A Phase II, Randomized, Blinded, Placebo-Controlled Study of Tiragolumab, An Anti-TIGIT Antibody, In Combination With Atezolizumab In Chemotherapy-Naïve Patients With Locally Advanced Or Metastatic Non-Small Cell Lung Cancer
Phase: PHASE2
Conditions: Non-small Cell Lung Cancer
Sponsor: Genentech, Inc.

PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (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 Genentech except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered.
MTIG7192A and Atezolizumab (MPDL3280A)—Genentech, Inc.
Protocol GO40290, Version 3
PROTOCOL
TITLE:
A PHASE II, RANDOMIZED, BLINDED, 
PLACEBO-CONTROLLED STUDY OF MTIG7192A, 
AN ANTI-TIGIT ANTIBODY, IN COMBINATION 
WITH ATEZOLIZUMAB IN CHEMOTHERAPY-NAIVE 
PATIENTS WITH LOCALLY ADVANCED OR 
METASTATIC NONSMALL CELL LUNG CANCER 
PROTOCOL NUMBER:
GO40290
VERSION NUMBER:
3
EUDRACT NUMBER:
2018-000280-81
IND NUMBER:
129258
NCT NUMBER:
NCT03563716
TEST PRODUCTS:
MTIG7192A (RO7092284)
Atezolizumab (RO5541267)
MEDICAL MONITOR:
, M.D.
SPONSOR:
Genentech, Inc.
APPROVAL DATE:
See electronic data stamp below.
 
06-Feb-2020 21:45:32
Title
Approver's Name
Company Signatory
Date and Time (UTC)

MTIG7192A and Atezolizumab (MPDL3280A)—Genentech, Inc.
2/Protocol GO40290, Version 3
PROTOCOL HISTORY
Protocol
Version
Date Final
2
10 December 2018
1
14 March 2018

MTIG7192A and Atezolizumab (MPDL3280A)—Genentech, Inc.
3/Protocol GO40290, Version 3
PROTOCOL AMENDMENT, VERSION 3:
RATIONALE
Protocol GO40290 has been amended to modify the safety information based on 
evolving clinical data observed to date.  
 
 
  Changes to the protocol, along with a rationale 
for each change, are summarized below:

The potential and identified risks for MTIG7192A and atezolizumab have been 
updated to align with current Investigator’s Brochures for MTIG7192A (also known 
as tiragolumab) and atezolizumab.  
 
 
 

To align with the Atezolizumab Investigator's Brochure, Version 15, 
"immune-related" has been changed to "immune-mediated" when describing events 
associated with atezolizumab
 

References to the Immune-Modified Response Evaluation Criteria in Solid Tumors
have been removed from the protocol to align with current changing 
practice-standards.  
 

Language has been revised to clarify the timing of adverse event reporting 
 

To address a request by the
 
 systemic immune activation has been replaced by 
hemophagocytic lymphohistiocytosis and macrophage activation syndrome in the 
list of potential risks for atezolizumab single agent and in combination with other 
modulating drugs
 and the management 
guidelines for systemic immune activation have been replaced with management 
guidelines for hemophagocytic lymphohistiocytosis and macrophage activation 
syndrome 
 

The Medical Monitor has been changed to 
, M.D., and contact 
information updated (Section 5.4.1).
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.

MTIG7192A and Atezolizumab (MPDL3280A)—Genentech, Inc.
4/Protocol GO40290, Version 3
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 13
PROTOCOL SYNOPSIS .................................................................................... 14
1.
BACKGROUND .......................................................................................... 28
1.1
Background on Lung Cancer................................................. 28
1.2
First-Line Treatment for NonSmall Cell Lung 
Cancer without an EGFR Mutation or ALK 
Rearrangement...................................................................... 29
1.3
TIGIT Pathway in Cancer as Potential Anti-
Cancer Therapy..................................................................... 33
1.4
PD-L1/PD-1 Pathway in Cancer ............................................ 34
1.5
Combined Inhibition of the TIGIT and PD-L1/PD-
1 Pathways as Potential Anti-Cancer Therapy ...................... 35
1.6
Background on MTIG7192A .................................................. 36
1.6.1
Summary of Nonclinical Data with MTIG7192A..................... 37
1.6.2
Clinical Experience with MTIG7192A .................................... 38
1.6.2.1
Ongoing Clinical Studies with MTIG7192A............................ 38
1.6.2.2
Clinical Safety of MTIG7192A................................................ 38
1.6.2.3
Clinical Activity of MTIG7192A Plus 
Atezolizumab......................................................................... 41
1.6.2.4
Clinical Pharmacokinetics and Immunogenicity of 
MTIG7192A ........................................................................... 42
1.7
Background on Atezolizumab................................................ 42
1.7.1
Summary of Nonclinical Studies for Atezolizumab ................ 43
1.7.2
Clinical Experience with Atezolizumab in NSCLC ................. 43
1.7.2.1
Ongoing Clinical Studies with Atezolizumab in 
NSCLC .................................................................................. 43
1.7.2.2
Clinical Safety of Atezolizumab ............................................. 45
1.7.2.3
Clinical Activity of Atezolizumab ............................................ 46
1.7.2.4
Clinical Pharmacokinetics and Immunogenicity of 
Atezolizumab......................................................................... 49
1.8
Study Rationale and Benefit-Risk Assessment...................... 50
1.8.1
Study Rationale ..................................................................... 50
1.8.2
BenefitRisk Assessment...................................................... 51

MTIG7192A and Atezolizumab (MPDL3280A)—Genentech, Inc.
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2.
OBJECTIVES AND ENDPOINTS ............................................................... 54
3.
STUDY DESIGN......................................................................................... 55
3.1
Description of the Study......................................................... 55
3.1.1
Treatment after Disease Progression .................................... 59
3.1.2
Internal Monitoring Committee............................................... 60
3.2
End of Study and Length of Study......................................... 61
3.3
Rationale for Study Design.................................................... 61
3.3.1
Rationale for Control Arm with Placebo Plus 
Atezolizumab in Patients with PD-L1Selected 
NSCLC .................................................................................. 61
3.3.2
Rationale for Testing MTIG7192A Plus 
Atezolizumab in Patients with PD-L1Selected 
NSCLC .................................................................................. 63
3.3.3
Rationale for PD-L1 Selection of Tumor Samples ................. 64
3.3.4
Rationale for Inclusion of Patients with 
Squamous and Non-Squamous NSCLC................................ 64
3.3.5
Rationale for Exclusion of Patients with 
Sensitizing EGFR Mutations and ALK 
Translocations ....................................................................... 65
3.3.6
Rationale for Dose and Schedule of 
Atezolizumab and MTIG7192A.............................................. 66
3.3.6.1
Rationale for Dose and Schedule of 
Atezolizumab......................................................................... 66
3.3.6.2
Rationale for Dose and Schedule of MTIG7192A.................. 66
3.3.7
Rationale for Biomarker Assessments................................... 66
3.3.7.1
Rationale for Collection of Mandatory Archival 
and/or Pretreatment Biopsy Tumor Specimens..................... 66
3.3.7.2
Rationale for Collection of Blood Samples for 
Biomarker Analyses............................................................... 67
3.3.7.3
Rationale for Collection of Optional Tumor 
Specimens, Including a Biopsy at the Time of 
Radiographic Progression ..................................................... 68
3.3.7.4
Rationale for Next-Generation Sequencing in 
Tumor and/or Blood Samples................................................ 68
3.3.7.5
Rationale for Optional Stool Sample Collection..................... 69

MTIG7192A and Atezolizumab (MPDL3280A)—Genentech, Inc.
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3.3.8
Rationale for Allowing Patients to Continue Study 
Treatment Beyond Initial Progression per 
RECIST v1.1.......................................................................... 69
3.3.9
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 70
4.
MATERIALS AND METHODS .................................................................... 70
4.1
Patients.................................................................................. 70
4.1.1
Inclusion Criteria.................................................................... 70
4.1.2
Exclusion Criteria................................................................... 73
4.1.2.1
Cancer-Specific Exclusions ................................................... 73
4.1.2.2
General Medical Exclusions .................................................. 75
4.1.2.3
Treatment-Specific Exclusions .............................................. 76
4.2
Method of Treatment Assignment and Blinding..................... 77
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 79
4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 79
4.3.1.1
MTIG7192A and Placebo ...................................................... 79
4.3.1.2
Atezolizumab......................................................................... 79
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 79
4.3.2.1
Atezolizumab......................................................................... 79
4.3.2.2
MTIG7192A and Placebo ...................................................... 80
4.3.2.3
Atezolizumab and MTIG7192A/Placebo................................ 82
4.3.3
Investigational Medicinal Product Accountability ................... 83
4.3.4
Continued Access to MTIG7192A and/or 
Atezolizumab......................................................................... 83
4.4
Concomitant Therapy ............................................................ 84
4.4.1
Permitted Therapy................................................................. 84
4.4.1.1
Cannabinoids......................................................................... 85
4.4.2
Prohibited Therapy ................................................................ 85
4.5
Study Assessments............................................................... 86
4.5.1
Informed Consent Forms and Screening Log........................ 86
4.5.2
Medical History and Demographic Data ................................ 87
4.5.3
Physical Examinations........................................................... 88

MTIG7192A and Atezolizumab (MPDL3280A)—Genentech, Inc.
7/Protocol GO40290, Version 3
4.5.4
Vital Signs.............................................................................. 88
4.5.5
Tumor and Response Evaluations......................................... 89
4.5.6
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 90
4.5.6.1
Local Laboratory Tests .......................................................... 90
4.5.6.2
Central Laboratory Assessments........................................... 91
4.5.7
Use and Storage of Remaining Samples from 
Study-Related Procedures..................................................... 95
4.5.8
Electrocardiograms................................................................ 95
4.5.9
Cancer-Related Procedures .................................................. 95
4.5.10
Anti-Drug Antibody Testing.................................................... 95
4.5.11
Patient-Reported Outcomes .................................................. 96
4.5.12
Optional Samples for Research Biosample 
Repository ............................................................................. 96
4.5.12.1
Overview of the Research Biosample Repository.................. 96
4.5.12.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 97
4.5.12.3
Sample Collection.................................................................. 97
4.5.12.4
Confidentiality........................................................................ 98
4.5.12.5
Consent to Participate in the Research 
Biosample Repository............................................................ 98
4.5.12.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 99
4.5.12.7
Monitoring and Oversight....................................................... 99
4.6
Treatment, Patient, Study, and Site 
discontinuation....................................................................... 99
4.6.1
Study Treatment Discontinuation........................................... 99
4.6.1.1
Study Treatment Discontinuation Visit................................. 100
4.6.1.2
Survival and Subsequent Anti-Cancer Therapy 
Follow-Up ............................................................................ 100
4.6.2
Patient Discontinuation from Study...................................... 101
4.6.3
Study Discontinuation.......................................................... 101
4.6.4
Site Discontinuation............................................................. 101
5.
ASSESSMENT OF SAFETY..................................................................... 102
5.1
Safety Plan .......................................................................... 102

MTIG7192A and Atezolizumab (MPDL3280A)—Genentech, Inc.
8/Protocol GO40290, Version 3
5.1.1
Risks Associated with MTIG7192A...................................... 102
5.1.1.1
Infusion-Related Reactions.................................................. 103
5.1.1.2
Immune-Mediated Adverse Events...................................... 103
5.1.1.3
Lymphopenia....................................................................... 104
5.1.2
Risks Associated with Atezolizumab ................................... 104
5.1.3
Risks Associated with MTIG7192A Plus 
Atezolizumab....................................................................... 104
5.1.4
Management of Patients Who Experience 
Adverse Events ................................................................... 105
5.1.4.1
Dose Modifications .............................................................. 105
5.1.4.2
Treatment Interruption ......................................................... 105
5.1.4.3
Management Guidelines...................................................... 106
5.2
Safety Parameters and Definitions ...................................... 106
5.2.1
Adverse Events ................................................................... 106
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 107
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................. 108
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 109
5.3.1
Adverse Event Reporting Period ......................................... 109
5.3.2
Eliciting Adverse Event Information..................................... 109
5.3.3
Assessment of Severity of Adverse Events ......................... 109
5.3.4
Assessment of Causality of Adverse Events ....................... 110
5.3.5
Procedures for Recording Adverse Events.......................... 111
5.3.5.1
Infusion-Related Reactions.................................................. 111
5.3.5.2
Diagnosis versus Signs and Symptoms............................... 111
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................. 112
5.3.5.4
Persistent or Recurrent Adverse Events.............................. 112
5.3.5.5
Abnormal Laboratory Values ............................................... 113
5.3.5.6
Abnormal Vital Sign Values ................................................. 113
5.3.5.7
Abnormal Liver Function Tests............................................ 114
5.3.5.8
Deaths ................................................................................. 114
5.3.5.9
Preexisting Medical Conditions............................................ 115

MTIG7192A and Atezolizumab (MPDL3280A)—Genentech, Inc.
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5.3.5.10
Lack of Efficacy or Worsening of NSCLC ............................ 115
5.3.5.11
Hospitalization or Prolonged Hospitalization........................ 115
5.3.5.12
Patient-Reported Outcome Data ......................................... 116
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 116
5.4.1
Emergency Medical Contacts.............................................. 117
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 117
5.4.2.1
Events That Occur prior to Study Drug Initiation.................. 117
5.4.2.2
Events That Occur after Study Drug Initiation...................... 117
5.4.3
Reporting Requirements for Pregnancies............................ 118
5.4.3.1
Pregnancies in Female Patients.......................................... 118
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 118
5.4.3.3
Congenital Anomalies/Birth Defects .................................... 119
5.4.3.4
Abortions ............................................................................. 119
5.4.4
Reporting Requirements for Cases of Accidental 
Overdose or Medication Error.............................................. 119
5.5
Follow-Up of Patients after Adverse Events ........................ 120
5.5.1
Investigator Follow-Up......................................................... 120
5.5.2
Sponsor Follow-Up .............................................................. 120
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period........................................................ 121
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 121
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 122
6.1
Determination of Sample Size ............................................. 122
6.2
Summaries of Conduct of Study.......................................... 124
6.3
Summaries of Demographic and Baseline 
Characteristics..................................................................... 124
6.4
Efficacy Analyses ................................................................ 124
6.4.1
Co-Primary Efficacy Endpoints............................................ 124
6.4.2
Secondary Efficacy Endpoints............................................. 125
6.5
Safety Analyses................................................................... 125
126

MTIG7192A and Atezolizumab (MPDL3280A)—Genentech, Inc.
10/Protocol GO40290, Version 3
6.7
Pharmacokinetic Analyses................................................... 126
6.8
Immunogenicity Analyses.................................................... 127
6.9
Patient-Reported Outcome Analyses .................................. 127
6.10
Interim Analyses .................................................................. 127
7.
DATA COLLECTION AND MANAGEMENT ............................................. 127
7.1
Data Quality Assurance....................................................... 127
7.2
Electronic Case Report Forms............................................. 128
7.3
Source Data Documentation................................................ 128
7.4
Use of Computerized Systems ............................................ 128
7.5
Retention of Records........................................................... 129
8.
ETHICAL CONSIDERATIONS.................................................................. 129
8.1
Compliance with Laws and Regulations .............................. 129
8.2
Informed Consent................................................................ 129
8.3
Institutional Review Board or Ethics Committee.................. 130
8.4
Confidentiality...................................................................... 131
8.5
Financial Disclosure ............................................................ 131
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 132
9.1
Study Documentation .......................................................... 132
9.2
Protocol Deviations.............................................................. 132
9.3
Site Inspections ................................................................... 132
9.4
Administrative Structure....................................................... 132
9.5
Publication of Data and Protection of Trade 
Secrets ................................................................................ 133
9.6
Protocol Amendments ......................................................... 134
10. REFERENCES ......................................................................................... 135

MTIG7192A and Atezolizumab (MPDL3280A)—Genentech, Inc.
12/Protocol GO40290, Version 3
Appendix 6
Anaphylaxis Precautions........................................................... 161
Appendix 7
Overall Guidelines for Management of Patients Who 
Experience Adverse Events...................................................... 162
Appendix 8
Risks Associated with Atezolizumab or MTIG7192A and 
Guidelines for Management of Adverse Events Associated 
with Atezolizumab or MTIG7192A............................................. 164

MTIG7192A and Atezolizumab (MPDL3280A)—Genentech, Inc.
13/Protocol GO40290, Version 3
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE II, RANDOMIZED, BLINDED, 
PLACEBO-CONTROLLED STUDY OF MTIG7192A, 
AN ANTI-TIGIT ANTIBODY, IN COMBINATION 
WITH ATEZOLIZUMAB IN CHEMOTHERAPY-NAIVE 
PATIENTS WITH LOCALLY ADVANCED OR 
METASTATIC NONSMALL CELL LUNG CANCER
PROTOCOL NUMBER:
GO40290
VERSION NUMBER:
3
EUDRACT NUMBER:
2018-000280-81
IND NUMBER:
129258
NCT NUMBER:
NCT03563716
TEST PRODUCTS:
MTIG7192A (RO7092284)
Atezolizumab (RO5541267)
MEDICAL MONITOR:
, M.D.
SPONSOR:
Genentech, Inc.
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by the contract research organization (
).

