  Descriptive statistics will include mean, medians range, standard deviation, coefficient 
of variation (CV%), geometric mean, and geometric mean coefficient of variation (CVb%) as 
appropriate. 
Additional PK and PD analyses will be conducted as appropriate. 
Immunogenicity Analysis 
The immunogenicity analyses will include patients with at least one predose and one post-dose 
ATA assessment, with patients grouped according to treatment received.  The numbers and 
proportions of ATA-positive patients and ATA-negative patients during both the treatment and 
follow-up periods will be summarized by treatment group.  Patients are considered to be ATA 
positive if they are ATA negative at baseline but develop an ATA response following study drug 
administration (treatment-induced ATA response), or if they are ATA positive at baseline and 
the titer of one or more post-baseline samples is at least 4-fold greater (i.e.,  ≥ 0.60 titer units) 
than the titer of the baseline sample (treatment-enhanced ATA response).  Patients are 
considered to be ATA negative if they are ATA negative at baseline and all post-baseline 
samples are negative, or if they are ATA positive at baseline but do not have any post-baseline 
samples with a titer that is at least 4-fold greater than the titer of the baseline sample (treatment 
unaffected). 
Biomarker Analysis 
Descriptive statistics will be utilized for the analysis and reporting of the exploratory biomarker 
objectives.  This may include appropriate multivariate analyses.  
Determination of Sample Size 
The primary efficacy endpoint for this study is PFS based on investigator tumor assessment.  
The primary PFS analysis will be performed when approamiately 115 PFS events have 
occurred. 
With approximately 200 patients randomized according to a 1:2 randomization (approximately 
67 patients will be randomized to Arm A and approximately 133 patients will be randomized to 
Arm B) the study has the estimated power for the PFS HRs.  The design considerations 
assumed proportional hazards, a cumulative dropout rate of 10% in each treatment arm and 
result in an estimated recruitment time of about 9 months (with ramp up in the first 4 months).  
The estimated time from FPI to primary PFS analysis is 15 to 17 months, depending on PFS 
HR assumption.   
Sample size and power calculations were performed using the East 6 software package 
(Cytel Inc.). 
Interim Analyses  
There is no planned interim efficacy analysis for PFS.   


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADC 
antibody−drug conjugate 
anti-HBc 
antibody to hepatitis B core antigen 
ATA 
anti-therapeutic antibody 
BC 
breast cancer 
CHF 
congestive heart failure 
CI 
confidence interval 
CNS 
central nervous system  
CR 
complete response 
CRC 
colorectal cancer 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome p450 
DOR 
duration of response 
EC 
Ethics Committee 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
FDA 
U.S. Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
FPI 
first patient enrolled 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HER2 
human epidermal growth factor 2 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
hazard ratio 
IB 
Investigator’s Brochure 
IC 
tumor-infiltrating immune cell 
ICH 
International Conference on Harmonisation 
IHC 
immunohistochemistry 
ILD 
interstitial lung disease 
IL 
interleukin 
iDCC 
independent Data Coordinating Center 


 
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Abbreviation 
Definition 
iDMC 
independent data monitoring committee 
IMP 
investigational medicinal product 
IND 
Investigation New Drug Application 
IRB 
Institutional Review Board 
IRF 
independent review facility 
IRR 
infusion-related reaction 
ISH 
in situ hybridization 
ITT 
intention-to-treat 
IV 
intravenous 
IxRS 
interactive Web or voice response system 
LABC 
locally advanced breast cancer 
LFT 
liver function test 
LPLV 
last patient last visit 
LVEF 
left ventricular ejection fraction 
MBC 
metastatic breast cancer 
MRI 
magnetic resonance imaging 
MUGA 
multi-gated acquisition scan 
NCI 
National Cancer Institute 
NGS 
next-generation sequencing 
NRH 
nodular regenerative hyperplasia 
NSCLC 
non−small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PD 
progressive disease 
PD-1 
programmed death−1 
PD-L1 
programmed death−ligand 1 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PO 
orally 
PR 
partial response 
q2w 
every 2 weeks 
q3w 
every 3 weeks 
RCC 
renal cell carcinoma 
RBR 
Research Biosample Repository 


 
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Abbreviation 
Definition 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAP 
Statistical Analysis Plan 
SIA 
systemic immune activation 
TC 
tumor cell 
TIL 
tumor-infiltrating lymphocyte  
TNBC 
triple-negative breast cancer 
TNF 
tumor necrosis factor 
TPC 
treatment of physician’s choice 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
WGS 
whole genome sequencing 
 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON BREAST CANCER  
Breast cancer (BC) is the most common cancer among women in the world with an 
estimated 1.67 million cases diagnosed globally per year and a mortality rate of 
approximately 520,000 deaths (Globocan 2012).  While advances in early diagnosis and 
adjuvant therapy have led to a decrease in mortality rates from BC in developed 
countries, the prevalence of metastatic breast cancer (MBC) is still high and it is not 
considered curable, with the main goals of treatment being to improve patients’ quality of 
life and prolong survival (Cardoso et al 2014). 
Human epidermal growth factor 2 (HER2), also known as erbB2, neu, and p185HER2, 
represents a prominent target in BC with approximately 15%−20% of patients with 
primary invasive BCs 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).   
Until recently, for patients with HER2-positive MBC, the combination of trastuzumab and 
a taxane was widely accepted as the first-line treatment option of choice 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 overall survival (OS) with a generally similar safety 
profile (Study WO20698/TOC4129g [Baselga et al. 2012]) and is the new standard of 
care in many countries.   
In patients with HER2-positive advanced BC 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]) or compared to a treatment of physicians’ choice in patients 
who previously received trastuzumab, taxane and lapatinib (Wilders 2015). Trastuzumab 
emtansine is considered standard of care in many countries in the aforementioned 
patient population. 
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 BC. 


 
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1.2 
BACKGROUND ON TRASTUZUMAB EMTANSINE  
Trastuzumab emtansine (Kadcyla®, trastuzumab emtansine is a novel 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.  Data from clinical 
trials of trastuzumab emtansine that are relevant to the design of the current trial are 
summarized in Sections 1.2.1 and 1.2.2.  Refer to the most recent version of the 
trastuzumab emtansine Investigator’s Brochure (IB) for further information on all of the 
completed and ongoing trastuzumab emtansine studies. 
1.2.1 
Study TDM4370g/BO21977 (EMILIA) 
Study TDM4370g/BO21977 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 + capecitabine arm, with a median duration of response (DOR) of 12.6 
months versus 6.5 months, respectively.   


 
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Trastuzumab emtansine was well tolerated, with no unexpected safety signals at the 
time of the primary analysis.  The most common Grade ≥ 3 adverse events in the 
trastuzumab emtansine arm were thrombocytopenia (12.9% vs. 0.2%, respectively), 
increased AST (4.3% vs. 0.8%), and increased ALT (2.9% vs. 1.4%); the most common 
Grade ≥ 3 adverse events in the lapatinib + 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 adverse events in the trastuzumab emtansine arm was 40.8% 
versus 57.0% in the lapatinib + 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 + capecitabine, compared with 30.9 months in patients treated with trastuzumab 
emtansine.   
The final descriptive OS analysis showed a consistent survival benefit for trastuzumab 
emtansine compared with lapatinib + 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 2015). 
1.2.2 
Study TDM4997g/BO25734 (TH3RESA) 
Study TDM4997g/BO25734 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. 


 
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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 
adverse events (32.3% vs. 43.5%).  Grade ≥ 3 adverse events 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 2nd 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 (Wildiers et al, 2015). 
1.3 
BACKGROUND ON ATEZOLIZUMAB  
Atezolizumab, an engineered anti-programmed death−ligand 1 (PD-L1) antibody, is a 
humanized immunoglobulin G1 monoclonal antibody consisting of two heavy chains 
(448 amino acids) and two light chains (214 amino acids) and is produced in Chinese 
hamster ovary cells.  Atezolizumab was engineered to eliminate Fc-effector function via 
a single amino acid substitution (asparagine to alanine) at position 298 on the heavy 
chain, which results in a non-glycosylated antibody that has minimal binding to Fc 
receptors and, consequently, eliminates detectable Fc-effector function and depletion of 
cells expressing PD-L1 in humans.   
PD-L1 is an extracellular protein, which down regulates immune responses primarily in 
peripheral tissues through binding to its two receptors: programmed death−1 (PD-1) and 
B7.1.  Many human tumors overexpress PD-L1, which acts to suppress anti-tumor 
immunity. PD-1 is an inhibitory receptor expressed on T cells following T-cell activation, 
which is sustained in states of chronic stimulation such as in chronic infection or cancer 
(Blank et al. 2005; Keir et al. 2008).  Ligation of PD-L1 with PD-1 inhibits T-cell 
proliferation, cytokine production, and cytolytic activity, leading to the functional 
inactivation or exhaustion of T cells.  B7.1 is a molecule expressed on 
antigen-presenting cells and activated T cells.  PD-L1 binding to B7.1 on T cells and 
antigen-presenting cells can mediate downregulation of immune responses, including 
inhibition of T-cell activation and cytokine production (Butte et al. 2007; Yang et al. 2011).  
Overexpression of PD-L1 on TCs has been reported to impede anti-tumor immunity, 
resulting in immune evasion (Blank and Mackensen 2007).  Therefore, interruption of the 
PD-L1/PD-1 and the PD-L1/B7.1 pathways represents an attractive strategy to 
reinvigorate tumor-specific T-cell immunity. 


 
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Atezolizumab targets human PD-L1 and inhibits its interaction with its receptors, PD-1, 
and B7.1 (CD80, B7-1).  Both of these interactions are reported to provide inhibitory 
signals to T cells.  
Atezolizumab is being investigated as a potential therapy against solid tumors and 
hematologic malignancies in humans.   
Atezolizumab was approved by the U.S. Food and Drug Administration (FDA) in May 
2016 for the treatment of patients with locally advanced or mUC who 1) have disease 
progression during or following platinum-containing chemotherapy or 2) have disease 
progression within 12 months of neoadjudvant or adjuvant treatment with platinum-
containing chemotherapy. 
Additionally, atezolizumab was approved by the U.S. FDA in October 2016 for the 
treatment of patients with metastatic non-small cell lung cancer who have disease 
progression during or following platinum-containing chemotherapy.  Patients with 
epidermal growth factor receptor or ALK genomic tumor aberrations should have 
disease progression on FDA-approved therapy for these aberrations prior to receiving 
atezolizumab. 
Refer to the most recent version of the Atezolizumab IB for further details.  
1.3.1 
Study PCD4989g 
Study PCD4989g is a Phase Ia, multicenter, first-in-human, open-label, dose-escalation 
study, evaluating the safety, tolerability, immunogenicity, pharmacokinetics, exploratory 
pharmacodynamics, and preliminary evidence of biologic activity of atezolizumab 
administered as a single agent by IV infusion q3w to patients with LABC or metastatic 
solid malignancies or hematologic malignancies. 
The safety data for atezolizumab have been derived mainly from the treatment of 
patients in Study PCD4989g.  As of 11 May 2015, there were 558 safety-evaluable 
patients from the Phase Ia study.  The median duration of treatment was 12.1 weeks 
(range: 0.0−71.4 weeks), and the median number of atezolizumab cycles administered 
was 5.0 (range: 1−19 cycles).  To date, no maximum tolerated dose, dose-limiting 
toxicities, or clear dose-related trends in the incidence of adverse events have been 
determined. 
Of the 558 treated patients in Study PCD4989g, 520 (93.2%) patients experienced an 
adverse event regardless of attribution to atezolizumab.  Treatment-related adverse 
events (per investigator’s assessment of causality) were reported in 376 patients 
(67.4%).  The majority of these adverse events were Grade 1 or 2 in maximum severity 
on the basis of the National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 4.0 (NCI CTCAE v4.0).   


 
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The most frequently observed adverse events (≥ 10% of patients) included fatigue, 
decreased appetite, nausea, pyrexia, constipation, cough, dyspnea, diarrhea, headache, 
back pain, vomiting, anemia, arthralgia, rash, insomnia, asthenia, abdominal pain, chills, 
pruritus, generalized pain, and peripheral edema.   
Grade 3 and 4 adverse events were reported in 239 patients (42.8%) of which 66 (11.8%) 
were considered related to study drug by the investigator.  Grade 3 and 4 adverse 
events considered related included dyspnea, pneumonitis, increased ALT, increased 
AST, increased gamma glutamyl transferase, decreased lymphocyte count, cardiac 
tamponade, asthenia, autoimmune hepatitis, pneumonia, influenza, and hypoxia.  Safety 
findings in the triple-negative breast cancer (TNBC) cohort of Study PCD4989g are 
consistent with the data observed in the overall study population. 
Anti-tumor activity, including Response Evaluation Criteria in Solid Tumors 
(RECIST)-based responses (i.e., RECIST Version 1.1 responses), have been observed 
in patients with different tumor types, including non−small cell lung cancer (NSCLC), 
renal cell carcinoma (RCC), melanoma, bladder cancer, colorectal cancer (CRC), head 
and neck cancer, gastric cancer, BC (including TNBC), and sarcoma treated with 
atezolizumab monotherapy in Study PCD4989g. 
Among 386 evaluable patients enrolled prior to 1 July 2013 (data cutoff of 1 January 
2014) there were 47 patients with responses with a median DOR of 75.7 weeks (range: 
11.7 + to 85.9 + weeks, where “+” denotes a censored value).  The majority of these 
responses have been durable, with 72.3% (34 of 47 patients) of responses ongoing as of 
the clinical cutoff date. 
Analyses of tumor-infiltrating immune cells (ICs) for PD-L1 expression on baseline tumor 
tissue have been performed for Study PCD4989g.  Preliminary results from Study 
PCD4989g suggest that PD-L1 expression in ICs is likely to be associated with response 
to atezolizumab. 
Refer to the most recent version of the Atezolizumab IB for updated details regarding 
clinical safety and efficacy. 
1.3.2 
Study GP28328 
Study GP28328 is a Phase Ib study evaluating the safety and pharmacology of 
atezolizumab administered with bevacizumab and/or chemotherapy to patients with 
advanced solid tumors.  Arm A is evaluating 1200 mg atezolizumab + bevacizumab 
administered q3w to patients with multiple solid tumor types, including separate 
expansion cohorts in CRC and RCC.  Arm B is evaluating atezolizumab + bevacizumab 
and oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) administered every 2 weeks 
(q2w) to patients with multiple solid tumor types, including CRC and BC.  Arms C, D, 
and E are evaluating atezolizumab administered q3w to chemotherapy-naive patients 
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carboplatin + nab-paclitaxel, respectively.  Arm F is evaluating atezolizumab 
administered q2w in combination with weekly nab-paclitaxel in patients with TNBC who 
have received ≤ 2 lines of prior therapy for metastatic disease. 
The primary objective is to evaluate the safety and tolerability.  Other endpoints include 
efficacy as per investigator review by use of RECIST v1.1 criteria (best overall response, 
ORR, DOR, PFS), pharmacokinetics, and biomarkers. 
For the initial metastatic TNBC safety cohort (n = 8), atezolizumab (800 mg) was 
administered q2w, and nab-paclitaxel (125 mg/m2) was given on a 3-week on, 1-week 
off schedule.  In the serial biopsy metastatic TNBC cohort (n = 24), patients received 
nab-paclitaxel only on Days 1 and 8 of Cycle 1; subsequently, patients received the 
planned study treatment as described above.  nab-Paclitaxel was administered for at 
least 4 cycles in the absence of disease progression or unacceptable toxicity.  
Atezolizumab and nab-paclitaxel could be administered as long as patients were 
experiencing clinical benefit per investigator discretion.  If nab-paclitaxel was 
discontinued due to toxicity, atezolizumab could be continued as monotherapy. 
As of 1 September 2015, safety data from 32 TNBC patients in GP28328 indicate that 
the combination appears to be well tolerated and is consistent with the known risks of 
nab-paclitaxel and atezolizumab.  Few patients (16%) experienced adverse events 
leading to discontinuation of nab-­paclitaxel and no patients discontinued atezolizumab 
due to an adverse event.  The most frequently reported adverse events (> 20%) included 
fatigue, pyrexia, diarrhea, nausea, alopecia, peripheral neuropathy and peripheral 
sensory neuropathy, infection, decreased neutrophil count, anemia, and bone pain.  
The majority of immune­mediated adverse events were Grade 1 or 2, and included 
dermatological events (41%), peripheral neuropathy (22%), liver enzymes increased, 
thyroid dysfunction, and pneumonitis.  There were no fatal adverse events due to study 
drug. 
The study demonstrated that the combination decreased tumor size (ORR, including 
confirmed responses) in 41.7% of patients, (n = 24; 95% CI: 22.1, 63.4) 
(Adams et al. 2015). 
Refer to the most recent version of the Atezolizumab IB for updated details on clinical 
activity and safety in all patients, regardless of tumor type. 
1.3.3 
Study WO29522 
Study WO29522 is an ongoing phase III multicenter, randomized, placebo-controlled 
study of atezolizumab (anti−PD-L1 antibody) in combination with nab-paclitaxel 
compared to placebo with nab-paclitaxel for patients with previously untreated metastatic 
triple-negative breast cancer. Up to 900 patients will receive either atezolizumab or 
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3 week on/1 week off schedule. The co-primary endpoints of the study are PFS by 
independent review and OS. 
1.3.4 
Study GO29831 
Study GO29831 is an ongoing Phase Ib open-label, two-arm study evaluating the safety 
and pharmacokinetics of atezolizumab (anti-PDL-1 antibody) in combination with 
trastuzumab emtansine or with trastuzumab and pertuzumab in patients with 
HER2-positive breast cancer.  The primary objective for this study is to evaluate the 
safety and tolerability of combination treatment with atezolizumab, trastuzumab, and 
pertuzumab or atezolizumab and trastuzumab emtansine in patients with HER2-positive 
MBC or treatment-naive patients with operable, or LABC, or inflammatory EBC. 
Stage 1 of the study consists of a 3-week safety run-in period for patients with 
HER2−positive MBC.   
• 
Safety Evaluation Cohort 1A:  Patients in Cohort 1A will receive atezolizumab 
(1200 mg q3w) in combination with trastuzumab (8-mg/kg loading dose, followed by 
a 6-mg/kg maintenance dose q3w) and pertuzumab (840-mg loading dose, followed 
by a 420-mg maintenance dose q3w). 
• 
Safety Evaluation Cohort 1B:  Patients in Cohort 1B will receive atezolizumab 
(1200 mg q3w) in combination with trastuzumab emtansine (3.6 mg/kg q3w).  
• 
Safety Evaluation Cohort 1F:  Patients in Cohort 1F will receive atezolizumab 
(1200 mg q3w) in combination with trastuzumab (8-mg/kg loading dose, followed by 
a 6-mg/kg maintenance dose q3w), pertuzumab (840-mg loading dose, followed by 
a 420-mg maintenance dose q3w), and docetaxel (75mg/m2 q3w). 
After 6 patients in the safety evaluation cohort have been treated in Cohort 1B with 
atezolizumab/trastuzumab emtansine for at least one cycle without experiencing 
more than one dose-limiting toxicity, an atezolizumab/trastuzumab emtansine safety 
expansion Cohort 2C will begin enrolling patients with HER2-positive MBC who 
have received prior treatment with trastuzumab and a taxane chemotherapy and 
who have progressed during or after the most recent treatment for locally advanced 
unresectable/MBC or within 6 months after completing adjuvant therapy.  Up to 
14 patients will be enrolled in Cohort 2C in order to gain additional safety and 
exploratory clinical activity data to inform potential future investigations of 
atezolizumab/trastuzumab emtansine in this patient population. A further 14 patients 
(previously progressed on trastuzumab and pertuzumab) will be enrolled in Cohort 
2D and receive atezolizumab (1200 mg q3w) in combination with trastuzumab 
(8-mg/kg loading dose, followed by a 6-mg/kg maintenance dose q3w) and 
pertuzumab (840-mg loading dose, followed by a 420-mg maintenance dose q3w). 
 
Stage 2 of the study will further explore the combination regimens in the neoadjuvant 
setting.  
Refer to the most recent version of the Atezolizumab IB for updated details on studies 
described above and clinical activity and safety in all patients, regardless of tumor type. 


 
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1.4 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Trastuzumab emtansine is an active regimen in HER2-positive MBC (Verma et al. 2012).  
It is currently unknown if the addition of atezolizumab will improve the efficacy outcomes 
observed with trastuzumab emtansine monotherapy.  Furthermore, conventional 
response criteria may not adequately assess the activity of immunotherapeutic agents 
because radiographic PD does not necessarily reflect therapeutic failure (Section 3).  
Therefore patients in the current study will have the option to be treated beyond 
progression to account for pseudo progression or delayed response to the combination 
therapy thereby minimizing the risk of discontinuing treatment prematurely.  Furthermore, 
the ongoing Phase Ib GO29831 study is evaluating the efficacy of trastuzumab 
emtansine in combination with atezolizumab by conventional RECIST 1.1 and 
immune-modified RECIST response criteria. 
The safety of trastuzumab emtansine is well established having been evaluated in 
1871 patients with BC in clinical studies.  It is generally well tolerated with the most 
common adverse events being nausea, fatigue, and headache.  Adverse events of 
particular relevance include thrombocytopenia, hemorrhage, hepatotoxicity (increases in 
serum transaminases and nodular regenerative hyperplasia [NRH] of liver), 
infusion-related reactions/hypersensitivity, cardiac dysfunction (left ventricular 
dysfunction), peripheral neuropathy, and pulmonary toxicity (interstitial lung disease).  
Atezolizumab, has also been generally well tolerated (refer to the most recent version of 
the Atezolizumab IB for more details); adverse events with potentially immune-mediated 
causes consistent with an immunotherapeutic agent, including rash, hypothyroidism, 
hepatitis/transaminitis, colitis, and myasthenia gravis, have been observed in ongoing 
studies of atezolizumab.  To date, the majority of these events have been manageable 
without requiring treatment discontinuation. 
The safety and tolerability of the combination of trastuzumab emtansine and 
atezolizumab is currently unknown and is being evaluated in an ongoing, Phase Ib study 
(Study GO29831; Section 1.3.4) whilst no dose-limiting toxicities have been observed in 
the the safety cohort of 6 pstients treated with trastzumab emtansine+atezolizumab, 
there remains the potential for unknown and overlapping toxicity.  To minimize this risk, 
stringent inclusion and exclusion criteria (Section 4.1), close safety monitoring 
(Section 5.3) together with rules for dose modifications and safety management 
guidelines for known risks of single-agent trastuzumab emtansine and atezolizumab 
have been implemented in the current study.  Furthermore, guidance on management of 
potential overlapping toxicities is described in Section 5.1.4.  An independent Data 
Monitoring Committee (iDMC) (Section 5.1) has also been incorporated into the trial 
design to periodically review aggregate safety data (refer to the iDMC Charter for a 
detailed monitoring plan).  


 
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2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy, safety, and pharmacokinetics of trastuzumab 
emtansine in combination with atezolizumab or placebo (atezolizumab/placebo) in 
patients with HER2-positive, locally advanced or MBC, who have received prior 
trastuzumab and taxane based therapy, either alone or in combination, and/or who have 
progressed within 6 months after completing adjuvant therapy.   
2.1 
EFFICACY OBJECTIVES 
2.1.1 
Primary Efficacy Objective 
The primary efficacy objective for this study is to evaluate the efficacy of the combination 
of trastuzumab emtansine plus atezolizumab compared with trastuzumab emtansine 
plus placebo on the basis of the following endpoint: 
• 
PFS, defined as the time from randomization to the first occurrence of disease 
progression, as determined by investigator assessment using RECIST v1.1, or 
death from any cause, whichever occurs first 
 
2.1.2 
Secondary Efficacy Objectives 
The secondary efficacy objectives for this study are to evaluate the efficacy of the 
combination of trastuzumab emtansine plus atezolizumab compared with trastuzumab 
emtansine plus placebo on the basis of the following endpoints: 
• 
OS, defined as the time from randomization to death from any cause 
• 
Objective response, 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 v1.1 
• 
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 
 
2.1.3 
Exploratory Efficacy Objectives 
The exploratory efficacy objectives for this study are to evaluate the efficacy of the 
combination of trastuzumab emtansine plus atezolizumab compared with trastuzumab 
emtansine plus placebo on the basis of the following endpoints: 
• 
PFS, defined as the time from randomization to the first occurrence of disease 
progression, as determined by investigator assessment using RECIST v1.1 or death 
from any cause, whichever occurs first, in the PD-L1 selected subgroup of patients 
defined as having tumor immune infiltrating cell expression of IC 1/2/3, as assessed 
by immunohistochemistry (IHC) 
• 
PFS, defined as the time from randomization to the first occurrence of disease 
progression, as determined by investigator assessment using immune-modified 
RECIST or death from any cause, whichever occurs first 


 
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• 
Objective response, defined as a CR or PR on two consecutive assessments, at 
least 28 days apart, as determined by investigator assessment using 
immune-modified RECIST 
• 
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 immune-modified RECIST or death from any cause, 
whichever occurs first 
• 
1-year survival rate 
 
2.2 
SAFETY OBJECTIVES 
The primary safety objectives for this study are to evaluate the overall safety of 
trastuzumab emtansine in combination with atezolizumab compared with trastuzumab 
emtansine in combination with placebo on the basis of the following:  
• 
Nature, frequency, severity, and timing of adverse events including cardiac, hepatic 
and pulmonary events 
• 
Clinical laboratory results during and following trastuzumab emtansine 
and atezolizumab administration 
 
2.3 
PHARMACOKINETIC OBJECTIVES 
The secondary pharmacokinetic (PK) objectives for this study are: 
• 
To characterize the pharmacokinetics of atezolizumab in the presence of 
trastuzumab emtansine 
• 
To characterize the pharmacokinetics of trastuzumab emtansine in the presence 
and absence of atezolizumab 
 
2.4 
IMMUNOGENICITY OBJECTIVES 
The secondary immunogenicity objectives for this study are: 
• 
To characterize the incidence of anti-therapeutic antibody (ATA) to atezolizumab in 
the presence of trastuzumab emtansine  
• 
To characterize the incidence of ATA to trastuzumab emtansine in the presence and 
absence of atezolizumab 
The exploratory immunogenicity objectives for this study are as follows: 
• 
To evaluate the relationship between ATA status, efficacy, safety, and/or 
pharmocokinetics 
 
2.5 
BIOMARKER OBJECTIVES 
The exploratory biomarker objectives for this study are as follows: 
• 
To assess if baseline PD-L1 expression is associated with efficacy 
• 
To assess if baseline immune status is associated with efficacy  
• 
To assess if baseline immune status together with HER2 expression level (mRNA, 
protein and/or gene copy number/ratio) are associated with efficacy 


 
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• 
To assess changes in expression levels of biomarkers or biomarker panels during 
and after investigational treatment with atezolizumab in combination with 
trastuzumab emtansine 
• 
To evaluate the relationship between tumor biomarkers and efficacy 
• 
To identify candidate biomarkers that correlate with safety signals 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is a Phase II, randomized, multicenter, international, two-arm, double-blind, 
placebo-controlled clinical trial designed to compare the efficacy and safety of 
trastuzumab emtansine in combination with either atezolizumab or placebo for patients 
with HER2-positive locally advanced or MBC who have received prior trastuzumab and 
taxane based therapy. 
Approximately 200 patients will be enrolled in the study at 100 sites worldwide (Figure 1).  
Patients will be randomized to treatment arms A and B in a 1:2 ratio by means of a 
permuted block randomization scheme through the use of an IxRS.  Randomization will 
be stratified according to 1) PD-L1 status (IC0 vs IC1/2/3), 2) World Region (Western 
Europe vs U.S. vs Rest of World) and 3) Presence of liver metastases (yes vs. no). 
Patients will be treated in one of the following arms: 
• 
Arm A: trastuzumab emtansine 3.6 mg/kg and placebo, q3w (approximately 
67 patients) 
• 
Arm B: trastuzumab emtansine 3.6 mg/kg and atezolizumab 1200 mg, q3w 
(approximately 133 patients) 
 
Arm A and Arm B will be blinded with respect to administration of atezolizumab or 
placebo.  Cross-over between treatment arms will not be permitted.  
Patients must have measurable disease at baseline that is evaluable per RECIST 1.1 
(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.   
Tumor assessments will be conducted approximately every 6 weeks (± 7 days) from the 
date of randomization, until investigator-assessed PD per RECIST 1.1 or death, 
whichever occurs first, regardless of dose delays or dose interruptions and even if study 
treatment has been discontinued as a result of patient or physician choice or 
unacceptable toxicity.  Tumor assessment scans will be collected prospectively by the 
Sponsor in the event that an independent review facility (IRF) will be utilized. 
Patients may remain on study treatment until investigator-assessed disease progression, 
unmanageable toxicity, or study termination by the Sponsor.  


 
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Patients who demonstrate control of their systemic disease, defined as having received 
clinical benefit (CR or PR of any duration or stable disease ≥ 4 months per RECIST v1.1; 
Appendix 4) from study therapy, but who newly develop isolated brain metastases that 
are treatable (e.g., with surgery, radiation or gamma-knife) may continue with study 
treatment until they experience systemic progression of their disease or further 
progression in the brain or both, based on investigator assessment.  Other requirements 
include the following: 
• 
The patient cannot miss more than one cycle (i.e., the maximum allowed time 
window between study treatments is 42 days) for the treatment of their brain 
disease. 
• 
The patient must have an Eastern Cooperative Oncology Group (ECOG) 
performance status of ≤ 2 to continue on study therapy. 
• 
Brain magnetic resonance imaging (MRI) or computed tomography (CT) scans are 
performed along with regularly scheduled tumor assessments (every 6 weeks) in 
these instances.  
• 
Every attempt should be made to discontinue corticosteroids within 2 weeks of the 
last day of radiation therapy. 
  