MTIG7192A and Atezolizumab (MPDL3280A)—Genentech, Inc.
14/Protocol GO40290, Version 3
PROTOCOL SYNOPSIS
TITLE:
A PHASE II, RANDOMIZED, BLINDED, PLACEBO-CONTROLLED 
STUDY OF MTIG7192A, AN ANTI-TIGIT ANTIBODY, IN 
COMBINATION WITH ATEZOLIZUMAB IN 
CHEMOTHERAPY-NAIVE PATIENTS WITH LOCALLY ADVANCED 
OR METASTATIC NONSMALL CELL LUNG CANCER
PROTOCOL NUMBER:
GO40290
VERSION NUMBER:
3
EUDRACT NUMBER:
2018-000280-81
IND NUMBER:
129258
NCT NUMBER:
NCT03563716
TEST PRODUCTS:
MTIG7192A (RO7092284)
Atezolizumab (RO5541267)
PHASE:
Phase II
INDICATION:
Nonsmall cell lung cancer
SPONSOR:
Genentech, Inc.
Objectives and Endpoints
This study will evaluate the safety and efficacy of MTIG7192A plus atezolizumab compared with
placebo plus atezolizumab in chemotherapy-naive patients with locally advanced unresectable 
or metastatic PD-L1selected nonsmall cell lung cancer (NSCLC), excluding patients with a 
sensitizing EGFR mutation or ALK translocation.  Specific objectives and corresponding 
endpoints for the study are outlined below.
Primary Efficacy Objective
Corresponding Endpoints
To evaluate the efficacy of MTIG7192A 
plus atezolizumab compared with placebo 
plus atezolizumab, as measured by 
objective response rate (ORR) and
progression-free survival (PFS) 
ORR, defined as a complete response or partial 
response on two consecutive occasions 4 weeks 
apart, as determined by the investigator according to 
RECIST v1.1
PFS, defined as the time from randomization to the 
first occurrence of disease progression, as determined 
by the investigator according to RECIST v1.1, or death 
from any cause, whichever occurs first 
Secondary Efficacy Objective
Corresponding Endpoints
To evaluate the efficacy of MTIG7192A 
plus atezolizumab compared with placebo 
plus atezolizumab, as measured by 
duration of objective response (DOR) and 
overall survival (OS)
DOR, defined as the time from the first occurrence of a 
documented objective response to disease 
progression, as determined by the investigator 
according to RECIST v1.1, or death from any cause, 
whichever occurs first
OS, defined as the time from randomization to death 
from any cause

MTIG7192A and Atezolizumab (MPDL3280A)—Genentech, Inc.
15/Protocol GO40290, Version 3
Safety Objective
Corresponding Endpoints
To evaluate the safety and tolerability of 
MTIG7192A plus atezolizumab compared 
with placebo plus atezolizumab 
Incidence, nature, and severity of adverse events, 
graded according to the NCI CTCAE v4.0
Clinically significant changes from baseline in vital 
signs, physical findings, and clinical laboratory results 
during and following administration of MTIG7192A plus 
atezolizumab compared with placebo plus 
atezolizumab
Pharmacokinetic Objective
Corresponding Endpoint
To characterize the PK profile of 
MTIG7192A and atezolizumab
Serum concentrations of MTIG7192A or atezolizumab 
at specified timepoints
Immunogenicity Objective
Corresponding Endpoint
To evaluate the immune response to 
MTIG7192A and atezolizumab
Incidence of treatment-emergent ADAs and their 
potential impact on safety, efficacy, and 
pharmacokinetics
Exploratory Patient-Reported Outcome 
Objective
Corresponding Endpoints
To evaluate the benefit of MTIG7192A 
plus atezolizumab compared with placebo 
plus atezolizumab, in terms of 
patient-relevant concepts including 
symptoms, daily functioning, and 
health-related quality of life (HRQoL)
Clinically significant changes in symptoms, function, 
and HRQoL scales from the patient-completed EORTC 
QLQ-C30
Exploratory Biomarker Objectives
Corresponding Endpoints

 
 

 

 
 
 
 

 
 
ADAanti-drug antibody; DORduration of response; EORTC QLQ-C30European Organisation for 
Research and Treatment of Cancer Quality of Life QuestionnaireCore 30; HRQoLhealth-related quality 
of life; NCI CTCAE v4.0National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 4.0; ORRobjective response rate; OSoverall survival; PFSprogression-free survival; 
PKpharmacokinetic; RECISTResponse Evaluation Criteria in Solid Tumors; TIGITT-cell 
immunoreceptor with Ig and ITIM domains.

MTIG7192A and Atezolizumab (MPDL3280A)—Genentech, Inc.
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
1L
first-line
2L
second-line
ADA
anti-drug antibody
ADCC
antibody-dependent cell-mediated cytotoxicity
ALK
anaplastic lymphoma kinase
antiCTLA-4
anti-cytotoxic T lymphocyteassociated protein 4
anti-HBc
antibody to hepatitis B core antigen
BSC
best supportive care
CHO
Chinese hamster ovary
CIT
cancer immunotherapy
CMV
cytomegalovirus
CR
complete response
CRO
contract research organization
CT
computed tomography
DLT
dose-limiting toxicity
DOR
duration of response
EAE
experimental autoimmune encephalitis
EBV
Epstein-Barr virus
EBNA
Epstein-Barr nuclear antigen
EC
Ethics Committee
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EGFR
epidermal growth factor receptor
EORTC QLQ-C30
European Organisation for Research and Treatment of 
Cancer Quality of Life QuestionnaireCore 30
FDA
(U.S.) Food and Drug Administration
FFPE
formalin-fixed, paraffin-embedded
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HLH
hemophagocytic lymphohistiocytosis
HNSCC
head and neck squamous cell carcinoma
HR
hazard ratio
HRQoL
health-related quality of life

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Abbreviation
Definition
IC
(tumor-infiltrating) immune cell
ICH
International Council for Harmonisation
IFN
interferon-gamma
IHC
Immunohistochemistry
IMC
Internal Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug (application)
IRB
Institutional Review Board
IRF
independent review facility
IRR
infusion-related reaction
ITT
intent-to-treat (population)
IxRS
interactive voice or web-based response system
KRAS
Kirsten rat sarcoma viral oncogene homolog
Mab
MAS
monoclonal antibody
macrophage activation syndrome
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI CTCAE
National Cancer Institute Common Terminology Criteria 
for Adverse Events
NGS
next generation sequencing
NK
natural killer cells
NSCLC
nonsmall cell lung cancer
ORR
objective response rate
OS
overall survival
PD
pharamcodynamic(s)
PFS
progression-free survival
PK
pharmacokinetic(s)
PR
partial response
PRO
patient-reported outcome
PS
performance status
PVR
poliovirus receptor
Q3W
every 3 weeks
RBR
Research Biosample Repository
RECIST
Response Evaluation Criteria in Solid Tumors
TC
tumor cell
TIGIT
T-cell immunoreceptor with Ig and ITIM domains

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Abbreviation
Definition
TNF-
tumor necrosis factor-
TPS
tumor proportion score
TTD
time to deterioration
ULN
upper limit of normal
WES
whole exome sequencing
WGS
whole genome sequencing

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1.
BACKGROUND
1.1
BACKGROUND ON LUNG CANCER
Lung cancer remains the leading cause of cancer deaths worldwide, accounting for 
approximately 13% of all new cancers in 2012 (Torre et al. 2015).  In 2017 in the 
United States, it was estimated that there were 222,500 new cases of lung cancer 
(116,990 in men and 105,510 in women) and 155,870 lung cancer deaths 
(American Cancer Society 2017). Similar data from Europe estimate that in 2017, there 
were 275,700 lung cancer deaths (183,400 in men and 92,300 in women) (Malvezzi 
et al. 2017).
Nonsmall cell lung cancer (NSCLC) is the predominant subtype, accounting for 
approximately 85% of all cases (Molina et al. 2008; Howlader et al. 2014).  NSCLC can 
be divided into two major histologic types:  adenocarcinoma and squamous cell 
carcinoma (Travis et al. 2011).  Adenocarcinoma histology accounts for more than half 
of all NSCLC, while squamous cell histology accounts for approximately 25% of NSCLC
(Langer et al. 2010).  The remaining cases of NSCLC are represented by large cell 
carcinoma, neuroendocrine tumors, sarcomatoid carcinoma, and poorly differentiated 
histology.
The overall 5-year survival rate for advanced disease treated with chemotherapy 
remains poor, depending on geographic location (Cetin et al. 2011).  Poor prognostic 
factors for survival in patients with NSCLC include advanced stage of disease at the time 
of initial diagnosis, poor performance status, and a history of unintentional weight loss.  
More than half of the patients with NSCLC are diagnosed with distant disease, which 
directly contributes to the poor survival prospects.
There are recognized differences in disease characteristics between adenocarcinoma 
and squamous NSCLC.  First, squamous tumors commonly present in the central 
airways and typically remain localized in the bronchial epithelium (Hirsch et al. 2008), 
whereas non-squamous tumors are more commonly located in the lung parenchyma 
distal to the central airways.  Evaluation of NSCLC tumor tissue reveals cytological 
differences between the squamous cell type (characterized by keratinization, intracellular 
bridges, and central necrosis) and adenocarcinoma (characterized by glandular 
architecture).  In cases where the tumor sample is poorly differentiated or there is limited 
tissue available, immunohistochemical (IHC) biomarkers may support the histological 
diagnosis.  Thyroid transcription factor-1 (TTF-1) is infrequently expressed in squamous 
cells and strongly expressed in adenocarcinoma.  In contrast, p63, CK5/6, and 34-E12 
are strongly expressed in squamous cell carcinoma and less frequently in 
adenocarcinoma (Travis et al. 2011).
Genetic changes that have prognostic and/or predictive significance in NSCLC include 
mutations in the epidermal growth factor receptor (EGFR) gene, rearrangements in the 
anaplastic lymphoma kinase (ALK) gene, and mutations in the Kirsten rat sarcoma viral 

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oncogene homolog (KRAS) gene.  The rates of these mutations differ between 
squamous cell carcinoma and adenocarcinoma.  For example, EGFR kinase domain 
mutations have been reported in 10%–40% of patients with adenocarcinoma NSCLC but 
are more frequently observed in patients with squamous NSCLC (Herbst et al. 2008).  
The ALK fusion oncogene, recognized as a driver of lung tumorigenesis, is very rare in 
the squamous histology but is observed in approximately 7% of patients with 
adenocarcinoma (Herbst et al. 2008; Langer et al. 2010).  In addition, KRAS mutations 
are rare in squamous NSCLC, while they can be observed in up to 30% of 
adenocarcinoma NSCLC (Travis et al. 2011).
1.2
FIRST-LINE TREATMENT FOR NONSMALL CELL LUNG 
CANCER WITHOUT AN EGFR MUTATION OR ALK 
REARRANGEMENT
Patients with previously untreated NSCLC that does not harbor a driver mutation that 
confers sensitivity to a targeted agent are typically treated with chemotherapy.  The first 
evidence that chemotherapy produced a significant survival benefit in patients with 
advanced NSCLC came in 1995; a meta-analysis showed that platinum-based doublet 
chemotherapy conferred a 2-month improvement in median survival over best supportive 
care (BSC) (NSCLC Collaborative Group 1995).  In addition, the European Big Lung 
Trial demonstrated the potential benefits of chemotherapy.  In this study, 725 patients 
with advanced NSCLC were randomly assigned to BSC plus cisplatin-based 
chemotherapy or BSC alone (Spiro et al. 2004).  Patients allocated to chemotherapy had 
a significantly longer median survival than did those patients managed with BSC alone
(8 vs. 5.7 months).
The benefit conferred by platinum-based chemotherapy regimens appears to have 
reached a plateau in objective response rate (ORR; approximately 15% to 22%) and 
median survival (710 months).  The addition of bevacizumab to carboplatin and 
paclitaxel in non-squamous NSCLC resulted in an increase in response rate from 15% to 
35% and an increase in median overall survival (OS) from 10 to 12 months (see Table 1).

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Table 1
Randomized Phase III Studies in Patients with Previously Untreated NonSmall Cell Lung Cancer
Treatment Group
ORR
(%)
Median PFS
(months)
Median OS
(months)
OS HR
(95% CI)
Chemotherapy a
Cisplatin and paclitaxel (n288)
21
3.4
7.8
Cisplatin and gemcitabine (n288)
22
4.2
8.1
Cisplatin and docetaxel (n289)
17
3.7
7.4
Carboplatin and paclitaxel (n290)
17
3.1
8.1
Chemotherapybiologic b
Carboplatin and paclitaxel (n444)
15
4.5
10.3
0.79
0.67, 0.92
Carboplatin, paclitaxel, and bevacizumab, non-squamous (n434)
35
6.2
12.3
Chemotherapy c 
Cisplatin and pemetrexed, overall (n 839) 
31
4.8
10.3
0.94
0.841.05
Cisplatin and gemcitabine, overall (n830)
28
5.1
10.3
Cisplatin and pemetrexed, non-squamous
NR
5.3
11.8
0.81
0.700.94
Cisplatin and gemcitabine, non-squamous
NR
4.7
10.4
Cisplatin and pemetrexed, squamous
NR
4.4
9.4
1.23
1.001.51
Cisplatin and gemcitabine, squamous
NR
5.5
10.8
Chemotherapy d
Carboplatin and nab-paclitaxel, overall (n521)
33
6.3
12.1
0.922
0.7971.066
Carboplatin and paclitaxel, overall (n531)
25
5.8
11.2
Carboplatin and nab-paclitaxel, non-squamous (n221)
26
6.9
13.1
0.950
NR
Carboplatin and paclitaxel, non-squamous (n292)
25
6.5
13.0
Carboplatin and nab-paclitaxel, squamous (n300)
41
5.6
10.7
0.890
0.7191.101
Carboplatin and paclitaxel, squamous (n229)
24
5.7
9.5

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Table 1
Randomized Phase III Studies in Patients with Previously Untreated NonSmall Cell Lung Cancer (cont.)
Treatment Group
ORR
(%)
Median PFS
(months)
Median OS
(months)
OS HR
(95% CI)
Chemotherapy biologic e
Cisplatin and vinorelbine (n 568) 
29
4.8
10.1
0.871
0.7620.996
Cisplatin, vinorelbine, and cetuximab (n557)
36
4.8
11.3
Immunotherapy f
Pembrolizumab, PD-L1 positive (TPS 50%) (n154)
Platinum-based chemotherapies, PD-L1 positive (TPS 50%) 
(n151)
45
28
10.3
6.0
Not reached
Not reached
0.60
0.41, 0.89
HRhazard ratio; NRnot reported; ORRobjective response rate; OSoverall survival; PFSprogression-free survival; TPStumor 
proportion score.
a Schiller et al. 2002.
b Sandler et al. 2006.
c Scagliotti et al. 2008.
d Socinski et al. 2012.
e Pirker et al. 2009.
f
Reck et al. 2016.

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Despite the limited survival benefit conferred by cytotoxic chemotherapy, platinum-based 
regimens remain the standard first-line (1L) option for most patients with metastatic
NSCLC not harboring an activating EGFR mutation or ALK gene rearrangement.  In 
particular, for newly diagnosed advanced-stage non-squamous NSCLC, standard of 
care is a platinum-based doublet with either cisplatin or carboplatin and a taxane or 
pemetrexed, with or without bevacizumab. The combination of a platinum-based doublet 
with pemetrexed has been more widely used because of a better tolerability and safety 
profile.  Currently, the standard of care for newly diagnosed advanced-stage squamous 
NSCLC includes gemcitabine in combination with a platinum agent.
Overall, these chemotherapy regimens are associated with substantial toxicities (such as 
febrile neutropenia, myelosuppression, nausea, alopecia, nephropathy, and neuropathy) 
and are generally poorly tolerated by elderly patients and by poor-performance-status 
patients.  Therefore, novel therapies that deliver an improved therapeutic index are 
urgently needed for NSCLC.
Immune checkpoint inhibitors, including PD-L1/PD-1 blocking antibodies, have emerged 
as a new therapeutic option for 1L treatment of metastatic NSCLC.  Study 
KEYNOTE-024 was a Phase III, randomized, open-label study evaluating the PD-1 
blocking antibody pembrolizumab given as monotherapy compared with platinum-based 
chemotherapy in patients who had previously untreated advanced NSCLC with PD-L1 
expression on at least 50% of tumor cells (TCs) (Reck et al. 2016).  In this study, median 
progression-free survival (PFS) was 10.3 months in the pembrolizumab group versus 
6 months in the chemotherapy group (hazard ratio [HR] 0.50; 95% CI: 0.37, 0.68; 
p 0.001).  The estimated rate of OS at 6 months was 80.2% (95% CI: 72.9%, 85.7%) in 
the pembrolizumab group versus 72.4% (95% CI: 64.5%, 78.9%) in the chemotherapy 
group; median OS was not reached in either group.  OS was significantly longer in the 
pembrolizumab group than in the chemotherapy group (HR 0.60; 95% CI: 0.41, 0.89; 
p 0.005).  On the basis of this study, pembrolizumab was approved by the U.S. Food 
and Drug Administration (FDA) and by the European Medicines Agency for 1L treatment 
of metastatic NSCLC in patients whose tumors have high PD-L1 expression (tumor 
proportion score [TPS] 50%) with no EGFR or ALK gene aberrations.
Despite improvements in the treatment of patients with advanced NSCLC that have 
resulted in longer survival times and reduced disease-related symptoms, nearly all 
patients experience disease progression.  Cancer immunotherapies, in particular
antibodies that block PD-L1/PD1, offer the possibility of long-term disease control.
Pembrolizumab is associated with significantly longer PFS and OS in previously 
untreated patients with advanced NSCLC (with PD-L1 expression on at least 50% of 
TCs) than was platinum-based chemotherapy (Reck et al. 2016).  In the second-line (2L) 
cancer immunotherapy (CIT)-naive metastatic NSCLC setting, the antiPD-L1 antibody 
atezolizumab (see Section 1.7), as well as the antiPD-1 antibodies nivolumab and 
pembrolizumab, provide similar clinically meaningful benefit in either unselected or 
PD-L1selected patients with advanced NSCLC; however, the majority of patients still 

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remain unresponsive or progress on antiPD-L1/PD-1 treatment, and the escape 
mechanisms to antiPD-L1/PD-1 treatment are poorly understood.  Consequently, new 
molecules and combinations, including novel immunotherapy combinations, are urgently 
needed to address this unmet medical need and are currently being evaluated in 
ongoing clinical studies to further enhance our understanding of the mechanisms 
underlying the potential efficacy of immunotherapy (Dempke et al. 2015).
1.3
TIGIT PATHWAY IN CANCER AS POTENTIAL ANTI-CANCER 
THERAPY
T-cell immunoreceptor with Ig and ITIM domains (TIGIT) is a novel immune inhibitory 
receptor that is a member of the immunoglobulin super family (Yu et al. 2009; Manieri
et al. 2017).  TIGIT is expressed on the surface of activated T-cell and natural killer 
(NK)-cell subsets and interacts with high affinity with CD155 (also known as poliovirus 
receptor [PVR]) (Yu et al. 2009).  Genetic ablation of TIGIT in T cells in mice results in 
exacerbated T-cell responses in preclinical models of autoimmune and viral infections, 
demonstrating the role of TIGIT in inhibiting T-cell responses (Joller et al. 2011; 
Johnston et al. 2014).  TIGIT expression is elevated in the tumor microenvironment in 
many human tumors, is coordinately expressed with other checkpoint immune-receptors 
such as PD-1, and is associated with impaired T-cell function and anti-tumor immunity 
(Johnston et al. 2014).  Activation of TIGIT on T cells and NK cells limits cellular 
proliferation, effector cytokine production, and killing of target TCs (Stanietsky et al. 2009; 
Yu et al. 2009; Johnston et al. 2014; Wang et al. 2015; Manieri et al. 2017).
TIGIT is expressed in a wide variety of human tumors, including NSCLC, and is highly 
correlated with T-cell infiltration and PD-1 expression (Johnston et al. 2014).  
Fluorescence-activated cell sorting analysis on fresh tumor samples showed that TIGIT 
and PD-1 are also co-expressed on tumor infiltrating T-cells.  TIGIT expression ranges 
from 30% to 80% and 50% to 80% on tumor-infiltrating CD4and CD8T cells, 
respectively (Johnston et al. 2014).  It has also been reported that tumor-infiltrating 
lymphocytes from early-stage primary NSCLCs co-express TIGIT with PD-1, suggesting 
that TIGIT expression may be important throughout the development of NSCLC (Tassi 
et al. 2017).
Therefore, TIGIT is a potential target for therapeutic intervention aimed at restoring the 
immune response against the tumor, especially in NSCLC.  Agents that inhibit the 
activity of TIGIT may relieve an important source of tumor-associated immune 
suppression and may enhance the activity of other immune-based therapies, such as 
atezolizumab.  Early nonclinical results using genetically deficient mice and blocking 
antibodies reveal a key role for TIGIT in regulating T-cell responses.  Together these 
data support the hypothesis that anti-TIGIT in combination with antiPD-L1 may 
reactivate anti-tumor immunity in NSCLC to provide clinical benefit to patients 
(see Section 1.5). 

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1.4
PD-L1/PD-1 PATHWAY IN CANCER
PD-L1 is a cell surface protein that is broadly expressed by TCs and tumor-infiltrating 
immune cells (ICs) in many human cancers, including lung cancer. PD-L1 binds to PD-1 
and B7.1, two known inhibitory receptors whose expression on activated T cells is 
sustained in states of chronic stimulation such as chronic infection or cancer (Blank et al. 
2005; Keir et al. 2008).  Ligation of PD-L1 with PD-1 or B7.1 inhibits T-cell proliferation, 
cytokine production, and cytolytic activity, leading to a functional inactivation or inhibition 
of T cells.  Aberrant expression 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 PD-L1/B7.1 pathways represents an 
attractive strategy to reinvigorate tumor-specific T-cell immunity.
Indeed, inhibitors of PD-L1 or PD-1 have demonstrated clinical efficacy or promising 
anti-tumor activity in a wide range of tumor types including NSCLC (Herbst et al. 2014, 
2016; Borghaei et al. 2015; Garon et al. 2015; Gettinger et al. 2015; Fehrenbacher et al. 
2016; Rosenberg et al. 2016).  The evidenced benefit has led to approvals of antiPD-1 
antibodies (nivolumab and pembrolizumab) and an antiPD-L1 antibody (atezolizumab) 
in metastatic NSCLC (see Keytruda[pembrolizumab] U.S. Package Insert, Opdivo
[nivolumab] U.S. Package Insert, and Tecentriq[atezolizumab] U.S. Package Insert).  
Nevertheless, many patients with NSCLC treated with PD-L1/PD-1 blockade alone do 
not experience sustained clinical benefit, underscoring the need to explore CIT
combinations with the potential to overcome intrinsic or acquired resistance to 
checkpoint inhibition. Antagonists that target additional inhibitory receptors have the 
potential to enhance such anti-tumor T-cell responses.  Hence, such co-inhibitory 
antagonists have emerged as attractive combination partners for antiPD-L1/PD-1 on 
the basis of their complementary mechanism of action.
Combined immune checkpoint inhibition has been shown to enhance efficacy in clinical 
studies.  It was first reported that a Phase I combination study of an antiPD-1 antibody 
(nivolumab) with an anti-cytotoxic T lymphocyteassociated protein 4 (antiCTLA-4)
antibody (ipilimumab) in patients with advanced melanoma resulted in rapid and 
pronounced tumor responses in patients receiving the maximum combination doses that 
were shown to be associated with an acceptable risk-benefit (Wolchok et al. 2013). This
combination of nivolumab and ipilimumab was also studied as a 1L treatment in patients 
with metastatic NSCLC in another Phase I study, yielding ORRs of 38% to 47% with two 
different dose schedules for ipilimumab, and median duration of response (DOR) was 
not yet reached at the time of reporting (Hellman et al. 2017).  However, this 
combination of nivolumab and ipilimumab results in increased toxicity, as Grade 34 
adverse events occurred in 33% to 37% of patients, with the most commonly reported 
treatment-related adverse events being increased lipase and pneumonitis.  A similar 
combination of the antiPD-L1 antibody durvalumab and the anti-CTLA-4 antibody 
tremelimumab in patients with NSCLC in a Phase Ib study reported an ORR of 23%, 
with similar increased adverse events (Antonia et al. 2016). Combined immune 

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Figure 1
Proposed Model for Re-Activating Tumor-Specific T Cells by 
TIGIT Inhibition and PD-L1 Inhibition
APCantigen-presenting cell, IFNinterferon-gamma, PVRpoliovirus receptor; TCRT-cell 
receptor; TIGITT-cell immunoreceptor with Ig and ITIM domains.
1.6
BACKGROUND ON MTIG7192A
MTIG7192A (also known as tiragolumab) is a fully human IgG1/kappa monoclonal
antibody (MAb)
 
 
 
 
 
 
Therapeutic blockade of TIGIT by MTIG7192A represents an attractive strategy for 
cancer therapy and is expected to enhance the magnitude and quality of the 
tumor-specific T-cell responses, which may result in improved meaningful anti-tumor 
activity when MTIG7192A is used as a single agent or in combination with other cancer 
immunotherapies.
MTIG7192A is being investigated as a potential therapy against tumors in humans.

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Please refer to the MTIG7192A Investigator’s Brochure for details on the adverse events 
observed in patients treated with MTIG7192A plus atezolizumab.
1.6.2.3
Clinical Activity of MTIG7192A Plus Atezolizumab
 
 
 
  
 
 
 
Please refer to the MTIG7192A Investigator’s Brochure for details on clinical activity in 
all patients treated to date with MTIG7192A as a single agent or in combination with 
atezolizumab, regardless of tumor type.

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1.7.1
Summary of Nonclinical Studies for Atezolizumab
The nonclinical strategy of the atezolizumab program was to demonstrate in vitro and 
in vivo activity, to determine the in vivo PK behavior, to demonstrate an acceptable 
safety profile, and to identify a Phase I starting dose.  Comprehensive pharmacologic, 
PK, and toxicologic evaluations were thus undertaken with atezolizumab. 
The safety, PK, and toxicokinetics of atezolizumab were investigated in mice and 
cynomolgus monkeys to support IV administration and to aid in projecting the 
appropriate starting dose in humans.  Given the similar binding of atezolizumab for 
cynomolgus monkey and human PD-L1, the cynomolgus monkey was selected as the 
primary and relevant nonclinical model for understanding the safety, PK, and 
toxicokinetics of atezolizumab.
Overall, the nonclinical PK and toxicokinetics observed for atezolizumab supported entry 
into clinical studies, including providing adequate safety factors for the proposed Phase I 
starting doses.  The results of the toxicology program were consistent with the 
anticipated pharmacologic activity of downmodulating the PD-L1/PD-1 pathway and 
supported entry into clinical studies in patients.
Please refer to the current Atezolizumab Investigator’s Brochure for further details on the 
nonclinical studies.
1.7.2
Clinical Experience with Atezolizumab in NSCLC 
1.7.2.1
Ongoing Clinical Studies with Atezolizumab in NSCLC
Atezolizumab is currently being tested in multiple Phase I, II, and III studies in NSCLC, 
both as monotherapy and in combination with several anti-cancer therapies (please see 
the Atezolizumab Investigator’s Brochure for study descriptions).  The single agent and 
combination safety and efficacy data for atezolizumab in NSCLC include, but are not 
limited to, data from the following studies: 

Study PCD4989g: a Phase Ia, first-in-human, open-label, dose-escalation study 
evaluating the safety, tolerability, immunogenicity, pharmacokinetics, exploratory 
pharmacodynamics, and preliminary evidence of activity of atezolizumab as a single 
agent in patients with locally advanced or metastatic malignancies, including 
NSCLC  

Study GO28753 (POPLAR): a randomized, Phase II, open-label study assessing 
the clinical benefit of atezolizumab versus docetaxel in patients with locally 
advanced or metastatic NSCLC that has progressed during or following treatment 
with a platinum-containing regimen 

Study GO28754 (BIRCH): a Phase II, open-label study assessing the clinical 
benefit of atezolizumab in patients with PD-L1selected locally advanced or 
metastatic NSCLC in all lines of therapy (previously untreated to heavily pretreated)

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
Study GO28915 (OAK): a randomized, Phase III, open-label study assessing the 
efficacy and safety of atezolizumab versus docetaxel in patients with locally 
advanced or metastatic NSCLC that has progressed during or following treatment 
with a platinum-containing regimen

Study GO29436 (IMpower150):  a randomized, Phase III, open-label study 
evaluating the efficacy and safety of atezolizumab plus carboplatin plus paclitaxel 
with or without bevacizumab compared with carboplatin plus paclitaxel plus
bevacizumab in chemotherapy-naive patients with Stage IV non-squamous NSCLC 
In addition, the following studies of atezolizumab as a single agent or in combination with 
chemotherapy and/or immunotherapy are currently enrolling patients with NSCLC, 
including chemotherapy-naive patients, or have completed enrollment and are awaiting 
study results: 

Study GO29431 (IMpower110):  a randomized, Phase III, open-label study 
evaluating the efficacy and safety of atezolizumab compared with 
cisplatin/carboplatin plus pemetrexed or cisplatin/carboplatin plus gemcitabine in 
PD-L1selected chemotherapy-naive patients with Stage IV non-squamous NSCLC

Study GO29437 (IMpower 131):  a randomized, Phase III, open-label study
evaluating the efficacy and safety of atezolizumab in combination with carboplatin 
plus paclitaxel or atezolizumab in combination with carboplatin plus nab-paclitaxel 
versus carboplatin plus nab-paclitaxel in chemotherapy-naive patients with Stage IV 
squamous NSCLC

Study GO29438 (IMpower132):  a randomized, Phase III, open-label study 
evaluating the efficacy and safety of atezolizumab in combination with carboplatin or 
cisplatin plus pemetrexed compared with carboplatin or cisplatin plus pemetrexed in 
chemotherapy-naive patients with Stage IV non-squamous NSCLC

Study GO29527 (IMpower010):  a randomized, Phase III, open-label study of 
atezolizumab compared with BSC following adjuvant cisplatin-based chemotherapy 
in patients with completely resected Stage IB to IIIA NSCLC

Study GO29537 (IMpower130):  a randomized, Phase III, open-label study 
evaluating the efficacy and safety of atezolizumab plus carboplatin plus
nab-paclitaxel compared with carboplatin plus nab-paclitaxel in chemotherapy-naive 
patients with Stage IV non-squamous NSCLC

Study BO39610 (MORPHEUS-Lung):  a randomized, Phase Ib/II, open-label
umbrella study evaluating the efficacy and safety of atezolizumab plus multiple 
immunotherapy-based treatment combinations in chemotherapy-naive and 
pre-treated patients with Stage IV NSCLC
Please refer to the Atezolizumab Investigator’s Brochure for full details on the clinical 
studies in all tumor types, including NSCLC.

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1.7.2.2
Clinical Safety of Atezolizumab
As of the clinical cutoff date of 17 May 2019 of the Atezolizumab Investigator’s Brochure, 
an estimated 21,000 patients with solid tumor and hematologic malignancies had 
received atezolizumab in clinical study participation as a single agent or in combination 
with cytotoxic chemotherapy and/or targeted therapy. 
Overall, treatment with atezolizumab is well tolerated with a manageable adverse event 
profile.  Currently, no MTD, no DLTs, and no clear dose-related trends in the incidence 
of adverse events have been determined.
Immune-mediated adverse events associated with atezolizumab include pneumonitis, 
hepatitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, hyperthyroidism, adrenal 
insufficiency, hypophysitis, Guillain-Barré syndrome, myasthenic syndrome/myasthenia 
gravis, meningoencephalitis, myocarditis, myositis, and nephritis.  IRRs are another 
identified risk of atezolizumab.
Potential risks of atezolizumab include immune-mediated ocular toxicity, 
immune-mediated severe cutaneous adverse reactions, immune-mediated vasculitis, 
autoimmune hemolytic anemia, and toxicity associated with ADAs.  Based on the 
mechanism of action, atezolizumab likely would result in fetal harm if administered to 
pregnant women. In addition, immune-mediated reactions may involve any organ 
system and may lead to HLH and macrophage activation syndrome (MAS). 
1.7.2.2.1
Clinical Safety of Atezolizumab as a Single Agent
As of the clinical cutoff date 17 May 2019, of the pooled 3178 patients with NSCLC,
urothelial carcinoma, renal-cell carcinoma, and other tumors who received single-agent 
atezolizumab, 96% experienced an adverse event regardless of attribution to 
atezolizumab. The majority of these adverse events were Grade 1 or 2 in maximum 
severity based on NCI CTCAE v4.0.
Safety findings of single-agent atezolizumab across multiple tumor types in the clinical 
development program are consistent with the known mechanism of action of 
atezolizumab and the underlying disease. The most frequently observed adverse events 
occurring in 10% of treated patients included fatigue, decreased appetite, cough, 
nausea, dyspnea, constipation, diarrhea, pyrexia, vomiting, arthralgia, back pain, 
asthenia, anemia, pruritus, rash, headache, urinary tract infection, and peripheral 
edema.
Grade 3 and Grade 4 adverse events were reported in 46.5% of patients with the most 
common (3% of patients) being anemia (5.0%), dyspnea (3.7%), fatigue (3.4%), 
hyponatremia (3.1%), and pneumonia (3.0%). Grade 3 and Grade 4 adverse events 
considered related to study drug by the investigator occurred in 15.6% of patients.

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1.7.2.2.2
Clinical Safety of Single-Agent Atezolizumab in Patients with 
NSCLC
Safety data for patients with metastatic NSCLC treated with single-agent atezolizumab 
are also derived from the following completed Phase II/III studies in NSCLC: GO28753 
(POPLAR), GO28915 (OAK), and GO28754 (BIRCH).  Overall, in the randomized 
studies (OAK and POPLAR), atezolizumab was well tolerated by patients with metastatic 
NSCLC, with fewer Grade 3 or Grade 4 adverse events and fewer discontinuations seen 
with atezolizumab versus the chemotherapy comparator arm of docetaxel. The most 
commonly reported adverse events (all grades) for patients treated with atezolizumab on 
these studies included fatigue, decreased appetite, constipation, cough, dyspnea, 
asthenia, diarrhea, and nausea.  The adverse event profiles observed in these studies 
for patients with metastatic NSCLC treated with single-agent atezolizumab is consistent 
with that observed in Study PCD4989g (in the overall and NSCLC patient populations).
1.7.2.2.3
Immune-Mediated Adverse Events of Atezolizumab as a 
Single Agent
Immune-mediated adverse events are consistent with the role of the PD-L1/PD-1 
pathway in regulating peripheral tolerance. Given the mechanism of action of 
atezolizumab, events associated with inflammation and/or immune-mediated adverse 
events are closely monitored during the atezolizumab clinical program. Although most 
immune-mediated adverse events observed with immunomodulatory agents have been 
mild and self-limiting, severe cases of immune-mediated toxicities may require acute 
management with topical corticosteroids, systemic corticosteroids, or other 
immunosuppressive agents.
For the most recent safety data, please refer to the Atezolizumab Investigator’s Brochure.
1.7.2.3
Clinical Activity of Atezolizumab
Anti-tumor activity, including RECIST-based responses (i.e., RECIST v1.1 responses), 
have been observed in patients with different tumor types, including NSCLC, treated with 
atezolizumab monotherapy in multiple Phase I, II, and III studies.
Please refer to the Atezolizumab Investigator’s Brochure for details on clinical activity in 
all patients treated to date, regardless of tumor type.
1.7.2.3.1
Clinical Activity of Atezolizumab in Patients with NSCLC
Study PCD4989g (NSCLC Cohort)
As of the clinical data cutoff date of 2 December 2014, 88 patients with locally advanced 
or metastatic NSCLC had enrolled in the NSCLC expansion cohort of this Phase I study.  
The majority of these patients had received multiple prior systemic therapies.  Overall, 
responses were observed in 20 of 88 patients (22.7%) with NSCLC and included 
responses in patients with non-squamous and squamous NSCLC (16 in 67 patients and 
4 in 21 patients, respectively).  

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17.3% to 27.0% for TC3 or IC3. The highest level of PD-L1 expression (TC3 or IC3) 
showed the highest ORRs across all lines of therapy.  At the time of the primary analysis 
on 28 May 2015, the median OS was not reached for all subgroups with the exception of 
TC2/3 or IC2/3 in Cohort 1 (chemotherapy-naive), where the median was 14.0 months 
(95% CI: 14.0not evaluable). 
An updated efficacy analysis (data cutoff date 1 August 2016) conducted for 
138 patients receiving 1L treatment (Cohort 1) with a minimum follow-up of 22.5 months 
provided evidence of a clinically meaningful benefit of atezolizumab as 1L treatment for 
patients with NSCLC, as demonstrated by a median OS of 23.5 months for all patients 
(TC2/3 or IC2/3).  ORR was 25% (95% CI: 18%, 33%) and median PFS was 7.3 months 
(95% CI: 5.7, 9.7 months) for all patients (TC2/3 or IC2/3); the median duration of 
response (DOR) was 9.8 months for all chemotherapy-naive patients (Peters et al. 
2017b).
Study GO28753 (POPLAR)
This randomized Phase II study in patients with advanced or metastatic NSCLC who 
failed prior platinum therapy enrolled 287 patients, who were randomized to treatment 
with atezolizumab or docetaxel chemotherapy (Fehrenbacher et al. 2016).  At the time of 
the primary analysis on 8 May 2015, a clinically meaningful and statistically significant 
improvement in OS was observed for patients treated with atezolizumab compared with 
docetaxel with a stratified HR of 0.73 (95% CI: 0.53, 0.99; p-value0.04).  The median 
OS was 12.6 months in the atezolizumab arm versus 9.7 months in the docetaxel arm.  
Improvement in OS in the atezolizumab arm relative to the docetaxel arm increased with 
increasing PD-L1 expression.  In the TC0 or IC0 subgroup, however, median OS was 
9.7 months in both the atezolizumab and docetaxel arms, suggesting that 
atezolizumab-treated patients in this subgroup also derived clinical benefit. 
Study GO28915 (OAK)
In this randomized Phase III study, patients with advanced or metastatic NSCLC who 
had failed prior platinum therapy were randomized to treatment with atezolizumab or 
docetaxel chemotherapy. The co-primary endpoints were OS in all randomized patients 
(intent-to-treat [ITT] population) and OS in a PD-L1selected subgroup in the primary 
analysis population (TC1/2/3 or IC1/2/3 by Ventana PD-L1 [SP142] IHC assay).  At the 
time of the primary analysis (data cutoff date 7 July 2016), which included data from the 
first 850 randomized patients, OS was significantly improved with atezolizumab 
compared with docetaxel (median OS, 13.8 vs. 9.6 months; HR 0.73; 95% CI: 0.62, 
0.87; p 0.0003).  For the TC1/2/3 or IC1/2/3 subgroups, OS was also significantly 
improved with atezolizumab compared with docetaxel (median OS, 15.7 vs. 10.3 months; 
HR 0.74; 95% CI: 0.58, 0.93; p 0.0102).
PFS was similar between the atezolizumab and docetaxel arms (median PFS, 2.8 vs.
4 months; HR 0.95; 95% CI: 0.82, 1.10).  Fifty-eight patients (14%) in the atezolizumab 
arm and 57 patients (13%) in the docetaxel arm achieved a confirmed objective 

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response per RECIST v1.1.  Objective responses with atezolizumab were durable, with 
a median duration of 16.3 months (95% CI: 10 months, not estimable) in the 
atezolizumab arm compared with 6.2 months (95% CI: 4.9, 7.6 months) in the docetaxel 
arm (Rittmeyer et al. 2017).
1.7.2.3.2
Clinical Activity of Atezolizumab Plus Chemotherapy in 
Patients with NSCLC
Study GO29436 (IMpower150)
This Phase III study enrolled patients with chemotherapy-naive metastatic NSCLC and 
randomized them to receive atezolizumab or placebo combined with carboplatin plus 
paclitaxel with or without bevacizumab.  As of the clinical data cutoff date of 
15 September 2017, the safety and efficacy evaluable population included 400 patients 
in each arm. PFS was increased in the atezolizumab plus chemotherapy plus
bevacizumab arm compared with the placebo plus chemotherapy plus bevacizumab arm 
(median PFS 8.3 months vs. 6.8 months; HR 0.617, 95% CI: 0.517, 0.737).  Although 
clinical benefit was seen across all PD-L1 subgroups, PFS was increased in the PD-L1 
IHC TC1/2/3 or IC1/2/3 group compared with the PD-L1 IHC TC0 or IC0 group (median 
PFS 11 months and 7.1 months, respectively).  The combination was well tolerated and 
was consistent with the known safety profile of atezolizumab, chemotherapy, and 
bevacizumab.  OS data was not mature at the time of the data cutoff (Reck et al. 2017).
Please refer to the Atezolizumab Investigator’s Brochure for the most recent information 
regarding clinical efficacy from the studies of atezolizumab in NSCLC.
1.7.2.4
Clinical Pharmacokinetics and Immunogenicity of 
Atezolizumab
Overall, atezolizumab exposures increased dose proportionally over the dose range of 
1 mg/kg to 20 mg/kg, including the fixed dose of 1200 mg administered Q3W.  The 
elimination half-life of atezolizumab was estimated to be 27 days, based on a Phase I 
population PK analysis that included 472 patients from Studies PCD4989g and 
JO28944.  ADAs to atezolizumab have been observed in some patients at all dosing 
levels, but the presence of ADAs did not appear to have a clinically significant impact on 
pharmacokinetics, safety, or efficacy of atezolizumab at the 1200-mg dose.  
 