Upon radiographic disease progression per RECIST v1.1, patients may optionally 
continue to receive trastuzumab emtansine with blinded atezolizumab or placebo, 
provided they meet the following criteria:  
• 
Evidence of clinical benefit as assessed by the investigator 
• 
Absence of symptoms and signs (including worsening of laboratory values 
[e.g., new or worsening hypercalcemia]) indicating clinically significant progression 
of disease 
• 
No decline in ECOG performance status that can be attributed to disease 
progression 
 
Absence of tumor progression at critical anatomical sites (e.g., newly developed 
leptomeningeal disease) that cannot be managed by protocol-allowed medical 
interventions (i.e., pain secondary to disease or unmanageable ascites, etc.), as 
determined by the investigator after an integrated assessment of radiographic data, 
biopsy results (if available), and clinical status. 
Patients should discontinue study therapy upon evidence of further progression, defined 
as at least a 20% increase in the sum of diameters of all target and selected new 
measurable lesions, taking as reference the smallest sum on study (nadir SLD; this 
includes the baseline sum if that is the smallest on study).  In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm 
or unequivocal worsening of non-target disease. 
In patients who continue treatment beyond radiographic disease progression per 
RECIST v1.1, tumor response will also continue to be assessed using immune-modified 


 
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RECIST criteria (Appendix 5) every 6 weeks (± 7 days) until study treatment 
discontinuation.  Immune-modified RECIST criteria may account for the possibility of 
delayed anti-tumor activity that may be preceded by initial apparent radiological 
progression, including the appearance of new lesions. 
For estimation of PFS, ORR, and DOR, tumor response will be based on both 
RECIST v1.1 (Appendix 4) and immune-modified RECIST (Appendix 5). 
Safety assessments will include the incidence, nature, and severity of adverse events 
and laboratory abnormalities graded per NCI CTCAE v4.0.  Laboratory safety 
assessments will include the regular monitoring of hematology and blood chemistry. 
Serum samples will be collected to monitor pharmacokinetics and to detect presence of 
antibodies to trastuzumab emtansine and atezolizumab.  Patient samples, including 
tumor tissues, as well as serum and plasma and whole blood, will be collected for 
exploratory biomarker assessments 
After the Study Drug Completion Visit, all patients (regardless of reason for 
discontinuation) will be followed up for their survival status 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. 
Patients who withdraw their consent from the study will be asked to participate in 
survival follow-up, where only information on the survival status of the patient will be 
collected.  Patients willing to share their survival information will receive a separate and 
specific Informed Consent Form for this purpose.   
A schedule of assessments is provided in Appendix 1 and the study schema is in 
Figure 1. 


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
HER2+ (central) MBC or LABC (n=200)

Prior taxane and trastuzumab

Progression on metastatic tx or within 6 mos of adjuvant tx

Measurable disease
T-DM1 3.6mg/kg +
Atezolizumab 1200 mg, q3w
n=133
T-DM1 3.6mg/kg +
Placebo 1200 mg, q3w
n=67
Randomization 1:2
Discontinue study treatment upon toxicity or disease 
progression per RECIST 1.1
Consideration of continuing study drug allowed, if:

Evidence of clinical benefit

No signs/symptoms of unequivocal disease 
progression

No decline in ECOG PS attributable to disease 
progression

No tumor growth at critical sites
Discontinue study treatment upon the following:

At least a 20% increase in the sum of diameters of all 
target and selected new measurable lesions, taking as 
reference the smallest sum on study (nadir SLD; this 
includes the baseline sum if that is the smallest on 
study).  In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at 
least 5 mm.

Unequivocal worsening of non-target disease
Survival Follow-Up


 
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3.2 
END OF STUDY AND LENGTH OF STUDY 
This study is anticipated to have a recruitment period of approximately 9 months.  
The final analysis of the primary efficacy endpoint will be conducted when approximately 
115 PFS events have occurred, based on investigator assessments.  This is assumed to 
be approximately 15−17 months after the enrollment of the first patient (FPI). 
The end of study is triggered by the final OS analysis following last patient last visit 
(LPLV) that is planned to occur approximately 24 months after the primary efficacy 
analysis or at approximately 50% OS events from 200 patients can be obtained, 
whichever occurs first.  The Sponsor may consider additional OS update(s) beyond 
24 months after primary PFS analysis if more mature OS data are requested by the 
Health Authority.  The Sponsor may also terminate the study at any time. 
The total duration of the study is expected to be approximately 40 months.  
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Atezolizumab Dose and Schedule 
The fixed dose of 1200 mg q3w (equivalent to an average body weight−based dose of 
15 mg/kg q3w) was selected on the basis of both nonclinical studies and available 
clinical data from Study PCD4989g.  Please refer to the most recent version of the 
Atezolizumab IB for further details.  
3.3.2 
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 + capecitabine in patients with 
HER2-positive MBC who were previously treated with trastuzumab and a taxane.  
An ongoing Phase Ib, GO29831 (cross-reference) will provide further information on the 
dose that is considered safe and tolerable to be combined with atezolizumab. 
3.3.3 
Rationale for Patient Population 
Therapy with trastuzumab emtansine, has been demonstrated in a randomized study to 
improve PFS and OS compared to lapatinib + capecitabine, 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, MBC 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.  


 
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3.3.4 
Rationale for Control Group  
Based on the results from TDM4370g/BO21977 (Section 1.2.1), (Verma et al. 2012), 
trastuzumab emtansine has become widely accepted as the standard of care in patients 
who have been previously exposed to trastuzumab and or taxane; the patient population 
being studied in the current trial (National Comprehensive Cancer Network Clinical 
Practice Guidelines in Oncology. 2014 and Cardoso et al. 2014). 
The control arm will be used to ascertain the individual contribution of atezolizumab to 
efficacy with trastuzumab emtansine.   
3.3.5 
Rationale for Biomarker Assessments 
Published results suggest that PD-L1 expression on TCs or ICs is associated with OS, 
PFS, and ORR in patients with advanced NSCLC treated with atezolizumab (Spigel et al. 
2015 and Spira et al. 2015).  Increased response was also observed in patients with 
urothelial carcinoma in patients with increased levels of PD-L1 expression on immune 
cells (Rosenberg et al. 2016).  This correlation was also observed in patients with 
various advanced incurable cancer types who were treated with atezolizumab (Herbst 
et al, 2014). 
The contribution of the immune system to pathologic complete response in the breast 
(pCR) after neoadjuvant docetaxel with trastuzumab, pertuzumab, or both, or 
monoclonal antibodies alone has been explored in Study WO20697 (Bianchini et al. 
2015).  Tumor-infiltrating lymphocytes as a continuous variable and PD-L1 protein 
expression assessed as single marker were not significantly associated with pCR; 
However expression of some immune genes/metagenes showed association with pCR, 
e.g., lower levels of MHC1 and CTLA4 showed higher benefit from THP.  The prognostic 
value of PD-L1 expression remains unclear in HER2-positive BC. 
This study will evaluate the potential predictive value of PD-L1 expression for treatment 
of HER2-positive MBC with atezolizumab and trastuzumab emtansine.  In addition, other 
exploratory biomarkers, such as potential predictive and prognostic markers that are 
related to PD-L1 activity, tumor immunobiology, mechanisms of resistance or tumor type 
may also be analyzed if supported by either nonclinical or clinical data.   
Recently published data by Rosenberg et al. (2016) in a study with patients with 
urothelial cancer treated with atezolizumab shows the importance of genomic, molecular 
and immunological factors in addition to PD-L1 expression on immune cells in 
understanding response to atezolizumab. 
Activating PIK3CA mutations in tumors have been evaluated as a resistance marker for 
HER2 targeted therapies in prior trials.  In metastatic HER2−positive BC, (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 


 
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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 will be measured in baseline tumor tissue to confirm the finding from Study 
TDM4370g/BO21977.  
Muller et al. (2015) demonstrated that trastuzumab emtansine increases tumor 
infiltrating lymphocytes (TILs) in human primary BC 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) recently 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 and on-treatment biopsies will assist in the study of pharmacodynamic 
changes related to the activity of trastuzumab emtansine with and without combination 
treatment with 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, including, but 
not limited to, cytokines such as interleukin (IL)-18 in blood samples.  
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.  
3.3.5.1 
Rationale for Collection of Archival and Metastatic Tumor 
Specimens 
If more than 1 formalin-fixed paraffin-embedded (FFPE) block exists from different time 
points e.g., initial diagnosis versus metastatic disease tissue, the most recently obtained 
block is mandatory to be sent and will be used for HER2 and PD-L1 analysis.  If the 
FFPE block from the earlier time point is available, then this would be requested to also 
be sent to enable evaluation of the impact of prior therapies on the expression pattern of 
PD-L1.  In addition to the assessment of PD-L1 status, other exploratory biomarkers such 
as potential predictive and prognostic markers related to the clinical benefit of 
trastuzumab emtansine plus atezolizumab, tumor immunobiology, mechanisms of 
resistance, or tumor type, may be evaluated.  These analyses may cover assessment of 
broad panels of genes (on both RNA and DNA level) that may contribute to the 
identification of biomarker signatures that are predictive of response to the combination 
of atezolizumab and trastuzumab emtansine. 


 
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HER2 status may be assessed on these paired samples as well to understand if HER2 
status changes as a result of prior therapies. 
3.3.5.2 
Rationale for Collection of Optional Pre-treatment and Cycle 2 
Biopsies 
As described in Section 3.3.5.1, the collection of serial tissue biopsies from patients 
undergoing study treatment will contribute to the biologic understanding of how this 
combination therapy works and may lead to the identification of novel biomarker(s) and 
or biomarker signatures that are predictive of which types of tumors benefit most from 
the combination of trastuzumab emtansine and atezolizumab treatment.  Additionally, 
these samples will give further insights in the early mechanisms of resistance and aid in 
the development of therapies to improve anti-tumor (immune) response.  
The biomarkers and biomarker panels in the tumor during treatment should ideally be 
compared to the baseline biomarker level(s) at the time study treatment was started.  
Tumor tissue collected from patients is however often archival as collected at time of first 
diagnosis or potentially at time of metastatic disease.  This tissue may therefore 
potentially not reliably reflect the biomarker status at time of treatment start in the current 
study and subsequently influence the assessment of biomarker changes over time 
during study treatment. 
Therefore, an optional biopsy collection has been included in this protocol to specifically 
evaluate these biomarker questions in the most accurate way.  This optional biopsy 
collection program will require an additional consent from the patient and will enable the 
collection or use of biopsy material at baseline (just before Cycle 1, Day 1) and collection 
at Cycle 2, Day 1.  
This additional consent will allow the collection of paired samples (pre-treatment and 
Cycle 2). PD-L1, CD8-positive T cells, and TILs in addition to other exploratory 
biomarkers will be evaluated on these samples. 
3.3.5.3 
Rationale for the Collection of Biopsy at the Time of 
Radiographic Progression 
If deemed clinically feasible, patients will undergo a tumor biopsy collection at the first 
evidence of radiographic disease progression.  Analysis of biological material (including, 
but not limited to, DNA and RNA) obtained from these specimens will help elucidate 
molecular changes associated with resistance, predictive of response to study drug, 
associated with progression to a more severe disease state, associated with 
susceptibility to developing adverse events, or can increase the knowledge and 
understanding of disease biology.  RNA extraction will be done to enable gene 
expression analyses.  DNA extraction on these samples will be done to enable analysis 
via e.g., whole genome sequencing (WGS) and/or next-generation sequencing (NGS) 
(e.g., whole exome or targeted sequencing).  


 
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Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS provides a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches.  If WGS data are generated, these will be analyzed in the context of this 
study but will also be explored in aggregate with data from other studies.  The availability 
of a larger dataset will assist in identification of important pathways, guiding the 
development of new targeted agents. 
3.3.6 
Rationale for Collection of PK and ATA Samples 
Both atezolizumab and trastuzumab emtansine single-agent pharmacokinetics have 
been characterized in multiple Phase I, II, and III studies.  Refer to the latest versions of 
the Trastuzumab Emtansine and Atezolizumab IBs for further details.  In this study, 
PK/ATA samples will be collected from all patients in both Arm A and Arm B as detailed 
in Appendix 2.  Sparse sampling will be used in this study.  PK and immunogenicity of 
atezolizumab (Arm B) and trastuzumab emtansine (Arm A and Arm B) will be assessed.  
The major objectives of the PK analysis for the current study are to characterize the 
pharmacokinetics of atezolizumab in the presence of trastuzumab emtansine and the 
pharmacokinetics of trastuzumab emtansine in the presence of atezolizumab.  The 
trastuzumab emtansine results from Arm A and Arm B will be used to evaluate the 
trastuzumab emtansine pharmacokinetics in the presence and absence of atezolizumab 
in this BC patient population.  The atezolizumab pharmacokinetics in the presence of 
trastuzumab emtansine will be evaluated and compared with historical data from 
single-agent atezolizumab studies.  
3.3.7 
Rationale for Allowing Patients to Continue Treatment Beyond 
Initial Progression per RECIST 1.1 
Conventional response criteria may not adequately assess the activity of 
immunotherapeutic agents because radiographic PD does not necessarily reflect 
therapeutic failure (Section 3.3.5).  In the Phase Ia Study PCD4989g, several patients 
who progressed per RECIST v1.1 continued on atezolizumab treatment and 
subsequently demonstrated durable anti-tumor activity.  Of the 21 patients with TNBC in 
the study who were evaluable for response (Section 1.2.2), 3 patients with IC2/3 TNBC 
showed evidence of target lesion shrinkage after an initial increase in tumor burden or 
following the appearance of new lesions.  These patients likely experienced pseudo 
progression or delayed response (Emens et al. 2015).  Additionally, in some responding 
patients with NSCLC in Study PCD4989g, the growth of known lesions or the 
appearance of new radiographic lesions were shown to contain immune cells and no 
viable cancer cells on biopsy (Gettinger et al. 2013). 
Pseudo-progression was observed in 3 out of 24 efficacy-evaluable patients who 
received atezolizumab in combination with nab-paclitaxel in Study GP28328 (Adams 
et al. 2015).  The most commonly observed pattern was the appearance of new lesions 


 
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(e.g., FDG-avid lymph nodes) in the context of decreased overall tumor burden at the 
first or second tumor assessment.   
The rate of progression or delayed anti-tumor immunity in (i) patients with HER2-positive 
metastatic breast cancer and/or (ii) when atezolizumab is administered in combination 
with trastuzumab emtansine is not known.  To account for the possibility of 
pseudo-progression or delayed anti-tumor immunity, upon the identification per RECIST 
v1.1 progression, patients in this study may optionally continue to receive blinded study 
treatment provided they meet the criteria listed in Section 3.3.  To mitigate the risk of 
continuing treatment in the face of true therapeutic failure, radiographic criteria for 
treatment discontinuation at the next scheduled assessment are described in Section 3.1. 
For equivocal findings of progression (e.g., very small or uncertain new lesions or lymph 
nodes; cystic changes or necrosis in existing lesions), the study permits treatment to 
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 is suspected (Appendix 4; Eisenhauer et al. 2009). 
Although the primary efficacy endpoint of PFS will be analyzed based on 
investigator-assessed PFS using RECIST v1.1, a non-comparative analysis of the 
PFS, ORR, and DOR endpoint will be performed with use of immune-modified RECIST 
(Appendix 5) for eligible patients who continue treatment beyond radiographic 
progression, as an explorative endpoint of this study.  The immune-modified RECIST 
instrument allows the incorporation of new lesions into the calculation of total tumor 
burden after baseline.  As with the immune-related response criteria (Wolchok et al. 
2009) it is recommended that radiographic progression be confirmed at a subsequent 
tumor assessment to take into account the potential for pseudo progression/tumor 
immune infiltration. 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
The study will enroll 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 within 6 months after completing adjuvant therapy.  Patients must comply 
with the following inclusion and exclusion criteria.  
4.1.1 
Inclusion Criteria 
Patients must meet ALL of the following inclusion criteria to be eligible for study entry: 
• 
Age ≥ 18 years. 
• 
Signed written informed consent approved by the institution’s Independent Ethical 
Committee/Institutional Review Board (IRB).  


 
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• 
Archival tumor samples must be obtained from primary and/or metastatic sites. 
Representative FFPE tumor specimens in paraffin blocks for central testing is 
required.  Different material as described in Appendix 3 may be accepted in 
exceptional cases (see Section 4.5.8.2.1).  Tumor tissue should be of good quality 
based on total and viable tumor content and must be evaluated for HER2 and 
PD-L1 expression prior to enrollment. 
• 
Patients must submit tumor tissue that is evaluable for PD-L1 expression to be 
eligible for this study.  If multiple tumor specimens are submitted (e.g., an archival 
specimen [from initial BC diagnosis] and tissue from metastatic or LABC disease), 
patients may be eligible if at least one specimen is evaluable for PD-L1.  
For the purpose of stratification, the PD-L1 score of the patient will be the 
maximum PD-L1 score among the samples.  Tumor tissue from bone 
metastases is not evaluable for PD-L1 expression and is therefore not 
acceptable.  
Patients who do not have tissue specimens that meet eligibility requirements 
may undergo a biopsy during the screening period.  Acceptable samples 
include core needle biopsies for deep tumor tissue (minimum three cores) or 
excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, 
or mucosal lesions.  Fine-needle aspiration, brushing, cell pellet from pleural 
effusion, bone metastases, and lavage samples are not acceptable. 
• 
HER2-positive BC as defined by an IHC score of 3 +  (Appendix 6) or gene amplified 
by in situ hybridization (ISH) as defined by a ratio of ≥ 2.0 (Appendix 7) for the 
number of HER2 gene copies to the number of chromosome 17 
copies, prospectively tested by a Sponsor- designated central laboratory prior to 
enrollment.  Both IHC and ISH assays will be performed; however, only one positive 
result is required for eligibility.  
If multiple tumor specimens are submitted, the HER2 IHC score and or ISH 
amplification ratio will first be assessed on the archival specimen for the 
purpose of determining eligibility.  For patients with bilateral BC, HER2 positivity 
must be demonstrated in both locations for archival tissue or in a metastatic 
biopsy. 
Centrally confirmed HER2 results (either IHC or ISH) from a current or previous 
Sponsor study can be used to determine eligibility for this study.  Approval must 
be obtained from the Medical Monitor prior to randomization.  
Progression must have occurred during or after most recent treatment for LABC 
or MBC or within 6 months after completing adjuvant therapy. 
• 
Histologically or cytologically confirmed invasive BC: incurable, unresectable, locally 
advanced BC previously treated with multimodality therapy or MBC. 
• 
Prior treatment for BC in the: adjuvant; unresectable locally advanced; or metastatic 
settings; which must include both, a taxane and trastuzumab (alone or in 
combination with another agent)  
• 
Patients must have measurable disease that is evaluable per RECIST 1.1.  


 
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• 
ECOG Performance Status of 0 or 1.  
• 
Adequate hematologic and end-organ function, as evidenced by the following local 
laboratory results obtained within 7 days prior to the first study treatment 
(Cycle 1, Day 1): 
Absolute neutrophil count ≥ 1500 cells/µL (without granulocyte-colony 
stimulating factor [support) within 7 days prior to Cycle 1, Day 1 
Platelet count ≥ 100,000/µL (without transfusion within 7 days prior 
to Cycle 1, Day 1) 
Hemoglobin ≥ 9.0 g/dL 
Patients may be transfused or receive erythropoietic treatment to meet this 
criterion. 
Albumin > 2.5g/dL 
AST, ALT, and alkaline phosphatase ≤ 2.5 × the upper limit of normal (ULN) with 
the following exceptions: 
Patients with documented bone metastases: alkaline phosphatase ≤ 5 × the 
ULN 
Total bilirubin ≤ 1.5 × the ULN 
INR and aPTT ≤ 1.5 × the ULN 
This applies only to patients who are not receiving therapeutic 
anticoagulation; patients receiving therapeutic anticoagulation should be 
on a stable dose. 
Calculated creatinine clearance ≥ 30 mL/min 
• 
Negative serum pregnancy test within 7 days of enrollment for pre-menopausal 
women and for women less than 12 months after the onset of menopause. 
• 
For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate 
of < 1% per year during the treatment period and for at least 7 months after the last 
dose of trastuzumab emtansine or 5 months after the last dose of 
atezolizumab/placebo, whichever is later. 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (≥ 12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus). 
Examples of contraceptive methods with a failure rate of < 1% per year include 
bilateral tubal ligation, male sterilization, established, proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, 
and copper intrauterine devices. 


 
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The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
• 
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm, as 
defined below: 
With female partners of childbearing potential, men must remain abstinent or 
use a condom plus an additional contraceptive method that together result in 
a failure rate of < 1% per year during the treatment period and for at least 
7 months after the last dose trastuzumab emtansine.  Men must refrain from 
donating sperm during this same period. 
With pregnant female partners, men must remain abstinent or use a condom 
during the treatment period and for at least 7 months after the last dose of 
trastuzumab emtansine to avoid exposing the embryo. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
 
4.1.2 
Exclusion Criteria 
Patients who meet any ONE of the following criteria will be excluded from study entry: 
• 
Prior treatment with trastuzumab emtansine, CD137 agonists, anti-PD-1, or 
anti-PD-L1 therapeutic antibody or pathway−targeting agents. 
• 
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. 
• 
Radiation therapy within 2 weeks prior to Cycle 1, Day 1 
The patient must have recovered from any resulting acute toxicity (to Grade ≤ 1) 
prior to randomization.  
• 
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.   


 
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• 
History of other malignancy within the previous 5 years, except for appropriately 
treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, 
Stage I uterine cancer, or patients who have undergone potentially curative therapy 
with no evidence of disease and are deemed by the treating physician to be at low 
risk for recurrence. 
• 
Cardiopulmonary dysfunction as defined by: 
Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg) 
Inadequate left ventricular ejection function at baseline, < 50% by either 
echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) 
History of symptomatic congestive heart failure (CHF)-Grade ≥ 3 per NCI 
CTCAE version 4.0 (Appendix 8) or Class ≥ II New York Health Association  
History of a decrease in left ventricular ejection function to < 40% or 
symptomatic CHF with prior trastuzumab treatment 
Myocardial infarction or unstable angina within 6 months of randomization  
Current dyspnoea at rest due to complications of advanced malignancy, or 
other disease requiring continuous oxygen therapy 
Serious cardiac arrhythmia not controlled by adequate medication 
• 
Patients with severe infection within 4 weeks prior to randomization, including but 
not limited to hospitalization for complications of infection, bacteremia, or severe 
pneumonia. 
• 
Current severe, uncontrolled systemic disease (e.g., clinically significant 
cardiovascular, pulmonary or metabolic disease; wound healing disorders; ulcers; 
bone fractures).  
• 
Major surgical procedure or significant traumatic injury within 28 days prior to 
randomization or anticipation of the need for major surgery during the course of 
study treatment. 
• 
Clinically significant history of liver disease, including cirrhosis, current alcohol 
abuse, autoimmune hepatic disorders, sclerosis cholangitis or active infection with 
HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV) 
Active infection is defined as requiring treatment with antiviral therapy or 
presence of positive test results for hepatitis B (hepatitis B surface antigen 
and/or total hepatitis B core antibody) or HCV antibody.  HIV, HBV, or HCV 
assessments are required at screening.  
Patients who test positive for hepatitis B core antibody are eligible only if test 
results are also positive for hepatitis B surface antibody and polymerase chain 
reaction is negative for HBV DNA. 
Patients who are positive for HCV serology are only eligible if testing for HCV 
RNA is negative. 


 
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• 
Need for current chronic corticosteroid therapy (≥ 10 mg of prednisone per day or an 
equivalent dose of other anti-inflammatory corticosteroids) 
Stable use (i.e., no change in dose within 3 months prior to Cycle 1, Day 1) of 
inhaled corticosteroids is allowed. 
• 
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. 
• 
Patients with known central nervous system (CNS) disease are not eligible, except 
for treated asymptomatic CNS metastases, provided that all of the following criteria 
are met: 
Only supratentorial and cerebellar metastases allowed (i.e., no metastases to 
midbrain, pons, medulla, or spinal cord) 
No ongoing requirement for corticosteroids as therapy for CNS disease  
No stereotactic radiation within 14 days prior to randomization 
No evidence of interim progression between the completion of CNS-directed 
therapy and the screening radiographic study 
• 
Note: Patients with new asymptomatic CNS metastases detected at the screening 
scan must receive radiation therapy and/or surgery for CNS metastases.  Following 
treatment, these patients may be eligible without the need for an additional brain 
scan prior to enrollment, if all other criteria are met. 
• 
Leptomeningeal disease 
• 
Symptomatic pleural effusion, pericardial effusion, or ascites.  
• 
Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or calcium > 12 mg/dL or 
corrected serum calcium greater than the ULN) or symptomatic hypercalcemia 
requiring continued use of bisphosphonate therapy.  
Patients who are receiving denosumab must discontinue use of denosumab 
and replace it with a bisphosphonate instead while on study. 
Patients who are receiving bisphosphonate therapy specifically to prevent 
skeletal events and who do not have a history of clinically significant 
hypercalcemia are eligible. 
• 
Current Grade ≥ 3 peripheral neuropathy (according to the NCI CTCAE v4.0). 
• 
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. 
• 
History of autoimmune disease (Appendix 10), including, but not limited to, 
myasthenia gravis, autoimmune myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular 
thrombosis associated with antiphospholipid syndrome, Wegener granulomatosis, 
Sjögren syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or 
glomerulonephritis.  


 
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Patients with a history of autoimmune-related hypothyroidism on a stable dose 
of thyroid replacement hormone may be eligible for this study. 
History of inflammatory bowel disease (e.g., Crohn’s disease or ulcerative 
colitis) or active bowel inflammation (e.g., diverticulitis). 
Patients with Type 1 diabetes mellitus will not be eligible unless controlled with 
the patient on a stable insulin regimen 
Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis would be 
excluded) are excluded unless they meet the following conditions: 
Rash must cover < 10% of body surface area. 
Disease is well controlled at baseline and requiring only low-potency 
topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 
0.1%, flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 
0.05%) 
No acute exacerbations of underlying condition within the last 
12 months (not requiring psoralen plus ultraviolet.  A radiation, 
methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or 
high-potency or oral steroids) 
Patients with psoriasis must have a baseline ophthalmologic exam to 
rule out ocular manifestations. 
• 
Prior allogeneic stem cell or solid organ transplantation. 
• 
History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced 
pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic 
organizing pneumonia), or evidence of active pneumonitis on screening chest 
CT scan. 
Patients with a history of radiation pneumonitis in the radiation field (fibrosis) are 
eligible. 
• 
Active tuberculosis. 
• 
Receipt of a live, attenuated vaccine within 4 weeks prior to randomization 
or anticipation that such a live, attenuated vaccine will be required during the study. 
• 
Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferons or IL-2) within 4 weeks or five half-lives of the drug (whichever is shorter) 
prior to randomization. 
• 
Treatment with systemic corticosteroids or other systemic immunosuppressive 
medications (including but not limited to prednisone, dexamethasone, 
cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−tumor 
necrosis factor [TNF] agents) within 2 weeks prior to randomization, or anticipated 
requirement for systemic immunosuppressive medications during the trial. 
Patients who need current chronic corticosteroid therapy (≥ 10 mg of 
prednisone per day or an equivalent dose of other anti-inflammatory 
corticosteroids) will be excluded 


 
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Patients who have received acute, lowdose, systemic 
immunosuppressant medications (e.g., a one-time dose of dexamethasone 
for nausea) may be enrolled in the study. 
Stable use (i.e., no change in dose within 3 months prior to Cycle 1, Day 1) 
of inhaled corticosteroids is allowed 
 
Breastfeeding, or intending to become pregnant during the study 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
4.2.1 
Number of Patients/Assignment to Treatment Groups 
Approximately 200 patients will be enrolled in the study and randomized to treatment 
arms A and B in a 1:2 ratio (approximately 67 patients in Arm A and 133 patients in 
Arm B).  An Interactive voice/ Web response system (IxRS) will be utilized to collect 
patient screening information and to randomize eligible patients to either treatment 
Arm A or B.  Patients will be randomized within 28 days from initiation of screening.  
Patients will be blinded as to whether they receive atezolizumab or placebo in 
combination with trastuzumab emtansine.  Investigators and study team members will 
also be blinded.   
A permuted block randomization scheme will be used to achieve balance in treatment 
assignment within the two treatment arms with respect to pre-specified stratification 
factors (Section 4.2.2). 
Patients who are randomized into this study will not be allowed to be re-randomized to 
receive a second course of study treatment. 
Once a patient has been randomized into the study, the IxRS will be used to assign the 
kit numbers for study drugs to be dispensed at each treatment visit.  It is important that 
the study drugs dispensed for each visit are the correct kit number, as assigned by the 
IxRS.  This will ensure that drug use by dates and automatic study drug resupply to sites 
are managed appropriately via the IxRS.  
4.2.2 
Stratification 
Randomization will be stratified based on the following three factors: 
 
Tumor PD-L1 Status (PD-L1 IC 0 vs. IC 1/2/3) 
 
World Region (Western Europe vs U.S. vs. Rest of World) 
 
Liver Metastases (yes vs. no) 
 
4.2.3 
Study Treatment Unblinding 
Unblinding of treatment assignment may occur either at patient or study level. 


 
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4.2.3.1 
Unblinding at Patient Level 
Unblinding of treatment assignment may occur either at patient or study level under the 
following two scenarios.  The reason and date of unblinding should be documented in 
the electronic data capture (EDC) system. 
4.2.3.1.1 
Emergency Unblinding 
Study treatment assignment may be unblinded for serious, unexpected study 
drug−related toxicity.  Emergency unblinding should be a last resort performed only in 
cases where knowledge of treatment assignment will affect ongoing treatment of the 
patient.  Investigators are permitted to perform emergency unblinding without prior 
approval from the Sponsor.  However, they are encouraged to consult with the Medical 
Monitor prior to performing emergency unblinding.  
4.2.3.1.2 
Non-Safety Unblinding 
Study treatment assignment for non-safety reasons may be unblinded only in situations 
where the patient is assessed as eligible for a clinical trial following discontinuation from 
the WO30085 study drug treatment and where the eligibility criteria requires the 
knowledge of prior treatment with cancer immunotherapy. This unblinding will require 
Sponsor assessment and approval.   
4.2.3.2 
Unblinding at Study Level 
For regulatory reporting purposes, if required by local health authorities, the Sponsor will 
break the treatment code for all serious, unexpected adverse reactions that are 
considered by the investigator or Sponsor to be related to study drug. 
Personnel responsible for performing PK and ATA assays will be unblinded to patients’ 
treatment assignments to identify appropriate PK and ATA samples to be analyzed and 
assist with cleaning of PK and ATA data.  While PK and ATA samples must be collected 
from patients assigned to the control arm to maintain the blinding of treatment 
assignment, PK and ATA assay results for these patients are generally not needed for 
the safe conduct or proper interpretation of this study.  Samples from patients assigned 
to the control arm will not be analyzed except by request (i.e., to evaluate a possible 
error in dosing). 
4.3 
STUDY TREATMENT  
The investigational medicinal products (IMP) for this study are trastuzumab emtansine, 
atezolizumab, and placebo.  Each will be labeled according to regulatory requirements in 
each country, as well as in accordance with International Conference of Harmonisation 
(ICH) Good Clinical Practice (GCP) guidelines, and will be labeled for investigational use 
only.  The Sponsor will provide trastuzumab emtansine, atezolizumab, and placebo free 
of charge to all study sites.   