 
 
Please refer to the Atezolizumab Investigator’s Brochure for details on the clinical PK of 
atezolizumab.

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1.8
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
1.8.1
Study Rationale
Encouraging clinical data emerging in the field of tumor immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant survival benefit in patients with metastatic cancer, including NSCLC.  
Recent approvals by the FDA in metastatic NSCLC of the PD-1 inhibitors
pembrolizumab in the 1L and 2L-plus settings, nivolumab in the 2L setting, and the 
PD-L1 inhibitor atezolizumab in the 2L-plus settings, as well as the observation of 
durable objective responses in clinical studies achieved with other antiPD-L1/PD-1
antibodies in patients with NSCLC, validate the inhibition of the PD-L1/PD-1 pathway for 
achieving clinical benefit in NSCLC. Furthermore, the safety profile of these 
immunotherapies, including PD-L1/PD-1 antibodies, appears to be more tolerable than 
many of the chemotherapy doublet combinations given in the front-line setting, which are 
associated with substantial toxicities and are often poorly tolerated by elderly and 
poor-performance status patients.
Nevertheless, despite the robust activity observed with anti-PD-L1/PD-1 agents, durable 
clinical benefit appears limited to a minority of treated patients.  Enrichment or selection 
strategies to identify those patients most likely to respond to PD-L1/PD-1 inhibitors are 
still evolving, but one area has focused on PD-L1selection of tumors, especially in 
earlier lines of therapy for metastatic NSCLC. For example, nivolumab, the first PD-1 
inhibitor approved for NSCLC, was approved for patients with NSCLC in the 2L setting, 
regardless of PD-L1 expression, although OS and PFS HRs in patients with 
non-squamous NSCLC trended lower with increasing PD-L1 expression (Opdivo U.S. 
Package Insert).  Pembrolizumab was the second PD-1 inhibitor approved by the FDA 
for metastatic NSCLC and was approved for patients whose tumors express PD-L1 on 
the basis of a study that demonstrated that PD-L1 expression tends to enrich for 
increased efficacy (Herbst et al. 2016). Atezolizumab was the first PD-L1 inhibitor 
approved for 2L NSCLC irrespective of PD-L1 expression, and there was also a clinically 
meaningful benefit observed with atezolizumab given as 1L treatment for 
PD-L1selected patients (TC2/3 or IC2/3) with NSCLC in Study GO28754 (BIRCH).
The PD-L1 expression level that is most predictive of response to PD-L1/PD-1 inhibitors 
remains unknown in the 1L setting for NSCLC, although current studies are focusing on 
a minimum level of PD-L1 expression to enroll.  For example, although pembrolizumab 
is approved in the 1L setting for metastatic NSCLC with a TPS cutoff of 50%, 
pembrolizumab is currently being tested at a TPS cutoff of 1% in the KEYNOTE-042 
study.  Similarly, atezolizumab is being studied as a 1L treatment for patients with 
metastatic NSCLC whose tumors have a minimum level of PD-L1 expression (1%) on 
TCs or ICs (TC1/2/3 or IC1/2/3) (Study GO29431, IMpower110).
Therefore, in the current study, in order to potentially select patients who may benefit 
from immunotherapy in the 1L setting, all patients, either on the experimental arm with 

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MTIG7192A plus atezolizumab or on the comparator arm with placebo plus 
atezolizumab, will need to have a minimum PD-L1 expression of TPS 1% by the PD-L1 
IHC 22C3 pharmDx assay in order to enroll in the study.  
Although PD-L1/PD-1 therapeutic antibodies may have a greater probability of 
potentially benefiting those patients whose tumors have PD-L1 expression, the majority 
of patients with metastatic NSCLC treated with PD-L1/PD-1 antibodies still do not 
experience sustained clinical benefit, despite the selection for PD-L1 expression.  It is 
hypothesized that many of these patients with metastatic NSCLC may have intrinsic or 
acquired resistance to checkpoint inhibition.  Thus, another strategy to increase the 
response to checkpoint inhibitors among patients has focused on treatment with novel 
immunotherapy combinations that may overcome such intrinsic or acquired resistance to 
PD-L1/PD-1 antibodies.
TIGIT is a novel inhibitory immunoreceptor that can limit the effector function of 
tumor-associated lymphocytes.  Unlike other inhibitory co-receptors, TIGIT is often 
coordinately expressed with PD-1 on infiltrating T cells in multiple tumors, including 
NSCLC.  Thus, the combined inhibition of the TIGIT and PD-L1/PD-1 pathways is a 
unique and attractive strategy to potentiate the activity of a PD-L1 antibody such as 
atezolizumab, due to the complementary mechanisms of action of anti-TIGIT and 
antiPD-L1.  In preclinical models, combined blockade of the TIGIT and PD-L1/PD-1 
pathways has shown superior efficacy compared with blockade of each pathway alone.  
 
 
 
Therefore, the current study is designed to evaluate whether the anti-tumor effects of 
atezolizumab, as measured by ORR, PFS, DOR, and OS, can be improved with the 
addition of the anti-TIGIT antibody MTIG7192A compared with placebo plus 
atezolizumab in patients with metastatic NSCLC who are selected on the basis of a 
minimum level of PD-L1 tumor expression (TPS 1%).  The PD-L1 IHC 22C3 pharmDx 
assay will be used to identify patients that are positive for tumor PD-L1 expression.
1.8.2
BenefitRisk Assessment
This study will enroll patients with locally advanced unresectable or metastatic 
PDL1selected NSCLC who are naive to chemotherapy treatment, and all patients will 
be administered atezolizumab, either in the experimental arm or in the placebo arm.  
The combination of MTIG7192A plus atezolizumab in the experimental arm can 
represent a potential valuable treatment option and can offer a reasonable benefitrisk 
balance for patients in this study. 

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To better understand the risks and benefits about participation on this study, patients will 
be fully informed of the current 1L treatment options for metastatic NSCLC, as approved 
in the United States by the FDA in 2017.  For all patients, the standard of care in the 1L
treatment of metastatic NSCLC without EGFR or ALK alterations is a chemotherapy 
doublet often consisting of a platinum chemotherapy agent.  Although chemotherapy 
combinations can result in significant toxicities, such regimens are still the approved 
standard of care in 1L metastatic NSCLC in many countries.  Furthermore, in the 
United States, for patients with metastatic NSCLC whose tumors have high PD-L1 
expression with a TPS 50% by the PD-L1 IHC 22C3 pharmDx assay, pembrolizumab
as a single agent is approved as a 1L treatment.  Finally, in the United States, for 
patients with non-squamous NSCLC, the combination of pembrolizumab with 
pemetrexed and carboplatin chemotherapy is also approved as a 1L treatment option, 
irrespective of PD-L1 expression.
 
 
, atezolizumab is approved by the FDA in the 2L-plus settings for 
all patients with metastatic NSCLC, irrespective of PD-L1 expression, based on 
prolonged OS in two randomized studies (see Section 1.7.2.3).  Atezolizumab has also 
been studied previously in 1L metastatic NSCLC in Study GO28754 (BIRCH), in which 
patients with PD-L1selected NSCLC had a median OS of 23.5 months (see 
Section 1.7.2.1).  Furthermore, multiple studies of atezolizumab as a single agent or 
in combination with other anti-cancer agents, including chemotherapy, are ongoing in 
1L metastatic NSCLC.  There is an ongoing study of single-agent atezolizumab in 
PDL1selected metastatic 1L NSCLC (Study GO29431, IMpower110) (see 
Section 1.7.2.1).  Atezolizumab is also being studied in combination with chemotherapy 
in 1L NSCLC; one such study (GO29436, IMpower150) with atezolizumab in 
combination with carboplatin and paclitaxel with bevacizumab in non-squamous 
1L NSCLC demonstrated improved PFS (Reck et al. 2017).  Finally, there is an ongoing 
study in 1L NSCLC of atezolizumab in combination with other anti-cancer agents, 
including immunotherapy (Study BO39610, MORPHEUS).
Therefore, atezolizumab as a single agent has clinical efficacy in metastatic NSCLC and 
is generally well tolerated (see Section 1.7.2 and Section 3.3.1).  Adverse events with 
potentially immune-mediated causes consistent with an immunotherapeutic agent, 
including rash, hypothyroidism, hepatitis/transaminitis, colitis, and myasthenia gravis 
have been observed with atezolizumab.  To date, however, these events have been 
manageable with treatment.  
 
  
 
 
 

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atezolizumab and of the combination of MTIG7192A plus atezolizumab appear to be 
similar, and generally mild and transient in nature, patients may not have increased 
toxicity with the combination of MTIG7192A and atezolizumab.  As the potential toxicities 
of atezolizumab or MTIG7192A plus atezolizumab do not overlap with the adverse 
effects of chemotherapy, patients who do not respond to study treatment with 
atezolizumab or atezolizumab plus MTIG7192A are considered likely to be able to 
subsequently receive standard therapies for which they would otherwise have been 
eligible.  In addition, PD-1 inhibitors, such as nivolumab and pembrolizumab, are also 
approved in 2L therapy for metastatic NSCLC.  Therefore, based on the above data that 
patients will be selected for this study based on tumor PD-L1 expression, that all patients 
in the study will receive atezolizumab, and that the preclinical and clinical data suggest
that patients with metatstatic NSCLC can respond to the combination of MTIG7192A 
plus atezolizumab without increased toxicity, the overall benefitrisk ratio is considered 
to be appropriate for the study population.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy and safety of MTIG7192A plus atezolizumab
compared with placebo plus atezolizumab in chemotherapy-naive patients with locally 
advanced unresectable or metastatic PD-L1selected NSCLC, excluding patients with a 
sensitizing EGFR mutation or ALK translocation.  
The primary population is defined as all randomized patients who are selected on the 
basis of a minimum level of PD-L1 expression (TPS 1%) using an FDA-approved
PD-L1 IHC 22C3 pharmDx assay performed locally or centrally.  Specific objectives and 
corresponding endpoints for the study are outlined below in Table 3.
Table 3
Objectives and Corresponding Endpoints
Primary Efficacy Objective
Corresponding Endpoints
To evaluate the efficacy of MTIG7192A
plus atezolizumab compared with
placebo plus atezolizumab, as measured 
by objective response rate (ORR) and 
progression-free survival (PFS)
ORR, defined as a complete response or partial 
response on two consecutive occasions 4 weeks 
apart, as determined by the investigator according to 
RECIST v1.1
PFS, defined as the time from randomization to the 
first occurrence of disease progression, as 
determined by the investigator according to RECIST 
v1.1, or death from any cause, whichever occurs first
Secondary Efficacy Objective
Corresponding Endpoints
To evaluate the efficacy of MTIG7192A
plus atezolizumab compared with
placebo plus atezolizumab, as measured 
by duration of objective response (DOR) 
and overall survival (OS)
DOR, defined as the time from the first occurrence of 
a documented objective response to disease 
progression, as determined by the investigator
according to RECIST v1.1, or death from any cause,
whichever occurs first
OS, defined as the time from randomization to death 
from any cause

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Eligible patients will be randomized 1:1 to receive either MTIG7192A plus atezolizumab 
or placebo plus atezolizumab.
Eligible patients will be stratified by the PD-L1 IHC 22C3 pharmDx assay result (TPS 1% 
to 49% vs. TPS 50%), tumor histology (non-squamous vs. squamous), and patient’s 
history of tobacco use (yes vs. no).
In the experimental arm, patients will receive atezolizumab at a fixed dose of 1200 mg 
administered by IV infusion Q3W on Day 1 of each 21-day cycle and MTIG7192A at its 
recommended Phase II dose of 600 mg administered by IV infusion Q3W on Day 1 of 
each 21-day cycle.  
In the control arm, patients will receive atezolizumab at a fixed dose of 1200 mg 
administered by IV infusion Q3W on Day 1 of each 21-day cycle and placebo
administered by IV infusion Q3W on Day 1 of each 21-day cycle.  
Patients will undergo tumor assessments by standard RECIST v1.1 at baseline and at 
every 6 weeks thereafter (approximately every 2 cycles) for the first 36 weeks 
(approximately up to Cycle 12) following randomization (see Section 4.5.5 and 
Appendix 1).  After 36 weeks (or after Cycle 12) from randomization, patients who have 
not experienced disease progression will undergo tumor assessment every 9 (1) weeks 
(approximately every 3 cycles). 
Treatment may be continued as long as patients are experiencing clinical benefit as 
assessed by the investigator in the absence of unacceptable toxicity or symptomatic 
deterioration attributed to disease progression after an integrated assessment of 
radiographic data, biopsy results (if available), and clinical status. Patients who meet 
criteria for disease progression per RECIST v1.1 will be permitted to continue treatment 
(MTIG7192A plus atezolizumab or placebo plus atezolizumab) if they meet all of the 
criteria specified in Section 3.1.1.
Patients will undergo tumor assessments until disease progression per RECIST v.1.1 or 
until treatment discontinuation, whichever occurs later.  In the absence of disease 
progression, tumor assessments should continue, if feasible, until patients start new 
anti-cancer therapy, consent is withdrawn, death, or study termination by the Sponsor, 
whichever occurs first. 
Patients in whom radiographic disease progression is confirmed at a subsequent tumor 
assessment may be permitted to continue study treatment (MTIG7192A plus 
atezolizumab or placebo plus atezolizumab) at the discretion of the investigator if they 
show evidence of clinical benefit and continue to meet the criteria listed above and as 
specified in Section 3.1.1.

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Primary imaging data used for tumor assessment will be collected by the Sponsor to 
enable centralized, independent review of response endpoints, if needed.
In order not to confound the OS endpoint, crossover will not be allowed from the control 
arm (placebo plus atezolizumab) to the experimental arm (MTIG7192A plus 
atezolizumab).
During the study, patients will also be asked to complete a patient-reported outcome 
(PRO) survey at the beginning of the study, at the same visits as tumor assessments are 
scheduled, and at treatment discontinuation (see Section 4.5.11 and Appendix 1).
During the study, serum samples will be collected to monitor MTIG7192A or 
atezolizumab PK and to detect the presence of antibodies to MTIG7192A or 
atezolizumab.  
 
Safety assessments will include the incidence, nature, and severity of adverse events, 
protocol-mandated vital signs, laboratory abnormalities, and other protocol-specified 
tests that are deemed critical to the safety evaluation of the study. Events and tests will 
be graded per NCI CTCAE v4.0.
After initiation of study treatment, all adverse events will be reported until 30 days after 
the last dose of study treatment or until initiation of another anti-cancer therapy, 
whichever occurs first.  After this period, investigators should report any serious adverse 
events or other adverse events of special interest until 90 days after the last dose of 
study treatment or until initiation of new systemic anti-cancer therapy, whichever 
occurs first. The investigator should follow each adverse event until the event has 
resolved to baseline grade or better, the event is assessed as stable by the investigator, 
the patient is lost to follow-up, or the patient withdraws consent.  Every effort should be 

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made to follow all serious adverse events considered to be related to study drug(s) or 
trial-related procedures until a final outcome can be reported.
After study treatment discontinuation, patients will be followed for survival status and 
subsequent anti-cancer therapies, approximately every 3 months until death, loss to
follow-up, withdrawal of consent, or study termination by the Sponsor, whichever occurs 
first (see Sections 4.6.1 and 4.6.1.1).
3.1.1
Treatment after Disease Progression
During the study, patients who meet criteria for disease progression per RECIST v1.1 
and show evidence of clinical benefit may continue treatment at the investigator’s 
discretion after discussion with the Medical Monitor and provided that the patients meet 
all of the following criteria (see Figure 3):

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 unequivocal progression of 
disease

No decline in ECOG Performance Status that can be attributed to disease 
progression

Absence of tumor progression at critical anatomical sites that cannot be readily 
managed and stabilized by protocol-allowed medical interventions prior to repeat 
dosing  
–
Critical anatomical sites include the CNS, central airway, the great vessels, and 
other organs or tissues where compromised function secondary to tumor 
progression would be expected to result acutely in severe and/or irreversible 
disability or death.

Written consent to acknowledge discussion with the treating investigator of the 
benefitrisk balance of continuing study treatment beyond radiographic progression, 
including deferring other treatment options
If radiographic disease progression is confirmed at a subsequent tumor assessment, 
patients may be considered for continued study treatment at the investigator’s discretion 
after discussion with the Medical Monitor, if they continue to meet the above criteria and 
have continued clinical benefit, as evidenced by at least one of the following:

Tumor shrinkage (at least 30% decrease in diameter from baseline) of one or more 
evaluable lesions, or

Improvement in one or more symptoms or signs attributable to the underlying 
cancer (e.g., decreased requirement for narcotics for pain, decreased dyspnea 
associated with pleural effusion, or weight gain) as assessed by the investigator
For patients who consented to treatment beyond progression, new lesions should be 
entered in the electronic Case Report Form (eCRF).  The Sponsor will derive overall 

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myelosuppression, and alopecia) that negatively impact quality of life.  Therefore, there 
is a continuing need for more efficacious, better-tolerated treatments.  
Inhibition of PD-L1/PD-1 signaling has been shown to produce durable responses in 
some patients with metastatic NSCLC, and expression of PD-L1 by TCs and/or ICs in 
NSCLC correlates with response to therapy (Topalian et al. 2012; Fehrenbacher et al. 
2016).  Atezolizumab monotherapy has demonstrated clinical efficacy and is generally 
well tolerated in patients with locally advanced unresectable or metastatic squamous or 
non-squamous NSCLC (Spigel et al 2015; Fehrenbacher et al. 2016; Peters et al. 
2017b; Rittmeyer et al. 2017).  Data from the Phase Ia atezolizumab study (PCD4989g) 
first suggested that tumor PD-L1 status as determined by IHC in patients with metastatic 
NSCLC correlates with response to atezolizumab (see Section 1.7.2.3.1 ).  In two 
randomized studies in NSCLC, Study GO28753 (POPLAR) and Study GO28915 (OAK), 
improvement in OS was observed with atezolizumab compared with docetaxel in 
previously treated patients with NSCLC (2L-plus), including patients with PD-L1 positive 
tumors categorized as TC1/2/3 or IC1/2/3 (Fehrenbacher et al. 2016; Rittmeyer et al. 
2017).  Data from Study GO28754 (BIRCH) demonstrated a clinically meaningful benefit 
of atezolizumab as 1L treatment for patients with PD-L1selected NSCLC (TC2/3 or 
IC2/3), as demonstrated by a median OS of 23.5 months (Peters et al. 2017b).  In 
addition, data from the Phase III Study GO29436 (IMpower150) demonstrated improved 
PFS for patients with PD-L1selected NSCLC (TC1/2/3 or IC1/2/3) treated with 1L
atezolizumab plus chemotherapy and bevacizumab compared with chemotherapy plus 
bevacizumab alone (Reck et al. 2017).
In this study, patients will be selected for PD-L1 status with the PD-L1 IHC 22C3 
pharmDx assay (TPS 1%), and all patients, whether in the experimental arm or in the 
control arm, will receive atezolizumab.  Although the PD-1 inhibitor pembrolizumab has 
demonstrated activity in metastatic NSCLC in a PD-L1selected population with 22C3 
IHC results of TPS 50% and is approved for these patients, there is accumulating data 
that immune checkpoint inhibitors, including atezolizumab, have activity in patients 
whose tumors have 22C3 IHC results of TPS 50%. Patients from the Phase III Study 
GO28915 (OAK) in metastatic NSCLC, were randomized to receive atezolizumab or 
docetaxel and PD-L1 IHC status was determined with the Ventana PD-L1 (SP142) IHC
assay. These patient samples were also tested by the PD-L1 IHC 22C3 pharmDx assay
(see Table 4; Gadgeel et al. 2017).  As expected, atezolizumab showed improved OS in 
the subset of patients who had tumors with 22C3 PD-L1 TPS 50% versus those 
patients who received docetaxel (median OS 18.6 months vs. 8.4 months, OS HR 0.49 
[95% CI: 0.29, 0.80]).  Furthermore, atezolizumab also showed improved OS in the 
PD-L1negative patients who had tumors with TPS 1% PD-L1 by the 22C3 IHC result 
compared with those treated with docetaxel (median OS 12.1 months vs 7.3 months, 
OS HR 0.61 [95% CI: 0.45, 0.84]).  Atezolizumab monotherapy is already approved in 
2L patients irrespective of PD-L1 status and is currently being tested in a population of 
patients with chemotherapy-naive metastatic 1L NSCLC whose tumors have a PD-L1 

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patients treated with atezolizumab compared with docetaxel, and OS was similar in 
patients treated with atezolizumab whose tumors had squamous histology (HR 0.73, 
95% CI: 0.54, 0.98) as compared with those patients whose tumors had non-squamous 
histology (HR 0.73, 95% CI: 0.60, 0.89) (Rittmeyer et al. 2017).  In the Phase II 
POPLAR study, atezolizumab demonstrated a statistically significant improvement in OS
in unselected NSCLC patients over docetaxel, and activity was observed in patients with
both squamous and non-squamous NSCLC treated with atezolizumab (median OS of 
10.1 vs. 8.6 months [HR 0.66] for squamous and 14.8 vs. 10.9 months [HR 0.69] for 
non-squamous, respectively) (Fehrenbacher et al. 2016). These data suggest that 
atezolizumab is active in patients with metastatic NSCLC, independent of histology.
Based on this data, patients with metastatic NSCLC, of either squamous or 
non-squamous histology, will be eligible to enroll in the current study, and all patients will 
receive atezolizumab.
3.3.5
Rationale for Exclusion of Patients with Sensitizing EGFR 
Mutations and ALK Translocations
Patients with tumors harboring sensitizing EGFR mutations or ALK translocations will not 
be eligible for this study. Genotype-directed therapy, rather than immunotherapy,
remains the standard of care in the 1L setting for these patients. For patients with 
NSCLC (of mainly non-squamous histology) with an EGFR mutation, randomized 
Phase III studies of the EGFR inhibitors gefitinib, erlotinib, and afatinib showed 
significant improvement of PFS and ORR compared with platinum doublet 
chemotherapy (Fukuoka et al. 2011; Rosell et al. 2012; Yang et al. 2012).  For patients 
with metastatic NSCLC with ALK rearrangements, crizotinib and alectinib have 
demonstrated increased efficacy (Shaw et al. 2013; Peters et al. 2017a).
When patients with metastatic NSCLC with EGFR mutations are treated with 
immunotherapy alone, there has been no increased OS benefit.  In the OAK study, 
metastatic NSCLC patients with EGFR mutation-positive disease had similar OS 
benefit with atezolizumab or with docetaxel (median OS of 10.5 months with 
atezolizumab vs. 16.2 months with docetaxel [HR 1.24]), whereas patients with EGFR
wild-type disease had improved OS with atezolizumab compared with docetaxel 
(15.3 months vs. 9.5 months, HR 0.69) (Rittmeyer et al. 2017).  Similarly, in the 
Phase III study of nivolumab versus docetaxel in 2L NSCLC (CheckMate-057), NSCLC 
patients with EGFR-mutation-positive disease had similar OS benefit with nivolumab or 
docetaxel (HR1.18), in contrast to patients with EGFR-wild-type disease who had 
improved OS with nivolumab compared with docetaxel (HR 0.66) (Borghaei et al. 
2015).  Patients with NSCLC with EGFR-mutation-positive disease were also excluded 
from the Phase III study of pembrolizumab versus chemotherapy in the 1L setting 
(KEYNOTE-024) (Reck et al. 2016).  It is hypothesized that this subgroup of patients 
with EGFR-mutation-positive NSCLC may have decreased immunogenicity.  Therefore, 
based on the above data, patients with known EGFR mutations or ALK translocations 
will be excluded from the current study.

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3.3.6
Rationale for Dose and Schedule of Atezolizumab and 
MTIG7192A
3.3.6.1
Rationale for Dose and Schedule of Atezolizumab
Atezolizumab will be administered to all patients at a fixed dose of 1200 mg IV Q3W, on 
Day 1 of each 21-day cycle, which is the approved dosage for atezolizumab 
(TecentriqU.S. Package Insert).  The fixed dose of 1200 mg Q3W (equivalent to an 
average body weightbased dose of 15 mg/kg Q3W) was selected on the basis of both 
nonclinical studies (Deng et al. 2016) and available clinical PK, efficacy, and safety data. 
In the Phase I study of atezolizumab as a single agent (Study PCD4989g), the MTD of 
atezolizumab was not reached, and no DLTs were observed at any dose. Anti-tumor 
activity was observed across doses ranging from 1 mg/kg to 20 mg/kg given Q3W. 
For further details, please refer to the Atezolizumab Investigator’s Brochure.
3.3.6.2
Rationale for Dose and Schedule of MTIG7192A
MTIG7192A will be administered to all patients on the experimental arm at a fixed dose 
of 600 mg IV Q3W on Day 1 of each 21-day cycle.  
 
 
 
 
 
 
 
 
 
 
 
 
For further details, please refer to the MTIG7192A Investigator’s Brochure.
3.3.7
Rationale for Biomarker Assessments
3.3.7.1
Rationale for Collection of Mandatory Archival and/or
Pretreatment Biopsy Tumor Specimens
Published results suggest that the expression of PD-L1 in tumors correlates with 
response to antiPD-L1/PD-1 therapy (Topalian et al. 2012).  This correlation was also 
observed with atezolizumab in NSCLC as a single agent in Studies PCD4989g 
(Herbst et al. 2014; Horn et al. 2015), GO28754 (BIRCH) (Besse et al. 2015), GO28753 
(POPLAR) (Fehrenbacher et al. 2016), GO28625 (FIR) (Spigel et al. 2015), and 
GO28915 (OAK) (Rittmeyer et al. 2017), and in combination with chemotherapy in 
Study GO29436 (IMpower150) (Reck et al. 2017). Similar observations have been 

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reported for other PD-L1 or PD-1 inhibitors (Higgs et al. 2015; Muro et al. 2015;
Seiwert et al. 2015).
In this study, archival and/or fresh tumor specimens from patients will be tested for 
PD-L1 expression by a local or central laboratory during the pre-screening period, and 
only patients with PD-L1selected tumors (defined by expression of PD-L1 with the 
PD-L1 IHC 22C3 pharmDx assay as a TPS 1%) will be enrolled.  
 
 
The efficacy endpoints will be analyzed in two PD-L1selected populations, TPS 1% to 
49% and TPS 50%.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.3.7.2
Rationale for Collection of Blood Samples for Biomarker
Analyses
 
 
 
 
 
 
 

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3.3.7.3
Rationale for Collection of Optional Tumor Specimens, 
Including a Biopsy at the Time of Radiographic Progression
Patients agreeing to optional tumor biopsies may undergo tissue collection at any time, if 
clinically feasible. However, it is preferable that optional tumor biopsies be collected at 
the first evidence of radiographic response or at the first evidence of radiographic 
disease progression. Anti-tumor immune responses such as those associated with 
atezolizumab may result in objective responses that are delayed and can be preceded 
by initial apparent radiographic progression.  This initial apparent progression may occur 
as a result of either delayed anti-tumor activity and/or robust tumor immune infiltration 
with a concomitant increase in tumor size.  In addition, lesions that would otherwise be 
undetectable with conventional imaging (i.e., micrometastatic disease) may increase in 
size as a result of these processes and be recorded as new lesions (Hales et al. 2010).
 
 
 
 
 
 
 
 
 
 
 
 
3.3.7.4
Rationale for Next-Generation Sequencing in Tumor and/or
Blood Samples
 
 
 
 

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3.3.9
Rationale for Patient-Reported Outcome Assessments
In the treatment of lung cancer, it is important to both increase survival and palliate 
symptoms because disease symptoms have negative impacts on health-related quality 
of life (HRQoL) (Hyde and Hyde 1974; Hopwood and Stephens 1995; Sarna et al. 2004).
The BR.21 study (erlotinib vs. BSC in second- or third-line NSCLC) demonstrated that 
longer TTD in the cough, pain, and dyspnea scales of the European Organisation for 
Research and Treatment of Cancer, Quality of Life QuestionnaireCore 30
(EORTC QLQ-C30) was consistent with the superior PFS, OS, and quality-of-life 
benefits in the erlotinib arm compared with the placebo arm (Aaronson et al. 1993;
Bergman et al. 1994; Bezjak et al. 2006). Patients in the afatinib LUX-Lung 1L study 
also reported a significant delay of TTD in lung cancer symptoms (cough, pain, and 
dyspnea) as measured by the EORTC QLQ-C30 (Yang et al. 2012). 
In order to assess the clinical benefit of MTIG7192A plus atezolizumab compared with 
placebo plus atezolizumab
 
, PRO data will be collected using the validated EORTC QLQ-C30
scale (see Appendix 3).
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 5065 sites globally will participate in the study and will enroll 
approximately 120 patients with previously untreated, locally advanced unresectable or
metastatic NSCLC that is PD-L1selected.
4.1.1
Inclusion Criteria
Patients must meet all of the following criteria to be eligible for study entry:

Signed Informed Consent Form

Age 18 years

Ability to comply with the study protocol, in the judgment of the investigator

ECOG Performance Status of 0 or 1 (see Appendix 5)

Histologically or cytologically documented locally advanced unresectable NSCLC 
(i.e., Stage IIIB not eligible for definitive chemoradiotherapy), recurrent, or 
metastatic NSCLC (i.e., Stage IV) (per the Union Internationale Contre le 
Cancer/American Joint Committee on Cancer [UICC/AJCC] staging system, 
Detterbeck et al. 2009) of either squamous or non-squamous histology
–
 

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–
A woman is considered to be of childbearing potential if she is postmenarchal, 
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.
–
Hormonal contraceptive methods must be supplemented by a barrier method 
plus spermicide.
–
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical study and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm, as 
specified below:
–
With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and for at 
least 90 days after the last dose of study treatment to avoid exposing the 
embryo.  Men must refrain from donating sperm during this same period.
–
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical study and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.
4.1.2
Exclusion Criteria
Patients who meet any of the criteria in the following sections will be excluded from 
study entry.
4.1.2.1
Cancer-Specific Exclusions
Patients who meet any of the following cancer-specific criteria will be excluded from 
study entry:

Patients with NSCLC known to have a sensitizing mutation in the EGFR gene or an 
ALK fusion oncogene are excluded from the study as follows:
–
 
  
–
 
–
 
  

Patients with the pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC 

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
Symptomatic, untreated, or actively progressing CNS metastases 
–
 
 
 
 
 
 
 
 

Spinal cord compression not definitively treated with surgery and/or radiation, and/or 
previously diagnosed and treated spinal cord compression without evidence that 
disease has been clinically stable for 2 weeks prior to screening

History of leptomeningeal disease

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (i.e., once monthly or more frequently)
–

Uncontrolled tumor-related pain
–
–
 
 
–
 
 
 

Uncontrolled hypercalcemia (ionized calcium 1.5 mmol/L or calcium 12 mg/dL or 
corrected serum calcium ULN) or symptomatic hypercalcemia requiring continued 
use of bisphosphonate therapy or denosumab
–
 
 

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–
 
 

Malignancies other than NSCLC within 5 years prior to randomization, with the 
exception of those with a negligible risk of metastasis or death and/or treated with 
expected curative outcome (such as adequately treated carcinoma in situ of the 
cervix, basal or squamous cell skin cancer, localized prostate cancer, ductal 
carcinoma in situ, or Stage I uterine cancer)
4.1.2.2
General Medical Exclusions
Patients who meet any of the following general medical criteria will be excluded from 
study entry:

Inability to comply with study and/or follow-up procedures

Pregnant, lactating, or breastfeeding women

Evidence of significant uncontrolled concomitant disease that could affect 
compliance with the protocol or interpretation of results (e.g., uncontrolled major 
seizure disorder or superior vena cava syndrome)

Known clinically significant liver disease, including active viral, alcoholic, or other 
hepatitis, cirrhosis, and inherited liver disease, or current alcohol abuse
Significant cardiovascular disease, such as New York Heart Association cardiac 
disease (Class II or greater), myocardial infarction or cerebrovascular accident 
within 3 months prior to randomization, unstable arrhythmias, or unstable angina

Severe infections within 4 weeks prior to initiation of study treatment, including but 
not limited to hospitalization for complications of infection, bacteremia, or severe 
pneumonia

Received oral or IV antibiotics (including antifungals) within 2 weeks prior to 
randomization
–
 

Major surgical procedure within 4 weeks prior to randomization, or anticipation of 
need for a major surgical procedure during the course of the study 

Inability to understand the local language(s) for which the EORTC QLQ-C30 is
available 

Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug, that may affect the interpretation 
of the results, or that may render the patient at high risk from treatment 
complications

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4.1.2.3
Treatment-Specific Exclusions
Patients who meet any of the following treatment-specific criteria will be excluded from 
study entry:

History of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric or humanized antibodies or fusion proteins

Known hypersensitivity or allergy to CHO cell products or any component of the 
atezolizumab formulation

Active or history of autoimmune disease 
–
 
 
–
 
–
 
 
 
 
 

Prior allogeneic bone marrow transplantation or prior solid organ transplantation

History of idiopathic pulmonary fibrosis (including pneumonitis), organizing 
pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), 
drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest computed tomography (CT) scan
–

Positive test for HIV at screening
–
 

Patients with active HBV infection, defined as having a positive hepatitis B surface 
antigen (HBsAg) test at screening
–
 
 
–
 

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
Patients with active HCV infection, defined as having a positive HCV antibody test 
followed by a positive HCV RNA test at screening
–
 

Patients with active EBV infection and patients with known or suspected chronic 
active EBV infection at screening
–

Active tuberculosis

Administration of a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment or anticipation that such a live attenuated vaccine will be required during 
the study
–
 

Treatment with systemic corticosteroids or other systemic immunosuppressive 
medications (including but not limited to prednisone 10 mg/day, cyclophosphamide, 
azathioprine, methotrexate, thalidomide, and tumor necrosis factor [TNF-]
antagonists) within 2 weeks prior to randomization
–
 
 
–
–
 
–
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
After written informed consent has been obtained and eligibility has been established
(including determination of tumor PD-L1 status by local or central testing), the study site 
will obtain the patient's identification number and blinded treatment assignment from the 
interactive voice or web-based response system (IxRS). Patients will be randomized to 
receive either MTIG7192A plus atezolizumab or placebo plus atezolizumab in a 1:1 
randomization ratio using a permuted-block randomization method. 
Randomization will be stratified by the following criteria:

PD-L1 IHC 22C3 results (TPS 1% to 49% vs. TPS 50%)

Histology of NSCLC (non-squamous vs. squamous)

History of tobacco use (yes vs. no)

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These stratification factors were chosen because of their known or suspected potential 
to affect prognosis in NSCLC.  Prospective stratification by these factors will minimize 
differences in the two treatment arms due to sources other than MTIG7192A.
The investigators and the patients will be blinded to treatment assignment until the 
primary analysis of the primary endpoints.
Because of the size of the study, use of IxRS, randomization, blinding, and expected 
lack of substantial emergency unblinding, collected data will be protected from any 
biases that would arise from subjectivity in the reporting of the outcome measures.  To 
further protect the integrity of the study, the results of interim safety and efficacy 
analyses will not be made known to the investigators.
The addition of MTIG7192A to atezolizumab is not expected to affect planned laboratory 
tests or adverse reactions to a degree that would significantly unblind patients or 
investigators.  All laboratory tests or blood specimens will be performed by a local 
laboratory, a central laboratory, or the Sponsor, as appropriate. 
While PK samples must be collected from patients assigned to the comparator arm to 
maintain the blinding of treatment assignment, PK assay results for these patients are 
generally not needed for the safe conduct or proper interpretation of this study.  
Laboratory personnel responsible for performing PK assays may be unblinded to 
patients’ treatment assignments to identify appropriate PK samples to be analyzed.  
Samples from patients assigned to the comparator arm will not be analyzed except by 
request (e.g., to evaluate a possible error in dosing).
If emergency unblinding is necessary for patient management (e.g., in the case of a
serious adverse event for which patient management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  This emergency unblinding may occur without prior authorization 
from the Sponsor. However, the investigator should document and provide an 
explanation to the Sponsor for any premature unblinding (e.g., unblinding due to a 
serious adverse event or accidental unblinding).  Treatment codes should not be broken 
except in emergency situations.  If the investigator wishes to know the identity of the 
study drug for any other reason, the investigator should contact the Medical Monitor 
directly. 
For regulatory reporting purposes and if required by local health authorities, the Sponsor 
may break the treatment code for all serious, unexpected suspected adverse reactions 
that are considered by the investigator or Sponsor to be related to study drug.
If an IMC safety review is necessary, as outlined in the guidelines of the IMC Charter, 
the IMC may instruct the IxRS to provide the treatment assignments for those patients of 
interest to evaluate unbalanced toxicity.

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4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal products (IMPs) for this study are MTIG7192A, placebo, 
and atezolizumab.  All patients will receive atezolizumab with either MTIG7192A or with 
placebo.
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
MTIG7192A and Placebo
MTIG7192A and placebo will be supplied by the Sponsor. 
For further information on the formulation and handling of MTIG7192A and placebo, 
please see the pharmacy manual and/or the MTIG7192A Investigator’s Brochure.
4.3.1.2
Atezolizumab
Atezolizumab drug product will be supplied by the Sponsor.
For further information on the formulation and handling of atezolizumab, please see the 
pharmacy manual and/or the Atezolizumab Investigator’s Brochure.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.
Atezolizumab and MTIG7192A/placebo should be given in a setting with emergency 
medical facilities and staff who are trained to monitor for and respond to medical 
emergencies.
 