 
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4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
Trastuzumab Emtansine 
The formulation, packaging, and handling should be performed according to the most 
recent version of the Trastuzumab Emtansine IB.  For further details, refer to the Study 
Pharmacy Binder®. 
4.3.1.2 
Atezolizumab 
The formulation, packaging and handling should be performed according to the most 
recent version of the Atezolizumab IB.  For further details, refer to the Pharmacy Manual.  
4.3.1.3 
Placebo 
The formulation of placebo is equivalent to atezolizumab but without the active agent. 
The handling of placebo should be followed as per Section 4.3.2.2. 
4.3.2 
Dosage, Administration, and Compliance 
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 and dose must be re-adjusted for 
weight changes ≥ 10% compared to the previous visit or baseline.  The investigator may 
choose to recalculate the dose at every cycle using actual weight at that time, according 
to their local practice.  Administration may be delayed to assess or treat adverse events.  
Dose reduction will be allowed, following the dose reduction levels provided in Table 4.  
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. 
Refer to Table 1 for guidelines on administration of first and subsequent infusions of 
trastuzumab emtansine. 


 
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Table 1 
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 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 prior infusions were well tolerated, subsequent 
doses may be administered as 30 minute 
infusions  
• 
Patient should be observed during the infusions 
and for at least 30 minutes after infusion. 
 
4.3.2.2 
Atezolizumab/Placebo 
Patients will receive 1200 mg of atezolizumab/placebo administered by IV infusion q3w.  
Atezolizumab/placebo infusions will be administered according to the instructions 
outlined in Table 2.  Guidelines for dosage modification and treatment interruption or 
discontinuation are provided in Section 5.1.3. 
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.   
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.   
Refer to Table 2 for guidelines on administration of first and subsequent infusions of 
atezolizumab. 


 
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Table 2 
Administration of First and Subsequent Infusions of 
Atezolizumab/Placebo 
First Infusion 
Subsequent Infusions 
• No premedication is administered. 
• Record patient’s vital signs (heart 
rate, respiratory rate, blood pressure, 
and temperature) within 60 minutes 
before starting infusion. 
• Infuse (one vial in 250 mL NaCl) over 
60 (± 15) minutes. 
• Record patient’s vital signs (heart rate 
• respiratory rate, blood pressure, and 
• temperature) during and after the 
infusion if clinically indicated 
• Patients will be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact 
their study physician if they develop 
such symptoms. 
• If patient experienced infusion-related reaction 
during any previous infusion, premedication with 
antihistamines may be administered for Cycles ≥ 2 
at the discretion of the treating physician. 
• Record patient’s vital signs (heart rate, respiratory 
rate, blood pressure, and temperature) within 
60 minutes before starting infusion. 
• If the patient tolerated the first infusion well without 
infusion-associated adverse events, the second 
infusion may be administered over 
30 (± 10) minutes. Continue to record vital signs 
within 60 minutes before starting infusion and 
during and after the infusion if clinically indicated. 
• If the patient had an infusion-related reaction during 
the previous infusion, the subsequent infusion must 
be delivered over 60 (± 15) minutes.  
• Record patient’s vital signs (heart rate, respiratory 
rate, blood pressure, and temperature) during the 
infusion 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 
adverse events are provided in Section 5.1. 
Refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, 
and administration of atezolizumab/placebo. 
4.3.4 
Investigational Medicinal Product Accountability 
All IMPs for the study drugs used in this study (trastuzumab emtansine, atezolizumab, 
and placebo) will be provided by the Sponsor.  The study site will acknowledge receipt of 
IMPs via the IxRS} to confirm the shipment arrival, condition and content.  Any damaged 
shipments will be replaced. 
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor accompanied with the 


 
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appropriate documentation.  The site's method of IMP destruction must be agreed to by 
the Sponsor.  The site must obtain written authorization from the Sponsor before any 
IMP is destroyed, and IMP destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 
4.3.5 
Post-Trial Access to Trastuzumab Emtansine and 
Atezolizumab 
The Sponsor will evaluate the appropriateness of continuing to provide trastuzumab 
emtansine and atezolizumab (where applicable) to patients on protocol treatment at the 
end of the study (see Section 3.2) in accordance with the Roche Global Policy on 
Continued Access to Investigational Medicinal Product, available at the following Web 
site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
4.4 
CONCOMITANT THERAPY 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
7 days prior to initiation of study treatment to the study treatment discontinuation visit.  
All such medications must 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  
The following therapies are permitted as concomitant medications in the study: 
• 
Prophylactic or therapeutic anticoagulation therapy (such as low−molecular weight 
heparin or warfarin at a stable dose level) 
• 
Palliative radiotherapy is permitted to treat pre-existing bone metastases only 
• 
Inactive influenza vaccinations during influenza season  
• 
Megestrol administered as an appetite stimulant 
• 
Inhaled corticosteroids for chronic obstructive pulmonary disease 
• 
Mineralocorticoids (e.g., fludrocortisone) 


 
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• 
Low-dose corticosteroids for patients with orthostatic hypotension or adrenocortical 
insufficiency 
• 
Bisphosphonates for prevention of skeletal related events  
 
In general, investigators should manage patient’s care with supportive therapies as 
clinically indicated and per local standards.  No protocol specified pre-medication with 
steroids for the first infusion trastuzumab emtansine or atezolizumab/placebo is required.  
If pre-medication with steroids is being considered, please contact the Medical Monitor 
for approval.  
Patients who experience infusion-associated symptoms may be treated symptomatically 
with acetaminophen, ibuprofen, diphenhydramine, and/or famotidine or another 
H2-receptor antagonist per standard practice (for sites outside the United States, 
equivalent medications may be substituted per local practice).  Serious 
infusion-associated events manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should 
be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen 
and β2-adrenergic agonists). 
4.4.2 
Prohibited Therapy 
The following medications are prohibited while a patient is receiving study treatment:  
• 
Traditional herbal medicines:  These therapies are not fully studied and their use 
may result in unanticipated drug-drug interactions that may cause or confound the 
assessment of toxicity. 
• 
Concomitant use of potent cytochrome (CYP) P450 3A4/5 inhibitors (such as 
ketoconazole and itraconazole) with trastuzumab emtansine should be avoided.  
Consider an alternate medication with no or minimal potential to inhibit CYP3A4/5.  
If a strong CYP3A4/5 inhibitor needs to be co-administered with trastuzumab 
emtansine, patients should be closely monitored for adverse reactions.  
• 
Excessive alcohol intake should be avoided (occasional to moderate use is 
permitted).  
• 
RANKL inhibitor (denosumab): Patients who are receiving denosumab prior to 
enrollment must be willing and eligible to receive a bisphosphonate instead while on 
study. 
• 
Immunomodulatory agents, including, but not limited to, interferons or IL-2, during 
the entire study; these agents could potentially increase the risk for autoimmune 
conditions when received in combination with atezolizumab. 
• 
Immunosuppressive medications, including, but not limited to, cyclophosphamide, 
azathioprine, methotrexate, and thalidomide; these agents could potentially alter the 
activity and the safety of atezolizumab. 


 
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• 
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. 
• 
Any live, attenuated vaccine (e.g., FluMist®) at any time during the study 
 
Systemic corticosteroids and anti−TNF-α agents may also attenuate potential beneficial 
immunologic effects of treatment with atezolizumab but may be administered at the 
discretion of the treating physician.  If feasible, alternatives to these agents should be 
considered. 
In addition, patients should not receive other immunomodulatory agents for 10 weeks 
after atezolizumab/placebo discontinuation. 
4.5 
STUDY ASSESSMENTS  
Please see Appendix 1 for the schedule of assessments performed during the study. 
4.5.1 
Informed Consent Forms and Screening Log 
Signed, written informed consent for participation in the study must be obtained before 
performing any study-related procedures.  Informed Consent Forms for enrolled patients 
and for patients who are not subsequently enrolled will be maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before randomization into the study.  The investigators will maintain a 
screening log to record details of all patients screened and to confirm eligibility or 
document reasons for screening failure, as applicable. 
4.5.2 
Medical History and Demographic Data 
Medical history includes prior cancer therapies and procedures, reproductive status, 
smoking history, use of alcohol and drugs of abuse, and all medications 
(e.g., prescription drugs, over−the-counter drugs, herbal or homeopathic remedies, and 
nutritional supplements) used by the patient within 7 days prior to the Cycle 1, Day 1 visit. 
BC history includes prior cancer therapies and procedures.   
Demographics will include age, gender, and self-reported race/ethnicity.  Local HER2 
testing information will also be collected. 
4.5.3 
Physical Examinations 
A complete physical examination should be performed at screening and should include 
an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, genitourinary, and 
neurological systems.  Any abnormality identified at baseline should be recorded on the 
General Medical History and Baseline Conditions eCRF. 


 
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At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF. 
4.5.4 
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, systolic and 
diastolic blood pressure while the patient is in a seated position, and temperature.  Refer 
to Appendix 1 for further details. 
4.5.5 
Tumor and Response Evaluations 
All sites of measurable and non-measurable disease must be documented at screening 
and re-assessed at each subsequent tumor evaluation.  Tumor assessments are to be 
performed at the timepoints specified in Appendix 1; a time window of ± 7 days is 
allowed for all timepoints regardless of drug delays or interruptions.  Tumor assessments 
will continue until disease progression, withdrawal of consent, death, or study 
termination by the Sponsor, whichever occurs first. 
Initial screening assessments must include CT scans (with oral or IV contrast unless 
contraindicated) or MRI scans of the chest, abdomen, and pelvis.  A bone scan or 
positron emission tomography (PET) scan should also be performed to evaluate for 
bone metastases.  MRI scans of the chest, abdomen, and pelvis or non-contrast CT 
scan may be used in patients for whom CT scans with contrast are contraindicated 
(i.e., patients with contrast allergy or impaired renal clearance). 
A CT (with contrast) or MRI scan of the head must be performed at screening to 
evaluate CNS metastasis in all patients.  A MRI scan of the brain is required to confirm 
or refute a diagnosis of CNS metastasis at screening in the event of an equivocal scan.  
Patients with active or untreated CNS metastasis are not eligible for this study 
(Section 4.1.2 for CNS-related exclusion criteria). 
If a CT scan for tumor assessment is performed as part of a PET/CT, the CT acquisition 
must be consistent with the standards for a full-contrast diagnostic CT scan. 
CT scans of the neck should also be performed if clinically indicated during the 
screening period.  At the investigator’s discretion, other methods of assessment of 
measurable disease according to RECIST v1.1 may be used. 
Evaluation of tumor response conforming to RECIST v1.1 (Appendix 4) and 
immune-modified RECIST (Appendix 5) will be performed every 6 weeks (± 7 days) 
following randomization, with additional scans performed as clinically indicated.  The 
same radiographic procedures used to assess measurable disease sites at screening 
should be used throughout the study (e.g., the same contrast protocol for CT and/or 
MRI scans).   


 
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All known sites of disease must be documented at screening and re-assessed at each 
subsequent tumor evaluation.  Tumor assessments performed after the screening period 
should consist of the following assessments every 6 weeks:  1) CT and/or MRI of the 
chest/abdomen/pelvis, as well as other known sites of disease, including brain, 2) If a 
patient has only bone as a site of involvement at screening which is determined to be 
measurable disease as per RECIST 1.1, then a bone scan or PET scan is mandated at 
every tumor assessment, otherwise, a bone scan or PET scan is to be performed as 
clinically indicated, e.g., suspicion of disease progression, 3) in cases where patients 
demonstrate control of their systemic disease but who newly develop isolated brain 
metastases and are eligible to remain on study treatment, brain MRI or CT are 
performed along with regularly scheduled tumor assessments, and 4) any other imaging 
studies felt to be clinically indicated by the treating physician. 
Response will be assessed by the investigator using RECIST v1.1 (Appendix 4) and 
immune-modified RECIST (Appendix 4 at each tumor assessment.  Assessments should 
be performed by the same evaluator, if possible, to ensure internal consistency across 
visits. 
At the investigator’s discretion, CT or other clinically appropriate scans may be repeated 
at any time if PD is suspected.  If the initial screening bone scan or PET scan indicates 
bone metastases and this is the only site of involvement and is determined to be 
measurable disease per RECIST 1.1, then a bone scan or PET scan needs to be 
performed every 6 weeks.  If the screening scan shows evidence of either non-
measurable bone metastases or no bone metastases, then these procedures do not 
need to be repeated unless clinically indicated or at the treating physician’s discretion.  
If the brain is not identified as a site of involvement at screening, then brain CT or MRI 
only needs to be repeated beyond screening, if clinically indicated.  In cases where a 
patient demonstrates control of their systemic disease but who newly develops isolated 
brain metastases and is eligible to remain on study treatment, brain MRI or CT are 
performed along with regularly scheduled tumor assessments (Section 3.1). 
If study drug treatment is discontinued prior to disease progression according to RECIST 
v1.1, tumor response assessment should continue to be performed as per the schedule 
specified in Appendix 1.  
In patients who continue treatment beyond radiographic disease progression per 
RECIST v1.1, tumor response will also continue to be assessed using immune-modified 
RECIST criteria as specified in Appendix 1, until study treatment discontinuation. 
All primary imaging data used for tumor assessment will be collected by the Sponsor to 
enable centralized, independent review of response endpoints, if needed. 


 
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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 if LVEF declines are 
clinically suspected at the discretion of the investigator. 
4.5.7 
Electrocardiogram 
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.  
ECG recordings must be performed after the patient has been resting in a supine 
position for at least 10 minutes. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Any morphologic waveform changes or other ECG abnormalities 
must be documented on the eCRF. 
4.5.8 
Laboratory, Biomarker, and Other Biological Samples  
4.5.8.1 
Laboratory Samples 
Samples obtained from the following laboratory tests will be sent to the study site’s local 
laboratory for analysis: 
• 
Hematology (CBC, including RBC count, hemoglobin, hematocrit, WBC count with 
differential [neutrophils, eosinophils, lymphocytes, monocytes, basophils, and other 
cells], and platelet count) 
• 
Serum chemistry (glucose, BUN or urea, creatinine, sodium, potassium, magnesium, 
chloride, bicarbonate, calcium, phosphorus, total bilirubin, ALT, AST, alkaline 
phosphatase, total protein, and albumin) 
• 
Coagulation (aPTT and INR) 
• 
Serum pregnancy test for women of childbearing potential, including women who 
have had a tubal ligation; urine pregnancy tests will be performed every third cycle 
during treatment.  If a urine pregnancy test is positive, it must be confirmed by a 
serum pregnancy test. 
Childbearing potential is defined as not having undergone surgical sterilization, 
hysterectomy, and/or bilateral oophorectomy or not being post-menopausal 
(≥ 12 months of amenorrhea).  
• 
Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood) 
• 
Thyroid function test (thyroid-stimulating hormone [TSH], free T3, and free T4) 
• 
HIV (tested prior to patient enrollment in the study) 
HIV-positive patients are excluded from study participation. 


 
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• 
HBV serology (HBsAg, antibody to HBsAg [anti-HBs], and anti-HBc) 
HBV DNA testing is required prior to or on Day 1 of Cycle 1 if a patient has 
negative serology for HBsAg and positive serology for anti-HBc.  
HCV serology (anti-HCV) 
 
The assessments listed below will be performed at a central laboratory or by the 
Sponsor.  Any remaining material from samples collected to enable these central 
assessments may be used for additional related safety assessments (e.g., ATA assay), 
exploratory biomarker profiling, and pharmacodynamic assay development purposes.  
Instruction manuals and supply kits will be provided for all central laboratory 
assessments. 
• 
Central HER2 testing (for eligibility assessment) and PD-L1 testing (for stratification) 
• 
Tumor and blood samples for RNA and DNA extraction for gene expression and 
genomic sequencing.  If gene expression or genomic sequencing is performed, 
samples will be sent to one or more laboratories for analysis.  
• 
Biomarker blood assays 
Blood samples will be processed to obtain blood cells, plasma, and serum for 
the determination of baseline level changes in surrogate pharmacodynamic 
biomarkers 
• 
C-reactive protein 
• 
Serum HER2 extra cellular domain at baseline 
• 
ATA assays  
Serum samples will be assayed for the presence of ATAs to atezolizumab and 
trastuzumab emtansine using validated immunoassays. 
• 
Auto-antibody testing:  The baseline sample will be collected on Cycle 1, Day 1, prior 
to the first dose of study drug.  For patients who show evidence of immune-mediated 
toxicity, additional samples may be collected and will be analyzed centrally. 
Anti-nuclear antibody 
Anti−double-stranded DNA 
Circulating anti-neutrophil cytoplasmic antibody 
Perinuclear anti-neutrophil cytoplasmic antibody 
• 
PK assays 
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. 
 


 
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4.5.8.2 
Biomarker Samples 
The schedule of tissue collection is described in Appendix 3.  Only at those sites where 
a legitimate site regulation renders submission of blocks impossible and only after 
having obtained the Sponsor's approval, submission of different material as described in 
Appendix 3 may be accepted.  
After completion of HER2 and PD-L1 testing, patient samples may also be tested with 
other exploratory assays/technologies to establish performance characteristics of these 
assays for both next generation diagnostic development and understanding treatment 
response associated to characteristics of the tumor microenvironment.  Testing could be 
performed on all screened patients (screen-failed and enrolled) and will be performed 
only after eligibility is established for each patient.  These exploratory testing data will 
have no impact on patient eligibility.   
After initial HER2 and mandatory biomarker testing, the tissue blocks will be used for 
midterm storage up to the time of final clinical study report before returning them to sites 
to allow for future biomarker analysis.  Hereafter, the blocks will be shipped back, unless 
the patient gives specific consent for the remainder of the samples to be stored for 
optional exploratory research (Research Biosample Repository [RBR]; Section 4.5.8).  
In cases where only slides were sent because of country or site regulations, a new 
request of slides will be sent to the sites in case additional markers or assays are 
defined up to final clinical study report.  The midterm storage of tissue and the possibility 
of requesting more slides up to the time of the final clinical study report extends the 
possibility of deciding on analyses of important additional markers or assays while the 
study is ongoing or until final study data are available. 
In cases where midterm storage of tumor tissue blocks is not allowed by local regulatory 
bodies (including IRB/EC policies) for patients without consent to RBR, the block will be 
sent back to the site no later than 3-6 months and requested at a later timepoint within 
the study in case additional analyses are defined.  If the patient provides consent for 
optional exploratory research (RBR), the samples will be stored until no longer required 
in accordance with the IRB/EC-approved Informed Consent Form and applicable laws 
(e.g., health authority requirements).  
If tissue material from more than one timepoint was submitted, the midterm storage only 
applies to the most recent sample and the archival tumor tissue block for all patients 
enrolled will be returned no later than 3-6 months after eligibility determination.  In case 
archival partial blocks or slides are sent, this tissue will not be returned. 
All tissue blocks from patients who are not eligible to enroll in the study will be returned 
no later than 3-6 months after eligibility determination.  Figure 2 gives an overview of the 
tissue flow in the trial. 


 
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All biomarker samples taken during the study are summarized in Table 3.  Exploratory 
biomarker research may include, but will not be limited to, the biomarkers listed in 
Table 3.  Such biomarker research may be required as science is rapidly and constantly 
evolving.  Therefore, a definitive list of analyzed biomarkers may include other or 
additional parameters as well as novel or alternative technologies. 
Table 3 
Proposed Biomarkers for Exploratory Research 
Sample Type  
Timing  
Biomarker 
Breast Cancer Tumor 
tissue (See Appendix 3) 
Mandatory Baseline 
(archival and/or 
metastatic) 
Optional Baseline (freshly 
taken) 
Cycle 2 (optional) 
Time of progression 
(mandatory, if  clinically 
feasible) 
• HER2  
• PD-L1  
• CD8 
• Tumor Infiltrating Lymphocytes  
DNA/RNA extracted from 
breast cancer tissue  
Baseline, Cycle 2 and time 
of progression (if biopsy 
clinically feasible)  
• Immune and cancer associated 
gene signatures (RNA) 
• Cancer related genes (DNA) 
Plasma 
Baseline and subsequent 
timepoints during 
treatment  
• HER ligands 
Serum 
Baseline and subsequent 
timepoints during 
treatment 
• Cytokines (e.g., IL-2, IFNg, IL-18) 
DNA extracted from 
Whole Blood 
Baseline (or later if missed 
at baseline) 
Polymorphisms in:  
• PD-L1, PD-1 
IL-8, IL-6, and related cytokines 
• Immune genes (NGS) 
Cancer related genes (NGS) 
Circulating tumor DNA 
isolated from plasma 
Baseline and subsequent 
timepoints during 
treatment 
• ctDNA HER2  
• ctDNA PIK3CA  
(RNA extracted from) 
Peripheral blood 
mononuclear cells 
(PBMCs) isolated from 
whole blood a 
Baseline (all patients) and 
subsequent timepoints 
during and after treatment 
(subset) 
• Immune gene expression profiles 
(e.g. PD-L1, PD-1) 
HER2 = human epidermal growth factor 2; IL = interleukin; NGS = next-generation sequencing; 
PD-1 = programmed death−1; PD-L1 = programmed death−ligand 1. 
a Serial sample collection will be collected on approximately the first 50 enrolled patients only. 
 


 
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4.5.8.2.1 
Tumor Tissue Samples 
The schedule of tissue collection is described in Appendix 3.  Only at those sites where 
a legitimate site regulation renders submission of blocks impossible and only after 
having obtained the Sponsor's approval, submission of different material as described in 
Appendix 3 may be accepted.  
After completion of HER2 and PD-L1 testing, patient samples may also be tested with 
other exploratory assays/technologies to establish performance characteristics of these 
assays for both next generation diagnostic development and understanding treatment 
response associated to characteristics of the tumor microenvironment.  Testing could be 
performed on all screened patients (screen-failed and enrolled) and will be performed 
only after eligibility is established for each patient.  These exploratory testing data will 
have no impact on patient eligibility.  
After initial HER2 and mandatory biomarker testing, the tissue blocks will be used for 
midterm storage up to the time of final clinical study report before returning them to sites 
to allow for future biomarker analysis.  Hereafter, the blocks will be shipped back, unless 
the patient gives specific consent for a remainder of the samples to be stored for 
optional exploratory research (RBR; Section 4.5.8).  In cases where only slides were 
sent because of country or site regulations, a new request of slides will be sent to the 
sites in case additional markers or assays are defined up to final clinical study report.  
The midterm storage of tissue and the possibility of requesting more slides up to the time 
of the final clinical study report extends the possibility of deciding on analyses of 
important additional markers or assays while the study is ongoing or until final study data 
are available. 
In cases where midterm storage of tumor tissue blocks is not allowed by local regulatory 
bodies (including IRB/EC policies) for patients without consent to RBR, the block will be 
sent back to the site no later than 3-6 months and requested at a later timepoint within 
the study in case additional analyses are defined.  If the patient provides consent for 
optional exploratory research (RBR), the samples will be stored until no longer required 
in accordance with the IRB/EC approved Informed Consent Form and applicable laws 
(e.g., health authority requirements).  
If tissue material from more than one timepoint was submitted, the midterm storage only 
applies to the most recent sample and the archival tumor tissue block for all patients 
enrolled will be returned no later than 3-6 months after eligibility determination.  In case 
archival partial blocks or slides are sent, this tissue will not be returned.  
All tissue blocks from patients who are not eligible to enroll in the study will be returned 
no later than 3-6 months after eligibility determination. 
Figure 2 gives an overview of the tissue flow in the trial. 


 
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Figure 2 Overview of Tissue Flow in the Study 
 
BM = biomarker; CSR = clinical study report; RBR = research biosample repository. 
* Central HER2 and PD-L1 testing is performed on all patients, but mandatory BM analysis and mid-term storage of tissue will only be performed on randomized 
patients; mid-term storage is until CSR finalization. 
** If both archival and metastatic tissue is available, both will be tested for PD-L1, while for HER2 only one sample will be used. 
 


 
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DNA and RNA from collected tumor tissue will be extracted and may enable targeted 
sequencing or whole exome sequencing (NGS and gene expression based methods) for 
exploratory research (that may include, but is not limited to, immune or cancer-related 
genes, PIK3CA mutation, mutational load and biomarkers associated with common 
molecular pathways). 
NGS may be conducted by Foundation Medicine on samples collected at time of disease 
progression.  If performed by Foundation Medicine, the investigator can obtain results 
from the samples collected at the time of disease progression in the form of an 
individualized report per patient, which is available upon request directly from 
Foundation Medicine.  The investigator may share and discuss the results with the 
patient, unless the patient chooses otherwise.  The Foundation Medicine NGS assay 
has not been cleared or approved by health authorities.  The NGS report is generated 
for research purposes and is not provided for the purpose of guiding future treatment 
decisions. 
4.5.8.2.2 
Blood Samples 
Blood samples are taken for cells, plasma, and serum collection (Table 3).  Whole blood 
samples may be analyzed by fluorescence-activated cell sorting and processed to obtain 
peripheral blood mononuclear cells (PBMCs) and their derivatives (e.g., proteins, RNA 
and DNA).  Serial whole blood samples for PBMC collection will be taken on 
approximately the first 50 patients only. 
Blood samples collected during the study may be evaluated for immune-related, tumor 
type−related, and other exploratory biomarkers (e.g., genetic alterations determined by 
DNA sequencing methods which may include NGS, and/or alterations in gene 
expression (Section 4.5.9). 
4.5.9 
Biomarker Sample Handling and Biomarker Results 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Given the complexity and exploratory nature of biomarker analyses, results from these 
analyses will not be shared with investigators or study participants, unless required by 
law, with the exception of NGS data on Disease Progression Samples in case performed 
by Foundation Medicine.  
The remaining samples obtained for study-related procedures will be destroyed no later 
than 5 years post final clinical study report has been completed, unless patient has 
consented to RBR (Section 4.5.10). 
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. 


 
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4.5.10 
Optional Samples for Research Biosample Repository  
4.5.10.1 
Overview of the Research Biosample Repository 
The RBR is a centrally administered group of facilities used for the long-term storage of 
human biologic specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides).  The collection, storage, and analysis of RBR 
specimens will facilitate the rational design of new pharmaceutical agents and the 
development of diagnostic tests, which may allow for individualized drug therapy for 
patients in the future. 
Specimens for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR specimens will be used to achieve the 
following objectives: 
• 
To study the association of biomarkers with efficacy, adverse events, or disease 
progression 
• 
To increase knowledge and understanding of disease biology 
• 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
• 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.10.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection and submission of biological samples to the RBR is contingent upon the 
review and approval of the exploratory research and the RBR portion of the Informed 
Consent Form by each site's IRB or Ethics Committee (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) will not be applicable at that site. 
4.5.10.3 
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 or disease under study: 
• 
Residual from tumor tissue block or slides 
• 
Whole Blood samples collected at baseline 
 
The above samples may be sent to one or more laboratories for DNA extraction to 
enable analysis of germline mutations, somatic mutations via WGS, NGS, or other 
genomic analysis methods.   
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS provides a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches.  Data will be analyzed in the context of this study but will also be explored 


 
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in aggregate with data from other studies.  The availability of a larger dataset will assist 
in identification of important pathways, guiding the development of new targeted agents. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.   
RBR specimens are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
4.5.10.4 
Confidentiality 
Specimens and associated data will be labeled with a unique patient identification 
number. 
Patient medical information associated with RBR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.  
Given the complexity and exploratory nature of the analyses, data derived from RBR 
specimens will generally not be provided to study investigators or patients unless 
required by law except if the analysis is performed by 
.  The aggregate results of any 
conducted research will be available in accordance with the effective Sponsor policy on 
study data publication. 
Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
4.5.10.5 
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 specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR specimens.  
Patients who decline to participate will not provide a separate signature. 


 
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The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF. 
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research. 
 
4.5.10.6 
Withdrawal from the Research Biosample Repository 
Patients who give consent to provide RBR specimens have the right to withdraw their 
specimens from the RBR at any time for any reason.  If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and, if the trial is ongoing, must enter the date of withdrawal on the 
RBR Research Sample Withdrawal of Informed Consent eCRF.  The patient will be 
provided with instructions on how to withdraw consent after the trial is closed.  
A patient's withdrawal from Study WO30085 does not, by itself, constitute withdrawal of 
specimens from the RBR.  Likewise, a patient's withdrawal from the RBR does not 
constitute withdrawal from Study WO30085. 
4.5.10.7 
Monitoring and Oversight 
RBR specimens will be tracked in a manner consistent with GCP by a quality-controlled, 
auditable, and appropriately validated laboratory information management system, to 
ensure compliance with data confidentiality as well as adherence to authorized use of 
specimens as specified in this protocol and in the 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 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following: 
• 
Patient withdrawal of consent at any time (and for any reason) 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues on the study 
• 
Investigator or Sponsor determines it is in the best interest of the patient to 
discontinue from the study 
• 
Patient non-compliance 
 


 
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Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced. 
4.6.2 
Study Treatment Discontinuation 
Patients must discontinue study treatment if they experience any of the following: 
• 
Intolerable toxicity related to study treatment 
• 
Any medical condition that may jeopardize the patient’s safety if he or she continues 
on study treatment 
• 
Use of another systemic anti-cancer therapy  
• 
Pregnancy 
• 
Radiographic disease progression according to RECIST v1.1, with the following 
exception: 
Patients may receive blinded atezolizumab/placebo in combination with 
trastuzumab emtansine until unacceptable toxicity or loss of clinical benefit, 
provided they meet all of the criteria specified in Section 3.1.  Patients must 
provide written consent to acknowledge deferring any standard treatment 
options that may exist in favor of continuing study treatment at the time of initial 
progression. 
 
The primary reason for study drug discontinuation should be documented on the 
appropriate eCRF.  
Patients who discontinue study treatment prematurely will not be replaced. 
4.6.3 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
• 
Patient enrollment is unsatisfactory. 
 
The Sponsor will notify the investigators if the study is placed on hold or if the Sponsor 
has decided to discontinue the study or the development program. 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 


 
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• 
Non-compliance with the ICH guideline for GCP 
• 
No study activity (i.e., all patients have completed 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.  Patients will undergo safety monitoring by an iDMC 
(Section 9.4) during the study, including assessment of the nature, frequency, and 
severity of adverse events; details of this safety monitoring will be specified in the iDMC 
Charter.  In addition, guidelines for managing adverse events, including criteria for 
dosage modification and treatment interruption or discontinuation, are provided below. 
Please refer to the latest versions of the trastuzumab emtansine and Atezolizumab IBs 
for a complete and most up to date summary of safety information.  
5.1.1 
Risks Associated with Trastuzumab Emtansine 
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.  Patients with dyspnea at rest due to complications of advanced 
malignancy and comorbidities may be at risk of pulmonary events. 
Patients who have experienced a pulmonary event should be carefully evaluated before 
commencing trastuzumab emtansine treatment. 
Guidelines for management of trastuzumab emtansine in patients who develop ILD or 
pneumonitis are provided in Section 5.1.4.2.  


 
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5.1.1.2 
Hepatotoxicity 
The following events have been reported with administration of trastuzumab emtansine: 
• 
Serious hepatobiliary disorders 
Serious hepatobiliary disorders, including nodular regenerative hyperplasia 
(NRH) of the liver and hepatobiliary disorders with a fatal outcome due to 
drug-induced liver injury, have been observed in patients treated with 
trastuzumab emtansine.  Some of the observed cases may have been 
confounded by concomitant medications with known hepatotoxic potential. 
• 
Increased serum transaminases 
Asymptomatic increases in serum transaminase concentration (transaminitis) 
have been observed.  Grade 1 and 2 events have been observed frequently; 
Grade 3 and 4 events have been observed less commonly.  The incidence of 
increased AST was substantially higher than that for increased ALT.  Increases 
in AST and ALT were commonly observed by Day 8 of each cycle and 
generally improved or returned to baseline by Day 21.  A cumulative effect of 
trastuzumab emtansine, that is, an increase in the proportion of patients with 
Grade 1 or 2 elevations in transaminases with successive cycles has been 
observed; however, there was no increase in the proportion of patients with 
Grade 3 abnormalities over time. 
• 
NRH  
Cases of NRH have been identified from liver biopsies in patients treated with 
trastuzumab emtansine who presented with signs and symptoms of portal 
hypertension.  NRH is a rare liver condition characterized by widespread benign 
transformation of hepatic parenchyma into small regenerative nodules.  NRH 
may lead to non-cirrhotic portal hypertension.  Diagnosis of NRH can only be 
confirmed by histopathology.  Biopsy-confirmed NRH leading to fatal hepatic 
failure has been reported. 
NRH should be considered in all patients with clinical symptoms of portal 
hypertension, even with normal transaminases, and no other manifestations of 
cirrhosis; in patients with a cirrhosis-like pattern seen on a CT scan of the liver; 
and/or in patients with liver failure following long-term treatment with 
trastuzumab emtansine.   
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 in 
Section 5.1.4.3.  


 
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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 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 Section 5.1.3.2.3. 
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 trastuzumab emtansine will be performed in a setting with access to 
emergency facilities and staff who are trained to monitor and respond to medical 
emergencies.  Patients should be closely monitored for IRRs during and after each 
infusion of trastuzumab emtansine, as described in Section 4.3.2.1.   
Guidelines for management of patients who experience IRRs or hypersensitivity 
reactions are provided in Section 5.1.4.1.  


 
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5.1.1.5 
Hematologic Toxicity 
Thrombocytopenia has been reported in patients in clinical trials of trastuzumab 
emtansine.  The majority of these patients had Grade 1 or 2 events (platelet count 
≥ 50,000/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).  In clinical 
trials, the incidence and severity of thrombocytopenia were higher in Asian patients.   
Patients with thrombocytopenia (≤ 100,000/mm3) and patients on anti-coagulant 
treatment should be monitored closely during treatment with trastuzumab emtansine.  
It is recommended that platelet counts are monitored prior to each trastuzumab 
emtansine dose.  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 Section 5.1.3.2.2. 
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). 


 
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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 Section 5.1.3.2.3. 
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.  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 
The PD-L1/PD-1 pathway is involved in peripheral tolerance; therefore, such 
atezolizumab therapy may increase the risk of immune-mediated adverse events, 
specifically the induction or enhancement of autoimmune conditions.  To date, 
immune-related adverse events associated with atezolizumab include hepatitis, 
pneumonitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, hyperthyroidism, 
adrenal insufficiency, Guillain-Barré syndrome, myasthenic syndrome/myasthenia gravis, 
myocarditis, hypophysitis, and meningoencephalitis.  In addition, systemic immune 
activation (described below) is a potential risk when atezolizumab is given in 
combination with other immunomodulating agents.  For further details regarding the 
up-to-date clinical safety of atezolizumab, see the most recent version of the 
Atezolizumab IB. 
Systemic immune activation is a rare condition characterized by an excessive immune 
response.  Given the mechanism of action of atezolizumab, systemic immune activation 
is considered a potential risk when atezolizumab is given in combination with other 
immunomodulating agents.  Systemic immune activation should be included in the 
differential diagnosis for patients who, in the absence of an alternative etiology, develop 
a sepsis-like syndrome after administration of atezolizumab, and the initial evaluation 
should include the following: 
• 
CBC with peripheral smear 
• 
PT, PTT, fibrinogen, and D-dimer 
• 
Ferritin 
• 
Triglycerides 


 
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• 
AST, ALT, and total bilirubin 
• 
LDH 
• 
Complete neurologic and abdominal examination (assess for hepatosplenomegaly) 
 
If systemic immune activation is still suspected after the initial evaluation, contact the 
Medical Monitor for additional recommendations. 
Although most immune-mediated adverse events observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications (Di Giacomo et al. 2010). 
Suggested workup and management guidelines for overlapping toxicities between 
atezolizumab and trastuzumab emtansine (i.e., IRR and Hypersensitivity reactions, 
suspected hepatotoxicity and pneumonitis) are provided in Section 5.1.4. 
5.1.3 
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. 
5.1.3.1 
Dose Modification 
Reasons for dose modifications or delays, the supportive measures taken, and the 
outcomes will be documented in the patient's chart and recorded on the eCRF.  
The severity of adverse events will be graded according to the NCI CTCAE v4.0. 
• 
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 accordingly. 
• 
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. 
• 
Dose interruptions for reason(s) other than adverse events, such as surgical 
procedures, may be allowed with Medical Monitor approval.  The acceptable length 
of interruption will depend on agreement between the investigator and the Medical 
Monitor. 


 
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• 
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 adverse events for > 42 days 
beyond when the next dose would have been given, then the patient will be 
discontinued from atezolizumab or placebo treatment and will be followed for safety 
and efficacy as specified in Section 3.1.  If, in the judgment of the investigator, the 
patient is likely to derive clinical benefit from resuming atezolizumab or placebo after 
a hold > 42 days, study drug may be restarted with the approval of the Medical 
Monitor. 
If patients must be tapered off steroids for the treatment of adverse events 
related to atezolizumab or placebo, study treatment may be withheld for 
> 42 days until steroids are discontinued or reduced to prednisone dose 
(or dose equivalent) ≤ 10 mg/day.  The acceptable length of interruption will 
depend on agreement between the investigator and the Medical Monitor. 
• 
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 (in consultation with the Sponsor’s Medical Monitor or designee 
when appropriate).  For example, alopecia even if considered related to 
trastuzumab emtansine would most likely not be considered to be significant.  
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 4), at the discretion 
of the investigator. Subsequent cycles should remain q3w, and patients should 
be assessed for toxicity as described in Section 5.1.3.  If a patient requires a 
dose reduction, dosing will be reduced by one dose level as per Table 4.  
A maximum of two dose reductions is allowed for trastuzumab emtansine.  
No dose re-escalation is permitted.  A patient treated with 2.4 mg/kg of 
trastuzumab emtansine who develops an Adverse Event requiring a dose 
reduction must discontinue study treatment and will be followed for safety, 
disease progression and survival (Appendix 1). 
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). 
 


 
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Table 4 
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. 
 
5.1.3.2 
Management of Patients who have Trastuzumab Emtansine 
Related Specific Adverse Events 
5.1.3.2.1 
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 3 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 3 for 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 


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Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
96/Protocol WO30085, Version 3 
5.1.3.2.2 
Hematological Toxicities 
See Table 5 for trastuzumab emtansine dose modification guidelines for hematological 
toxicities, including thrombocytopenia. 
Table 5 
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. 
 
5.1.3.2.3 
Neuropathy 
See Table 6 for trastuzumab emtansine dose modification guidelines for neuropathy. 
Table 6 
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. 
 


 
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5.1.3.3 
Management of Patients Who Have 
Atezolizumab/Placebo-Related Specific Adverse Events 
For details on the management of infusion-related reactions and all other 
immune-related adverse events, including but not limited to, gastrointestinal, 
dermatologic, endocrine, pulmonary toxicity, hepatotoxicity, pancreatic, or eye toxicity, 
refer to the most recent version of the Atezolizumab IB.  
Guidelines for the management of patients who experience specific adverse events (other 
than systemic immune activation) are provided in the most recent version of the 
Atezolizumab IB. 
No dose modification for atezolizumab is allowed. 
5.1.4 
Management of Patients who have Potential Overlapping 
Toxicities Associated with Trastuzumab Emtansine and 
Atezolizumab/Placebo 
5.1.4.1 
Infusion-Related Reactions 
No premedication is indicated for the administration of atezolizumab/placebo in Cycle 1.  
Patients who experience an IRR at Cycle 1 of atezolizumab/placebo treatment may 
receive premedication with antihistamines or antipyretics/analgesics 
(e.g., acetaminophen) for subsequent infusions. 
Table 7 
Management Guidelines for Atezolizumab/Placebo 
Infusion-Related Reactions 
Severity 
Management 
Grade 1  
• 
Reduce infusion rate to half the rate being given at the time of event onset. 
• 
After the event has resolved, the investigator should wait for 30 minutes while 
delivering the infusion at the reduced rate. 
• 
If tolerated, the infusion rate may then be increased to the original rate. 
Grade 2 
• 
Interrupt atezolizumab/placebo infusion. 
• 
Administer aggressive symptomatic treatment. 
• 
Restart only after the symptoms have adequately resolved to baseline grade. 
• 
The infusion rate at restart should be half of the infusion rate that was in 
progress at the time of the onset of the IRR. 
• 
At next cycle, administer oral premedication with antihistamine and anti-pyretic 
and monitor closely for infusion reaction.  
Grades 3−4 
• 
Stop infusion. 
• 
Proper medical management which may include oral or IV antihistamine, 
anti-pyretic, glucocorticoids, epinephrine, bronchodilators, and oxygen 
• 
Discontinue atezolizumab/placebo treatment. 
• 
Contact the Medical Monitor if atezolizumab/placebo is discontinued.  
IRR = infusion-related reactions; IV = intravenous. 
 


 
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Table 8 
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 appropriate, at the investigator’s discretion.  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 at the investigator’s discretion. 
Grade 3 
reaction  
Stop trastuzumab emtansine infusion.  Administer supportive care with oxygen, 
β−agonists, antihistamines, antipyretics, or corticosteroids, as appropriate, at the 
investigator’s discretion.  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 at the investigator’s discretion.  
Grade 4 
reaction 
Stop trastuzumab emtansine infusion.  Administer supportive care with oxygen, 
β-agonists, antihistamines, antipyretics, or corticosteroids, as appropriate, at the 
investigator’s discretion.  Monitor patient until complete resolution of symptoms. 
Discontinue trastuzumab emtansine. 
 
5.1.4.2 
Pulmonary Events:  Atezolizumab and Trastuzumab Emtansine 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been 
associated with the administration of atezolizumab and have primarily been observed in 
patients with underlying NSCLC. 
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 
 


 
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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 9 for 
management guidelines for pulmonary events and pneumonitis.  
In this study, atezolizumab and trastuzumab emtansine are discontinued for all grades of 
interstitial lung disease and pneumonitis.  Refer to Section 5.1.4.2 for details on 
trastuzumab emtansine and pulmonary events. 
Table 9 
Management Guidelines for Interstitial Lung Disease and 
Pneumonitis 
Severity 
Atezolizumab/Placebo 
Trastuzumab Emtansine  
Grade 
1 − 4 
Discontinue atezolizumab/placebo 
treatment 
Refer to the most recent version of the 
Atezolizumab IB for further management 
guidance 
Discontinue trastuzumab emtansine 
treatment.   
IB = Investigator’s Brochure. 
 
5.1.4.3 
Hepatic Events:  Atezolizumab and Trastuzumab Emtansine 
Immune-mediated hepatitis has been associated with the administration of atezolizumab.  
Eligible patients must have adequate liver function, as manifested by measurements of 
total bilirubin and hepatic transaminases.  Liver function will be monitored throughout 
study treatment. 
While on this study, patients who present with right upper-quadrant abdominal pain 
and/or unexplained nausea or vomiting should have liver function tests (LFTs) performed 
immediately and reviewed before administration of the next dose of study drug. 
If outcome of LFTs is worsening, concurrent medications, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate.  Imaging of 
the liver, gall bladder, and biliary tree should be performed to rule out neoplastic or other 
causes for worsening outcome of LFTs.  Anti-nuclear antibody, perinuclear 
anti-neutrophil cytoplasmic antibody, anti-liver kidney microsomal antibodies, and 
anti-smooth muscle antibody tests should be performed if an autoimmune etiology 
is considered.  See Table 10 for management guidelines for atezolizumab/placebo and 
trastuzumab emtansine hepatic events. 
Note:  No dose modification for atezolizumab/placebo is indicated on the basis of 
hyperbilirubinemia alone. 


 
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Table 10 Management Guidelines for Increased Transaminases (AST/ALT) 
and Hepatic Events 
Severity 
Atezolizumab/Placebo 
Trastuzumab Emtansine 
ALT or AST 
increase that meets 
Hy's law criteria:  
ALT or AST 
> 3 × ULN in 
combination with 
TBILI > 2 × ULN or 
clinical jaundice 
Discontinue atezolizumab/placebo 
treatment. 
Discontinue trastuzumab 
emtansine treatment. 
ALT or AST 
increase that does 
not meet Hy's law 
criteria 
ALT/AST Grade 1 
(> 1-0−3.0 × ULN) 
 
Treat at the same dose level. 
Continue LFT monitoring. 
Treat at the same dose level. 
ALT/AST Grade 2 
(> 3.0−5.0 × ULN)  
Withhold atezolizumab/placebo dose. 
If persists > 5−7 days:  Consider 
starting 1−2 mg/kg/day prednisone or 
equivalent per day; when 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. 
Treat at the same dose level. 


 
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Table 10 Management Guidelines for Increased Transaminases (AST/ALT) 
and Hepatic Events (cont.)  
Severity 
Atezolizumab/Placebo 
Trastuzumab Emtansine 
ALT/AST Grade 3 
(> 5.0−20.0 × ULN) 
Discontinue atezolizumab/placebo 
dose. 
Consider GI consult and liver biopsy to 
establish etiology of hepatic injury if 
necessary. 
Start 60 mg prednisone or equivalent 
per day. 
If LFT results do not decrease within 
48 hours after initiation of systemic 
steroids, addition of an alternative 
immunosuppressive agent 
(e.g., mycophenolate or TNF-α 
antagonist) 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. 
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. 
ALT/AST Grade 4 
(> 20.0 × ULN) 
Discontinue atezolizumab/placebo 
treatment. 
Consider GI consult and liver biopsy to 
establish etiology of hepatic injury if 
necessary. 
Start 60 mg prednisone or equivalent 
per day. 
If LFT results do not decrease within 
48 hours after initiation of systemic 
steroids, addition of an alternative 
immunosuppressive agent 
(e.g., mycophenolate or TNF-α 
antagonist) 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. 
Discontinue trastuzumab 
emtansine treatment. 
Laboratory tests may be 
repeated (within 24 hours) to 
exclude laboratory error prior 
to discontinuing trastuzumab 
emtansine. 


 
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Table 10 Management Guidelines for Increased Transaminases (AST/ALT) 
and Hepatic Events (cont.)  
Severity 
Atezolizumab/Placebo 
Trastuzumab Emtansine 
NRH 
If there are signs of 
portal hypertension 
(e.g., ascites and/or 
varices) and/or a 
cirrhosis-like pattern 
is seen on a CT 
scan of the liver, the 
possibility of NRH 
should be 
considered.   
Discontinue atezolizumab/placebo 
treatment 
Discontinue trastuzumab 
emtansine 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.  
 
5.1.4.4 
Hyperbilirubinemia:  Trastuzumab Emtansine 
See Table 11 for dose modifications of trastuzumab emtansine for hyperbilirubinemia. 
Table 11 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 until total bilirubin recovers to 
Grade ≤ 1 and then resume at the same dose 
level. 
Grade 3 
(> 3 to ≤ 10 × ULN) 
Withhold 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. 
 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
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5.2.1 
Adverse Events 
According to the ICH guideline for GCP, an adverse event is any untoward medical 
occurrence in a clinical investigation subject administered a pharmaceutical product, 
regardless of causal attribution.  An adverse event can therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.10 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Is fatal (i.e., the adverse event actually causes or leads to death) 
• 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death. 
• 
Requires or prolongs inpatient hospitalization (Section 5.3.5.11) 
• 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions) 
• 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
Section 5.3.3); the event itself may be of relatively minor medical significance and thus 
deemed “not serious” (such as severe headache without any further findings). 


 
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Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after becoming aware of the event; see 
Section 5.4.2 for reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the event; 
see Section 5.4.2 for reporting instructions).  Adverse events of special interest for this 
study include the following: 
• 
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 (Section 5.3.5.7) 
• 
Suspected transmission of an infectious agent by the study drug, as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
• 
Pneumonitis 
• 
Colitis 
• 
Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency, or 
hyperthyroidism 
• 
Hepatitis 
• 
Transaminitis Grade ≥ 2 (AST or ALT > 3 × the ULN and bilirubin > 2 × the ULN or 
AST/ALT > 10 × the ULN) 
• 
Systemic lupus erythematosus 
• 
Neurological:  Guillain-Barré syndrome, myasthenia gravis, and 
meningoencephalitis 
• 
Nephritis 
• 
Events suggestive of hypersensitivity, cytokine release, influenza-like illness, 
systemic inflammatory response syndrome, systemic immune activation (SIA), and 
infusion-reaction syndrome 
 


 
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5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.4 and 5.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(Section 5.3.3), and causality (Section 5.3.4).   
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study drug, all adverse events will be reported until 30 days after the 
last dose of study drug or initiation of another anti-cancer therapy (whichever occurs 
first).   
Serious adverse events and adverse events of special interest will continue to be 
reported (independent of causality) until 90 days after the last dose of study drug or until 
initiation of new systemic anti-cancer therapy, whichever occurs first.  
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event or adverse event of special interest that occur after the end of the adverse 
event reporting period (defined as 90 days after the last dose of study drug), if the event 
is believed to be related to prior treatment with study drug, regardless if the patient has 
initiated another anti-cancer therapy treatment (Section 5.6). 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 


 
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5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale as per the latest NCI CTCAE (v4.0) will be 
used for assessing adverse event severity.  Table 12 will be used for assessing severity 
for adverse events that are not specifically listed in the NCI CTCAE v4.0. 
Table 12 Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE v4.0 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration: 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 


 
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• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 
Table 13 Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.   
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
 
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 and avoid colloquialisms 
and abbreviations when recording adverse events on the Adverse Event eCRF.   
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Infusion-Related Reactions  
Adverse events that occur during or within 24 hours after study drug administration 
should be captured as individual signs and symptoms on the Adverse Event eCRF 
rather than an overall diagnosis (e.g., record dyspnea and hypotension as separate 
events rather than a diagnosis of infusion-related reaction or allergic reaction. 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
For adverse events other than infusion-related [or] allergic reactions (Section 5.3.5.1), a 
diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 


 
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eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
• 
If neutropenia is accompanied by a mild, non-serious infection, only neutropenia 
should be reported on the eCRF. 
• 
 If neutropenia is accompanied by a severe or serious infection, both events should 
be reported separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 


 
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5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events. 
 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 × ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  


 
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It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × ULN) in combination with either an elevated 
total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with total bilirubin 
> 2 × ULN 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (Section 5.3.5.2) and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event), either as a serious adverse event or an adverse event of special interest 
(Section 5.4.2). 
Nodular Regenerative Hyperplasia  
NRH, whether or not accompanied by abnormal LFTs, should be reported to the 
Sponsor as a serious adverse event. 
5.3.5.8 
Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (Section 5.3.1) that are attributed by 
the investigator solely to progression of MBC should be recorded on the Study 
Completion/Early Discontinuation eCRF.  All other on-study deaths, regardless of 
relationship to study drug, must be recorded on the Adverse Event eCRF and 
immediately reported to the Sponsor (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 


 
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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"). 
During survival follow-up, deaths attributed to progression of MBC should be recorded 
on the Survival eCRF. 
5.3.5.9 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.10 
Lack of Efficacy or Worsening of Metastatic Breast Cancer 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on 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 adverse event. 
5.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.   
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for study drug administration 


 
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• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
The patient has not experienced an adverse event 
• 
Hospitalization due solely to progression of the underlying MBC 
 
An event that leads to hospitalization under the following circumstances is not 
considered to be serious adverse event, but should be reported as adverse events 
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 adverse event, 
but does not meet the definition of an overnight admission (e.g., tooth extraction) 
 
5.3.5.12 
Adverse Events Associated with an Overdose or Error in Drug 
Administration 
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, unless it results in untoward medical.   
Any study drug overdose or incorrect administration of study drug should be noted on 
the Study Drug Administration eCRF. 
All adverse events associated with an overdose or incorrect administration of study drug 
should be recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; Section 5.4.2). 
Adverse events associated with an overdose of trastuzumab emtansine in previous 
clinical studies include thrombocytopenia and increased ALT.  There was one case of 
overdose in which the patient died.  No information on overdose has been established at 
this time for atezolizumab. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting from the investigator to the Sponsor to allow 
the Sponsor to immediately put into place appropriate measures to address potential 
new risks in this or related clinical trials.  The investigator must report such events to the 
Sponsor immediately; under no circumstances should reporting take place more than 
24 hours after the investigator learns of the event.  The following is a list of events that 


 
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the investigator must report to the Sponsor within 24 hours after learning of the event, 
regardless of relationship to study drug: 
• 
Serious adverse events (see Section 5.4.2 for further details) 
• 
Adverse events of special interest (see Section 5.2.3 for further details) 
• 
Pregnancies (see Section 5.4.3 for further details) 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
Medical Monitor Contact Information  
Medical Monitor 
 M.D. 
Telephone No.: 
 
 
Mobile Telephone No.: 
 
 
 
Medical Monitor 
 Ph.D. 
Telephone No.: 
 
 
Mobile Telephone No.: 
 
 
 
 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators.  


 
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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 Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to investigators should be completed and submitted to the Sponsor or it`s designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and emailing the form using the fax number or email address provided to 
investigators. 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, all serious adverse events and adverse events of special 
interest will be reported until 90 days after the last dose of study drug (regardless of 
causality) or until initiation of new systemic anti-cancer therapy after the last dose of 
study treatment, whichever occurs first.  All other adverse events, regardless of 
relationship to study treatment, will be reported until 30 days after the last dose of study 
treatment until initiation of new systemic anti-cancer therapy after the last dose of study 
treatment, 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, generate a report and submit the report via the EDC system to 
Roche Safety Risk Management. 
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.   
Instructions for reporting post-study adverse events are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the treatment period and for 5 months after 
the last dose of atezolizumab/placebo or 7 months after the last dose of trastuzumab 
emtansine, whichever occurs last.   
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 


 
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counsel the patient, discussing the risks of the pregnancy and the possible effects on the 
fetus.  Monitoring of the patient should continue until conclusion of the pregnancy.  
Any serious adverse events associated with the pregnancy (e.g., an event in the fetus, 
an event in the mother during or after the pregnancy, or a congenital anomaly/birth 
defect in the child) should be reported on the Adverse Event eCRF.  Additional 
information on any atezolizumab/placebo or trastuzumab emtansine-exposed pregnancy 
and infant will be requested by Roche Drug Safety at specific time points (i.e., after 
having received the initial report during the first trimester, at the end of the second 
trimester, 2 weeks after the expected date of delivery, and at 3, 6, and 12 months of the 
infant’s life).  In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available.  
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 trastuzumab emtansine.   
A paper Clinical Trial Pregnancy Reporting Form should be completed and submitted 
to the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of 
the pregnancy), either by faxing or by scanning and emailing the form using the fax 
number or email address provided to investigators.  Attempts should be made to collect 
and report details of the course and outcome of any pregnancy in the partner of a male 
patient exposed to study drug.  When permitted by the site, the pregnant partner would 
need to sign an Authorization for Use and Disclosure of Pregnancy Health Information 
to allow for follow up on her pregnancy.  If the authorization has been signed, the 
investigator should submit a Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available.  Additional 
information on any atezolizumab/placebo or trastuzumab emtansine-exposed pregnancy 
and infant will be requested by Roche Drug Safety at specific time points (i.e., after 
having received the initial report during the first trimester, at the end of the second 
trimester, 2 weeks after the expected date of delivery, and at 3, 6, and 12 months of the 
infant’s life).  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 
Any abortion should be classified as a serious adverse event (as the Sponsor considers 
abortions to be medically significant), recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; Section 5.4.2).   


 
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5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born by a female patient exposed to study 
drug (or the female partner of a male patient exposed to study drug) should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; 
Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, the patient has died, or the patient withdraws consent.  Every effort should be 
made to follow all serious adverse events considered to be related to study drug or 
trial-related procedures until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case.  Pathologic material, if 
already obtained to evaluate the event, may be requested for review. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
After initiation of study treatment, all adverse events will be reported 30 days after the 
last dose of study drug or until initiation of new systemic anti-cancer therapy, whichever 
occurs first.  
Serious adverse events and adverse events of special interest will continue to be 
reported (independent of causality) until 90 days after the last dose of study drug or until 
initiation of new systemic anti-cancer therapy, whichever occurs first.  
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event or adverse event of special interest that occur after 90 days after the last 
dose of study drug (Section 5.3.1), if the event is believed to be related to prior study 
drug treatment.   


 
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The investigator should report these events directly to the Sponsor or its designee, either 
by faxing or by scanning and emailing the Serious Adverse Event/Adverse Event of 
Special Interest Reporting Form using the fax number or email address provided to 
investigators. 
During survival follow-up, deaths attributed to progression of MBC should be recorded 
on the Death Attributed to Progressive Disease eCRF.  
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and non-serious adverse 
events of special interest against cumulative product experience to identify and 
expeditiously communicate possible new safety findings to investigators, IRBs, ECs, and 
applicable health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the most recent version of the following 
reference documents: 
• 
Trastuzumab Emtansine IB 
• 
Atezolizumab IB  
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator’s assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
An iDMC will regularly monitor the incidence of the above-listed anticipated events 
during course of the study.  An aggregate report of any clinically relevant imbalances 
that do not favor the test product will be submitted to health authorities. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
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 primary efficacy endpoint for this study is PFS based on investigator tumor 
assessment.  The primary PFS analysis will be performed when approximately 115 PFS 
events have occurred.   


 
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With approximately 200 patients randomized according to a 1:2 randomization 
(approximately 67 patients will be randomized to Arm A and approximately 133 patients 
will be randomized to Arm B) the study has the estimated power for the PFS HRs 
presented in Table 14.  
Table 14 Estimated Power at Primary PFS Analysis for Different PFS HRs 
PFS HR 
Estimated power for log-rank test 
0.50 
94% 
0.55 
86% 
0.60 
73% 
0.65 
58% 
HR = Hazard ratio; PFS = progressive-free survival. 
Estimated power figures calculated using a 2-sided log-rank test at 0.05 alpha level 
when 115 PFS events have been observed, assuming a median PFS of 6.2 months 
for trastuzumab emtansine plus placebo. 
 
The above study design considerations assume proportional hazards, a cumulative 
dropout rate of 10% in each treatment arm and result in an estimated recruitment time of 
about 9 months (with ramp up in the first 4 months).  The estimated time from FPI to 
primary PFS analysis is 15 to 17 months, depending on PFS HR assumption.   
Sample size and power calculations were performed using the East 6 software package 
(Cytel Inc.). 
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, 
BC history, baseline disease characteristics, and patient treatment history.  Data will be 
summarized by the treatment arm to which patients were randomized.  
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 BC 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. 


 
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6.4 
EFFICACY ANALYSES 
6.4.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint for this study is PFS based on investigator tumor 
assessment.  The intention-to-treat (ITT) population is the primary analysis population 
for the primary efficacy endpoint 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. 
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.  When disease progression or death occurs after two or 
more consecutive missed (or “unevaluable”) tumor assessments, these events will not 
be counted; rather, the patient will be censored at the patient’s last tumor assessment 
prior to the first missing (or “unevaluable”) assessment.  If disease progression or death 
occurs after one missed (or “unevaluable”) tumor assessment, the event will be counted 
at the respective event date. 
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 Section 4.2.2 (excluding liver metastases), will be used to compare PFS 
between the treatment arms at the overall two-sided significance level of 5%.  Liver 
metastases will be excluded because of the potential that some of the strata may have 
very few patients, which would result in a loss of power.  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 liver 
metastases, will be used to estimate the HR and to calculate the 95% CI of the HR. 
The primary PFS analysis will be performed when approximately 
115 investigator-assessed PFS events have been observed and is anticipated to occur 
approximately 15 to 17 months from FPI, depending on PFS HR assumptions 
(Section 6.1).   
Several sensitivity analyses will be performed to assess the robustness of the primary 
efficacy analysis, see the SAP for details.   


 
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In order to assess the consistency of treatment benefit with respect to the primary 
efficacy endpoint PFS 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 PD-L1 expression, ECOG status and hormone receptor status.  
A multivariate Cox regression analysis will be performed on the primary efficacy 
endpoint of investigator-assessed PFS controlling for important baseline characteristics.  
Further methodological details will be provided in the SAP. 
6.4.2 
Secondary Efficacy Endpoints 
The ITT population will be the analysis population used for evaluation of the secondary 
efficacy endpoints. 
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.  
The first analysis of OS will be performed at the time of the primary PFS analysis.  
Another update for OS will be performed at approximately 12 months after the primary 
PFS analysis.  The final OS analysis will be performed at approximately 24 months 
after the primary PFS analysis or when ~50% OS events from 200 patients can be 
obtained, whichever occurs first.  The Sponsor may consider additional OS updates 
beyond 24 months after primary PFS analysis if more mature OS data are requested by 
the Health Authority. 
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 (Blyth-Still-Casella) 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 liver metastases) 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 


 
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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.  
6.4.3 
Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints will be evaluated at time of primary efficacy analysis. 
The ITT population will be the analysis population used for evaluation of the exploratory 
efficacy endpoints. 
PFS Assessed in the PD-L1 Selected Subgroup 
The analysis methods are similar to those described for the primary efficacy endpoint. 
PFS Assessed using Immune-Modified RECIST 
PFS is defined as the time from randomization to first occurrence of disease progression 
as determined by investigator assessment using immune-modified RECIST or death 
from any cause, whichever occurs earlier.  Only patients who are clinically eligible for 
treatment beyond disease progression (as defined in Section 3.1) will be included in this 
analysis.  The analysis methods are similar to those described for the primary efficacy 
endpoint.  
Objective Response Rate based on Immune Modified RECIST 
Objective response, defined as a complete response (CR) or partial response (PR), will 
be determined by investigator tumor assessment using immune-modified RECIST.  
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 (Blyth-Still-Casella) 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 liver metastases) 
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 based on Immune-Modified RECIST 
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 immune-modified RECIST, or death from any cause, whichever occurs first.  The 
analysis methods are similar to those described for the primary efficacy endpoint PFS.  
1-Year Survival Rate 
Kaplan-Meier methodology will be used to estimate 1-year survival rates and 95% CIs 
for each treatment arm.  Also, differences in 1-year survival rates between treatment 
arms will be calculated together with 95% CIs. 