 
 
Any overdose or incorrect administration of atezolizumab and/or MTIG7192A/placebo 
should be noted on the Study Drug Administration eCRF.  Adverse events associated 
with an overdose or incorrect administration of any of the study treatments should be 
recorded on the Adverse Event eCRF.
Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Section 5.1 and in Appendix 7 and Appendix 8.
4.3.2.1
Atezolizumab
All patients will receive 1200 mg atezolizumab administered by IV infusion on Day 1 of 
each 21-day cycle (see Section 3.3.6.1).  The atezolizumab dose is fixed and is not 
dependent on body weight. 
Atezolizumab infusions will be administered per the instructions outlined 

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For anaphylaxis precautions, please see Appendix 6.  For management of IRRs, 
including premedications, please see Appendix 7 and Appendix 8.
There will be no dose reduction for atezolizumab in this study.  Guidelines for dosage 
modification and treatment interruption or discontinuation are provided in Section 5.1.  
Guidance on study drug administration in the context of management of specific adverse 
events is provided in Section 5.1.4. 
For further details on dose preparation, storage, and administration instructions for 
atezolizumab, please refer to the pharmacy manual and/or the Atezolizumab 
Investigator’s Brochure. 
4.3.2.2
MTIG7192A and Placebo
, patients will receive 600 mg 
MTIG7192A/placebo administered by IV infusion on Day 1 of each 21-day cycle (see 
Section 3.3.6.2).  The MTIG7192A/placebo dose is fixed and is not dependent on body 
weight.  MTIG7192A/placebo infusions will be administered per the instructions outlined 
For anaphylaxis precautions, please see Appendix 6.  For management of IRRs, 
including guidance on premedication, please see Appendix 7 and Appendix 8.  
There will be no dose reduction for MTIG7192A/placebo in this study.  Guidelines for 
dosage modification and treatment interruption or discontinuation are provided in 
Section 5.1.  Guidance on study drug administration in the context of management of 
specific adverse events is provided in Section 5.1.4. 
 
For further details on dose preparation, storage, and administration instructions for 
MTIG7192A/placebo, please refer to the pharmacy manual and/or the MTIG7192A 
Investigator’s Brochure. 

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
 
 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (MTIG7192A and matching placebo, as 
well as atezolizumab) will be provided by the Sponsor where required by local health 
authority regulations.  The study site will acknowledge receipt of IMPs supplied by the 
Sponsor, using the IxRS to confirm the shipment condition and content.  Any damaged 
shipments will be replaced. 
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or be returned to the Sponsor (if supplied by the Sponsor) 
with the appropriate documentation.  The site’s method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor.  The site must obtain written authorization from 
the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must 
be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.4
Continued Access to MTIG7192A and/or Atezolizumab
The Sponsor (Genentech, a member of the Roche Group) will offer continued access to 
Genentech IMPs (MTIG7192A and atezolizumab) free of charge to eligible patients in 
accordance with the Roche Global Policy on Continued Access to Investigational 
Medicinal Product, as outlined below.
 

 


 
 

 
 

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
 


 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-
counter drugs, vaccines, herbal or homeopathic remedies, or nutritional supplements) 
used by a patient in addition to protocol-mandated treatment from 7 days prior to 
screening to the treatment discontinuation visit.  All such medications should be reported 
to the investigator and recorded on the Concomitant Medications eCRF.
4.4.1
Permitted Therapy 
Patients who experience infusion-related symptoms may be treated symptomatically with 
acetaminophen, ibuprofen, diphenhydramine, and/or ranitidine or another H2 receptor 
antagonist, as per standard practice (for sites outside the United States, equivalent 
medications may be substituted per local practice).  Serious infusion-related events 
manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced 
oxygen saturation, or respiratory distress should be managed with supportive therapies 
as clinically indicated (e.g., supplemental oxygen and 2-adrenergic agonists; see
Appendix 6).  
Systemic corticosteroids and other immune-modulating medications may in theory
attenuate the potential beneficial immunologic effects of treatment with MTIG7192A 
and/or atezolizumab but should be administered at the discretion of the treating 
physician in line with the management guidelines in Section 5.1.  Premedication for 
MTIG7192A/placebo and/or atezolizumab may be administered for Cycles 2 at the 
discretion of the treating physician after consultation with the Medical Monitor.  The use 
of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with 
orthostatic hypotension or adrenocortical insufficiency is allowed.  Physiologic doses of 
corticosteroids for adrenal insufficiency are allowed.  Megestrol administered as an 
appetite stimulant is acceptable while the patient is enrolled in the study.  Planned use of 
other medications should be discussed with the Medical Monitor.
Patients who use oral contraceptives, hormone-replacement therapy, prophylactic or 
therapeutic anticoagulation therapy (such as low molecular weight heparin or warfarin at 
a stable dose level), or other maintenance therapy for non-malignant indications should 

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
Receptor activator of nuclear factor kappa B (RANK) inhibitor (i.e., denosumab).  
This class has the potential to alter the activity and the safety of atezolizumab
(Cheng and Fong 2014).
 

Live, attenuated vaccines (e.g., FluMistinfluenza vaccine) are prohibited at any 
time during the study, and for 5 months following the last dose of study treatment.
 
 
4.5
STUDY ASSESSMENTS 
Study assessments are defined in the sections below.  See Appendix 1 and 
for the schedule of activities to be performed during the study. Patients will be closely 
monitored for safety and tolerability throughout the study.  All assessments must be 
performed and documented for each patient. 
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable.
All assessments will be performed on the day of the scheduled visit date unless a time 
window is specified.  Assessments scheduled on the days of study treatment should be 
performed before the infusion of study drug(s) unless otherwise noted.  If the timing of a 
study visit coincides with a holiday, weekend, or other administrative disruption that 
precludes the visit, the visit should be scheduled on the nearest following feasible date, 
with subsequent visits rescheduled accordingly.
Collection of any nonsafety-related data or patient samples may be terminated by the 
Sponsor at any time if further collection of such data or samples is also not related to the 
study’s primary objective(s).  The decision to discontinue any data collection will be 
communicated to sites (Institutional Review Boards [IRBs] and Ethics Committees [ECs]) 
by means of a memorandum and will not require a protocol amendment.
4.5.1
Informed Consent Forms and Screening Log
This study requires documentation of consent for the following components of study 
participation, as applicable:

Participation in Study GO40290:  Written informed consent for participation in the 
study must be documented by signing the relevant page before any study-specific 
screening tests or evaluations are performed.  

Consent for Treatment Continuation after Possible Disease Worsening:  This 
consent applies only to patients who continue study treatment beyond radiographic 
progression in the study (see Section 3.1.1).

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Informed Consent Forms for enrolled patients and for patients who are not subsequently 
enrolled will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment in the study.  The investigator will maintain a 
screening log to record details of all patients screened and to confirm eligibility or record 
reasons for screening failure, as applicable.
4.5.2
Medical History and Demographic Data
Medical history includes clinically significant diseases, surgeries, non-NSCLC cancer 
history (including prior cancer therapies and procedures), smoking history, use of alcohol 
and/or drugs of abuse, 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 screening visit.
Demographic data will include age, sex, and self-reported race/ethnicity.  Race/ethnicity 
is recorded because of the potential contribution of this variable to differences in 
observed pharmacokinetics, pharmacodynamics, toxicity, and/or response to treatment.
NSCLC cancer history will include prior cancer therapies, procedures, and an 
assessment of tumor mutational status (e.g., sensitizing EGFR mutation, ALK fusion 
status).  
 
 
  
 

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rate associated with an arrhythmia) should be recorded in the eCRF. All vital signs 
collected per protocol should be documented in the patient's medical record.
Blood oxygen saturation will be measured at baseline by pulse oximetry and as clinically 
indicated thereafter.
4.5.5
Tumor and Response Evaluations
Screening and subsequent tumor assessments must include CT scans (with IV contrast 
unless contraindicated and oral contrast as appropriate per institutional standards) or 
MRI scans of the chest, abdomen, and pelvis.  A spiral CT scan of the chest may be 
obtained but is not a requirement.  MRI scans of the chest, abdomen, and pelvis with a 
non-contrast CT scan of the chest may be used in patients for whom CT scans with 
contrast are contraindicated (i.e., patients with contrast allergy or impaired renal 
clearance).  If a CT scan for tumor assessment is performed in a positron emission 
tomography (PET)/CT scanner, the CT acquisition must be consistent with the standards 
for a full-contrast CT scan.  
Patients with active or untreated CNS metastases are not eligible for this study (see 
Section 4.1.2 for CNS-related exclusions).  At screening, a CT (with contrast) or MRI 
scan of the brain should be performed to document stability of all previously treated 
brain metastases.  Brain scans should also be performed at screening to rule out the 
presence of untreated CNS metastases and then when clinically indicated thereafter 
(e.g., in patients with neurologic symptoms).  In the event of an equivocal head CT scan 
at any tumor assessment, a brain MRI scan is required to clarify the presence or extent 
of suspected brain metastases.  At subsequent (post-screening) tumor assessments, 
brain scans are not required for any patient unless clinically indicated. 
Further investigations such as bone scans and CT scans of the neck should also be 
performed as indicated and if there is any clinical suspicion of disease at any site that 
may not be demonstrated by the minimum schedule of activities listed above.  At the 
investigator’s discretion, other methods of assessment of measurable disease as per 
RECIST v1.1 may be used. 
All known sites of disease, including measurable and/or nonmeasurable disease, must 
be documented at screening and re-assessed at each subsequent tumor evaluation. 
Patients with a history of irradiated brain metastases at screening are not required to 
undergo brain scans at subsequent tumor evaluation unless scans are clinically 
indicated.  The same radiographic procedures used to assess disease sites at screening 
should be used throughout the study (e.g., the same contrast protocol for CT scans).  All 
known sites of disease must be documented at screening and re-assessed at each 
subsequent tumor evaluation. Stable brain metastases must be evaluated with each 
tumor assessment with the same radiographic procedure as the baseline study.  
Patients without brain metastases do not need a brain scan for tumor assessment 
unless clinically warranted.  Response will be assessed by the investigator on the 

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imaging modalities detailed above, using RECIST v1.1 (see Appendix 4).  The 
investigator’s assessment of overall tumor response at all timepoints should be also
based on RECIST v1.1.  The Sponsor will derive the overall tumor assessment as per 
RECIST v1.1 based on entries for all target lesions, non-target lesions, and new lesions.  
Assessments should be performed by the same evaluator if possible to ensure internal 
consistency across visits.  
Tumor assessments are to be performed per the schedule provided in Appendix 1, 
3 business days regardless of drug delays or interruptions (i.e., independent of 
treatment cycles). At the investigator’s discretion, scans may be performed at any time if 
progressive disease or loss of clinical benefit is suspected.
Patients who discontinue study treatment for reasons other than disease progression 
(e.g., toxicity) should continue to undergo scheduled tumor assessments, if feasible, until
initiation of subsequent anti-cancer therapy, disease progression, death, loss to 
follow-up, withdrawal of consent, or study termination, whichever occurs first. Patients 
who are discontinued from study treatment because of disease progression will be 
asked to return to the clinic for a confirmatory tumor assessment at 6 (2) weeks later, if 
feasible, after experiencing disease progression unless the patient initiates another 
anti-cancer therapy. 
Patients who continue treatment beyond radiographic disease progression per RECIST 
v1.1 will be monitored with a follow-up scan in 6 (2) weeks (i.e., at the next scheduled 
tumor assessment when the scan frequency is every 2 cycles or as an unscheduled 
tumor assessment when the scan frequency is every 3 cycles) or earlier if clinically 
indicated.  Tumor assessments should be continued every 2 cycles thereafter until two 
consecutive scans demonstrate stability or improvement with respect to the first scan 
that showed radiographic disease progression, at which point the scan frequency should 
revert or transition to every 3 cycles if applicable.  For patients who consented to 
treatment beyond radiographic disease progression (see Section 3.1.1), new lesions are 
to be assessed according to RECIST v1.1 and applicable measurements should be 
entered into the eCRF.  The Sponsor will derive overall tumor assessment as per 
RECIST v1.1 and the investigator assessment of overall tumor response at all timepoints
should be also based on RECIST v1.1.
4.5.6
Laboratory, Biomarker, and Other Biological Samples
4.5.6.1
Local Laboratory Tests
The following laboratory tests will be performed by the study site's local laboratory:

Hematology 
 
 

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Serum chemistries 
 
 

Serum ferritin and C-reactive protein (CRP)

Coagulation 

Pregnancy test: 
 
 
  

Urinalysis 

Thyroid function testing 

EBV serology 
–
 
 

Cytomegalovirus (CMV) serology 

HBV serology 
 
–
 
 

HCV serology (anti-HCV)
–
 

All patients will be tested for HIV prior to inclusion into the study, and HIV-positive 
patients will be excluded from the clinical trial.
4.5.6.2
Central Laboratory Assessments
Samples for the assessments listed below will be sent to one or several central 
laboratories or to Genentech. 
Instruction manual and supply kits will be provided for these central assessments.  
Please refer to the laboratory manual for additional details on sample handling.

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4.5.7
Use and Storage of Remaining Samples from Study-Related 
Procedures
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.12), biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exceptions:

Serum samples collected for PK or immunogenicity analysis may be needed for 
additional immunogenicity characterization and PK, immunogenicity, and biomarker
assay development and validation; 
 
 


4.5.8
Electrocardiograms
A 12-lead ECG is required at screening, at the treatment discontinuation visit, and when 
clinically indicated.  ECGs for each patient should be obtained from the same machine 
wherever possible.  Lead placement should be consistent as possible.  ECG recordings 
must be performed after the patient has been resting in a supine position for at least 
10 minutes.
 
 
 
4.5.9
Cancer-Related Procedures
Collection of cancer-related medical, surgical, and radiation procedures will begin on 
Day 1 and be performed throughout the treatment period and during the survival 
follow-up period of the study.
4.5.10
Anti-Drug Antibody Testing
MTIG7192A and/or atezolizumab may elicit an immune response against itself.  Patients 
with signs of any potential immune response to MTIG7192A/placebo and/or 
atezolizumab will be closely monitored.  
 
 
 
 
 

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4.5.11
Patient-Reported Outcomes
PROs will be collected by the EORTC QLQ-C30 to more fully characterize the clinical 
profile of the study drugs. 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
4.5.12
Optional Samples for Research Biosample Repository
4.5.12.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection, 
storage, and analysis of RBR specimens will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
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.  
 
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4.5.12.2
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/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 4.5.12) will not be applicable at that site.
4.5.12.3
Sample Collection
 
 

 
–

 
–
 
  
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For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  

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4.5.12.4
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.
 
 
 
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.
4.5.12.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR specimens.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research.

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4.5.12.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR specimens have the right to withdraw their 
consent at any time for any reason.  However, if RBR specimens have been tested prior 
to withdrawal of consent, results from those tests will remain as part of the overall 
research data.  If a patient wishes to withdraw consent to the testing of his or her 
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 study 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 study is closed.  A patient's withdrawal from Study GO40290
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 GO40290.
4.5.12.7
Monitoring and Oversight
RBR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to 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
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must discontinue study treatment if they experience any of the following:

Symptomatic deterioration (i.e., uncontrollable pain secondary to disease or 
unmanageable ascites, etc.) attributed to disease progression as determined by the 
investigator after integrated assessment of radiographic data, biopsy results, and/or
clinical status

Intolerable toxicity related to study treatment, including development of 
immune-mediated adverse events (see Section 5.1.1.1), determined by the 
investigator to be unacceptable given the individual patient’s potential response to 
therapy and severity of the event

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues on study treatment

Investigator or Sponsor determines it is in the best interest of the patient

Use of a non-protocol systemic anti-cancer therapy (see Section 4.4.2)

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Radiographic disease progression per RECIST v1.1
Exception:  Patients will be permitted to continue study treatment after 
RECIST v1.1 criteria for progressive disease are met if they meet all of the 
criteria in Section 3.1.1.
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be
replaced.
Patients who discontinue study treatment primarily for reasons other than disease 
progression will continue tumor assessments (see Section 4.5.5) if feasible, until disease 
progression, initiation of another systemic anti-cancer therapy, death, loss to follow-up, 
withdrawal of consent, or study termination, whichever occurs first. All patients who 
discontinue study treatment will continue to be followed for survival every 3 months
unless consent is withdrawn. 
4.6.1.1
Study Treatment Discontinuation Visit
Patients who discontinue study treatment will be asked to return to the clinic for a 
treatment discontinuation visit at 30 days after the last administration of study 
treatment.
 
 
 
See the schedule of activities provided in Appendix 1 for the respective assessments to 
be performed at the treatment discontinuation visit.
4.6.1.2
Survival and Subsequent Anti-Cancer Therapy Follow-Up
Following study treatment discontinuation, all patients will be followed for survival and 
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4.6.2
Patient Discontinuation from Study
Patient discontinuation from the study is distinguished from discontinuation of study 
treatment (see Section 4.6.1) and occurs when the patient dies, is lost to follow-up, or 
withdraws consent to be followed. 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

Study termination or site closure

Patient non-compliance, defined as failure to comply with protocol requirements 
determined by the investigator or Sponsor
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.
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients.

Unsatisfactory patient enrollment

Inaccurate or incomplete data recording
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice (GCP)

No study activity (i.e., all patients have completed the study and all obligations have 
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5.1.1.1
Infusion-Related Reactions
While clinical evaluation of MTIG7192A is limited and not all risks are known, some 
patients receiving either single-agent MTIG7192A or MTIG7192A plus atezolizumab, 
have experienced IRRs.  IRRs are considered an identified risk for MTIG7192A and 
have been Grade 1 and 2 and have included symptoms of pyrexia, chills, nausea, and 
hypertension.
To minimize the risk and sequelae of IRRs, the initial dose of MTIG7192A/placebo will be 
administered over 60 minutes followed by a 60-minute observation period, and 
subsequent infusions as well as observation times may be shortened only if the initial 
dose administration is well tolerated.  All infusions will be administered in an appropriate 
medical setting.  Please see Section 4.3 for detailed guidance on administration of 
atezolizumab as well as MTIG7192A/placebo in this study.  Please see Appendix 6 for 
guidance on anaphylaxis precautions, and see Appendix 7 and Appendix 8for guidance 
on management of IRRs and risks associated with atezolizumab, respectively. 
5.1.1.2
Immune-Mediated Adverse Events
Nonclinical models have suggested a role of TIGIT signaling interruption in autoimmunity.  
In a knockout model (TIGIT/), loss of TIGIT signaling resulted in hyperproliferative 
T-cell responses and exacerbation of experimental autoimmune encephalitis (EAE).  
TIGIT/and wild-type B6 mice were immunized with myelin oligodendrocyte 
glycoprotein (MOG) peptide in an EAE using suboptimal doses.  In contrast to the 
wild-type B6 mice, the majority of the TIGIT /mice developed severe EAE 
(Joller et al. 2011).
Clinical experience with therapeutics intended to enhance anti-tumor T-cell responses 
has demonstrated that development of autoimmune inflammatory conditions is a general 
risk and may therefore be considered a potential risk of MTIG7192A.  Such 
immune-mediated adverse events have been described for virtually all organ systems 
and include, but are not limited to, colitis, hepatitis, pneumonitis, endocrinopathy, ocular 
toxicity, pancreatic toxicity, neurologic toxicity, myocarditis, nephritis, myositis, and rash.  
Rash and hypothyroidism have been reported in patients treated with MTIG7192A with 
or without atezolizumab.
Patients with a history of autoimmune disease (other than autoimmune thyroid disease 
managed with thyroid hormone replacement or vitiligo) will be excluded from this study
(see Section 4.1.2).  
Management guidelines for individual suspected immune-mediated adverse events are 
provided in Appendix 7 and Appendix 8.