 
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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. 
Study Drug Exposure  
The number of patients who experience any dose modification (including dose delay, 
dose reduction and dose interruption), or dose discontinuation, and reasons for study 
treatment discontinuation will be summarized for each of the treatment arm regimens.  
In addition, the number of patients that discontinue from trastuzumab emtansine-
containing and/or atezolizumab-containing treatment because of toxicity and/or receive 
other non-protocol anti-cancer therapy will be summarized.   
Descriptive statistics will be presented for total cumulative dose, number of cycles, dose 
intensity, infusion time by cycle, and weeks of exposure for trastuzumab emtansine, and 
atezolizumab. 
Adverse Events  
Safety will be assessed through summaries of adverse events, changes in laboratory test 
results, changes in vital signs, study treatment exposures, and immunogenicity as 
measured by ATA and will be presented by treatment arm. 
Verbatim descriptions of adverse events will be mapped to Medical Dictionary for 
Regulatory Activities (MedDRA) thesaurus terms and graded according to the 
NCI CTCAE v4.0.  The following events occurring on or after the first dose of study drug 
(i.e., treatment-emergent adverse events) will be summarized by NCI CTCAE grade: 
• 
All adverse events 
• 
Serious adverse events 
• 
Adverse eventsleading to death 
• 
Adverse eventsleading to study drug discontinuation 
• 
Adverse eventsleading to dose reduction 
• 
Sponsor-defined adverse events of special interest 
 
For events of varying severity, the highest grade will be used in the summaries. 
Deaths and causes of death will be summarized.  Selected adverse events will be 
summarized by NCI CTCAE grade for each treatment arm based on pre-specified 
category definitions, including (but not limited to) hepatotoxicity, cardiac dysfunction, and 
thrombocytopenia.  In addition, adverse eventsoccurring within 1 day (24 hours) of the 
first dose of each treatment cycle will be summarized to help characterize potential 
infusion-related reactions.  
Additional safety analyses may be performed as indicated. 


 
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Laboratory Data  
For laboratory parameters, descriptive summary tables of change from baseline over 
time based on System International units will be produced.  Summary tables for the 
shifts in NCI CTCAE v4.0 grades from baseline to the worst grade observed during 
treatment will be presented. 
6.6 
PHARMACOKINETIC ANALYSES  
The PK analyses will include patients with at least one post-dose PK assessment. 
Individual serum atezolizumab, trastuzumab emtansine, total trastuzumab levels and 
plasma DM1 concentrations versus time will be tabulated and summarized by treatment 
arm and study visit day.  Descriptive statistics will include mean, medians range, 
standard deviation, coefficient of variation (CV%), geometric mean, and geometric mean 
coefficient of variation (CVb%) as appropriate. 
Additional PK and PD analyses will be conducted as appropriate. 
6.7 
IMMUNOGENICITY ANALYSES  
The immunogenicity analyses will include patients with at least one predose and one 
post-dose ATA assessment, with patients grouped according to treatment received.  
The numbers and proportions of ATA-positive patients and ATA-negative patients during 
both the treatment and follow-up periods will be summarized by treatment 
group.  Patients are considered to be ATA positive if they are ATA negative at baseline 
but develop an ATA response following study drug administration (treatment-induced 
ATA response), or if they are ATA positive at baseline and the titer of one or more 
post-baseline samples is at least 4-fold greater (i.e., ≥0.60 titer units) than the titer of the 
baseline sample (treatment-enhanced ATA response).  Patients are considered to be 
ATA negative if they are ATA negative at baseline and all post-baseline samples are 
negative, or if they are ATA positive at baseline but do not have any post-baseline 
samples with a titer that is at least 4-fold greater than the titer of the baseline sample 
(treatment unaffected). 
Methodological details on immunogenicity analyses will be described in the SAP. 
6.8 
BIOMARKER ANALYSES  
Descriptive statistics will be utilized for the analysis and reporting of the exploratory 
biomarker objectives outlined in Section 4.5.8.2.  This may include appropriate 
multivariate analyses. Further details can be found in the SAP. 


 
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6.9 
INTERIM ANALYSIS 
There is no planned interim efficacy analysis for PFS.  
Overall safety will be monitored on a regular basis by an iDMC.  Further details, 
including iDMC composition and meeting frequency, will be provided in the iDMC 
Charter. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data. Central laboratory data and any other 
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. 
7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.  


 
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Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, 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 7.5.  
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, name of the 
person making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for at least 15 years 
after completion or discontinuation of the study, or for the length of time required by 
relevant national or local health authorities, whichever is longer.  After that period of time, 
the documents may be destroyed, subject to local regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 


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


 
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Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.  
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 


 
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Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., 1 year after last 
patient last visit [LPLV]). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
9.3 
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 


 
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permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
This study will be sponsored and managed by F. Hoffmann-La Roche Ltd.   
Treatment assignment will be handled through the IxRS system. 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.  
Tumor assessment scans will be collected prospectively by the Sponsor in the event that 
an independent review facility (IRF) will be utilized. 
A Steering Committee (SC) will be set up to provide guidance on the protocol, study 
design and the statistical analysis plan, 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 
patient safety data in unblinded fashion 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. 
9.5 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of this trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site: 
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective clinical study report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 


 
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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. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 


 
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Yang J, Riella LV, Chock S. The novel costimulatory programmed death ligand 1/B7.1 
pathway is functional in inhibiting alloimmune responses in vivo. J Immunol 2011; 
187:1113−9. 
Zhang H, Zhang S, Wang Y, et al. Re-evaluation of HER2 status in 1 501 invasive breast 
cancers according to the 2013 American Society of Clinical Oncology/College of 
American Pathology guidelines. 2015;44:42−7. 


 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
135/Protocol WO30085, Version 3 
Appendix 1  
Schedule of Assessments 
Assessment  
or Procedure 
Screening  
Period 
Treatment Period  
(Cycles 1 through Study Treatment Discontinuation) Study Treatment 
Completion/Early 
Discontinuation a 
Follow-Up 
(± 14 Days) b 
Days −28 
to −1 
Day 1  
(± 3 Days) 
Informed consent c 
x 
 
 
 
Demographics d 
x 
 
 
 
Medical history e 
x 
 
 
 
Central HER2 and PDL-1 testing f  
x 
 
 
 
Complete physical examination g 
x 
 
 
 
Limited physical examination h 
 
x 
x 
 
ECOG performance status 
x 
x 
x 
 
Weight i 
x 
x h 
 
 
Vital signs j 
x 
x i 
 
 
Hematology k 
(7 days prior to C1D1) 
x 
x 
 
Serum chemistry l 
(7 days prior to C1D1) 
x k 
x k 
 
Thyroid function test (TSH, free 
T3, and free T4) 
x 
C1D1 and every 4th cycle 
x 
 
C-reactive protein 
x 
 
 
 
INR and aPTT 
x 
As clinically indicated 
 
 
HIV, HCV, and HBV serology m 
x 
 
 
 
Urinalysis n 
x 
As clinically indicated 
 
 
Pregnancy test o 
x 
x 
x 
x 
Tumor and response assessment p 
x  
x  
 
 


 
 
 
Appendix 1  
Schedule of Assessments (cont.) 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
136/Protocol WO30085, Version 3 
Assessment  
or Procedure 
Screening  
Period 
Treatment Period  
(Cycles 1 through Study Treatment Discontinuation)
Study Treatment 
Completion/Early
Discontinuation a 
Follow-Up 
( 14 Days) b
Days 28 
to 1 
Day 1  
( 3 Days) 
Bone scan/PET q 
x 
Perform as clinically indicated or as scheduled 
tumor assessment if only bone involvement at 
baseline 
 
 
CT or MRI of Brain r 
Mandatory  
at screening 
Perform as clinically indicated or as scheduled 
tumor assessment r 
 
 
12-Lead electrocardiogram s 
x 
Perform as clinically indicated 
 
 
NYHA classification 
x 
 
 
 
ECHO or MUGA scan t 
x 
x 
Day 15–21 of Cycle 1, every fourth cycle thereafter. 
Additional LVEF measurements may be performed 
if LVEF declines are clinically suspected at the 
discretion of the investigator 
x 
If not performed 
within 6 weeks of 
this visit 
 
Atezolizumab/placebo 
administration 
 
x w 
 
 
Trastuzumab emtansine 
administration 
 
x x 
 
 
PK/ATA 
 
x (See Appendix 2) 
x 
 
Blood Sample for Biomarker 
Analysis 
 
x (See Appendix 3) 
x 
 
Sample for auto-antibodies u 
x 
 
 
 
Tissue Sample for Biomarker 
Analysis v 
 
x (See Appendix 3) 
x 
 
Concomitant medications 
x 
x 
x 
 


 
 
 
Appendix 1  
Schedule of Assessments (cont.) 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
137/Protocol WO30085, Version 3 
Assessment  
or Procedure 
Screening  
Period 
Treatment Period  
(Cycles 1 through Study Treatment Discontinuation)
Study Treatment 
Completion/Early
Discontinuation a 
Follow-Up 
( 14 Days) b
Days 28 
to 1 
Day 1  
( 3 Days) 
Adverse events 
x 
x 
x 
x 
Survival follow-up  
 
 
 
x b 
Initiation of anti-cancer treatments 
 
 
 
x b 
 
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; 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.  
Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to enrollment may be 
used; such tests do not need to be repeated for screening. 
a The treatment completion/discontinuation visit will optimally be scheduled for 28  42 days after the last dose of study treatment. 
b Patients will be followed for survival, serious adverse events and adverse events of special interest considered as related to study drug 
(Section 5.3.1) and subsequent anti-cancer therapies (not all concomitant medications) need to be reported approximately every 3 months 
starting from the Study Drug Completion Visit until death, loss to follow-up, withdrawal of consent, or study discontinuation by the Sponsors. 
Survival follow-up information will be collected every 3 months via telephone calls, patient medical records, and/or clinic visits.  Study staff may 
use a public information source (e.g., county records) to obtain information about survival status only.  
c Written informed consent must be obtained before any study-specific screening assessments are performed. 
d Demographics include age, sex, and self-reported race/ethnicity. 


 
 
 
Appendix 1  
Schedule of Assessments (cont.) 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
138/Protocol WO30085, Version 3 
e Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), reproductive 
status, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, and nutritional supplements) used 
by the patient within 7 days prior to the Cycle 1, Day 1 visit.  Breast cancer history includes prior cancer therapies and procedures. 
f Refer to Appendix 3 for tissue requirements related to eligibility.  HER2 and or PDL-1 status may be determined outside of the screening window 
of 28 days. 
g A complete physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems.  Record abnormalities observed at baseline on the 
General Medical History and Baseline Conditions eCRF.  Record new or worsened clinically significant abnormalities on the Adverse Event 
eCRF. 
h A limited physical examination consists of a symptom-driven physical examination that focuses on organ systems related to potential and 
ongoing adverse events and is based on the patient’s clinical course during study treatment, the patient’s medical history, and/or the known 
adverse event profiles of the study medications.  Record new or worsened clinically significant abnormalities 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.  
j Vital signs include respiratory rate, pulse rate, and systolic and diastolic blood pressures while the patient is in a seated position, and 
temperature.  Vital signs should be obtained and reviewed before and after each study treatment administration but are not required to be 
reported on the eCRF during study treatment.  Record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
k Hematology includes CBC, with RBC count, hemoglobin, hematocrit, WBC count with differential (neutrophils, eosinophils, lymphocytes, 
monocytes, basophils, and other cells), and platelet count.  Screening laboratory tests are to be performed within 7 days prior 
to randomization.  Screening laboratory assessments may be done on the day of randomization, and their results may be used for randomization 
visit purposes.  Results must be reviewed and documented prior to administration of the first dose of study treatment.  Hematologic evaluations 
should be completed prior to dosing on Day 1 of each indicated cycle (or up to 3 days before).   
l Serum chemistry includes glucose, BUN or urea, creatinine, sodium, potassium, magnesium, chloride, bicarbonate, calcium, phosphorus, total 
bilirubin, ALT, AST, alkaline phosphatase, total protein, and albumin.  Screening laboratory tests are to be performed within 7 days prior 
to randomization.  Screening laboratory assessments may be done on the day of randomization, and their results may be used for randomization 
visit purposes.  Results must be reviewed and documented prior to administration of the first dose of study treatment.  Chemistry evaluations 
should be completed prior to dosing on Day 1 of each indicated cycle (or up to 3 days before). 
m All patients will be tested for HIV prior to the inclusion into the study; HIV-positive patients will be excluded from the study.  HBV DNA must be 
collected on or before Cycle 1, Day 1, in patients who have negative serology for hepatitis B surface antigen and positive serology for anti-HBc.   
n Urinalysis includes specific gravity, pH, glucose, protein, ketones, and blood. 


 
 
 
Appendix 1  
Schedule of Assessments (cont.) 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
139/Protocol WO30085, Version 3 
o All women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test within 7 days prior to 
enrollment.  During the treatment period, urine pregnancy test in women of childbearing potential in both treatment arms must be performed 
within 3 days prior study drug administration of every 3 cycles of protocol mandated therapy.  If a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test. For patients who discontinue therapy before end of planned therapy, a pregnancy test must be done at the 
completion/early termination visit (approximately 28−42 days after the last dose of HER2-targeted therapy), and at 3 months and for 
HER2-targeted therapy, additionally at 6 months after the discontinuation of study treatment.  
p Tumor assessments performed as standard of care prior to obtaining informed consent and within 28 days of Cycle 1, Day 1, may be used rather 
than repeating tests.  All measurable and evaluable lesions should be assessed and documented at the screening visit.  Radiologic imaging 
performed during the screening period should consist of 1) CT (with oral or IV contrast unless contraindicated) and/or MRI of the chest, abdomen, 
and pelvis, 2) bone scan or PET scan, 3) Brain MRI/CT and 4) any other imaging studies (CT of neck, plain films, etc.) as clinically indicated by 
the treating physician.  The same radiographic procedures and technique must be used throughout the study for each patient (e.g., if the patient 
had CT of chest, abdomen, and pelvis performed during screening, then the patient should subsequently undergo CT performed using the same 
radiologic protocol throughout the remainder of the study).  
 Tumor assessments will be performed at baseline, every 6 weeks ( 7 days) following randomization, with additional scans as clinically indicated.  
All known sites of disease documented at screening should be re-assessed at each subsequent tumor evaluation.  Tumor assessments 
performed after the screening period should consist of the following assessments every 6 weeks:  1) CT and/or MRI of the chest/abdomen/pelvis, 
as well as other known sites of disease, including brain, 2) If a patient has only bone as a site of involvement at screening which is determined 
to be measurable disease as per RECIST 1.1, then a bone scan or PET scan is mandated at each tumor assessment. Otherwise, a bone scan 
or PET scan is to be performed as clinically indicated, e.g., suspicion of disease progression, and 3) in cases where patients demonstrate control 
of their systemic disease but who newly develop isolated brain metastases and are eligible to remain on study treatment, brain MRI or CT are 
performed along with regularly scheduled tumor assessments, and 4) any other imaging studies felt to be clinically indicated by the treating 
physician.  Tumor response will be evaluated using RECIST v1.1 (Appendix 4 and immune-modified RECIST Appendix 5).  In the absence of 
disease progression, tumor assessments should continue regardless of whether patients discontinue study treatment, unless they withdraw 
consent or the study is terminated by the Sponsor, whichever occurs first.  Results must be reviewed by the investigator before dosing at the 
next cycle.   
q An isotope 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. 


 
 
 
Appendix 1  
Schedule of Assessments (cont.) 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
140/Protocol WO30085, Version 3 
r CT/MRI scan of the brain is mandatory at screening and should be performed 1) with scheduled tumor assesssments when identified as a site of 
involvement at baseline, 2) as clinically indicated, or 3) if a patient demonstrates control of systemic disease but has a newly developed 
isolated brain metastases and is eligible to remain on study treatment, a brain MRI or CT will be performed along with regularly scheduled 
tumor assessments. 
s A 12-lead ECG is required at screening.  Subsequent ECGs may be performed as clinically indicated.  ECGs for each patient should be obtained 
from the same machine wherever possible.  ECG recordings must be performed after the patient has been resting in a supine position for at 
least 10 minutes. 
t 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. 
u Auto-antibody testing includes anti-nuclear antibody, antidouble-stranded DNA, and circulating and perinuclear cytoplasmic antibody.  The 
baseline sample will be obtained pre-treatment Cycle 1, Day 1, before the first dose of study drug.  For patients who show evidence of 
immune-mediated toxicity, additional samples may be collected.  All samples will be analyzed centrally. 
v At screening, the FFPE archival tumor block from the most recently collected, available tumor tissue or fresh core biopsy (3 cores) is mandated.  
If more than 1 FFPE blocks exists from different time points e.g. initial diagnosis vs. metastatic disease tissue, the most recent block is 
mandatory to be sent. If the FFPE block from the earlier timepoint is available then this would be requested to also be sent. In the cases of 
bilateral breast cancer, an additional 8 unstained slides from the contralateral breast to where FFPE block have been provided.  20-25 freshly cut, 
unstained slides will be acceptable in lieu of the FFPE block. Optional core biopsies will be obtained at Cycle 1, Day 1 and Cycle 2, Day 1 
( 3 days) if patient consented. At the study drug discontinuation/early study completion visit, if reason for discontinuation is disease progression, 
a biopsy must be taken (if deemed clinically feasible) before next line of therapy begins, unless purely anti-hormonal therapy.  
w 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.  
For the first infusion of atezolizumab or placebo, vital signs should be determined within 60 minutes before, every 15 ( 5) minutes during, and 
30 ( 10) minutes after the infusion, if clinically indicated.  For subsequent infusions, vital signs do not need to be obtained during the infusion if 
the prior infusion was tolerated without symptoms. 
x 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.  For patients assigned to trastuzumab emtansine therapy, trastuzumab emtansine should be administered over approximately 
90 minutes for the first dose and, in the absence of infusion-related adverse events, over approximately 30 minutes in subsequent doses.  Vital 
signs should be taken before and after the trastuzumab emtansine infusion. Patients will be monitored for any untoward effects for at least 
90 minutes after completion of the first trastuzumab emtansine infusion and, in the absence of infusion-related events, for a minimum of 
30 minutes at subsequent infusions.   


 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
141/Protocol WO30085, Version 3 
Appendix 2  
Schedule of Pharmacokinetic and Immunogenicity Samples 
 
Table 1 Anti-Therapeutic Antibody and Pharmacokinetic Assessments for 
Atezolizumab1 
Visit 
Timepoint 
Sample Typea 
Cycle 1, Day 1 and Cycle 4 
Day 1 
Pre-infusionb of 
atezolizumab or placebo  
Serum sample for 
atezolizumab 
pharmacokinetics 
Serum sample for ATA 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 b of 
atezolizumab or placebo 
Serum sample for 
atezolizumab 
pharmacokinetics 
Serum sample for ATA to 
atezolizumab  
Study treatment/early 
discontinuation visit 
At any time during visit 
Serum sample for 
atezolizumab 
pharmacokinetics 
Serum sample for ATA to 
atezolizumab 
120 days (± 28 days) after 
treatment completion or 
discontinuation 
At any time during visit 
Serum sample for 
atezolizumab 
pharmacokinetics 
Serum sample for ATA to 
atezolizumab 
ATA = anti-therapeutic antibody. 
a Blood for PK/ ATA should not be obtained through the same line that atezolizumab or 
placebo is infused. 
b Within 24 hours prior to atezolizumab infusion. 
 


Appendix 2  
Schedule of Pharmacokinetic and Immunogenicity Samples 
(cont.) 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
142/Protocol WO30085, Version 3 
Table 2 Anti-Therapeutic Antibody and Pharmacokinetic Assessments for 
Trastuzumab Emtansine1 
Visit 
Timepoint 
Sample Typea 
Cycle 1, Day 1 and 
Cycle 4 Day 1 
Pre-infusionb of 
trastuzumab emtansine 
Serum sample for 
trastuzumab emtansine and 
total trastuzumab 
pharmacokinetics  
Serum HER2 ECD (Cycle 1 
only) 
Plasma sample for DM1 
(Cycle 1 only)  
Serum sample for ATA 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 and 
total trastuzumab 
Plasma sample for DM1 
Cycle 2, Day 1 ( 3 days) 
Pre-infusion b of 
trastuzumab emtansine Serum sample for 
trastuzumab emtansine and 
total trastuzumab 
 
Study treatment/early 
discontinuation visit 
At any time during visit 
Serum sample for 
trastuzumab emtansine 
pharmacokinetics 
Serum sample for ATA to 
trastuzumab emtansine 
120 days ( 28 days) after 
treatment completion or 
discontinuation 
At any time during the 
visit 
Serum sample for ATA to 
trastuzumab emtansine 
ATA  anti-therapeutic antibody. 
a Blood for PK/ ATA should not be obtained through the same line that trastuzumab 
emtansine is infused. 
b  Within 24 hours prior to Trastuzumab emtansine administration. 


 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
143/Protocol WO30085, Version 3 
Appendix 3  
Schedule of Biomarker Samples 
Table 3 Blood Samples for Biomarker Analysis 
Visit 
Timepoint 
Sample Type 
Cycle 1, Day 1  
Pre-infusion   
Whole blood sample a 
Whole blood RBR sample for 
genetic research 
Blood for serum/plasma 
Cycle 2, Day 1  
Pre-infusion   
Whole blood sample a 
Blood for serum/plasma 
Cycle 3, Day 1 
Pre-infusion   
Blood for serum/plasma 
Cycle 8, Day 1 
Pre-infusion   
Blood for serum/plasma 
Study treatment/early 
discontinuation visit 
At any time during visit 
Whole blood sample a 
Blood for serum/plasma 
120 days (± 28 days) after 
treatment completion or 
discontinuation 
At any time during visit 
Whole blood sample a 
Blood for serum/plasma 
a 
 Whole blood sample will be taken from all patients enrolled on the study.  Serial 
sample collection will be collected on approximately the first 50 enrolled patients 
only. 
 


Appendix 3  
Schedule of Biomarker Samples (cont.) 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
144/Protocol WO30085, Version 3 
Table 4 Tissue Sample for Biomarker Analysis 
Visit 
Timepoint 
Requirement 
Sample Type 
Screening  
Pre-infusion   
Mandatory 
FFPE archival tumor block or partial 
block most recently collected, available 
tumor tissue or 
Fresh core biopsy (3 cores) 
If more than 1 FFPE blocks exists from 
different time points e.g. initial diagnosis 
vs. metastatic disease tissue, the most 
recent block or partial block is mandatory 
to be sent. If the FFPE block from the 
earlier timepoint is available then this 
would be requested to also be sent. 
In the cases of bilateral breast cancer, 
an additional 8 unstained slides from the 
contralateral breast to where FFPE block 
have been provided  
Upon discussion with the Medical 
Monitor (in case of site regulations that 
prevent sending a block), 20 freshly cut, 
unstained slides will be acceptable in 
lieu of FFPE block. 
If only fewer than 20 unstained slides are 
available at baseline (but no fewer than 
15), discuss with the Medical Monitor to 
decide on eligibility.   
Cycle 1 Day 1 
Pre-infusion (within 
28 days of C1D1) 
Optional 
Fresh Core Biopsy (3 cores) 
FFPE block or partial block preferred or 
freshly cut, unstained 15 slides 
Cycle 2 Day 1 
Pre-infusion (within 
3 days prior to 
C2D1 or up to 
5 days after C2D1) 
Optional  
Fresh Core Biopsy (3 cores) 
FFPE block or partial block preferred or 
freshly cut, unstained 15 slides 
Study 
treatment/early 
discontinuation 
visit  
Reason: Disease 
Progression 
At time of Study 
treatment/early 
discontinuation visit 
(if the reason for 
discontinuation was 
PD) 
Must be taken 
before next line of 
therapy begins.  
In case new line 
therapy is purely 
anti-hormonal, 
biopsy could be 
taken after it is 
started.  
Mandatory  
(if deemed 
clinically 
feasible) 
Fresh Core Biopsy (3 cores) at site of 
progression if accessible or from any 
other lesion 
FFPE block preferred or freshly cut, 
unstained 15 slides  


 
 
 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
145/Protocol WO30085, Version 3 
Appendix 4  
Response Evaluation Criteria in Solid Tumors, Version 1.1 
The following is a modified excerpt from the original publication (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). 
1. Measurability of Tumor at Baseline  
Definitions  
At baseline, tumor lesions/lymph nodes will be categorized measurable or 
non-measurable as follows:  
Measurable tumor lesions  
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size of:  
10 mm by CT or MRI scan (CT/MRI scan slice thickness/interval no greater than 5 mm).  
10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable).  
20 mm by chest X-ray (CXR).  
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be not greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed.  See also paragraph below on “Baseline 
documentation of target and non-target lesions” for information on lymph node 
measurement.  
Non-Measurable Tumor Lesions  
Non-measurable tumor lesions encompass small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include: 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques.  
Special Considerations Regarding Lesion Measurability  
Bone lesions, cystic lesions, and lesions previously treated with local treatment require 
particular comment:  
Bone lesions:  
Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions.  However, these techniques can be used to confirm the 
presence or disappearance of bone lesions.  


Appendix 4  
Response Evaluation Criteria in Solid Tumors, Version 1.1 (cont.)  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
146/Protocol WO30085, Version 3 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can 
be considered as measurable lesions if the soft tissue component meets the 
definition of measurability described above.  
Blastic bone lesions are non-measurable.  
Cystic lesions:  
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts.  
“Cystic lesions” thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions.  
Lesions with prior local treatment:  
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional treatment, are usually not considered measurable unless there has 
been demonstrated progression in the lesion.  Trial protocols should detail the 
conditions under which such lesions would be considered measurable.  
 
2. Target lesions:  Specifications by methods of measurements  
Measurement of lesions  
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment.  
Method of assessment  
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during 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 diameter as assessed using calipers (e.g., skin nodules).  
For the case of skin lesions, documentation by color photography including a ruler to 
estimate the size of the lesion is suggested.  
Chest X-ray:  Chest CT is preferred over CXR, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions.  However, lesions on CXR may be considered measurable if they are clearly 
defined and surrounded by aerated lung.  


Appendix 4  
Response Evaluation Criteria in Solid Tumors, Version 1.1 (cont.)  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
147/Protocol WO30085, Version 3 
CT, MRI:  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less.  When CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness.  MRI is also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans with IV 
contrast due to allergy or renal insufficiency, the decision as to whether a non-contrast 
CT or MRI (without IV contrast) will be used to evaluate the patient at baseline and 
during the study, should be guided by the tumor type under investigation and the 
anatomic location of the disease.  For patients who develop contraindications to contrast 
after baseline contrast CT is done, the decision as to whether non-contrast CT or MRI 
(enhanced or non-enhanced) will be performed, should also be based on the tumor type, 
anatomic location of the disease and should be optimized to allow for comparison to 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.  
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement.  
Endoscopy, Laparoscopy, Tumor markers, Cytology, Histology:  The utilization of these 
techniques for objective tumor evaluation cannot generally be advised but will be 
dependent on the study design.  
3. Tumor response evaluation  
Assessment of overall tumor burden and measurable disease  
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements.  Measurable disease is defined by the presence of at least one 
measurable lesion (as detailed above).  
Baseline documentation of “target” and “non-target” lesions  
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  
This means in instances where patients have only one or two organ sites involved a 
maximum of two (one site) and four lesions (two sites), respectively, will be recorded.  


Appendix 4  
Response Evaluation Criteria in Solid Tumors, Version 1.1 (cont.)  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
148/Protocol WO30085, Version 3 
Other lesions (albeit measurable) in that organ will be recorded as non-measurable 
lesions (even if size is greater than 10 mm by CT scan).  
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be 
reproducible in 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 which can be measured reproducibly should be selected.  
Lymph nodes merit special mention since they are normal anatomical structures which 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes which are defined as measurable and may be identified as target lesions must 
meet the criterion of a short axis of ≥ 15 mm by CT scan.  Only the short axis of these 
nodes will contribute to the baseline sum.  The short axis of the node is the diameter 
normally used by radiologists to judge if a node is involved by solid tumor.  Nodal size is 
normally reported as two dimensions in the plane in which the image is obtained (for CT 
scan this is almost always the axial plane; for MRI the plane of acquisition may be axial, 
sagittal or coronal).  The smaller of these measures is the short axis.  For example, an 
abdominal node which is reported as being 20 mm × 30 mm has a short axis of 20 mm 
and qualifies as a malignant, measurable node.  In this example, 20 mm should be 
recorded as the node measurement.  All other pathological nodes (those with short axis 
≥ 10 mm but < 15 mm) should be considered non-target lesions.  Nodes that have a short 
axis < 10 mm are considered non-pathological and should not be recorded or followed.  
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters.  If lymph 
nodes are to be included in the sum, then as noted above, only the short axis is added 
into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.  
All other lesions (or sites of disease) including pathological lymph nodes should 
be identified as non-target lesions and should also be recorded at baseline.  
Measurements are not required and these lesions should be followed as “present,” 
“absent,” or in rare cases “unequivocal progression” (see also “Special notes on 
assessment of progression of non-target disease”).  
In addition, it is possible to record multiple non-target lesions involving the same organ 
as a single item on the case report form (e.g., “multiple enlarged pelvic lymph nodes” or 
“multiple liver metastases”).  


Appendix 4  
Response Evaluation Criteria in Solid Tumors, Version 1.1 (cont.)  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
149/Protocol WO30085, Version 3 
Response criteria  
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions.  
Evaluation of target lesions  
CR:  Disappearance of all target lesions.  Any pathological lymph nodes (whether target 
or non-target) must have reduction in short axis to < 10 mm.  
PR:  At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters.  
Progressive Disease (PD):  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study including baseline (nadir).  
In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  (Note: the appearance of one or more new lesions is also 
considered progression).  
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD.  
Special notes on the assessment of target lesions  
Lymph nodes:  Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to below 10 mm on study.  This means 
that when lymph nodes are included as target lesions, the “sum” of lesions may not be 
zero even if CR criteria are met, since a normal lymph node is defined as having a short 
axis of < 10 mm.  
Target lesions that become “too small to measure”:  while on study, all lesions (nodal 
and non-nodal) recorded at baseline should have their actual measurements recorded at 
each subsequent evaluation, even when very small (e.g., 2 mm).  However, sometimes 
lesions or lymph nodes which are recorded as target lesions at baseline become so faint 
on CT scan that the radiologist may not feel comfortable assigning an exact measure 
and may report them as being “too small to measure.”  When this occurs it is important 
that a value be recorded on the Case Report Form:  
If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm.  
If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and BML (below measurable limit) 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 


Appendix 4  
Response Evaluation Criteria in Solid Tumors, Version 1.1 (cont.)  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
150/Protocol WO30085, Version 3 
such as in the retroperitoneum; however, if a lymph node is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well and BML should also be ticked).  
To reiterate, however, if the radiologist is able to provide an actual measure, that 
should be recorded, even if it is below 5 mm and in that case BML should not be 
ticked (BML is equivalent to a less than sign <).  
Lesions that split or coalesce on treatment:  when non-nodal lesions “fragment,” the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion.  If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the “coalesced lesion.” 
Evaluation of non-target lesions  
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions.  While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the time points specified in the protocol.  
CR:  Disappearance of all non-target lesions (and, if applicable, normalization of tumor 
marker level).  All lymph nodes must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits. 
Progressive Disease (PD):  Unequivocal progression of existing non-target lesions.  
The appearance of one or more new lesions is also considered progression. 
Special notes on assessment of progression of non-target disease 
When the patient also has measurable disease:  in this setting, to achieve 
“unequivocal progression” on the basis of the non-target disease, there must be 
an overall level of substantial worsening in non-target disease in a magnitude that, 
even in presence of SD or PR in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of treatment.  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 disease in the face of SD or PR of target disease will 
therefore be extremely rare. 


Appendix 4  
Response Evaluation Criteria in Solid Tumors, Version 1.1 (cont.)  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
151/Protocol WO30085, Version 3 
When the patient has only non-measurable disease:  this circumstance arises in some 
Phase III studies when it is not a criterion of study entry to have measurable disease.  
The same general concepts apply here as noted above, however, in this instance there 
is no measurable disease assessment to factor into the interpretation of an increase in 
non-measurable disease burden.  Because worsening in non-target disease cannot be 
easily quantified (by definition: if all lesions are truly non-measurable) a useful test that 
can be applied when assessing patients for unequivocal progression is to consider if the 
increase in overall disease burden based on the change in non-measurable disease is 
comparable in magnitude to the increase that would be required to declare PD for 
measurable disease:  i.e., an increase in tumor burden representing an additional 73% 
increase in “volume” (which is equivalent to a 20% increase diameter in a measurable 
lesion).  Examples include an increase in a pleural effusion from “trace” to “large,” an 
increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as “sufficient to require a change in treatment.”  If “unequivocal 
progression” is seen, the patient should be considered to have had overall PD at that 
point.  While it would be ideal to have objective criteria to apply to non-measurable 
disease, the very nature of that disease makes it impossible to do so; therefore the 
increase must be substantial. 
New lesions 
The appearance of new malignant lesions denotes PD; 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: 
i.e., 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 PD. 
If a new lesion is equivocal, for example because of its small size, continued treatment 
and follow-up evaluation will clarify if it represents truly new disease.  If repeat scans 
confirm there is definitely a new lesion, then progression should be declared using the 
date of the initial scan.  


Appendix 4  
Response Evaluation Criteria in Solid Tumors, Version 1.1 (cont.)  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
152/Protocol WO30085, Version 3 
Evaluation of response  
Timepoint Response (Overall response)  
It is assumed that at each protocol specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint.  
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used. 
Table 1:  Timepoint Response 
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
Not Evaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease. 
 


Appendix 4  
Response Evaluation Criteria in Solid Tumors, Version 1.1 (cont.)  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
153/Protocol WO30085, Version 3 
Table 2:  Timepoint Response 
Non-Target lesions 
New Lesions 
Overall response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/Non-PD* 
Not all evaluated 
No 
Not Evaluable 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response; PD = progressive disease; SD = stable disease. 
* “Non-CR/non-PD” is preferred over “stable disease” for non-target disease since SD is 
increasingly used as endpoint for assessment of efficacy in some studies so to assign this 
category when no lesions can be measured is not advised. 
 
Missing assessments and not-evaluable designation  
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable at that time point.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that time point, unless 
a convincing argument can be made that the contribution of the individual missing 
lesion(s) would not change the assigned time point response.  This would be most likely 
to happen in the case of PD.  
For example, if a patient had a baseline sum of 50 mm with three measured lesions and 
during the study only two lesions were assessed, but those gave a sum of 80 mm, the 
patient will have achieved PD status, regardless of the contribution of the missing lesion.  
If one or more target lesions were not assessed either because the scan was not done, 
or could not be assessed because of poor image quality or obstructed view, the 
Response for Target Lesions should be “Unable to Assess” since the patient is not 
evaluable.  Similarly, if one or more non-target lesions are indicated as ‘not assessed’, 
the response for non-target lesions should be “Unable to Assess” (except where there is 
clear progression).  Overall response would be “Unable to Assess” if either the target 
response or the non-target response is “Unable to Assess” (except where this is clear 
evidence of progression) as this equates with the case being not evaluable at that time 
point. 


Appendix 4  
Response Evaluation Criteria in Solid Tumors, Version 1.1 (cont.)  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
154/Protocol WO30085, Version 3 
Table 3:  Best Overall Response when Confirmation is required 
Overall response 
First time point 
Overall response 
Subsequent time point 
BEST Overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PR* 
CR 
SD 
SD provided minimum criteria 
for SD duration met, otherwise 
PD 
CR 
PD 
SD provided minimum criteria 
for SD duration met, otherwise 
PD 
CR 
Not Evaluable 
SD provided minimum criteria 
for SD duration met, otherwise 
Not Evaluable 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria 
for SD duration met, otherwise 
PD 
PR 
Not Evaluable 
SD provided minimum criteria 
for SD duration met, otherwise 
Not Evaluable 
Not Evaluable 
Not Evaluable 
Not Evaluable  
CR = complete response; PD = progressive disease; PR = partial response; SD = stable 
disease. 
* If a CR is truly met at first time point then any disease seen at a subsequent time point, 
even disease meeting PR criteria relative to baseline, makes the disease PD at that 
point (since disease must have reappeared after CR).  Best response would depend on 
whether minimum duration for SD was met.  However, sometimes “CR” may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the 
patient had PR not CR at the first time point.  Under these circumstances the original CR 
should be changed to PR and the best response is PR. 
 
Special notes on response assessment  
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (< 10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to 


Appendix 4  
Response Evaluation Criteria in Solid Tumors, Version 1.1 (cont.)  
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
155/Protocol WO30085, Version 3 
overstate progression should it be based on increase in size of the nodes.  As noted 
earlier, this means that patients with CR may not have a total sum of “zero” on the eCRF.  
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of PD 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 objective response 
status of such patients is to be determined by evaluation of target and non-target 
disease as shown in Tables 1–3.  
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.  
In studies where patients with advanced disease are eligible (i.e., primary disease still or 
partially present), the primary tumor should be also captured under target or non-target 
lesions as appropriate.  This is to avoid wrong assessments of complete overall 
response by statistical programs while the primary is still present but not evaluable.  


 
 
 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
156/Protocol WO30085, Version 3 
Appendix 5  
Immune-Modified Response Evaluation Criteria in Solid Tumors  
Conventional response criteria may not be adequate to characterize the anti-tumor 
activity of immunotherapeutic agents like atezolizumab, which can produce delayed 
responses that may be preceded by initial apparent radiological progression, including 
the appearance of new lesions.  Therefore, immune-modified response criteria have 
been developed that account for the possible appearance of new lesions.   
Immune-modified RECIST is derived from RECIST, Version 1.1 (v1.1) conventions and 
immune-related response criteria (irRC).  When not otherwise specified, RECIST v1.1 
conventions will apply. 
Immune-Modified RECIST and RECIST v1.1:  Summary of Changes 
 
RECIST v1.1 
Immune-Modified RECIST 
New lesions after baseline 
Define progression 
New measurable lesions are added 
to the total tumor burden 
calculation (?) and followed. 
Non-target lesions 
May contribute to the 
designation of overall 
progression 
Contribute only in the assessment 
of a complete response 
Radiographic progression 
First instance of ≥ 20% 
increase in the sum of 
diameters or unequivocal 
progression in non-target 
disease 
Determined only on the basis of 
measurable disease 
RECIST = Response Evaluation Criteria in Solid Tumors. 
 
A.  DEFINITIONS OF MEASURABLE/NON-MEASURABLE LESIONS 
All measurable and non-measurable lesions should be assessed at Screening and at the 
protocol-specified tumor assessment timepoints.  Additional assessments may be 
performed, as clinically indicated for suspicion of progression.   
A.1  
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 CT or MRI scan (CT/MRI scan slice thickness/interval no greater than 
5 mm) 
• 
10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable) 
 


Appendix 5  
Immune-Modified Response Evaluation Criteria in Solid Tumors 
(cont.) 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
157/Protocol WO30085, Version 3 
Malignant Lymph Nodes.  To be considered pathologically enlarged and measurable, 
a lymph node must be ≥ 15 mm in the short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm).  At baseline and follow-up, 
only the short axis will be measured and followed. 
A.2  
NON-MEASURABLE LESIONS 
Non-measurable tumor lesions encompass small lesions (longest diameter < 10 mm or 
pathological lymph nodes with short axis ≥ 10 but < 15 mm), as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques. 
A.3 
SPECIAL CONSIDERATIONS REGARDING LESION 
MEASURABILITY 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
Bone Lesions 
Bone scan, PET scan, or plain films are not considered adequate imaging techniques for 
measuring bone lesions.  However, these techniques can be used to confirm the 
presence or disappearance of bone lesions. 
Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross-sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
Blastic bone lesions are non-measurable. 
Cystic Lesions 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above.  However, if 


Appendix 5  
Immune-Modified Response Evaluation Criteria in Solid Tumors 
(cont.) 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
158/Protocol WO30085, Version 3 
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.   
B.   
TUMOR RESPONSE EVALUATION 
B.1  
DEFINITIONS OF TARGET/NON-TARGET LESIONS 
Target Lesions 
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one 
or two organ sites involved, a maximum of two lesions (one site) and four lesions 
(two sites), respectively, will be recorded.  Other lesions (albeit measurable) in those 
organs will be recorded as non-measurable lesions (even if the size is > 10 mm by 
CT scan). 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but in addition, should lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance, the next largest lesion that can be measured reproducibly should be 
selected. 
Lymph nodes merit special mention since they are normal anatomical structures 
that may be visible by imaging even if not involved by tumor.  As noted above, 
pathological nodes that are defined as measurable and may be identified as target 
lesions must meet the criterion of a short axis of ≥ 15 mm by CT scan.  Only the short 
axis of these nodes will contribute to the baseline sum.  The short axis of the node is the 
diameter normally used by radiologists to judge if a node is involved by solid tumor.  
Nodal size is normally reported as two dimensions in the plane in which the image is 
obtained (for CT, this is almost always the axial plane; for MRI, the plane of acquisition 
may be axial, sagittal, or coronal).  The smaller of these measures is the short axis.  
For example, an abdominal node that is reported as being 20 mm × 30 mm has a short 
axis of 20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm 
should be recorded as the node measurement.  All other pathological nodes (those with 


Appendix 5  
Immune-Modified Response Evaluation Criteria in Solid Tumors 
(cont.) 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
159/Protocol WO30085, Version 3 
short axis ≥ 10 mm but < 15 mm) should be considered non-target lesions.  Nodes that 
have a short axis of < 10 mm are considered non-pathological and should not be 
recorded or followed. 
Lesions irradiated within 3 weeks prior to Cycle 1 Day 1 may not be counted as target 
lesions. 
Non-Target Lesions 
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 
are not required. 
It is possible to record multiple non-target lesions involving the same organ as a single 
item on the eCRF (e.g., “multiple enlarged pelvic lymph nodes” or “multiple liver 
metastases”). 
After baseline, changes in non-target lesions will contribute only in the assessment 
of CR (i.e., a CR is attained only with the complete disappearance of all tumor lesions, 
including non-target lesions) and will not be used to assess progressive disease. 
New Lesions 
During the study, all new lesions identified and recorded after baseline must be 
assessed at all tumor assessment timepoints.  New lesions will also be evaluated for 
measurability with use of the same criteria applied to prospective target lesions at 
baseline per RECIST, (e.g., non−lymph node lesions must be ≥ 10mm; see note for new 
lymph node lesions below).  Up to a maximum of five new lesions total (and a maximum 
of two lesions per organ), all new lesions with measurements obtained at all timepoints, 
can be included in the tumor response evaluation.  New lesion types that would not 
qualify as target lesions per RECIST cannot be included in the tumor response 
evaluation. 
New lesions that are not measurable at first appearance but meet measurability criteria 
at a subsequent timepoint will be measured from that point on and contribute to the sum 
of longest diameters (SLD), if the maximum number of 5 measurable new lesions being 
followed has not been reached.  
B.2  
CALCULATION OF SUM OF THE DIAMETERS 
A sum of the diameters (longest axis for non-nodal lesions, short axis for nodal lesions) 
of all target lesions will be calculated as a measure of tumor burden. 


Appendix 5  
Immune-Modified Response Evaluation Criteria in Solid Tumors 
(cont.) 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
160/Protocol WO30085, Version 3 
The sum of the diameters is calculated at baseline and at each tumor assessment for 
the purpose of classification of tumor responses. 
Sum of the Diameters at Baseline:  The sum of the diameters for all target lesions 
identified at baseline prior to treatment on Day 1. 
Sum of the Diameters at On-Study Tumor Assessment:  For every on-study tumor 
assessment collected per protocol or as clinically indicated the sum of the diameters at 
tumor assessment will be calculated using tumor imaging scans.  All target lesions 
selected at baseline and up to five new measurable lesions (with a maximum of two new 
lesions per organ) that have emerged after baseline will contribute to the sum of the 
diameters at tumor assessment.  Hence, each net percentage change in tumor burden 
per assessment with use of immune-modified RECIST accounts for the size and growth 
kinetics of both old and new lesions as they appear. 
Note:  In the case of new lymph nodes, RECIST v1.1 criteria for measurability 
(equivalent to baseline target lesion selection) will be followed.  That is, if at first 
appearance the short axis of a new lymph node lesion ≥ 15 mm, it will be considered a 
measureable new lesion and will be tracked and included in the SLD.  Thereafter, the 
lymph node lesion will be measured at subsequent timepoints and measurements will be 
included in the SLD, even if the short axis diameter decreases to < 15 mm (or even 
< 10 mm).  However, if it subsequently decreases to < 10 mm, and all other lesions are 
no longer detectable (or have also decreased to a short axis diameter of < 10 mm if 
lymph nodes), then a response assessment of CR may be assigned. 
If at first appearance the short axis of a new lymph node is ≥ 10 mm and < 15 mm, the 
lymph node will not be considered measurable but will still be considered a new lesion.  
It will not be included in the SLD unless it subsequently becomes measurable (short axis 
diameter ≥ 15 mm). 
The appearance of new lymph nodes with diameter < 10 mm should not be considered 
pathological and not considered a new lesion. 
B.3  
RESPONSE CRITERIA 
Timepoint Response 
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint. 
CR:  Disappearance of all target and non-target lesions.  Lymph nodes that shrink to 
< 10 mm short axis are considered normal. 


Appendix 5  
Immune-Modified Response Evaluation Criteria in Solid Tumors 
(cont.) 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
161/Protocol WO30085, Version 3 
PR:  At least a 30% decrease in the sum of the diameters of all target and all new 
measurable lesions, taking as reference the baseline sum of diameters, in the absence 
of CR. 
Note:  The appearance of new measurable lesions is factored into the overall tumor 
burden, but does not automatically qualify as progressive disease until the sum of the 
diameters increases by ≥ 20% when compared with the sum of the diameters at nadir. 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum of the diameters while 
on study. 
Progressive Disease (PD):  At least a 20% increase in the sum of diameters of all 
target and selected new measurable lesions, taking as reference the smallest sum on 
study (nadir SLD; this includes the baseline sum if that is the smallest on study).  
In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. 
Impact of New Lesions on Immune-Modified RECIST 
New lesions alone do not qualify as progressive disease.  However, their contribution to 
total tumor burden is included in the sum of the diameters, which is used to determine 
the overall immune-modified RECIST tumor response. 
Missing Assessments and Not Evaluable Designation 
When no imaging/measurement is done at all at a particular assessment timepoint, the 
patient is considered not evaluable (NE) at that timepoint.  If only a subset of lesion 
measurements are made at an assessment, usually the case is also considered NE at 
that timepoint, unless a convincing argument can be made that the contribution of the 
individual missing lesion(s) would not change the assigned timepoint response.  This 
would only happen in the case of PD.  For example, if a patient had a baseline sum of 
50 mm with three measured lesions and at follow-up only two lesions were assessed but 
those gave a sum of 80 mm, the patient will be assigned PD status, regardless of the 
contribution of the missing lesion. 


Appendix 5  
Immune-Modified Response Evaluation Criteria in Solid Tumors 
(cont.) 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
162/Protocol WO30085, Version 3 
Table 1 
Immune-Modified RECIST Timepoint Response Definitions 
% Change in Sum of the Diameters a 
Non-Target Lesion 
Response 
Assessment 
Overall Immune-Modified 
RECIST Timepoint Response 
− 100% from baseline b 
CR 
CR 
− 100% from baseline b 
Non-CR or not all 
evaluated 
PR 
≤  − 30% from baseline 
Any 
PR 
>  − 30% to < + 20% 
Any 
SD 
Not all evaluated 
Any 
NE 
≥  + 20%from nadir SLD 
Any 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial 
response; RECIST = Response Evaluation Criteria in Solid Tumors; SD = stable disease; 
SLD = sum of the longest diameter. 
a Percent change in sum of the diameters (including measurable new lesions when present). 
b When lymph nodes are included as target lesions, the % change in the sum of the 
diameters may not be 100% even if complete response criteria are met, since a normal 
lymph node is defined as having a short axis of < 10 mm.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm in order to meet 
the definition of CR. 
 


Appendix 5  
Immune-Modified Response Evaluation Criteria in Solid Tumors 
(cont.) 
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd 
163/Protocol WO30085, Version 3 
REFERENCES 
Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;2:228-47. 
Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of 
anti−PD-1 antibody in cancer. N Engl J Med 2012;366:2443−54. 
Wolchok JD, Hoos A, O'Day S et al. Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune-related response criteria. Clin Cancer Res. 
2009;23:7412-20. 
Nishino M, Gargano M, Suda M, et al. Optimizing immune-related tumor response 
assessment: does reducing the number of lesions impact response assessment in 
melanoma patients treated with ipilimumab? J Immunother Cancer. 2014;2:17. 
Nishino M, Giobbie-Hurder A, Gargano A et al. Developing a Common Language for 
Tumor Response to Immunotherapy: Immune-related Response Criteria using 
Unidimentional measurements. Clin Cancer Res. 2013;14:3936−43. 


 
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164/Protocol WO30085, Version 3 
Appendix 6  
Ventana HER2 IHC Assay 
The PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody 
(PATHWAYHER2 [4B5]) is a rabbit monoclonal antibody intended for laboratory use for 
the semi-quantitative detection of HER2 antigen in sections of formalin-fixed, paraffin-
embedded breast cancer tissue to determine tumor HER2 immunohistochemistry (IHC) 
status and to select HER2-positive patients for enrollment in study WO30085.  The 4B5 
IHC assay is currently being developed by Ventana Medical Systems as a companion 
diagnostic to ado-trastuzumab emtansine and will be used for investigational purposes 
only. 
Device Description 
The PATHWAY HER2 (4B5) IHC assay is an automated immunohistochemical staining 
assay system comprising a pre-dilute, ready-to-use, rabbit monoclonal primary 
antibody(clone 4B5) directed against the internal domain of HER2, the BenchMark 
ULTRA automated slide staining platform, and ultraView universal DAB detection kit. 
The reagents and the IHC procedure are optimized for use on the BenchMark ULTRA 
automated slide stainer, utilizing VSS software (Ventana System Software). Details of 
the staining protocol and scoring criteria can be found in instruction for use and 
interpretation guide published by Ventana. 
  


 
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165/Protocol WO30085, Version 3 
Appendix 7  
Ventana HER2 ISH Assay 
Probe Cocktail is intended to determine the ratio of the HER2 gene to chromosome 
17using two-color chromogenic in situ hybridization (ISH) in formalin-fixed, paraffin-
embedded human breast cancer tissue to determine tumor HER2 gene status and select 
HER2-positive patients for enrollment in study BO28407. The INFORMHER2 Dual ISH 
DNA Probe Cocktail is currently being developed by Ventana Medical Systems as a 
companion diagnostic to ado-trastuzumab emtansine and will be used for investigational 
purposes only for Study WO30085. 
The Ventana INFORM HER2 Dual ISH assay consists of a dinitrophenyl (DNP)-labeled 
double stranded probe that targets the HER2 gene region of chromosome 17 and a 
digoxigenin (DIG)-labeled double stranded probe that hybridizes to repetitive sequences 
in the centromeric region of chromosome 17 (INFORM Chromosome 17 probe). The 
probes are packaged as a mixture and require the use of Ventana’s ultraView™ 
SISHDNP Detection Kit, ultraView Red DIG Detection Kit, and other accessory reagents 
to stain routinely processed, FFPE tissue sections on Ventana automated slide stainer 
instruments. 


 
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Appendix 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. 
 


 
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167/Protocol WO30085, Version 3 
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 
  
 
 
 


 
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168/Protocol WO30085, Version 3 
Appendix 10  
 
Preexisting Autoimmune Diseases 
Patients should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease.  Patients with any history of immune 
deficiencies or autoimmune disease listed in the table below are excluded from 
participating in the study. Possible exceptions to this exclusion could be subjects with a 
medical history of such entities as atopic disease or childhood arthralgias for which 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).  Contact the Medical Monitor regarding any 
uncertainty about autoimmune exclusions. 
Autoimmune Diseases and Immune Deficiencies 
Acute disseminated encephalomyelitis 
Addison’s disease 
Ankylosing spondylitis 
Antiphospholipid antibody syndrome 
Aplastic anemia 
Autoimmune hemolytic anemia 
Autoimmune hepatitis 
Autoimmune hypoparathyroidism 
Autoimmune hypophysitis 
Autoimmune myocarditis 
Autoimmune myositis 
Autoimmune oophoritis 
Autoimmune orchitis 
Autoimmune thrombocytopenic purpura 
Behçet disease 
Bullous pemphigold 
Chronic fatigue syndrome 
Chronic inflammatory demyelinating polyneuropathy 
Chung-Strauss syndrome 
Crohn disease  
Dermatomyositis 
Diabetes mellitus, type 1 
Dysautonomia 
Epidermolysis bullosa acquista 
Gestational pemphigoid 
Giant cell arteritis 
Goodpasture syndrome  
Glomerulonephritis 
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 nodusa 
Polyarthritis 
Polyglandular autoimmune syndrome 
Primary biliary cirrhosis 
Psoriasis 
Reiter syndrome 
Rheumatoid arthritis 
Sarcoidosis 
Scleroderma 
Sjögren syndrome 
Stiff-Person syndrome 
Takayasu arteritis 
Ulcerative colitis  
Vasculitis 
Vitiligo 
Vogt-Kovanagi-Harada disease 
Wegener granulomatosis 
 


 
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169/Protocol WO30085, Version 3 
Appendix 11  
 
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. 

SAP_001.pdf: 
Official Title: 
A Randomized, Multicenter, Double-Blind, Placebo-Controlled 
Phase II Study Of The Efficacy And Safety Of Trastuzumab 
Emtansine In Combination With Atezolizumab Or Atezolizumab-
Placebo In Patients With HER2-Positive Locally Advanced Or 
Metastatic Breast Cancer Who Have Received Prior Trastuzumab 
And Taxane Based Therapy 
NCT Number: 
NCT02924883 
Document Date: 
Statistical Analysis Plan Version 1: 16 Oct 2017 


STATISTICAL ANALYSIS PLAN APPROVAL
CONFIDENTIAL
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd.
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan WO30085
STATISTICAL ANALYSIS PLAN
TITLE:
A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, 
PLACEBO-CONTROLLED PHASE II STUDY OF 
THE EFFICACY AND SAFETY OF TRASTUZUMAB 
EMTANSINE IN COMBINATION WITH 
ATEZOLIZUMAB OR ATEZOLIZUMAB-PLACEBO 
IN PATIENTS WITH HER2-POSITIVE LOCALLY 
ADVANCED OR METASTATIC BREAST CANCER 
WHO HAVE RECEIVED PRIOR TRASTUZUMAB 
AND TAXANE BASED THERAPY
PROTOCOL NUMBER:
WO30085
STUDY DRUG:
Trastuzumab Emtansine (RO5304020)
Atezolizumab (RO5541267)
VERSION NUMBER:
1
IND NUMBER:
71,072
EUDRACT NUMBER:
2015-004189-27
SPONSOR:
F. Hoffmann-La Roche Ltd 
PLAN PREPARED BY:
 Ph.D.
DATE FINAL:
See electronic date stamp below.
Name
Reason for Signing
Date and Time
(UTC)
16-Oct-2017 04:50:27
Company Signatory


Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd
2/Statistical Analysis Plan WO30085
TABLE OF CONTENTS
1.
BACKGROUND ............................................................................................ 4
2.
STUDY DESIGN........................................................................................... 4
2.1
Protocol Synopsis.................................................................... 4
2.2
Endpoints................................................................................. 4
2.3
Determination of Sample Size ................................................. 5
2.4
Analysis Timing ....................................................................... 5
3.
STUDY CONDUCT....................................................................................... 6
3.1
Randomization Issues ............................................................. 6
3.2
Data Monitoring ....................................................................... 6
4.
STATISTICAL METHODS ............................................................................ 6
4.1
Analysis Populations ............................................................... 6
4.1.1
Intention-to-Treat Population ................................................... 6
4.1.2
Safety Population .................................................................... 6
4.2
Analysis of Study Conduct....................................................... 6
4.3
Analysis of Treatment Group Comparability ............................ 7
4.4
Efficacy Analysis...................................................................... 7
4.4.1
Primary Efficacy Endpoint........................................................ 7
4.4.2
Secondary Efficacy Endpoints................................................. 8
4.4.2.1
Overall Survival ....................................................................... 8
4.4.2.2
Objective Response ................................................................ 8
4.4.2.3
Duration of Response.............................................................. 8
4.4.3
Exploratory Efficacy Endpoints................................................ 9
4.4.3.1
Progression-Free Survival Assessed in the PD-
L1 Selected Subgroup ............................................................. 9
4.4.3.2
Progression-Free Survival Assessed Using 
Immune-Modified RECIST....................................................... 9
4.4.3.3
Objective Response Based on Immune-Modified 
RECIST ................................................................................... 9
4.4.3.4
Duration of Response Based on Immune-
Modified RECIST..................................................................... 9
4.4.3.5
One-Year Survival Rate........................................................... 9
4.4.4
Sensitivity Analyses............................................................... 10


Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd
3/Statistical Analysis Plan WO30085
4.4.5
Subgroup Analyses ............................................................... 10
4.5
Pharmacokinetic Analyses..................................................... 10
4.6
Immunogenicity Analyses...................................................... 11
4.7
Biomarker Analyses............................................................... 11
4.8
Safety Analyses..................................................................... 12
4.8.1
Exposure to Study Drug......................................................... 12
4.8.2
Adverse Events ..................................................................... 12
4.8.3
Laboratory Data..................................................................... 13
4.8.4
Vital Signs.............................................................................. 13
4.8.5
Left Ventricular Ejection Fraction Assessments..................... 13
4.9
Missing Data.......................................................................... 13
4.10
Interim Analyses .................................................................... 14
LIST OF TABLES
Table 1
Estimated Power at Primary PFS Analysis for Different PFS 
HRs............................................................................................... 5
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ....................................................................... 15
Appendix 2
Schedule of Assessments........................................................... 26
Appendix 3
Schedule of Pharmacokinetic and Immunogenicity Samples...... 32
Appendix 4
Schedule of Biomarker Samples................................................. 34


Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd
4/Statistical Analysis Plan WO30085
1.
BACKGROUND
This Statistical Analysis Plan (SAP) describes the analyses that are planned to be 
performed for the Study WO30085 (KATE2). The SAP overrides the analyses described 
in the statistical section of the protocol.
2.
STUDY DESIGN
Study WO30085 is a Phase II, randomized, multicenter, international, two-arm, 
double-blind, placebo-controlled clinical trial designed to compare the efficacy and safety 
of trastuzumab emtansine in combination with either atezolizumab or placebo for 
patients with human epidermal growth factor receptor 2 (HER2)-positive locally 
advanced or metastatic breast cancer (MBC) who have received prior trastuzumab and 
taxane based therapy.
Approximately 200 patients will be enrolled in the study at 100 sites worldwide.  Patients 
will be randomized to treatment arms A and B in a 1:2 ratio by means of a permuted 
block randomization scheme through the use of an interactive Web or voice response 
system (IxRS).  Randomization will be stratified according to 1) tumor programmed 
deathligand 1 (PD-L1) status (IC10 vs IC1/2/3), 2) World Region (Western Europe vs 
U.S. vs Rest of World) and 3) Presence of liver metastases (yes vs. no).
Patients will be treated in one of the following arms:

Arm A: trastuzumab emtansine 3.6 mg/kg and placebo, every 3 weeks (q3w) 
(approximately 67 patients)

Arm B: trastuzumab emtansine 3.6 mg/kg and atezolizumab 1200 mg, q3w 
(approximately 133 patients)
Arm A and Arm B will be blinded with respect to administration of atezolizumab or 
placebo.  Cross-over between treatment arms will not be permitted.
The study schema can be found in the protocol.
2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis is in Appendix 1.  For additional details, see the Schedule of 
Assessments in Appendix 2 to Appendix 4.
2.2
ENDPOINTS
See the Protocol Synopsis in Appendix 1 for a description of the endpoints.
                                           
1 ICtumor-infiltrating immune cells


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2.3
DETERMINATION OF SAMPLE SIZE
The primary efficacy endpoint for this study is progression-free survival (PFS) based on 
investigator tumor assessment using Response Evaluation Criteria in Solid Tumors
(RECIST) v1.1.  The primary analysis for PFS will be performed when approximately 
115 PFS events have occurred.
With approximately 200 patients randomized according to a 1:2 randomization 
(approximately 67 patients will be randomized to the trastuzumab emtansine plus 
placebo arm and approximately 133 patients will be randomized to the trastuzumab 
emtansine plus atezolizumab arm) the study has the estimated power for the PFS 
hazard ratios (HRs) presented in Table 1.
Table 1
Estimated Power at Primary PFS Analysis for Different PFS HRs
PFS HR
Estimated power for log-rank test
0.50
94%
0.55
86%
0.60
73%
0.65
58%
HRHazard ratio; PFSprogressive-free survival.
Estimated power figures calculated using a 2-sided log-rank test at 0.05 alpha level 
when 115 PFS events have been observed, assuming a median PFS of 6.2
months for trastuzumab emtansine plus placebo.
The above study design considerations assume proportional hazards, a cumulative 
dropout rate of 10% in each treatment arm and an estimated recruitment time of about 9 
months (with ramp up in the first 4 months).  The estimated time from first patient in (FPI) 
to primary PFS analysis is 15 to 17 months, depending on PFS HR assumption.
Sample size and power calculations were performed using the East 6 software package 
(Cytel Inc.).
2.4
ANALYSIS TIMING
The primary PFS analysis will be performed when approximately 
115 investigator-assessed PFS events have been observed which is anticipated to 
occur approximately 15 to 17 months from first patient enrolled (FPI), depending on PFS 
HR assumptions.
The first analysis of overall survival (OS) will be performed at the time of the primary 
PFS analysis.  Another update for OS will be performed at approximately 12 months
after the primary PFS analysis.  The final OS analysis will be performed at approximately 
24 months after the primary PFS analysis or when ~50% OS events from 200 patients 
can be obtained, whichever occurs first.  The Sponsor may consider additional OS 


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6/Statistical Analysis Plan WO30085
updates beyond 24 months after primary PFS analysis if more mature OS data are 
requested by the Health Authority.
3.
STUDY CONDUCT
3.1
RANDOMIZATION ISSUES
Eligible patients will be randomized in a 1:2 ratio to either the trastuzumab emtansine 
plus placebo arm or the trastuzumab emtansine plus atezolizumab arm. A permuted 
block randomization scheme will be used to achieve balance in treatment assignment 
within the two treatment arms with respect to the following stratification factors:

PD-L1 Status (PD-L1 IC 0 vs. IC 1/2/3)

World Region (Western Europe vs U.S. vs. Rest of World)

Liver Metastases (Yes vs. No)
3.2
DATA MONITORING
An independent Data Monitoring Committee (iDMC) composed of a group of 
independent experts external to the Sponsor, with the aid of an independent Data 
Coordinating Center (iDCC), will monitor patient safety data in an unblinded fashion 
during the course of the study. Details of the committee’s composition, meeting 
timelines, and the members’ roles and responsibilities are specified in the iDMC Charter.
4.
STATISTICAL METHODS
The analyses outlined in this SAP supersede those specified in the protocol.
4.1
ANALYSIS POPULATIONS
4.1.1
Intention-to-Treat Population
The intention-to-treat (ITT) population includes all patients who are randomized to the 
study, whether or not they receive any study drug. Patients will be grouped according to 
the treatment assigned at randomization by the IxRS. The ITT population is the analysis 
population for all efficacy endpoints.
4.1.2
Safety Population
The safety analysis population includes all randomized patients who receive at least one 
full or partial dose of study drug, with patients grouped according to the treatment
received. Patients who received any amount of atezolizumab will be included in the 
atezolizumab treatment arm; all other treated patients will be included in the control arm.
4.2
ANALYSIS OF STUDY CONDUCT
Patient enrollment, duration of follow-up, discontinuation from treatment and from study, 
and discontinuation reasons will be descriptively summarized by treatment arm.  In 
addition, protocol violations will be summarized by treatment arm.