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5.1.1.3
Lymphopenia
Given the IgG1 backbone of MTIG7192A with intact Fc-effector function, 
ADCC-mediated reduction in lymphocyte count is a potential risk.  In the repeat-dose 
toxicity study in cynomolgus monkeys, however, there were no MTIG7192A-related 
decreases in overall lymphocyte counts. 
Transient lymphocyte count decreases without clinical sequelae have been observed in 
patients treated with MTIG7192A with or without atezolizumab.
Due to this potential risk of MTIG7192A to induce lymphopenia, patients with a 
lymphocyte count 500 cells/L will be excluded from this study (see Section 4.1.1), and 
complete blood counts will be monitored regularly during the study (see Appendix 1).
5.1.2
Risks Associated with Atezolizumab
Atezolizumab has been associated with risks such as the following:  IRRs, 
immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré
syndrome, myasthenic syndrome or myasthenia gravis, meningoencephalitis, 
myocarditis, myositis, and nephritis. Immune-mediated adverse reactions may involve 
any organ system and may lead to HLH and MAS. Please refer to Appendix 8 of this 
protocol and Section 6 of the Atezolizumab Investigator’s Brochure for a detailed 
description of anticipated safety risks for atezolizumab.
5.1.3
Risks Associated with MTIG7192A Plus Atezolizumab 
Based on nonclinical and/or clinical studies with each molecule as a single agent, clinical 
data from Study GO30103 with MTIG7192A plus atezolizumab, and data from molecules 
with similar mechanisms of action, there is a potential for overlapping toxicity in patients 
treated with MTIG7192A plus atezolizumab.  Because the expected pharmacologic
activity of these two molecules is to increase adaptive T-cell immune responses, there is 
the possibility of heightened immune responses.  
The following adverse events are potential overlapping toxicities associated with 
combination use of MTIG7192A plus atezolizumab: immune-mediated pulmonary, 
hepatic, gastrointestinal, endocrine, ocular, pancreatic, dermatologic, neurologic adverse 
events, as well as immune-mediated myocarditis and meningoencephalitis. In addition, 
HLH and MAS (described in Appendix 8) is a potential risk when atezolizumab is given 
in combination with other immunomodulating agents such as MTIG7192A.
It is anticipated that immune-mediated adverse events following treatment with 
MTIG7192A and atezolizumab will be amenable to monitoring and manageable in the
setting of this combination study.  The extensive experience with immune checkpoint 
inhibitors to date has been incorporated into the design and safety management plan 
(see Section 5.1) in order to reduce the potential risks to participating patients.  Patients 
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
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 (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study 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; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
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5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  
 
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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5.7.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4).  
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 until initiation of new systemic anti-cancer therapy, whichever 
occurs first, and serious adverse events and adverse events of special interest will 
continue to be reported until 90 days after the last dose of study treatment or until 
initiation of new systemic anti-cancer therapy, whichever occurs first.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?" 
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 6 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.

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Table 6
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (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 (see also
Table 7):

Temporal relationship of event onset to the initiation of study drug(s)

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug(s), or reintroduction of study drug(s) (as applicable)

Known association of the event with the study drug(s) or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medication(s) known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
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Table 7
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(s), 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(s); and/or the 
adverse event abates or resolves upon discontinuation of the study drug(s) 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(s)
(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(s) (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 when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Infusion-Related Reactions
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug infusion(s) should be captured as a diagnosis of 
“infusion-related reaction” on the Adverse Event eCRF.  
 
 
 
 
 
 
5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events other than IRRs (see Section 5.3.5.1), a diagnosis (if known) should 
be recorded on the Adverse Event eCRF rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases).  However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, each 
individual event should be recorded on the Adverse Event eCRF.  If a diagnosis is 
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symptoms should be nullified and replaced by one adverse event report based on the 
single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis.
5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
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.  Details regarding any increases or decreases in severity will be captured on the 
Adverse Event Intensity or Grade Changes 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 studies, certain abnormal values may not qualify as 
adverse events.
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 

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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 only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3baseline value) in combination with either 
an elevated total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:


The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2).
5.3.5.8
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.3.1) that are attributed 
by the investigator solely to progression of NSCLC should be recorded on the Death 
Attributed to Progressive Disease eCRF.  All other deaths that occur during the adverse 
event reporting period, regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  The 
IMC will monitor the frequency of deaths from all causes.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
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be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.10
Lack of Efficacy or Worsening of NSCLC
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on RECIST v1.1.  In rare cases, the determination of clinical 
progression will be based on symptomatic deterioration.  However, every effort should 
be made to document progression through use of objective criteria.  If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported 
as an adverse event.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient 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 cancer
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.12
Patient-Reported Outcome Data
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  Sites are not expected to review the 
PRO data for adverse events.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical study.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)

Accidental overdoses or medication errors (see Section 5.4.4 for details on reporting 
requirements)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

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In the event that the EDC system is unavailable, the paper Clinical Trial 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 in Section 5.4.2.1.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.  
Instructions for reporting serious adverse events that occur after the last dose of study 
treatment are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 5 months after the last 
dose of study drug(s).  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 in Section 5.4.2.1.  Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue the study drug(s) and counsel the patient, discussing the risks of the 
pregnancy and the possible effects on the fetus.  Monitoring of the patient should 
continue until conclusion of the pregnancy.  Any serious adverse events associated with 
the pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy
becomes available.  
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 
90 days after the last dose of study drug.  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 in 
Section 5.4.2.1.  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(s).  
When permitted by the site, the pregnant partner would need to sign an Authorization for 
Use and Disclosure of Pregnancy Health Information to allow for follow-up on her 
pregnancy.  If the authorization has been signed, the investigator should submit a 
Clinical Trial Pregnancy Reporting Form when updated information on the course and 
outcome of the pregnancy becomes available.  An investigator who is contacted by the 
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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
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug(s) or the female partner of a male patient exposed to study drug(s) should be 
classified as a serious adverse event, recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 4.5.2).
5.4.3.4
Abortions
Any abortion should be classified as a serious adverse event (as the Sponsor considers 
abortions to be medically significant), recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 4.5.2).
5.4.4
Reporting Requirements for Cases of Accidental Overdose or 
Medication Error
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.
Special situations are not in themselves adverse events, but may result in adverse 
events.  All special situations associated with MTIG7192A and/or atezolizumab, 
regardless of whether they result in an adverse event, should be recorded on the 
Adverse Event eCRF and reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event).  Special situations should be recorded as described 
below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

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
Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.
For MTIG7192A and atezolizumab, each adverse event associated with a special 
situation should be recorded separately on the Adverse Event eCRF.  If the associated 
adverse event fulfills seriousness criteria, the event should be reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  
For MTIG7192A and atezolizumab, adverse events associated with special situations 
should be recorded as described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.
As an example, an accidental overdose that resulted in a headache would require the 
completion of two eCRF pages, one to report the accidental overdose and one to report 
the headache.  The "Accidental overdose" and "Medication error" boxes would need to 
be checked on both eCRF pages.
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug(s) or study-related 
procedures until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.

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5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
After the end of the adverse event reporting period (defined as 30 days after the last 
dose of study drug), serious adverse events and adverse events of special interest will 
continue to be reported until 90 days after the last dose of study treatment or until 
initiation of new systemic anti-cancer therapy, whichever occurs first. Beyond 90 days 
after last dose of study treatment, all deaths, regardless of cause, should be reported 
through use of the Long-Term Survival Follow-Up eCRF.
In addition, if the investigator becomes aware of a serious adverse event that is believed 
to be related to prior exposure to study drug(s), the event should be reported through 
use of the Adverse Event eCRF.  However, if the EDC system is not available, the 
investigator should report these events directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form using the fax number or email 
address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents:

MTIG7192A Investigator's Brochure

Atezolizumab Investigator’s Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
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 IMC will monitor safety data during the study.  An aggregate report of any clinically 
relevant imbalances that do not favor the test product will be submitted to health 
authorities.

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6.2
SUMMARIES OF CONDUCT OF STUDY
Enrollment, study treatment administration, and discontinuation from the study will be 
summarized by treatment arm. The reasons for study treatment discontinuation will also 
be tabulated. Major protocol deviations, including major deviations with regard to the 
inclusion and exclusion criteria, will be listed by treatment arm and evaluated for their 
potential effects on the interpretation of study results.
6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics will be summarized by treatment arm for all 
randomized patients. Descriptive summaries of continuous data will present the group 
mean, standard deviation, median, minimum, and maximum.  Descriptive summaries of 
discrete data will present the category counts as frequencies and percentages.
6.4
EFFICACY ANALYSES
 
 
 Specifically, estimates in the difference in ORR 
between the two study arms and PFS HRs will be computed along with their 90% CIs. 
Hypothesis testing of the co-primary efficacy endpoints will also be conducted in the
primary patient population. The DOR secondary endpoint in the primary population will 
also be analyzed at this point. 
 
 
 
All co-primary analyses of disease progression and objective response will be based on 
investigator review of tumor assessments using RECIST v1.1. 
6.4.1
Co-Primary Efficacy Endpoints
PFS is defined as the time from randomization to the date of first documented disease 
progression or death, whichever occurs first. Disease progression for PFS analysis will 
be determined on the basis of investigator assessment using RECIST v1.1.
 
 
Data for a patient without disease progression or death as of the clinical data cutoff date 
will be censored at the time of the last tumor assessment (or at the date of 
randomization plus 1 day if no tumor assessment was performed after the baseline visit). 
Data from a patient who is lost to follow-up will be included in the analysis and censored 
on the last date of tumor assessment that the patient was known to be progression free.

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ORR is defined as the percentage of patients who have experienced a CR or PR on two 
consecutive occasions 4 weeks apart, as determined by the investigator according to 
RECIST v1.1. Objective response will be evaluated by treatment arm. Patients without 
postbaseline overall response assessments will be counted as non-responders.
 
 
 
6.4.2
Secondary Efficacy Endpoints
 
 
 
 
 
 
 
 
 
 
 
 
6.5
SAFETY ANALYSES
Safety analyses will be conducted in all randomized patients who received at least one 
dose of MTIG7192A/placebo or atezolizumab.  
Safety analyses will be performed by treatment arm and will be based on actual 
treatment received.  Specifically, a patient will be included in the MTIG7192A plus
atezolizumab arm in the safety analyses if the patient receives any amount of 
MTIG7192A, regardless of the initial treatment assignment at randomization.

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Safety endpoints will include incidence, nature, and severity of adverse events (using 
NCI CTCAE v4.0), including serious adverse events and adverse events of special 
interest, changes from baseline in vital signs, physical findings, and clinical laboratory 
results following the administration of MTIG7192A/placebo plus atezolizumab.  Drug 
exposure will be summarized, including duration, dosage, and dose intensity.  Verbatim 
description of adverse events will be mapped to the MedDRA thesaurus terms and 
graded according the NCI CTCAE v4.0.  All adverse events that occur during or after the 
first study treatment, until 30 days after the last dose of study drug or initiation of another 
systemic anti-cancer therapy, whichever occurs first, will be summarized by treatment 
arm and NCI CTCAE grade.  In addition, serious adverse events and adverse events
leading to study treatment discontinuation or interruption will be summarized accordingly.  
Multiple occurrence of the same event will be counted once at the maximum severity.  
Laboratory data with values outside of the normal ranges will be identified.  
 
 
  Vital signs will also be summarized by treatment arm and visit.  Deaths and 
causes of deaths will be summarized. 
Analyses of safety endpoints will be conducted at the time of the primary efficacy 
analysis.
 
 
 
 
 
 
 
6.7
PHARMACOKINETIC ANALYSES
Serum concentrations, as appropriate, of MTIG7192A and atezolizumab versus time will 
be tabulated, and summary statistics will be computed for each scheduled sampling time.
 
 
 
 
 

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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 subject 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 and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical study.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
study-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 

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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 
IMPs, including eCRFs, paper PRO data, 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.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form will be provided to each site.  If 
applicable, it will be provided in a certified translation of the local language.  The 
Sponsor or its designee must review and approve any proposed deviations from the 
Sponsor's sample Informed Consent Forms or any alternate consent forms proposed by 
the site (collectively, the "Consent Forms") before IRB/EC submission.  The final 
IRB/ECapproved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements.
 
 
  

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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.
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, 

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policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
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.
 
 
 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).

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9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This study will be sponsored by F. Hoffmann-La Roche Ltd. and will be managed by 
Genentech and a contract research organization (CRO). The CRO will provide clinical 
operations management, data management, and medical monitoring.
Approximately 5065 sites globally will participate in the study and approximately 
120 patients will be randomized. Randomization will occur through an IxRS. Central 
facilities will be used for study assessments throughout the study (e.g., specified 
laboratory tests and PK analyses). Accredited local laboratories will be used for routine 
monitoring; local laboratory ranges will be collected. Data will be recorded via an EDC 
system with the use of eCRFs (see Section 7.2).
An IMC will monitor and evaluate patient safety throughout the study.  

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9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a study, the Sponsor is dedicated to openly providing 
information on the study to healthcare professionals and to the public, both at scientific 
congresses 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 studies in patients involving an IMP for which a marketing authorization 
application has been filed or approved in any country, the Sponsor aims to submit a 
journal manuscript reporting primary clinical study results within 6 months after the 
availability of the respective Clinical Study Report.  In addition, for all clinical studies in 
patients involving an IMP for which a marketing authorization application has been filed 
or approved in any country, the Sponsor aims to publish results from analyses of 
additional endpoints and exploratory data that are clinically meaningful and statistically 
sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
center data.  In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.

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9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).

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10.
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2015;33(18 Suppl):LBA6008.
Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced 
ALK-positive lung cancer. N Engl J Med 2013; 368:238594.
Socinski MA, Bondarenki I, Karaseva NA, et al. Weekly nab-paclitaxel in combination 
with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line 
therapy in patients with advanced non-small-cell lung cancer: final results of a 
phase III trial. J Clin Oncol 2012;30:205562.
Spigel DR, Chaft JE, Gettinger SN, et al. Clinical activity and safety from a phase II 
study (FIR) of MPDL3280A (anti-PDL1) in PD-L1-selected patients with non-small 
cell lung cancer (NSCLC). J Clin Oncol 2015;33(15 Suppl):8028.
Spiro SG, Rudd RM, Souhami RL, et al. Chemotherapy versus supportive care in 
advanced non-small cell lung cancer: improved survival without detriment to quality 
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Stanietsky N, Simic H, Arapovic J, et al. The interaction of TIGIT with PVR and PVRL2 
inhibits human NK cell cytotoxicity. Proc Natl Acad Sci USA 2009;106:1785863.
Stinchcombe TE and Socinski MA. Considerations for second-line therapy of non-small 
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pdf.

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Appendix 1
Schedule of Activities (cont.)
MTIG7192A and Atezolizumab (MPDL3280A)—Genentech, Inc.
144/Protocol GO40290, Version 3
f
Tumor assessments performed as standard of care prior to obtaining informed consent and within 28 days prior to randomization may be used 
rather than repeating tests.  All measurable and evaluable lesions should be assessed and documented at the screening visit. Screening and 
subsequent tumor assessments should include CT scans (with IV contrast unless contraindicated and oral contrast per institutional standards) of 
the chest, abdomen, and pelvis.  After screening, CT scans can be limited to include an evaluation of all sites of known disease.  CT scans may 
be substituted by MRI scans, if clinically indicated.  Brain imaging (either MRI or contrast-enhanced CT) is required at screening for all patients to 
evaluate for presence of CNS metastases, and as clinically indicated.  Bone scans should also be performed, if clinically indicated.  If a CT scan 
for tumor assessment is performed in a PET/CT scanner, the CT acquisition must be consistent with the standards of a full-contrast CT scan.  
The same imaging modality and radiographic procedure must be used throughout the study for each patient.  Results must be reviewed by the 
investigator before dosing at the next cycle.  Tumor assessments will be performed at baseline and every 6 weeks (approximately every 2 cycles)
(3 business days) thereafter for 36 weeks (or approximately up to Cycle 12) following randomization. After 36 weeks (or after Cycle 12), 
patients who have not experienced disease progression will undergo tumor assessment every 9 (1) weeks (approximately every 3 cycles).  
Additional scans should be performed as clinically indicated.  If an optional biopsy is to be performed at approximately the same timepoint of a 
tumor assessment or as a result of the radiographic determination (e.g., response or progression), samples should be acquired after all imaging 
scans have been performed, if at all possible. Investigators may perform additional scans or more frequent assessments, if clinically indicated.
g Patients who are discontinued from study treatment because of disease progression will be asked to return for a repeat tumor assessment in 
6 (2) weeks, if feasible, after experiencing disease progression unless the patient initiates subsequent anti-cancer therapy. 
h Patients who discontinue study treatment for reasons other than disease progression (e.g., toxicity) should continue to undergo scheduled tumor 
assessments until disease progression, initiation of subsequent anti-cancer therapy, death, loss to follow-up, withdrawal of consent, or study 
termination, whichever occurs first. The schedule of these tumor assessments will be approximately every 12 (1) weeks (as long as the patient 
has not started new treatment).  Scans can be performed locally, if feasible.
i
The EORTC QLQ-C30 questionnaire will be completed at baseline (prior to dosing on C1D1), and then administered and recorded prior to 
dosing at the first cycle visits after tumor assessments (i.e., at C3D1, C5D1, C7D1, etc.) and at the study treatment discontinuation visit at the 
investigational site until disease progression or treatment discontinuation, whichever occurs later (see Section 4.6.1). The EORTC QLQ C30 is 
required to be administered prior to administration of study drug and prior to any other study assessment(s) that might bias the answers to the 
questionnaire.
j
Complete and limited physical examinations are defined in the protocol (see Section 4.5.3). 
k ECOG Performance Status, limited physical examination, and local laboratory assessments may be obtained 96 hours before Day 1 of each 
cycle.  