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4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
The evaluation of treatment arm comparability will include summaries of demographics, 
breast cancer (BC) history, baseline disease characteristics, patient treatment history, 
and a summary of randomization stratification factors.
Descriptive statistics (mean, median, SD, 25th percentile, 75th percentile, and range) will 
be presented by treatment arm for continuous variables such as age or time since initial 
BC 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 drug.
4.4
EFFICACY ANALYSIS
All efficacy analyses will be performed based on the ITT population.
4.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint for this study is PFS based on investigator tumor
assessment per RECIST v1.1.
Progression-free survival is defined as the time from randomization to first documented 
disease progression as determined by the investigator using RECIST v1.1 or death from 
any cause, whichever occurs earlier.  Data for patients without disease progression or 
death from any cause as of the data cutoff 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, will be censored at the time of randomization plus 
one 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.  When disease progression or death occurs after two or 
more consecutive missed (or “unevaluable”) tumor assessments, these events will not 
be counted; rather, the patient will be censored at the patient’s last tumor assessment 
prior to the first missing (or “unevaluable”) assessment.  If disease progression or death 
occurs after one missed (or “unevaluable”) tumor assessment, the event will be counted 
at the respective event date.
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 world region 
(Western Europe vs U.S. vs Rest of World) and PD-L1 status (IC 0 vs IC 1/2/3), based 
on data collected by the IxRS, will be used to compare PFS between treatment arms at 
the overall two-sided significance level of 5%. Liver metastases will be excluded 
because of the potential that some of the strata may have very few patients, which would 
result in a loss of power. Results from an unstratified analysis and a stratified analysis 
with stratification factors collected on the electronic Case Report Form (eCRF) will also 
be provided. The Cox proportional hazards model, stratified by the previous noted 


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8/Statistical Analysis Plan WO30085
stratification factors, excluding liver metastases, will be used to estimate the HR and to 
calculate the 95% CI of the HR.
4.4.2
Secondary Efficacy Endpoints
4.4.2.1
Overall Survival
Overall survival is defined as the time from randomization to the date of death from any 
cause.  Patients who are alive as of the data cutoff date for 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 Kaplan-Meier method will be 
used to estimate median OS and the corresponding 95% CIs for each treatment arm.  
The 2-sided log-rank test, stratified by world region (Western Europe vs U.S. vs Rest of 
World) and PD-L1 status (IC 0 vs IC 1/2/3), will be used to compare OS between 
treatment arms.  The unstratified log-rank test result will also be provided.  The Cox
proportional hazards model, stratified by the previous noted stratification factors, 
excluding liver metastases, will be used to estimate the HR and to calculate the 95% CI
of the HR.
4.4.2.2
Objective Response
Objective response, defined as a complete response (CR) or partial response (PR), will 
be determined by investigator tumor assessment using RECIST v1.1. Only patients with 
measurable disease at baseline will be included in the analysis of objective response. 
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.  Objective responses must be confirmed at least 28 days
after the initial documentation of response.  An estimate of the ORR and its 95% CI
(Blyth-Still-Casella) will be calculated for each treatment arm.  The 
Cochran-Mantel-Haenszel Chi-squared test stratified by world region (Western Europe 
vs U.S. vs Rest of World) and PD-L1 status (IC 0 vs IC 1/2/3) 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.
4.4.2.3
Duration of Response
Only patients with an objective response will be included in the analysis of duration of 
response (DOR).  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.  The Kaplan-Meier approach will be used to estimate the median DOR and 
the corresponding 95% CIs for each treatment arm. The stratified Cox proportional 
hazards model, stratified by world region (Western Europe vs U.S. vs Rest of World) and 
PD-L1 status (IC 0 vs IC 1/2/3), will be used to estimate the HR and to calculate the 95% 
CI of the HR.  Because of the non-randomized nature of the subgroup of patients who 
achieve an objective response, the analysis of DOR will be considered descriptive.


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4.4.3
Exploratory Efficacy Endpoints
The exploratory efficacy endpoints will be evaluated at time of primary efficacy analysis.
4.4.3.1
Progression-Free Survival Assessed in the PD-L1 Selected 
Subgroup
Progression-free survival, 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 earlier, in the PD-L1 selected subgroup of 
patients defined as having tumor immune infiltrating cell expression of IC 1/2/3, as 
assessed by immunohistochemistry (IHC). The analysis methods are similar to those 
described for the primary efficacy endpoint.
4.4.3.2
Progression-Free Survival Assessed Using Immune-Modified 
RECIST
Progression-free survival, defined as the time from randomization to first occurrence of 
disease progression, will be determined by investigator assessment using 
immune-modified RECIST or death from any cause, whichever occurs earlier.  The 
analysis methods are similar to those described for the primary efficacy endpoint.
4.4.3.3
Objective Response Based on Immune-Modified RECIST
Objective response, defined as a CR or PR, will be determined by investigator tumor 
assessment using immune-modified RECIST.  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.  
The analysis methods are similar to those described for the secondary efficacy endpoint
ORR.
4.4.3.4
Duration of Response Based on Immune-Modified RECIST
Duration of response, defined as the time from first occurrence of a documented 
objective response (PR or CR) to disease progression, will be determined by investigator 
tumor assessment using immune-modified RECIST, or death from any cause, whichever 
occurs first.  The analysis methods are similar to those described for the secondary
efficacy endpoint DOR.
4.4.3.5
One-Year Survival Rate
Kaplan-Meier methodology will be used to estimate one-year survival rates and 95% CIs
for each treatment arm.  Also, differences in one-year survival rates between treatment 
arms will be calculated together with 95% CIs. The p-value and the 95% CI will be 
computed using Greenwood’s estimate of the standard error.


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4.4.4
Sensitivity Analyses
Censoring for non-protocol therapy
Non-protocol therapy (NPT) is defined as any anti-cancer therapy other than study 
treatment the patient receives that is intended to treat his or her metastatic breast cancer
(MBC) prior to documented disease progression. The impact of NPT on the primary 
endpoint of investigator-assessed PFS by RECIST v1.1 will be evaluated.  A sensitivity 
analysis will be performed in which data for patients who received NPT will be censored 
at the last tumor assessment date before the patient received NPT.
Missed Tumor Assessments
A sensitivity analysis will be performed on the primary endpoint of PFS. Specifically, if a 
patient has a documented progression after two or more missing or unevaluable 
assessments, the patient’s progression event will still be recorded as an event at the 
documented progression date.
Additional sensitivity analyses may be considered if appropriate.
4.4.5
Subgroup Analyses
In order to assess the consistency of treatment benefit with respect to the primary 
efficacy endpoint PFS across important subgroups, forest plots (including estimated HRs) 
will be provided for the following variables: 

Race

Age (65 years and 65 years)

World region

Baseline PD-L1 expression

Liver metastases

Eastern Cooperative Oncology Group (ECOG) status

Hormone receptor status

Visceral disease

The number of lines of prior therapy for locally advanced or metastatic disease.
Visceral disease is defined as the presence of disease in the lung, liver, adrenal gland, 
central nervous system, pleural cavity or peritoneal cavity. Additional variables may be 
considered if necessary.  A multivariate Cox regression analysis will be performed on the 
primary efficacy endpoint of investigator-assessed PFS controlling for important baseline 
characteristics.
4.5
PHARMACOKINETIC ANALYSES
The pharmacokinetic (PK) analyses will include patients with at least one post-dose PK 
assessment. Individual serum atezolizumab, trastuzumab emtansine, total trastuzumab 
levels and plasma DM1 concentrations versus time will be tabulated and summarized by 
treatment arm and study visit day.  Descriptive statistics will include mean, median, 


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range, SD, coefficient of variation (CV%), geometric mean, and geometric mean
coefficient of variation (CVb%) as appropriate.  The pharmacokinetics of atezolizumab in 
the presence of trastuzumab emtansine will be assessed. The pharmacokinetics of 
trastuzumab emtansine in the presence and absence of atezolizumab will be assessed 
and compared.
Additional exploratory PK/PD analyses may be conducted if deemed appropriate.
4.6
IMMUNOGENICITY ANALYSES
The immunogenicity analyses will be conducted for both trastuzumab emtansine and 
atezolizumab, and include patients with at least one predose and one post-dose 
anti-therapeutic antibody (ATA) assessment, with patients grouped according to 
treatment received.  The numbers and proportions of ATA-positive patients and 
ATA-negative patients during both the treatment and follow-up periods will be 
summarized by treatment group.  Patients are considered to be ATA-positive if they are 
ATA-negative at baseline but develop an ATA response following study drug 
administration (treatment-induced ATA response), or if they are ATA-positive at baseline 
and the titer of one or more post-baseline samples is at least four-fold greater 
(i.e.,0.60 titer units) than the titer of the baseline sample (treatment-enhanced ATA 
response).  Patients are considered to be ATA-negative if they are ATA-negative at 
baseline and all post-baseline samples are negative, or if they are ATA-positive at 
baseline but do not have any post-baseline samples with a titer that is at least four-fold 
greater than the titer of the baseline sample (treatment unaffected).
The relationship of the immunogenicity response with pharmacokinetics, safety, and 
efficacy may also be evaluated if appropriate.
4.7
BIOMARKER ANALYSES
Baseline biomarker expression levels will be summarized by treatment arm. Descriptive 
statistics (mean, median, SD and range) will be presented for continuous biomarker data. 
Frequency counts will be presented for categorical biomarker data.
Exploratory biomarker analyses will be performed in an effort to understand the 
association with study drug response, including efficacy. Due to the availability of 
samples, only biomarkers in tumor tissue samples will be analyzed at the time of primary 
analysis, including:

PD-L1 IHC status

HER2 expression level

CD8/PanCK IHC expression

Immune or cancer-related gene signatures

PIK3CA mutation status

Tumor mutational burden (TMB)


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4.8
SAFETY ANALYSES
Safety analyses will be performed based on the safety analysis population.
4.8.1
Exposure to Study Drug
The number of patients who experience any dose modification (including dose delay, 
dose reduction and dose interruption) or dose discontinuation will be summarized for 
each of the treatment arm regimens.  In addition, the number of patients that discontinue 
from trastuzumab emtansine and/or atezolizumab/placebo because of toxicity will be 
summarized.
Descriptive statistics will be presented for total cumulative dose, number of cycles, dose 
intensity, and weeks of exposure for trastuzumab emtansine, and atezolizumab.
4.8.2
Adverse Events
Verbatim descriptions of adverse events (AEs) will be mapped to Medical Dictionary for 
Regulatory Activities (MedDRA) thesaurus terms and graded according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03.  
The following events occurring on or after the first dose of study drug (i.e., 
treatment-emergent AEs) will be summarized by NCI CTCAE v4.03 grade:

All AEs

Serious adverse events

AEs leading to death

AEs leading to study drug discontinuation

AEs leading to dose reduction and interruption
For events of varying severity, the highest grade will be used in the summaries.
Deaths and causes of death will be summarized.  Selected AEs will be summarized by 
NCI CTCAE v4.03 grade for each treatment arm based on pre-specified category 
definitions, including (but not limited to) hepatotoxicity, cardiac dysfunction, 
thrombocytopenia, infusion-related reactions/hypersensitivity, pulmonary toxicity, 
peripheral neuropathy, hemorrhage, and immune-related AEs associated with 
atezolizumab, including but not limited to hepatitis (diagnosis and laboratory abnormal), 
hypothyroidism, hyperthyroidism, adrenal insufficiency, pneumonitis, colitis, 
Guillain-Barré syndrome, myasthenia gravis, meningoencephalitis, pancreatitis, diabetes 
mellitus, myositis, nephritis, rash, rhabdomyolysis, systemic immune activation, 
meningitis, encephalitis, ocular inflammatory toxicity, vasculitis, hypophysitis, myocarditis, 
severe cutaneous reaction and hemolytic anemia.  Additional analyses may be 
performed as indicated.


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4.8.3
Laboratory Data
For laboratory parameters, descriptive summary tables of change from baseline over 
time based on System International (SI) units will be produced.  Summary tables for
laboratory abnormality and the shifts in NCI CTCAE v4.03 grades from baseline to the 
worst post-baseline value will be presented.
A Hy’s law analysis will be provided.  The potential Hy’s law quadrant is defined as ALT 
or AST increases above 3-fold the upper limit of normal (ULN) with concomitant total 
bilirubin increases above 2-fold the ULN.
4.8.4
Vital Signs
Vital signs will be summarized descriptively over time including change from baseline.
4.8.5
Left Ventricular Ejection Fraction Assessments 
The number of patients with a drop in Left Ventricular Ejection Fraction (LVEF) of10 
ejection fraction points from baseline to a LVEF50% will be summarized.  The 
maximum decrease in LVEF from baseline will be summarized by treatment arm.  In 
addition, the lowest available ejection fraction 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.
4.9
MISSING DATA
For the analyses of PFS and DOR, data for patients without disease progression or 
death from any cause as of the data cutoff 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, will be censored at the time of randomization plus 
one day).  Data from patients who are lost to follow-up will be included in the analyses 
as censored observations on the date of the last tumor assessment that the patient was 
known to be progression-free.  When disease progression or death occurs after two or 
more consecutive missed (or “unevaluable”) tumor assessments, these events will not 
be counted; rather, the patient will be censored at the patient’s last tumor assessment 
prior to the first missing (or “unevaluable”) assessment. If disease progression or death 
occurs after one missed (or “unevaluable”) tumor assessment, the event will be counted 
at the respective event date.
For the analysis of OS, patients who are alive as of the data cutoff date for 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.
For the analysis of ORR, patients without a post-baseline tumor assessment will be 
considered non-responders.


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4.10
INTERIM ANALYSES
There is no planned interim efficacy analysis for PFS.


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Appendix 1
Protocol Synopsis
TITLE:
A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, 
PLACEBO-CONTROLLED PHASE II STUDY OF THE EFFICACY 
AND SAFETY OF TRASTUZUMAB EMTANSINE IN COMBINATION 
WITH ATEZOLIZUMAB OR ATEZOLIZUMAB-PLACEBO IN 
PATIENTS WITH HER2-POSITIVE LOCALLY ADVANCED OR 
METASTATIC BREAST CANCER WHO HAVE RECEIVED PRIOR 
TRASTUZUMAB AND TAXANE BASED THERAPY
PROTOCOL NUMBER:
WO30085
VERSION NUMBER:
3
EUDRACT NUMBER:
2015-004189-27
IND NUMBER:
71,072
TEST PRODUCT:
Trastuzumab Emtansine (RO5304020)
Atezolizumab (RO5541267)
PHASE:
Phase II
INDICATION:
Locally advanced or metastatic breast cancer
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy, safety, and pharmacokinetics of trastuzumab emtansine 
in combination with atezolizumab or placebo (atezolizumab-placebo) in patients with human 
epidermal growth factor 2 (HER2)-positive, locally advanced or metastatic breast cancer (MBC), 
who have received prior trastuzumab and taxane based therapy, either alone or in combination, 
and/or who have progressed within 6 months after completing adjuvant therapy.  Specific 
objectives and corresponding endpoints for the study are outlined below.
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of the combination of 
trastuzumab emtansine plus atezolizumab compared with trastuzumab emtansine plus placebo 
on the basis of the following endpoint:

Progression-free survival (PFS), defined as the time from randomization to the first 
occurrence of disease progression, as determined by investigator assessment using
RECIST v1.1, or death from any cause, whichever occurs first
Secondary Efficacy Objective
The secondary efficacy objectives for this study are to evaluate the efficacy of the combination 
of trastuzumab emtansine plus atezolizumab compared with trastuzumab emtansine plus 
placebo on the basis of the following endpoints:

Overall survival (OS), defined as the time from randomization to death from any cause

Objective response, 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 Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1


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
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
Exploratory Efficacy Objective
The exploratory efficacy objectives for this study are to evaluate the efficacy of the combination 
of trastuzumab emtansine plus atezolizumab compared with trastuzumab emtansine plus 
placebo on the basis of the following endpoints:

PFS, defined as the time from randomization to the first occurrence of disease progression, 
as determined by investigator assessment using RECIST v1.1 or death from any cause, 
whichever occurs first, in the programmed deathligand 1 (PD-L1) selected subgroup of 
patients defined as having tumor immune infiltrating cell (IC) expression of IC 1/2/3, as 
assessed by immunohistochemistry

PFS, defined as the time from randomization to the first occurrence of disease progression, 
as determined by investigator assessment using immune-modified RECIST or death from 
any cause, whichever occurs first

Objective response, defined as a CR or PR on two consecutive assessments, at least 
28 days apart, as determined by investigator assessment using immune modified RECIST

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 
immune-modified RECIST or death from any cause, whichever occurs first

1-year survival rate
Safety Objective
The primary safety objectives for this study are to evaluate the overall safety of trastuzumab 
emtansine in combination with atezolizumab compared with trastuzumab emtansine in 
combination with placebo on the basis of the following: 

Nature, frequency, severity, and timing of adverse events including cardiac, hepatic and 
pulmonary events

Clinical laboratory results during and following trastuzumab emtansine and atezolizumab 
administration
Pharmacokinetic Objective
The secondary pharmacokinetic (PK) objectives for this study are:

To characterize the pharmacokinetics of atezolizumab in the presence of trastuzumab 
emtansine

To characterize the pharmacokinetics of trastuzumab emtansine in the presence and 
absence of atezolizumab
Immunogenicity Objective
The secondary immunogenicity objectives for this study are:

To characterize the incidence of anti-therapeutic antibody (ATA) to atezolizumab in the 
presence of trastuzumab emtansine 

To characterize the incidence of ATA to trastuzumab emtansine in the presence and 
absence of atezolizumab
The exploratory immunogenicity objectives for this study are as follows:

To evaluate the relationship between ATA status, efficacy, safety, and/or pharmacokinetics
Biomarker Objective

To assess if baseline PD-L1 expression is associated with efficacy

To assess if baseline immune status is associated with efficacy 

To assess if baseline immune status together with HER2 expression level (mRNA, protein 
and/or gene copy number/ratio) are associated with efficacy

To assess changes in expression levels of biomarkers or biomarker panels during and after 
investigational treatment with atezolizumab in combination with trastuzumab emtansine


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
To evaluate the relationship between tumor biomarkers and efficacy

To identify candidate biomarkers that correlate with safety signals 
Study Design
Description of Study
This is a Phase II, randomized, multicenter, international, two-arm, double-blind, 
placebo-controlled clinical trial designed to compare the efficacy and safety of trastuzumab 
emtansine in combination with either atezolizumab or placebo for patients with HER2-positive 
locally advanced or MBC who have received prior trastuzumab and taxane based therapy.
Approximately 200 patients will be enrolled in the study at 100 sites worldwide.  Patients will be 
randomized to treatment arms A and B in a 1:2 ratio by means of a permuted block
randomization scheme through the use of an interactive Web or voice response system.  
Randomization will be stratified according to 1) PD-L1 status (IC0 vs IC1/2/3), 2) World Region 
(Western Europe vs U.S. vs Rest of World) and 3) Presence of liver metastases (yes vs. no).  
Patients will be treated in one of the following arms:

Arm A: trastuzumab emtansine 3.6 mg/kg and placebo, every 3 weeks (q3w) 
(approximately 67 patients)

Arm B: trastuzumab emtansine 3.6 mg/kg and atezolizumab 1200 mg, q3w (approximately 
133 patients)
Arm A and Arm B will be blinded with respect to administration of atezolizumab or placebo.  
Cross-over between treatment arms will not be permitted.
Number of Patients
Approximately 200 patients will be enrolled in the study and randomized to treatment arms A 
and B in a 1:2 ratio (approximately 67 patients in Arm A and 133 patients in Arm B).
Target Population
Inclusion Criteria
Patients must meet ALL of the following inclusion criteria to be eligible for study entry:

Age 18 years.

Signed written informed consent approved by the institution’s Independent Ethical 
Committee/Institutional Review Board. 

Archival tumor samples must be obtained from primary and/or metastatic sites. 
Representative FFPE tumor specimens in paraffin blocks for central testing is required.  
Different material as described in Appendix 3 may be accepted in exceptional cases.  
Tumor tissue should be of good quality based on total and viable tumor content and must 
be evaluated for HER2 and PD-L1 expression prior to enrollment.

Patients must submit tumor tissue that is evaluable for PD-L1 expression to be eligible for 
this study.  If multiple tumor specimens are submitted (e.g., an archival specimen [from 
initial BC diagnosis] and tissue from metastatic or locally advanced breast cancer [LABC] 
disease), patients may be eligible if at least one specimen is evaluable for PD-L1. 
For the purpose of stratification, the PD-L1 score of the patient will be the maximum 
PD-L1 score among the samples.  Tumor tissue from bone metastases is not 
evaluable for PD-L1 expression and is therefore not acceptable. 
Patients who do not have tissue specimens that meet eligibility requirements may 
undergo a biopsy during the screening period.  Acceptable samples include core 
needle biopsies for deep tumor tissue (minimum three cores) or excisional, incisional, 
punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions.  
Fine-needle aspiration, brushing, cell pellet from pleural effusion, bone metastases, 
and lavage samples are not acceptable.

HER2-positive breast cancer (BC) as defined by an immunohistochemistry (IHC) score of 
3 or gene amplified by in situ hybridization (ISH) as defined by a ratio of 2.0 for the 
number of HER2 gene copies to the number of chromosome 17 copies, prospectively 
tested by a Sponsor- designated central laboratory prior to enrollment.  Both IHC and ISH 
assays will be performed; however, only one positive result is required for eligibility. 


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If multiple tumor specimens are submitted, the HER2 IHC score and or ISH amplification 
ratio will first be assessed on the archival specimen for the purpose of determining 
eligibility.  For patients with bilateral BC, HER2 positivity must be demonstrated in both 
locations for archival tissue or in a metastatic biopsy.
Centrally confirmed HER2 results (either IHC or ISH) from a current or previous Sponsor 
study can be used to determine eligibility for this study.  Approval must be obtained from 
the Medical Monitor prior to randomization. 
Progression must have occurred during or after most recent treatment for LABC or MBC 
or within 6 months after completing adjuvant therapy.

Histologically or cytologically confirmed invasive BC: incurable, unresectable, locally 
advanced BC previously treated with multimodality therapy or MBC.

Prior treatment for BC in the: adjuvant; unresectable locally advanced; or metastatic 
settings; which must include both, a taxane and trastuzumab (alone or in combination with 
another agent) 

Progression must have occurred during or after most recent treatment for LABC/MBC or 
within 6 months after completing adjuvant therapy.

Patients must have measurable disease that is evaluable per RECIST 1.1. 

Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. 

Adequate hematologic and end-organ function, as evidenced by the following local 
laboratory results obtained within 7 days prior to the first study treatment (Cycle 1, Day 1):
Absolute neutrophil count 1500 cells/L (without granulocyte-colony stimulating factor 
[support) within 7 days prior to Cycle 1, Day 1
Platelet count 100,000/L (without transfusion within 7 days prior to Cycle 1, Day 1)
Hemoglobin 9.0 g/dL
Patients may be transfused or receive erythropoietic treatment to meet this 
criterion.
Albumin 2.5g/dL
AST, ALT, and alkaline phosphatase 2.5 the upper limit of normal (ULN) with the 
following exceptions:
Patients with documented bone metastases: alkaline phosphatase 5 the ULN
Total bilirubin 1.5 the ULN
INR and aPTT 1.5 the ULN
This applies only to patients who are not receiving therapeutic anticoagulation; 
patients receiving therapeutic anticoagulation should be on a stable dose.
Calculated creatinine clearance 30 mL/min

Negative serum pregnancy test within 7 days of enrollment for pre-menopausal women and 
for women less than 12 months after the onset of menopause.

For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate of 1% 
per year during the treatment period and for at least 7 months after the last dose of 
trastuzumab emtansine, or 5 months after the last dose of atezolizumab/placebo, whichever 
is later.
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).
Examples of contraceptive methods with a failure rate of 1% per year include bilateral 
tubal ligation, male sterilization, established, proper use of hormonal contraceptives 
that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 


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(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.

For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential, men must remain abstinent or use a 
condom plus an additional contraceptive method that together result in a failure rate 
of 1% per year during the treatment period and for at least 7 months after the last 
dose trastuzumab emtansine.  Men must refrain from donating sperm during this same 
period.
With pregnant female partners, men must remain abstinent or use a condom during 
the treatment period and for at least 7 months after the last dose of trastuzumab 
emtansine 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.
Exclusion Criteria
Patients who meet any ONE of the following criteria will be excluded from study entry:

Prior treatment with trastuzumab emtansine, CD137 agonists, anti- programmed death1 
(PD-1), or anti-PD-L1 therapeutic antibody or pathwaytargeting agents.

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.

Radiation therapy within 2 weeks prior to Cycle 1, Day 1
The patient must have recovered from any resulting acute toxicity (to Grade 1) prior 
to randomization. 

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.  

History of other malignancy within the previous 5 years, except for appropriately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or 
patients who have undergone potentially curative therapy with no evidence of disease and 
are deemed by the treating physician to be at low risk for recurrence.

Cardiopulmonary dysfunction as defined by:
Uncontrolled hypertension (systolic 150 mm Hg and/or diastolic 100 mm Hg)
Inadequate left ventricular ejection function at baseline, 50% by either ECHO or 
MUGA
History of symptomatic congestive heart failure (CHF)-Grade 3 per National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 
or Class II New York Health Association 
History of a decrease in left ventricular ejection function to 40% or symptomatic CHF 
with prior trastuzumab treatment
Myocardial infarction or unstable angina within 6 months of randomization 
Current dyspnoea at rest due to complications of advanced malignancy, or other 
disease requiring continuous oxygen therapy
Serious cardiac arrhythmia not controlled by adequate medication


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
Patients with severe infection within 4 weeks prior to randomization, including but not 
limited to hospitalization for complications of infection, bacteremia, or severe pneumonia.

Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, 
pulmonary or metabolic disease; wound healing disorders; ulcers; bone fractures). 

Major surgical procedure or significant traumatic injury within 28 days prior to randomization 
or anticipation of the need for major surgery during the course of study treatment.

Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, 
autoimmune hepatic disorders, sclerosis cholangitis or active infection with HIV, hepatitis B 
virus (HBV), or hepatitis C virus (HCV)
Active infection is defined as requiring treatment with antiviral therapy or presence of 
positive test results for hepatitis B (hepatitis B surface antigen and/or total hepatitis B 
core antibody) or HCV antibody.  HIV, HBV, or HCV assessments are required at 
screening. 
Patients who test positive for hepatitis B core antibody are eligible only if test results 
are also positive for hepatitis B surface antibody and polymerase chain reaction is 
negative for HBV DNA.
Patients who are positive for HCV serology are only eligible if testing for HCV RNA is 
negative.

Need for current chronic corticosteroid therapy (10 mg of prednisone per day or an 
equivalent dose of other anti-inflammatory corticosteroids)
Stable use (i.e., no change in dose within 3 months prior to Cycle 1, Day 1) of inhaled
corticosteroids is allowed.

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.

Patients with known central nervous system (CNS) disease are not eligible, except for 
treated asymptomatic CNS metastases, provided that all of the following criteria are met:
Only supratentorial and cerebellar metastases allowed (i.e., no metastases to midbrain, 
pons, medulla, or spinal cord)
No ongoing requirement for corticosteroids as therapy for CNS disease 
No stereotactic radiation within 14 days prior to randomization
No evidence of interim progression between the completion of CNS-directed therapy 
and the screening radiographic study

Note: Patients with new asymptomatic CNS metastases detected at the screening scan 
must receive radiation therapy and/or surgery for CNS metastases.  Following treatment, 
these patients may be eligible without the need for an additional brain scan prior to 
enrollment, if all other criteria are met.

Leptomeningeal disease

Symptomatic pleural effusion, pericardial effusion, or ascites. 

Uncontrolled hypercalcemia (1.5 mmol/L ionized calcium or calcium 12 mg/dL or 
corrected serum calcium greater than the ULN) or symptomatic hypercalcemia requiring 
continued use of bisphosphonate therapy. 
Patients who are receiving denosumab must discontinue use of denosumab and 
replace it with a bisphosphonate instead while on study.
Patients who are receiving bisphosphonate therapy specifically to prevent skeletal 
events and who do not have a history of clinically significant hypercalcemia are 
eligible.

Current Grade 3 peripheral neuropathy (according to the NCI CTCAE v4.0).

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.


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
History of autoimmune disease, including, but not limited to, myasthenia gravis, 
autoimmune myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid 
arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid 
syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, multiple 
sclerosis, vasculitis, or glomerulonephritis. 
Patients with a history of autoimmune-related hypothyroidism on a stable dose of
thyroid replacement hormone may be eligible for this study.
History of inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis) or 
active bowel inflammation (e.g., diverticulitis).
Patients with Type 1 diabetes mellitus will not be eligible unless controlled with the 
patient on a stable insulin regimen
Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis would be excluded) are 
excluded unless they meet the following conditions:
Rash must cover 10% of body surface area.
Disease is well controlled at baseline and requiring only low-potency topical 
steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, 
flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%)
No acute exacerbations of underlying condition within the last 12 months 
(not requiring psoralen plus ultraviolet.  A radiation, methotrexate, retinoids, 
biologic agents, oral calcineurin inhibitors, or high-potency or oral steroids)
Patients with psoriasis must have a baseline ophthalmologic exam to rule out 
ocular manifestations.

Prior allogeneic stem cell or solid organ transplantation.

History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, 
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or 
evidence of active pneumonitis on screening chest computed tomography scan.
Patients with a history of radiation pneumonitis in the radiation field (fibrosis) are 
eligible.

Active tuberculosis.

Receipt of a live, attenuated vaccine within 4 weeks prior to randomization or anticipation 
that such a live, attenuated vaccine will be required during the study.

Treatment with systemic immunostimulatory agents (including, but not limited to, interferons 
or IL-2) within 4 weeks or five half-lives of the drug (whichever is shorter) prior to 
randomization.

Treatment with systemic corticosteroids or other systemic immunosuppressive medications 
(including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, 
methotrexate, thalidomide, and anti-tumor necrosis factor agents) within 2 weeks prior to 
randomization, or anticipated requirement for systemic immunosuppressive medications 
during the trial.
Patients who need current chronic corticosteroid therapy (10 mg of prednisone per 
day or an equivalent dose of other anti-inflammatory corticosteroids) will be excluded
Patients who have received acute, lowdose, systemic immunosuppressant 
medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled in 
the study.
Stable use (i.e., no change in dose within 3 months prior to Cycle 1, Day 1) of inhaled 
corticosteroids is allowed

Breastfeeding, or intending to become pregnant during the study
End of Study
The end of study is triggered by the final OS analysis following last patient last visit that is 
planned to occur approximately 24 months after the primary efficacy analysis or at 
approximately 50% OS events from 200 patients can be obtained, whichever occurs first.  
The Sponsor may consider additional OS update(s) beyond 24 months after primary PFS 


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22/Statistical Analysis Plan WO30085
analysis if more mature OS data are requested by the Health Authority.  The Sponsor may 
also terminate the study at any time.
Length of Study
The total duration of the study is expected to be approximately 40 months.
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 intravenous (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 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.  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.
Patients will receive 1200 mg of atezolizumab/placebo administered by IV infusion q3w.  
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.  
All the study drugs are to be administered to patients intravenously.  Atezolizumab or placebo 
will be administered first, followed by trastuzumab emtansine.  
Statistical Methods
Primary Efficacy Analysis
The primary efficacy endpoint for this study is PFS based on investigator tumor assessment.  
The intention-to-treat (ITT) population is the primary analysis population for the primary efficacy 
endpoint 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.
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.  When disease progression or 
death occurs after two or more consecutive missed (or “unevaluable”) tumor assessments, 
these events will not be counted; rather, the patient will be censored at the patient’s last tumor 
assessment prior to the first missing (or “unevaluable”) assessment.  If disease progression or 
death occurs after one missed (or “unevaluable”) tumor assessment, the event will be counted 
at the respective event date.
The Kaplan-Meier method will be used to estimate median PFS and the corresponding 
95% confidence intervals (CIs) for each treatment arm.  The 2-sided log-rank test, stratified 
by the factors specified in the protocol (excluding liver metastases), will be used to compare 
PFS between the treatment arms at the overall two-sided significance level of 5%.  Liver 
metastases will be excluded because of the potential that some of the strata may have very few 
patients, which would result in a loss of power.  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 


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23/Statistical Analysis Plan WO30085
the previous noted stratification factors, excluding liver metastases, will be used to estimate 
the HR and to calculate the 95% CI of the HR.
The primary PFS analysis will be performed when approximately 115 investigator-assessed 
PFS events have been observed and is anticipated to occur approximately 15 to 17 months 
from first patient enrolled (FPI), depending on PFS HR assumptions.  
Several sensitivity analyses will be performed to assess the robustness of the primary efficacy 
analysis, see the SAP for details.  
In order to assess the consistency of treatment benefit with respect to the primary efficacy 
endpoint PFS 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 PD-L1 expression, ECOG status and hormone receptor status.  A multivariate Cox 
regression analysis will be performed on the primary efficacy endpoint of investigator-assessed 
PFS controlling for important baseline characteristics. 
Secondary Efficacy Analysis
The ITT population will be the analysis population used for evaluation of the secondary efficacy 
endpoints.
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. 
The first analysis of OS will be performed at the time of the primary PFS analysis.  Another 
update for OS will be performed at approximately 12 months after the primary PFS analysis.  
The final OS analysis will be performed at approximately 24 months after the primary PFS 
analysis or when ~50% OS events from 200 patients can be obtained, whichever occurs first.  
The Sponsor may consider additional OS updates beyond 24 months after primary PFS 
analysis if more mature OS data are requested by the Health Authority. 
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 objective response 
rate (ORR) and its 95% CI (Blyth-Still-Casella) will be calculated for each treatment arm.  The 
Cochran-Mantel-Haenszel Chi-squared test stratified according to the factors specified in the 
protocol (excluding liver metastases) 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. 
Exploratory Efficacy Analysis
The exploratory efficacy endpoints will be evaluated at time of primary efficacy analysis.  The 
ITT population will be the analysis population used for evaluation of the exploratory efficacy 
endpoints.
PFS Assessed in the PD-L1 Selected Subgroup
The analysis methods are similar to those described for the primary efficacy endpoint.


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24/Statistical Analysis Plan WO30085
PFS Assessed Using Immune-Modified RECIST
PFS is defined as the time from randomization to first occurrence of disease progression as 
determined by investigator assessment using immune-modified RECIST or death from any 
cause, whichever occurs earlier.  Only patients who are clinically eligible for treatment beyond 
disease progression will be included in this analysis.  The analysis methods are similar to those 
described for the primary efficacy endpoint. 
Objective Response Rate based on Immune Modified RECIST
Objective response, defined as a complete response (CR) or partial response (PR), will be 
determined by investigator tumor assessment using immune-modified RECIST.  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 (Blyth-Still-Casella) will be calculated for each treatment 
arm.  The Cochran-Mantel-Haenszel Chi-squared test stratified according to the factors 
specified in the protocol (excluding liver metastases) 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 based on Immune-Modified RECIST
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 
immune-modified RECIST, or death from any cause, whichever occurs first. The analysis 
methods are similar to those described for the primary efficacy endpoint PFS. 
1-Year Survival Rate
Kaplan-Meier methodology will be used to estimate 1-year survival rates and 95% CIs for each 
treatment arm.  Also, differences in 1-year survival rates between treatment arms will be 
calculated together with 95% CIs.
Safety Analysis
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.
Study Drug Exposure 
The number of patients who experience any dose modification (including dose delay, dose 
reduction and dose interruption), or dose discontinuation, and reasons for study treatment 
discontinuation will be summarized for each of the treatment arm regimens.  In addition, the 
number of patients that discontinue from trastuzumab emtansine-containing and/or 
atezolizumab-containing treatment because of toxicity and/or receive other non-protocol 
anti-cancer therapy will be summarized.  
Descriptive statistics will be presented for total cumulative dose, number of cycles, dose 
intensity, infusion time by cycle, and weeks of exposure for trastuzumab emtansine, and 
atezolizumab.
Adverse Events 
Safety will be assessed through summaries of adverse events, changes in laboratory test 
results, changes in vital signs, study treatment exposures, and immunogenicity as measured 
by ATA and will be presented by treatment arm.
Verbatim descriptions of adverse events will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms and graded according to the NCI CTCAE v4.0.  The 
following events occurring on or after the first dose of study drug (i.e., treatment-emergent 
adverse events) will be summarized by NCI CTCAE grade:

All adverse events

Serious adverse events

Adverse eventsleading to death

Adverse eventsleading to study drug discontinuation


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25/Statistical Analysis Plan WO30085

Adverse eventsleading to dose reduction

Sponsor-defined adverse events of special interest
For events of varying severity, the highest grade will be used in the summaries.
Deaths and causes of death will be summarized.  Selected adverse events will be summarized 
by NCI CTCAE grade for each treatment arm based on pre-specified category definitions, 
including (but not limited to) hepatotoxicity, cardiac dysfunction, and thrombocytopenia.  
In addition, adverse eventsoccurring within 1 day (24 hours) of the first dose of each treatment 
cycle will be summarized to help characterize potential infusion-related reactions.  
Additional safety analyses may be performed as indicated.
Laboratory Data 
For laboratory parameters, descriptive summary tables of change from baseline over time 
based on System International units will be produced.  Summary tables for the shifts in 
NCI CTCAE v4.0 grades from baseline to the worst grade observed during treatment will be 
presented.
Pharmacokinetic Analysis
The PK analyses will include patients with at least one post-dose PK assessment.
Individual serum atezolizumab, trastuzumab emtansine, total trastuzumab levels and plasma 
DM1 concentrations versus time will be tabulated and summarized by treatment arm and study 
visit day.  Descriptive statistics will include mean, medians range, standard deviation, coefficient 
of variation (CV%), geometric mean, and geometric mean coefficient of variation (CVb%) as 
appropriate.
Additional PK and PD analyses will be conducted as appropriate.
Immunogenicity Analysis
The immunogenicity analyses will include patients with at least one predose and one post-dose 
ATA assessment, with patients grouped according to treatment received.  The numbers and 
proportions of ATA-positive patients and ATA-negative patients during both the treatment and 
follow-up periods will be summarized by treatment group. Patients are considered to be ATA 
positive if they are ATA negative at baseline but develop an ATA response following study drug 
administration (treatment-induced ATA response), or if they are ATA positive at baseline and 
the titer of one or more post-baseline samples is at least 4-fold greater (i.e., 0.60 titer units) 
than the titer of the baseline sample (treatment-enhanced ATA response). Patients are 
considered to be ATA negative if they are ATA negative at baseline and all post-baseline 
samples are negative, or if they are ATA positive at baseline but do not have any post-baseline 
samples with a titer that is at least 4-fold greater than the titer of the baseline sample (treatment 
unaffected).
Biomarker Analysis
Descriptive statistics will be utilized for the analysis and reporting of the exploratory biomarker 
objectives.  This may include appropriate multivariate analyses. 
Determination of Sample Size
The primary efficacy endpoint for this study is PFS based on investigator tumor assessment.  
The primary PFS analysis will be performed when approamiately 115 PFS events have 
occurred.
With approximately 200 patients randomized according to a 1:2 randomization (approximately
67 patients will be randomized to Arm A and approximately 133 patients will be randomized to 
Arm B) the study has the estimated power for the PFS HRs.  The design considerations 
assumed proportional hazards, a cumulative dropout rate of 10% in each treatment arm and 
result in an estimated recruitment time of about 9 months (with ramp up in the first 4 months).  
The estimated time from FPI to primary PFS analysis is 15 to 17 months, depending on PFS 
HR assumption.  
Sample size and power calculations were performed using the East 6 software package 
(Cytel Inc.).
Interim Analyses
There is no planned interim efficacy analysis for PFS.


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26/Statistical Analysis Plan WO30085
Appendix 2
Schedule of Assessments
Assessment 
or Procedure
Screening 
Period
Treatment Period 
(Cycles 1 through Study Treatment Discontinuation)
Study Treatment 
Completion/Early
Discontinuation a
Follow-Up
(14 Days) b
Days 28
to 1
Day 1 
(3 Days)
Informed consent c
x
Demographics d
x
Medical history e
x
Central HER2 and PDL-1 testing f
x
Complete physical examination g
x
Limited physical examination h
x
x
ECOG performance status
x
x
x
Weight i
x
x h
Vital signs j
x
x i
Hematology k
(7 days prior to C1D1)
x
x
Serum chemistry l
(7 days prior to C1D1)
x k
x k
Thyroid function test (TSH, free 
T3, and free T4)
x
C1D1 and every 4th cycle
x
C-reactive protein
x
INR and aPTT
x
As clinically indicated
HIV, HCV, and HBV serology m
x
Urinalysis n
x
As clinically indicated
Pregnancy test o
x
x
x
x
Tumor and response assessmentp
x
x


Appendix 2
Schedule of Assessments (cont.)
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27/Statistical Analysis Plan WO30085
Assessment 
or Procedure
Screening 
Period
Treatment Period 
(Cycles 1 through Study Treatment Discontinuation)
Study Treatment 
Completion/Early
Discontinuation a
Follow-Up
(14 Days) b
Days 28
to 1
Day 1 
(3 Days)
Bone scan/PET q
x
Perform as clinically indicated or as scheduled 
tumor assessment if only bone involvement at 
baseline
CT or MRI of Brain r
Mandatory 
at screening
Perform as clinically indicated or as scheduled 
tumor assessment r
12-Lead electrocardiogram s
x
Perform as clinically indicated
NYHA classification
x
ECHO or MUGA scan t
x
x
Day 15–21 of Cycle 1, every fourth cycle thereafter. 
Additional LVEF measurements may be performed 
if LVEF declines are clinically suspected at the 
discretion of the investigator
x
If not performed 
within 6 weeks of 
this visit
Atezolizumab/placebo 
administration
x w
Trastuzumab emtansine 
administration
x x
PK/ATA
x (See Appendix 3) 
x
Blood Sample for Biomarker 
Analysis
x (See Appendix 4)
x
Sample for auto-antibodies u
x
Tissue Sample for Biomarker 
Analysis v
x (See Appendix 4)
x
Concomitant medications
x
x
x


Appendix 2
Schedule of Assessments (cont.)
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28/Statistical Analysis Plan WO30085
Assessment 
or Procedure
Screening 
Period
Treatment Period 
(Cycles 1 through Study Treatment Discontinuation)
Study Treatment 
Completion/Early
Discontinuation a
Follow-Up
(14 Days) b
Days 28
to 1
Day 1 
(3 Days)
Adverse events
x
x
x
x
Survival follow-up 
x b
Initiation of anti-cancer treatments
x b
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; 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. 
Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to enrollment may be 
used; such tests do not need to be repeated for screening.
a The treatment completion/discontinuation visit will optimally be scheduled for 2842 days after the last dose of study treatment.
b Patients will be followed for survival, serious adverse events and adverse events of special interest considered as related to study drug 
(Section 5.3.1) and subsequent anti-cancer therapies (not all concomitant medications) need to be reported approximately every 3 months 
starting from the Study Drug Completion Visit until death, loss to follow-up, withdrawal of consent, or study discontinuation by the Sponsors. 
Survival follow-up information will be collected every 3 months via telephone calls, patient medical records, and/or clinic visits.  Study staff may 
use a public information source (e.g., county records) to obtain information about survival status only. 
c Written informed consent must be obtained before any study-specific screening assessments are performed.
d Demographics include age, sex, and self-reported race/ethnicity.


Appendix 2
Schedule of Assessments (cont.)
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29/Statistical Analysis Plan WO30085
e Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), reproductive 
status, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, and nutritional supplements) used
by the patient within 7 days prior to the Cycle 1, Day 1 visit.  Breast cancer history includes prior cancer therapies and procedures.
f
Refer to Appendix 4 for tissue requirements related to eligibility.  HER2 and or PDL-1 status may be determined outside of the screening window 
of 28 days.
g A complete physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems.  Record abnormalities observed at baseline on the 
General Medical History and Baseline Conditions eCRF.  Record new or worsened clinically significant abnormalities on the Adverse Event 
eCRF.
h A limited physical examination consists of a symptom-driven physical examination that focuses on organ systems related to potential and 
ongoing adverse events and is based on the patient’s clinical course during study treatment, the patient’s medical history, and/or the known 
adverse event profiles of the study medications.  Record new or worsened clinically significant abnormalities 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. 
j
Vital signs include respiratory rate, pulse rate, and systolic and diastolic blood pressures while the patient is in a seated position, and 
temperature.  Vital signs should be obtained and reviewed before and after each study treatment administration but are not required to be 
reported on the eCRF during study treatment.  Record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
k Hematology includes CBC, with RBC count, hemoglobin, hematocrit, WBC count with differential (neutrophils, eosinophils, lymphocytes, 
monocytes, basophils, and other cells), and platelet count.  Screening laboratory tests are to be performed within 7 days prior 
to randomization. Screening laboratory assessments may be done on the day of randomization, and their results may be used for randomization 
visit purposes. Results must be reviewed and documented prior to administration of the first dose of study treatment.  Hematologic evaluations 
should be completed prior to dosing on Day 1 of each indicated cycle (or up to 3 days before).  
l
Serum chemistry includes glucose, BUN or urea, creatinine, sodium, potassium, magnesium, chloride, bicarbonate, calcium, phosphorus, total 
bilirubin, ALT, AST, alkaline phosphatase, total protein, and albumin.  Screening laboratory tests are to be performed within 7 days prior 
to randomization. Screening laboratory assessments may be done on the day of randomization, and their results may be used for randomization 
visit purposes. Results must be reviewed and documented prior to administration of the first dose of study treatment.  Chemistry evaluations 
should be completed prior to dosing on Day 1 of each indicated cycle (or up to 3 days before).
m All patients will be tested for HIV prior to the inclusion into the study; HIV-positive patients will be excluded from the study.  HBV DNA must be 
collected on or before Cycle 1, Day 1, in patients who have negative serology for hepatitis B surface antigen and positive serology for anti-HBc.  
n Urinalysis includes specific gravity, pH, glucose, protein, ketones, and blood.


Appendix 2
Schedule of Assessments (cont.)
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd
30/Statistical Analysis Plan WO30085
o All women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test within 7 days prior to 
enrollment.  During the treatment period, urine pregnancy test in women of childbearing potential in both treatment arms must be performed 
within 3 days prior study drug administration of every 3 cycles of protocol mandated therapy.  If a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test. For patients who discontinue therapy before end of planned therapy, a pregnancy test must be done at the 
completion/early termination visit (approximately 28−42 days after the last dose of HER2-targeted therapy), and at 3 months and for 
HER2-targeted therapy, additionally at 6 months after the discontinuation of study treatment. 
p Tumor assessments performed as standard of care prior to obtaining informed consent and within 28 days of Cycle 1, Day 1, may be used rather 
than repeating tests.  All measurable and evaluable lesions should be assessed and documented at the screening visit.  Radiologic imaging 
performed during the screening period should consist of 1) CT (with oral or IV contrast unless contraindicated) and/or MRI of the chest, abdomen, 
and pelvis, 2) bone scan or PET scan, 3) Brain MRI/CT and 4) any other imaging studies (CT of neck, plain films, etc.) as clinically indicated by 
the treating physician.  The same radiographic procedures and technique must be used throughout the study for each patient (e.g., if the patient 
had CT of chest, abdomen, and pelvis performed during screening, then the patient should subsequently undergo CT performed using the same 
radiologic protocol throughout the remainder of the study). 
Tumor assessments will be performed at baseline, every 6 weeks (7 days) following randomization, with additional scans as clinically indicated.  
All known sites of disease documented at screening should be re-assessed at each subsequent tumor evaluation.  Tumor assessments 
performed after the screening period should consist of the following assessments every 6 weeks:  1) CT and/or MRI of the chest/abdomen/pelvis, 
as well as other known sites of disease, including brain, 2) If a patient has only bone as a site of involvement at screening which is determined 
to be measurable disease as per RECIST 1.1, then a bone scan or PET scan is mandated at each tumor assessment. Otherwise, a bone scan 
or PET scan is to be performed as clinically indicated, e.g., suspicion of disease progression, and 3) in cases where patients demonstrate control 
of their systemic disease but who newly develop isolated brain metastases and are eligible to remain on study treatment, brain MRI or CT are 
performed along with regularly scheduled tumor assessments, and 4) any other imaging studies felt to be clinically indicated by the treating 
physician.  Tumor response will be evaluated using RECIST v1.1 (Appendix 4 and immune-modified RECIST Appendix 5).  In the absence of 
disease progression, tumor assessments should continue regardless of whether patients discontinue study treatment, unless they withdraw 
consent or the study is terminated by the Sponsor, whichever occurs first.  Results must be reviewed by the investigator before dosing at the 
next cycle.  
q An isotope 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.


Appendix 2
Schedule of Assessments (cont.)
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd
31/Statistical Analysis Plan WO30085
r
CT/MRI scan of the brain is mandatory at screening and should be performed 1) with scheduled tumor assesssments when identified as a site of 
involvement at baseline, 2) as clinically indicated, or 3) if a patient demonstrates control of systemic disease but has a newly developed 
isolated brain metastases and is eligible to remain on study treatment, a brain MRI or CT will be performed along with regularly scheduled 
tumor assessments.
s A 12-lead ECG is required at screening.  Subsequent ECGs may be performed as clinically indicated.  ECGs for each patient should be obtained 
from the same machine wherever possible.  ECG recordings must be performed after the patient has been resting in a supine position for at 
least 10 minutes.
t
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.
u Auto-antibody testing includes anti-nuclear antibody, antidouble-stranded DNA, and circulating and perinuclear cytoplasmic antibody.  The 
baseline sample will be obtained pre-treatment Cycle 1, Day 1, before the first dose of study drug.  For patients who show evidence of 
immune-mediated toxicity, additional samples may be collected.  All samples will be analyzed centrally.
v At screening, the FFPE archival tumor block from the most recently collected, available tumor tissue or fresh core biopsy (3 cores) is mandated.  
If more than 1 FFPE blocks exists from different time points e.g. initial diagnosis vs. metastatic disease tissue, the most recent block is 
mandatory to be sent. If the FFPE block from the earlier timepoint is available then this would be requested to also be sent. In the cases of 
bilateral breast cancer, an additional 8 unstained slides from the contralateral breast to where FFPE block have been provided.  20-25 freshly cut, 
unstained slides will be acceptable in lieu of the FFPE block. Optional core biopsies will be obtained at Cycle 1, Day 1 and Cycle 2, Day 1 
(3 days) if patient consented. At the study drug discontinuation/early study completion visit, if reason for discontinuation is disease progression, 
a biopsy must be taken (if deemed clinically feasible) before next line of therapy begins, unless purely anti-hormonal therapy. 
w 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.  
For the first infusion of atezolizumab or placebo, vital signs should be determined within 60 minutes before, every 15 (5) minutes during, and 
30 (10) minutes after the infusion, if clinically indicated.  For subsequent infusions, vital signs do not need to be obtained during the infusion if 
the prior infusion was tolerated without symptoms
x 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.  For patients assigned to trastuzumab emtansine therapy, trastuzumab emtansine should be administered over approximately 
90 minutes for the first dose and, in the absence of infusion-related adverse events, over approximately 30 minutes in subsequent doses.  Vital 
signs should be taken before and after the trastuzumab emtansine infusion. Patients will be monitored for any untoward effects for at least 
90 minutes after completion of the first trastuzumab emtansine infusion and, in the absence of infusion-related events, for a minimum of 
30 minutes at subsequent infusions.  


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Appendix 3
Schedule of Pharmacokinetic and Immunogenicity Samples
Table 1
Anti-Therapeutic Antibody and Pharmacokinetic Assessments 
for Atezolizumab1
Visit
Timepoint
Sample Typea
Cycle 1, Day 1 and Cycle 4 
Day 1
Pre-infusionb of 
atezolizumab or placebo
Serum sample for 
atezolizumab 
pharmacokinetics
Serum sample for ATA 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 b of 
atezolizumab or placebo
Serum sample for 
atezolizumab 
pharmacokinetics
Serum sample for ATA to 
atezolizumab 
Study treatment/early 
discontinuation visit
At any time during visit
Serum sample for 
atezolizumab 
pharmacokinetics
Serum sample for ATA to 
atezolizumab
120 days (28 days) after 
treatment completion or 
discontinuation
At any time during visit
Serum sample for 
atezolizumab 
pharmacokinetics
Serum sample for ATA to 
atezolizumab
ATAanti-therapeutic antibody.
a Blood for PK/ ATA should not be obtained through the same line that atezolizumab or
placebo is infused.
b Within 24 hours prior to atezolizumab infusion.


Appendix 3
Schedule of Pharmacokinetic and Immunogenicity Samples
(cont.)
Trastuzumab Emtansine and Atezolizumab—F. Hoffmann-La Roche Ltd
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Table 2
Anti-Therapeutic Antibody and Pharmacokinetic Assessments 
for Trastuzumab Emtansine1
Visit
Timepoint
Sample Typea
Cycle 1, Day 1 and 
Cycle 4 Day 1
Pre-infusionb of 
trastuzumab emtansine
Serum sample for 
trastuzumab emtansine and 
total trastuzumab 
pharmacokinetics 
Serum HER2 ECD (Cycle 1 
only)
Plasma sample for DM1 
(Cycle 1 only) 
Serum sample for ATA 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 and 
total trastuzumab
Plasma sample for DM1
Cycle 2, Day 1 (3 days)
Pre-infusion b of 
trastuzumab emtansine
Serum sample for 
trastuzumab emtansine and 
total trastuzumab
Study treatment/early 
discontinuation visit
At any time during visit
Serum sample for 
trastuzumab emtansine 
pharmacokinetics
Serum sample for ATA to 
trastuzumab emtansine
120 days (28 days) after 
treatment completion or 
discontinuation
At any time during the 
visit
Serum sample for ATA to 
trastuzumab emtansine
ATAanti-therapeutic antibody.
a Blood for PK/ ATA should not be obtained through the same line that trastuzumab 
emtansine is infused.
b Within 24 hours prior to Trastuzumab emtansine administration.


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Appendix 4
Schedule of Biomarker Samples
Table 3
Blood Samples for Biomarker Analysis
Visit
Timepoint
Sample Type
Cycle 1, Day 1 
Pre-infusion  
Whole blood sample a
Whole blood RBR sample for 
genetic research
Blood for serum/plasma
Cycle 2, Day 1 
Pre-infusion  
Whole blood sample a
Blood for serum/plasma
Cycle 3, Day 1
Pre-infusion  
Blood for serum/plasma
Cycle 8, Day 1
Pre-infusion  
Blood for serum/plasma
Study treatment/early 
discontinuation visit
At any time during visit
Whole blood sample a
Blood for serum/plasma
120 days (28 days) after 
treatment completion or 
discontinuation
At any time during visit
Whole blood sample a
Blood for serum/plasma
a
Whole blood sample will be taken from all patients enrolled on the study.  Serial 
sample collection will be collected on approximately the first 50 enrolled patients 
only.


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Table 4
Tissue Sample for Biomarker Analysis
Visit
Timepoint
Requirement
Sample Type
Screening 
Pre-infusion  
Mandatory
FFPE archival tumor block or partial 
block most recently collected, available 
tumor tissue or
Fresh core biopsy (3 cores)
If more than 1 FFPE blocks exists from 
different time points e.g. initial diagnosis 
vs. metastatic disease tissue, the most 
recent block or partial block is mandatory 
to be sent. If the FFPE block from the 
earlier timepoint is available then this 
would be requested to also be sent.
In the cases of bilateral breast cancer, 
an additional 8 unstained slides from the 
contralateral breast to where FFPE block 
have been provided 
Upon discussion with the Medical 
Monitor (in case of site regulations that 
prevent sending a block), 20 freshly cut, 
unstained slides will be acceptable in 
lieu of FFPE block.
If only fewer than 20 unstained slides are 
available at baseline (but no fewer than 
15), discuss with the Medical Monitor to 
decide on eligibility.  
Cycle 1 Day 1
Pre-infusion (within
28 days of C1D1)
Optional
Fresh Core Biopsy (3 cores)
FFPE block or partial block preferred or 
freshly cut, unstained 15 slides
Cycle 2 Day 1
Pre-infusion (within 
3 days prior to 
C2D1 or up to 
5 days after C2D1)
Optional 
Fresh Core Biopsy (3 cores)
FFPE block or partial block preferred or 
freshly cut, unstained 15 slides
Study 
treatment/early 
discontinuation 
visit 
Reason: Disease 
Progression
At time of Study 
treatment/early 
discontinuation visit 
(if the reason for 
discontinuation was 
PD)
Must be taken 
before next line of 
therapy begins.  
In case new line 
therapy is purely 
anti-hormonal, 
biopsy could be 
taken after it is 
started. 
Mandatory 
(if deemed 
clinically 
feasible)
Fresh Core Biopsy (3 cores) at site of 
progression if accessible or from any 
other lesion
FFPE block preferred or freshly cut, 
unstained 15 slides