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Appendix 3
European Organisation for Research and Treatment of Cancer 
Quality-of-Life Questionnaire:  EORTC QLQ-C30

Appendix 3
European Organisation for Research and Treatment of Cancer 
Quality-of-Life Questionnaire:  EORTC QLQ-C30 (cont.)
MTIG7192A and Atezolizumab (MPDL3280A)—Genentech, Inc.
150/Protocol GO40290, Version 3

MTIG7192A and Atezolizumab (MPDL3280A)—Genentech, Inc.
151/Protocol GO40290, Version 3
Appendix 4
Response Evaluation Criteria in Solid Tumors,
Version 1.1 (RECIST v1.1)
Selected sections from the Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1) (Eisenhauer et al. 2009) are presented below, with slight modifications 
from the original publication and the addition of explanatory text as needed for clarity.1
TUMOR MEASURABILITY
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as described below.  All measurable and non-measurable lesions 
should be assessed at screening and at subsequent protocol-specified tumor 
assessment timepoints.  Additional assessments may be performed as clinically 
indicated for suspicion of progression.
DEFINITION OF MEASURABLE LESIONS
Tumor Lesions
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size as follows: 

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval 5 mm)

10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable)

20 mm by chest X-ray
Malignant Lymph Nodes
To be considered pathologically enlarged and measurable, a lymph node must be 
15 mm in the short axis when assessed by CT scan (CT scan slice thickness 
recommended to be 5 mm).  At baseline and follow-up, only the short axis will be 
measured and followed.  Additional information on lymph node measurement is provided 
below (see "Identification of Target and Non-Target Lesions" and "Calculation of Sum of 
Diameters").
                                           
1 For clarity and for consistency within this document, the section numbers and cross-references 
to other sections within the article have been deleted and minor changes have been made.

Appendix 4
Response Evaluation Criteria in Solid Tumors, Version 1.1
(RECIST v1.1) (cont.)
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152/Protocol GO40290, Version 3
DEFINITION OF NON-MEASURABLE LESIONS
Non-measurable tumor lesions encompass small lesions (longest diameter 10 mm or 
pathological lymph nodes with short axis 10 mm but 15 mm) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques.
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.
Bone Lesions:

Technetium-99m bone scans, sodium fluoride positron emission tomography scans, 
and plain films are not considered adequate imaging techniques for measuring bone 
lesions.  However, these techniques can be used to confirm the presence or 
disappearance of bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue 
components that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered measurable lesions if the soft tissue component 
meets the definition of measurability described above.

Blastic bone lesions are non-measurable.
Cystic Lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts.

Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions.
Lesions with Prior Local Treatment:

Tumor lesions situated in a previously irradiated area or in an area subjected to 
other loco-regional therapy are usually not considered measurable unless there has 
been demonstrated unequivocal progression in the lesion and the previously 
irradiated lesion is not the only site of measurable disease. 

Appendix 4
Response Evaluation Criteria in Solid Tumors, Version 1.1
(RECIST v1.1) (cont.)
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153/Protocol GO40290, Version 3
METHODS FOR ASSESSING LESIONS
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option.
CLINICAL LESIONS
Clinical lesions will only be considered measurable when they are superficial and 
10 mm in diameter as assessed using calipers (e.g., skin nodules).  For the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size 
of the lesion, is suggested.
CHEST X-RAY
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, because CT is more sensitive than X-ray, particularly in identifying new lesions.  
However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung.
CT AND MRI SCANS
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  In this guideline, the definition of measurability of lesions on 
CT scan is based on the assumption that CT slice thickness is 5 mm.  When CT scans 
have slice thickness of 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a non-contrast CT or MRI (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 and the anatomic location of the disease, and should 
be optimized to allow for comparison with the prior studies if possible.  Each case should 
be discussed with the radiologist to determine if substitution of these other approaches is 

Appendix 4
Response Evaluation Criteria in Solid Tumors, Version 1.1
(RECIST v1.1) (cont.)
MTIG7192A and Atezolizumab (MPDL3280A)—Genentech, Inc.
154/Protocol GO40290, Version 3
possible and, if not, the patient should be considered not evaluable from that point 
forward.  Care must be taken in measurement of target lesions and interpretation of 
non-target disease or new lesions on a different modality, since the same lesion may 
appear to have a different size using a new modality.
ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOR MARKERS, 
CYTOLOGY, HISTOLOGY
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be 
used for objective tumor evaluation.
ASSESSMENT OF TUMOR BURDEN
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements.
IDENTIFICATION OF TARGET AND NON-TARGET LESIONS
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one
or two organ sites involved, a maximum of two lesions (one site) and four lesions (two 
sites), respectively, will be recorded.  Other lesions (albeit measurable) in those organs 
will be considered non-target lesions.  
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and should be representative of all involved organs, but in addition should lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be 
selected.
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of 15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Lymph node size is 
normally reported as two dimensions in the plane in which the image is obtained (for CT, 
this is almost always the axial plane; for MRI, the plane of acquisition may be axial, 

Appendix 4
Response Evaluation Criteria in Solid Tumors, Version 1.1
(RECIST v1.1) (cont.)
MTIG7192A and Atezolizumab (MPDL3280A)—Genentech, Inc.
155/Protocol GO40290, Version 3
sagittal, or coronal).  The smaller of these measures is the short axis.  For example, an 
abdominal node that is reported as being 20 mm30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node.  In this example, 20 mm should be recorded 
as the node measurement.  All other pathological nodes (those with short axis 10 mm 
but 15 mm) should be considered non-target lesions.  Nodes that have a short axis of 
10 mm are considered non-pathological and should not be recorded or followed.
All lesions (or sites of disease) not selected as target lesions (measurable or 
non-measurable), including pathological lymph nodes, should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements are not required.  It is 
possible to record multiple non-target lesions involving the same organ as a single item 
on the Case Report Form (CRF) (e.g., "multiple enlarged pelvic lymph nodes" or 
"multiple liver metastases").
CALCULATION OF SUM OF DIAMETERS
A sum of the diameters (longest diameter for nonlymph node lesions, short axis for 
lymph node lesions) will be calculated for all target lesions at baseline and at each 
subsequent tumor assessment as a measure of tumor burden.
Measuring Lymph Nodes
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the node regresses to 10 mm during the study.  Thus, when 
lymph nodes are included as target lesions, the sum of diameters may not be zero even 
if complete response criteria are met, since a normal lymph node is defined as having a 
short axis of 10 mm.
Measuring Lesions That Become Too Small to Measure
During the study, all target lesions (lymph node and nonlymph node) recorded at 
baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm).  However, sometimes lesions or lymph 
nodes that are recorded as target lesions at baseline become so faint on CT scan that 
the radiologist may not feel comfortable assigning an exact measurement and may 
report them as being too small to measure.  When this occurs, it is important that a value 
be recorded on the CRF, as follows:

If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm.

Appendix 4
Response Evaluation Criteria in Solid Tumors, Version 1.1
(RECIST v1.1) (cont.)
MTIG7192A and Atezolizumab (MPDL3280A)—Genentech, Inc.
156/Protocol GO40290, Version 3

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 "too small to measure" should be 
ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat 
such as in the retroperitoneum; however, if a lymph node is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well and "too small to measure" should also be 
ticked).
To reiterate, however, if the radiologist is able to provide an actual measurement, that 
should be recorded, even if it is 5 mm, and in that case "too small to measure" should 
not be ticked.
Measuring Lesions That Split or Coalesce on Treatment
When nonlymph node lesions fragment, the longest diameters of the fragmented 
portions should be added together to calculate the sum of diameters.  Similarly, as 
lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximum longest diameter for the coalesced lesion.
EVALUATION OF NON-TARGET LESIONS
Measurements are not required for non-target lesions, except that malignant lymph node 
non-target lesions should be monitored for reduction to 10 mm in short axis.  
Non-target lesions should be noted at baseline and should be identified as "present" or 
"absent" and (in rare cases) may be noted as "indicative of progression" at subsequent 
evaluations.  In addition, if a lymph node lesion shrinks to a non-malignant size (short 
axis 10 mm), this should be captured on the CRF as part of the assessment of non-
target lesions.
RESPONSE CRITERIA
CRITERIA FOR TARGET LESIONS
Definitions of the criteria used to determine objective tumor response for target lesions 
are provided below:

CR:  Disappearance of all target lesions
Any pathological lymph nodes must have reduction in short axis to 10 mm.

PR:  At least a 30% decrease in the sum of diameters of all target lesions, taking as 
reference the baseline sum of diameters, in the absence of CR

Appendix 4
Response Evaluation Criteria in Solid Tumors, Version 1.1
(RECIST v1.1) (cont.)
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157/Protocol GO40290, Version 3

Progressive disease (PD):  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum of diameters at prior timepoints
(including baseline) 
In addition to the relative increase of 20%, the sum of diameters must also 
demonstrate an absolute increase of 5 mm.

Stable disease (SD):  Neither sufficient shrinkage to qualify for CR or PR nor 
sufficient increase to qualify for PD
CRITERIA FOR NON-TARGET LESIONS
Definitions of the criteria used to determine the tumor response for the group of non-
target lesions are provided below.  While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints specified in the schedule of activities.

CR:  Disappearance of all non-target lesions 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 lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits

PD:  Unequivocal progression of existing non-target lesions
SPECIAL NOTES ON ASSESSMENT OF PROGRESSION OF NON-TARGET 
LESIONS
Patients with Measurable and Non-Measurable Disease
For patients with both measurable and non-measurable disease to achieve unequivocal 
progression on the basis of the non-target lesions, there must be an overall level of 
substantial worsening in non-target lesions in a magnitude that, even in the presence of 
SD or PR in target lesions, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest increase in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status.  The 
designation of overall progression solely on the basis of change in non-target lesions in 
the face of SD or PR in target lesions will therefore be extremely rare.
NEW LESIONS
The appearance of new malignant lesions denotes disease progression; therefore, some
comments on detection of new lesions are important.  There are no specific criteria for 

Appendix 4
Response Evaluation Criteria in Solid Tumors, Version 1.1
(RECIST v1.1) (cont.)
MTIG7192A and Atezolizumab (MPDL3280A)—Genentech, Inc.
158/Protocol GO40290, Version 3
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some "new" bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient’s baseline lesions show PR or 
CR.  For example, necrosis of a liver lesion may be reported on a CT scan report as a
"new" cystic lesion, which it is not.
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, progression should be declared using the date of the 
initial scan.
CRITERIA FOR OVERALL RESPONSE AT A SINGLE TIMEPOINT
Table 1 provides a summary of the overall response status calculation at each response 
assessment timepoint for patients who have measurable disease at baseline.
Table 1
Criteria for Overall Response at a Single Timepoint:  Patients 
with Target Lesions (with or without Non-Target Lesions)
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not all evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial 
response; SDstable disease.

Appendix 4
Response Evaluation Criteria in Solid Tumors, Version 1.1
(RECIST v1.1) (cont.)
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159/Protocol GO40290, Version 3
MISSING ASSESSMENTS AND NOT-EVALUABLE DESIGNATION
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If measurements are made on only a subset of target 
lesions at a timepoint, usually the case is also considered not evaluable at that timepoint, 
unless a convincing argument can be made that the contribution of the individual missing 
lesions would not change the assigned timepoint response.  This would be most likely to 
happen in the case of PD.  For example, if a patient had a baseline sum of 50 mm with 
three measured lesions and during the study only two lesions were assessed, but those 
gave a sum of 80 mm, the patient will have achieved PD status, regardless of the 
contribution of the missing lesion. 
SPECIAL NOTES ON RESPONSE ASSESSMENT
Patients with a global deterioration in health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
"symptomatic deterioration."  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target lesions as shown in Table 1.
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
REFERENCE
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.  

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

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Appendix 6
Anaphylaxis Precautions
These guidelines are intended as a reference and should not supersede pertinent local 
or institutional standard operating procedures.
EQUIPMENT NEEDED

Tourniquet

Oxygen

Epinephrine for subcutaneous, intravenous, and/or endotracheal use in accordance 
with standard practice

Antihistamines

Corticosteroids

Intravenous infusion solutions, tubing, catheters, and tape
PROCEDURES
In the event of a suspected anaphylactic reaction during study drug infusion, the
following procedures should be performed:
1.
Stop the study drug infusion.
2.
Apply a tourniquet proximal to the injection site to slow systemic absorption of study 
treatment.  Do not obstruct arterial flow in the limb.
3.
Maintain an adequate airway.
4.
Administer antihistamines, epinephrine, or other medications as required by patient 
status and directed by the physician in charge.
5.
Continue to observe the patient and document observations.

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Appendix 8
Risks Associated with Atezolizumab or MTIG7192A and 
Guidelines for Management of Adverse Events Associated with 
Atezolizumab or MTIG7192A
Toxicities associated or possibly associated with atezolizumab or MITG7192A treatment 
should be managed according to standard medical practice.  Additional tests, such as 
autoimmune serology or biopsies, should be used to evaluate for a possible 
immunogenic etiology.
Although most immune-mediated adverse events observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications.  Discontinuation of atezolizumab 
and MTIG7192A may not have an immediate therapeutic effect, and in severe cases, 
immune-mediated toxicities may require acute management with topical corticosteroids, 
systemic corticosteroids, or other immunosuppressive agents. 
The investigator should consider the benefitrisk balance a given patient may be 
experiencing prior to further administration of atezolizumab.  In patients who have met 
the criteria for permanent discontinuation, resumption of atezolizumab and/or 
MTIG7192A may be considered if the patient is deriving benefit and has fully recovered 
from the immune-mediated event.  Patients can be re-challenged with atezolizumab 
and/or MTIG7192A only after approval has been documented by both the investigator 
(or an appropriate delegate) and the Medical Monitor. 
PULMONARY EVENTS
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been 
associated with the administration of atezolizumab.  Immune-mediated pulmonary events 
are a potential risk with MTIG7192A.  Patients will be assessed for pulmonary signs and
symptoms throughout the study and will also have computed tomography (CT) scans of 
the chest performed at every tumor assessment.  
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension.  

Appendix 8
Risks Associated with Atezolizumab or MTIG7192A and
Guidelines for Management of Adverse Events Associated with 
Atezolizumab or MTIG7192A (cont.)
MTIG7192A and Atezolizumab (MPDL3280A)—Genentech, Inc.
166/Protocol GO40290, Version 3
HEPATIC EVENTS
  
 
  
 
 
 
 
 
 
 
 
  
Eligible patients for this study must have adequate liver function, as manifested by 
measurements of total bilirubin and hepatic transaminases, and liver function will be 
monitored throughout study treatment.  
 
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or 
vomiting should have liver function tests (LFTs) performed immediately and reviewed 
before administration of the next dose of study drug(s).
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate.

Appendix 8
Risks Associated with Atezolizumab or MTIG7192A and
Guidelines for Management of Adverse Events Associated with 
Atezolizumab or MTIG7192A (cont.)
MTIG7192A and Atezolizumab (MPDL3280A)—Genentech, Inc.
170/Protocol GO40290, Version 3
ENDOCRINE EVENTS
 
 
 
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of thyroid, 
pituitary, or adrenal endocrinopathies.  The patient should be referred to an 
endocrinologist if an endocrinopathy is suspected.  Thyroid-stimulating hormone (TSH) 
and free triiodothyronine and thyroxine levels should be measured to determine whether 
thyroid abnormalities are present.  Pituitary hormone levels and function tests (e.g., TSH, 
growth hormone, luteinizing hormone, follicle-stimulating hormone, testosterone, 
prolactin, adrenocorticotropic hormone [ACTH] levels, and ACTH stimulation test) and 
magnetic resonance imaging (MRI) of the brain (with detailed pituitary sections) may 
help to differentiate primary pituitary insufficiency from primary adrenal insufficiency.

Appendix 8
Risks Associated with Atezolizumab or MTIG7192A and
Guidelines for Management of Adverse Events Associated with 
Atezolizumab or MTIG7192A (cont.)
MTIG7192A and Atezolizumab (MPDL3280A)—Genentech, Inc.
175/Protocol GO40290, Version 3
IMMUNE-MEDIATED MYOCARDITIS
 
 Immune-mediated myocarditis 
should be suspected in any patient presenting with signs or symptoms suggestive of 
myocarditis, including, but not limited to, laboratory (e.g., B-type natriuretic peptide) or 
cardiac imaging abnormalities, dyspnea, chest pain, palpitations, fatigue, decreased 
exercise tolerance, or syncope.  Immune-mediated myocarditis needs to be distinguished 
from myocarditis resulting from infection (commonly viral, e.g., in a patient who reports a 
recent history of gastrointestinal illness), ischemic events, underlying arrhythmias, 
exacerbation of preexisting cardiac conditions, or progression of malignancy.  
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  An
endomyocardial biopsy may be considered to enable a definitive diagnosis and 
appropriate treatment, if clinically indicated.
 

Appendix 8
Risks Associated with Atezolizumab or MTIG7192A and
Guidelines for Management of Adverse Events Associated with 
Atezolizumab or MTIG7192A (cont.)
MTIG7192A and Atezolizumab (MPDL3280A)—Genentech, Inc.
177/Protocol GO40290, Version 3
INFUSION-RELATED REACTIONS
No premedication is indicated for the administration of Cycle 1 of MTIG7192A/placebo 
and atezolizumab.  However, patients who experience an infusion-related reaction (IRR) 
with Cycle 1 of MTIG7192A/placebo and atezolizumab may receive premedication with 
antihistamines or antipyretics/analgesics (e.g., acetaminophen) for subsequent infusions.
Metamizole (dipyrone) is prohibited in treating MTIG7192A/placebo- and/or 
atezolizumab-associated IRRs because of its potential for causing agranulocytosis.
  For 
subsequent cycles, IRRs should be managed according to institutional guidelines.

Appendix 8
Risks Associated with Atezolizumab or MTIG7192A and
Guidelines for Management of Adverse Events Associated with 
Atezolizumab or MTIG7192A (cont.)
MTIG7192A and Atezolizumab (MPDL3280A)—Genentech, Inc.
181/Protocol GO40290, Version 3
DERMATOLOGIC EVENTS
 The majority of the cases of 
rash were mild in severity and self-limited, with or without pruritus.  A dermatologist 
should evaluate persistent and/or severe rash or pruritus.  A biopsy should be 
considered unless contraindicated.  
 

Appendix 8
Risks Associated with Atezolizumab or MTIG7192A and
Guidelines for Management of Adverse Events Associated with 
Atezolizumab or MTIG7192A (cont.)
MTIG7192A and Atezolizumab (MPDL3280A)—Genentech, Inc.
185/Protocol GO40290, Version 3
RENAL EVENTS
 
  Eligible patients must have adequate renal 
function. Renal function, including serum creatinine, should be monitored throughout 
study treatment.  Patients with abnormal renal function should be evaluated and treated 
for other more common etiologies (including prerenal and postrenal causes, and 
concomitant medications such as non-steroidal anti-inflammatory drugs).  Refer the 
patient to a renal specialist if clinically indicated.  A renal biopsy may be required to 
enable a definitive diagnosis and appropriate treatment.
 

Appendix 8
Risks Associated with Atezolizumab or MTIG7192A and
Guidelines for Management of Adverse Events Associated with 
Atezolizumab or MTIG7192A (cont.)
MTIG7192A and Atezolizumab (MPDL3280A)—Genentech, Inc.
188/Protocol GO40290, Version 3

Appendix 8
Risks Associated with Atezolizumab or MTIG7192A and
Guidelines for Management of Adverse Events Associated with 
Atezolizumab or MTIG7192A (cont.)
MTIG7192A and Atezolizumab (MPDL3280A)—Genentech, Inc.
191/Protocol GO40290, Version 3
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage 
activation syndrome complicating systemic juvenile idiopathic arthritis: a 
European League Against Rheumatism/American College of 
Rheumatology/Paediatric Rheumatology International Trials Organisation 
Collaborative Initiative. Ann Rheum Dis 2016;75:4819.